Benign Prostate Syndrome: Diagnostics and Therapy of the BPS 3662670569, 9783662670569

Citation preview

Benign Prostate Syndrome Diagnostics and Therapy of the BPS

Christopher Netsch Andreas J. Gross Editors

123

Benign Prostate Syndrome

Christopher Netsch · Andreas J. Gross (Editors)

Benign Prostate Syndrome Diagnostics and Therapy of the BPS

Editors Christopher Netsch Klinik für Urologie Asklepios Klinik Barmbek Hamburg, Germany

Andreas J. Gross Klinik für Urologie Asklepios Klinik Barmbek Hamburg, Germany

ISBN 978-3-662-67056-9 ISBN 978-3-662-67057-6  (eBook) https://doi.org/10.1007/978-3-662-67057-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE, part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

V

Preface Twenty years have passed since the last edition of the Springer textbook “Benign Prostatic Hyperplasia—A Guide for the Clinic and Practice” by the editorial team Klaus Höfner, Christian Stief & Udo Jonas. Twenty years—two decades—represent half an eternity in science. A rough PubMed-based literature search with the search term “benign prostatic hyperplasia” and the input period 2000–2021 yielded 16,746 hits on May 18, 2021, 10 pm! But not only scientifically a lot has happened. While the editorial team was still studying (pre-clinic: C. Netsch) or looking for a chief physician position (senior physician: A. J. Gross) at that time, the reading and working habits in the medical field have also changed fundamentally in the two decades due to the triumph of the World Wide Web and social media platforms such as YouTube. Digital media are the rule in 2021 and not the exception as in 2000. Back then, downloading pdfs was still a pleasant exception for the editor (C. Netsch) when doing literature research for his dissertation. Reading microfiche and ordering articles from other libraries was more the standard than the exception. Why publish a textbook in 2021, when search engines can find everything on the Internet (PubMed, Wikipedia) in milliseconds? The half-life of information has noticeably decreased due to an almost unmanageable number of new urological journals (with and without peer review), which all want or have to be filled with articles on a monthly basis. Journals/articles are created in monthly cycles, whose scientific value sometimes cannot be checked so quickly. These journals today compete with the institutions of then AND today, such as the Journal of Urology or the British Journal of Urology. As a result, a quick, targeted information search in the data jungle of the Internet and a multitude of duplicate publications in important and less important journals with and without impact factors (“publish by numbers”) is not easier for urologists who are not “inside” the topic than in 2000. That is why, we think, textbooks are needed! Here we see all the more the justification for a textbook, whether as a digital or paper edition: to guide the reader through the topic as up-to-date as possible (and necessary) by a selection of high-caliber authors. Why of all things a book about benign prostate syndrome (BPS)? In a currently oncologically dominated urology, where immunotherapies, receptor blockers or the appropriate sequence therapy for prostate, bladder or renal cell carcinoma are discussed, BPS still represents THE operative backbone of every urological clinic, and this will remain so in the future due to an aging society. Operative therapies of BPH have come and gone in the last 20 years on the graveyard of medical procedures! Nevertheless, the therapy of BPH is more than tamsulosin, monopolar TUR-P or open simple prostatectomy (OPS)! MTOPS or ComBAT trial have significantly influenced the medical therapy in the last 20 years. Laser ablation procedures with the holmium, thulium, or green light laser have emerged on the surgical horizon to stay permanently. In addition, the so-called Minimally-Invasive Surgical Therapies (MIST: iTind, Urolift, Rezum, Aquabeam, prostate artery embolization) for an individualized tailor-made therapy of BPH are on everyone's lips. Whether these MIST therapies deliver what they promise remains to be seen.

VI

Preface

A critical examination of the mentioned therapies can only succeed in a book with a certain time delay, as the elaborate production of a book always lags behind an original work or a review in terms of time. However, we see this time delay positively: The first “hype” about “new” and “complication-free” procedures is usually gone, critical publications that highlight the disadvantages of certain procedures also appear only with a time delay (or the flow of publications about a procedure dries up slowly). Therefore, a book succeeds much better in critically condensing what a urologist needs to know or what one can know than by skimming articles on various online portals of professional societies or publishers. Finally, we are pleased that we were able to unite such high-caliber authors from the BPH and Endourology working groups of the German Society of Urology e. V. for the collaboration on this book. We thank all the staff of Springer-Verlag in Berlin and thank them for their great help and uncomplicated cooperation, especially Ms. Ina Conrad, Ms. Susanne Sobich, Ms. Ellen Blasig and Mr. Amose Stanislaus. Springer-Verlag and all authors hope that this textbook will be a help and guidance for the urologist working in clinic and practice, provide pleasure in reading and above all serve the well-being of our patients. Christopher Netsch Andreas J. Gross

Hamburg in November 2021

VII

Contents 1

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Andreas J. Gross and Christopher Netsch

Prevalence and Incidence of LUTS and BPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Natural Course and Risks of Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 BPS in Germany: Herne LUTS/BPS Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.1 1.2 1.3

2

Anatomy of the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Andreas J. Gross

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.1 2.2

3

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Stephan Madersbacher

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Concept of Age-Associated Tissue Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Lifestyle Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Bladder Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3.1 3.2 3.3 3.4 3.5 3.6 3.7

4

Symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Benedikt Becker

Complications and Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Classification of Benign Prosta te Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Symptom Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

4.1 4.2 4.3

5

Clinical Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Benedikt Becker

Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Assessment of the Upper Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Prostate-Specific Antigen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Kidney Function Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Optional Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

5.1 5.2 5.3 5.4 5.5 5.6 5.7

VIII

Contents

6

Imaging Techniques for the Benign Prostate Syndrome . . . . . . . . . . . . . . . . . . . . 37 Matthias Oelke

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Other Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

6.1 6.2 6.3

7

Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Benedikt Becker

Indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Cystoscopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Diagnostic Performance in BPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

7.1 7.2 7.3 7.4 7.5

8

Uroflow and Residual Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Clemens Mathias Rosenbaum

Uroflowmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Residual Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 8.1 8.2

9

Urodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Clemens Mathias Rosenbaum

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Cystometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Pressure-Flow Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Other Examination Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

9.1 9.2 9.3 9.4 9.5

10

Controlled Waiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Andreas J. Gross

Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

10.1 10.2 10.3 10.4

11

Pharmacological Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Lukas Lusuardi

Phytopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Alpha-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5-Alpha-Reductase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Phosphodiesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Antimuscarinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Beta-3-Agonist Mirabegron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Combination Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 11.1 11.2 11.3 11.4 11.5 11.6 11.7

IX Contents

12

Surgical Techniques: Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Christopher Netsch

Surgical Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Surgical Principles: Vaporization, Enucleation, Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Lasers: Basic Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Lasers in the Treatment of Benign Prostatic Hyperplasia (BPH) . . . . . . . . . . . . . . . . . . . . . . 106 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

12.1 12.2 12.3 12.4

13

Ablative Procedures: Enucleation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Christopher Netsch

Open Simple Prostatectomy (OSP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Laparoscopic Simple Prostatectomy (LSP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Robot-Assisted Simple Prostatectomy (RASP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Transurethral Enucleation of the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

13.1 13.2 13.3 13.4 13.5

14

Ablative Procedures: Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Christopher Netsch

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Transurethral Resection of the Prostate (TUR-P) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Ablative Procedures: Thulium VapoResection of the Prostate (ThuVARP) . . . . . . . . . . . . 138 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

14.1 14.2 14.3

15

Ablative Procedures—Vaporization: Bipolar and Photoselective Vaporization of the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 Malte Rieken

Bipolar Transurethral Vaporization of the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Greenlight Laser Vaporization of the Prostate (PVP, Photoselective Vaporization of the Prostate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

15.1 15.2

16

Ablative Procedures—Robotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Malte Rieken

Procedure and Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Functional Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Peri- and Postoperative Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 High Risk Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

16.1 16.2 16.3 16.4

17

Non-Ablative Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Malte Rieken

Urolift® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Rezum® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 iTind® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Prostatic Arterial Embolization (PAE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

17.1 17.2 17.3 17.4



X

Contents

18

Economic Aspects of BPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Andreas J. Gross

Life Expectancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Cost Relevance of a Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Costs of Lost Working Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Costs due to Complications After Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Overall View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

18.1 18.2 18.3 18.4 18.5

19

Patient Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Andreas J. Gross

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Factors Influencing the Indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Morbidity and Follow-Up Treatment Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Individual Therapy between Expectations and Reality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

19.1 19.2 19.3 19.4

20

Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Christopher Netsch

What is the Purpose of a Guideline? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Effectiveness and Quality of Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Criticism and Error-Proneness of Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Comparison of EAU, AUA and DGU Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

20.1 20.2 20.3 20.4 20.5

21

Prevention of Benign Prostate Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Matthias Oelke

Forms of Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

21.1 21.2 21.3 21.4

22

The Geriatric Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Peter Olbert

Introduction and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 The Importance of Pre-Therapeutic Evaluation: The Geriatric Assessment . . . . . . . . . . . 221 Specifics of the Pharmacological Therapy of BPS in the Geriatric Patient . . . . . . . . . . . . 222 Surgical Therapy in Geriatric Patients—Outcomes and Complications . . . . . . . . . . . . . . 226 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

22.1 22.2 22.3 22.4

23

Controversies in Conservative and Surgical BPS Therapy . . . . . . . . . . . . . . . . . . . 231 Christopher Netsch and Andreas J. Gross

23.1 23.2

Does the Normal-Sized Prostate Correspond to A Chestnut, is it 20 g in Size? . . . . . . . 234 Is there a Bladder Outlet Obstruction (BOO) in Case of a Large Prostate? . . . . . . . . . . . . 234

XI Contents

Are Bladder Trabeculae Composed of Hypertrophied Muscle and are they Signs of Bladder Outlet Obstruction (BOO)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 23.4 What are Bladder Diverticula and Bladder Pseudodiverticula? . . . . . . . . . . . . . . . . . . . . . . 235 23.5 Is Urethrocystoscopy Suitable for the Diagnosis of Bladder Outlet Obstruction (BOO)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 23.6 Does BPS Progress in Stages? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 23.7 Is Residual Urine Formation Caused by Bladder Outlet Obstruction? . . . . . . . . . . . . . . . . 236 23.8 Does Residual Urine (RU) Lead to Urinary Tract Infections (UTIs)? . . . . . . . . . . . . . . . . . . . 237 23.9 Does RU Lead to Urinary Retention? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 23.10 Does RU Formation Lead to Renal Dysfunction? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 23.11 Can Drugs Reduce Bladder Outlet Obstruction (BOO)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 23.12 “Transurethral Enucleation Procedures take too Long Time. For Open Simple Prostatectomy (OSP) I just need 40 min” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 23.13 Is Resection to the Prostate Capsule Essential for an Optimal Result of TUR-P? . . . . . . 239 23.14 What is Meant by Long-Term Data in Surgical BPS Therapy? . . . . . . . . . . . . . . . . . . . . . . . . . 240 23.15 Is a Histology Necessary After the Surgical Treatment of BPS? . . . . . . . . . . . . . . . . . . . . . . . 240 23.16 Can I Perform a HoLEP with the Thulium Laser? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 23.17 Are the Clinical (Long-Term) Data for GreenLight Vaporisation of the Prostate (PVP), Aquabeam®, iTind®, Rezum® and Urolift® convincing? . . . . . . . . . . . . . . . 241 23.18 Is it Possible to Treat a 150-g Prostate by TUR-P? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 23.19 Is the Learning Curve (LC) of (Laser) Enucleation of the Prostate Longer than that of TUR-P? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 23.20 We Perform Robotic-Assisted Simple Prostatectomy (RASP) Because Patients are Incontinent and Bleed After Transurethral Enucleation . . . . . . . . . . . . . . . . . . . . . . . . . . 244 23.21 “The GreenLight Laser Is Not Suitable for BPS Surgery. Finally, You Have To Take the Loop.” Is a Surgical (Laser) Procedure for the Treatment of BPS Unreasonable, Because Finally One Takes a Loop for Coagulation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 23.22 We Perform Transurethral (Laser) Enucleation of the Prostate in Prostates larger than 60 g, Below that TUR-P Because of Training the Residents. We Perform Open Simple Prostatectomy Because of Training the Residents . . . . . . . . 245 23.23 Are more Patients Incontinent After Laser Surgery of the Prostate than After TUR-P? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 23.24 Do Patients Develop more Urge Symptoms After Laser Surgery of the Prostate than After TUR-P and Open Simple Prostatectomy (OSP)? . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 23.25 Do have New-Minimally Invasive Procedures such as Aquabeam®, Rezum® or Urolift® No Serious Complications? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 23.3



Contributors

Benedikt Becker  Asklepios Klinik Barmbek, Hamburg, Germany Andreas J. Gross  Department of Urology, Asklepios Klinik Barmbek, Hamburg, Germany Lukas Lusuardi  Paracelsus Medical University for Urology and Andrology, SALK, Salzburg, Austria Stephan Madersbacher  Department of Urology, Vienna, Austria Christopher Netsch  Clinic for Urology, Asklepios Klinik Barmbek, Hamburg, Germany Matthias Oelke  Clinic for Urology, Pediatric Urology and Urological Oncology, St. Antonius-Hospital, Gronau, Germany Peter Olbert  Specialist Practice for Urology and Andrology, Brixsana Private Clinic, Brixen, Italy Malte Rieken  alta uro AG, Basel, Switzerland Clemens Mathias Rosenbaum  Asklepios Klinik Barmbek, Hamburg, Germany

1

1

Epidemiology Andreas J. Gross and Christopher Netsch Contents 1.1 Prevalence and Incidence of LUTS and BPS – 2 1.2  Natural Course and Risks of Progression – 3 1.3 BPS in Germany: Herne LUTS/BPS Study – 4 References – 6

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_1

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2

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A. J. Gross and C. Netsch

z Introduction

Benign prostatic hyperplasia (BPH) or benign prostatic syndrome (BPS) are counted among the “common diseases” due to the high prevalences. BPH increases with age and is found in about 50% of all men between the 5th and 6th and in 90% between the 8th and 9th decade of life (Berry SJ et al. 1984). Similarly, BPS is chronically progressive. BPS describes prostate-related bladder dysfunction caused by benign prostatic obstruction (BPO). Characteristic are the insidious onset and the variation of the individual disease components such as symptoms “lower urinary tract symptoms”, benign prostatic enlargement (BPE), BPO and their relationship between each other. About 5 million German men are affected by BPS, of whom about half are under medical treatment (Berges RR et al. 2001b). The vast majority of German men with BPS seek medical help because of LUTS (78.2%) (Berges RR et al. 2001a). In addition, increased IPSS values and residual urine (RU) >50 ml are significant factors for a medical consultation (Kok E et al. 2006). Only a smaller part is examined and treated for BPS as part of cancer prevention (Hutchinson A et al. 2006). With average costs for diagnosis and therapy of about € 900 per BPS patient/ year (Van Exel NJ et al. 2006), the German health system has to spend about € 2.2 billion/year for this disease. With the increasing age of the male population in Germany (or Europe), it becomes evident that the number of those with BPH or BPS will increase - and therefore challenge the health systems of the affected countries. 1.1  Prevalence and Incidence

of LUTS and BPS

BPS is the most common urological disease and the fourth most common and fifth most expensive disease in men ≥50 years

in the western industrialized nations (Issa MM et al. 2006). International studies reported a considerably varying prevalence and incidence of male LUTS. Published data from the largest epidemiological studies such as the “Olmsted County Survey” (Donovan JL et al. 1996, 1999), databases from the Netherlands (IPCI, “Integrated-Primary-Care-Information” [Verhamme KL et al. 2002, 2005]) and Great Britain (GPRD, “General Practice Research Database” [Logie J et al. 2005]) used different definitions for BPS, which explain these differences. The retrospective analysis of the IPCI database with 84,774 individuals with a follow-up of 141,035 person-years included 2181 incident and 5605 prevalent LUTS patients. The incidence for LUTS/BPH was 15/1000 men-years with a linear increase, starting at 45-year-olds with 3/1000 manyears up to 38/1000 man-years at 75-yearolds (r = 0.99). Likewise, the prevalence climbed from 2.7% at 45-year-olds to 24% at over 79-year-olds. Overall, the prevalence was 10% (Verhamme KL et al. 2002, 2005). z Olmsted County Survey

The “Olmsted County Survey” shows an ambivalent course of the incidence of LUTS/BPH. The age-specific incidence in this study is 34/100,000 for 20- to 39-yearolds, rises to 2567.8/100,000 for 60- to 69-year-old men and falls to 1108.6/100,000 for ≥80-year-old men (Chung WS et al. 2004; Fitzpatrick JM, 2006; Sarma AV et al. 2003). The annual incidence rate shows a clear increase at the beginning of the observation period 1987 and a decrease in incidence at the end of 1997. The authors attribute the introduction of the PSA value and the increased awareness of prostate cancer for the rise in the 1990s, but also the increased medical consultations due to LUTS after the introduction of drug and/or minimally invasive treatment methods. Sim-

3 Epidemiology

ilarly, the decline in the incidence was explained, among other things, by a more accurate differentiation between actual BPS and LUTS due to other causes, but also by the decline in TUR-P numbers in the USA after the introduction of drug therapy (Chung WS et al. 2004; Fitzpatrick JM 2006; Sarma AV et al. 2003). z Global meta-analysis

Lee et al. conducted a systematic review & meta-analysis in 2017 to evaluate the global prevalence of BPH/LUTS. A major drawback of this meta-analysis is that the inclusion criteria for BPH/LUTS varied considerably in the included literature. Often there was a blurred separation between the histological diagnosis of BPH, LUTS (e.g. IPSS >7/>14) and a consideration of different age cohorts (Lee SWH et al. 2017). Nevertheless, 30 studies from Europe, Asia and New Zealand were included in the meta-analysis. The calculated (combined) lifetime prevalence for BPH (or BPS) was 26.2% and 28.8% (only studies with IPSS/ AUA score included). As expected, the prevalence increases with age with the highest prevalence in ≥70 year olds. The pooled age-specific prevalence of LUTS/BPH was 14.8%, 20%, 29.1%, 36.8% and 38.4% for the age cohorts 40–49, 50–59, 60–69, 70–79 years and ≥80 years. In addition, the prevalence of LUTS/BPH over the survey periods of the studies was examined: The prevalence did not change significantly in the study periods 1990–1999, 2000–2009 and 2010–2017 and was 26.6%, 27.8% and 22.8% (Lee SWH et al. 2017). While data on the prevalence of BPH in autopsy studies were collected, the prevalence of the partial components of BPS in the German-speaking area was investigated in the “Herner LUTS/BPS study” (Berges RR et al. 2001a, b).

1

1.2  Natural Course and Risks

of Progression

Epidemiological studies and drug trials suggest that LUTS/BPS is a progressive disease. Risk parameters for progression are (Berges R 2003, 2004; Lowe FC et al. 2005; Speakman M et al. 2005): 5 Age, 5 Prostate volume (PV), 5 Degree of urinary stream weakening, 5 RU and 5 Symptom severity. Data on the natural course come from longitudinal cohort studies (Jacobsen SJ et al. 1993, 2003) or from placebo-controlled drug studies with observation periods of up to 5 years (Emberton M 2006). Among the cohort studies, the “Olmsted County Survey” (Jacobsen SJ et al. 1993) is one of the largest studies on this topic with initially 2115 men, who have been observed since 1990. Analyses from the 9-year follow-up showed an increase of LUTS in 5.7% of the affected per year (IPSS increase ≥4 points). A progression to acute urinary retention was observed in 0.6% of the affected per year (Jacobsen SJ et al. 2003; Lieber MM et al. 2003). Men with higher age and poor urinary flow (Qmax) had an 8- and 4-fold increase in the risk of suffering a urinary retention (Jacobsen SJ et al. 2003). Men with an IPSS > 7 and a PV >30 ml had a 3-fold increased risk. z Drug studies

The two largest drug studies on BPH, “Proscar Long-Term Efficacy and Safety Study” (PLESS) (Bruskewitz R et al. 1999) and the NIH study “Medical Therapy of Prostatic Symptoms” (MTOPS; Mcconnell JD et al. 2003), were specifically designed

4

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A. J. Gross and C. Netsch

to calculate risk parameters: In PLESS, men with LUTS/BPH and enlarged prostate (mean PV: 55 ml; PSA: 2.8 ng/ml) were observed for 4 years. After 4 years, 7% of these men (placebo arm) had suffered from acute urinary retention, which was classified as spontaneous in 4% and as related to a surgical procedure, certain drugs or urinary tract infections (UTIs) in 3%. During the observation period, 10% of the men in the placebo arm underwent prostate surgery. The risk of urinary retention or surgery increased with PV or PSA level. The greatest predictive value for the occurrence of urinary retention were: PV >40 ml, PSA >2 ng/ml or high IPSS. A high irritative IPSS subscore was associated with a higher probability of surgery (Roehrborn CG et al. 1999). In MTOPS, 3047 men with LUTS/BPH (mean PV: 36 ml, PSA: 2.4 ng/ml) were observed for 4–6 years. The primary endpoint of the study was a “clinical progression”, defined as symptomatic progress (IPSS increase ≥4), occurrence of acute urinary retention, incontinence (not further defined), recurrent UTIs/urosepsis or the occurrence of renal insufficiency (Mcconnell JD et al. 2003). In MTOPS, the course was progressive in 17% of the subjects in the placebo arm within 5 years, with 80% suffering a

Total Age distribution

50 - 59

60 - 69

LUTS - Study

70 and older BPH - Study

symptomatic progress. After a 4-year follow-up, 2.4% of the patients under placebo therapy had spontaneous urinary retention; 5% underwent surgery. A large PV, high PSA level, low Qmax and RU were associated with urinary retention or surgery probability (Crawford ED et al. 2006). 1.3  BPS in Germany: Herne LUTS/

BPS Study

In Germany, data on BPS were summarized in the “Herne LUTS/BPS Study” (Berges R et al. 2000), a prospective longitudinal observation of an age-stratified sample of men ≥50 years old, which included a questionnaire part for the subjective assessment of the symptoms and a clinical examination for the diagnosis of BPS. The most important parameters for BPS in Germany are presented below: z LUTS

The increase of LUTS requiring treatment (IPSS >7) in the different age groups is shown in . Fig. 1.1: Up to 40% of subjects over 70 years of age are affected. These IPSS score data were confirmed in the interview: 32.5% of men reported suffering from micturition complaints (Berges

Age distribution for IPSS < 7

50 - 59

60 - 69

LUTS - Study

70 and older BPH - Study

Age distribution in IPSS > 7

50 - 59

60 - 69

LUTS - Study

70 and older BPH - Study

. Fig. 1.1  a Age distribution between the subjects in the clinical examination and those from the original LUTS study. No significant shifts occurred, so that the data from the clinical examination can also be considered representative. Age distribution of subjects without b and with c LUTS requiring treatment from both studies

5 Epidemiology

R et al. 2000, 2001a, b, 2002a, b).Nocturia is the most common single symptom. Only 33.3% of subjects reported not having to visit the toilet at least once at night. “Urgency” reported 17.2%, a weakened urinary stream 54.7% and incontinence 7% (Berges R et al. 2000, 2001a, b, 2002a, b; Berges 2008).

1

Mcconnell JD et al. 2003). The calculated progression risk (27%) of BPH in Germany is similar to that of other countries (Jimenez-Cruz F 2003). Risk factors for disease progression (values from the MTOPS study) (McConnell JD et  al. 2003) are shown in the following overview.

z DRE, PV and PSA

Risk factors for disease progression

In 4.2% a suspicious digital rectal examination was found. The PV was classified by DRE as normal in 22.4%, as enlarged in 70.2% and as greatly enlarged in 5%. The mean PV was 30 ml and the PSA value was 2.39 ng/ml (Berges R et al. 2000, 2001a, b, 2002a, b; Berges 2008).

5 Age (>62 years) 5 moderate to severe bladder symptoms (IPSS >17) 5 prostate enlargement (>31 ml) 5 PSA concentration in serum >1.6 μg/l 5 weakened urinary stream (Qmax 39 ml).

z Micturition parameters

The mean RU was 35 ml and the maximum urinary flow (Qmax) was 15.7 ± 10.1  ml/s. Qmax and RU were significantly different between symptomatic (IPSS >7) and asymptomatic men (IPSS  ≤7) (Berges R et al. 2000, 2001a, b, 2002a, b). Based on the population figures in 2000 and the data mentioned, 3,230,000 out of 11,674,900 German men over 50 years of age have a BPE (PV >25 ml). 1,500,000 men with LUTS requiring treatment (IPSS >7) have a PV >40 ml, i.e. a BPS a high risk of progression. 2,080,000 men probably suffer from an obstruction (Qmax There is a clear relationship between symptom severity and consultation of both groups of physicians (urologists and general practitioners), with urologists being consulted more frequently in case of more severe LUTS and more distress. Demographic developments suggest an increase in the number of BPS patients for Germany (Berges R 2008). ► Conclusions 5 BPS refers to micturition complaints due to BPH with a wide range of variation in symptom severity, prostate enlargement and bladder emptying parameters. 5 The lifetime prevalence for BPH (or BPS) worldwide ranges between 25 and 30% and increases with age. 5 The Herner LUTS study showed for Germany that men over 50 years have LUTS in 40.5%, BPE in 26.9% and a significantly reduced Qmax in 17.3%, which is suspicious for BPO. 5 About 27% (overall progression) of German men aged  ≥50 years experience a worsening of LUTS ≥4 IPSS points (18.5%), develop acute urinary retention (2.4%) or require prostate surgery (4.7%) within the next 5 years. 5 The epidemiological indicators show that BPS and its consequences must be classified as a common disease. ◄

References Berges R (2003) Impact of therapy used in clinical practice on lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) disease progression. Eur Urol Suppl 2:19–24 Berges R (2004) The impact of treatment on lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) progression. Eur Urol Suppl 3:12–17 Berges R (2008) Epidemiologie des benignen Prostatasyndroms. Assoziierte Risiken und Versorgungsdaten bei deutschen Männern über 50. Urologe A 47:141–148 Berges R, Oelke M (2011) Age-stratified normal values for prostate volume, PSA, maximum urinary flowrate, IPSS, and other LUTS/BPH indicators in the German male community-dwelling population aged 50years or older. World J Urol 29:171–178 Berges R, Pientka L, Höfner K et al (2000) Herne LUTS study: health care seeking behaviour among men aged 50 to 80 with Lower Urinary Tract Symptoms (LUTS) in Germany. J Urol 163:251 Berges RR, Pientka L, Hofner K et al (2001a) Male lower urinary tract symptoms and related health care seeking in Germany. Eur Urol 39:682–687 Berges R, Kühne K, Cubick G et al (2001b) Prevalence of lower urinary tract symptoms (LUTS) related to benign prostatic enlargement (BPE) and their impact on health care seeking. J Urol 165:266 Berges R, Kühne K, Cubick G et al (2002a) Prävalenz von prostatabedingten Miktionsbeschwerden bei Deutschen Männern im Alter über 50 Lebensjahren. Die Herner LUTS-Studie. Urologe A Suppl 1:47A Berges R, Spiegel T, Senge T (2002b) Gesundheitsbezogene Lebensqualität nach radikaler Prostatektomie und Behandlungszufriedenheit in der Langzeitnachsorge. Urologe B 42:106–108 Berry SJ, Coffey DS, Walsh PC et al (1984) The development of human benign prostatic hyperplasia with age. J Urol 132:474–479 Bruskewitz R, Girman CJ, Fowler J et al (1999) Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. PLESS study group. Proscar long-term efficacy and safety study. Urology 54:670–678 Chung WS, Nehra A, Jacobson DJ et al (2004) Lower urinary tract symptoms and sexual dysfunction in community-dwelling men. Mayo Clin Proc 79:745–749

7 Epidemiology

Crawford ED, Wilson SS, Mcconnell JD et al (2006) Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 175:1422–1426 (discussion 1426–1427) Donovan JL, Abrams P, Peters TJ et al (1996) The ICS-‘BPH’ Study: the psychometric validity and re-liability of the ICSmale questionnaire. Br J Urol 77:554–562 Donovan JL, Brookes ST, De La Rosette JJ et al (1999) The responsiveness of the ICSmale questionnaire to outcome: evidence from the ICS‘BPH’ study. BJU Int 83:243–248 Emberton M (2006) Definition of at-risk patients: dynamic variables. BJU Int (Suppl 2) 97:12–15 (discussion 21–22) Fitzpatrick JM (2006) The natural history of benign prostatic hyperplasia. BJU Int (Suppl 2) 97:3–6 (discussion 21–22) Hutchison A, Farmer R, Chapple C et al (2006) Characteristics of patients presenting LUTS/BPH in six European countries. Eur Urol 50:555–562 Issa MM, Fenter TC, Black L et al (2006) An assessment of the diagnosed prevalence of diseases in men 50 years of age or older. Am J Manag Care 12:S83–S89 Jacobsen SJ, Guess HA, Panser L et al (1993) A population-based study of health care-seeking behavior for treatment of urinary symptoms. The Olmsted county study of urinary symptoms and health status among men. Arch Fam Med 2:729–735 Jacobsen SJ, Jacobsen DJ, Girman CJ et al (2003) Acute urinary retention in community-dwelling men: 9-year follow-up of the Olmsted county study of urinary symptoms and health status among men. J Urol Suppl 169:365 (Abstr. 1364) Jimenez-Cruz F (2003) Identifying patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) at risk for progression. Eur Urol Suppl 2:6–12 Kok E, Groeneveld F, Gouweloos J et al (2006) Determinants of seeking of primary care for lower urinary tract symptoms: the Krimpen study in community-dwelling men. Eur Urol 50:811–817 Lee SWH, Chan EMC, Lai Y (2017) The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. Sci Rep 7:7984. 7 https://doi. org/10.1038/s41598-017-06628-8 Lieber MM, Jacobsen DJ, Girman CJ et al (2003) Incidence of lower urinary tract symptom progres-

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sion in community-dwelling men: 9-year follow-up of the Olmsted county study of urinary symptoms and health status among men. J Urol Suppl 169:366 (Abstr. 1369) Logie J, Clifford GM, Farmer RD (2005) Incidence, prevalence and management of lower urinary tract symptoms in men in the UK. BJU Int 95:557–562 Lowe FC, Batista J, Berges R et al (2005) Risk factors for disease progression in patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH): a systematic analysis of expert opinion. Prostate Cancer Prostatic Dis 8:206–209 Mcconnell JD, Roehrborn CG, Bautista OM et al (2003) The long-term effect of doxazosin, finasteride, and combination therapy on the clinical pro-gression of benign prostatic hyperplasia. N Engl J Med 349:2387–2398 Roehrborn CG, Mcconnell JD, Lieber MM et al (1999) Serum prostate-specific antigen concent-ration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group Urol 53:473–480 Sarma AV, Wei JT, Jacobson DJ et al (2003) Comparison of lower urinary tract symptom severity and associated bother between community-dwelling black and white men: the Olmsted county study of urinary symptoms and health status and the flint men’s health study. Urology 61:1086–1091 Speakman M, Batista J, Berges R et  al (2005) Inte-grating risk profiles for disease progression in the treatment choice for patients with lower urina-ry tract symptoms/benign prostatic hyperplasia: a combined analysis of external evidence and clinical expertise. Prostate Cancer Prostatic Dis 8:369–374 Van Exel NJ, Koopmanschap MA, McDonnell J et al (2006) Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six european countries: report of the TRIUMPH study. Eur Urol 49:92–102 Verhamme KM, Dieleman JP, Bleumink GS et al (2002) Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care–the triumph project. Eur Urol 42:323–328 Verhamme KM, Dieleman JP, Van Wijk MA et al (2005) Low incidence of acute urinary retention in the general male population: the triumph project. Eur Urol 47:494–498

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Anatomy of the Prostate Andreas J. Gross Contents 2.1 Introduction – 10 2.2 Structure – 10 References – 13

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_2

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2.1  Introduction

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It is astonishing how sparsely the anatomy and function of the prostate are taken into account in textbooks. Apart from the rough anatomical location and average size, there is rarely any further information. Historically, Vesal (1514–1564) can be regarded as the founder of morphological anatomy. Until then, the work of Galen (ca. 128–200 AD) on the anatomy and physiology of the human body dominated medicine. Unlike his “predecessor” in this field, Vesal conducted studies on human cadavers, because he was of the opinion that one could only gain an understanding of medicine on humans by studying the human body (Vesalius, von Kühn). There were always further insights into the prostate over a long period of time, such as by the Berlin physiologist and anatomist Johannes Müller (1801–1858). However, the modern understanding of this organ is based essentially on the work of the American pathologist John McNeal (1930– 2005). And here the driving force was the increasing diagnosis and therapy in the area of prostate cancer. However, some relevant aspects have been worked out in this context, which are also relevant for the understanding of BPH and its treatment. 2.2  Structure

The prostate has no uniform internal structure in the sense of a homogeneous gland. The prostate rather consists of three different zones, which are arranged concentrically around the urethra, the central and the peripheral zone and in between the transition zone. These zones do not enclose the urethra like onion layers. The central zone, which accounts for about 5–10% of the prostate, only surrounds the urethra between the colliculus seminalis and the bladder neck. The inner zone has a much wider

rim at the bladder neck, which narrows towards the colliculus seminalis and represents about 20–25% of the prostate. The rest is made of the outer zone which accounts for about 70% of the total gland. Contrary to the previous understanding, the prostate has no thick capsule, but rather a capsule of only 0.5 mm thickness, which consists of tough connective tissue (Brooks). The neighboring structures of the prostate are of subordinate relevance in the consideration of BPH, especially before a possible surgery. Towards the rectum, there is the Denenonvillier’s fascia. The dorsal venous bundle can hardly be reached by a transurethral procedure, and the neurovascular bundle is also clearly beyond the capsule. Although the prostate of a young healthy man is often described as chestnut-sized, this description is misleading in terms of size, as there are clearly different sized chestnuts. Nevertheless, the description of the prostate as chestnut-shaped comes very close, namely heart-shaped with a concave dorsal surface (Oelke et al. 2019). At birth, a boy’s prostate weighs about 2 g and at 20 years of age about 19 g, with a considerable variation in size already. Purely histopathologically, the gland of a 20-year-old already shows some hyperplasia, which, however, does not become clinically relevant in the sense of BPH. Testosterone and estrogen then play a role in the further growth, especially in the area of the lateral transition zone. It is common knowledge among urologists that growth does not automatically mean bladder outlet obstruction (BOO). The  direction of the urethra through the prostate can vary greatly and does not pass through the prostate in a straight line. It is closer to the anterior surface than to the posterior one. The curve of the prostatic urethra from the colliculus seminalis can be at different angles. In most cases, this angle is about 35°, but it can vary widely, namely

2

11 Anatomy of the Prostate

from 0 to 90°. More for oncological than for functional reasons, it is important to mention that the prostatic urethra is also lined with a thin layer of urothelium. Lee et al. divided the following four groups based on the example of 156 patients, whereby the anatomical situation at the apex is particularly relevant for the operating urologist (Lee 2006): 1. The apex overlaps the membranous part of the prostate both anteriorly and posteriorly. This was found in 38% of the examined patients.

2. The apex overlaps the membranous part of the prostate only anteriorly. This was found in 25% of the examined patients.

4. There is no overlap of the apex with the membranous part of the prostate. This was found in 22% of the examined patients.

For the continence mechanism the sphincter complex is relevant, which is more than a sphincter. It consists of the internal Lisso sphincter of smooth muscle and an external Rhabdo sphincter of striated muscle. A relevant part consists of a type of muscle that can neither be trained consciously nor fatigues. The sphincter complex wraps cylindrically around the urethra from the bladder neck to the perineal membrane (. Fig. 2.1). The Rhabdo sphincter is most pronounced around the membranous por-

1 2

7

3. The apex overlaps the membranous part of the prostate only posteriorly. This was found in 15% of the examined patients.

5

3 4 6 . Fig. 2.1  Sphincter complex of the male urethra. Bladder muscle (1), proximal portion of the Lisso sphincter (2), distal portion of the Lisso sphincter (3), Rhabdo sphincter (4), prostatic portion of the Rhabdo sphincter (5), perineal membrane (6), prostate (7). (After Mamdouh 2008)

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2

. Fig. 2.2  Arterial supply of the prostate. (After Flocks 1937)

tion and becomes thinner towards the bladder neck. Conversely, the Lisso sphincter is most pronounced at the bladder neck and then becomes thinner to its distal portion. The Lisso sphincter is essentially responsible for the continence mechanism at rest. The Rhabdo sphincter has two functions, namely continence when the intra-abdominal pressure increases and support of the antegrade ejaculation (Mamdouh 2008). The blood supply of the prostate is fed in most cases from the A. vesicalis inferior, which divides into two branches each before entering the prostate, of which an outer one supplies the prostatic capsule and an inner one the gland itself. These enter in the area of the bladder neck at 1, 5, 7 or 11 o’clock. The largest branches are posteriorly and then run parallel to the urethra caudally. These arteries also supply the part of the hyperplastic prostate (7). In a transurethral resection or enucleation, one encounters exactly these arteries, more at the bladder neck and there preferably at 4 and 8 o’clock. It is important that the capsular arteries penetrate the prostate at right angles and then branch off in the gland. This explains the essential difference between the

bleeding situation in a prostate enucleation as opposed to a resection (. Fig. 2.2). The nerve supply follows the capsule arteries from the plexus pelvicus. Parasympathetic nerves end at the glands and are responsible for secretion. The sympathetic nerves are responsible for the contraction of the smooth muscle in the area of the capsule and the stroma. This is whyα-blockers come into play, which also cause relaxation in the area of the preprostatic sphincter. Afferent neurons run via the plexus pelvicus to the thoracolumbar centers in the spinal cord. Possibly, this would be the therapeutic approach for patients with chronic prostatitis, who cannot be treated successfully with local procedures. The membranous part of the urethra extends from the apex of the prostate to the perineal membrane and is between 2 and 2.5 cm long. Around this structure, the M. sphincter urethrae externus wraps, but not completely circular, but rather horseshoe-shaped with the opening to the posterior part. Only the inner layer of this muscle encircles the urethra circularly. This explains why the anterior part of the sphincter is the vulnerable part in­

13 Anatomy of the Prostate

transurethral operations of the prostate and why special caution is required at 12 o’clock in lithotomy position. The M. sphincter urethrae externus is a striated muscle, which means that it can be influenced voluntarily and supports the continence by active tension. But since it is a striated muscle, it is subject to fatigue, which explains that other mechanisms must apply for the continuous closure of the urethra. Myers et al. have published a comprehensive review article on the anatomy of the prostate, which is highly recommended for further interest (Myers et al. 2010).

References Brooks JD (2007) Anatomy of the lower urinary tract and male genitalia. Campbell-Walsh Urol 1(9):61 ff.

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Flocks RH (1937) The arterial distribution within the prostate gland: its role in transurethral resection. J Urol 37:524–548 Lee SE, Byun SS, Lee HJ, Song SH, Chang IH, Kim YJ, Gill MC, Hong SK (2006) Impact of variations in prostatic apex shape on early recovery of urinary continence after radical retropubic prostatectomy. Urol 68(1):137–141 Mamdouh MK (2008) The male urethral sphincter complex revisited: an anatomical concept and its physiological correlate. J Urol 179(5):1683–1689 Myers RP, Cheville JC, Pawlina W (2010) Making anatomic terminology of the prostate and contiguous structures clinically useful: historical review and suggestions for revision in the 21st. Anat 23(1):18–29 Oelke M, Bschleipfer T, Höfner K (2019) Hartnäckige Mythen zum Thema BPS – und was davon wirklich stimmt. Urologe A 58(3):271–283 Rosier PF, De La Rosette JJ (1995) Is there a correlation between prostate size and bladder-outlet obstruction? World J Urol 13:9–13 Vesalius A: Scholae Medicorum Patauinae Professoris, De humani corporis fabrica libri septem von Kühn KG (1821–1833) Claudii Galeni Opera omnia. 20 Bände. Leipzig

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Pathophysiology Stephan Madersbacher Contents 3.1 Introduction – 16 3.2 Histology – 16 3.3 Endocrinology – 16 3.4 Concept of Age-Associated Tissue Remodeling – 19 3.5 Lifestyle Factors – 19 3.6 Metabolic Syndrome – 19 3.7 Bladder Dysfunction – 20 References – 22

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_3

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3.1  Introduction

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The pathophysiology of benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE) is still not completely understood. However, the dominant role of the androgen balance and the androgen receptor has been known for decades (Madersbacher et al. 2019). In addition to the androgen balance, local auto- and paracrine factors, local inflammation, the microbiome, arteriosclerosis, but also modifiable lifestyle factors such as the metabolic syndrome play a role (Madersbacher et al. 2019). The three essential urodynamic aspects of lower urinary tract symptoms (LUTS) in BPH/BPE are bladder outlet obstruction (BOO)/benign prostatic obstruction (BPO), detrusor overactivity (DO) and detrusor underactivity (DU), which can occur in isolation or in various combinations. The term “benign prostate syndrome” was developed in Germany by the BPS working group and describes the interplay between LUTS, BPE and BPO. This chapter attempts to summarize the current state of knowledge regarding the pathophysiology of BPH/BPE (with a focus on clinically relevant aspects) and the associated bladder dysfunction. A presentation of genetic and molecular biological aspects would go beyond the scope of this chapter (Cartwright et al. 2014; Hellwege et al. 2019; Middleton et al. 2019). 3.2  Histology

The adult prostate is divided into five anatomical compartments or zones, which are not only important for organogenesis, but also for the development of various prostatic pathologies: 5 anterior fibromuscular stroma, 5 periurethral glandular tissue, 5 transition zone, 5 central zone, 5 peripheral zone (Helpap 2000).

The parenchymal component consists of basal, luminal and neuroendocrine cells, the fibromuscular stroma surrounds the epithelial acini. The epithelial-stromal interaction is responsible for the normal and pathological growth of the prostate. The interested reader is referred to the very detailed and excellent chapter on this topic by Helpap (2000). No clinically relevant new aspects have been published in the field of histology in recent years. 3.3  Endocrinology

The prostate is dependent on a intact androgen balance/metabolism for its development and function. In boys, the prostate is small and weighs two grams. During puberty, it shows an exponential growth to about 20 g, which correlates with the increase in serum testosterone levels. After puberty, the weight of the prostate remains relatively stable for two decades due to a steady-state of proliferation and cell death (apoptosis). Only afterwards, a BPH/BPE begin to develop, primarily due to a growth of the periurethral zone. Around the 40th year of life, the size growth of the transition zone begins at about 1.6% per year, with the growth rate increasing with age. z Androgen balance

The relationship between BPH/BPE and androgen balance has been known for decades, based on the observation that men who were castrated around puberty or in young adulthood develop only a rudimentary prostate (Madersbacher et al. 2019) (. Fig. 3.1). In addition, men with a congenital 5-α-reductase type II deficiency also develop only a rudimentary prostate (Madersbacher et al. 2019). Paradoxically, however, there is no correlation between the serum testosterone level in adolescence or the second half of life and the occurrence of BPH/BPE, which develop in a phase of life characterized by declining serum tes-

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17 Pathophysiology

Bladder dysfunction

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. Fig. 3.1  Overview of the relationship between bladder dysfunction—BPH/BPE—LUTS. Bladder dysfunction: Distribution of DO, DU and BOO/BPO according to Jeong et al. (2012), the arrows next to BPO, DU and DO indicate the age-associated trend (Jeong et al. 2012; Rodrigues et al. 2009). BPH/BPE: this scheme shows the complex interplay of the factors presented in this chapter, which intervene in the pathophysiology of BPH/BPE

tosterone levels (Schatzl et al. 2000). There is also no correlation between serum testosterone level and prostate volume or clinical symptoms (Schatzl et al. 2000). Since the DHT levels do not change with age, it is suspected that the 5α-reductase and the androgen receptor (AR) play an important role in the pathogenesis. The importance of DHT is highlighted by the fact that BPH can be induced in the castrated dog by means of DHT. In the prostate tissue, the serum testosterone is reduced to DHT by three 5α-reductase isoenzymes (expressed by the SRD5A1, SRD5A2 and SRD5A3 genes), which binds 2 to 5 times  more strongly to the AR than testosterone and leads to a 10-fold higher AR activity. The dominant 5α-reductase isoenzyme in the human prostate is type II, whereby this enzyme is expressed in both epithelium and stroma (Madersbacher et al. 2019). The AR belongs to the large family of nuclear receptors. At the carboxy-terminal end of

the receptor is the steroid or ligand-binding domain (so-called zinc finger). Here, the specific binding of the androgens takes place. Presence of androgens, 5α-reductase activity and AR expression are essential prerequisites for the development of BPH/ BPE (Madersbacher et al. 2019). z Estrogen levels

In addition to the androgens, the estrogens are also attributed an important role in the development of BPH/BPE (. Fig. 3.1). In contrast to androgens, serum estrogen levels increase with age in men, and both isoforms of the estrogen receptor (ER-α and ER-ß) are detectable in BPH tissue (Madersbacher et al. 2019). Experimental data suggest that the androgen-mediated homeostasis in the adult prostate is mainly controlled by AR in stromal cells. Via auto- and paracrine mechanisms, growth and apoptosis of epithelial and stromal cells are regulated (Madersbacher et al. 2019).

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z Growth factors

3

In the prostate, a number of growth factors such as the insulin-like growth factor (IGF-I//IGF-II), the epidermal growth factor (EGF), the fibroblast-growth factor (FGF) and the transforming growth factor-ß (TGF-ß) are also detectable (. Fig. 3.1). These growth factors regulate cell growth, whereby their production is regulated by androgens/estrogens. It has therefore also been postulated that BPH/ BPE arises as a result of an imbalance of these factors. The role of neuroendocrine cells is still unclear. z Intraprostatic inflammation

The high rate of histologically detectable inflammation in BPH/BPE led to the hypothesis that chronic inflammation plays a role in the pathophysiology. This local inflammation may be triggered by viruses or bacteria and leads to the secretion of cytokines, chemokines and growth factors. These factors maintain the local inflammation and induce the growth of epithelial and stromal prostate cells. It has been postulated that this inflammatory process is maintained by the release of prostatic autoantigens. According to de Nunzio et al. (2020), this intraprostatic inflammation is induced/propagated by the following factors (. Fig. 3.1): (i) infections (bacterial/viral, sexually transmitted diseases), (ii) hormones, (iii) metabolic syndrome/diet (iv) autoimmune processes/diseases, (v) aging processes and (vi) intraprostatic urine reflux. This intraprostatic inflammation induces the development and progression of BPH/LUTS via a proliferation of epithelial and stromal cells and a tissue remodeling. The clinical relevance of intraprostatic inflammation is documented by two large clinical studies. The REDUCE study was a placebo-controlled prostate cancer prevention study with dutasteride. In this study,

over 8000 patients were initially biopsied and followed up for 4 years. In a secondary analysis, Nickel et al. (2016) correlated the presence and extent of intraprostatic inflammation (based on the prostate biopsy at study entry) with the clinical course in the placebo arm (n = 4109).  The authors were able to show that chronic inflammation in the initial biopsy was associated with an increased risk of acute urinary retention (HR 1.6–1.8, p  35 kg/m2) had a 3.5-fold increased risk of an enlarged prostate, compared to those with a BMI  1x

74

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Pollakisuria > 8x

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25 Symptomatology

The current guidelines of the European Association of Urology (EAU) use the term “Lower Urinary Tract Symptoms” (LUTS) to categorize BPH (Miernik and Gratzke 2020). This term covers both, the storage and micturition symptoms, which is why the term LUTS has also become established in German to describe the complaints of patients with BPH. 4.1  Complications and Late

Effects

If left untreated, a BPS due to BPH can lead to serious complications (Chughtai et al. 2016). These include urinary retention or an overflow bladder, urinary tract infections, bladder stones, macrohematuria and the development of renal insufficiency (McConnell et al. 2003; Oelke et al. 2012). 1. Urinary retention: Epidemiological studies show that age, prostate volume, PSA concentration, Qmax, LUTS and residual urine are risk factors for developing urinary retention. Since all of these factors are also significantly associated with BPS, it is plausible that this is the main cause of urinary retention (McConnell et al. 2003; Jacobsen et al. 1997). 2. Urinary tract infections: A BPH-induced urinary stasis and accompanying bladder stones or diverticula represent predisposing factors for the development of a urinary tract infection (UTI). The predominance of symptoms such as dysuria, strangury or other irritative voiding symptoms often delays the consideration of the role of BPH-induced anomalies in the development of the UTI. Recurrent or chronic UTI are also considered to be an indication for a necessary intervention (McVary 2003).

4

3. Bladder stones: There are few studies that investigate the correlation between bladder stones and BPS. In the existing analyses, it was shown that the majority of patients with bladder stones also had symptoms of bladder emptying. These data suggest that bladder stones remain in the bladder due to incomplete bladder emptying and thus every patient with RU is exposed to the risk of developing bladder stones (Douenias et al. 1991; Millán-Rodríguez et al. 2004). 4. Macrohematuria: BPH is the most common cause of macrohematuria in men over 60 years of age (McVary 2003). Usually, the BPH-associated hematuria is “initial” or “terminal”, but BPH can also lead to significant bleeding complications, which require the placement of an catheter or an acute intervention. 5. Renal insufficiency: Due to the maximum expression of BPH, a progressive renal insufficiency can occur, which is secondary to a usually bilateral hydronephrosis. In the Olmsted-County study, it was shown that in symptomatic men (IPSS > 7) with low maximum urinary flow rate (Qmax  100 mL, a deterioration of renal function is present (Rule et al. 2005). Other symptoms can affect the continence and the erectile dysfunction. However, these symptom complexes are not specific to BPH and are also present in other pathologies of the lower urinary tract (e.g. infection, postoperative, traumatic) or caused by neurological bladder dysfunction (e.g. multiple sclerosis, Parkinson’s disease or previous stroke). In the presence of polyuria and/or nocturia, other diseases, such as diabetes mellitus and right heart failure, should be excluded.

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4.2  Classification of Benign

Prosta te Syndrome

4

In 1955, Alken and Staehler classified different stages of BPS to standardize the indication for the treatment of BPS (. Table 4.2) (Alken and Staehler 1973). In the irritative stage (stage 1), the patients report obstructive and/or irritative voiding complaints, without evidence of residual urine (RU). In this stage, the patients are usually treated with medication. In stage 2, the patients have RU volumes of 100–150 mL, with a frequently associated detrusor hypertrophy. Here, patients are usually treated medically or in special cases surgically. Stage 3 describes an overflow bladder with urinary retention. Due to the lack of urine flow, there can be a backlog of urine into the upper urinary tract with development of a postrenal renal failure. Here, the patient should be provided with a urinary bladder catheter (transurethral or suprapubic). If the renal retention parameters increase due to the lack or reduced urine flow,

a normalization of the renal retention parameters should be awaited in case of patient`s desire for a surgical treatment. Another classification of BPH was described by Vahlensieck and Vahlensieck in 1983 (Vahlensieck and Vahlensieck 1983). As an extension, this classification also captures functional changes of the urinary stream in addition to the pure categorization of the pathological features of micturition. Furthermore, the anatomical effects on the bladder and on the upper urinary tract are described (see . Table 4.3). These outdated classifications are only of minor importance in today’s nomenclature and in the current guidelines. The criticism of both classification systems refers to the facts  that the complaints are formulated in a very general manner and an objectification of the symptoms is therefore is difficult to  delineate. In many scientific works, these classifications still exist, which is the reason why they are listed here for the sake of completeness. 4.3  Symptom Scores

. Table 4.2  Classification of benign prostate syndrome. (According to Alken and Staehler 1973) Stage 1 Irritation stage

Compensated disease with delayed onset of urination, frequency and nocturia, no residual urine

Stage 2 Residual urine stage

Beginning decompensation with increase of dysuric complaints (frequency) residual urine (100–150 mL)

Stage 3 Decompensation stage

Decompensated disease with overflow bladder, urinary retention, hydronephrosis, renal insufficiency

For an objective assessment of the symptomatology in a BPS, validated questionnaires should be used. There are different symptom scores, which sensitively capture changes in micturition and are suitable for follow-up examinations of the disease (Barry et al. 1992; Donovan et al. 2000; Schou et al. 1993; Barqawi et al. 2011). These questionnaires are helpful in quantifying LUTS and identifying which symptoms most impair the patient. However, these are neither disease-, gender- nor age-specific. This type of data collection serves not only the physician and the patient for quality control, but also provides valuable information for the evaluation of different treatment methods for the same disease. This can give an impression in terms of an efficiency and quality assess-

27 Symptomatology

. Table 4.3  Classification of benign prostatic syndrome. (According to Vahlensieck and Vahlensieck (1983)) Stage I No micturition disorders More or less pronounced BPH Uroflow > 15 mL/s No residual urine No trabeculated bladder Stage II Varying micturition disorders (e.g. frequency) More or less pronounced BPH Uroflow between 10 and 15 mL/s No or incipient trabecular bladder Stage III Permanent micturition disorders (e.g. frequency) More or less pronounced BPH Uroflow  50 mL Trabecular bladder Stage IV Permanent micturition disorders (e.g. frequency) More or less pronounced BPH Uroflow 1.6 ng/mL, >2.0 ng/mL and >2.3 ng/mL are approximate age-specific values for the detection of prostate glands over 40 ml for men with BPH in their 50s, 60s and 70s (Roehrborn et al. 1999). A Dutch study also demonstrated a strong association between PSA and PV (Bohnen et al. 2007). A PSA threshold value of 1.5 ng/ml was best able to indicate a PV of >30 mL with a positive predictive value of 78% in this study. The predictive value of the PV can also be based on the total and free PSA. Both PSA forms predict the PV measured by TRUS with ±20% in >90% of cases (Kayikci et al. 2012).

z Digital rectal examination

The DRE is the simplest way to determine the prostate volume (PV), the tenderness and the consistency. Overall, the correlation of the DRE to the actual PV is low and decreases with increasing PV (Roehrborn 1998). Transrectal ultrasound of the prostate (TRUS) is more suitable for the assessment of the PV than the DRE. For the early detection of carcinoma, the DRE has a sensitivity of < 30% in some studies and only in one third of the patients with a suspicious palpation finding, a prostate carcinoma could be histologically confirmed by a needle biopsy (Gratzke et al. 2015). However, since the DRE is quick and easy to perform and at the same time the sphincter tone, bulbocavernosus reflex and the rectum can be examined, this examination is an obligatory part of the clinical examination. 5.4  Urinalysis

z PSA and predictive value of complications

Urinalysis using a urine stick or by means of urine sediment should be performed in every patient presenting with LUTS to identify urinary tract infections, microhematuria and/or diabetes mellitus (Ezz el Din et al. 1996). Depending on the test result, further investigations are necessary.

Serum PSA is a stronger predictor of prostate growth than the PV itself (Roehrborn et al. 2000). Roehrborn et al. were able to show in a study that the PSA not only correlated with the PV, but also predicted changes in symptoms, quality of life and maximum urinary flow rate (Qmax)

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(Roehrborn et al. 1999). In a longitudinal study with conservatively treated men, the PSA was a highly significant predictor of the clinical progression of the disease (Patel et al. 2018). In other placebo-controlled double-blind studies, the PSA predicted the risk of acute urinary retention and a necessary BPH-related surgery (McConnell et al. 2003). An equivalent association was also confirmed by the “Olmsted County” study. The probability of a necessary therapy was higher in men with a baseline PSA value of >1.4 ng/mL compared to men with lower PSA (Jacobsen et al. 1999). 5.6  Kidney Function

Measurement

Kidney function can be assessed either by serum creatinine or by the calculated glomerular filtration rate (eGFR). Bilateral hydronephrosis, renal insufficiency or acute urinary retention occur more frequently in patients with symptoms of BPH overall (Gerber et al. 1997). Gerber et al. reported in their study that 11% of men with LUTS had concurrent renal insufficiency. However, no correlation of symptomatology and/or quality of life with an elevated serum creatinine level could be found. In these 11% of men, diabetes mellitus or hypertension were the most likely causes for the increased creatinine concentration, and not primarily BPH (Gerber et al. 1997). In the “Olmsted County” cross-sectional study, a relationship was seen in patients with LUTS and chronic kidney disease (Rule et al. 2005). Mebust et al. described that patients with renal insufficiency have an increased risk of developing postoperative complications (Mebust et  al. 1989).

5.7  Optional Diagnostics

If there are still unclear issues after basic diagnostics, a voiding diary can be performed. The diary should be carried out for at least 2 days, better for 3 days (EAU guidelines). Ultimately, the duration should be kept long enough to avoid sampling errors, but short enough to avoid “noncompliance” (Bright et al. 2011). Here, the patient measures and records the amount of drinking, the voiding frequency and the voiding volume. The voiding diary can provide information on unclear voiding history between pollakisuria and polyuria. Endoscopic examinations and urethrocystography are limited to specific questions, e.g. to clarify micro- or macrohematuria, to exclude a bladder tumor or an urethral stricture.

References Barry MJ, Fowler FJ, O’Leary MP et al (1992) The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148:1549–1557 (discussion 1564). 7 https://doi.org/10.1016/s0022-5347(17)36966-5 Bright E, Drake MJ, Abrams P (2011) Urinary diaries: evidence for the development and validation of diary content, format, and duration. Neurourol Urodyn 30:348–352. 7 https://doi.org/10.1002/ nau.20994 Bohnen AM, Groeneveld FP, Bosch JLHR (2007) Serum prostate-specific antigen as a predictor of prostate volume in the community: the Krimpen study. Eur Urol 51:1645–1652 (discussion 1652–1653). 7 https://doi.org/10.1016/j.eururo.2007.01.084 Chandiramani VA, Palace J, Fowler CJ (1997) How to recognize patients with parkinsonism who should not have urological surgery. Br J Urol 80:100–104. 7 https://doi.org/10.1046/ j.1464-410x.1997.00249.x Ezz el Din K, Koch WF, de Wildt MJ et al (1996) The predictive value of microscopic haematuria in patients with lower urinary tract symptoms and benign prostatic hyperplasia. Eur Urol 30:409–413. 7 https://doi.org/10.1159/000474207

35 Clinical Diagnostics

Gerber GS, Goldfischer ER, Karrison TG, Bales GT (1997) Serum creatinine measurements in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Urology 49:697–702. 7 https://doi.org/10.1016/S0090-4295(97)00069-1 Gratzke C, Bachmann A, Descazeaud A et al (2015) EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including Benign prostatic obstruction. Eur Urol 67:1099–1109. 7 https://doi.org/10.1016/j.eururo.2014.12.038 Griffiths D, Harrison G, Moore K, McCracken P (1994) Long-term changes in urodynamic studies of voiding in the elderly. Urol Res 22:235–238. 7 https://doi.org/10.1007/BF00541899 Jacobsen SJ, Jacobson DJ, Girman CJ et al (1999) Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol 162:1301–1306 Kaplan SA, Reis RB (1996) Significant correlation of the American Urological Association symptom score and a novel urodynamic parameter: detrusor contraction duration. J Urol 156:1668–1672 Kayikci A, Cam K, Kacagan C et al (2012) Free prostate-specific antigen is a better tool than total prostate-specific antigen at predicting prostate volume in patients with lower urinary tract symptoms. Urology 80:1088–1092. 7 https://doi.org/10.1016/j.urology.2012.08.004 Koch WF, Ezz el Din K, de Wildt MJ et al (1996) The outcome of renal ultrasound in the assessment of 556 consecutive patients with benign prostatic hyperplasia. J Urol 155:186–189 Madersbacher S, Klingler HC, Djavan B et al (1997) Is obstruction predictable by clinical evaluation in patients with lower urinary tract symptoms? Br J Urol 80:72–77. 7 https://doi.org/10.1046/ j.1464-410x.1997.00220.x

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McConnell JD, Roehrborn CG, Bautista OM et al (2003) The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2387–2398. 7 https://doi. org/10.1056/NEJMoa030656 Mebust WK, Holtgrewe HL, Cockett AT, Peters PC (1989) Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 141:243–247. 7 https://doi. org/10.1016/s0022-5347(17)40731-2 Patel DN, Feng T, Simon RM et al (2018) PSA predicts development of incident lower urinary tract symptoms: results from the REDUCE study. Prostate Cancer Prostatic Dis 21:238–244. 7 https:// doi.org/10.1038/s41391-018-0044-y Roehrborn CG (1998) Accurate determination of prostate size via digital rectal examination and transrectal ultrasound. Urology 51:19–22. 7 https://doi.org/10.1016/s0090-4295(98)00051-x Roehrborn CG, Boyle P, Gould AL, Waldstreicher J (1999) Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 53:581–589. 7 https:// doi.org/10.1016/s0090-4295(98)00655-4 Roehrborn CG, McConnell J, Bonilla J et al (2000) Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study. J Urol 163:13–20 Rule AD, Jacobson DJ, Roberts RO et al (2005) The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men. Kidney Int 67:2376–2382. 7 https://doi. org/10.1111/j.1523-1755.2005.00344.x Schleicher C, Neumann R, Kaiser WA, Stein G (1997) Indications for intravenous urography. Med Klin (Munich) 92:79–82. 7 https://doi.org/10.1007/BF03042289

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Imaging Techniques for the Benign Prostate Syndrome Matthias Oelke Contents 6.1

Introduction – 38

6.2 Ultrasound – 38 6.3 Other Methods – 46 References – 48

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_6

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6.1  Introduction

6

With imaging methods, the position, shape and size of the kidneys, bladder and prostate can be assessed and also the presence or absence of a bladder outlet obstruction detected non-invasively (Berges et al. 2009). When imaging the kidneys, the adjacent retroperitoneum can also be examined simultaneously. All questions regarding patients with benign prostatie syndrome (BPS) can be answered in principle with ultrasound examinations. Radiological examinations (conventional X-ray, computed tomography) or magnetic resonance imaging are only necessary in rare cases to differentiate BPS from other diseases. The benefit of the radiological examinations should always be weighed against the radiation exposure: i.e. a critical check of the indication. 6.2  Ultrasound

Ultrasound devices with different percutaneous or intracavitary transducers are available in most  urology  departments. Ultrasound is the basic examination for all patients with BPS due to the easy performance and the non- or minimally -invasive technique without radiation exposure (Berges et al. 2009). Since lower urinary tract dysfunction can also cause morphological and functional changes in the upper urinary tract (e.g. hydronephrosis due to high residual urine formation or low-compliance bladder), the kidneys should also always be examined with ultrasound in every patient with BPS. The orienting sonographic examination of the upper and lower urinary tract is performed with a sector or convex transducer with a frequency of 3.5–5 MHz on the lying patient. In contrast, the transrectal ultrasound examination (TRUS) of the prostate is performed with a rod transducer with an ultrasound frequency ≥ 7.5 MHz in the

l­ateral or supine position. All findings, including the respective position of the transducer in relation to the examined patient as a pictogram, should be documented, not only for forensic reasons. It should be ensured that the orientation of the ultrasound images recommended by professional societies is followed: In the vertical representation of a structure (e.g. longitudinal axis of the kidney), the cranial parts of the patient should appear on the left and the caudal parts on the right on the ultrasound image. In the horizontal representation of a structure (e.g. transverse axis of the kidney), all right-sided parts of the patient should appear on the left on the ultrasound image and all left-sided parts of the patient on the right. In addition to the examined organs, the date of the examination, the surname, first name and date of birth of the patient as well as the name of the examiner should also be noted. Furthermore, all measurements of distances, areas or volumes must be traceable in the ultrasound image, so that the examination results are examiner-independent and comparable. 6.2.1  Kidney, Ureter

and Retroperitoneum

The retroperitoneal position of the kidneys in the perirenal fat tissue allows their high-resolution and detailed ultrasound examination. The ventral overlay by bowel and air can be circumvented by the dorsal transducer position, in which the kidneys are displayed in the middle to posterior axillary line at the level of the 11th and 12th rib. Often, the good representation of the kidneys is achieved when the ultrasound waves are conducted through parenchymal organs (right the liver, left the spleen). The overlay by the rib shadow can be avoided by deep inspiration, ipsilateral arm elevation, extension of the trunk and possibly turning the patient to the opposite

39 Imaging Techniques in Benign Prostatic Syndrome

side. According to the recommendations of the German Society for Ultrasound in Medicine (DEGUM), the kidneys should always be displayed in two planes. Accordingly, the kidneys are first displayed in the longitudinal axis and scanned from ventral to dorsal. Subsequently, the kidneys are displayed in the transverse axis and examined from caudally to cranially. Pathological findings should be documented at least in two planes. The renal parenchyma appears as a bean-shaped, hypoechoic structure and is isoechogenic compared to healthy liver or spleen tissue. Roughly oriented, the kidney has a size of 12 × 6 × 3 cm (length × width × depth). Occasionally, the slightly less hypoechoic, triangular medullary pyramids are visible in the renal parenchyma. The thickness of the renal parenchyma (15–20 mm) correlates with the renal function in healthy individuals. The adipose tissue in the renal hilum, on the other hand, appears hyperechoic. The renal pelvis-calyx system is delicate in the normal state, hidden in the adipose tissue

6

of the renal hilum and therefore not visible (. Fig. 6.1, left). In addition to the morphological assessment of the urinary tract, occasionally the assessment of renal blood flow using color-flow Doppler or duplex sonography is relevant (e.g. representation of renal perfusion). Using this method, the flow direction and flow velocity of the blood are color-coded, while points that are constant in location remain gray. The color assignment can be determined by the examiner in principle, but usually a flow away from the transducer is shown in red and a flow towards the transducer is shown in blue. In the systematic examination of the upper urinary tract, pathological renal findings are often visible in patients with BPS, which are caused primarily or secondarily by the bladder outlet obstruction. In BPS patients with high residual urine volumes and/or low-compliance bladder—but also in men with ureteral stones, neurogenic dysfunction of the lower urinary tract, a bladder tumor at the ureteral orifice, prostate cancer or vesico-ureteral reflux—there is

. Fig. 6.1  Sonographic representation of a normal kidney (left half of the image) and a kidney with dilatation of the renal pelvis-calyx system (hydronephrosis, right half of the image). Renal calyces, calyx necks, renal pelvis and proximal ureter are usually not visible in a normal kidney, but appear hypoechoic in hydronephrosis. Source Private image collection M. Oelke, Clinic for Urology, St. Antonius-Hospital Gronau

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often a dilatation of the renal pelvis-calyx system (hydronephrosis). In hydronephrosis, the renal pelvis-calyx system becomes visible as a hypoechoic, tree-like structure in the hyperechoic renal hilum adipose tissue (. Fig. 6.1, right). Different degrees of dilatation are distinguished depending on the classification system (e.g. Emmett grade 1–5) (Emmett and Witten 1971). However, a dilatation of the upper urinary tract is not always synonymous with a hydronephrotic kidney, as a dilatation does not always imply a congestion with pressure increase in the renal pelvis system (e.g. in vesico-ureteral reflux); this distinction is only achieved with renal scintigraphy after intravenous injection of the diuretic furosemide (Lasix®). A typical finding in patients with BPS is a bilateral dilatation of the upper urinary tract due to primary dysfunction of the lower urinary tract. In contrast, unilateral dilatation indicates a unilateral, ipsilateral pathology, e.g. ureteral stone, bladder tumor at the ureteral orifice or prostate cancer. If hydronephrosis is present, the ureter should also be followed and assessed sonographically as far as possible, as the hydronephrosis may be relevant for the assessment or as a starting point for a therapeutic at the lower urinary tract. 6.2.2  Urinary Bladder

Ultrasound (US) of the urinary bladder should always be performed with a filled urinary bladder, alternatively after retrograde (via a transurethral catheter) or antegrade (via a suprapubic catheter) filling with saline. The focus during the US examination  lies on the assessment of the bladder wall and intraluminal changes. Usually, a suprapubically placed 3.5 MHz sector or convex transducer is used. For large-capacity bladders or pathologies at the posterior bladder wall, a transrectally positioned rod transducer with a frequency  ≥ 7.5 MHz can also be useful.

The bladder lumen appears homogeneously hypoechoic, typically a dorsal sound enhancement can be seen at the bladder base. The border of the urinary bladder wall is smooth. Occasionally, bladder trabeculae can be seen, which consist of deposits of collagen and elastic fibers in the bladder mucosa. Immediately after micturition (up to 60 s), the  residual urine (RU) volume can also be measured by US (. Fig. 6.2): The urinary bladder must be displayed via the suprapubic sound window in the sagittal and transverse planes. By measuring the bladder volume, the bladder filling volume or the RU volume can be determined by an approximation formula using the volume ellipsoid formula: Bladder volume [cm3] = (width [cm] × height [cm] × depth [cm]) × π/6 (= 0.52)

During systematic US of the urinary bladder, pathological findings can occasionally be detected, which serve to differentiate between LUTS or RU, e.g. bladder tumors or bladder diverticula. Bladder tumors are usually carcinomas, which appear hyperechoic on the US image, always have contact with the bladder wall, are constant in location and, depending on the growth type, lie as smooth or papillary masses in the hypoechogenic urine. Bladder diverticula are protrusions from the bladder wall, usually at the bladder base or the dorsal side walls (. Fig. 6.3). Bladder diverticula indicate a bladder outlet obstruction (Oelke et al. 2012). Acquired diverticula are pseudodiverticula, which are composed only of mucosa and adventitia (Oelke et al. 2019). In the diverticula, urine accumulates in the storage phase, and additionally urine is pressed into the diverticulum during micturition. After micturition, the urine collected in the diverticulum flows back into the bladder back and can thus

41 Imaging Techniques in Benign Prostatic Syndrome

6

. Fig. 6.2  Sonographic representation of the urinary bladder for RU measurement (left longitudinal view, right transverse view). A RU volume of 236 cm3 (mL) was measured in 3 planes by US in this male person. Source Private image collection M. Oelke, Clinic for Urology, St. Antonius-Hospital Gronau

cause or ­aggravate RU (see also . Fig. 6.9). In US of the urinary bladder, the connection of the diverticulum to the bladder, the so-called diverticulum neck, can often be demonstrated. z Measurement of detrusor  wall thickness (DWT) for non-invasive detection of bladder outlet obstruction

Bladder wall hypertrophy is the physiological response of the urinary bladder to a bladder outlet obstruction (Kato et al. 1990; Levin et al. 2000), in order to increase the detrusor force, so as to enable micturition in the presence of an increased bladder outlet resistance (Oelke et al. 2002; Oelke and Wijkstra 2006). The longer the bladder outlet obstruction persists and the higher the bladder outlet resistance is, the thicker the bladder wall becomes due to detrusor

thickening (Levin et al. 2000). The ventral bladder wall (bladder anterior wall) is best suited to non-invasively display the detrusor with US. To ensure a good resolution of the US image, a detailed representation of the target region and an accurate measurement of the DWT, high-frequency ultrasound probes (≥7.5 MHz) must be used, which penetrate the tissue less deeply, but have a high spatial resolution of With increasing age, there is a decrease in voiding volume, which also leads to a reduction in the average urinary flow rate. Most authors as well as national and international guidelines recommend a minimum voiding volume of 150 mL (Gravas et al. 2021; Dreikorn et al. 1999; Rosier and de la Rosette 1995).

To achieve a volume-independent interpretation of the uroflow curves, various nomograms and indices were developed. Drake was the first to develop a “corrected peak flow rate” (Qmax/[square root of voiding volume]) (Drake 1948). The Siroky nomogram is based on studies of 300 urinary flow measurements in healthy subjects. Here, non-obstructive patients show a deviation of the Qmax value from the mean of less than 2 standard deviations, while 89% of the patients with obstruction had a deviation of more than 2 standard deviations (Siroky et al. 1979). Later, however, urodynamic obstruction could actually be demonstrated in only 75% of the patients who were obstructive according to the Siroky nomogram (Siroky et al. 1980). Furthermore, attempts were made to develop three-dimensional nomograms for volume- and age-independent Qmax determination (Drach et al. 1979).

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► Conclusions However, none of the nomograms and indices mentioned found their way into clinical practice and are also not used in studies. To note, uroflow values should always be evaluated in relation to other findings and complaints of the patient. ◄

z Uroflowmetry in BPH

8

As part of BPH, there is a statistically significant deterioration of the voiding volume, the flow time, Qmax and time to Qmax. In addition, the variability between Qmax values increases (Golomb et al. 1992). While uroflowmetry documents these changes in the context of BPH, its diagnostic value with regard to the symptoms of the patients, the prostate size, the individual degree of obstruction and a possible surgical success is low (Jensen 1995; Nielsen et al. 1994). The historical assumption that an increase in prostate size leads to a weakening of the urinary stream has been refuted (Rosier and de la Rosette 1995; Barry et al. 1993; Girman et al. 1995). A correlation between the prostate size in transrectal ultrasound and Qmax could also be refuted (Rosier and de la Rosette 1995). Also, the symptoms of the patients showed no correlation to the values of uroflowmetry (Barry et al. 1993; McLoughlin et al. 1990; Poulsen et al. 1994). Urodynamic studies  in BPH patients further relativize the significance of uroflowmetry. Thus, pathological changes could be detected in patients with normal Qmax values, e.g. a mechanical obstruction with a compensatory detrusor hypertrophy and high intravesical pressures (Reynard et al. 1998). > A decrease in Qmax, on the other hand, is considered to be a reliable sign of a pathological change in the lower urinary tract. It can be caused by a mechanical obstruction such as BPH or a urethral

stricture. Differentially, a weakening of the urinary stream can also be caused by a hypotonic detrusor with consequent reduced intravesical pressures (Siroky et al. 1979).

Based on uroflowmetry alone, no conclusion can be drawn about a possible existing obstruction. Thus, no therapy indication can be derived from the uroflow alone. Nevertheless, uroflowmetry is an internationally standardized, reproducible method for the description of the urinary stream. Unlike urodynamics, uroflowmetry is non-invasive, easy to perform and can be repeated easily. Thus, the examination represents an indispensable standard in diagnostics both in everyday clinical situations and in studies. 8.2  Residual Urine

Determination of residual urine (RU) is an important part in the diagnosis of BPH due to its simple sonographic measurement. When interpreting RU, methodological and differential diagnostic considerations as well as pathophysiological basics should be taken into account. RU is defined as the fluid volume remaining in the bladder, immediately after the end of voiding (Abrams et al. 2003). RU formation can develop acutely or chronically and can be simulated by bladder diverticula or a ureterovesical reflux. When measuring biological systems such as micturition, the situation of the patient must be taken into account. The test results can be influenced by stress, for example. A wrong timing (not representative bladder volumes) or ending the micturition too early can simulate pathological results. It should be ensured, similar to uroflowmetry, by questioning that a representative micturition is available for evaluation. Determination of RU must be done directly

63 Uroflow and Residual Urine

after the end of micturition according to the definition. z Residual urine determination invasive or non-invasive

Determination of RU can be done invasively (catheterization, endoscopic, radiological) or non-invasively by means of transabdominal sonography. The invasive catheterization of the bladder was considered to be the standard for a long time. However, catheterization also depends on the experience of the examiner; even after optimizing the technique, there still remains an error rate (Stoller and Millard 1989). Mainly because of their invasiveness, methods such as endoscopic determination of RU, contrast agent or radioisotope determinations were abandoned again, and the sonographic RU determination prevailed due to the easy handling, the lack of invasiveness and the low costs. Sonographic calculation of RU as a spherical or elliptical body can be done by various formulas. Approximately, the formula 0.5 × d1 × d2 × d3 can determine RU. Usually, the volume calculation is already done by the ultrasound devices. For normal persons, the average RU volume was determined to be below 12 mL, in 78% of the cases below 5 mL (Hinman and Cox 1966). The amount of RU is subject to, as mentioned, intraindividual variations (Birch et al. 1988; Jensen et al. 1988). Birch found in BPH patients in 66% of the cases significantly different amounts  of RU in multiple measurements on one day (Birch et al. 1988). As causes for this, both measurement inaccuracies and circadian fluctuations were discussed. This illustrates on the one hand the necessity of multiple measurements and on the other hand the classification of the RU values in the clinical context or the assignment to the other findings obtained.

8

z Clinical significance and interpretation

In BPH patients, RU might increase over the course of the disease (Golomb et al. 1992). Formation of RU is not specific to BPH. Differential diagnoses must exclude obstructions of other origin, decreased detrusor function, a sensory or motor innervation disorder of the bladder, and medication induced RU formation (especially substances from the group of antihistamines, antidepressants, anticholinergics and sympathomimetics) as causes. The bladder reacts to an obstruction with an increase in the intravesical pressure. > The intravesical pressure increase results here according to the Hill equation from a decreased urine flow rate and not—as often assumed—by a compensatory increasing contraction force (Ruud Bosch 1995; Griffiths 1973; Williams et  al. 1993).

The cause of a RU formation in BPH is discussed as morphological changes of the lower urinary tract with an increase in the contractile elements, an atrophy of the smooth muscle and an axonal degeneration.

References Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P, Victor A, Wein A (2003) Standardisation Sub-Committee of the International Continence S. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 61(1):37–49 Barry MJ, Cockett AT, Holtgrewe HL, McConnell JD, Sihelnik SA, Winfield HN (1993) Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 150(2 Pt 1):351–358 Barry MJ, Girman CJ, O’Leary MP, Walker-Corkery ES, Binkowitz BS, Cockett AT, Guess HA (1995) Using repeated measures of symptom score,

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­ ­roflowmetry and prostate specific antigen in the u clinical management of prostate disease. Benign Prostatic Hyperplasia Treatment Outcomes Study Group. J Urol 153(1):99–103 Birch NC, Hurst G, Doyle PT (1988) Serial residual volumes in men with prostatic hypertrophy. Br J Urol 62(6):571–575 Christmas TJ, Chapple CR, Rickards D, Milroy EJ, Turner-Warwick RT (1989) Contemporary flow meters: an assessment of their accuracy and reliability. Br J Urol 63(5):460–461 Drach GW, Layton TN, Binard WJ (1979) Male peak urinary flow rate: relationships to volume voided and age. J Urol 122(2):210–214 Drake WM Jr (1948) The uroflometer; an aid to the study of the lower urinary tract. J Urol 59(4):650– 658 Dreikorn K, Berges R, Höfner K, Madersbacher S, Michel MC, Muschter R, Oelke M, Reich O, Rulf W, Tschuschke C, Tunn U (1999) s2 Leitlinie Diagnostik und Differenzialdiagnostik des benignen Prostatasyndroms (BPS). 7 https://www.awmf. org/uploads/tx_szleitlinien/043-034l_S2e_Benignes_Prostatasyndrom_Diagnostik_Differenzialdiagnostik_abgelaufen.pdf Gravas S, Cornu JN, Gacci M, Gratzke C, Herrmann TRW, Mamoulakis C, Rieken M, Speakman MJ, Tikkinen KAO (2021) EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO) 2021 [cited 2021]. 7 https://uroweb.org/wp-content/uploads/ EAU-Guidelines-on-Management-of-Non-Neurogenic-Male-LUTS-2021.pdf Girman CJ, Jacobsen SJ, Guess HA, Oesterling JE, Chute CG, Panser LA, Lieber MM (1995) Natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 153(5):1510–1515 Golomb J, Lindner A, Siegel Y, Korczak D (1992) Variability and circadian changes in home uroflowmetry in patients with benign prostatic hyperplasia compared to normal controls. J Urol 147(4):1044–1047 Griffiths DJ (1973) The mechanics of the urethra and of micturition. Br J Urol 45(5):497–507 Hinman F Jr, Cox CE (1966) Residual urine volume in normal male subjects. Trans Am Assoc Genitourin Surg 58:82–89

Jensen KM (1995) Uroflowmetry in elderly men. World J Urol 13(1):21–23 Jensen KM, Jorgensen JB, Mogensen P (1988) Urodynamics in prostatism. II. Prognostic value of pressure-flow study combined with stop-flow test. Scand J Urol Nephrol Suppl. 114:72–77 Jorgensen JB, Jensen KM, Bille-Brahe NE, Morgensen P (1986) Uroflowmetry in asymptomatic elderly males. Br J Urol 58(4):390–395 McLoughlin J, Gill KP, Abel PD, Williams G (1990) Symptoms versus flow rates versus urodynamics in the selection of patients for prostatectomy. Br J Urol 66(3):303–305 Nielsen KK, Nordling J, Hald T (1994) Critical review of the diagnosis of prostatic obstruction. Neurourol Urodyn 13(3):201–217 Poulsen EU, Kirkeby HJ (1988) Home-monitoring of uroflow in normal male adolescents. Relation between flow-curve, voided volume and time of day. Scand J Urol Nephrol Suppl. 114:58–62 Poulsen AL, Schou J, Puggaard L, Torp-Pedersen S, Nordling J (1994) Prostatic enlargement, symptomatology and pressure/flow evaluation: interrelations in patients with symptomatic BPH. Scand J Urol Nephrol Suppl 157:67–73 Reynard JM, Peters TJ, Lim C, Abrams P (1996) The value of multiple free-flow studies in men with lower urinary tract symptoms. Br J Urol 77(6):813–818 Reynard JM, Yang Q, Donovan JL, Peters TJ, Schafer W, de la Rosette JJ, Dabhoiwala NF, Osawa D, Lim AT, Abrams P (1998) The ICS-‘BPH’ Study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 82(5):619–623 Rosier PF, de la Rosette JJ (1995) Is there a correlation between prostate size and bladder-outlet obstruction? World J Urol 13(1):9–13 Ruud Bosch JL (1995) Postvoid residual urine in the evaluation of men with benign prostatic hyperplasia. World J Urol 13(1):17–20 Siroky MB, Olsson CA, Krane RJ (1979) The flow rate nomogram: I development. J Urol 122(5):665–668 Siroky MB, Olsson CA, Krane RJ (1980) The flow rate nomogram: II clinical correlation. J Urol 123(2):208–210 Stoller ML, Millard RJ (1989) The accuracy of a catheterized residual urine. J Urol 141(1):15–16 Williams JH, Turner WH, Sainsbury GM, Brading AF (1993) Experimental model of bladder outflow tract obstruction in the guinea-pig. Br J Urol 71(5):543–554

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Urodynamics Clemens Mathias Rosenbaum Contents 9.1

Introduction – 66

9.2 Procedure – 67 9.3 Cystometry – 68 9.4 Pressure-Flow Measurement – 69 9.5 Other Examination Techniques – 72 References – 73

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_9

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9.1  Introduction

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The benign prostatic syndrome (BPS) refers to the subjective complaints and objective changes that arise when bladder emptying is obstructed by the prostate. It can manifest itself through obstructive symptoms, such as delayed onset of micturition, weak urinary stream, dribbling, incomplete emptying up to acute urinary retention, as well as through irritative symptoms, such as pollakisuria, imperative urgency up to urge incontinence and nocturia. Both storage and emptying disorders can be attributed to a dysfunction of the detrusor or the bladder outlet. As mixed forms, detrusor- and outlet-related disorders of storage and emptying function occur in all conceivable combinations (Gravas et al. 2021; Oelke et al. 2008; Oh et al. 2011). Disorders of urine storage can be diagnosed with the measurement of the detrusor pressure in the filling phase (cystomanometry) and disorders of the bladder emptying with the measurement of the detrusor pressure and the urinary flow during the emptying phase (pressure-flow measurement). In the urodynamic examination of men with lower urinary tract dysfunction, three main findings can be distinguished that are essentially independent of each other: 5 Bladder outlet obstruction 5 Detrusor hypocontractility 5 Detrusor overactivity These findings can be detected in isolation or in different combinations (Oelke et al. 2008; Oh et al. 2011). In addition, bladder hypersensitivity and bladder hyposensitivity, which can cause symptoms through an increased or decreased bladder filling sensation, should also be added. These urodynamic findings can be attributed to both a mechanical bladder outlet obstruction and other causes such as age-related visceral or neurogenic changes, without a clear distinc-

tion being possible in individual cases with the diagnostic methods (Oelke and Höfner 2012). There are currently no data that compare the standard examinations for BPS (uroflow (Qmax), post-void residual urine (PVR) measurement) with urodynamics in terms of a surgical therapy and its success. A meta-analysis by Clement et al. shows that urodynamics reduces the likelihood of surgical therapy. However, this meta-analysis could not provide any evidence for the change of symptoms by a possibly more precise diagnosis by urodynamics in the context of BPS evaluation (Clement et al. 2015). The results of the UPSTREAM trial will fill this gap, but the data have not yet been published (Urodynamics for Prostate Surgery Trial 2021). Urodynamics thus represents an optional diagnostic tool for BPS at the present time and should only be performed after unsuccessful medical therapy (Gravas et al. 2021). The indication should be made in the following findings (1) 5 Reproducible voided volume  10 mL/s in men with predominantly obstructive voiding symptoms 5 Spontaneous voiding with reproducible PVR > 300 mL 5 in men who are younger than 50 years or older than 80 years 5 after radical surgery (e.g. rectal resection) or radiation in the small pelvis 5 in case of evident neurological disease or neurological deficits 5 in case of persistence of voiding symptoms despite already performed invasive therapy

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9.2  Procedure

For the urodynamic diagnosis of BPS, two examination methods are especially relevant: The filling cystometry and the pressure-flow measurement. Ideally, both measurements are performed in one examination. The measurement technique is standardized today and should be performed according to the recommendations of the International Continence Society (ICS) (Abrams et al. 2003). For the diagnosis of the mechanical obstruction, absolute values of pressure and flow are used. Therefore, controls of the plausibility of the measured values before and during the examination are necessary. During the whole examination, i.e. both during the filling cystometry and during the pressure-flow measurement,  uroflow (Q), bladder pressure (pves) and abdominal pressure (pabd) are recorded. The detrusor pressure (pdet) results from the subtraction of bladder pressure minus abdominal pressure. The detrusor pressure is the reference value for all pressure-flow analyses and the quantification of the mechanical obstruction. An

9

accurate calibration and interference-free recordings of bladder pressure and abdominal pressure are therefore absolutely necessary. The following prerequisites should be checked before urodynamics 5 The reference height for the pressure transducers should correspond to the height of the bladder. 5 Bladder pressure and abdominal pressure should be zero when the external pressure transducers are open to the atmospheric pressure. Bladder pressure and abdominal pressure are at rest (empty bladder, no abdominal strain) between 10 and 40 cm water column and should be equal. The detrusor pressure should then be zero. 5 After insertion of the catheters (vesical and abdominal), the patient should cough. The resulting cough spikes should have the same height in the bladder and abdomen. Thus, the displayed detrusor pressure should no longer show any spikes (. Fig. 9.1).

Fine structure

Cough

Cough

Fine structure

. Fig. 9.1  Fine structure during urodynamic measurement. In addition, cough spikes are visible in the vesical and abdominal recording, but not in the detrusor pressure curve, which is to be interpreted as a sign of correctly positioned measuring probes

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5 Cough tests (. Fig. 9.1) should be performed regularly (e.g. after every 100 mL filling volume). This can ensure that the pressure meters still work properly and no catheter dislocation has occurred during the measurement. 5 During the measurement, bladder pressure, abdominal pressure and detrusor pressure curves show a typical fine structure. This fine structure is caused by minimal pressure changes, e.g. by movement of the patient (. Fig 9.1).

9.3  Cystometry

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Cystometry is the simultaneous recording of vesical and abdominal pressure during continuous bladder filling. The detrusor pressure is calculated and displayed from the difference of these two pressures. In cystometry the storage function of the bladder (bladder sensitivity, bladder capacity, detrusor instability) and detrusor extensibility (compliance) are recorded. Cystometry only provides a state picture of the bladder function and not its cause. For the diagnosis of detrusor overactivity cystometry is the relevant examination. A bladder outlet obstruction can only be diagnosed by means of a pressure-flow measurement. z Relevant parameters of cystometry are

5 Sensitivity: Urge to urinate must be present. Lack of urge to urinate and/or the occurrence of vegetative reactions with increasing filling such as sweating, blood pressure changes etc. indicate the presence of a neurogenic component. 5 Capacity: The maximum bladder capacity results from voiding volume and residual urine. The maximum capacity can sometimes exceed the filling volume considerably, which is due to the patient’s

own diuresis. The effective bladder capacity is calculated from the maximum bladder capacity minus residual urine. 5 Stability: An increase in detrusor pressure during filling is independent of duration and height of the amplitude to define as detrusor instability. A correlation of detrusor instability and symptomatic BPH is known (Oelke et al. 2008; Abrams et al. 1979; Ameda et al. 1994; Koyanagi et al. 1995; Nitti et al. 1994) and is regularly found (Oelke et al. 2008; Abrams et al. 1979; Andersen 1982). However, detrusor instability also occurs in healthy older men with a prevalence of 13%. The detrusor instability is therefore not specific for a bladder outlet obstruction (Andersen et al. 1978; Andersen 1976). After desobstruction, the detrusor instability is eliminated in 54–69% (Abrams et al. 1979; Andersen 1976; Cote et al. 1981; Rao et al. 1979). However, a prediction of the extent to which a planned therapy can improve the detrusor instability cannot be made (Abrams et al. 1979; Andersen 1982; Kim et al. 2019). 5 Elasticity: The elasticity of the detrusor defines its ability to respond to a physiological filling without significant pressure increase. In cystometry, the value is given as compliance. The calculation is done by forming the quotient of volume change per pressure change. The reduced compliance is relevant. The limitation of elasticity is responsible for the development of a vesical high pressure system and consequently for the damage of the upper urinary tract. The relationship between reduced compliance and bladder outlet obstruction and chronic urinary retention is proven (Abrams et al. 1978; Styles et al. 1991; Sullivan and Yalla 1996). After desobstruction, the compliance and the resulting ­ damage of the upper urinary tract are improved (Styles et al. 1988, 1991).

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9.4  Pressure-Flow Measurement

With the pressure-flow measurement the contractility of the detrusor and the degree of obstruction can be assessed (Gravas et al. 2021; Parsons et al. 2011) in comparison to free uroflowmetry. The conventional way of curve representation is the parallel recording of pressure values (vesical, abdominal, detrusor) and uroflow in a time axis. From the simultaneous representation of pressure and flow, classical corresponding pressure-flow values can be read, which are relevant for the further pressure-flow evaluation. A requirement for the detection of corresponding pressure-flow values is the simultaneous recording of pressure and flow. For each micturition, depending on the urethral resistance, a certain detrusor pressure is required to open the urethra (Popen). At this point, the registration of the uroflow begins. Physiologically, detrusor pressure and flow curve increase simultaneously until the detrusor pressure is reached at maximum flow (Pqmax). The detrusor pressure then drops with simultaneously decreasing flow until the micturition is finished and the urethra closes again (Pclos) (. Fig. 9.2).

. Fig. 9.2  Scheme of a pressure-flow measurement. At the pressure Popen (Gravas et al. 2021) the urethra opens and the urine flow begins. The micturition reaches the pressure Pqmax (Oelke et al. 2008) with increasing flow rate and increasing detrusor pressure. With simultaneous decrease of detrusor pressure and urine stream, the urethra closes at the point Pclos (Oh et al. 2011), where the micturition also ends

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By the parallel representation of pressure values (vesical, abdominal, detrusor) and urine stream in a time axis, a distinction between bladder outlet obstruction and detrusor hypocontractility can be made in most cases. z Urethral resistance relation

A precondition for the more precise diagnosis of quality and quantity of a mechanical obstruction is the representation of pressure and flow in a diagram (. Fig. 9.3). In this representation of corresponding pressure-flow values, a micturition loop without a time axis is created. The characteristic, corresponding pressure-flow values (Popen, Pqmax, and Pclos) are recognizable and show the direction of the development of the loop during micturition (. Fig. 9.3). The pressure-flow plot is also called urethral resistance relation (URR), as changes in urethral resistance during micturition are shown in the pressure-flow plot. The pressure-flow plot is the basis of any further pressure-flow analysis to quantify urethral resistance and detrusor contractility. In patients with BPS, the determination of

. Fig. 9.3  Pressure-flow curve as a diagram of uroflow and detrusor pressure. The identified corresponding values of pressure and flow (Gravas et al. 2021) to (Oh et al. 2011) are apparent

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­ rethral resistance and detrusor contractilu ity is the actual goal of pressure-flow measurement. z Passive urethral resistance relation

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Since the mechanical resistance corresponds to the residual resistance after full relaxation of the closure, the detrusor pressure in relation to the urinary stream (i.e. the micturition loop) reaches its lowest value. In the pressure-flow plot, this area corresponds to the so-called low-pressure flank of the micturition loop. To mark the low-pressure flank of the pressure-flow plot as a criterion for mechanical obstruction, a curve is used that is called passive urethral resistance relation (PURR) (. Fig. 9.4). The PURR corresponds to a graphical representation of the mechanical resistance of micturition. On the PURR as a graphical representation of the mechanical resistance, more or less all existing concepts for urodynamic diagnosis or classification of obstruction and contractility are based. The starting point for the classification is a numerical quantification of the PURR: The PURR curve is defined by a specific

foot point (intersection with the pressure axis) and a curve slope. The PURR foot point is representative for the closure of the urethra, the slope for the urethral properties during micturition. The length of the PURR curve is a parameter to describe the detrusor contractility. With different types of obstruction, both the foot point and the slope of the PURR curve can be changed independently of each other. A higher urethral resistance exists both when the entire PURR curve is shifted into a higher pressure range (increasing foot point, constant slope) (. Fig. 9.5a) or a decrease in the steepness of the PURR curve (constant foot point, decrease in slope) (. Fig. 9.5b). With different types of obstruction, the foot point and slope can be changed independently of each other, whereby the change in the global position of the PURR (foot point change) determines the degree of obstruction, the change in slope determines the type of obstruction. During normal micturition, the curve is steep and lies with the foot point in the low pressure range (. Fig. 9.6). In urethral strictures, the foot point is normal as with normal micturition, but the PURR is flat (the urethra opens at low detrusor pressure, but during micturition the pressure increases sharply due to the limitation of the maximum flow to the flow capacity of the stricture). The obstructive BPH has a foot point in the higher pressure range and is very variable in the slope angle. A bladder neck sclerosis shows a high foot point with always a flat slope. z ICS nomogram

. Fig. 9.4  Marking of the low-pressure flank by the PURR as a graphic for the mechanical resistance

Besides the PURR curve, there are simpler methods that allow a classification of the obstruction. The simplification of the analysis is done by reducing the pressure-flow plot to single points, which can be determined from the conventional representation of pressure and flow on the time axis. The detrusor pressure at maximum flow is used

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71 Urodynamics

. Fig. 9.5  PURR shapes with increasing urethral resistance. a Increasing foot point, b decreasing slope. In both cases, a reduction in the Qmax (Gravas et al. 2021; Oelke et al. 2008; Oh et al. 2011) results

Bladder neck sclerosis

obstructive

a

Stricture

Abrams/Griffiths Number

are Gray

Non obstructive

normal . Fig. 9.7  ICS nomogram with Abrams/Griffiths number

. Fig. 9.6  PURR shapes with classic micturition disorders

for the classification (see . Figs. 9.7 and 9.8). This point is plotted in nomograms (ICS nomogram, Schäfer nomogram) or used for the definition of numerical values. The ICS recommends a modification of the Abrams-Griffiths nomogram as the standard of the ICS (Abrams et al. 2003). In the Abrams-Griffiths nomogram, based on pressure-flow measurements on obstructive and non-obstructive subjects, three zones (obstructive, gray zone, non-obstruc-

tive) were empirically defined (Abrams and Griffiths 1979). The classification of the obstruction results from entering the detrusor pressure at maximum flow into the nomogram. The Abrams-Griffiths number is a pressure value (Lim and Abrams 1995). It is determined by drawing a line parallel to the boundary line between the obstructive zone and the gray zone on the pressure axis from the detrusor pressure at maximum flow. The Abrams-Griffiths number, however, is rarely used in clinical practice, unlike the ICS nomogram. The Schäfer nomogram contains seven degrees of obstruction (Schafer 1995). In

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Increase

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Footpoint . Fig. 9.8 CHESS classification for quadratic (PURR) and linear PURR (linPURR). The given limits for the slope of the linear PURR correspond to the ICS axis orientation (x-axis = flow, y-axis = detrusor pressure)

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addition to the classification of the obstruction, the classification of the contractility of the detrusor can also be done. The detrusor pressure at maximum flow is also entered into the Schäfer nomogram. z CHESS

CHESS is a two-dimensional, separate classification of foot point and rise of the square or linear PURR in four categories each, resulting in a 4 × 4 grid (Hofner et al. 1995). Following a chessboard, the foot point was classified with the letters A–D and the rise with the numbers 1–4, so that a total of 16 degrees of obstruction can be defined. CHESS is the only classification that can distinguish between obstruction degrees (foot point A–D) and obstruction types (classification of the rise 1–4). A compressive obstruction is present when the rise is classified with 1–2, a constrictive obstruction, when the rise is classified with 3 or 4. z Differences of the classifications

The differences of the individual classifications result mainly from the accuracy of the classification. The definition of the boundaries between obstructive and non-obstructive in the different concepts is almost the same. If only one point from the pressure-flow plot is used, the information

about the patient’s micturition is also reduced to this point. The point of the detrusor pressure at Qmax corresponds approximately to the endpoint of the PURR. The PURR concept makes clear that only the characteristics of the micturition after opening of the urethra are captured with the pressure at maximum flow. The individual micturition can reach the detrusor pressure at Qmax in very different ways, so that a micturition with an urethral stricture can have the same value for the detrusor pressure at Qmax as the one with the micturition of a BPH patient. The necessary detection of the minimum micturition pressure is lost, so that the distinction of different obstruction types such as compressive and constrictive is not possible. The decision which concept is applied depends on various factors. The most important factor is probably the clinical experience of the examiner with one or the other nomogram. It has become standard by now that several possibilities are available in parallel. 9.5  Other Examination

Techniques

The derivation of the urethral pressure profile is a static examination and cannot be used to detect an obstruction. The possibility of determining the prostate size from the functional urethral length (Kondo et al. 1979) has only historical significance due to the transrectal ultrasound. The micturition urethral pressure profile was first described by Scott et al. and technically modified by Yalla et al. for BPH (Yalla et al. 1980; McConnell et al. 1994). Studies by Asklin et al. confirmed that it is possible with the micturition urethral pressure profile to detect the location, type and diameter of the obstruction and the resistance of the obstructed urethral segment (Asklin et al. 1984). In comparison to other concepts for detecting the mechanical obstruction, there is a good correlation

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(DuBeau et al. 1995). Nevertheless, the micturition urethral pressure profile has not found the way into broad clinical practice. Also video urodynamics with simultaneous display of urodynamic curves and X-ray image is not a standard in the diagnosis of BPH (Gravas et al. 2021).

References Abrams PH, Griffiths DJ (1979) The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 51(2):129–134 Abrams PH, Dunn M, George N (1978) Urodynamic findings in chronic retention of urine and their relevance to results of surgery. Br Med J 2(6147):1258–1260 Abrams PH, Farrar DJ, Turner-Warwick RT, Whiteside CG, Feneley RC (1979) The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 121(5):640–642 Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P, Victor A, Wein A (2003) Standardisation Sub-Committee of the International Continence S. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 61(1):37–49 Ameda K, Koyanagi T, Nantani M, Taniguchi K, Matsuno T (1994) The relevance of preoperative cystometrography in patients with benign prostatic hyperplasia: correlating the findings with clinical features and outcome after prostatectomy. J Urol 152(2 Pt 1):443–447 Andersen JT (1976) Detrusor hyperreflexia in benign infravesical obstruction. A cystometic study. J Urol 115(5):532–534 Andersen JT (1982) Prostatism. III. Detrusor hyperreflexia and residual urine. Clinical and urodynamic aspects and the influence of surgery on the prostate. Scand J Urol Nephrol 16(1):25–30 Andersen JT, Jacobsen O, Worm-Petersen J, Hald T (1978) Bladder function in healthy elderly males. Scand J Urol Nephrol 12(2):123–127 Asklin B, Erlandson BE, Johansson G, Pettersson S (1984) The micturitional urethral pressure profile. Scand J Urol Nephrol 18(4):269–276 Clement KD, Burden H, Warren K, Lapitan MC, Omar MI, Drake MJ (2015) Invasive urodynamic studies for the management of lower urinary tract symptoms (LUTS) in men with voiding dysfunction. Cochrane Database Syst Rev 2015(4):CD011179

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Cote RJ, Burke H, Schoenberg HW (1981) Prediction of unusual postoperative results by urodynamic testing in benign prostatic hyperplasia. J Urol 125(5):690–692 DuBeau CE, Sullivan MP, Cravalho E, Resnick NM, Yalla SV (1995) Correlation between micturitional urethral pressure profile and pressure-flow criteria in bladder outlet obstruction. J Urol 154(2 Pt 1):498–503 Gravas S, Cornu JN, Gacci M, Gratzke C, Herrmann TRW, Mamoulakis C, Rieken M, Speakman MJ, Tikkinen KAO (2021) EAU guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO). [cited 2021]. 7 https://uroweb. org/wp-content/uploads/EAU-Guidelines-on-Management-of-Non-Neurogenic-Male-LUTS-2021. pdf Hofner K, Kramer AE, Tan HK, Krah H, Jonas U (1995) CHESS classification of bladder-outflow obstruction. A consequence in the discussion of current concepts. World J Urol 13(1):59–64 Kim M, Jeong CW, Oh SJ (2019) Effect of urodynamic preoperative detrusor overactivity on the outcomes of transurethral surgery in patients with male bladder outlet obstruction: a systematic review and meta-analysis. World J Urol 37(3):529– 538 Kondo A, Narita H, Otani T, Takita T, Kobayashi M, Mitsuya H (1979) Weight estimation of benign prostatic adenoma with urethral pressure profile. Br J Urol 51(4):290–294 Koyanagi T, Ameda K, Nantani M, Taniguchi K, Matsuno T, Shinno Y (1995) Preoperative cystometrography in patients with clinical benign prostatic hypertrophy. World J Urol 13(1):24–29 Lim CS, Abrams P (1995) The Abrams-Griffiths nomogram. World J Urol 13(1):34–39 McConnell JD, Barry MJ, Bruskewitz RC (1994) Benign prostatic hyperplasia: diagnosis and treatment. Agency for health care policy and research. Clin Pract Guidel Quick Ref Guide Clin 1994(8):1–17 Nitti VW, Kim Y, Combs AJ (1994) Correlation of the AUA symptom index with urodynamics in patients with suspected benign prostatic hyperplasia. Neurourol Urodyn 13(5):521–527 (discussion 7–9) Oelke M, Höfner K (2012) Spezielle Urodynamik des Mannes. In: Schultz-Lampel D GM, Haferkamp A (eds) Urodynamik. Springer, Berlin Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Hofner K (2008) Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol 54(2):419–426 Oh MM, Choi H, Park MG, Kang SH, Cheon J, Bae JH, du Moon G, Kim JJ, Lee JG (2011) Is there a

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correlation between the presence of idiopathic detrusor overactivity and the degree of bladder outlet obstruction? Urology 77(1):167–170 Parsons BA, Bright E, Shaban AM, Whitehouse A, Drake MJ (2011) The role of invasive and non-invasive urodynamics in male voiding lower urinary tract symptoms. World J Urol 29(2):191–197 Rao MM, Ryall R, Evans C, Marshall VR (1979) The effect of prostatectomy on urodynamic parameters. Br J Urol 51(4):295–299 Schafer W (1995) Analysis of bladder-outlet function with the linearized passive urethral resistance relation, linPURR, and a disease-specific approach for grading obstruction: from complex to simple. World J Urol 13(1):47–58 Styles RA, Neal DE, Griffiths CJ, Ramsden PD (1988) Long-term monitoring of bladder pressure in chronic retention of urine: the relationship be-

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tween detrusor activity and upper tract dilatation. J Urol 140(2):330–334 Styles RA, Ramsden PD, Neal DE (1991) The outcome of prostatectomy on chronic retention of urine. J Urol 146(4):1029–1033 Sullivan MP, Yalla SV (1996) Detrusor contractility and compliance characteristics in adult male patients with obstructive and nonobstructive voiding dysfunction. J Urol 155(6):1995–2000 Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) (2021) 7 https://clinicaltrials.gov/ct2/ show/NCT02193451 Yalla SV, Sharma GV, Barsamian EM (1980) Micturitional static urethral pressure profile: a method of recording urethral pressure profile during voiding and the implications. J Urol 124(5):649–656

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Controlled Waiting Andreas J. Gross Contents 10.1

Principle – 76

10.2 Indication – 76 10.3 Risk Factors – 76 10.4 Assessment – 79 References – 79

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_10

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10.1  Principle

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The terms “watchful waiting (WW)” or “active surveillance (AS)” are more common in the field of prostate cancer than in BPH. Nevertheless, it also makes sense to differentiate between these two treatment strategies here. WW means that one does nothing at all until problems occur, while AS involves regular examinations to check whether dynamics come into the disorder, from which one can or must derive further diagnostic or therapeutic measures. Both groups include patients with mild to moderate symptoms. Such patients are often appeased by being told, after appropriate medical history and physical examination, that they are in an age-typical and not worrying situation with their complaints. Depending on the situation, one can then offer both ways to the patient: i.e. WW or AS. The patient sets the direction. In both groups, BPH develops depending on the individual risk. While changes can be detected faster with AS, patients who have opted for WW only being treated when relevant symptoms become apparent. 10.2  Indication

There are surprisingly few data on WW and which parameters should be included before to encourage a patient to go this way. Certain external factors play a role, such as the patient’s age, family predisposition, genetic origin, geographical location, nutrition, body mass index etc. All of these factors are described as having an influence on the development of BPH (Parsons 2010). Most aging men have at least one (n = 1) symptom of BPH, which can be stable for a very long time and even regress (Société Internationale d’Urologie, SIU 2013).

However, patients should be advised that a long-standing, untreated BPH can lead to significant and irreversible organic damage. This, in turn, speaks more for AS, although there are only vague indications of the intervals at which a patient should present himself. The literature, which indicates that not much happens within one year in patients with mild symptoms, is already over 20 years old (Netto et al. 1999). The endpoints of BPH, such as acute urinary retention, kidney damage and/ or stone formation are surprisingly rare in this group (Kirby 2000). In the overall population of over 70-year-olds, the risk of developing urinary retention within 5 years is given as 10%. In the over 80-year-olds, this rate is even over 30%. Here, however, one has to consider differential diagnoses, as neurogenic causes also may come into play in this age group (Dougherty and Aeddula 2020). 10.3  Risk Factors

The risk factors capture the negative predictive influences, i.e. parameters that favor a progression of the disease or a complication. Only if these are not present, one can recommend "wait and see" with good conscience to the patient. Among the risk factors, there are those that can be influenced and those that have to be accepted. One cannot change one’s genetic origin, and rarely is a geographical change possible or reasonable in the corresponding age group. In cohort studies, it has been shown that first-degree relatives of BPH patients have a fourfold risk of developing BPH. This becomes even more evident in twins, where monozygotic twins have a higher common incidence of LUTS. The influence of the environment on the development of BPH is noted in this study at 10%

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(Gasperi et al. 2019). Genetic tests can also show that there are significant differences between Europeans, Africans or Asians (Su et al. 2017). A worldwide increasing problem is the nutritional status of people and as a consequence the rapidly growing number of patients with a metabolic syndrome (MetS). The metabolic syndrome includes the simultaneous occurrence of 5 Overweight (especially with abdominal obesity) 5 Dyslipidemia (elevated triglycerides; low HDL cholesterol) 5 Elevated blood sugar or glucose metabolism disorder (glucose intolerance, insulin resistance) 5 Hypertension.

In a robust study from South Korea, in which the data of over 130,000 patients were processed, it was found that the prevalence of a treatment-requiring BPH in men with MetS is significantly increased, provided they are older than 50 years (Sangjun et al. 2019). However, MetS also leads to a higher prevalence of BPH overall. The same observation is made with regular alcohol consumption. The strongest correlation between MetS and treatment-requiring BPH, however, existed with low HDL cholesterol in all age groups. The reverse observation is also interesting: Overall, 26.5% of men with BPH have MetS, whereas in a matched-paired analysis it turned out that 20.9% of men without BPH have MetS. The absolute difference of 5.6% may seem small, but it is statistically significant (P 25. Accordingly, it is not surprising that this group of overweight people also has a higher risk for LUTS (Wang et al. 2012). However, it is interesting to see what influence a change in BMI may have on LUTS. Khan et al. compared two groups of patients, one whose members were overweight for their entire lives, and one whose members only gained weight later. It turned out—with relatively small numbers—that it actually does not make a difference whether one was always overweight or became so later. However, it is postulated that reducing weight can have a positive influence on LUTS and on nocturia (Khan et al. 2021). > Overweight men and men with MetS can therefore be advised with good conscience to undergo LUTS treatment if they are willing to change something about the underlying problems.

z Placebo

In the so-called CONDUCT study, it was first noticed that patients who opted for WW (watchful waiting) had an equally good improvement in their quality of life and in the IPSS (International Prostate Symptom Score) as patients who immediately underwent drug therapy. This was initially interpreted as a placebo effect. ­However, since patients whose IPSS or BII

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(BPH Impact Index) worsened during the observation period were redirected to another therapy arm, the WW group had to be evaluated differently, and the argument of the placebo effect cannot be maintained here (Roehrborn et al. 2017). Nevertheless, Hamburg scientists have found that placebos—in this case painkillers—have both a biochemically and an anatomically verifiable effect (Zunhammer et al. 2021). In the MRI, three brain regions were identified as particularly active: the amygdala, the periaqueductal gray, and the rostral anterior cingulate. It is known that these three regions are involved in pain processing. Here, the morphine-like substances of the endorphins, which are produced by the body itself, act. Morphine-containing drugs work in the same way. Therefore, it can be assumed that placebos do indeed trigger a biochemical reaction, which then also becomes anatomically detectable at a corresponding location in the brain. The data on patients with whom WW vs. AS (active surveillance) vs. therapy initiation were compared should be treated with caution, because they come from different sources. Some come from studies by general practitioners, some from urologists, and probably the largest group are affected people who are not medically supervised. The approach of data collection is probably very different for the two groups of doctors. As the consequences, which are drawn from it. Rosenberg and his colleagues from the Department of Family Medicine in Michigan deal with the question of how far the non-urologist can and may become active in the diagnosis and treatment (Rosenberg et al. 2013). They call this STEP (Simplified Treatment of the Enlarged Prostate). First, simple questions are used to d ­ ifferentiate

the overactive bladder (OAB) from the prostate problem. Overview a) Do you have sudden urge to urinate? How often do you have to go to the toilet? Do you have to get up at night? → further towards OAB b) How is your urine stream? Do you have difficulty starting? Do you feel residual urine? → further towards benign prostate syndrome (BPS).

When BPH has been diagnosed, a step-bystep plan is applied, in which the urologist only comes into play at the last step. All measures up to this point are of a conservative/medicinal nature. An urologist will naturally perform more comprehensive examinations during first contact, to differentiate BPH from the suspicion of prostate cancer, but also possibly intervene earlier, because economic self-interests may become relevant here. Affected people can nowadays obtain comprehensive information on diagnoses and therapies in modern media. However, coping without medical consultation is certainly the worst advise. Thus, a meta-analysis of eight studies on “self-management” in men with LUTS shows that in seven of them there is a bias, which in turn questions the value of this approach considerably (Albarqouni et al. 2021). This is even more pronounced in information about the surgical treatment of benign prostatic enlargement: e.g. information on YouTube. In a paper from St. Gallen, 159 videos are reported, which had up to over two million views. Here, in only 21 videos (13.2%) no misinformation was spread (Betschart et al. 2020).

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10.4  Assessment

References

The concern of men to undergo the diagnosis or therapy of BPH is both emotionally and factually justified. The emotional part is explained by the almost mystified attitude towards the affected organ, which is also called the “G-spot of the man”, although most men have little or no idea where the gland is located or what its function is. The factual aspect is to be found in the history of the surgical treatment of BPH. From the beginning of the transurethral resections 90 years ago to the beginning of this century, this operation was accompanied by considerable risks : i.e. high morbidity and mortality rates. The fear of incontinence and impotence is widespread, because many men know someone who is affected in the context of this so frequently performed operation. Despite significant improvement in the development of the instruments, equally significant improvement in the endoscopic surgical techniques as well as improved surgical training through video operations, continuing education in the modern media and mentoring programs, there is still a great respect for an intervention. Even if it is difficult for a surgeon to admit, the significant improvement in the perioperative management, especially in the field of anesthesia, has contributed to a lower rate of serious complications. In consequence, patients with increased risk factors, poorer ASA score and higher age are operated, thus the indication for surgery has been expanded. Therefore, the option of WW or AS appears in a different light. On the one hand, one does not have to wait until a compelling indication for surgery, on the other hand, one can weigh up, in view of the considerations presented, when a therapy should be started.

Albarqouni L, Sanders S, Clark J, Tikkinen KAO, Glasziou P (2021) Self-management for men with lower urinary tract symptoms: a systematic review and meta-analysis. Ann Fam Med 19(2):157–167 Betschart P, Pratsinis M, Müllhaupt G, Rechner R, Herrmann TRW, Gratzke C, Schmid H-P, Zumstein V, Abt D (2020) Information on surgical treatment of benign prostatic hyperplasia on YouTube is highly biased and misleading. BJU Int 125(4):595–601 DiBello JR, Ioannou C, Rees J, Challacombe B, Maskell J, Choudhury N, Kastner C, Kirby M (2016) Prevalence of metabolic syndrome and its components among men with and without clinical benign prostatic hyperplasia: a large, cross-sectional, UK epidemiological study. BJU Int 117(5):801–808 Dougherty JM, Aeddula NR (2020) Male urinary retention. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL) Gasperi M, Krieger JN, Panizzon MS, Goldberg J, Buchwald D, Afari N (2019) Genetic and environmental influences on urinary conditions in men: a classical twin study. Urology 129:54–59 Khan S, Wolin KY, Pakpahan R, Grubb III RL, Colditz GA, Ragard L, Mabie J, Breyer BN, Andriole GL, Sutcliffe S (2021) Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia. BMC Urol Vol 47:1–13 Kirby RS (2000) The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 56:3 Li J, Peng L, Cao D, Gou H, Li Y, Wei Q (2020) The association between metabolic syndrome and benign prostatic hyperplasia: a systematic review and meta-analysis. Aging Male 2:1–12 Netto NR Jr et al (1999) Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urology 53:314 Parsons JK (2010) Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors. Curr Bladder Dysfunct Rep 5(4):212–218 Roehrborn CG, Oyarzabal Perez I, Roos EPM, Calomfirescu N, Brotherton B, Palacios JM, Vasylyev V, Manyak MJ (2017) Can we use baseline characteristics to assess which men with moderately symptomatic benign prostatic hyperplasia at risk of progression will benefit from treatment? A post hoc analysis of data from the 2-year CONDUCT studyWorld. J Urol 35(3):421–427

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Rosenberg MT, Staskin D, Riley J, Sant G, Miner M (2013) The evaluation and treatment of prostate-related LUTS in the primary care setting: the next STEP. Curr Urol Rep 14(6):595–605 Société Internationale d’Urologie (SIU) (2013) In: Chapple C, Abrams P (eds) Lower urinary tract symptoms (LUTS): an international consultation on male LUTS. 7 https://www.siu-urology.org Su XJ, Zeng X-T, Fang C, Liu T-Z, Wang X-H (2017) Genetic association between PSA-158G/A polymorphism and the susceptibility of benign prostatic hyperplasia: a meta-analysis. Oncotarget 8(20):33953–33960

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Wang S, Mao Q, Lin Y, Wu J, Wang X, Zheng X et al (2012) Body mass index and risk of BPH: a meta-analysis. Prostate Cancer Prostatic Dis 15(3):265–272 Yoo S, Oh S, Park J, Cho SY, Cho MC, Jeong H, Son H (2019) The impacts of metabolic syndrome and lifestyle on the prevalence of benign prostatic hyperplasia requiring treatment: historical cohort study of 130 454 men. BJU Int 123(1):140–148 Zunhammer M, Spisák T, Wager TD, Bingel U (2021) Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data Placebo Imaging Consortium. Nat Commun 12(1):1391

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Pharmacological Therapy Lukas Lusuardi Contents 11.1 Phytopharmaceuticals – 82 11.2 Alpha-Blockers – 83 11.3 5-Alpha-Reductase Inhibitors – 87 11.4 Phosphodiesterase Inhibitors – 88 11.5 Antimuscarinics – 89 11.6 Beta-3-Agonist Mirabegron – 89 11.7 Combination Therapies – 89 References – 92

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_11

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In the absence of operative necessity, pharmacological therapy is the treatment of choice for BPS. Approved drug classes are 5 alpha1-adrenoceptor antagonists (alpha-blockers), 5 phosphodiesterase type 5 inhibitors (PDE5-I), 5 5-alpha-reductase inhibitors (5ARI), 5 m-cholinoreceptor antagonists (antimuscarinics), 5 beta-3-adrenoceptor agonists (beta-3-agonists) and 5 phytopharmaceuticals.

grasses (Hypoxis rooperi) and rye (Secale cereale). In the pharmacological treatment of BPS, phytopharmaceuticals are the second most frequently prescribed substance group after alpha-blockers (Fourcade et al. 2008). There are vast international differences in this respect, which are attributed to different legal frameworks in marketing. The EAU guidelines do not give a clear recommendation for the use of phytopharmaceuticals, as no clear conclusions can be drawn about the efficacy due to the vast differences of the marketed preparations.

The choice of the drug depends on the predominant symptoms of the patient. Both monotherapies and combinations of drug classes are used. Before making a therapeutic decision, the expected mode of action and potential risks should be discussed with the patient.

z Seronea repens: Saw palmetto

11.1  Phytopharmaceuticals

Therapy with plant extracts has increased in the last decades. Both preparations from single plants and combination preparations from different plant extracts are used. Components of these preparations are phytosterols, plant oils, plant fatty acids and phytoestrogens. The exact mode of action of these preparations has not been clarified yet despite some in vitro studies and various animal models. Among other things, the inhibition of 5-alpha-reductase, an anti-inflammatory effect, inhibition of growth factors and promotion of apoptosis are suspected. Various substances with great differences in composition and manufacturing are marketed. The most commonly used therapeutics are derived from dwarf palm (Sabal serrulata), saw palmetto (Serenoa repens), African plum (Pygeum africanum), African

Among the phytopharmaceuticals, saw palmetto (Serenoa repens) is the most studied active ingredient. The preparation Permixon® is widely used here in a dosage of 320 mg, taken daily with meals. Reported side effects are gastrointestinal symptoms and in some cases interactions with anticoagulants (especially warfarin). The suspected mode of action is, among other things, an inhibition of the 5-alpha-reductase isoenzymes I and II, which is attributed to the presence of free fatty acids in the dwarf palm extract (Rhodes et al. 1993). However, this effect could only be observed in the context of in vitro studies and could not be confirmed by studies of human prostate tissue (Weisser et al. 1996). In a study by Carraro et al. (1996), Serenoa repens was compared with finasteride, and no effect on the PSA value could be detected (Carraro et al. 1996). Another problem of this active ingredient lies in the already mentioned large differences of the preparations. In a study by Booker et al. from 2014, 57 different Serenoa repens preparations from different countries were analyzed and differences in the content of free fatty acids of up to 460% compared to the content indicated on the package were found (Booker et al. 2014).

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Long-term studies show no influence on IPSS score, prostate volume or peak flow compared to a placebo in monotherapy, but in combination with tamsulosin an improvement of quality of life and IPSS score could be demonstrated (Barry et al. 2011; Bent et al. 2006; Alcaraz et al. 2020). z Pygeum Africanum: African plum

In Europe, the extract of the African plum has been used in the therapy of BPS since the late 1960s. The suspected mode of action here is a change in bladder contraction, which could only be described in animal experiments (Levin et al. 1996). The most commonly used dosages in the studies range between 100 and 200 mg daily and show a moderate effect on the symptoms of the patients. Due to the lack of standardization in the assessment of the symptoms, these studies are only of limited validity. Pygeum Africanum can nevertheless be used as a safe and effective drug in the treatment of BPH (Salinas-Casado et al. 2020). z Hypoxis rooperi: African grasses

Another herbal therapeutic agent in the treatment of BPS is beta-sitosterol, which is derived from African grasses (Hypoxis rooperi). The presumed mode of action is based on anti-inflammatory effects by inhibiting the prostaglandin metabolism. Preparations are marketed under the names Harzol® and Azuprostat®. In a pooled analysis by Wilt et al. from 1999, a reduction of the IPSS score by 4.9 points and an increase of the peak flow by 3.91 ml/s with a significant difference to the placebo with a marked reduction of the residual urine (28.6 ml) were shown. At the same time, doubts about the reliability of the collected data arise due to the high efficacy of the preparations in this analysis; only a short follow-up (4–26 weeks) was performed (Timothy J Wilt et al. 1999).

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z Other phytotherapeutics

Numerous other substances are marketed as phytotherapeutics for the treatment of BPS. However, there are usually no reliable data to adequately assess the therapeutic efficacy. Cernilton, which is derived from the pollen of rye, showed an improvement of the symptoms in self-assessment and in nocturnal pollakisuria compared to a placebo, but had no effect on peak flow and urinAry flow. In general, however, the studies lack sufficient follow-up and quality (Timothy J Wilt et al. 1999). Lycopene, which occurs in high concentration in tomatoes, shows antioxidant and anti-inflammatory activity and modulates cell growth in the prostate by inhibiting 5-alpha-reductase and IL-6 signals. Similarly, selenium affects prostate growth (Holzapfel et al. 2013; Vinceti et al. 2014). A combination of both with Serenoa repens is marketed under the name Profluss®. In combination with an alpha-blocker, improvements in the symptoms and peak flow could be achieved over a twelve-month period (Morgia et al. 2014). ► Conclusions Phytotherapeutics include a variety of preparations with large differences in composition and production. There are no reliable studies on the mode of action, effects and long-term effects of phytotherapeutics. Presumed mechanisms include anti-inflammatory effects, inhibition of 5-alpha-reductase and inhibition of cell growth. There is no clear recommendation for phytotherapeutics in the EAU guidelines. ◄

11.2  Alpha-Blockers

Alpha-blockers are the substance group of first choice in the pharmacological therapy of BPS.

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Alpha-blockers were first used in the therapy of BPS in the 1970s. Caine et al. were able to demonstrate (1978) in a study a significant improvement of uroflowmetry and symptoms with the non-selective alpha-blocker phenoxybenzamine (Caine et al. 1978). However, due to the non-selective alpha-blockade, there were serious cardiovascular complications, which is why phenoxybenzamine was no longer used for the treatment of BPS. Due to the dominance of the alpha-1 receptors on the prostate and urethra, substances with selective binding to these receptors were developed to block them more specifically. Prazosin was the first selective alpha-1 blocker developed with a good efficacy profile and lower side effects than phenoxybenzamine (C R Chapple et al. 1992; R S Kirby et al. 1987). A disadvantage of prazosin, however, was the rapid elimination from the serum, which required a dose at least twice a day. As a result, doxazosin and terazosin were developed, which require a dose once a day. However, both preparations had again serious cardiovascular side effects due to the relaxation of the smooth muscle of the vessels. Subsequently, uroselective preparations such as tamsulosin, alfuzosin, silodosin and naftodipil were developed with high affinity to alpha-1-a and alpha-1-d receptors. z Mode of action

The contraction of the smooth muscle in the prostate and urethra is largely controlled by alpha-1-adrenergic receptors. Alpha-1-AR can also be divided into three different subtypes (alpha-1a, alpha-1b, alpha-1d). The alpha-1a subtype is most prevalent in the prostate (approx. 70%) (Andersson 2002). In a study by Moriyama et al. from 1999, it was shown that the expression of

all three alpha-1-receptor subgroups was increased in the tissue with BPS, with the alpha-1a subtype having the largest proportion (Moriyama et al. 1998). Similar results were also found for urothelial tissue, especially at the bladder neck and prostatic urethra (Andersson 2002). Alpha-1-adrenergic receptors respond mainly to the neurotransmitter norepinephrine and cause contraction of the smooth muscle. An increased expression of these receptors leads to the typical symptoms of bladder emptying. The blockade of the alpha-1 receptors results in relaxation of the smooth muscle at the prostate and bladder neck. z Tamsulosin

Tamsulosin is a uroselective alpha-blocker with high affinity to alpha-1-a and alpha-1-d receptors. The efficacy and safety of tamsulosin was investigated in various randomized controlled trials. In a meta-analysis of these studies by Wilt et al. from 2003, tamsulosin showed an improvement of the symptom scores between 20 and 48% as well as an improvement of the peak flow between 1.2 and 4 ml/s (T J Wilt et al. 2003). The effect of tamsulosin is slightly better with higher dosage (0.8 mg), but also associated with an increase of side effects, which is why the dosage of 0.4 mg daily has been established. Patients should be informed about side effects such as rhinitis, dizziness and retrograde ejaculation. Effects on blood pressure have been described in studies in both hypertensive and normotensive patients. An increase in peak flow is detectable 4–8 h after intake, a symptom improvement after one-week intake (H Lepor 1998). In addition, tamsulosin shows a significant reduction of nocturnal pollakisuria as well as an improvement of the urinary stream (Yoshida et al. 2010; Aikawa et al. 2015).

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z Alfuzosin

Alfuzosin has a preference for prostatic tissue with a lower effect on vascular tissue as well as a low diffusion into the central nervous system. Due to these properties, it shows a high efficacy in the treatment of BPS with a low rate of side effects (Mottet et al. 2003; Rouquier et  al. 1994). Initially, alfuzosin was marketed in a dosage of 2.5 mg 3 times daily. Meanwhile, a once daily intake of 10 mg has been established (Al Bawab et al. 2020). A titrating dosage is not necessary. In a meta-analysis, a good efficacy in terms of symptom scores and uroflowmetry was demonstrated. The most frequently reported side effect is dizziness which occurs in 1.7 to 11.8% of patients. Other side effects such as hypotension, syncope or somnolence are described in less than 2% of patients (MacDonald and Wilt 2005). z Terazosin

Terazosin is considered as a second-line drug for the treatment of BPS due to its side-effect on blood pressure. The highest efficacy has been demonstrated in a 10-mg dose once daily. Due to the increased discontinuation rates due to side effects, a slow dose escalation should be performed, starting with 1 mg and weekly increase to 2, 5 and 10 mg (T.J. Wilt et al. 2002). The efficacy of terazosin has been well described in various studies. Significant improvements are shown in both uroflowmetry and symptom scores (H Lepor et al. 1996a, b; Fusco et al. 2016). At the same time, side effects such as dizziness and weakness are very common; a discontinuation rate of almost 20% is reported (Claus G Roehrborn et al. 1995). In a study the blood pressure changes under terazosin intake, Kirby et al. (1998) were able to demonstrate effects mainly in patients with untreated or poorly controlled blood pressure. Patients with normotensive and well-controlled blood pressure val-

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ues showed no significant or no changes in blood pressure (R S Kirby 1998). z Doxazosin

Doxazosin belongs to the second-line agents due to its effect on blood pressure similar to terazosin. A dose escalation is recommended, starting with 1 mg per day and weekly increase to 2, 5 and 10 mg. Analyses of placebo-controlled studies show the occurrence of dizziness in about 11% of patients and a 2.7-fold increased risk of orthostatic hypotension with doxazosin intake. At the same time, high efficacy in terms of symptom scores and uroflowmetry was demonstrated in various studies (Fawzy et al. 1995; Andersen et al. 2000). z Silodosin

Silodosin is the alpha-blocker with the highest affinity for alpha-1-a receptors. At a dosage of 8 mg per day, an IPSS reduction of 6.4 points was demonstrated after 12 weeks. The most common side effect reported is retrograde ejaculation in about 28% of cases, with only 2.8% of patients discontinuing therapy because of this (Marks et al. 2009). In case of anejaculation, the therapeutic success, measured by IPSS score and uroflowmetry, was higher (C G Roehrborn et al. 2011). At the same time, an improvement in erectile function was shown in patients without anejaculation (Cihan et al. 2020). In comparison, silodosin and tamsulosin show similar results with slightly different side effect profiles, with more cardiovascular side effects with tamsulosin and anejaculation with silodosin. z Comparison of alpha blockers in different patient groups

With regard to the hemodynamic effects of alpha blockers, the non-uroselective alpha blockers terazosin and doxazosin show a stronger reduction of systolic and diastolic blood pressure. This is due to the high

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affinity to the alpha-1b receptor, which is widely distributed in the blood vessels. Clinically, this manifests itself by dizziness, weakness, headache, palpitations and syncope. Dizziness and weakness are described as the main cause for discontinuation of alpha blockers (C G Roehrborn and Siegel 1996). It can be assumed that not only the peripheral blockade but also an effect on the central nervous system plays a role here (Andersson and Gratzke 2007). Since the risk of orthostatic hypotension is highest at the beginning of therapy, a careful dose titration is recommended for terazosin and doxazosin (de Mey 1998). For uroselective alpha blockers, alfuzosin is attributed a slightly higher effect on blood pressure. For tamsulosin and silodosin, less hemodynamic effects could be demonstrated, but a connection to the occurrence of syncope, especially in patients without antihypertensive medication, could be shown (Ding et al. 2013; Novara et al. 2013; Ohyama et al. 2019). A combined administration of two alpha blockers is not recommended. > In principle, uroselective and non-uroselective alpha blockers are both associated with the occurrence of syncope.

Patients with cardiovascular pre-existing conditions: Originally developed for the treatment of arterial hypertension, alpha blockers are no longer the first choice of therapy here, as beta blockers and ACE inhibitors have shown significantly better results. In patients with antihypertensive medication, a therapy with alpha blockers should be considered with care. Alfuzosin intake is associated with an increased risk of cardiovascular events in these patients (Lukacs et al. 2000). Analyses of tamsulosin and silodosin in patients with antihypertensive medication showed no increased rate of cardiovascular side effects (Lowe 1997; Michel et al. 1998; Novara et al. 2013).

Geriatric patients: For older patients, side effects such as dizziness and orthostatic hypotension are potentially more serious, as they can lead to falls and consequently to fractures and hospitalizations (Welk et al. 2015). In addition, especially older patients should be informed about the first-dose hypotension of alpha blockers before starting therapy (Bird et al. 2013). Sexual function: LUTS are a risk factor for sexual dysfunction and impair the quality of life of patients (Rosen et al. 2003). A positive effect of alpha blockers on this is often described and mainly attributed to the improvement of LUTS symptoms and thus improved quality of life (Gacci et al. 2011; Dijk et al. 2006). At the same time, alpha blockers are also linked to ejaculation problems, especially retrograde ejaculation. The main cause was initially assumed to be a relaxation of the smooth muscle of the bladder neck, but effects of alpha blockers on the seminal vesicles are also discussed (Andersson and Gratzke 2007). In addition, a central effect on ejaculation via dopamine-2-like and serotonin receptors is considered (Rosen et al. 2003). The probability of ejaculation disorders is higher under silodosin therapy than under tamsulosin (Gacci et al. 2014). The non-selective alpha blockers doxazosin and terazosin are not suspected of having effects on ejaculation. Floppy Iris Syndrome: The intraoperative floppy-iris syndrome (IFIS) is a possible complication during cataract surgery and is associated with the intake of alpha blockers. Patients with planned cataract surgery should not start or pause a therapy with alpha blockers preoperatively. In addition, a dose reduction could lead to a lower incidence of IFIS, as data from Japan has shown, since tamsulosin is administered in reduced dosage according to the recommendation there. According to current knowledge, IFIS is irreversible and can still occur even after years of discontinued

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alpha blocker therapy (Lunacek et al. 2018; Yang et al. 2020). ► Conclusions Alpha blockers are the first-line agents in the treatment of micturition disorders in BPS. The mechanism of action is a relaxation of the smooth muscle at the prostate and bladder neck. Due to the safety profile, tamsulosin and silodosin are the most frequently used preparations. Doxazosin, terazosin and alfuzosin are considered second-line agents due to increased cardiovascular side effects. Known side effects of therapy with alpha blockers include hypotension (and associated effects such as dizziness, weakness, syncope and falls) as well as retrograde ejaculation. ◄

11.3  5-Alpha-Reductase Inhibitors

In the hormonal therapy of BPS, 5-alpha-reductase inhibitors (5-ARIs) have been established. The advantage of this therapy, unlike other hormonal therapeutics such as e.g. GnRH analogues, is the lack of interaction with the hypothalamic-pituitary axis. 5-ARIs suppress the conversion of testosterone to the more potent metabolite dihydrotestosterone (DHT). This is mediated by the enzyme 5-alpha-reductase, of which two isoforms exist. The type I isoform is formed in the prostate and in various tissue types such as liver and skin, the type II isoform is formed almost exclusively in the prostate and genital tissue. Treatment with the 5-ARIs finasteride and dutasteride should be continued for at least 6 months. Patients with larger prostates seem to have a better response. The PSA value decreases by an average of 50%. Patients should be informed about side effects such as sexual dysfunction and depression. Studies show a lower incidence of newly diagnosed prostate carcinomas, but at

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the same time an increased incidence of highgrade carcinomas, which is why 5-ARIs are not suitable for the prevention of prostate carcinomas (Thompson et al. 2003). z Finasteride

Finasteride preferentially inhibits the type II isoform of 5-alpha-reductase. By the uninhibited type I enzyme, a castration is avoided. The standard dosage is 5 mg per day and must be taken for at least 6 months. Studies have shown a decrease in prostate volume, a reduction in PSA value by about 50%, and an improvement in symptom scores. In addition, there is a lower rate of urinary retention and the risk of needing surgical treatment decreases (Gormley et al. 1992; J D McConnell et al. 1998). The therapeutic success is higher in patients with a larger prostate volume (>40 ml) (Tacklind et al. 2010). Known side effects of finasteride are sexual dysfunction (partly permanent with long-term use), loss of libido and gynecomastia. Before starting therapy, the PSA value should be checked to be able to classify it in the early detection of prostate carcinomas. In long-term studies, a lower incidence of prostate carcinomas was shown under finasteride intake, but at the same time an increased rate of high-grade prostate carcinomas. In addition, there are indications of a possible reduction of bladder cancer, in which an ethnic component also seems to be relevant (Zhu et al. 2021). z Dutasteride

Dutasteride inhibits type I and type II isoenzyme of 5-alpha-reductase both. This leads to a ca. 90-percent reduction of the serum DHT concentration (Clark et al. 2004). The dosage is 0.5 mg once daily and should be administered for at least 6 months. The side effects of dutasteride are comparable to finasteride (sexual dysfunction, loss of libido and gynecomastia). In the second year of intake, a decrease of side ef-

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fects have been reported (Claus G Roehrborn et al. 2002; Clark et al. 2004; Na et al. 2012). Similar results have been shown after one year regarding symptom scores, peak flow, PSA decrease and reduction of prostate volume compared with finasteride (Clark et al. 2004; Nickel et al. 2011). Additionally, an improvement of nocturnal pollakisuria is noticeable, which however does not coincide with an improvement of sleep quality (Kuhlmann et al. 2021).Just like under finasteride therapy, there is a decrease of prostate carcinomas under dutasteride therapy, but also here an increase of high-grade prostate carcinomas is described (Gleason score 8 or more). For this reason, there is also no recommendation for dutasteride for prostate carcinoma prophylaxis. z Side effect profile of 5-alpha-reductase inhibitors

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Overall, both finasteride and dutasteride have only a low rate of side effects. The most frequently reported are sexual side effects such as erectile dysfunction, loss of libido and ejaculation disorders (lower ejaculate volume). The exact mechanisms are unclear, a reduction of nitric oxide and nitric oxide synthase due to a lower DHT concentration in the corpus cavernosum is suspected. Under long-term therapy, these complaints can also be permanent in some patients. The relative risk for this is described as 1.55 (Corona et al. 2017; Liu et al. 2016). It is still controversial whether the complaints decrease under long-term therapy (Moinpour et al. 2007; Liu et al. 2016). Furthermore, 5-ARIs seem to increase the risk for depression; a higher incidence of suicides under 5-ARI therapy is shown especially in younger patients (Nguyen et al. 2021). Patients should therefore be informed exactly about the risk of developing a depression.

In various publications, there were also reports of an increased risk for diabetes, decrease of bone density and increased incidence of heart failure and myocardial infarction, which all turned out to be not significant in more detailed analyses (Unger et al. 2016; Matsumoto et al. 2002; Skeldon et al. 2017). ► Conclusion 5-alpha-reductase inhibitors cause on average a 20% reduction of prostate volume as well as a moderate improvement in symptoms and uroflowmetry. A therapeutic success occurs only with long-term intake (at least 6 months). The therapeutic success is higher in patients with larger prostates. Side effects of 5-alpha-reductase are sexual complaints and an increased risk for depression. The intake for prevention of prostate carcinomas is not recommended. ◄

11.4  Phosphodiesterase

Inhibitors

The smooth muscle of the lower urinary tract also produces the enzyme phosphodiesterase type 5. This has the task of breaking down cGMP, which in turn plays a role in vasodilation. Inhibition of phosphodiesterase-5 thus results in vasodilation. Originally used to treat erectile dysfunction, an effect has also been shown in the treatment of LUTS. The exact mechanism is not fully understood, but an increased oxygenation of prostate and bladder tissue and an anti-inflammatory effect are suspected (Morelli et al. 2013; Vignozzi et al. 2013). Due to the favorable profile (long half-life), tadalafil is currently the only approved phosphodiesterase inhibitor for the treatment of BPS in patients with or without erectile dysfunction. A dose of 5 mg per day is recommended.

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Evaluations show a reduction in IPSS and QoL score as well as an improvement in nocturnal pollakisuria. At the same time, there is no effect on uroflowmetry (Hatzimouratidis et al. 2014; Dmochowski et al. 2010; Dong et al. 2013). Tadalafil is well tolerated; side effects such as dyspepsia, back pain and headache occur in about 2% of patients (Gacci et al. 2015; McVary et al. 2007). Compared with alpha-blockers, there is a similar efficacy with regard to IPSS scores, quality of life, uroflow and residual urine volumes (Dahm et al. 2017). Treatment with tadalafil is therefore considered to be a good alternative in patients with moderate symptoms and concomitant erectile dysfunction and shows superiority over tamsulosin (Oelke et al. 2013; Guo et al. 2020). 11.5  Antimuscarinics

Antimuscarinics are the standard therapy for overactive bladder and block the M2 and M3 receptors of the bladder. This results in a reduction of involuntary bladder contractions, less urgency and an increased bladder volume (Christopher R Chapple et al. 2002). Antimuscarinics can contribute to an improvement of symptoms in certain patient groups. Contraindications for therapy with antimuscarinics are patients in urinary retention and those with increased residual urine volume (>200 ml), since antimuscarinics are associated with an increased risk for these. Monotherapy with antimuscarinics is a controversial issue in patients with BPS. In some studies, an improvement in IPSS, especially with regard to irritative symptoms, has been be shown (Liao et al. 2013; Kaplan et al. 2006). Side effects of antimuscarinics include dry mouth, constipation, nasopharyngitis, dizziness and CNS impairment.

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11.6  Beta-3-Agonist Mirabegron

Mirabegron is a relatively new approved beta-3-agonist that is used to treat overactive bladder. Newer data show a benefit in the treatment of urinary flow disorders in patients with BPH. The recommended dose is initially 25 mg per day and can be increased to 50 mg. The effect of mirabegron occurs via stimulation of beta-3-receptors, which are the dominant beta-receptors on the bladder. This results in relaxation of the smooth muscle of the detrusor and consequently in an increase in bladder capacity without effects on residual urine volumes or voiding pressure (Leon et al. 2008; Yamaguchi and Chapple 2007). Placebo studies show a reduction in micturition frequency and in the incidence of bladder contractions (Nitti et al. 2013). Furthermore, Alexandre et al. reported an effect of mirabegron on the smooth muscle of the urethra and prostate (Alexandre et al. 2016). Known side effects of mirabegron include headache and nasopharyngitis. Mirabegron administration is not recommended in patients with uncontrolled hypertension (Tubaro et al. 2017; Malik et al. 2012). 11.7  Combination Therapies z Combination of alpha-blockers and 5-alpha-reductase inhibitors

The combination of an alpha-blocker and a 5-ARI has the advantage of a fast symptom improvement by the alpha-blocker and a long-term reduction of the prostate size with avoidance of urinary retention by the 5-ARI. After 6 months, a discontinuation of the alpha-blocker can be considered in case of a good response to the therapy, without having to fear a worsening of the symptoms (Barkin et al. 2003).

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In randomized-controlled trials, no advantage of a combination therapy over a monotherapy with alpha-blockers could be demonstrated. However, all studies had a maximum duration of one year (Herbert Lepor et al. 1996a, b; Debruyne et al. 1998; Roger S Kirby et al. 2003). In the MTOPS Trial (Medical Therapy of Prostatic Symptoms Trial) by McConnell et al. from 2003, the combination therapy of doxazosin and finasteride was investigated in over 3000 patients over a period of four years (John D McConnell et al. 2003): The patients were randomized into four groups and received either two placebos, a monotherapy of finasteride or doxazosin with a placebo and combination therapy of finasteride with doxazosin. At the end of the study, the group that had received the combination therapy showed the lowest progress of BPS. Patients with finasteride mono- and combination therapy had a lower risk of urinary retention and surgical interventions. In terms of symptom scores, peak flow, PSA reduction and prostate volume, the combination therapy was superior to both, doxazosin and finasteride monotherapy. The risk of progression was lowest in patients with initially high PSA levels and prostate volume in the combination therapy. With regard to side effects, patients with combination therapy were most affected. When analyzing the drug-specific side effects, similar numbers were found as in the respective monotherapy. The side effects were highest in the first year of therapy and decreased in the following years. The CombAT study by Roehrborn et al. from the year 2008, which lasted for four years, compared the combination of dutasteride and tamsulosin. Over 4800 patients were randomized into three groups and received dutasteride with a placebo, tamsulosin with a placebo or dutasteride and tamsulosin. In contrast to the MTOPS

study, only patients with a prostate volume over 30 ml and PSA levels of more than 1.5 ng/ml were included (Claus G Roehrborn et al. 2010). Similar to the MTOPS study, patients with combination therapy or dutasteride monotherapy had a lower risk of urinary retention or surgical interventions. In terms of disease progression and symptom improvement, the combination therapy was superior to both monotherapies. The occurrence of side effects was highest in the combination therapy, but here too, similar numbers of study dropouts were found in the monotherapies. z Combination of alpha-blockers and antimuscarinics

A combination therapy of alpha-blockers with antimuscarinics is indicated for patients with persistent irritative voiding symptoms after previous alpha-blocker therapy. No dose adjustment is required. There are several randomized controlled trials that have addressed the combination of different antimuscarinics with alpha-blockers. Kaplan et al. investigated (2006) the combination of tolterodine and tamsulosin in patients with an IPSS of over 12 and irritative symptoms. This was superior to placebo and both substances as monotherapy in terms of IPSS reduction, voiding frequency and the general perception of treatment success by the patients (Kaplan et al. 2006). Similar results could be shown in another study for the combination of doxazosin 4 mg and propiverine 20 mg. It is noteworthy that there was an increase in residual urine volume of 20 ml without urinary retention and an increased rate of side effects (Lee et al. 2005). Since in clinical practice BPS usually involves an initial therapy with alpha-blockers, various studies were conducted in which

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the patients first received a monotherapy with alpha-blockers for at least one month and then a combination therapy of alpha-blocker and antimuscarinic. Here, significant improvements in symptom scores and quality of life were shown in the combinations of oxybutynin and tamsulosin (MacDiarmid et al. 2008), tolterodine and alpha-blocker (C. Chapple et al. 2009), solifenacin and tamsulosin (Drake et al. 2015). z Combination of alpha-blockers and mirabegron

The combination of alpha-blockers with the beta-3 agonist mirabegron has been investigated in few clinical studies. Patients with BPS and overactive bladder could benefit from this. In the studies, a significant reduction in symptom scores and improvement in quality of life without changes in residual urine volumes was shown. There is only one randomized controlled study with 94 patients in which the combination therapy of mirabegron and tamsulosin was compared with tamsulosin monotherapy. Here, an advantage of the combination therapy over the monotherapy in terms of symptom improvement could be demonstrated. Especially for irritative voiding symptoms, improvements were shown by the combination therapy. However, it is noteworthy that there was a significant increase in residual urine, although only one case of urinary retention was reported (Ichihara et al. 2015; Matsuo et al. 2016; Wada et al. 2016). 5 Drug therapy is the therapy of choice for patients with moderate symptoms without an indication for surgery. 5 The choice of drug group depends on the predominant symptoms of the patient. 5 Phytotherapeutics can be used in patients with mild symptomatology, if

side effects of pharmacotherapy are feared. 5 Only spares data exist that could prove the effect of phytotherapeutics. 5 Alpha blockers are drugs with a fast onset of action and improve the symptomatology of patients (IPSS) as well as the uroflowmetry. 5 5-alpha-reductase inhibitors are particularly effective in patients with moderate symptomatology and increased risk of progression of BPS. 5 5-alpha-reductase inhibitors require about 6 months until the onset of action and therefore belong to the longterm treatment. 5 Phosphodiesterase inhibitors are especially recommended for patients with LUTS and concomitant erectile dysfunction. 5 Antimuscarinics are actually used in the treatment of overactive bladder, but can also be used in patients with irritative symptomatology. Contraindications for a therapy with antimuscarinics in BPS are patients in urinary retention and those with increased residual urine volume (>200 ml). 5 Mirabegron shows mainly a benefit in patients with urinary outflow disorders in BPS.

Combination therapies 5 The combination of alpha blockers with 5-alpha-reductase inhibitors has the advantage of rapid symptom improvement and a long-term reduction of the prostate size. After 6 months, the alpha blocker can be discontinued if there is a good r­ esponse. 5 The combination of alpha blockers with antimuscarinics is effective in patients who have not achieved any improvement with monotherapy so far.

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References

11

Aikawa K, Kataoka M, Ogawa S, Akaihata H, Sato Y, Yabe M, Hata J et al (2015) Elucidation of the pattern of the onset of male lower urinary tract symptoms using cluster analysis: efficacy of tamsulosin in each symptom group. Urology 86(2):349–353. 7 https://doi.org/10.1016/j.urology.2015.04.036 Alcaraz A, Alfredo R-A, Joaquín C-R, David C-D, Manuel E-F, José MC-O, Vincenzo F et al (2020) Clinical benefit of tamsulosin and the hexanic extract of serenoa repens, in combination or as monotherapy, in patients with moderate/severe LUTS-BPH: a subset analysis of the QUALIPROST study. J Clin Med 9(9). 7 https://doi. org/10.3390/jcm9092909 Alexandre EC, Kiguti LR, Calmasini FB, Silva FH, da Silva KP, Ferreira R, Ribeiro CA, Mónica FZ, Pupo AS, Antunes E (2016) Mirabegron relaxes urethral smooth muscle by a dual mechanism involving Β3 -Adrenoceptor activation and Α1 -Adrenoceptor blockade. Br J Pharmacol 173(3):415–428. 7 https://doi.org/10.1111/ bph.13367 Andersen M, Dahlstrand C, Hoye K (2000) Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia. Eur Urol 38(4):400–409. 7 https://doi. org/10.1159/000020315 Andersson K-E (2002) α-Adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with α-Adrenoceptor antagonists. World J Urol 19(6):390–396. 7 https://doi.org/10.1007/ s00345-001-0237-0 Andersson K-E, Gratzke C (2007) Pharmacology of Alpha1-Adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol 4(7):368–378. 7 https://doi. org/10.1038/ncpuro0836 Barkin J, Guimarães M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB (2003) Alpha-Blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur Urol 44(4):461–466. 7 https://doi.org/10.1016/ s0302-2838(03)00367-1 Barry MJ, Meleth S, Lee JY, Kreder KJ, Avins AL, Curtis Nickel J, Roehrborn CG et al (2011) Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA 306(12):1344–1351. 7 https://doi. org/10.1001/jama.2011.1364 Bawab AQAl, Alkhalidi BA, Albarahmieh E, Qassim SMA, Al‐Saifi MAD, Al‐Saifi B, Ling J, Al‐

Qerem W (2020) Pharmacokinetics and bioequivalence estimation of two formulations of Alfuzosin extended-release tablets. Clin Pharmacol Drug Develop 9(7):780–784. 7 https://doi. org/10.1002/cpdd.860 Bent S, Kane C, Shinohara K, Neuhaus J, Hudes ES, Goldberg H, Avins AL (2006) Saw palmetto for benign prostatic hyperplasia. N Engl J Med 354(6):557–566. 7 https://doi.org/10.1056/NEJMoa053085 Bird ST, Delaney JAC, Brophy JM, Etminan M, Skeldon SC, Hartzema AG (2013) Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40–85 years in the United States: risk window analyses using between and within patient methodology. BMJ (Clinical Research Ed.) 347(November):f6320. 7 https://doi.org/10.1136/bmj.f6320 Booker A, Suter A, Krnjic A, Strassel B, Zloh M, Said M, Heinrich M (2014) A phytochemical comparison of saw palmetto products using gas chromatography and 1H nuclear magnetic resonance spectroscopy metabolomic profiling. J Pharm Pharmacol 66(6):811–822. 7 https://doi. org/10.1111/jphp.12198 Caine M, Perlberg S, Meretyk S (1978) A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Br J Urol 50(7):551–554. 7 https://doi.org/10.1111/j.1464-410X.1978.tb06210.x Carraro J-C, Raynaud J-P, Koch G, Chisholm GD, Di Silverio F, Teillac P, Silva FCD et al (1996) Comparison of phytotherapy (Permixon®) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 29(4):231–240. 7 https://doi. org/10.1002/(SICI)1097-0045(199610)29:4%3c231 ::AID-PROS4%3e3.0.CO;2-E Chapple CR, Stott M, Abrams PH, Christmas TJ, Milroy EJ (1992) A 12-Week placebo-controlled double-blind study of prazosin in the treatment of prostatic obstruction due to benign prostatic hyperplasia. Br J Urol 70(3):285–294. 7 https:// doi.org/10.1111/j.1464-410x.1992.tb15733.x Chapple C, Herschorn S, Abrams P, Sun F, Brodsky M, Guan Z (2009) Tolterodine treatment improves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. Eur Urol 56(3):534–541. 7 https://doi.org/10.1016/j. eururo.2008.11.026 Chapple CR, Tomonori Y, Chess-Williams R (2002) Muscarinic receptor subtypes and management of the overactive bladder. Urology 60(5 Suppl 1):82–88 (discussion 88–9). 7 https://doi. org/10.1016/s0090-4295(02)01803-4 Cihan A, Kazaz İO, Yıldırım Ö, Deliktaş H, Ongün Ş, Gül Ü, Şahin B, Üre İ, Özkara H (2020)

93 Pharmacological Therapy

­ hanging aspects of male sexual functions acC companying treatment of benign prostatic hyperplasia with silodosin 8 Mg Per Day. J Sex Med 17(6):1094–1100. 7 https://doi.org/10.1016/j. jsxm.2020.02.023 Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S (2004) Marked Suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab 89(5):2179–2184. 7 https://doi. org/10.1210/jc.2003-030330 Corona G, Tirabassi G, Santi D, Maseroli E, Gacci M, Dicuio M, Sforza A, Mannucci E, Maggi M (2017) Sexual dysfunction in subjects treated with inhibitors of 5α-Reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis. Andrology 5(4):671–678. 7 https:// doi.org/10.1111/andr.12353 Dahm P, Brasure M, MacDonald R, Olson CM, Nelson VA, Fink HA, Rwabasonga B, Risk MC, Wilt TJ (2017) Comparative effectiveness of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review and meta-analysis. Eur Urol 71(4):570–581. 7 https://doi.org/10.1016/j.eururo.2016.09.032 de Mey C (1998) Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol 34(Suppl. 2):18–28. 7 https://doi. org/10.1159/000052284 Debruyne FMJ, Jardin A, Colloi D, Resel L, Witjes WPJ, Delauche-Cavallier MC, McCarthy C, Geffriaud-Ricouard C (1998) Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 34(3):169–175. 7 https://doi. org/10.1159/000019706 Ding H, Du, Wan, Hou Z-Z, Wang H-Z, Wang Z-P (2013) Silodosin is effective for treatment of LUTS in men with BPH: a systematic review. Asian J Androl 15(1):121–128. 7 https://doi. org/10.1038/aja.2012.102 Dmochowski R, Roehrborn C, Klise S, Xu, Lei, Kaminetsky J, Kraus S (2010) Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-Week clinical trial. J Urol 183(3):1092– 1097. 7 https://doi.org/10.1016/j.juro.2009.11.014 Dong Y, Hao L, Shi Z, Wang G, Zhang Z, Han C (2013) Efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a meta-analysis. Urol Int 91(1):10–18. 7 https://doi. org/10.1159/000351405

11

Drake, MJ, Chapple C, Sokol R, Oelke M, Traudtner K, Klaver M, Drogendijk T, Van Kerrebroeck P, NEPTUNE Study Group (2015) Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE Study and NEPTUNE II Open-Label Extension. Eur Urol 67(2):262–270. 7 https:// doi.org/10.1016/j.eururo.2014.07.013 Fawzy A, Braun K, Lewis GP, Gaffney M, Ice K, Braun K, Dykatra M et al (1995) Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study * Multicenter Study Grou P. Albertsen, Farmington, Connecti. By AMERICAN UROLOGICAL. ASSOCIATION, INC. Bd 0 Fourcade RO, Theret N, Taieb C, BPH Usage Study Group (2008) Profile and management of patients treated for the first time for lower urinary tract symptoms/benign prostatic hyperplasia in four European countries. BJU Int 35(5):1111– 1118. 7 https://doi.org/10.1016/S17012163(15)30736-2 Fusco F, Palmieri A, Ficarra V, Giannarini G, Novara G, Longo N, Verze P, Creta M, Mirone V (2016) Α1-Blockers improve benign prostatic obstruction in men with lower urinary tract symptoms: a systematic review and meta-analysis of urodynamic studies. Eur Urol 69(6):1091–1101. 7 https://doi.org/10.1016/j.eururo.2015.12.034 Gacci M, Eardley I, Giuliano F, Hatzichristou D, Kaplan SA, Maggi M, McVary KT, Mirone V, Porst H, Roehrborn CG (2011) Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 60(4):809–825. 7 https://doi.org/10.1016/j.eururo.2011.06.037 Gacci M, Ficarra V, Sebastianelli A, Corona G, Serni S, Shariat SF, Maggi M, Zattoni F, Carini M, Novara G (2014) Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis. J Sex Med 11(6):1554–1566. 7 https://doi.org/10.1111/ JSM.12525 Gacci M, Andersson K-E, Chapple C, Maggi M, Mirone V, Oelke M, Porst H, Roehrborn C, Stief C, Giuliano FO (2015) Benign prostatic enlargement latest evidence on the use of phosphodiesterase type 5 inhibitors for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 7 https:// doi.org/10.1016/j.eururo.2015.12.048 Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS (1992)

94

11

L. Lusuardi

The effect of finasteride in men with benign prostatic hyperplasia. The finasteride study group. N Engl J Med 327(17):1185–1191. 7 https://doi. org/10.1056/NEJM199210223271701 Guo B, Chen X, Wang M, Hou H, Zhang Z, Liu M (2020) Comparative effectiveness of tadalafil versus tamsulosin in treating lower urinary tract symptoms suggestive of benign prostate hyperplasia: a meta-analysis of randomized controlled trials. Med Sci Monit Int Med J Exp Clin Res 26(April):e923179. 7 https://doi.org/10.12659/ MSM.923179 Hatzimouratidis K, Eardley I, Giuliano F, Hatzichristou D, Moncada I, Salonia A, Vardi Y, Wespes E (2014) Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. 7 https://uroweb.org/wp-content/uploads/14-Male-Sexual-Dysfunction_LR.pdf Holzapfel NP, Holzapfel BM, Champ S, Feldthusen J, Clements J, Hutmacher DW (2013) The potential role of lycopene for the prevention and therapy of prostate cancer: from molecular mechanisms to clinical evidence. Int J Mol Sci 14(7):14620– 14646. 7 https://doi.org/10.3390/ijms140714620 Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y (2015) A randomized controlled study of the efficacy of tamsulosin monotherapy and its combination with mirabegron for overactive bladder induced by benign prostatic obstruction. J Urol 193(3):921–926. 7 https://doi. org/10.1016/j.juro.2014.09.091 Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z (2006) Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 296(19):2319–2328. 7 https://doi.org/10.1001/ jama.296.19.2319 Kirby RS (1998) Terazosin in benign prostatic hyperplasia: effects on blood pressure in normotensive and hypertensive men. Br J Urol 82(3):373–379. 7 https://doi.org/10.1046/ j.1464-410x.1998.00747.x Kirby RS, Coppinger SW, Corcoran MO, Chapple CR, Flannigan M, Milroy EJ (1987) Prazosin in the treatment of prostatic obstruction. A placebo-controlled study. Br J Urol 60(2):136–142. 7 https:// doi.org/10.1111/j.1464-410x.1987.tb04950.x Kirby RS, Roehrborn C, Boyle P, Bartsch G, Jardin A, Cary MM, Sweeney M, Grossman EB (2003) Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) Trial. Urology 61(1):119–126. 7 https://doi.org/10.1016/S00904295(02)02114-3

Kuhlmann PK, Fischer SC, Howard LE, Moreira DM, Andriole GL, Hopp ML, Roehrborn CG, Bliwise DL, Freedland SJ (2021) Dutasteride improves nocturia but does not lead to better sleep: results from the REDUCE clinical trial. J Urol. 7 https://doi.org/10.1097/JU.0000000000001640 Lee K-S, Choo M-S, Kim D-Y, Kim JC, Kim H-J, Min KS, Lee JB, Jeong HJ, Lee T, Park WH (2005) Combination treatment with propiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter st. J Urol 174(4 Part 1):1334–1338. 7 https://doi.org/10.1097/01. ju.0000173630.94559.fd Leon LA, Hoffman BE, Gardner SD, Laping NJ, Evans C, Lashinger ESR, Su X (2008) Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther 326(1):178–185. 7 https://doi. org/10.1124/jpet.108.138651 Lepor H (1998) Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin investigator group. Urology 51(6):892–900. 7 https://doi.org/10.1016/ s0090-4295(98)00126-5 Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G, Haakenson C, Machi M, Narayan P, Padley RJ (1996a) The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. veterans affairs cooperative studies benign prostatic hyperplasia study group. N Engl J Med 335(8):533–539. 7 https://doi.org/10.1056/ NEJM199608223350801 Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G, Haakenson C, Machi M, Narayan P, Padley RJ (1996b) The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 335(8):533–540. 7 https://doi.org/10.1056/NEJM199608223350801 Levin RM, Riffaud JP, Bellamy F, Rohrmann D, Habib M, Krasnopolsky L, Zhao Y, Wein AJ (1996) Protective effect of tadenan on bladder function secondary to partial outlet obstruction. J Urol 155(4):1466–1470. 7 http://www.ncbi.nlm.nih. gov/pubmed/8632612 Liao C-H, Kuo Y-C, Kuo H-C (2013) Predictors of successful first-line antimuscarinic monotherapy in men with enlarged prostate and predominant storage symptoms. Urology 81(5):1030–1033. 7 https://doi.org/10.1016/j.urology.2013.01.018 Liu L, Zhao S, Li F, Li E, Kang R, Luo L, Luo J, Wan S, Zhao Z (2016) Effect of 5α-reductase

95 Pharmacological Therapy

i­nhibitors on sexual function: a meta-analysis and systematic review of randomized controlled trials. J Sex Med 13(9):1297–1310. 7 https://doi. org/10.1016/J.JSXM.2016.07.006 Lowe FC (1997) Coadministration of tamsulosin and three antihypertensive agents in patients with benign prostatic hyperplasia: pharmacodynamic effect. Clin Ther 19(4):730–742. 7 https://doi. org/10.1016/s0149-2918(97)80097-5 Lukacs B, Grange JC, Comet D (2000) One-Year follow-up of 2829 patients with moderate to severe lower urinary tract symptoms treated with alfuzosin in general practice according to IPSS and a health-related quality-of-life questionnaire. Urology 55(4):540–546. 7 https://doi.org/10.1016/ S0090-4295(99)00539-7 Lunacek A, Al-Ali BM, Radmayr C, Weber M, Horninger W, Findl O, Plas E (2018) Ten years of intraoperative floppy iris syndrome in the era of α-blockers. Cent Eur J Urol 71(1):98–104. 7 https://doi.org/10.5173/ceju.2017.1234 MacDiarmid SA, Peters KM, Chen A, Armstrong RB, Orman C, Aquilina JW, Nitti VW (2008) Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc 83(9):1002–1010. 7 https://doi. org/10.4065/83.9.1002 MacDonald R, Wilt TJ (2005) Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 66(4):780–788. 7 https://doi.org/10.1016/j. urology.2005.05.001 Malik M, Van Gelderen EM, Lee JH, Kowalski DL, Yen M, Goldwater R, Mujais SK et al (2012) Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin Pharmacol Ther 92(6):696– 706. 7 https://doi.org/10.1038/clpt.2012.181 Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G (2009) Rapid efficacy of the highly selective alpha1A-Adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol 181(6):2634–2640. 7 https://doi.org/10.1016/j.juro.2009.02.034 Matsumoto AM, Tenover LISA, McClung M, Mobley D, Geller J, Michael S, John G et al (2002) The long-term effect of specific type II 5α-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 167(5):2105–2108. 7 https:// doi.org/10.1016/S0022-5347(05)65095-1

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Matsuo T, Miyata Y, Kakoki K, Yuzuriha M, Asai A, Ohba K, Sakai H (2016) The efficacy of mirabegron additional therapy for lower urinary tract symptoms after treatment with Α1-Adrenergic receptor blocker monotherapy: prospective analysis of elderly men. BMC Urol 16(1):45. 7 https:// doi.org/10.1186/s12894-016-0165-3 McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P et al (1998) The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride long-term efficacy and safety Study group. N Engl J Med 338(9):557–563. 7 https:// doi.org/10.1056/NEJM199802263380901 McConnell JD, Roehrborn CG, Bautista OM, Andriole GL, Dixon CM, Kusek JW, Lepor H et al (2003) The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349(25):2387–2398. 7 https://doi. org/10.1056/NEJMoă56 McVary KT, Monnig W, Camps JL, Young JM, Tseng L-J, van den Ende G (2007) Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 177(3):1071–1077. 7 https://doi.org/10.1016/j.juro.2006.10.055 Michel MC, Mehlburger L, Bressel H-U, Goepel M (1998) Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prostatic Dis 1(6):332–335. 7 https://doi.org/10.1038/sj.pcan.4500267 Moinpour CM, Darke AK, Donaldson GW, Thompson IM, Langley C, Ankerst DP, Patrick DL et al (2007) Longitudinal analysis of sexual function reported by men in the prostate cancer prevention trial. JNCI J Nat Cancer Inst 99(13):1025–1035. 7 https://doi.org/10.1093/jnci/djm023 Morelli A, Comeglio P, Filippi S, Sarchielli E, Vignozzi L, Maneschi E, Cellai I et al (2013) Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: an experimental study in the rabbit. Prostate 73(4):428–441. 7 https://doi.org/10.1002/ pros.22584 Morgia G, Russo GI, Voce S, Palmieri F, Gentile M, Giannantoni A, Blefari F et al (2014) Serenoa repens, lycopene and selenium versus tamsulosin for the treatment of LUTS/BPH. An Italian multicenter double-blinded randomized study between single or combination therapy (PROCOMB Trial). Prostate 74(15):1471–1480. 7 https://doi.org/10.1002/pros.22866

96

11

L. Lusuardi

Moriyama N, Yamaguchi T, Takeuchi T, Sakamoto E, Ueki T, Tsujimoto G, Kawabe K (1998) Semiquantitative evaluation of Α1A-Adrenoceptor subtype MRNA in human hypertrophied and non-hypertrophied prostates: regional comparison. Life Sci 64(3):201–210. 7 https://doi. org/10.1016/S0024-3205(98)00552-9 Mottet N, Bressolle F, Delmas V, Robert M, Costa P (2003) prostatic tissual distribution of alfuzosin in patients with benign prostatic hyperplasia following repeated oral administration. Eur Urol 44(1):101–105. 7 https://doi.org/10.1016/S03022838(03)00154-4 Na Y, Ye Z, Zhang S (2012) Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia. Clin Drug Investig 32(1):29–39. 7 https://doi.org/10.2165/11593750000000000-00000 Nguyen D-D, Marchese M, Cone EB, Paciotti M, Basaria S, Bhojani N, Trinh Q-D (2021) Investigation of suicidality and psychological adverse events in patients treated with finasteride. JAMA Dermatol 157(1):35–42. 7 https://doi. org/10.1001/jamadermatol.2020.3385 Nickel JC, Roehrborn C, Montorsi F, Wilson TH, Rittmaster RS (2011) Dutasteride reduces prostatitis symptoms compared with placebo in men enrolled in the REDUCE study. J Urol 186(4):1313–1318. 7 https://doi.org/10.1016/j. juro.2011.05.071 Nitti VW, Rosenberg S, Mitcheson DH, He W, Fakhoury A, Martin NE (2013) Urodynamics and safety of the Β3-Adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol 190(4):1320–1327. 7 https://doi.org/10.1016/j. juro.2013.05.062 Novara G, Tubaro A, Sanseverino R, Spatafora S, Artibani W, Zattoni F, Montorsi F, Chapple CR (2013) Systematic review and meta-analysis of randomized controlled trials evaluating silodosin in the treatment of non-Neurogenic male lower urinary tract symptoms suggestive of benign prostatic enlargement. World J Urol 31(4):997– 1008. 7 https://doi.org/10.1007/s00345-012-09448 Oelke M, Porst H, Goldfischer ER, Cox D, Watts S, Dey D, Viktrup L (2013) Efficacy and safety of tadalafil 5 Mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology 82(3):667–673. 7 https:// doi.org/10.1016/j.urology.2013.05.005

Ohyama K, Hori Y, Sugiura M (2019) evaluation of syncope association with Α1-Adrenoceptor blockers in males using the FAERS database: impact of concomitant hypertension. Pharmazie 74(12):755–759. 7 https://doi.org/10.1691/ ph.2019.9706 Rhodes L, Primka RL, Berman C, Vergult G, Gabriel M, Pierre-Malice M, Gibelin B (1993) Comparison of finasteride (Proscar), a 5 alpha reductase inhibitor, and various commercial plant extracts in in vitro and in vivo 5 alpha reductase inhibition. Prostate 22(1):43–51. 7 https://doi. org/10.1002/pros.2990220107 Roehrborn CG, Siegel RL (1996) Safety and efficacy of doxazosin in benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. Urology 48(3):406–415. 7 https://doi.org/10.1016/S0090-4295(96)00208-7 Roehrborn CG, Joseph EO, Stephen A, Stephen AK, L KL, Douglas EM, Robert JP, Claus GR (1995) The hytrin community assessment trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia*. Bd 47. 7 https://d1wqtxts1xzle7.cloudfront.net/48792983/ s0090-4295_2899_2980409-920160913-15166164ocat.pdf ?1473754485=&response-content-disposition=inline%3B+filename%3DThe_hytrin_ community_assessment_trial_st.pdf&Expires=1618680232&Signature=FMVE0UDRkROzeQdQ4~OqSWGVTnSTYnlVxawBDoSX9CNRiGVpsoiMZcs0VWG2S7PL2qe52hNWnh Z r 0 B b Z N o J V j q d k W D w f w e Y I m h 6 o 9 TbEqO~nX0TDpc35tGv8oSDuly~AztrNVSWyqwQa~stpIjmkkpMgJs4a6ZohJU7T2Y5zAg63g0NJiqHgpyM3EmIcaFFwaAviSViu-uz1F9NuHrZmhSEP4fxNlAI0sv6uNV-kZiy7Vz~3NR-HbUA2vPC2IiphZyLl40gKd-cA3kksV7o1-RVPC5neeiVCCy~x9LJIKclumYYI4gTNWVTQXnDH6QUVi7bhr0R1ebRYWI6p3fgcrA__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G, ARIA3001 ARIA3002 and ARIA3003 Study Investigators (2002) Efficacy and safety of a dual inhibitor of 5-Alpha-reductase types 1 and 2 (Dutasteride) in men with benign prostatic hyperplasia. Urology 60(3):434–441. 7 https://doi. org/10.1016/s0090-4295(02)01905-2 Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Paul Gagnier R, Montorsi F, CombAT Study Group (2010) The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes

97 Pharmacological Therapy

in men with symptomatic benign prostatic hyperplasia: 4-Year results from the CombAT study. Eur Urol 57(1):123–131. 7 https://doi.org/10.1016/j.eururo.2009.09.035 Roehrborn CG, Kaplan SA, Lepor H, Volinn W (2011) Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH. Prostate Cancer Prostatic Dis 14(2):143–148. 7 https://doi.org/10.1038/pcan.2010.46 Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E, O’Leary MP, Puppo P, Robertson C, Giuliano F (2003) Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 44(6):637–649. 7 https://doi.org/10.1016/j. eururo.2003.08.015 Rouquier L, Claustre Y, Benavides J (1994) Α1-adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study. Eur J Pharmacol 261(1– 2):59–64. 7 https://doi.org/10.1016/0014-2999(94 )90300-X Salinas-Casado J, Esteban-Fuertes M, Carballido-Rodríguez J, Cozar-Olmo JM (2020) Review of the experience and evidence of pygeum africanum in urological practice. Actas Urol Esp 44(1):9–13. 7 https://doi.org/10.1016/j. acuro.2019.08.002 Skeldon SC, Macdonald EM, Law MR, Anjie Huang J, Paterson M, Mamdani MM, Juurlink D (2017) The cardiovascular safety of dutasteride. J Urol 197(5):1309–1314. 7 https://doi.org/10.1016/J. JURO.2016.11.082 Tacklind J, Howard AF, Macdonald R, Rutks I, Wilt TJ (2010) Finasteride for benign prostatic hyperplasia. Cochrane Database Syst Rev 10(October):CD006015. 7 https://doi. org/10.1002/14651858.CD006015.pub3 Thompson IM, Goodman PJ, Tangen CM, Scott Lucia M, Miller GJ, Ford LG, Lieber MM et al (2003) The influence of finasteride on the development of prostate cancer. N Engl J Med 349(3):215–224. 7 https://doi.org/10.1056/NEJMoa030660 Tubaro A, Batista JE, Nitti VW, Herschorn S, Chapple CR, Blauwet MB, Siddiqui E, Huang M, Oelke M (2017) Efficacy and safety of daily mirabegron 50 Mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol 9(6):137–154. 7 https://doi. org/10.1177/1756287217702797 Unger JM, Cathee Till, Thompson IM, Tangen CM, Goodman PJ, Wright JD, Barlow WE, Ramsey SD, Minasian LM, Hershman DL (2016) Long-term consequences of finasteride vs

11

­ lacebo in the prostate cancer prevention trial. J p Natl Cancer Inst 108(12):djw168. 7 https://doi. org/10.1093/jnci/djw168 van Dijk MM, Jean JMCH de la Rosette, Michel MC (2006) Effects of alpha(1)-adrenoceptor antagonists on male sexual function. Drugs 66(3):287–301. 7 https://doi.org/10.2165/00003495-20066603000002 Vignozzi L, Gacci M, Cellai I, Santi R, Corona G, Morelli A, Rastrelli G et al (2013) Fat boosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation. Prostate 73(8):789–800. 7 https://doi.org/10.1002/ pros.22623 Vinceti M, Dennert G, Crespi CM, Zwahlen M, Brinkman M, Zeegers MPA, Horneber M, D’Amico R, Giovane CD (2014) Selenium for preventing cancer. Cochra Data Syst Rev 2014(3):CD005195. 7 https://doi.org/10.1002/14651858.CD005195.pub3 Wada N, Hiromichi I, Masafumi K, Kazumi H, Seiji M, Hidehiro K (2016) Urodynamic efficacy and safety of mirabegron add-on treatment with tamsulosin for Japanese male patients with overactive bladder. LUTS: Lower Urin Tract Symptoms 8(3):171–176. 7 https://doi.org/10.1111/luts.12091 Weisser H, Tunn S, Behnke B, Krieg M (1996) Effects of the sabal serrulata extract IDS 89 and its subfractions on 5 alpha-reductase activity in human benign prostatic hyperplasia. Prostate 28(5):300– 306. 7 https://doi.org/10.1002/(SICI)1097-0045(1 99605)28:5%3c300::AID-PROS5%3e3.0.CO;2-F Welk B, McArthur E, Fraser L-A, Hayward J, Stephanie Dixon Y, Hwang J, Ordon M (2015) The risk of fall and fracture with the initiation of a prostate-selective α antagonist: a population based cohort study. BMJ (Clinical Research Ed.) 351(October):h5398. 7 https://doi.org/10.1136/bmj.h5398 Wilt TJ, Areef I, Rutks I, Macdonald R (1999) Phytotherapy for benign prostatic hyperplasia. 459–72. 7 https://www.cambridge.org/core Wilt TJ, Howe W, MacDonald R (2002) Terazosin for treating symptomatic benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int 89(3):214–225. 7 https://doi.org/10.1046/j.1464-4096.2001.02537.x-i1 Wilt TJ, Mac Donald R, Rutks I (2003) Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 1:CD002081. 7 https://doi. org/10.1002/14651858.CD002081 Yamaguchi O, Chapple CR (2007) Β3-Adrenoceptors in urinary bladder. Neurourol Urodyn 26(6):752– 756. 7 https://doi.org/10.1002/nau.20420 Yang X, Liu Z, ZFan Z, Grzybowski A, Wang N (2020) A narrative review of intraoperative floppy iris syndrome: an update 2020. Ann Transl Med

98

L. Lusuardi

8(22):1546–1546. 7 https://doi.org/10.21037/atm20-3214 Yoshida M, Inadome A, Masunaga K, Nagata T, Yoshiyasu T (2010) Effectiveness of tamsulosin hydrochloride and its mechanism in improving nocturia associated with lower urinary tract symptoms/benign prostatic hyperplasia.

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­ eurourol Urodyn 29(7):1276–1281. 7 https:// N doi.org/10.1002/nau.20872 Zhu D, Srivastava A, Agalliu I, Fram E, Kovac EZ, Aboumohamed A, Schoenberg MP, Sankin AI (2021) Finasteride use and risk of bladder cancer in a multiethnic population. J Urol. 7 https://doi. org/10.1097/JU.0000000000001694

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Surgical Techniques: Basics Christopher Netsch Contents 12.1

Surgical Basics – 100

12.2 Surgical Principles: Vaporization, Enucleation, Resection – 100 12.3 Lasers: Basic Knowledge – 101 12.4 Lasers in the Treatment of Benign Prostatic Hyperplasia (BPH) – 106 References – 111

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_12

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100

C. Netsch

12.1  Surgical Basics

12.2  Surgical Principles:

Vaporization, Enucleation, Resection

In general, any type of transurethral prostatectomy, whether performed with the laser or with mono or bipolar current, can be divided into three basic surgical principles: 5 Vaporization (evaporation of prostate tissue) 5 Resection (cutting out small tissue chips, which are then removed with the syringe) 5 Enucleation (removal of the adenoma by detaching it from the surgical pseudocapsule with subsequent morcellation of the tissue in the bladder) The domain of the monopolar or bipolar current is transurethral resection of

Volume reduction extraanatomical techniques gradual ablation of the transitional cell zone

0

20

ITIND

Greenlight PVP

40

Aquaablation REZUM

Enucleation anatomical techniques complete removal of the transition zone 60

80

HoLEP ThuLEP ThuVEP

Embol

Urolift

12

As a starting point for a consideration of all relevant established old and new surgical procedures for the therapy of the BPS, a distinction should be made between ablative and non-ablative procedures. Under direct ablative procedures, all interventions that involve an immediate tissue removal of the prostate are summarized (resection, vaporization, enucleation, aquablation). In contrast, there are so-called nonor secondary ablative procedures such as iTind®, Rezum®, Urolift® or prostate artery embolization (PAE). While iTind® creates a pressure necrosis in the prostatic urethra by means of temporary stenting, Urolift® performs a tissue tightening of the prostate using small anchors. Rezum® or PAE lead to a delayed, secondary prostate volume reduction by water vapor application or artery occlusion using microcoils. If one uses the PSA value as a surrogate parameter for the completeness of the removal of the prostate adenoma (transitional cell zone), the mentioned procedures show a different effectiveness (. Fig. 12.1).

Of course, there are other procedures with different functional principles. However, in this book only relevant procedures will be discussed, which actually have relevance in practice.

BipolEP GreenLEP

. Fig. 12.1  Comparison of different therapies for benign prostatic hyperplasia

100

101 Surgical Techniques: Basics

the prostate (TUR-P). A vaporization or mono- or bipolar enucleation of the prostate is also possible. Since the chapter focuses on laser basics, these possibilities will not be discussed here. Based on the laser-tissue interaction, the appropriate laser or the suitable laser fiber can be selected. For example, a side-fire laser fiber is advantageous for vaporization of the prostate, because here the energy can be applied directly to the prostate tissue. In enucleation, on the other hand, an end-fire laser fiber seems to be advantageous: The laser fiber tip mimics the surgeon’s index finger during open simple prostatectomy (OSP). The wavelength is another important factor. During laser enucleation, the surgeon works on the layer of the surgical pseudocapsule. A laser with a superficial penetration depth seems to be advantageous, because the attached structures (neurovascular bundles) can be respected. On the other hand, one will choose a laser with a higher penetration depth for patients with a coagulation disorder or on oral anticoagulants or anti-platelet therapy (. Tab. 12.1). (Bach et al. 2012). In principle, vaporization, resection, and enucleation techniques are possible with any laser that is used for the treatment of BPH. However, certain lasers have

12

­revailed for the respective surgical techp nique over the last 20 years (. Tab. 12.2). 12.3  Lasers: Basic Knowledge

In his publication on quantum theory Albert Einstein 1917 predicted another emission process, the stimulated (or induced) emission, the phenomenon of extremely focused light beams (Einstein 1917). In reality, it took another 43 years from Einstein’s theory to Maiman’s publication of a commercially available ruby laser (Maiman 1960). The acronym LASER was postulated by Gould in 1957 and means Light Amplification by Stimulated Emission of Radiation, or: light amplification by stimulated emission of radiation (Gross and Herrmann 2007). Immediately after the first description, various lasers were developed and found an application in medicine. However, the uncritical use of lasers in the 1980s damaged the reputation of lasers. Eventually, it became clear that a basic understanding of the laser principles is necessary to find the appropriate laser for the respective medical application (Nazif et al. 2004; Teichmann et al. 2007; Marks and Teichman 2007). The following content tries to create an understanding of

. Tab. 12.1  Wavelength and penetration depth of different laser systems for the treatment of benign prostatic syndrome Wavelength, nm

Optical penetration depth in the target chromophore in mm

KTP/LBO

532

0.8

Diode laser

940, 980, 1318, 1470

0.5–5 mm

Nd:YAG

1064

10

Thulium:YAG, (superpulsed) thulium fiber laser

2013/1940

0.2

Holmium:YAG

2100

0.4

KTP = Potassium-Titanyl-Phosphate; LBO = Lithium-Triborate; Nd = Neodymium; YAG = Yttrium–Aluminium-Garnet

102

C. Netsch

. Tab. 12.2  Suitability of different lasers for laser prostatectomy Laser

Vaporization

GreenLight (KTP/LBO)

+++

 + 

Diode laser

 + 

 + 

Thulium:YAG, Thulium-fiber laser

++

Holmium:YAG

Resection

Enucleation

++

+++

 + 

+++ 

KTP = Potassium-Titanyl-Phosphate; LBO = Lithium-Triborate; YAG = Yttrium–Aluminium-Garnet

where the ­advantages and disadvantages of the c­ urrent lasers in the treatment of BPS lie. Important here is the optimization of the absorption process of light in the tissue, since laser radiation represents directed, parallel light of a postulated wavelength or a single color that applies to all regions of the invisible and visible electromagnetic spectrum (Gross 2012). z Generation of Laser Radiation

12

All lasers consist of 3 components: an external pump source, the active laser medium and a resonator. Laser light is generated by the principle of quantum mechanics of the “stimulated emission of radiation” of an excited state (active media: e.g. gas, crystals, glass, dye). The excitation of the laser medium can be achieved by different principles (e.g. excitation by photons of a flash lamp, semiconductor): Some of the excitation photons are absorbed by the active medium, leading to an increased energy level (excited states). According to the theory of spontaneous emission, these excited states return to the ground state, statistically releasing a photon at a characteristic wavelength. If these spontaneously emitted photons hit another excited laser medium ion, it stimulates the excited ion to return to the ground state by emitting a further photon with the same wavelength and direction of propagation. This is called stimulated emission of radiation (. Fig. 12.2) (Nazif et al. 2004; Teichmann et al. 2007; Marks and

Absorption

Spontaneous emission

Stimulated emission

. Fig. 12.2  Spontaneous and stimulated emission of radiation. Courtesy of Roland Sroka, Munich, Germany (Bach et al. 2012)

Teichman 2007; Bach et al. 2012). The emitted wavelength is characteristic for the optically active component of the lasing medium (Bach et al. 2012). For the targeted excitation of the laser medium, an optical resonator is an essential component of every laser. The resonator consists of two parallel mirrors in the simplest design. It serves to define the direction of the induced emission. Only photons emitted along the resonator run back and forth several times and stimulate mainly emission in this direction. In addition, in the case of low-gain active media, each photon must be used better by multiple passes to stimulate further emission. From a few light waves, countless “copies” are created. This is done with the help of mirrors. They trap the light waves—just so that the individual waves lie on top of each other and oscillate in sync. Such a structure

103 Surgical Techniques: Basics

is called a standing wave. One of the resonator mirrors shows a reflection of the laser wavelength of almost 100% (high reflector) and the other is partly transparent to let the laser radiation out of the resonator (output coupler). The laser radiation is emitted from the resonator as a continuous wave (continuous wave [cw]) or pulsed, depending on the design of the laser (e.g. depending on excitation source, characteristics of the laser medium) or additional optical elements, such as a Q-switch (quality switch) (Bach et al. 2012). A quality switch, also Q-switch, is an optoelectronic component within the (pulse-)laser resonator. It allows short high pulse peak powers by storing the energy in the laser medium until the maximum. The quality switch opens and closes periodically. The quality switch initially creates high resonator losses, so that the light emitted by the medium does not remain in the resonator. When the quality switch is closed, the population inversion is increased by the continuous excitation process. The energy stored in the laser medium is increased to the maximum. In the state of maximum gain, the resonator quality is suddenly increased. The radiation is reflected at the end mirror of the resonator and runs back to the active medium. This is followed by a chain reaction with an exponential increase in the number of photons and thus the intensity of the laser (depletion of the population inversion). In this way, high pulses with rapid pulse repetition can be generated (Bach et al. 2012). In frequency doubling, so-called second harmonic generation (SHG), radiation with double the frequency is generated when irradiating some materials under certain conditions. This corresponds to a halving of the wavelength. For example, green light (“GreenLight”) of wavelength 532 nm (potassium-titanyl-phosphate [KTP]-laser) can be generated from the infrared radiation of a Nd:YAG-laser (λ = 1064  nm).

12

In diode lasers, a semiconductor laser diode is used to generate laser radiation. The semiconductor used defines the wavelength. Electric current flow is used to stimulate the semiconductor, which emits laser radiation after exceeding a threshold value. Diode lasers achieve a high (electrical to optical) energy conversion efficiency (Bach et al. 2012). Laser systems frequently used in urology (holmium, thulium, GreenLight) are solid-state lasers and use a yttrium-aluminum-garnet (YAG) crystal as the laser medium. By replacing a part of the yttrium3+ ions of the YAG crystal at the crystallographic C-position (doping) by trivalent rare earths such as neodymium3+, holmium3+, thulium3+ or erbium3+, which define the actual laser characteristics, optically active solid-state lasers are generated. The YAG crystal has excellent mechanical and thermal properties. In order to achieve energy absorption in the active medium, electrons have to be lifted to a higher energy level. This process is called pumping. Solid-state lasers are always optically, i.e. by radiation, pumped. The effective pump light wavelength results from the characteristic energy difference between the lower and upper energy level for the doping ions. Optical fibers finally transmit the laser radiation safely and efficiently to the target: The laser radiation has to be transferred from the generator to the fiber and in the fiber to the desired target (Bach et al. 2012). A laser fiber consists of a circular quartz fiber core, which transmits the laser radiation. To suppress the loss of laser radiation, the core is surrounded by an optical layer. This consists of a transparent material with a lower refractive index (Nazif et al. 2004). The other attached layers serve to keep the laser radiation in the core of the fiber and to ensure the integrity of the fiber (Teichmann et al. 2007).Standard quartz fibers are effectively used for visible light, while the transmission of 2-µm radiation is done

104

C. Netsch

via flexible quartz fibers (Teichmann et al. 2007). To couple the laser radiation into the optical fiber, a focused lens (fiber coupling lens) is required. The fiber connection at the laser generator is a critical point of power transmission (Nazif et al. 2004): A deviation of the focus of the fiber coupling lens leads to laser radiation absorption and to overheating of the connection (Bach et al. 2012). z Laser Fiber Types: Fiber Endings

12

Regardless of the fiber type, the laser beam is transmitted through the optical core of the fiber (Nazif et al. 2004; Teichmann et al. 2007; Marks and Teichmann 2007; Bach et al. 2012). With side-fire laser fibers, the laser beam is reflected at the fiber tip by an oblique surface and directed at an oblique angle of approx. 70° onto the tissue. By moving the beam and changing the distance between the fiber tip and the tissue surface, coagulation or vaporization can be achieved. The disadvantage of the side-fire laser fiber is the limited lifetime at the exit point of the laser beam, which leads to fiber damage and a loss of efficiency (Nazif et al. 2004). A possible solution is a continuous flushing of the fiber tip with an irrigation solution, as realized for example with the MoXy™ fiber of the GreenLight laser: By increasing the diameter of the optical core and introducing a liquid cooling and a metal cap at the fiber tip, the lifetime of the fiber can be increased (Bach et al. 2012). With an end or front-firing laser fiber, the laser radiation is transmitted directly from the tip onto the tissue and leads to a rapid heating of the tissue in a small tissue area. Tissue effects such as vaporization and cell damage can be achieved in this way. With the so-called Twister fiber for contact vaporization, a vapor bubble is generated at the fiber tip and a vaporiza-

tion within the vapor bubble and secondary by the heated fiber tip in button form is achieved (Bach et al. 2012). z Pulsed and Continuous Wave (Continuous Wave) Lasers

Laser radiation is generated by the resonator as continuous wave (continuous wave [cw]) or pulsed and depends on: a) Laser generator (excitation source, characteristics of the laser medium) b) Presence of additional optical elements, such as the Q-switch(Q-switch). Holmium lasers are usually excited by flash lamps, which limits the repetition rate due to heat storage in the laser crystal, while Tm:YAG lasers operate in a cw mode when excited by a laser diode. Pulsed holmium lasers produce large pulsating vapor bubbles in the irrigation solution around the laser fiber tip, while the vapor bubbles are much smaller for cw lasers (. Fig. 12.3a, b). With the holmium laser, a vapor bubble corresponds to the duration of a laser pulse (~500 µs) (Gross 2012). The expanding gas bubble is used for the spreading of the adenoma from the pseudo capsule of the prostate in the holmium laser enucleation of the prostate (HoLEP). Coagulation is achieved by the heat within the gas bubble. With cw thulium lasers, a constant vapor bubble is formed between the fiber tip and the tissue. This vapor bubble provides the optical contact for the laser radiation into the tissue. Cw thulium lasers allow for clean smooth cuts, compared to the pulsed mode of a holmium laser (Gross 2012). However, the cw mode of the thulium laser cannot be used for lithotripsy due to the lack of pulse mode (Rink et al. 1995; Gross 2012). z Light-tissue Interaction

The basic principles of light-tissue interaction consist of reflection, scattering, remission and absorption by the target chromo-

105 Surgical Techniques: Basics

12

. Fig. 12.3  (a) Large vapor bubble at the end of a 550-μm laser fiber when activating the holmium laser (Gross 2012). (b) Relatively constant gas bubble at the end of a 550-μm laser fiber during the activation of a Tm:YAG laser (Gross 2012)

phore in the tissue. The light distribution and the absorption effect of the optical penetration is wavelength-dependent. For thermal laser-tissue effects, absorption is the most important factor (Teichmann et al. 2007). When the laser beam hits tissue, part of it is reflected at the boundary layer. The reflected radiation is not only lost for surgical applications, but may also pose a risk for the surrounding tissue. The reflection depends on the optical properties of the tissue and the irrigation solution that surrounds the tissue, but is not necessarily dependent on the wavelength and can be neglected when the wavelength is evaluated for surgical use. Since tissue is not homogeneous, part of the laser beam is scattered and takes the applied laser beam out of the intended direction. The degree of scattering depends on the size of the particles that the laser beam emits, and thus on the wavelength. Shorter wavelengths are scattered to a higher degree than longer wavelengths: blue laser radiation is scattered more than green, green more than red, and red more than infrared. The scattering fraction of the laser energy is not only lost for the intended application, but may also cause unintended side effects (Teichmann et al. 2007; Gross 2012).

To achieve absorption, a target chromophore is needed. Meaningful body chromophores are melanin, blood, and water (Nazif et al. 2004; Teichmann et  al. 2007; Marks and Teichmann 2007; Lerner and Tyson 2009; Bach et al. 2012). The dependence of absorption on the wavelength of lasers is shown in . Fig. 12.4. The absorption length defines the optical path at which 63% of the intended laser energy is absorbed. The extinction length, on the other hand, defines the depth at which 90% of the laser beam is absorbed and converted into heat (Teichmann et al. 2007). With the knowledge of the absorption process, laser-tissue interaction is easier to understand—both, the intended and the unintended. Upon entering the absorbing medium, the intensity of the laser beam decreases exponentially (Lambert–Beer’s law). The absorbed laser energy is converted into heat and causes a temperature increase. Depending on the density of the absorbed heat, the impact on the tissue varies between coagulation and vaporization. The temperature increase in the tissue increases with the density of heat per tissue volume. This results in the possibilities of vaporization or vaporesection in the treatment of BPH (Bach et al. 2012; Teichmann et al. 2007).

C. Netsch

107 106 105 104 103 102 101 100 10-1 10-2 10-3 10-4

KTP (Nd:YAG SHG) Tm:YAG Nd:YAG Ho:YAG Er:YAG

CO2

Melanin Hb ox Hb

0,1

1 nm 10 nm 100 nm Water 1 µm 10 µm 100 µm 1 mm 1 cm 10 cm 1m 10m 100 m 100

Depth of Pentration in Media Absorption Length

Absorption Coefficient [cm-1]

106

0,5

1

2 3 10 Wavelength [µm]

. Fig. 12.4  Absorption spectrum of different target chromophores in the body at the wavelengths of various lasers (Teichmann et al. 2007; Bach et al. 2012)

12

The tissue effect is defined by the density of the absorbed laser power. This principle is crucial for any surgical laser application. At the same laser power, a wavelength with a long absorption will produce a deep necrosis, while a laser with a short absorption length will limit the absorbed laser length to a much smaller tissue volume: This results in a temperature rise above the boiling point and an immediate vaporization of the tissue (Bach et al. 2012; Teichmann et al. 2007; Gross 2012). 12.4  Lasers in the Treatment

of Benign Prostatic Hyperplasia (BPH)

12.4.1  Holmium Laser

The holmium laser is the longest-used laser for the treatment of BPH. By replacing part of the yttrium3+ ions at the crystallographic C-position (doping) of the YAG

crystal with holmium3+− -ions (active laser medium), the optically active Ho:YAG solid-state laser is produced (Teichmann et al. 2007; Bach et al. 2012). The flash lamp (typically xenon or krypton) is the photon source that is required to excite the Ho:YAG laser medium. However, most of the energy of the flash lamp is wasted and is converted into heat in the Ho:YAG laser cavity: The flash lamp emits radiation in a broad spectrum, while the holmium laser absorbs energy in a narrow spectrum with a maximum overlap of the spectrum of 7–8%. Therefore, holmium lasers require adequate water cooling. Furthermore, the Ho:YAG crystal limits the limit for the power and frequency at which a single Ho:YAG cavity can operate (80 ml despite the use of minimally-invasive transurethral enucleation procedures. Excellent functional (longterm) results are achieved with OSP. However, OSP is associated with a non-contemporary perioperative morbidity. Although OSP is being replaced by minimally-invasive methods in western countries, OSP is the most important therapeutic option for large prostate volumes in less developed countries. Minimally-invasive transurethral procedures were developed to combine the advantages of the transurethral access (low morbidity due to “natural orifice surgery”) with the advantages of OSP (high effectiveness due to complete removal of the adenoma). Since the introduction of transurethral holmium laser enucleation of the prostate (HoLEP) into the therapy of BPS, this technique has gained worldwide acceptance, as complete removal of prostatic adenoma tissue leads to excellent functional (long-term) results and this is achieved with a very low perioperative morbidity (Cornu et al. 2015). Based on the HoLEP technique, other techniques have been described utilizing other lasers (e.g. thulium, ERASER, diode, GreenLight laser) or mono- or bipolar high-frequency current as energy sources for transurethral enucleation of the prostate. The following chapter will provide a comprehensive overview of the different enucleation techniques.

13.1  Open Simple Prostatectomy

(OSP)

The first enucleation of the enlarged “prostate” from the so-called prostatic pseudocapsule was performed by William Belfield in 1890. Eugene Fuller described the transvesical approach in 1894, which was popularized by Sir Peter Freyer in 1901, so that transvesical OSP is mainly associated with his name. He described the first 4 cases of a transvesical OSP (Freyer 1901). 13.1.1  Transvesical OSP (Freyer):

Surgical Principle

The access is made through a lower midline incision or a Pfannenstiel incision. After opening the fascia longitudinally in the midline or transversely by Pfannenstiel incision, the two rectus abdominis muscles are exposed, separated from each other in the midline, down to the symphysis. The anterior wall of the bladder is exposed. The bladder is opened between two holding sutures. The mucosa over the protruding “adenoma” is cutted by the electric knife. Then the finger of the surgeon enters the bladder neck. In the 12 o’clock position, the socalled anterior commissure is bluntly severed. The index finger of the surgeon now bluntly finds a layer between the so-called surgical pseudocapsule (actual prostate) and the lobes of benign prostatic hyperplasia, so that they can be bluntly enucleated, like a tangerine from its peel. Afterwards, the bladder outlet is readjusted and the existing bleedings are exposed. They usually originate from the bladder neck. Therefore, deep sutures are placed at the 5 o’clock and 7 o’clock positions. After removal of the adenoma, a three-way catheter is inserted. Some surgeons block the catheter in the bladder, others in the prostatic fossa. Various surgical modifications have been

115 Ablative Procedures: Enucleation

. Fig. 13.1  Entering the bladder neck, bluntly cutting the anterior commissure from the bladder neck with the index finger (Höfner 2000)

described to minimize the postoperative bleeding risk (. Fig. 13.1). 13.1.2  Retropubic OSP (Millin):

Surgical Principle

Van Stockum described the retropubic approach in 1909, which was taken up again by Terrence Millin in 1945. Retropubic OSP has been bearing his name since then (Millin 1945). The approach and the technique differ only marginally from the previously described procedure: Two holding sutures are placed on the prostatic capsule, which is opened and the enucleation is performed directly from the opened prostate. One disadvantage for the less experienced of this method is the deeper location of the access to the prostate in the small pelvis and the risk of entering periprostatic veins or even those of the Santorini plexus (Fig. 13.2).

13

. Fig. 13.2  Approach to retropubic enucleation according to Millin (Höfner 2000)

13.1.3  Outcomes of OSP

The functional results (IPSS, post-void residual urine (PVR), Qmax) of OSP are excellent at the long term (>5 years) (Cornu et al. 2015). 8 years after OSP (n = 2452  patients), a significantly lower rate of secondary interventions compared to TUR-P (n =  20,671 patients) was shown (9.5 vs. 14.7%) (Madersbacher et al. 2005). ► Important OSP has a significant perioperative morbidity. ◄

Gratzke and colleagues analyzed the data of 902 patients who underwent OSP (Gratzke et al. 2007). The early functional results were convincing (Qmax 23.1 ml/s at discharge vs. 10.6 ml/s preoperatively) but with a significant perioperative morbidity (transfusion rate 7.5%, mean hospital stay 11.9 days, morbidity 17.3%, mortality 0.2%). Newer data from Gilfrich and colleagues confirmed the results of the study

116

C. Netsch

(Gilfrich et al. 2016). They analyzed health insurance data of 95,577 patients from the period 2008–2013 who received a surgical therapy for LUTS. The data confirmed: 5 a consistently high proportion of OSP among all surgeries over the period (8.04–9.23%/year) 5 a low 1-year reintervention rate (5.04%) 5 a high perioperative morbidity (mortality 0.51%, transfusion rate 14.49%, complication rate 24.42%). Compared to laser vaporization, TUR-P and laser enucleation, OSP had the highest perioperative morbidity. In a follow-up study, the long-term effectiveness was confirmed based on the 5-year data (Gilfrich et al. 2021): A significantly lower reintervention rate was observed after OSP, compared to TUR-P and laser vaporization, but not compared to laser enucleation of the prostate. ► Conclusion

13

In summary, OSP is still frequently used despite high perioperative morbidity but very good long-term effectiveness, not only in developing countries, but also in developed countries. ◄

13.2  Laparoscopic Simple

Prostatectomy (LSP)

Mariano and colleagues first described LSP in a patient with benign prostatic hyperplasia (BPH) (Mariano et al. 2002). In this case report, a longitudinal vesicocapsular incision was used to remove a 120-g adenoma with 4 hemostatic sutures. Since then, many studies have been conducted that implemented OSP in a laparoscopic manner. Comparable functional results were achieved, but advantages in terms of perioperative morbidity for the laparoscopic approach were demonstrated.

Van Velthoven et al. described their first experiences with the laparoscopic extraperitoneal Millin prostatectomy in 18 patients following the open technique (Van Velthoven et al. 2004). Sotelo et al. showed a technique of horizontal incision of the bladder above the cystoprostatic junction, corresponding to the laparoscopic Freyer surgery (Sotelo et al. 2005). ► Conclusion Overall, more than 1200 cases have been published in the literature, with the advantages of less invasiveness and reduced morbidity, a lower blood loss, transfusion rate, short hospitalization and rare reoperations (. Table 13.1). The largest study on LSP was published in 2019: 272 patients had a median IPSS of 4 and a Qmax of 23 ml/s 3  months postoperatively (Zarraonandia Andraca et al. 2019). Due to the longer learning curve and the increasing spread of robotic systems, LSP is rather rarely performed. ◄

13.3  Robot-Assisted Simple

Prostatectomy (RASP)

Sotelo et al. published the first transperitoneal RASPs (Sotelo et al. 2008), John and colleagues 2009 the first extraperitoneal RASP (John et al. 2009). 13.3.1  RASP: Surgical Principle

Most surgeons prefer the transperitoneal approach due to the experience with robotic radical prostatectomy. In principle, the transvesical procedure of RASP follows that of transvesical OSP. In the initial description, a transverse cystostomy was performed, but a longitudinal incision of the bladder is also possible. In most centers, the dorsal venous plexus is ligated to avoid

2005

2005

2006

Rey et al.

Baumert et al.

2004

2005

Van Velthoven et al.

Rehman et al.

Laparoscopic transperitoneal

2006

Sotelo et al.

Year

Mariano et al.

Laparoscopic transperitoneal

Author

2

18

30

5

17

60

Number of Patients [n]

180

145

115

95

156

138

OR time [min]

125

192

367

NA

516

330

Blood loss [ml]

0

0

3

NA

29

0

Transfusions [%]

120

48

77

76

72

131

Resection weight [g]

. Table 13.1  Laparoscopic simple prostatectomy (LSP): transperitoneal and extraperitoneal approach

NA

3

4

NA

6

5

Catheter time [days]

0

6

0

0.9

0

NA

Revision [%]

NA

6

5

2.3

2

3

Hospital stay [days]

Ablative Procedures: Enucleation 117

13

118

C. Netsch

back bleeding during enucleation. The direct view into the prostate fossa allows for RASP the visually controlled coagulation of bleeding vessels and dissection of the adenoma from the sphincter. Some perform a continuous vesicourethral anastomosis. A plication of the posterior prostate capsule was also suggested to achieve better bleeding control. In a pilot study (14 patients), the urethra-sparing RASP with preservation of antegrade ejaculation (93% preservation of antegrade ejaculation) was recently evaluated (Wang et al. 2018). 13.3.2  Results on RASP

13

Since the first description, the safety and efficiency of RASP (low perioperative morbidity, short hospital stay) has been demonstrated in large, retrospective multicenter studies (Autorino et al. 2015). So far, there are no prospective randomized studies that compare RASP with OSP, LSP or transurethral enucleation procedures, but only retrospective comparisons. RASP is superior to OSP in terms of perioperative morbidity (transfusions, complications) as well as catheter duration and hospital stay. These advantages outweigh the longer duration of the procedure and the higher intraoperative costs of RASP compared to OSP (Mourmouris et  al. 2019). Comparing RASP with LSP, there are no advantages or disadvantages for either technique. However, it is technically hardly possible to perform an intraprostatic reconstruction with conventional laparoscopy. Furthermore, studies on LSP with excellent results are from centers that have a excellent laparoscopic expertise (Pavan et al. 2016). So far, no randomized studies have been published that compare RASP with transurethral enucleation techniques. Nevertheless, catheter duration and hospital stay after transurethral enucleation of the prostate seem shorter than after RPE (Umari et al.

2017). Other data such as reintervention rates or perioperative morbidity are difficult to compare, as the studies come from centers for the respective technique. Robotic surgeons argue with the long learning curve of transurethral enucleation (50 procedures). In contrast, the learning curve for RASP is given as 5–10 cases—for urologists with robotic experience (surgeons > 250 performed robot-assisted prostatectomies) (John et al. 2021; Johnson et al. 2018). ► Conclusion RASP is a good option for large prostate volumes. Regarding perioperative morbidity, RASP shows no differences to transurethral enucleation techniques, but disadvantages in terms of catheter duration and hospital stay. Cost analyses on RASP have not been published so far. Advantages in favor of RASP are conceivable, especially in terms of early continence, since transurethral manipulation of the sphincter is omitted. The indications for RASP are 5 the simultaneous treatment of bladder diverticula, stones, 5 the lack of expertise in transurethral enucleation techniques, 5 the oversized adenoma (i.e. the bladder neck is not reachable with the resectoscope) and 5 patients with continued anticoagulation, i.e. the vesicourethral suture causes a tightening of the prostate capsule or the (large) wound surface. ◄

13.4  Transurethral Enucleation

of the Prostate

Basically, all transurethral enucleation procedures of the prostate are based on the work of Hiraoka et al. (Hiraoka 1983; Hiraoka and Akimoto 1989) and the working group of Peter Gilling (Gilling et al. 1998; Fraundorfer and Gilling 1998): Either the tip of the resectoscope is used to

119 Ablative Procedures: Enucleation

bluntly separate the prostate adenoma from the surgical pseudocapsule and then perform a coagulation of the bleeding vessels with the respective energy source, or the energy source is continuously applied to the enucleation layer between adenoma and surgical pseudocapsule. The enucleation of the prostate is performed in an en-bloc, 2- or 3-lobe technique. The enucleated tissue is either left on a pedicle at the bladder neck, then resected with the resection loop (mushroom technique) (Hochreiter et al. 2002) or vaporized with the laser or pushed into the bladder and then morcellated with morcellators (Gilling et al. 1998, Fraundorfer and Gilling 1998). The acronym AEEP (Anatomical Endoscopic Enucleation of the Prostate) was introduced in the EAU guideline 2016 to describe the procedure of transurethral enucleation independent of the energy source (Gravas et al. 2016). Described below are transurethral enucleation techniques with their different acronyms in order of their temporal emergence. 13.4.1  Monopolar Enucleation

of the Prostate (MEP)

The principle of monopolar transurethral enucleation of the prostate with a special enucleation electrode was described by Hiraoka and colleagues in the 1980s, but was not really pursued scientifically (Hiraoka 1983; Hiraoka and Akimoto 1989; Enikeev et al. 2018a, b). 13.4.2  Holmium Laser Enucleation

of the Prostate (HoLEP)

The basic principle of MEP was taken up again by Fraundorfer and Gilling at the end of the 1990s with holmium laser enucleation of the prostate (HoLEP) (Fraundorfer and Gilling 1998). The HoLEP mimics the technique of OSP: the

13

­ olmium:YAG laser fiber moves in the layer h between adenoma tissue and surgical pseudocapsule—like the index finger of the surgeon during OSP. Initially, HoLEP was described in a 3-lobe technique (Fraundorfer and Gilling 1998). Meanwhile, a variety of technical modifications have been published: high power (>100  W) (Baazeem et  al. 2010), low power ( The HoLEP is not a beginner’s operation. The learning curve of the procedure should not be underestimated. Depending on the literature and the type of training, 20 (mentoring) (El Hakim and Elhilali 2002) to 50 procedures (self taught) (Placer et al. 2009) are required to perform HoLEP safely. Therefore, patients should be carefully selected when learning a transurethral enucleation technique.

13.4.4  Results on HoLEP

Since the introduction of HoLEP in the treatment of BPH, the HoLEP technique has gained worldwide acceptance, as this procedure allows a complete removal of the prostatic adenoma from the surgical pseudocapsule of the prostate with a very low perioperative morbidity. Prospective randomized trials as well as systematic reviews and meta-analyses have shown that HoLEP is a size-independent, safe and effective procedure with excellent long-term results regarding reoperation and complication rates (Ahyai et al. 2010; Cornu et al. 2015). Perioperatively, HoLEP has a lower morbidity (e.g. transfusion rates, complications) as well as lower hospital stay and catheter duration compared to TUR-P and OSP. In the long term, HoLEP is equivalent to TUR-P and OSP with regard to improving functional parameters and has a low re-intervention rate as OSP. A negative effect on potency could not be demonstrated for HoLEP, apart from retrograde ejaculation (Ahyai et al. 2010; Cornu et al. 2015). In addition, retrospective studies have been published that evaluated HoLEP in patients on continued anticoagulation: The highest transfusion rates were found in patients on bridging or continuous oral anticoagulation

121 Ablative Procedures: Enucleation

(up to 15%), while on platelet inhibition the transfusion rates did not exceed 3% (Netsch et al. 2021). ► Conclusion HoLEP is the best-studied transurethral enucleation procedure with the highest level of evidence (1a) and is recommended by the guidelines of the European Association of Urology (EAU) as an alternative to TUR-P and OSP (Gravas et al. 2020). ◄

13.4.5  Bipolar Enucleation of the

Prostate (BipolEP)

Neill et al. conducted a prospective randomized study in 2006 and compared plasma kinetic enucleation of the prostate (PkEP) with the HoLEP. They found longer OR times and a prolonged postoperative irrigation in the PkEP group, while other perioperative parameters did not differ. After one year, there were no differences regarding the functional parameters and the complication rates of the procedures (Neill et al. 2006). The working group of Liu published 2010 a retrospective study with 1100 patients, who were treated by BipolEP (prostate volume 35 to 256 g) in mushroom technique. The perioperative morbidity of BipolEP was extremely low (transfusion rate 0.8%, catheter duration 1.8 days). Six months postoperatively, the PSA level, as a marker for the complete removal of the prostatic adenoma, had dropped significantly (7.8 vs. 0.89 ng/ml). The functional parameters improved immediately and remained significantly improved. Urethral strictures and bladder neck strictures occurred in 1.1 and 0.9% of the patients. The authors concluded that BipolEP is an alternative to TUR-P and OSP (Liu et al. 2010). Zhu and colleagues conducted a prospective randomized study on patients with

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prostate volumes ≥70 ml, who were treated either by PkEP or bipolar TUR-P. They found a lower blood loss, a shorter hospital and catheter stay after PkEP. The functional parameters were initially comparable in both groups postoperatively—at longterm follow-up after 36-, 48- and 60 months in the PkEP group, however, significantly better than after bipolar TUR-P (Zhu et al. 2013). Rao and colleagues conducted a prospective randomized study on patients with prostate volumes >80 ml and compared PkEP with OSP. OSP was associated with a significantly lower morbidity, catheter and hospital stay (Rao et al. 2013). The working group of Chen confirmed the results of other studies with an excellently prospective randomized non-inferiority study, which compared PkEP with OSP for prostate volumes >100 ml. Hemoglobin loss, transfusion rate, catheter, hospital stay and perioperative morbidity (22.5 vs. 42.5%) were significantly lower after PkEP than after OSP. At 6-year follow-up, there were no differences regarding the functional parameters (Chen et al. 2014). Boeri and colleagues performed a retrospective analysis of patients who received HoLEP or BipolEP under oral anticoagulation/platelet inhibition. They found no differences in bleeding complications between the procedures. The transfusion rate was 2.8% after BipolEP. Clavien I, II and III complications occurred in 4.2%, 13.3% and 0.7% of the patients, respectively (Boeri et al. 2020). ► Conclusion In summary, the current literature shows that BipolEP is a size-independent, safe and effective procedure for the treatment of BPH. The available studies show a lower morbidity of BipolEP compared to TUR-P and OSP. The EAU guidelines were therefore revised in 2016 and now bipolar enucleation was recommended as a treatment option for

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prostate volumes >80 ml (“offer endoscopic enucleation …”) (Gravas et al 2016). ◄

13.4.6  ThuliumVapoEnucleation

of the Prostate (ThuVEP)

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ThuVEP using a thulium:YAG laser with subsequent mechanical morcellation was described in 2009 by the working group of Gross as a safe and effective procedure and introduced into the therapy of BPS (Bach et al. 2009, 2010). The initial description of the surgical technique corresponds in the essential features to a 3-lobe HoLEP technique, whereby the laser energy is continuously applied in the layer between adenoma and prostatic pseudocapsule (Bach et al. 2009). Netsch et al. were able to show that ThuVEP is a size-independent, safe and effective procedure in the treatment of BPH with a low perioperative morbidity (Bach et al. 2011; Netsch et al. 2014a, b, c): In the largest study of the group, the low perioperative morbidity (transfusion rate 1.7%, catheter duration 2  days, hospital stay 4 days) of ThuVEP, independent of prostate size, was demonstrated in 1080 patients (Gross et al. 2014). The prostate volume and PSA reduction 5 years after ThuVEP (>80%) proved the complete removal of the adenoma (Bach et al. 2011; Gross et al. 2017). Also, the lasting improvement of functional parameters with a low rate of late complications (urethral stricture 0.8– 3.1%, bladder neck sclerosis 1.6–3.1%, recurrent adenoma 0–2.3%) after 4 or 5 years was demonstrated (Netsch et al. 2014a, b, c; Gross et al. 2017). Tiburtius et al. were able to prove that the erectile function is not impaired by ThuVEP (Tiburtius et al. 2014). Furthermore, the feasibility of ThuVEP in high-risk patients was demonstrated: Netsch and colleagues evaluated the safety of ThuVEP in 56 high-risk patients un-

der continued anticoagulant therapy. Four patients received a blood transfusion and 4 patients (7.1%) were re-treated due to bleeding (7.1%). In the 24-month follow-up, a significant improvement of functional parameters was found and a PSA reduction of 81% was demonstrated (Netsch et al. 2014a, b, c). Bach and colleagues presented for the first time multicenter “real-life” data and found among 2648 patients who received TUR-P, GreenLight vaporization or ThuVEP, 237 patients who were treated under anticoagulation by means of ThuVEP. The transfusion rates were 5.5% for prostate volumes 80 ml. Bach and colleagues concluded that the bleeding complications are underestimated in prospective randomized studies (Bach et al. 2016). Castellani and colleagues found significantly lower bleeding complications in 88 patients who received ThuVEP under anticoagulation: bladder tamponade (2.2%), blood transfusions (2.2%), reinterventions (4.5%) and intensive care treatment (2.2%) were the most common complications. The PSA reduction and improvement of functional parameters 12 months after surgery confirmed the results of previous studies (Castellani et al. 2020). In a prospective analysis of the learning curve of the ThuVEP technique, it could be demonstrated that with a structured mentored-based approach, both the safety and the efficiency of the procedure are guaranteed after 8 to 16 procedures (Netsch et al. 2013). Furthermore, no differences were found regarding the perioperative morbidity using thulium fiber (wavelength 1940 nm) and thulium:YAG lasers (2.013 nm) (Tiburtius et al. 2015). Netsch et al. conducted a prospective randomized study and compared ThuVEP with HoLEP. They were able to demon-

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strate comparable and low perioperative complications. Both procedures led to an improvement of functional parameters immediately after surgery and after 6 months. PSA (4.14 vs. 0.71 µg/l) and the prostate volume (80 vs. 16 ml) were significantly improved after 6 months in both groups and not different between the procedures. No patient was reoperated during 6-month follow-up (Netsch et al. 2017; Becker et al. 2018). ► Conclusion ThuVEP is a size-independent, safe and effective procedure in the treatment of BPS. The available studies indicate a comparable morbidity of ThuVEP and the HoLEP procedure. The EAU guidelines were therefore revised in 2016 and now recommend ThuVEP as a treatment option for prostate volumes >80 ml (“offer endoscopic enucleation …”). ◄

13.4.7  Thulium Laser Enucleation

of the Prostate (ThuLEP)

ThuLEP is a blunt, laser-assisted, transurethral enucleation technique. The tip of the resectoscope is used for the blunt detachment of the adenoma from the pseudocapsule of the prostate—bleeding vessels are simultaneously or after the enucleation vaporized using the thulium laser (Herrmann et al. 2010). The current results of prospective randomized studies show comparable results for ThuLEP and HoLEP: a low perioperative morbidity, efficient tissue reduction and sufficient improvement of functional micturition parameters (Zhang et al. 2012; Yang et al. 2013a, b; Feng et al. 2016). There is a tendency to shorter operating times when utilizing the thulium laser compared to the holmium laser. The working group of Kim introduced en bloc ThuLEP in 2015 (Kim et al. 2015). Castellani et al. recently evaluated 412 pa-

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tients who received an en bloc ThuLEP: 46 patients were treated under continued anticoagulation. Nevertheless, the postoperative complication rate was very low (Clavien I 9.2%, II 2.7%, III 1.2% and IV 0.7%). Also in this study, the functional parameters were significantly improved 1 year postoperatively (Castellani et al. 2019). 13.4.8  GreenLight Laser

Enucleation of the Prostate (GreenLEP)

The GreenLEP technique using the 180-W XPS GreenLight laser was first published in 2015 (Goméz Sancha et al. 2015). Peyronnet et al. analyzed the learning curves of en-bloc GreenLEP and two-lobe HoLEP in two surgeons inexperienced in transurethral enucleation. Despite larger prostate volume, the surgical time was shortened for GreenLEP. The functional results of both groups were comparable after 6 months. The authors found a shorter learning curve for GreenLEP (14–30 cases) compared to HoLEP (22–40 cases). However, this might be rather based on the surgical techniques (en-bloc vs. two-lobe technique) and not the energy sources (Peyronnet et al. 2017). In a retrospective comparison, photoselective vaporization of the prostate (PVP) was compared with GreenLEP for prostate volumes >80 ml. The perioperative morbidity was comparable, with shorter surgical times in GreenLEP. The functional parameters were comparable after 6 months, but Qmax was higher after GreenLEP than after PVP. Also, the PSA reduction after GreenLEP was higher than after PVP (67% vs. 40%). The perioperative morbidity of GreenLEP was low (hematuria 5%, transfusions 1.6%, reoperation rate 3.3%) despite a high proportion of anticoagulated patients (31 patients) (Misrai et al. 2016). In a retrospective analysis, OSP was compared with GreenLEP: the catheter

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­ uration and the hospital stay were longer d after OSP and the transfusion (8.3 vs. 0.5%) and complication rates (37.2 vs. 20.6%) were higher after OSP compared to GreenLEP (Misrai et al. 2018). ► Conclusion Transurethral enucleation is possible with a GreenLight laser. However, no prospective randomized studies have been published comparing GreenLEP with other enucleation techniques or TUR-P. The major drawback of the GreenLEP technique is the high cost of the single-use laser fiber. ◄

13.4.9  ERASER Laser Enucleation

of the Prostate (ELEP)

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ELEP uses a continuous wave diode laser (ERASER laser) with a wavelength of 1318 nm. ELEP was first described in 2011 in a prospective randomized study that compared ELEP with bipolar TUR-P (30 vs. 30 patients). Here, ELEP showed superiority over bipolar TUR-P in terms of perioperative morbidity (postoperative blood loss) as well as catheter duration and hospital stay. The functional parameters (Qmax, PVR, IPSS, QoL) improved significantly after ELEP and bipolar TUR-P without differences between the procedures and remained stable during a 6-month follow-up (Lusuardi et al. 2011). At 6-month follow-up, no reinterventions were necessary. The results were confirmed by further prospective studies from this working group (Hruby et al. 2013; Lusuardi et al. 2015). Although data from a single-center prospective randomized study are available (evidence level 1b), these are only 6-month data. Long-term data or studies from other working groups have not been published so far.

13.4.10  Diode Laser Enucleation

of the Prostate (DiLEP)

Buisan and colleagues first described DiLEP in 2011 on 17 patients using a pulsed 980 nm diode laser. In addition to low perioperative morbidity, a significant improvement of functional parameters was demonstrated 3  months postoperatively (Buisan et al. 2011). Yang et al. published in a retrospective non-randomized comparative study the “4-U incision DiLEP technique”. After DiLEP, there was a lower Hb drop and a shorter catheter and hospital stay compared to TUR-P. After 12 months, the functional parameters were significantly improved in both groups, without differences between the procedures (Yang et al. 2013a, b). So far, one prospective randomized study has been published that compared DiLEP with plasma kinetic enucleation and resection of the prostate (PKERP). The Hb drop and catheter duration were significantly lower and the total operation time was significantly shorter for DiLEP than for PKERP. After 12 months, the functional parameters were significantly improved in both groups, without differences between the procedures. Reoperations were not necessary in both groups (Xu et al. 2013). Zhang and colleagues published a prospective randomized study comparing DiLEP (with a 1470 nm diode laser) with plasma kinetic resection of the prostate. While perioperative parameters such as duration of irrigation, catheter duration, hospital stay and Hb loss were in favor of DiLEP, there were no differences in terms of complications and functional parameters after 12 months (Zhang et al. 2019). The same working group published a retrospective study on 49 patients who were

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treated on under continued anticoagulant/ platelet inhibitor therapy. The complications were minor: transfusions (2%), secondary bleeding (4.1%) and bladder tamponade (4.1%) occurred. Bleeding-related reinterventions were not necessary (Zhang et al. 2020). ► Conclusion In summary, DiLEP seems to be associated with low intra- and perioperative morbidity, although only a few studies have been published. Prospective randomized studies comparing DiLEP with standard procedures such as TUR-P, OSP or HoLEP have not been published so far. ◄

13.4.11  Photoselective

VapoEnucleation of the Prostate (PVEP)

In PVEP, a VapoEnucleation of the prostate is performed utilizing the 180-W XPS GreenLight laser. A prospective randomized non-inferiority study (HoLEP vs. PVEP) was published in 2015 (Elshal et al. 2015). Although the perioperative morbidity of PVEP and the postoperative outcome 12 months postoperatively were not inferior to HoLEP, a higher intraoperative conversion rate to TUR-P was found for PVEP compared to HoLEP (24.5% vs. 4%). Furthermore, the PSA drop 12 months after PVEP was significantly lower compared to HoLEP (45.9 vs. 82.6%), which indicates that PVEP is less radical than HoLEP. As expected, the laser fiber costs were higher for PVEP than for HoLEP. Further studies with a follow-up ≥12 months are not available so far. However, a higher reoperation rate after PVEP at long-term follow-up can be assumed due to the low PSA drop.

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13.4.12  Thulium Fiber Laser

Enucleation of the Prostate (ThuFLEP)

In ThuFLEP, the transurethral enucleation is performed with a pulsed (so-called super pulsed) 1.94 μm thulium fiber laser. The first clinical studies were published in 2018 and appear to duplicate the excellent results of HoLEP (Enikeev et al. 2018a, b; Morozov et al. 2020). 13.4.13  MOSES Laser Enucleation

of the Prostate (MoLEP)

For MoLEP, a holmium:YAG laser (Lumenis Pulse P120H®) is used. This device has a special laser pulse mode: a vapor bubble (laser pulse) is immediately followed by a second vapor bubble. This splits the water in front of the target tissue (“Moses effect”) and improves the energy transmission to the tissue. First studies have been published and indicate a faster enucleation and improved hemostasis compared to conventional holmium:YAG laser pulse settings (Large et al. 2020). 13.5  Conclusions

5 Retropubic and transvesical OSP are still the most widely used techniques for large prostate adenomas worldwide. OSP represents the standard therapy in the current guidelines of the EAU, AUA and DGU for prostate volumes >80 ml despite the use of minimally invasive transurethral enucleation procedures. Excellent functional (long-term) results are achieved, however, at the expense of a non-contemporary perioperative morbidity.

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5 LSP implements OSP in a laparoscopic manner. Comparable functional results as with OSP were achieved, but with advantages in terms of perioperative morbidity for the laparoscopic approach. 5 The major disadvantage of LSP is the learning curve: The laparoscopic expertise required for the procedure is high, which is reflected by the literature. Studies only exist from laparoscopic centers. Prospective randomized studies comparing the procedure with the standard procedure (OSP) are not available. 5 RASP is superior to OSP in terms of perioperative morbidity. These advantages outweigh the longer surgical times and the higher intraoperative material costs of RASP compared to OSP. In addition, the robot-assisted procedure appears to be easier to learn than LSP, which is reflected in a significantly higher number of publications for RASP compared to LSP. The procedure seems to be particularly suitable as an alternative to OSP, if there is no expertise for transurethral enucleation procedures, but in robotics. 5 HoLEP is the best-studied procedure for transurethral enucleation of the prostate with the highest level of evidence (1a), based on meta-analyses of prospective randomized studies. HoLEP is size-independent, safe, effective with a lower perioperative morbidity than TUR-P and OSP and has a comparable reoperation and complication rate at long-term follow-up. 5 BipolEP shows in prospective randomized studies a significantly lower morbidity compared to bipolar TUR-P and OSP and comparable results with regard to reoperation rates at long-term follow-up and improvement of functional parameters (level of evidence 1b). Good evidence is also now available for ThuVEP/ThuLEP.

5 The level of evidence for other minimally-invasive transurethral enucleation procedures such as GreenLEP, ELEP, DiLEP, PVEP is still limited. Although all procedures are based on a transurethral enucleation technique, the procedures have limitations: 1. For GreenLEP/PVEP, a disposable fiber is used, which is significantly more expensive compared to that of other laser systems. In addition, a so-called “side-fire” laser fiber is used, which has disadvantages compared to a bare ended laser fiber for enucleation—i. e. “the laser works around the corner” 2. Diode lasers (e.g. ERASER laser) are a heterogeneous group of lasers with different wavelengths and therefore different tissue effects: i.e. a partially deep penetration depth and thus significant side effects on continence (urge and or stress incontinence, dysuria) and potency. In addition, the evidence for diode lasers is limited by sparse clinical data. 5 ThuFLEP and MoLEP are procedures based on further developments of the thulium and holmium lasers: the superpulsed thulium fiber laser and the holmium laser with the Moses effect. Both show very good results in studies and will establish themselves on the market in the near future.

References Ahyai SA, Gilling P, Kaplan SA et al (2010) Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol 58:384–397 Autorino R, Zargar H, Mariano MB et al (2015) Perioperative outcomes of robotic and laparoscopic simple prostatectomy: a European- American multi-institutional analysis. Eur Urol 68:86–94

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Baazeem AS, Elmansy HM, Elhilali MM (2010) Holmium laser enucleation of the prostate: modified technical aspects. BJU Int 105:584–585 Bach T, Wendt-Nordahl G, Michel MS, Herrmann TR, Gross AJ (2009) Feasibility and efficacy of Thulium:YAG laser enucleation (VapoEnucleation) of the prostate. World J Urol 27:541–545. 7 https://doi.org/10.1007/s00345-008-0370-0 Epub 2009 Jan 28 Bach T, Netsch C, Haecker A, Michel MS, Herrmann TRW, Gross AJ (2010) Thulium:YAG laser enucleation (VapoEnucleation) of the prostate: safety and durability during intermediate-term follow-up. World J Urol 28:39–43 Bach T, Netsch C, Pohlmann L, Herrmann TR, Gross AJ (2011) Thulium:YAG vapoenucleation in large volume prostates. J Urol 186:2323–2327 Bach T, Wölbling F, Gross AJ, Netsch C, Tauber S, Pottek T, Wülfing C, Brunken C (2016) Prospective assessment of perioperative course in 2648 patients after surgical treatment of benign prostatic obstruction. World J Urol 35:285–292 Baumert H, Ballaro A, Dugardin F, Kaisary AV (2006) Laparoscopic versus open simple prostatectomy: a comparative study. J Urol 175:1691–1694 Becker B, Herrmann TRW, Gross AJ, Netsch C (2018) Thulium vapoenucleation of the prostate versus holmium laser enucleation of the prostate for the treatment of large volume prostates: preliminary 6-month safety and efficacy results of a prospective randomized trial. World J Urol 36:1663–1671 Boeri L, Capogrosso P, Ventimiglia E, Fontana M, Sampogna G, Zanetti SP, Pozzi E, Zuabi R, Schifano N, Chierigo F, Longo F, Gadda F, Dell’Orto PG, Scattoni V, Montorsi F, Montanari E, Salonia A (2020) Clinical comparison of holmium laser enucleation of the prostate and bipolar transurethral enucleation of the prostate in patients under either anticoagulation or antiplatelet therapy. Eur Urol Focus 6:720–728. 7 https://doi.org/10.1016/j. euf.2019.03.002 Epub 2019 Mar 11 Buisan O, Saladie JM, Ruiz JM, Bernal S, Bayona S, Ibarz L (2011) Diode laser enucleation of the prostate (Dilep): technique and initial results. Actas Urol Esp 35:37–41. 7 https://doi.org/10.1016/j. acuro.2010.08.003 Epub 2011 Jan 5 Castellani D, Pirola GM, Gasparri L, Pucci M, Di Rosa M, Carcano G, Saredi G, Dellabella M (2019) Are outcomes of thulium laser enucleation of the prostate different in men aged 75 and over? A propensity score analysis. Urology 132:170–176. 7 https://doi.org/10.1016/j.urology.2019.06.025 Epub 2019 Jun 26 Castellani D, Di Rosa M, Gasparri L, Pucci M, Dellabella M (2020) Thulium Laser Vapoenucleation of the Prostate (ThuVEP) in men at high cardiovascular risk and on antithrombotic therapy: A sin-

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gle-center experience. J Clin Med 2020(9):917. 7 https://doi.org/10.3390/jcm9040917 Chen S, Zhu L, Cai J, Zheng Z, Ge R, Wu M, Deng Z, Zhou H, Yang S, Wu W, Liao L, Tan J (2014) Plasmakinetic enucleation of the prostate compared with open prostatectomy for prostates larger than 100 grams: a randomized noninferiority controlled trial with long-term results at 6 years. Eur Urol 66:284–291 Cornu JN, Ahyai S, Bachmann A, de la Rosette J, Gilling P, Gratzke C, McVary K, Novara G, Woo H, Madersbacher S (2015) A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol 67:1066–1096 Cracco CM, Scoffone CM (2017) Low-power versus high-power en-bloc no-touch holmium laser enucleation of the prostate (HoLEP); comparing feasibility, safety and efficacy. J Endourol 31(S2):A304 El-Hakim A, Elhilali MM (2002) Holmium laser enucleation of the prostate can be taught: the first learning experience. BJU Int 90:863–869 Elshal AM, Elkoushy MA, El-Nahas AR, Shoma AM, Nabeeh A, Carrier S, Elhilali MM (2015) GreenLight™ laser (XPS) photoselective vapo-enucleation versus holmium laser enucleation of the prostate for the treatment of symptomatic benign prostatic hyperplasia: a randomized controlled study. J Urol 193:927–934. 7 https://doi.org/10.1016/j.juro.2014.09.097 Epub 2014 Sep 28 Endo F, Shiga Y, Minagawa S, Iwabuchi T, Fujisaki A, Yashi M, Hattori K, Muraishi O (2010) Anteroposterior dissection HoLEP: a modification to prevent transient stress urinary incontinence. Urology 76:1451–1455 Enikeev D, Glybochko P, Rapoport L, Gahan J, Gazimiev M, Spivak L, Enikeev M, Taratkin M (2018a) A randomized trial comparing the learning curve of 3 endoscopic enucleation techniques (HoLEP, ThuFLEP, and MEP) for BPH using mentoring approach-initial results. Urology 121:51–57 Enikeev D, Glybochko P, Okhunov Z, Alyaev Y, Rapoport L, Tsarichenko D, Enikeev M, Sorokin N, Dymov A, Taratkin M (2018b) Retrospective analysis of short-term outcomes after monopolar versus laser endoscopic enucleation of the prostate: A single center experience. J Endourol 32:417–423 Feng L, Zhang D, Tian Y, Song J (2016) Thulium laser enucleation versus plasmakinetic enucleation of the prostate: a randomized trial of a single center. J Endourol 30:665–670 Fraundorfer MR, Gilling PJ (1998) Holmium:YAG laser enucleation of the prostate combined with me-

128

13

C. Netsch

chanical morcellation: preliminary results. Eur Urol 1998(33):69–72 Freyer PJ (1901) A clinical lecture on total extirpation of the prostate for radical cure of enlargement of that organ: with four successful cases: delivered at the medical Graduates’ college, London, June 26th. Br Med J 2:125–129 Geavlete B, Stanescu F, Iacoboaie C, Geavlete P (2013) Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign prostatic hyperplasia cases – a medium term, prospective, randomized comparison. BJU Int 111:793–803 Gilfrich C, Leicht H, Fahlenbrach C, Jeschke E, Popken G, Stolzenburg JU, Weißbach L, Zastrow C, Günster C (2016) Morbidity and mortality after surgery for lower urinary tract symptoms: a study of 95 577 cases from a nationwide German health insurance database. Prostate Cancer Prostatic Dis 19:406–411 Gilfrich C, May M, Fahlenbrach C, Günster C, Jeschke E, Popken G, Stolzenburg JU, Weissbach L, von Zastrow C, Leicht H (2021) Surgical reintervention rates after invasive treatment for lower urinary tract symptoms due to benign prostatic syndrome: a comparative study of more than 43,000 patients with long-term followup. J Urol 205:855–863 Gilling P (2008) Holmium Laser Enucleation of the Prostate (HoLEP). BJU 101:131–142 Gilling PJ (2013) Laser enucleation is increasingly becoming the standard of care for treatment of benign prostatic hyperplasia of all sizes. Eur Urol 63:868–869 Gilling PJ, Kennett K, Das AK, Thompson D, Fraundorfer MR (1998) Holmium Laser Enucleation of the Prostate (HoLEP) combined with transurethral tissue morcellation: an update on the early clinical experience. J Endourol 12:457–459 Gomez Sancha F, Rivera VC, Georgiev G, Botsevski A, Kotsev J, Herrmann T (2015) Common trend: move to enucleation-Is there a case for GreenLight enucleation? Development and description of the technique. World J Urol 33:539–547. 7 https://doi. org/10.1007/s00345-014-1339-9 Gong YG, He DL, Wang MZ, Li XD, Zhu GD, Zheng ZH, Du YF, Chang LS, Nan XY (2012) Holmium laser enucleation of the prostate: a modified enucleation technique and initial results. J Urol 187:1336–1340 Gratzke C, Schlenker B, Seitz M, Karl A, Hermanek P, Lack N, Stief CG, Reich O (2007) Complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol 177:1419–1422 Gravas S, Bach T, Bachmann A, Drake M, Gacci M, Gratzke C, Madersbacher S, Mamoulakis S, Tik-

kinen KAO (2016) Guidelines on the management of non-neurogenic male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO) EAU, 7 http://uroweb.org/guideline/treatment-of-non-neurogenicmale-luts/. Accessed Mar 2016 Gravas S, Cornu JN, Gacci M, Gratzke C, Herrmann TRW, Mamoulakis C, Rieken M, Speakman MJ, Tikkinen KAO (2020) Management of non-neurogenic male Lower Urinary Tract Symptoms (LUTS), EAU, 2020, 7 https://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/#5 Gross AJ, Netsch C, Knipper S, Hölzel J, Bach T (2014) Complications and early postoperative outcome in 1080 patients after thulium vapoenucleation of the prostate: results at a single institution. Eur Urol 63:859–867 Gross AJ, Orywal AK, Becker B, Netsch C (2017) Five-year outcomes of thulium vapoenucleation of the prostate for symptomatic benign prostatic obstruction. World J Urol 35:1585–1593 Herrmann TR, Bach T, Imkamp F, Georgiou A, Burchardt M, Oelke M, Gross AJ (2010) Thulium Laser Enucleation of the Prostate (ThuLEP): transurethral anatomicalprostatectomy with laser support. Introduction of a novel technique for the treatment of benign prostatic obstruction. World J Urol 28:45–51. 7 https://doi.org/10.1007/s00345009-0503-0 Hiraoka Y (1983) A new method of prostatectomy, transurethral detachment and resection of benign prostatic hyperplasia. Nihon Ika Daigaku Zasshi. 50:896–898 Hiraoka Y, Akimoto M (1989) Transurethral enucleation of benign prostatic hyperplasia. J Urol 1989(142):1247–1250 Hochreiter WW, Thalmann GN, Burkhard FC, Studer UE (2002) Holmium laser enucleation of the prostate combined with electrocautery resection: the mushroom technique. J Urol 168:1470–1474 Hruby S, Sieberer M, Schätz T, Jones N, Zimmermann R, Janetschek G, Lusuardi L (2013) Eraser laser enucleation of the prostate: technique and results. Eur Urol 63:341–6. 7 https://doi.org/10.1016/j.eururo.2012.08.049. Epub 2012 Aug 29 John H, Bucher C, Engel N, Fischer B, Fehr JL (2009) Preperitoneal robotic prostate adenomectomy. Urology 73:811–815 John H, Wagner C, Padevit C, Witt JH (2021) From open simple to Robotic-Assisted Simple Prostatectomy (RASP) for large benign prostate hyperplasia: the time has come. World J Urol. 7 https:// doi.org/10.1007/s00345-020-03508-1 Johnson B, Sorokin I, Singla N, Roehrborn C, Gahan JC (2018) Determining the learning curve for robot-assisted simple prostatectomy in surgeons fa-

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miliar with robotic surgery. J Endourol 32:865– 870 Kim YJ, Lee YH, Know JB, Cho SR, Kim JS (2015) A novel one lobe technique of thulium laser enucleation of the prostate: “All-in-One” techinique. Korean J Urol 2015(56):769–774 Large T, Nottingham C, Stoughton C, Williams J Jr, Krambeck A (2020) Comparative study of holmium laser enucleation of the prostate with moses enabled pulsed laser modulation. Urology 136:196–201. 7 https://doi.org/10.1016/j.urology.2019.11.029 Epub 2019 Nov 30 Liu C, Zheng S, Li H et al (2010) Transurethral enucleation and resection of prostate in patients with benign prostatic hyperplasia by plasma kinetics. J Urol 184:2440–2445 Lusuardi L, Myatt A, Sieberer M, Jeschke S, Zimmermann R, Janetschek G (2011) Safety and efficacy of eraser laser enucleation of the prostate: preliminary report. J Urol 186:1967–1971 Lusuardi L, Hruby S, Janetschek G, Mitterberger M, Sieberer M, Colleselli D, Kunit T, Hitzl W, Kloss B (2015) Laparoscopic adenomectomy versus eraser laser enucleation of the prostate. World J Urol 33:691–696 Madersbacher S, Lackner J, Brössner C, Röhlich M, Stancik I, Willinger M, Schatzl G; Prostate Study Group of the Austrian Society of Urology (2005) Reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. Eur Urol 47:499–504 Mariano MB, Graziottin TM, Tefilli MV (2002) Laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. J Urol 167:2528– 2529 Millin T (1945) Retropubic prostatectomy: a new extravesical technique. Lancet II:693–696 Misrai V, Kerever S, Phe V, Zorn KC, Peyronnet B, Rouprêt M (2016) Direct comparison of greenlight laser XPS photoselective prostate vaporization and greenlight laser en bloc enucleation of the prostate in enlarged glands greater than 80 ml: a study of 120 patients. J Urol 195:1027–1032. 7 https://doi.org/10.1016/j.juro.2015.10.080 Epub 2015 Oct 17 Misraï V, Pasquie M, Bordier B, Elman B, Lhez JM, Guillotreau J, Zorn K (2018) Comparison between open simple prostatectomy and green laser enucleation of the prostate for treating large benign prostatic hyperplasia: a single-centre experience. World J Urol 36:793–799. 7 https://doi. org/10.1007/s00345-018-2192-z Epub 2018 Jan 25 Morozov A, Taratkin M, Kozlov V, Tarasov A, Bezrukov E, Enikeev M, Afyouni AS, Okhunov Z, Glybochko P, Enikeev D (2020) Retrospective assessment of endoscopic enucleation of prostate com-

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plications: a single-center experience of more than 1400 patients. J Endourol 34:192–197. 7 https:// doi.org/10.1089/end.2019.0630 Mourmouris P, Keskin SM, Skolarikos A et al (2019) A prospective comparative analysis of robot-assisted vs open simple prostatectomy for benign prostatic hyperplasia. BJU Int 123:313–317 Neill MG, Gilling PJ, Kennett KM, Frampton CM, Westenberg AM, Fraundorfer MR, Wilson LC (2006) Randomized trial comparing holmium laser enucleation of prostate with plasmakinetic enucleation of prostate for treatment of benign prostatic hyperplasia. Urology 68:1020–1024 Netsch C, Bach T, Herrmann TR, Neubauer O, Gross AJ (2013) Evaluation of the learning curve for Thulium VapoEnucleation of the Prostate (ThuVEP) using a mentor-based approach. World J Urol 31:1231–1238 Netsch C, Engbert A, Bach T, Gross AJ (2014a) Longterm outcome following Thulium VapoEnucleation of the prostate. World J Urol 32:1551–1558 Netsch C, Stoehrer M, Brüning M, Gabuev A, Bach T, Herrmann TR, Gross AJ (2014b) Safety and effectiveness of Thulium VapoEnucleation of the Prostate (ThuVEP) in patients on anticoagulant therapy. World J Urol 32:165–172 Netsch C, Tiburtius C, Bach T, Knipper S, Gross AJ (2014c) Association of prostate size and perioperative morbidity in thulium:YAG vapoenucleation of the prostate. Urol Int 93:22–28 Netsch C, Becker B, Tiburtius C, Moritz C, Becci AV, Herrmann TRW, Gross AJ (2017) A prospective, randomized trial comparing thulium vapoenucleation with holmium laser enucleation of the prostate for the treatment of symptomatic benign prostatic obstruction: perioperative safety and efficacy. World J Urol 35:1913–1921 Netsch C, Herrmann TRW, Bozzini G, Berti L, Gross AJ, Becker B (2021). Recent evidence for Anatomic Endoscopic Enucleation of the Prostate (AEEP) in patients with benign prostatic obstruction on antiplatelet or anticoagulant therapy. World J Urol. Mar 15. Online ahead of print Pavan N, Zargar H, Sanchez-Salas R et al (2016) Robot-assisted versus standard laparoscopy for simple prostatectomy: multicenter comparative outcomes. Urology 91:104–110 Peyronnet B, Robert G, Comat V, Rouprêt M, Gomez-Sancha F, Cornu JN, Misrai V (2017) Learning curves and perioperative outcomes after endoscopic enucleation of the prostate: a comparison between GreenLight 532-nm and holmium lasers. World J Urol 35:973–983. 7 https://doi. org/10.1007/s00345-016-1957-5 Epub 2016 Oct 20 Placer J, Gelabert-Mas A, Vallmanya F, Manresa JM, Mene´ndez V, Cortadellas R, Arango O, (2009) Holmium laser enucleation of prostate: outcome

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and complications of self-taught learning curve. Urology 73:1042–1048 Rao JM, Yang JR, Ren YX, He J, Ding P, Yang JH (2013) Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia >80 ml: 12-month follow-up results of a randomized clinical trial. Urology 82:176–181 Rehman J, Khan SA, Sukkarieh T, Chughtai B, Waltzer WC (2005) Extraperitoneal laparoscopic prostatectomy (adenomectomy) for obstructing benign prostatic hyperplasia: transvesical and transcapsular (Millin) techniques. J Endourol 19:491–496 Rey D, Ducarme G, Hoepffner JL, Staerman F (2005) Laparoscopic adenectomy: a novel technique for managing benign prostatic hyperplasia. BJU Int 95:676–678 Scoffone CM, Cracco CM (2016) The en-bloc notouch Holmium Laser Enucleation of the Prostate (HoLEP) technique. World J Urol 34:1175–1181 Sotelo R, Spaliviero M, Garcia-Segui A et al (2005) Laparoscopic retropubic simple prostatectomy. J Urol 173:757–760 Sotelo R, Clavijo R, Carmona O et al (2008) Robotic simple prostatectomy. J Urol 179:513–515 Tiburtius C, Knipper S, Gross AJ, Netsch C (2014) Impact of thulium vapoenucleation of the prostate on erectile function: a prospective analysis of 72 patients at 12-month follow-up. Urology 83:175–180 Tiburtius C, Gross AJ, Netsch C (2015) A prospective, randomized comparison of a 1940 nm and a 2013 nm thulium:yttrium-aluminum-garnet laser device for Thulium VapoEnucleation of the prostate (ThuVEP): first results. Indian J Urol 31:47–51 Umari P, Fossati N, Gandaglia G et al (2017) Robotic assisted simple prostatectomy versus holmium laser enucleation of the prostate for lower urinary tract symptoms in patients with large volume prostate: a comparative analysis from a high volume center. J Urol 197:1108–1114 van Velthoven R, Peltier A, Laguna MP, Piechaud T (2004) Laparoscopic extraperitoneal adenomectomy (Millin): pilot study on feasibility. Eur Urol 45:103– 109 (discussion 109)

Wang P, Xia D, Ye S et al (2018) Robotic-assisted urethra-sparing simple prostatectomy via an extraperitoneal approach. Urology 119:85–90 Xu A, Zou Y, Li B et al (2013) A randomized trial comparing diode laser enucleation of the prostate with plasmakinetic enucleation and resection of the prostate for the treatment of benign prostatic hyperplasia. J Endourol 27:1254–1260 Yang Z, Wang X, Liu T (2013a) Thulium laser enucleation versus plasmakinetic resection of the prostate: a randomized prospective trial with 18 month follow-up. Urology 81:396–400 Yang SS, Hsieh CH, Lee YS et al (2013b) Diode laser (980 nm) enucleation of the prostate: a promising alternative to transurethral resection of the prostate. Lasers Med Sci 28:353–360 Zarraonandia Andraca A, Lombardo R, Carrion Valencia A et al (2019) Laparoscopic simple prostatectomy: a large single center prospective cohort study. Minerva Urol Nefrol. 7 https://doi. org/10.23736/S0393-2249.19.03567-7 Zhang F, Shao Q, Herrmann TR, Tian Y, Zhang Y (2012) Thulium laser versus holmium laser transurethral enucleation of the prostate: 18-month follow-up data of a single center. Urology 79:869–874 Zhang J, Wang X, Zhang Y, Shi C, Tu M, Shi G (2019) 1470 nm diode laser enucleation vs plasmakinetic resection of the prostate for benign prostatic hyperplasia: a randomized study. J Endourol 33:211– 217. 7 https://doi.org/10.1089/end.2018.0499 Epub 2019 Jan 9 Zhang J, Li J, Wang X, Shi C, Tu M, Shi G (2020) Efficacy and safety of 1470-nm diode laser enucleation of the prostate in individuals with benign prostatic hyperplasia continuously administered oral anticoagulants or antiplatelet drugs. Urology 138:129–133. 7 https://doi.org/10.1016/j.urology.2020.01.008 Epub 2020 Jan 21 Zhu L, Chen S, Yang S, Wu M, Ge R, Wu W, Liao L, Tan J (2013) Electrosurgical enucleation versus bipolar transurethral resection for prostates larger than 70 ml: a prospective, randomized trial with 5-year followup. J Urol 189:1427–1431

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Ablative Procedures: Resection Christopher Netsch Contents 14.1 Introduction – 132 14.2 Transurethral Resection of the Prostate (TUR-P) – 132 14.3 Ablative Procedures: Thulium VapoResection of the Prostate (ThuVARP) – 138 References – 140

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_14

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14.1  Introduction

Despite the increasing establishment of minimally invasive treatment methods, transurethral resection of the prostate (TUR-P) is still the most frequently used procedure in Germany with a proportion of almost 80% of all BPH operations according to a survey by the General Local Health Insurance Fund (AOK) (Gilfrich et al. 2016). This result reflects the recommendations of the European Association of Urology (EAU): Monopolar TUR-P (M-TUR-P) is the standard operative therapy for men with lower urinary tract symptoms (LUTS) due to benign prostate syndrome (BPS) and a prostate volume (PV) between 30 and 80 ml (Gravas et al. 2016, 2020). The effectiveness of M-TUR-P in terms of improving LUTS has been demonstrated in numerous studies: M-TUR-P is the only endoscopic-surgical procedure with a long-term follow-up >20 years (Reich et al. 2006). 14.2  Transurethral Resection

of the Prostate (TUR-P)

14

Technical improvements (refinement of the mechanics, development of more powerful optics, improvements of the high-frequency technology [mono, bipolar current]) and an improved anesthesiological management have significantly improved the perioperative morbidity and the effectiveness of TUR-P. The operation is performed in lithotomy position. With a diathermy loop inserted into the resection slide, the prostate tissue is cut into individual resection chips under vision and removed via the instrument shaft. A distinction is made between TUR-P with intermittent and continuous irrigation. While with the intermittent irrigation method (high-pressure irrigation) the bladder is filled after a few cutting sequences

and emptied via the instrument shaft, with the continuous irrigation (low-pressure irrigation) the irrigation fluid is permanently guided into the bladder through an irrigation channel by means of a continuous irrigation or reflux resectoscope or a suprapubic trocar and suctioned off through a second one. With the latter procedure, the risk of absorption of the irrigation fluid into the body via opened prostate veins or via a thinned prostate capsule is minimized by low, constant pressures in the bladder. z Monopolar and Bipolar TUR-P

In M-TUR-P (monopolar high-frequency current application), the current flows from an active electrode through the patient’s body to a large-area neutral electrode and further to the ground. In B-TUR-P, the current does not flow through the body, but remains local: The current flows between 2 active electrodes which are as close as possible. The arrangement of the electrodes in B-TUR-P corresponds more to the definition of a monopolar procedure, since there is only one active electrode and the second electrode only serves for the return flow of low-density energy (quasi-bipolar). The energy is limited between the active (resection loop) and the passive pole on the resectoscope tip (“true” bipolar systems) or the shaft (“quasi” bipolar systems). The main difference between M-TUR-P and B-TUR-P lies in the type of irrigation fluid: In B-TUR-P, highly conductive fluids (physiological saline solution) are used to ensure the current flow from the active electrode to the outflowing electrode. Thus, only low current flow through the body. In M-TUR-P, on the other hand, an irrigation solution is required that has a higher resistance than the tissue (electrolyte-free solution) to ensure the current flow from the active electrode through the tissue to the neutral electrode. The advantage of B-TUR-P lies in the use of physiological saline solution (NaCL 0.9%) as ir-

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rigation fluid: A TUR syndrome can be avoided. Nevertheless, relevant amounts of irrigation fluid can be absorbed and lead to normotonic hyperhydration and acute right heart strain. The prostate resection is identical in B-TUR-P and M-TUR-P. However, B-TURP requires less energy/voltage, since less tissue is interposed. The TUR Syndrome Consists of 3 Factors 5 Reduction of cardiac output due to fluid overload (hypokinetic, hypotensive syndrome) 5 Cerebral edema due to lowered serum osmolality 5 Direct myocardial damage due to interstitial dilatation, myoglobin leakage, inflammation and destruction of the cytoarchitecture

The myocardial damage is mainly caused by glycine, while inflammation and dilatation can be caused by all electrolyte-free solutions. The flushing of hypotonic irrigation fluid (sorbitol-mannitol solution: osmolarity 178 mosmol/l) intravascularly can be reduced by resection with the backflush resectoscope (Iglesias), resection with su-

prapubic fistula or trocar, or by resection with a low-hanging irrigator when using a resectoscope without backflush. > The TUR syndrome is caused by flushing of irrigation fluid intravascularly through a dilutional hyponatremia and hypervolemia (up to 2.0% incidence).

Clinically, the TUR syndrome manifests itself by three symptom complexes (. Table 14.1). The hypervolemia manifests itself primarily by increased systolic and diastolic blood pressure. Initially, circulatory symptoms usually occur, while in prolonged flushing of hypotonic solutions, cerebral manifestations due to brain edema occur later (Hofmann 2018). If the patient has a spinal anesthesia, yawning is often a first sign, then increasing restlessness and confusion and, if pulmonary edema develops, dyspnea and cyanosis occur. Nausea, vomiting, abdominal pain and chills are possible. Acute renal failure and cerebral and pulmonary edema are life-threatening signs of hypervolemia. In patients under general anesthesia, the TUR syndrome can initially remain hidden. The diagnosis is made by lowering the serum sodium level to 120 mval/l. If there is clinical

. Table 14.1  TUR syndrome symptom complexes. (From Hofmann 2018)

Cardiopulmonary

Renal/hematological

Central nervous

Hypertension

Hyperglycemia

Nausea/vomiting

Bradycardia

Hyperammonemia

Confusion/Dizziness

Arrhythmia

Hyponatremia

Vision loss

ARDS

Hemolysis Acute renal failure (ARF)

Cramps

Cyanosis

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Hyperkalemia

Lethargy/paralysis

Hypotension

Ha molyse/Anemia

Pupil dilation

Shock

ANV

Coma

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suspicion, immediate action is required: administration of 250–500 ml 5% NaCl and 40 mg furosemide i. v. (Hofmann 2018). Table from the book Endoscopic Urology, R. Hofmann (2018). 14.2.1  Resection Technique

14

Various techniques of a TUR-P have been described. Thus, Barnes and Nesbit (1943) developed the technique practiced in the USA, first to resect the ventral parts of the prostate (between 11 and 1 o’clock), then the lateral lobes from ventral to dorsal and finally to resect the middle lobe and the apical region (Nesbit 1943, 1947, 1954). Alcock and Flocks (1943) described the technique of first removing the middle lobe and then dividing the lateral lobes at 9 o’clock and 3 o’clock. The lower parts are removed and then the ventral and apical parts (Flocks 1937; Flocks and Culp 1954). Blandy favored the method of first removing the middle lobe area, then resecting the lateral lobes from 12 o’clock starting from ventral to dorsal (Blandy 1986). The method described here is based on the work of W. Mauermayer and R. Hartung (Hartung and May 2002; Mauermayer 1981; Hofmann 2018). The key to the success of the surgery is to adhere to the systematics of the procedure. First, the following 3 landmarks are displayed: external sphincter, colliculus, bladder neck. The Resection of the Prostate can be Divided into 4 Sub-Steps 1. Resection of the median lobe to the colliculus 2. Paracollicular resection 3. Resection of the lateral lobes and ventral parts 4. Apical and repeated paracollicular resection

1. Resection of the Median Lobe The resection of the median lobe is started at 6 o’clock. A careful inspection of the bladder is required to keep the position of the ureteral orifices in mind. A voluminous median lobe can lift the ureteral orifices and, as a consequence, can be over-resected during the median lobe resection. Two situations can now arise: 5 A: The length of the prostatic urethra is shorter than the loop: A resection with control of the endpoint is now performed, with the colliculus as the endpoint covered by the shaft. 5 B: The prostatic urethra is longer than the loop: Cut with control of the insertion point and division of the cut length to the colliculus (. Fig. 14.1). A longitudinal section is performed by inserting the extended loop in the middle lobe area, switching on the cutting current and pulling the instrument back to the end point with the extended loop. When the colliculus is reached as the end point, the loop is pulled back with the cutting current switched on and the middle lobe resection is completed. However, this technique is only recommended for the experienced resector, as otherwise the end point can easily be overrun. The movement of the instrument can also be complex by arc-shaped resection. For a small adenoma, the resection is continued by direct transition from the middle lobe to the lateral lobes. Here, special attention must be paid to creating a smooth resection surface by placing adjacent cuts and continuously rotating the resectoscope shaft. Only when the cranial portions of the prostate are completely removed on all sides, the resection of the apex prostatae is performed with care (Hofmann 2018). 2. Paracollicular resection

135 Ablative Procedures: Resection

14

3. Lateral lobe resection

1

2

3

1

2

3

a

b

c . Fig. 14.1  a–b Technique of the divided cut for a large, long median lobe. a First step is the control of the insertion point, b then extension of the cut, c final cut with control of the endpoint (Figure from the book Endoscopic Urology, R. Hofmann 2018)

After resection of the middle lobe area between about 5 and 7 o’clock, the paracollicular resection is performed. For this purpose, the resection in the middle lobe area between 4 and 8 o’clock is widened and resected next to the colliculus. The instrument is lowered into the tissue and a deep resection lateral to the colliculus is performed. The colliculus is now free. A paracollicular resection is thus possible without risk, but a sphincter test should always be performed in the individual case to clarify the anatomical conditions.

For a small adenoma, the resection is performed from the last middle lobe cut starting cranially to the right. A resection groove is placed next to the other, with the end point always being the distal end point of the paracollicular resection. By continuously rotating the instrument after each cut, a smooth resection surface is created up to about 11 o’clock. Now the same procedure is performed on the left side also up to about 1 o’clock (or one starts exactly the other way around). By rotating the entire instrument and changing the grip, the ventral adenoma area can now be resected. z Resection of a voluminous lateral lobe

If a large lateral lobe is resected, this can be done in the same way as the resection of small lateral lobes from caudal to cranial, but there may be orientation difficulties due to overhanging tissue. By dividing the lateral lobe at 9 o’clock or 3 o’clock, the lateral lobe is divided into a cranial and a caudal segment. With deep cuts, a groove is resected from the bladder neck to the apex to the capsule. Then, with long, fast cuts, the resection is performed from this groove downward, where the connection to the already resected middle lobe is found. By deep resection and coagulation at 8–9 o’clock and 3–4 o’clock, the supplying arteries to the adenoma are coagulated early, so that further resection is less bloody. The resection of the partial areas from 9–7 o’clock, 9–12 o’clock, 3–5 o’clock and 3–12 o’clock is performed with good overview to the striated capsule tissue. 4. Apical resection Starting from paracollicular, the apical tissue is resected all around with short clamp cuts, whereby one loop is placed next to the other. Important here is the control of the endpoint, which now lies slightly distal

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to the proximal end of the colliculus. The positional relationship to the sphincter is checked with the hydraulic sphincter test. At the end of the apical resection, there is usually still some apical tissue that can fall in valve-like, especially from ventrally and ventrally-laterally. If this tissue is left, it can act as an obstacle during micturition (flap, valve effect). This tissue can be removed by targeted clamp cuts. The resection of the apex requires special care, whereby the colliculus seminalis always serves as a guide. The resection margin does not necessarily have to lie at the level of the colliculus, in larger adenomas it might be distally to the colliculus. Finally, after removal of the resection pieces, hemostasis is performed with the resection loop. After the resection, a three-way catheter is inserted. Some surgeons block the catheter in the bladder, others in the prostatic fossa (Hofmann 2018). As an alternative, the transurethral incision of the prostate (TUIP) is available. In TUIP, an incision of the bladder outlet is performed without removal of prostate tissue. This technique can be applied in selected patients, especially those with a prostate volume However, it is important to consider that in most patients the therapy was discontinued or a bridging was performed, so that at the time of the operation patients were not on OAC or PAI. A meta-analysis of 11 studies, which included a total of 2295 patients and considered all laser generations of PVP, could only show a reduction of 0.54 days in the duration of catheterization in patients without OAC/PAI compared to those with OAC/PAI (Zheng 2019). Therefore, it would be useful in clinical practice to inform this patient population about the potential need for a longer catheterization period.

Regarding other examined parameters such as operative time, blood transfusions, reoperation rate or the rate of postoperative dysuria, there were no significant differences between patients with and without OAC/ PAI. In a retrospective case series of 180-W PVP in 384 patients, 164 (38%) were under therapy with acetylsalicylic acid, 34 patients (8.9%) under therapy with clopidogrel and 57 patients (14.8%) under therapy with OAC (Lee et al. 2016). It is noteworthy in this context that the combination of 2 medications occurred in 9.3% and of 3 medications in 1.7% of the cases. A perioperative blood transfusion was not observed in this patient population, furthermore, only one patient required a reoperation due to bleeding. In contrast, a retrospective study of a population of patients who underwent surgery with the 80-W and 120-W laser showed that macrohematuria was relatively frequent (33.8%) during an average postoperative course of 33 months (Jackson et al. 2013). Another study on PVP with the 180-W laser showed no difference between the control group and patients with OAC or PAI regarding the overall incidence of postoperative complications. However, the

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authors noted that the rate of high-grade complications (≥Clavien III a) was significantly higher in the group of patients with OAC or PAI. Looking at these data in detail, it can be stated that these were not bleeding complications, but a higher incidence of sepsis, bladder neck sclerosis or capsule perforation, which are not related to the medications (Knapp et al. 2017). 15.2.5  Data from Case Series

15

Even though RCTs as well as systematic reviews and meta-analyses derived from them represent a high scientific evidence, case series with sufficiently documented data provide a good overview of the application of surgical techniques and their results in clinical practice. A recently published case series included data from 3627 patients who underwent PVP with the 180-W laser in 7 international centers between 2011 and 2019 (Law et al. 2021). Of these patients, 551 patients had a PV of >100 ml. The median hospital stay was 2 days. Regarding complications, 0.8% of the patients required a perioperative blood transfusion, of which 50% of the patients had received antithrombotic therapy. Furthermore, 2.8% of the patients required a conversion to a TUR-P due to bleeding complications. Due to the retrospective analysis, the validity of the postoperative reoperation rate is only limited. In 3.3% of the patients, a medical therapy and in 1.5% of the patients, a surgical reoperation due to a recurrent obstruction was required during 5-year follow-up. A recently published case series of 370 patients with an average PV of 79 ml reported a significant improvement of all functional parameters with a reoperation rate due to bladder neck stenosis of 1.6% and adenoma recurrence of 1%. However, after 5 years, only data from 69 patients were available (Ajib et al. 2018). The efficacy of PVP in patients with a PV >100 ml was

also investigated in case series. In a multicenter study, the results of 55 patients with a PV of 100 to 199 ml were compared with those of 33 patients with a PV greater than 200 ml (Valdivieso et al. 2018). Data are available up to 3 years postoperatively and show a comparable reoperation rate of 9% and 5%. However, for large PV, the operation time of more than 2 hours on average and the need to use several laser fibers are potential limitations. 15.2.6  Impact of PVP on Sexual

Function and EjaculationPreserving Techniques

Data from meta-analyses show no significant difference between PVP and TUR-P regarding the postoperative course of the IIEF. In contrast, a study with the 80-W laser showed that in patients with a preoperative IIEF of more than 19, i.e. a sufficient erectile function, postoperatively a significant reduction occurred during 2-year follow-up (Bruyere et al. 2010). To reduce the rate of retrograde ejaculation, technical modifications of PVP were developed. These modifications include sparing the tissue in the area of the verumontanum, the apical portions and the prostate tissue lateral to the verumontanum. In a RCT, 49 patients were assigned to a standard PVP or an ejaculation-preserving PVP (Abolazm 2020). The primary endpoint of the study was the preservation of antegrade ejaculation 1  year postoperatively. Antegrade ejaculation was reported in 85% after ejaculation-preserving and 31.6% after standard PVP. Regarding the functional results, a significant improvement was observed after one year in all relevant parameters. Also in the postoperative urodynamic evaluation, a comparable reduction of the bladder outlet obstruction index was observed. Three patients each had to be operated again due to a recurrent obstruction

149 Ablative Procedures—Vaporization: Bipolar and Photoselective …

by adenoma or a bladder neck stenosis after one year. In another study, 27 patients were randomized and assigned to either an ejaculation-preserving PVP or an ejaculation-preserving plasma vaporization (Kini 2020). The primary endpoint of this study was also the preservation of ejaculation after 6 months. The rate of ejaculation preservation was 85% for ejaculation-preserving PVP and 78% for ejaculation-preserving TUVP. Furthermore, there were no significant differences between the two groups regarding the improvement of the micturition parameters. > In summary, ejaculation-preserving techniques of PVP seem to have no negative impact on the functional results in the early postoperative course, while they are associated with a preservation of antegrade ejaculation of 85%.

References Abolazm AE, El-Hefnawy AS, Laymon M, ShehabEl-Din AB, Elshal AM (2020) Ejaculatory hood sparing versus standard laser photoselective vaporization of the prostate: sexual and urodynamic assessment through a double blinded, randomized trial. J Urol 203(4):792–801 Ajib K, Mansour M, Zanaty M, Alnazari M, Hueber PA, Meskawi M, Valdivieso R, Tholomier C, Pradere B, Misrai V, Elterman D, Zorn KC (2018) Photoselective vaporization of the prostate with the 180-w xps-greenlight laser: five-year experience of safety, efficiency, and functional outcomes. Can Urol Assoc J 12(7):E318–E324 Al-Ansari A, Younes N, Sampige VP, Al-Rumaihi K, Ghafouri A, Gul T, Shokeir AA (2010) Greenlight HPS 120-W laser vaporization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia: a randomized clinical trial with midterm follow-up. Eur Urol 58(3):349– 355 Bruyere F, Puichaud A, Pereira H, Faivre d’Arcier B, Rouanet A, Floc’h AP, Bodin T, Brichart N (2010) Influence of photoselective vaporization of the prostate on sexual function: results of a prospective analysis of 149 patients with long-term follow-up. Eur Urol 58(2):207–211

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Capitan C, Blazquez C, Martin MD, Hernandez V, de la Pena E, Llorente C (2011) Greenlight HPS 120-W laser vaporization versus transurethral resection of the prostate for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: a randomized clinical trial with 2-year follow-up. Eur Urol 60(4):734–739 Cornu JN, Ahyai S, Bachmann A, de la Rosette J, Gilling P, Gratzke C, McVary K, Novara G, Woo H, Madersbacher S (2015) A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol 67(6):1066–1096 Elmansy H, Baazeem A, Kotb A, Badawy H, Riad E, Emran A, Elhilali M (2012) Holmium laser enucleation versus photoselective vaporization for prostatic adenoma greater than 60 ml: preliminary results of a prospective, randomized clinical trial. J Urol 188(1):216–221 Ghobrial FK, Shoma A, Elshal AM (2020) A randomized trial comparing bipolar transurethral vaporization of the prostate with greenlight laser (xps-180watt) photoselective vaporization of the prostate for treatment of small to moderate benign prostatic obstruction: outcomes after 2 years. BJU Int 125(1):144–152 Jackson RE, Casanova NF, Wallner LP, Dunn RL, Hedgepeth RC, Faerber GJ, Wei JT (2013) Risk factors for delayed hematuria following photoselective vaporization of the prostate. J Urol 190(3):903–908 Kini M, Alexis TE, Kashanian JA, Kaplan S, Chughtai B (2020) Ejaculatory hood-sparing photoselective vaporization of the prostate vs bipolar button plasma vaporization of the prostate in the surgical management of benign prostatic hyperplasia. J Endourol 34(3):322–329 Knapp GL, Chalasani V, Woo HH (2017) Perioperative adverse events in patients on continued anticoagulation undergoing photoselective vaporisation of the prostate with the 180-W greenlight lithium triborate laser. BJU Int 119(Supplement 5):33–38 Lai S, Peng P, Diao T, Hou H, Wang X, Zhang W, Liu M, Zhang Y, Seery S, Wang J (2019) Comparison of photoselective green light laser vaporisation versus traditional transurethral resection for benign prostate hyperplasia: an updated systematic review and meta-analysis of randomised controlled trials and prospective studies. BMJ Open 9(8):e028855. 10.1136/bmjopen-2018-028855. PMID: 31439603; PMCID: PMC6707662

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Tholomier C, Nguyen DD, Sadri I, Couture F, Zakaria AS, Bouhadana D, Bruyère F, Cash H, Reimann M, Cindolo L, Ferrari G, Vasquez-Lastra C, Borelli-Bovo TJ, Becher EF, Misrai V, Elterman D, Bhojani N, Zorn KC (2021) Global Greenlight Group: largest international Greenlight experience for benign prostatic hyperplasia to assess efficacy and safety. World J Urol 39(12):4389–4395. 10.1007/s00345-021-03688-4. Epub 2021 Apr 10. PMID: 33837819 Lee SW, Choi JB, Lee KS, Kim TH, Son H, Jung TY, Oh SJ, Jeong HJ, Bae JH, Lee YS, Kim JC (2013) Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and meta-analysis. Int Neurourol J 17(2):59–66 Lee DJ, Rieken M, Halpern J, Zhao F, Pueschel H, Chughtai B, Kaplan SA, Lee RK, Bachmann A, Te AE (2016) laser vaporization of the prostate with the 180-W XPS-greenlight laser in patients with ongoing platelet aggregation inhibition and oral anticoagulation. Urology 91:167–173 Pereira-Correia JA, de Moraes Sousa KD, Santos JB, de Morais Perpetuo D, Lopes-da-Silva LF, Krambeck RL, Muller VJ, Vaz FP (2012) Greenlight HPS 120-W laser vaporization vs transurethral resection of the prostate ( For patients with a PV of 50– 80 ml, the aquablation arm of the study showed a significant advantage of 3.5 points in the IPSS reduction at the 3-year follow-up. The PSA-reduction was about 24% after aquablation and 33% after TUR-P. These values are lower for both aquablation and the TUR-P than the reported reduction of about 50–60% after TUR-P in comparable literature.

z WATER-II Study: Patients with PV >80 ml

For patients with larger PV, the 2-year data of the WATER-II study have been published so far (Desai et al. 2020). WATER-II is a prospective multicenter cohort study conducted in the USA and Canada. Men between 45 and 80 years of age with a PV between 80 and 150 ml, an IPSS ≥ 12 and a previous unsuccessful medical therapy were included. The average IPSS improved from 23.2 points to 5.8 points after 2 years. Furthermore, the 2-year IPSS values were independent of the baseline values and the prostate size. QoL dropped from 4.6 to 1.1 points after 2 years. Qmax improved from 8.7 to 18.2 ml/s and PVR decreased from 131 ml to 45 ml. Regarding the PSA-reduction, a decrease from 7.1 µg/l to 4.9 µg/l was observed, corresponding to a reduction of 38%. The functional results of aquablation could also be confirmed in a French cohort study (Misrai et al. 2019) and in a German cohort study (Bach et al. 2019). Comparing

. Table 16.1  Functional results of the WATER study after 3 years (Gilling et al. 2020) Baseline value

Change after 3 years

p-value

Mean (standard deviation)

Aquablation (n = 117)

TUR-P (n = 67)

Aquablation (n = 97)

TUR-P (n = 55)

IPSS

22.9 (6.0)

22.2 (6.1)

−14.4 (6.8)

−13.9 (8.6)

0.68

PVR (ml)

97 (79)

1123)

−52 (163)

−53 (224)

0.98

Qmax (ml/ sec)

9.4 (3.0)

9.1 (2.7)

11.6 (14)

8.2 (8)

0.84

PSA (µg/L)

3.7 (3.0)

3.3 (2.3)

−0.9

−1.1

0.59

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the data of the WATER and WATER-II study, a significantly longer resection time is found in the WATER-II study (8 min vs. 3.9 min) (Nguyen et al. 2020). The operation time is also longer with 37.4 min than in the group of patients with smaller PV (32.8 min). Furthermore, the catheterization time of the WATER-II study is significantly longer than in the WATER study (3.9 vs. 2 days). The hospitalization time is also significantly longer than in the WATER study (1.6 vs. 1.4 days). Regarding the functional results, there are no significant differences in the reduction of IPSS and the improvement of Qmax and PVR. In a subgroup analysis of the WATER study, the urodynamic efficacy of aquablation was also investigated and compared with TUR-P (Pimentel et al. 2019). 6  months postoperatively, the pdet at Qmax decreased by 35 and 34 cm H2O after aquablation and TUR-P, respectively. The proportion of patients who were classified as deobstructed based on a urodynamic examination was comparable between both groups. Regarding the influence on sexual function, the WATER study shows a reduction of the IIEF-5 in 33% of the patients after aquablation compared to 56% after TUR-P (Gilling et al. 2017). Furthermore, the IIEF-15 values in sexually active men were unchanged in the aquablation arm, but showed a reduction in the TUR-P arm. These results are confirmed by other cohort studies, which also showed no significant change in erectile function after aquablation. Another relevant aspect of the technique is the postulated preservation of antegradeejaculation. In the WATER study, a preservation of antegrade ejaculation was observed in 90% of the patients (Gilling et al. 2017). The ejaculatory function according to MSHQ-EjD was unchanged after aquablation while a significant deterioration occurred after TUR-P. In the French cohort study, an antegrade ejaculation was

observed in 73.3% of the patients after 1 year (Misrai et al. 2019). ► Conclusion 5 Aquablation achieves a significant improvement in micturition symptoms and objective micturition parameters. 5 The improvement of the symptoms seems to be independent of PVs ranging from 30 to 150 ml. 5 The significantly higher rate of preservation of antegrade ejaculation compared to other techniques, as well as the lack of negative impact on erectile function, makes aquablation an attractive alternative, especially for men who wish to preserve their sexual function. 5 However, the results of RCTs comparing other techniques such as laser vaporization of the prostate or endoscopic enucleation of the prostate, as well as longterm data, are still lacking. ◄

In addition, the available data from the WATER and WATER-II studies are manufacturer-funded studies. Regarding the learning curve, there are currently no sufficient studies, but based on the available data, a short learning curve of a few procedures is postulated (Sadri et al. 2020). 16.3  Peri- and Postoperative

Safety

With regard to the perioperative safety, hemostasis is of particular interest in aquablation, as there have been relevant adjustments in this context since the initial presentation of the technique. In aquablation, hemostasis is performed after tissue ablation using various techniques. z Bleeding Complications

Since in the early phase of the implementation of this technique hemostasis was not

155 Ablative Procedures—Robotics

standardized, relatively high rates of bleeding complications were found. In the WATER study, a significantly higher hemoglobin drop than after TUR-P was found. However, the transfusion rate for aquablation was 0.9% (Gilling et al. 2017). In this study, hemostasis was achieved by means of cautery (40%) or balloon tamponade in the prostatic fossa (60%). In contrast, in the WATER-II study, a rate of bleeding complications of 9.9% and of transfusions of 5.9% was observed (Desai et al. 2019). This high rate of bleeding complications in the WATER-II study can be explained by on the one hand by larger prostate volumes (80–150 ml), and on the other hand by the hemostasis performed exclusively by means of traction of the catheter balloon at the bladder neck (97%) or by means of balloon tamponade of the prostatic fossa (3%). Thus, the exclusive use of athermal hemostasis in this study seems to be the reason for the significantly higher rate of bleeding complications. The manufacturer of the technique also recommended initially a specific, so-called catheter tensioning device (CTD) for permanent traction on the catheter. Based on the transfusion rate of 9.9% in the WATER-II study, the manufacturer has recommended since the end of 2019 to perform a focal resection and coagulation of the bladder neck after aquablation. The CTD has not been commercially distributed since 2019. In a recently published cohort study of 2089 patients with an average prostate volume of 87 ml, a postoperative transfusion rate of 0.8% and an operative revision rate due to bleeding of 0.6% were shown (Elterman et al. 2021). This value is significantly lower than the previously published rate of 3.9% (Elterman et al. 2020). Thus, in this context, the resection of ablated tissue in the area of the bladder neck with consecutive coagulation seems to have significantly reduced the rate of perioperative bleeding complications.

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z Other Complications

With regard to other complications, aquablation seems to be comparable to other surgical techniques. In the WATER study, aquablation had fewer persistent grade I and ≥ grade II events after 3 months than the TUR-P arm (26% versus 42%). The biggest difference between the two groups after 3 months was the rate of retrograde ejaculation (Gilling et al. 2017). Over the course of 3 years, there was no significant difference between the two arms in the WATER study regarding the occurrence of complications (Gilling et  al. 2020). The rate of retrograde ejaculation was still significantly lower in the aquablation group than after TUR-P (11% vs. 29%). Likewise, there was no significant difference in the rate of urethral strictures after aquablation and TUR-P (0% vs. 1.5%). The reoperation rate was 4.3% after aquablation and 1.5% after TUR-P. In the WATER II study, 2% of patients required a reoperation due to BPO recurrence (Desai et al. 2020). In the French cohort study, a rate of Clavien-Dindo grade II and III complications of 13.3% each was shown (Misrai et al. 2019). Regarding the onset of stress urinary incontinence, in the WATER II study 2% of the patients showed a persistent incontinence for more than 1 year. When comparing the data of the WATER and WATER-II study, the risk of complications, especially of Clavien-Dindo grade 3 and 4, increases with larger prostate volume (. Table 16.2), whereby this refers in particular to the higher bleeding complications in the WATER-II study (Nguyen et al. 2020). ► Conclusion 5 In summary, aquablation therapy seems to be an alternative to TUR-P for PV between 30 and 80 ml at the present time. The data from the methodologically high-quality WATER-I study confirm this.

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. Table 16.2  Complications according to WATER (30–80 ml) and WATER II (80–150 ml), by Clavien-Dindo grade within the first 210 days (Nguyen et al. 2020) Clavien-Dindo grade

WATER

WATER II

Affected patients (%)

Affected patients (%)

p-value

I (non-persistent)

47 (4.5)

33 (32.7)

0.77

I (persistent*)

7 (6)

18 (17.8)

0.003

II

20 (17.2)

22 (21.8)

0.14

III

6 (5.2)

13 (12.9)

0.02

IV

1 (0.9)

5 (5)

0.05

* The complications mentioned here are: anejaculation, erectile dysfunction, persistent incontinence, which requires wearing a pad

5 The WATER-II data also confirm sufficient efficacy for PV up to 150 ml. 5 Nevertheless, aquablation and the literature should not be viewed uncritically. There are hardly any independent studies or studies in which at least one author does not declare a conflict of interest with the product manufacturer. 5 Furthermore, although there is a high number of publications for this new procedure, in fact the majority of publications is based directly or indirectly (including pooled analyses) on the WATER-I and WATER-II study. 5 The number of clinical case series, on the other hand, is still limited. ◄

16.4  High Risk Patients

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One limitation is that the procedure is not approved for use under continued anticoagulant therapy. High risk patients cannot be treated with the technique. Other procedures with expertise must be available, especially for large Pas (>250 ml). Furthermore, there is currently no consensus on the type of optimal coagulation. Independent publications on the learning curve of aquablation are not available. In the WATER-I and -II study, the procedures were accompanied by proctors. Independent long-term data from patients with

large PV are pending. Another aspect concerns the costs of the procedure. The costs for the single-use handpiece are over 1000 € per procedure. With an additional intraoperative use of a laser technology (e.g. Greenlight) for hemostasis or laser vaporization or laser enucleation, the costs increase even more.

References Bach T, Giannakis I, Bachmann A, Fiori C, Gomez-Sancha F, Herrmann TRW, Netsch C, Rieken M, Scoffone CM, Tunc L, Rassweiler JJ, Liatsikos E (2019) Aquablation of the prostate: single-center results of a non-selected, consecutive patient cohort. World J Urol 37(7):1369–1375 Desai M, Bidair M, Bhojani N, Trainer A, Arther A, Kramolowsky E, Doumanian L, Elterman D, Kaufman RP Jr, Lingeman J, Krambeck A, Eure G, Badlani G, Plante M, Uchio E, Gin G, Goldenberg L, Paterson R, So A, Humphreys M, Roehrborn C, Kaplan S, Motola J, Zorn KC (2019) WATER II (80–150 mL) procedural outcomes. BJU Int 123(1):106–112 Desai M, Bidair M, Bhojani N, Trainer A, Arther A, Kramolowsky E, Doumanian L, Elterman D, Kaufman RP Jr, Lingeman J, Krambeck A, Eure G, Badlani G, Plante M, Uchio E, Gin G, Goldenberg L, Paterson R, So A, Humphreys MR, Roehrborn CG, Kaplan S, Motola J, Zorn KC (2020) Aquablation for benign prostatic hyperplasia in large prostates (80–150 cc): 2-year results. Can J Urol 27(2):10147–10153

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Elterman D, Bach T, Rijo E, Misrai V, Anderson P, Zorn KC, Bhojani N, El Hajj A, Chughtai B, Desai M (2020) Transfusion rates after 800 aquablation procedures using various haemostasis methods. BJU Int 125(4):568–572 Elterman DS, Foller S, Ubrig B, Kugler A, Misrai V, Porreca A, Abt D, Zorn KC, Bhojani N, Kriteman L, Mehan R, McDonald M, Kaplan SA (2021) Focal bladder neck cautery associated with low rate of post-Aquablation bleeding. Can J Urol 28(2):10610–10613 Gilling P, Anderson P, Tan A (2017) Aquablation of the prostate for symptomatic benign prostatic hyperplasia: 1-year results. J Urol 197(6):1565– 1572 Gilling P, Barber N, Bidair M, Anderson P, Sutton M, Aho T, Kramolowsky E, Thomas A, Cowan B, Kaufman RP Jr, Trainer A, Arther A, Badlani G, Plante M, Desai M, Doumanian L, Te AE, DeGuenther M, Roehrborn C (2020) Three-year outcomes after aquablation therapy compared to TUR-P: results from a blinded randomized trial. Can J Urol 27(1):10072–10079 Gilling P, Reuther R, Kahokehr A, Fraundorfer M (2016) Aquablation—image-guided robot-assisted waterjet ablation of the prostate: initial clinical experience. BJU Int 117(6):923–929

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Misrai V, Rijo E, Zorn KC, Barry-Delongchamps N, Descazeaud A (2019) Waterjet ablation therapy for treating benign prostatic obstruction in patients with small- to medium-size glands: 12-month results of the first french aquablation clinical registry. Eur Urol 76(5):667–675 Nguyen DD, Barber N, Bidair M, Gilling P, Anderson P, Zorn KC, Badlani G, Humphreys M, Kaplan S, Kaufman R, So A, Paterson R, Goldenberg L, Elterman D, Desai M, Lingeman J, Roehrborn C, Bhojani N (2020) Waterjet Ablation Therapy for Endoscopic Resection of prostate tissue trial (WATER) vs WATER II: comparing aquablation therapy for benign prostatic hyperplasia in 30–80 and 80–150 mL prostates. BJU Int 125(1):112–122 Pimentel MA, Yassaie O, Gilling P (2019) Urodynamic outcomes after aquablation. Urology 126:165–170 Sadri I, Arezki A, Couture F, Nguyen DD, Schwartz R, Zakaria AS, Elterman D, Rijo E, Misrai V, Bach T, Roehrborn CG, Zorn KC (Jul 2021) Reasons to overthrow TURP: bring on Aquablation. World J Urol 39(7):2291–2299.10.1007/s00345020-03390-x. Epub 2020 Aug 1. PMID: 32740805

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Non-Ablative Procedures New Techniques Malte Rieken Contents 17.1 Urolift® – 160 17.2  Rezum® – 162 17.3  iTind® – 164 17.4  Prostatic Arterial Embolization (PAE) – 166 References – 167

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_17

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17.1  Urolift®

The “prostatic urethral lift” system (PUL, Urolift®) is a minimally-invasive procedure for the treatment of symptomatic prostate enlargement. The principle of action of the Urolift® system is based on creating an anterior channel within the prostatic urethra from the bladder neck to the colliculus with the aim of reducing the bladder outlet obstruction. For this purpose, the anterior portions of the prostatic lateral lobes are compressed by means of mechanically applied implants. The first case series was published in 2011 (Woo et al. 2011). Data from a prospective randomized study comparing Urolift® with a sham procedure (Roehrborn et al. 2017), a prospective randomized study comparing Urolift® with TURP (Gratzke et al. 2017) and data from numerous cohort studies are available. 17.1.1  Procedure and Mechanism

of Action

17

The Urolift® system consists of 2 essential components: the Urolift®-delivery device and the permanent Urolift®-implant. The implant in turn consists of a capsular Nitinol anchor (0.6 mm), an adjustable, non-resorbable monofilament PET thread of 0.4 mm diameter and a luminal anchor made of surgical steel (Westhofen et al. 2018). Each delivery device is only loaded with one Urolift®-implant. This means that for multiple implants, a corresponding number of delivery devices are used one after the other. The delivery device is compatible with a standard endoscope and is inserted through a 20-French cystoscope. After activating the trigger mechanism, a curved 19-G needle is executed, which passes through the prostate tissue to the outer wall of the prostatic capsule. At the end of this hollow needle, the capsular Nitinol anchor is located. By activating the

trigger again, the needle is completely retracted, while the Nitinol anchor is placed on the outside of the capsule. The suture is thus put under tension. Finally, by pressing a head on the delivery device, the suture is tightened, the luminal anchor made of surgical steel is fixed and at the same time the suture is shortened to the appropriate length. The procedure is basically possible as an outpatient procedure and under local anesthesia, but in many studies sedation or general anesthesia was used. Under cystoscopic control, the implants are inserted anterolaterally between 10 o’clock and 2 o’clock in lithotomy position using the delivery device. This positioning of the implants is intended to ensure optimal protection of the venous plexus and the neurovascular bundle. The placement of the first implant of each lateral lobe of the prostate should be about 1.5 cm distally to the bladder neck. It is important that not too much pressure is exerted on the prostate tissue when applying the implants, in order to avoid accidental injury to the pubic bone. Another implant is inserted immediately anterior to the colliculus. Depending on the prostate size and the extent of the created anterior channel, it may be necessary to place additional implants. > In most cases, no postoperative catheterization is required. With regard to the ideal patient selection, a prostate volume (PV) up to 80 ml seems possible. Patients with larger prostate volumes and prominent median lobes were excluded from the initial clinical studies.

17.1.2  Functional Results

The longest available follow-up exists from a prospective multicenter double-blind randomized trial, the LIFT trial, in which 140 patients Urolift® received and 66 pa-

161 Non-Ablative Procedures

tients a sham procedure (only cystoscopy) (Roehrborn et al. 2017). The inclusion criteria of this study were, among others, an IPSS > 12, a PV of 30–80 ml and a maximum urinary flow rate ≤ 12  ml/s. After 5 years, there was a significant improvement in IPSS from 22.3 to 14.5, an improvement in QoL from 4.6 to 2.5 and an improvement in Qmax from 7.9 to 11.4 ml/s. However, a moderate decrease in IPSS improvement was observed during the 5-year follow-up period. Furthermore, a slight decrease in MSHQ-EjD bother scores was reported, but there was no de novo ejaculatory or erectile dysfunction. z BPH-6 Study

In the so-called BPH-6 study, 80 patients with a PV up to 60 ml, an IPSS > 12 and a Qmax of less than 15 ml/s were randomized 1:1 to Urolift® or TUR-P. The primary endpoint of this study was a newly created endpoint, which consists of 6 validated instruments and allows an evaluation of the health status at the 1-year follow-up: IPSS, Sexual Health Inventory for Men (SHIM), Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD), Incontinence Severity Index (ISI), Quality of Recovery visual analogue score (QoR VAS) and the Clavien-Dindo classification of complications. The study was designed as a non-inferiority trial of Urolift® versus TUR-P. In the analysis of the primary endpoint after one year, it was shown that with regard to the BPH 6 endpoint Urolift® was not only non inferior, but superior to TUR-P (Sønksen et al. 2015). The reduction in IPSS after 12 months was 11.4 points after Urolift® compared to 15.4 points after TUR-P, which was a significant difference. Furthermore, after 12 months, there was a significantly higher reduction in post-void residual urine (PVR) and a significantly stronger improvement in Qmax after TUR-P (Sønksen et al. 2015). After 2 years, there was an

17

average reduction in IPSS of 9.2 points after Urolift®, compared to 15.3 points after TUR-P (P = 0.004). Also, Qmax was significantly more improved after TUR-P with 15.8 ml/s than after Urolift® with 5.0 ml/s (Gratzke et al. 2017). z Further Meta-Analysis

A recently published meta-analysis includes, in addition to the two above-mentioned prospective randomized trials (RCT), 3  cohort studies (Tanneru et  al. 2020). At 24 month follow-up, data from 322 patients were available. The mean reduction in IPSS was 10.4 points in the cohort studies, the average improvement in Qmax was 3 ml/s and the improvement in QoL was 2.2 points. The application of Urolift® outside the strict inclusion criteria of RCTs was investigated in a prospective study of 5 centers in Germany, which included 86 patients with the indication for TUR-P. Of these, 33 patients showed severe obstruction, which was defined as urinary retention, high PVR or pronounced prostate enlargement. In this study, there was a significant improvement in IPSS (51%), QoL (52%), PVR (70%) and Qmax (27%), which remained stable over a 2-year follow-up. From this cohort, 11 patients (12.8%) needed a reoperation due to persistent LUTS (Sievert et al. 2019). 17.1.3  Peri- and Postoperative

Safety

In the 5-year data of the LIFT study comparing Urolift® with a sham procedure, 13 patients required removal of implants that dislocated into the bladder. Furthermore, the reoperation rate was 13.6%. Most adverse effects were limited to the first 3 months and consisted of mild to moderate dysuria or hematuria. More severe complications within the first year included, among others, a bladder tampon-

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ade as a result of starting oral anticoagulation therapy (Roehrborn et al. 2017). > In the BPH-6 study, Urolift® was significantly superior to TUR-P in terms of postoperative convalescence. Regarding postoperative complications, there were significant differences in favor of Urolift® compared to TUR-P in terms of urinary incontinence (2% vs. 17%) and retrograde ejaculation (0% vs. 20%) (Sønksen et al. 2015).

The superiority in preserving ejaculatory function could also be confirmed by validated questionnaires. During 2 year follow-up, 6 patients (13.6%) after Urolift® and 2 patients after TUR-P (5.7%) underwent further therapy due to the recurrence of LUTS. Regarding the spectrum of reoperations, these consisted of the application of an additional Urolift®, intravesical Botox administration, laser therapy of the prostate, and a TUR-P. One patient after Urolift® had to undergo removal of the implant, as it was placed too far proximally and thus led to repeated macrohematuria (Gratzke et al. 2017). Regarding the sexual function, a recently published meta-analysis also showed no patients who reported de novo retrograde ejaculation (Tanneru et al. 2020). The reoperation rate in this analysis was 2–3% per year. In the German cohort study, 11 patients (12.8%) needed a reoperation after 2 years due to persistent LUTS (Sievert et al. 2019).

17

17.2  Rezum®

Rezum® is a minimally-invasive therapy for the treatment of symptomatic prostate enlargement. By injecting water vapor into the prostate tissue, a secondary ablation of the tissue is achieved. Currently, data from a prospective randomized study (with a sham procedure as control arm) with a 5

year follow-up (McVary et al. 2021) and cohort studies are available. 17.2.1  Procedure and Mechanism

of Action

The mechanism of action of Rezum® is based on the thermodynamic properties of water vapor, which induces tissue ablation by means of convective and not conductive heat transfer (Higazy et al. 2021). When the water vapor condenses to water within the adenoma tissue of the prostate, the heat is released to the tissue and leads to necrosis of the cells. The goal of Rezum® is to achieve a focused ablation of the adenoma tissue of the prostate without injuring the urethra or the natural zonal anatomy of the prostate. The main components of the system are a radiofrequency generator, the disposable transurethral applicator with a 30°-optic and 18 G-injection needle, and a saline irrigation. The function of the radiofrequency generator is to convert sterile water into vapor and to control the amount of energy that is applied to the target tissue (Doppalapudi and Gupta 2021). The transurethral applicator allows the surgeon to apply the injection needle under vision into the lateral lobes of the prostate. The needle contains of 12 holes, which are located circumferentially at a distance of 120° and thus should allow an adequate distribution of the water vapor through the adenoma tissue. With the injection needle, the water vapor is applied at a fixed depth of about 10 mm for 9 s. The saline irrigation is used to maintain a good vision during the operation and to cool the prostatic urethra between the vapor applications. The procedure is performed in lithotomy position (LP) and is basically possible in local anesthesia with a prostate block. However, most cases are performed under sedation. After inserting the applicator and

163 Non-Ablative Procedures

measuring the distance between the bladder neck and the verumontanum, water vapor is applied starting from 1 cm distally to the bladder neck at 3 o’clock and 9 o’clock at a distance of about 1 cm along the prostatic urethra into the lateral lobes. Each injection applies 0.5 ml of water vapor with a temperature of 103° and increases the temperature of the tissue to 70°. After each injection, the needle should remain in the tissue for a few seconds after the water vapor application has ended to prevent the escape of the water vapor at the puncture site. After each injection, the needle is withdrawn and 1 cm further distal to the previous injection site inserted again into the tissue. The procedure can also be adapted to patients with a large median lobe, where the water vapor is applied laterally into the median lobe at a 45° angle. The maximum amount of water vapor applications is limited to 15 applications. After therapy, a transurethral catheter is inserted, which is removed in most cases after 3–5 days depending on the prostate size and the number of water vapor applications. If a preoperative drug therapy for the LUTS exists, it should be discontinued 3–4 weeks after the procedure (Higazy et al. 2021). Since this form of therapy leads to necrosis of the tissue, a secondary ablation of the tissue and an improvement of the LUTS occur. In MRI-based studies, a PV reduction of about 26–33% was observed after 4 months.

17

apy with Rezum® in the sense of a crossover group. For this reason, the study design is often criticized for not being a randomized trial, but rather a cohort study. Over 5 year follow-up, the IPSS showed a significant reduction from 22.0 to 11.1 points, the QoL improved from 4.4  to 2.2  and the Qmax improved from 9.9 to 14.0 ml/s (McVary et al. 2021). In a recent review article, which summarizes the results after Rezum® in the currently available cohort studies, a postoperative improvement of IPSS between 39 and 78%, an improvement of QoL between 37% and 73%, an improvement of Qmax between 28.7% and 51.4% and a reduction of PVR between 17% and 51.1% were shown (Higazy et al. 2021). In a recently published case series, the data of 36 men with a PV ≥80 ml (average PV 107 ml) after therapy with Rezum® were analyzed and compared with patients with a PV The initiation of therapy begins with a value of more than seven and a corresponding level of suffering.

As a relative indication, one can acknowledge if the patient’s quality of life is compromised by the symptoms of a BPS. These include pollakisuria, multiple nocturia (if perceived as disturbing) and urinary urgency with or without urinary incontinence. For patients who either do not tolerate or refuse medication, one may possibly talk directly about surgery or intervention. > A prophylactic surgery is nonsense. Nevertheless, it is often asked for, because one is worried that a few years later one may not be fit enough for a procedure. However, one should not be tempted by such requests.

z AUA-Symptom Score

19

If there is no absolute indication, one can objectify the symptoms of the patients without much effort by using questionnaires or scores. The most commonly used score is the International Prostate Symptom Score (IPSS). It comprises eight questions, of which seven are about symptoms and one is about the quality of life of the patients. Since the score was originally presented by the American Urological Association, it is also referred to as the “AUA-Symptom Score”. The seven questions about the symptoms deal with residual urine sensation, repeated urinary urgency two hours after the last toilet visit, urinary hesitancy, inability to delay urination, weak stream, straining during urination and nocturia.

Since the questions are simple and easy to understand, the questionnaire can be filled out by most patients themselves and helps the doctor to make a first assessment of the situation (. Fig. 19.1). One can also use the IPSS well in the course of the treatment to evaluate the effectiveness of a initiated therapy. The questionnaire is neither intended nor suitable for screening. Actually, one would expect that with increasing symptoms the patient’s desire for surgery becomes stronger and stronger. And there are studies supporting this (McConnell et al. 1994). However, there are also good arguments against this linear approach: 5 The degree of obstruction and the symptoms do not correlate with each other 5 The size of the gland does not correlate with the degree of symptoms 5 The response to therapy does not correlate with the degree of symptoms z Early versus Delayed Surgical Intervention

The question of an early versus a delayed surgical intervention can be very controversially discussed. An argument for an early intervention is the rapid and objective success of a procedure (. Fig. 19.2). A delay could lead to deterioration and permanent damage. And a drug therapy also has side effects and is not necessarily cost-effective, especially not if surgery is eventually required. The volume reduction illustrated in the Figure assumes that this step is accompanied by a linear improvement of the

19

183 Patient Selection

Rarely Less Dangerous than in frequently in half of cincm of than in half the five cases of the cases cases

Never How often have you felt that your bladder was not completely empty after urinating?

0

How many times did you have to urinate a second time within 2 hours?

In more than half of all cases

Almost always

4

5

1

2

3

0

1

2

3

4

5

How often have you had to stop and start again several times when urinating (urinary stuttering)?

0

1

2

3

4

5

How often have you had difficulty delaying urination?

0

1

2

3

4

5

How often have you had a weak stream when urinating?

0

1

2

3

4

5

How often did you have to push or strain to start urinating?

0

1

2

3

4

5

On average, how many times did you get up at night to urinate?

Never 0

Once 1

Twice 2

Three times 3 Four times 4 times or more 5

. Fig. 19.1  International Prostate Symptom Score

No BOO

borderline

BOO

Prostate volume -TRUS (cm3) (number of paents)

. Fig. 19.2  Bladder outlet obstruction compared to prostate volume

184

A. J. Gross

symptoms, which cannot be concluded easily. An argument against an early intervention is that one has not tried the possible success of a change in lifestyle or low-sideeffect drugs. For the surgical success, a delayed procedure or a previous drug therapy is not decisive. And the morbidity is probably much higher with surgery than with drug treatment (Fogaing et al. 2021). Due to the increasing use of drugs, the number of surgeries in this century has accordingly decreased significantly. Nevertheless, the ideal timing for surgery or intervention remains unclear. Interestingly, there is only sparse literature with regard to this topic. Very vaguely, one can say that patients with larger, higher PSA value—after excluding PCa—and a worse IPSS benefit more from an earlier intervention (Presicce et al. 2018). > However, it has been repeatedly proven that a higher prostate volume does not automatically have to be associated with a bladder outlet obstruction (. Fig. 19.2 from Oelke et  al. 2019) (Kang et  al. 2016).

. Fig. 19.2 shows that almost 20% of the patients with a PV of >80 cm3 have no or only a borderline bladder outlet obstruction. Younger patients in the age group of 41 to 50 years with LUTS have only a low percentage of BPH (ca. 5%). Also in the next age group of 51–60 years, this rate is still only 8%, which then increases significantly to 27% (Sundaram et al. 2017). Therefore, an indication for an intervention in the age group under 60 years should be made with caution. > The size of the gland seems to play a role for the postoperative outcome. Thus, patients with small prostate volumes have worse urodynamic values and a higher rate of postoperative complications (Singh et al. 2017). Therefore, certain procedures are quite reasonable when dealing with a prostate that is rather small, because it is not so much about volume reduction but eliminating the obstruction (. Fig. 19.3).

Volume reduction extraanatomical techniques gradual removal of the transitional zone

0

20

ITIND

Greenlight PVP

40

Aquaablation Urolift

60

80

HoLEP ThuLEP ThuVEP

Embol

19

Enucleation anatomical techniques complete removal of the transitional zone

REZUM

BipolEP GreenLEP

. Fig. 19.3  Impact of different interventions/operations on prostate volume

100

19

185 Patient Selection

19.2.1  Age

The aging process plays a significant role in BPH in many respects. On the one hand, aging has a considerable influence on the neuro-physiological processes not only in the whole body, but also in the lower urinary tract. Many things are not yet understood here. In addition, there is the aging process of the anatomical structures: BPH of the prostate on the one hand and M. Detrusor vesicae on the other hand. The fact that women also have an increasing nocturia in old age, for example, illustrates this impressively (Bosch and Weiss 2013) (. Fig. 19.4). Therefore, it is reasonable that between 14% and 30% of patients have persistent problems after TUR-P and (still) require medication. It is important to identify this subgroup of patients before the procedure, which may spare them a surgery (Reitz et al. 2019).

19.2.2  Comorbidities

Patients with a BPS belong to a higher age group, who on the one hand often have further medical problems that oppose a urological treatment, and on the other hand have urological problems due to these medical problems. The common non-urological problems include obesity, diabetes and various cardiac preconditions. Here again, medications are used that can compromise a urological intervention. Anticoagulants are prescribed by doctors for various reasons, but also taken by patients without such a prescription. Even before inserting a suprapubic catheter as the simplest intervention for a bladder outlet obstruction, it is therefore important to ask the patient about the intake of such medication. An urologist alone should not

>1 void/night

>1 void/night

>2 voids/night (or >1)

>2 voids/night (or >1)

>3 voids/night

>3 voids/night

>4 voids/night

>4 voids/night

Definition not stated

Definition not stated

Prevalence (%)

Prevalence (%)

> Age itself is not the relevant criterion to consider an operation. More important is the statistical or the individual life expectancy of the patient. The statistical life expectancy is calculated from the cohort, while the individual—and consequently more realistic—life expectancy takes into account the comorbidities and the biological age of the patient.

A patient with a very limited life expectancy can certainly be permanently provided with a catheter, whereby a suprapubic catheter is preferable to a transurethral catheter (Ringert and Gross 1996; Becker et al. 2018). The contraindications for the insertion of a suprapubic catheter include the intake of anticoagulants, bladder cancer or previous operations in the lower abdomen.

Age (years)

. Fig. 19.4  Nocturia in the course of age in women (left) and men (right)

Age (years)

186

A. J. Gross

decide whether and how long the anticoagulation should be discontinued or bridged. This is especially true for patients with a recent thrombosis with or without embolism, patients with mechanical heart valves, atrial fibrillation or cardiac stents. > The risk of significant bleeding is low for prostate biopsies or laser surgery on the prostate, even if aspirin is continued. Open prostate surgery can also be performed under aspirin with a low risk of bleeding. If necessary, one should bridge with heparin (Culkin et al. 2014).

Unfortunately, no timetable can be derived from the literature for bridging anticoagulants in prostate surgery. In our own cdepartment, the following scheme for discontinuing anticoagulants before a urological procedure has proven successful (. Table 19.1): Marcumar can be paused for seven days without bridging at low risk of thromboem-

bolism. At medium or high risk, Marcumar should be paused for eight to nine days preoperatively. From about five days preoperatively, bridging with Mono-Embolex 8000 IE or Clexane once or twice daily depending on the risk group should be performed. ► Conclusion Transurethral laser  surgery of the prostate under anticoagulation is feasible. However, the complications become more frequent, but not more severe in this subgroup of patients (Netsch et al. 2021; Deuker et al. 2021). ◄

19.2.3  Patient`s Requests

Three areas are regularly questioned before a procedure: 5 Continence 5 Potency 5 Ejaculation

. Table 19.1  Discontinuation of anticoagulation therapy before urological surgery Active ingredient

Kidney function (GFR ml/min)

ASA 100 Dabigatran

Rivaroxaban

Apixaban

19

Edoxaban

Low bleeding risk

High bleeding risk

5 days

7 days

>80

1 day

2 days

>50 to The patient’s request that the problem is solved once and for all by a treatment can hardly ever be fulfilled.

Medications in the field of BPH are usually a long-term medication, whose various side effects are discussed elsewhere. And with regard to surgeries, all relevant consequences have to be discussed in detail with the patient. 19.3.1  Drug Side Effects

The side effects of drugs for BPH are discussed elsewhere. > It is also important to pay attention to which drugs patients take that can either cause urological problems or have to be considered for their side effects in a urological treatment.

z Polymedication

According to information from the Federal Ministry of Education and Research, people between 60 and 64 years of age receive an average of about 2 to 3 different drugs per day. For over 80-year-olds, it is 4 to 5, or more in other statistics (Bundesministerium für Bildung und Forschung (BMBF)). Essentially, these are drugs for cardiovascular diseases. ACE inhibitors and AT1 blockers are the most commonly used drugs. In the second place were anticoagulants. In a publication of the International Consultation of Urological Diseases (ICUD), an attempt was made to capture the management of blood-thinning drugs in urological patients (Culkin et al. 2014). Also frequently used are drugs for hormonal and metabolic disorders, e.g. for lipid disorders, diabetes or thyroid diseases.

188

A. J. Gross

Also cholesterol-lowering drugs are among the very frequently prescribed drugs in the mentioned age group. However, here negative influences on urological problems or interactions with drugs that are prescribed for urological reasons are rare. The same applies to drugs for pain, where non-steroidal anti-inflammatory drugs are particularly frequently used. > Within the neuropsychiatric drugs, antidepressants, sedatives, drugs for memory disorders and drugs for agitation are frequently represented. Drugs from this area, however, often have a significant influence on urological functions.

19.3.2  Consequences of Surgery

Bladder dysfunction can be a consequence of interventions beyond the urological specialty. In this context, mainly neurosurgical and visceral surgical interventions in the small pelvis have to be considered. Damage to the supramotoric neuron as part of spinal cord interventions or interventions on the central nervous system can lead to a relevant bladder dysfunction, which manifests itself in the sense of an urge incontinence with or without involuntary urine loss. Here, in addition to a neurological evaluation, an urodynamic examination is urgently indicated. If the motor neuron itself is damaged in the course of the above-mentioned interventions, it

rather leads to a flaccid bladder emptying disorder, because the detrusor vesicae is no longer innervated properly. The same phenomena occur with damage to the peripheral nerves. 19.4  Individual Therapy

between Expectations and Reality

Besides the medical reasons for a therapy decision, economic reasons also play a role for the selection of the patients or the recommended therapy. One can calculate with relative weights (RW) how the health system rewards the work of a doctor. Here factors such as operation time, professional competence, technical and mental effort, assessment of the overall situation and stress are taken into account. These relative weights should reflect the complexity and the time spent in an appropriate way. In an American study, 27,664 data sets of patients who had been surgically treated for BPS were evaluated. The recommended relative weights were calculated by the responsible commission and compared with the actual assessment (. Table 19.2). Interestingly, with TUR-P an old surgical treatment method remains at the highest level both in terms of recommendation and actual benefit. It is difficult to understand why the technically simpler laser surgery, namely the photovaporisation, is rated much higher than the more demanding hol-

. Table 19.2  Difference between recommended and calculated relative weight of a procedure

19

Operation

Recommended RW

Calculated RW

TUR-P

12.2(100%)

19.1(156% = +56%)

Photovaporisation

12.2(100%)

15.5(127% = +27%)

Suprapubic surgery

9.3(76%)

7.6(81% = −19%)

Retropubic surgery

9(74%)

10.2(113% = +13%)

HoLEP

7.3(60%)

9.4(129% = +29%)

189 Patient Selection

mium laser surgery. Nevertheless, one can deduce from these data why it is tempting to select patients into one or the other group (Da David et al. 2021). ► Conclusion While before the turn of the millennium the decision about one or the other therapy was still strongly in the hands of the urologist, the situation has changed significantly in favor of the patients due to the modern social media (Stoevelaar et al. 1999; Lamers et al. 2020). ◄

References Abedi AR, Ghiasy S, Fallah-Karkan M, Rahavian A (2020 Mar) Allameh F (2020) The management of patients diagnosed with incidental prostate cancer. Res Rep Urol 16(12):105–109 Alloussi SH, Lang C, Eichel R, Alloussi S (2014 Jan) Ejaculation-preserving transurethral resection of prostate and bladder neck: short- and long-term results of a new innovative resection technique. J Endourol 28(1):84–89 Bach T, Wölbling F, Gross AJ, Netsch C, Tauber S, Pottek T, Wülfing C, Brunken C (2017 Feb) Prospective assessment of perioperative course in 2648 patients after surgical treatment of benign prostatic obstruction. World J Urol 35(2):285–292 Bach T, Geavlete B, Pfeiffer D, Wendt-Nordahl G, Michel MS (2009 Jan) Gross AJ (2009) TURP in patients with biopsy-proven prostate cancer: sensitivity for cancer detection. Urology 73(1):100–104 Becker B, Witte M, Gross AJ, Netsch C (2018 Nov) Iatrogenic hypospadias classification: a new way to classify hypospadias caused by long-term catheterization. Int J Urol 25(11):980–981 Becker B, Netsch C, Bozzini G, Herrmann TRW, Bach T, Enikeev D, Gross AJ (2021) Reasons to go for thulium-based anatomical endoscopic  enucleation of the prostate. World J Urol. May 4 Bosch JL, Weiss JP (2013 Jan) The prevalence and causes of nocturia. J Urol 189(1 Suppl):S86-92 Clemens JQ, Markossian T (2009 Apr) Calhoun EA (2009) Comparison of economic impact of chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/painful bladder syndrome. Urology 73(4):743–746 Culkin DJ, Exaire EJ, Grenn D, Soloway MS, Gross AJ, Desai MR, White JR, Lightner DJ (2014 Oct) Anticoagulation and antiplatelet therapy in urological practice: ICUD/AUA review paper. J Urol 192(4):1026–1034

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Da David J, Mitchell H, Kyle AG, Ruslan K, Andrew AW, Jason CH, Nicholas HC (2021) Misaligned incentives in benign prostatic enlargement surgery: more complex and efficacious procedures are earning fewer relative value units. J Endourol Jan 25 Davis SN, Binik YM, Amsel R, Carrier S (2013 Jan) (2013) Is a sexual dysfunction domain important for quality of life in men with urological chronic pelvic pain syndrome? Signs “UPOINT” to yes. J Urol 189(1):146–151 Deuker M, Rührup J, Karakiewicz PI, Welte M, Kluth LA, Banek S, Roos FC, Mandel P, Chun FK (2021 Apr) Becker A (2021) Holmium laser enucleation of the prostate: efficacy, safety and preoperative management in patients presenting with anticoagulation therapy. World J Urol 39(4):1219– 1226 Fogaing C, Alsulihem A, Campeau L, Jacques C (2021 Apr 9) Is early surgical treatment for benign prostatic hyperplasia preferable to prolonged medical therapy: pros and cons. Medicina (Kaunas) 57(4):368 Herden J, Schwarte A, Boedefeld EA, Weissbach L (2021) Active surveillance for incidental (cT1a/b) prostate cancer: long-term outcomes of the prospective noninterventional HAROW study. Urol Int 105(5–6):428–435 Herrmann TR (2016) Enucleation  is  enucleation is enucleation is enucleation. World J Urol. Oct;34(10):1353–1355 Houssin V, Olivier J, Brenier M, Pierache A, Laniado M, Mouton M, Pierre ET, Hervé B, Richard M, Thibault M, Arnauld V, Grégoire R, Jerome R (2021) Predictive factors of urinary incontinence after holmium laser enucleation of the prostate: a multicentric evaluation. World J Urol 39(1):143– 148 Kang M, Kim M, Choo MS, Paick JS (2016 Mar) Oh SJ (2016) Urodynamic features and significant predictors of bladder outlet obstruction in patients with lower urinary tract symptoms/benign prostatic hyperplasia and small prostate volume. Urology 89:96–102 Kutzenberger J, Domurath B, Sauerwein D (2005 Mar) Spastic bladder and spinal cord injury: seventeen years of experience with sacral deafferentation and implantation of an anterior root stimulator. Artif Organs 29(3):239–241 Lamers RED, van der Wijden FC, de Angst IB, de Vries M, Cuypers M, van Melick HHE, de Beij JS, Oerlemans DJAJ, van de Beek K (2020 Mar) Bosch RJLHR, Kil PJM (2020) Treatment preferences of patients with benign prostatic hyperplasia before and after using a web-based decision aid. Urology 137:138–145 Litwin MS, McNaughton-Collins M, Fowler FJ,  Nickel JC, Calhoun EA, Pontari MA, Alexander

190

A. J. Gross

RB, Farrar JT, O’Leary MP (1999) The national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network. J Urol Aug;162(2):369–75 Magistro G, Wagenlehner FM, Grabe M, Weidner W, Stief CG, Nickel JC(2016) Contemporary Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Eur Urol 69(2):286–97 Magistro G, Stief CG, Wagenlehner FME (2020) Chronische prostatitis/chronische Beckenschmerzsyndrom. Urologe A 59(6):739–748 Matanhelia DM, Croghan S, Nason GJ, O’Connell C Galvin DJ (2019 Feb 14) The management of incidental prostate cancer following TURP. Ir Med J 112(2):866 McConnell JD, Barry MJ, Bruskewitz RC (1994) Benign prostatic hyperplasia: diagnosis and treatment. Agency for health care policy and research. Clin Pract Guidel Quick Ref Guide Clin. Feb;(8):1–17 Medikamente im Alter. Herausgeber Bundesministerium für Bildung und Forschung (BMBF) Referat Gesundheitsforschung; Medizintechnik 11055 Berlin Netsch C, Herrmann TRW, Bozzini G, Berti L, Gross AJ, Becker B (2021) Recent evidence for anatomic endoscopic enucleation of the prostate (AEEP) in patients with benign prostatic obstruction on antiplatelet or anticoagulant therapy. World J Urol. Mar 15 Noordhoff TC, Groen J, Scheepe JR, Blok BFM (2019 Sep) Surgical management of anatomic bladder outlet obstruction in males with neurogenic bladder dysfunction: a systematic review. Eur Urol Focus 5(5):875–886 Oelke M, Bschleipfer T, Höfner K (2019 Mar) Hartnäckige Mythen zum Thema BPS – und was davon wirklich stimmt! Urologe A. 58(3):271–283 Pelletier J, Cyr SJ, Julien AS, Fradet Y, Lacombe L, Toren P (2018) Contemporary outcomes of palliative transurethral resection of the prostate in patients with locally advanced prostate cancer. Urol Oncol. Aug;36(8):363.e7–e363 Presicce F, De Nunzio C, Tubaro A (2018 Jul 9) Clinical implications for the early treatment of Benign Prostatic Enlargement (BPE): a systematic review. Curr Urol Rep 19(9):70

19

Reitz A, Hüsch T, Axel H (2019 Sep) Persistent storage symptoms after TURP can be predicted with a nomogram derived from the ice water test. Neurourol Urodyn 38(7):1844–1851 Ringert RH, Gross AJ (1996) Bladder catheter or suprapubic fistula? Indications and contraindications. Langenbecks Arch Chir. 113:713–717 Schoeb DS, Schlager D, Boeker M, Wetterauer U, Schoenthaler M, Herrmann TRW, Miernik A (2017 Nov) (2017) Surgical therapy of prostatitis: a systematic review. World J Urol 35(11):1659– 1668 Se Young C, Bumjin L, Byung HC, Jung HK, Wonchul L, Yoon SK, Dalsan Y, Ho-Young S, Choung-Soo K (2021) Efficacy and tolerability of metallic stent in patients with malignant prostatic obstruction secondary to prostatic cancer. Low Urin Tract Symptoms. Mar 25 Stoevelaar HJ, Van de Beek C, Casparie AF, McDonnell J, Nijs HG (1999 Jan) Treatment choice for benign prostatic hyperplasia: a matter of urologist preference? J Urol 161(1):133–138 Sundaram D, Sankaran PK, Raghunath G, Vijayalakshmi S, Vijayakumar J, Yuvaraj MF, Kumaresan M, Begum Z (2017) Correlation of prostate gland size and uroflowmetry in patients with lower urinary tract symptoms. J Clin Diagn Res May;11(5):AC01–AC04 Singh K, Sinha RJ, Sokhal A, Singh V (2017) Does prostate size predict the urodynamic characteristics and clinical outcomes in benign prostate hyperplasia? Urol Ann. 2017 Jul-Sep;9(3):223–229 Tiburtius C, Knipper S, Gross AJ, Netsch C (2014 Jan) Impact of thulium VapoEnucleation of the prostate on erectile function: a prospective analysis of 72 patients at 12-month follow-up. Urology 83(1):175–180 Tonyali S, Ceylan C, Aglamis E, Dogan S, Tastemur S, Karaaslan M (2021 Mar 18) Is there a PSA cutoff value indicating incidental prostate cancer in patients undergoing surgery for benign prostatic hyperplasia? Arch Ital Urol Androl 93(1):31–34 Zugor V, Labanaris AP, Porres D, Witt JH (2012 May) Surgical, oncologic, and short-term functional outcomes in patients undergoing robot-assisted prostatectomy after previous transurethral resection of the prostate. J Endourol 26(5):515–519 7 www.uroweb.org/guidelines/2020 editon, S. 161

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Guidelines Christopher Netsch Contents 20.1 What is the Purpose of a Guideline? – 192 20.2 Effectiveness and Quality of Guidelines – 193 20.3 Criticism and Error-Proneness of Guidelines – 194 20.4 Comparison of EAU, AUA and DGU Guidelines – 195 20.5 Summary – 205 References – 206

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_20

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z Introduction

20

Medical diagnosis and therapy of any kind should ideally, following the Hippocratic tradition, be guided by the following principle: “Primum nihil nocere, secundum cavere, tertium sanare”, that is: “First do no harm, second be careful, third heal”. From this, a diagnosis and a therapy can be derived that do as little harm as possible, and a procedure that is determined by evidence and not financial or personal (e.g. academic, financial) interests, that helps the patient and is as cost-effective as possible. To meet this ancient statement, guidelines were developed to facilitate daily decision-making. Unfortunately, medicine, like life, does not always work on the basis of simple decision trees and algorithms, that is, if-then decisions. The human individual is more complex … For the German urologist, the guidelines of the German Society of Urology (DGU), the European Society of Urology (EAU) and the American Society of Urology (AUA) are relevant. A German guideline for the diagnosis and therapy of the benign prostate syndrome (BPS) was published for the first time in 2003 (Berges R et al. 2003a, b; Höfner K 2004), revised in 2009 (Berges R et al. 2009a, b) and 2016 (Bschleipfer T et al. 2016, Höfner K et al. 2016) and is currently undergoing another revision. The BPS guidelines of AUA (Lerner LB et al. 2021a, b) and EAU are revised annually (Gravas S et al. 2021). Anyone who expects the current guidelines of the DGU, EAU or AUA to be regurgitated and celebrated in strengths and weaknesses can skip the chapter. Due to the fast pace, especially of international guidelines, a detailed presentation of the guidelines in book form lags behind the current “online” guidelines already at the time of the publication of the book. The author of the chapter therefore tries to lay out the basics of guidelines with the

underlying levels of evidence at the beginning of the chapter. Subsequently, the different guidelines and the relevant differences are highlighted. 20.1  What is the Purpose of a

Guideline?

Guidelines have the task of explicitly presenting the extensive knowledge (scientific evidence and practical experience) on specific care problems, evaluating them under methodological and clinical aspects, clarifying contradictory positions, and defining the current approach of choice by weighing up the benefits and harms. They are not binding, unlike policies. The applicability of a specific recommendation in the individual situation must be checked taking into account the prevailing circumstances (e.g. comorbidities of the patient, available resources). z Objectives of Guidelines

The primary objective of guidelines is to improve the quality of medical care by transferring knowledge. Guidelines aim to promote good clinical practice, taking into account the available resources, to inform the public about it, to base decisions in medical care on a more rational basis, to strengthen the position of the patient as a partner in the decision-making process, and to improve the quality of care. Guidelines 5 are systematically developed, scientifically based and practice-oriented decision aids for the appropriate medical approach to specific health problems, 5 represent the consensus of several experts from different disciplines and working groups (preferably involving patients and other health professions) on certain medical procedures,

193 Guidelines

achieved according to a defined, transparently made procedure, 5 should be regularly checked for their currentness and updated if necessary, 5 are orientation aids in the sense of “action and decision corridors”, from which deviations can or must be made in justified cases (7 https://www.leitlinien.de/hintergrund/leitliniengrundlagen#).

20.2  Effectiveness and Quality

of Guidelines

The effectiveness and benefit of guidelines depend on their quality. Quality criteria that high-quality guidelines should meet are defined internationally in a uniform way. The positive influence of guidelines on the process and outcome quality in the health care system is scientifically proven. However, the effectiveness and ultimately the benefit of a single guideline depend crucially on its quality and its implementation. Accordingly, certain criteria that high-quality guidelines should meet are defined today internationally in a uniform way. This is especially important for the representativeness of the guideline panel for

20

the user group, the systematic search, selection and evaluation of the literature, and the methodology of consensus finding. While the evidence base is crucial for the scientific legitimacy of a guideline, the representative participation of the users and the structured consensus finding are decisive for the acceptance and implementation. To provide guideline users with guidance on the extent to which these aspects are considered, four classes of guidelines are distinguished according to the classification of the Association of the Scientific Medical Societies (AWMF) (7 https://www.leitlinien.de/hintergrund/leitliniengrundlagen#, . Table 20.1): z Guidelines as Decision Aids

A National Health Care Guideline is a systematically developed decision aid for the appropriate medical approach to specific health problems within the framework of structured medical care and thus a guidance tool in the sense of “action and decision proposals” from which deviations can or even must be made in justified cases (BÄK 1997). The decision whether to follow a certain recommendation must be made individually, taking into account the circumstances and preferences of the individual patient as well as the available resources (Council of Europe 2002).

. Table 20.1  Grading of guidelines Designation

Characteristics

Scientific legitimacy of the method

Legitimacy for the implementation

S1: Expert recommendation

Consensus finding in an informal procedure

Low

Low

S2k: Consensus-based guidelines

Representative panel, structured consensus finding

Low

High

S2e: Evidence-based guidelines

Systematic search, selection, evaluation of literature

High

Low

S3: Evidence- and consensus-based guidelines

Representative panel, systematic search, selection, evaluation of literature, structured consensus finding

High

High

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C. Netsch

An National Health Care Guideline only becomes effective when its recommendations are taken into account in patient care. > The applicability of a guideline or individual guideline recommendations must be checked in the individual situation, according to the principles of indication, consultation, preference elicitation and participatory decision making (AWMF 2012).

As with any other medical guideline, an National Health Care Guideline is explicitly not a guideline in the sense of a regulation of action or omission that has been consented, written down and published by a legally legitimate institution, is binding for the legal area of this institution and whose non-compliance entails defined sanctions (BÄK 1997). z Guidelines are not Subject to Competition Law

The Higher Regional Court of Cologne ruled in 2012 that medical guidelines are exempt from competition law assessment because of their purely scientific objective. Due to the freedom of expression of Article 5 (1) of the Constitutional Law, authors of guidelines have a considerable margin of discretion, provided that the requirements of neutrality, objectivity, expertise and care were met in the development of guidelines. 20.3  Criticism and Error-

Proneness of Guidelines

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The noble aim of a guideline, as Gutsch and colleagues formulated in 2016, is to make the medical susceptibility to errors calculable by means of formalisation procedures, i.e. the conception of “evidence-based medicine” and “evidence-based guidelines”

(Gutsch J et al. 2016). Quantified objective statements about the therapeutic effectiveness of a treatment are intended to make the individual medical assessment of the therapeutic effectiveness superfluous. The compliance with formal rules is decisive for answering the question of the truth value and the reality reference (Gutsch J et al. 2016). To develop evidence-based guidelines, the results of randomised controlled trials (RCT) or meta-analyses of such trials are primarily used. Gutsch et al. analysed the evidence-based judgement formation using the example of the S3 guideline “Malignant Melanoma” for the effectiveness of an unconventional therapy—here with a mistletoe preparation. The RCT used for the assessment of this unconventional therapy is analysed more closely in terms of methodology. Although it does not allow a statistically based statement, a guideline recommendation was derived on the basis of this study. Gutsch et al. showed that 1. the mere existence of a single RCT with high evidence is equated, 2. the results are incorporated into an S3 guideline despite considerable misinterpretations and 3. opinions are processed instead of critical scientific analyses. The authors formulated that no matter how sophisticated epistemological and methodological formalities are, they do not relieve the physician of the duty to assess the reality value of the information available to him on the basis of his medical experience and professional competence (Gutsch J et al. 2016). Gutsch and colleagues thus show the limitations of evidence-based guidelines. For the clinician this means: Evidence from a single RCT with possibly flawed study design does not replace or is not equivalent to evidence from excellently controlled uni- or multicentric pro- or retrospective case-control or case studies!

195 Guidelines

z Critical Points of Guidelines

For the critical reader of a guideline, the following points are of interest: 5 Is there (at all) an evidence level or which evidence level is the guideline aimed for? 5 Who decides on the composition of the guideline panel (Who decides which persons are allowed to decide on the composition)? 5 What conflicts of interest exist among persons of the guideline panel? Are all conflicts of interest disclosed? 5 What are the selection criteria for the literature search? Who conducts the literature search? Is the literature search carried out independently (e.g. external institute)? 5 Who supports the development of a guideline financially (professional societies, industry, third-party funds) and personally (e.g. independent statisticians)? 5 How long should the guideline be valid? 5 What is the methodology of consensus finding? Overview From a guideline, the logical questions arise: 5 Do guidelines reflect reality? 5 What does guideline adherence look like in reality? These questions, however, go beyond the scope and aim of the (book) chapter.

20.4  Comparison of EAU, AUA

and DGU Guidelines

z Evidence of the Guidelines

From the perspective of a practicing urologist, dealing with the evidence levels of the AUA, DGU and EAU guidelines is difficult to understand and often purely academic—

20

they lead to the same result despite different evidence levels. Practically, one expects a recommendation in a guideline. There is scientific knowledge that cannot be changed in the evidence level by appropriate statistical processing, but is assessed differently depending on the guideline (degree of recommendation). 20.4.1  Guidelines for the

Diagnosis of BPS

Basic Diagnosis of BPS The basic diagnosis of BPS includes: 5 History, including a detailed medication history 5 Quantification of symptoms and suffering/quality of life (e.g. IPSS) 5 Physical examination with digital rectal examination (DRE) 5 Urine status (Stix/Microscopy) 5 PSA 5 Uroflowmetry 5 Sonography of bladder (including post-void residual urine (PVR) determination) and prostate (preferably TRUS) 5 Assessment of the upper urinary tract (sonography of the kidneys/serum creatinine).

Here, the AUA- (Lerner LB et al. 2021a, b), EAU- (Gravas S et al. 2021) and the expired DGU-guideline (7 https://www.awmf.org/ uploads/tx_szleitlinien/043-034l_S2e_Benignes_Prostatasyndrom_Diagnostik_Differenzialdiagnostik_abgelaufen.pdf) agree. Only about the value of the uroflow and the residual urine in the diagnosis of BPS there is disagreement. The AUA-guideline recommends a separate diagnosis for high residual urine (>300 mL), regardless of the symptoms.

196

C. Netsch

Urodynamics and cystoscopy are recommended for persistent complaints despite dietary modification, behavioral modification or drug therapy (Lerner LB et al. 2021a, b) (. Fig. 20.1). Also in the EAU-guidelines, a cystoscopy or urodynamic examination is only recommended in case of uncertainties in the diagnosis (Gravas S et al. 2021) (. Fig. 20.2). ► Conclusion The current guidelines are quite similar in terms of diagnosis. There are gradual differences regarding special situations (e.g. high residual urine) and the timing of applying special examinations (urodynamics, cystoscopy). ◄

20.4.2  Guidelines for the Drug

Therapy of BPS

When dealing with the pharmacological therapy of BPS, it is worth taking a look at the past, more precisely: at the last edition of the book “Benign Prostatic Hyperplasia. A Guide for Practice.” (Höfner K et al. 2000, . Fig. 20.3): Here, the pharmacological therapy of BPS with alpha-blockers and/or 5-alpha-reductase inhibitors is recommended. A possible phytotherapy is already put in brackets at that time. In the last edition of the BPS guideline (Bschleipfer T et al. 2016) the pharmacological therapy already looks more differentiated (. Fig. 20.4). One can see that the group of drugs of antimus-

BOTHERSOME LUTS RECOMMENDED TESTS: • Obtain medical history • Perform physical examination • Administer International Prostate Symptom Score (IPSS) • Perform a urinalysis • If equipment available, consider PVR and/or uroflowmetry. • *If PVR > 300 cc, irrespective of symptoms, see white paper on *Non-Neurogenic Chronic Urinary Retention: Consensus Definition Management Strategies, and Future Opportunities*

Standard Treatment • Alter modifiable factors such as caffeine, fluids, contributing medications when possible • Lifstyle discussion • Trial of Medical Therapy Algorithm

Improvement/ symptoms tolerable

Lack or incomplete response/contiued bothersome symptoms

Continue therapy, routine follow-up

Frequency volume chart PVR/Uroflow (if not obtained earlier, these tests are recommended at this point*) Urodynamics Cystoscopy

OAB predominant (storage symptoms) See OAB Guideline

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Mixed OAB/800 Follow 800 pathway and see OAB Guideline for options regarding storage symptoms

Evidence of 800

Nocturia is majaor complaint

Frequency volume chart Medication trial

Lack of resolution with medication

Consider other work up and eitologies, such as sleep disorders (i.e. sleep apnea)

See Surgical Managment Algorithm

. Fig. 20.1  Flowchart for the diagnosis of BPS, AUA-guideline. (From Lerner LB et al. 2021a)

197 Guidelines

Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis

Evaluate according to relevant guidelines or clinical standard

Treat underlying condition (if any, otherwise return to initial assessment)

Male LUTS

Manage according to EAU mLUTS treatment algorithm

History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA (if diagnosis of PCa will change the management – discuss with patient) Measurement of PVR

No

20

Bothersome symptoms

Yes Significant PVR

US of kidneys +/- Renal function assessment

FVC in cases of predominant strorage LUTS/nocturia US assessment of prostate Uroflowmetry

Medical treatment according to treatment algorithm

Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT

Endoscopy (if test would alter the choice of surgical modality) Pressure flow studies (see text for specific indications)

Surgical treatment according to treatment algorithm . Fig. 20.2  Flowchart for the diagnosis of BPS, EAU-guideline. (From Gravas S et al. 2021)

carinics and PDE5 inhibitors have meanwhile been added (Bschleipfer T et al. 2016) (. Fig. 20.4). In the EAU guideline, the pharmacological treatment of lower urinary tract symp-

toms (LUTS) is considered more differentiated than in the DGU guideline. In particular, nocturia is treated separately (possibly therapy with vasopressin analogues) and differentiated when a therapy of predomi-

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C. Netsch

Information about therapy advantages and disadvantages

symptomatic therapy: a. drug therapy: Medicinal α1-blockers 5α-Reductase Inhibitors (Phytotherapy*) b. instrumental/ operational: low-energy TUMT *see chap. 20.2.1.2 . Fig. 20.3  Treatment diagram. (From Höfner et al. 2000)

nant storage disorders with antimuscarinics or beta-3 agonists should be initiated. In addition, a therapy with 5-alpha-reductase inhibitors is recommended in prostates with a prostate volume (PV) > 40 mL (Gravas S et al. 2021). An important and relevant aspect of the EAU guideline is patient education (“Education”) by the physician and change of lifestyle (dietary modification and behavioral modification) (. Fig. 20.5). In the AUA guidelines, regarding the treatment of storage symptoms (over active bladder symptoms [OAB]), reference is made to the OAB guideline. Otherwise, the recommendations of the AUA are in line with those of the EAU. First, a therapy

BPS

+

Absolute OP-Indikation

+

-

Leidensdruck

+

klinisch relevante BOO*

Patientenwunsch gegen OP oder Kontraindikation für ablative Therapie

-

+ Instrumentelle/ operative Verfahren

Watchful Waiting

Prostatavolumen

+

-

5ARIs Monotherapie** α-Blocker & SARIs (α-Blocker od. PDE5-1)***

α-Blocker Antimuskarinika (AM) α-Blocker & AM PDE5-Inhibitoren

Therapieversager

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-

. Fig. 20.4  Flow chart for the therapy of BPS, DGU-Guideline. (From Bschleipfer T et al. 2016)

199 Guidelines

20

Male LUTS (without indications for surgery)

Bothersome symptoms?

no

no

Prostate volume > 40 mL?

no

Education + lifestyle advice with or without α1-b;locker/PDE5I

yes

no

Nocturnal polyuria predominant

Storage symptoms predominant?

yes

yes

yes

Long-term treatment?

no

yes Residual storage symptoms

Watchful waiting with or without education + lifestyle advice

Add muscarinic receptor antagonist/beta -3 agonist

Education + lifestyle advice with or without 5α-reductase inhibitor ± α 1blocker/PDE5I

Education + lifestyle advice with or without muscarinic receptor antagonist/beta -3 agonist

Education + lifestyle advice with or without vasopressin analogue

. Fig. 20.5  Flow chart for the pharmacological therapy of BPS, EAU-Guideline. (From Gravas S et al. 2021)

with alpha blockers should be performed, if there is little symptom relief, a therapy with PDE-5 inhibitors can be considered,

for PV >30 mL a therapy with 5-alpha-reductase inhibitors (Lerner LB et al. 2021a) (. Fig. 20.6).

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C. Netsch

Alpha Blocker as initial therapy * If patient also has ED, can start with PED5 as initial therapy

Lack of or incomplete response to Alpha Blocker and/or cannot toelreate

Consider trail of PDE5

Lack of and/or incomplete response to therapy

Prostate >30cc, consider addition of 5ARI

Discuss surgical options, see Surgical Management Algorithm

Lack of and/or incomplete response to therapy

. Fig. 20.6  Flow chart for pharmacological therapy of BPS, AUA guideline. (From Lerner LB et al. 2021a)

20

► Conclusion

20.4.3  Guidelines for the Surgical

5 The differences between the various guidelines are gradual regarding the pharmacological therapy of BPS and due to the currentness of the respective guideline. 5 Alpha-blockers remain the standard drug in the therapy of BPS. 5 Phytotherapeutics are not recommended for the treatment of BPS. 5 5-alpha-reductase inhibitors are recommended in all guidelines, whether used at 30 or 40 mL PV, is under discussion. 5 PDE-5 inhibitors can be used in case of alpha-blocker intolerance or concomitant erectile dysfunction. 5 The EAU guideline explicitly addresses the use of antimuscarinics and beta-3 agonists. 5 The EAU and AUA guidelines emphasize the patient’s own responsibility by means of dietary modification and behavioral modification. ◄

When talking about the procedures for the surgical therapy of BPS, a lot has happened during the past last 10 years. The various so-called “minimally-invasive surgical techniques” or MIST procedures have been discussed in detail in the corresponding chapters. While a low re-intervention rate (RR) in the long-term follow-up is considered to be an ideal in the surgical therapy of BPS (TUR-P, transurethral/open/laparoscopic/ robotic enucleation procedures), new procedures with different study endpoints have been added. In principle, the comparability of these procedures with the corresponding studies is complicated by these different study endpoints. The possible study endpoints/relevant parameters include:

Therapy of BPS

201 Guidelines

the book “Benign Prostatic Hyperplasia. A Guide for Practice” (Höfner K et al. 2000, . Fig. 20.7)? The conclusion at that time was:

5 Low RR at long-term follow-up (e.g. enucleation procedures, TUR-P) 5 Preservation of antegrade ejaculation (e.g. Aquaablation®, Rezum®, iTind®, Urolift®) 5 Omitting  prostate-specific medication (e.g. iTind®, Urolift®, Rezum®) 5 Performance in local anesthesia (especially Urolift®, iTind®, prostate artery embolization (PAE))

“All instrumental transurethral or operative procedures have the goal of deobstructing the BPO with ablation of prostate tissue, except for low-energy (NE)-TUMT. With increasing ablation, the obstruction decreases, while the treatment morbidity increases (e.g. urethral strictures, bladder neck sclerosis, ejaculatory disorders, urinary tract infections, incontinence, impotence)

But at the beginning of this section, the view should again be directed to the past. What has happened since the last edition of

Standard diagnostics for LUTS Medical history, physical Examination, urine status, serum creatinine, PSA, IPSS, Uroflow, Restham

PCA? PCA-Therapy

BPS?

absolute indication for surgery?

20

other disease? further diagnostics and therapy

Surgery (stents, ASA 3-4) BPS+ Suffering 1/2 yearly check

B00 Urodynamics? Information about therapy advantages and disadvantages

ablative therapy: instrumental/surgical: TUR-P,TUIP, open surgery, LASER vaporization, high-energy TUMT, TUNE

Information about therapy advantages and disadvantages

Symptomatic therapy: a. Medicinal α1Blocker 5α-Reductase Inhibitors ("Phytotherapy"). b. instrumental/ operational: low energy TUMT *see chap. 20.2.1.2

. Fig. 20.7  Treatment diagram. (From Höfner et al. 2000)

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C. Netsch

5 TUR-P leads to the best treatment results. Data on complication and recurrence rates are inconsistent 5 The open operation can be used for large gland volume, TUIP for a volume   80 mL

The AUA guideline recommends laparoscopic/robot-assisted prostate adenoma enucleation, although no RCTs are available that compare these procedures with the standard procedures (open/transurethral prostate adenoma enucleation). Considering that laparoscopic/robot-assisted prostate adenoma enucleation mimics open surgery, it is obvious, despite the lack of evidence, that the results would be comparable.

20

203 Guidelines

BPS

Absolute surgery indication

+

+

-

Instrumental/ operative procedures

Suffering

+

clinically relevant BOO*

Patient request against surgery or contraindication for ablative therapy

-

+

Prostate volume

Watchful Waiting

+

-

5 ARIs monotherapy** α-blockers & 5ARIs (α-blocker or PDE5-1)***

α-blockers Antimuscarinics (AM) α-blockers & AM PDE5 inhibitors

Therapy Failure . Fig. 20.8  Flowchart for the therapy of BPS, DGU-Guideline. (From Bschleipfer T et al. 2016)

z PV 30–80 mL

The AUA guideline recommends Aquablation®, Rezum®, Urolift®, TUR-P, laser enucleation (HoLEP, ThuLEP) and vaporization procedures (PVP). Aquablation® and Rezum® were included in the guideline based on excellently conducted (albeit company-sponsored) RCTs. Independent RCTs are still lacking for both procedures. Also, parts of the guideline panel have significant conflicts of interest with these studies (principal investigators of these studies are part of the guideline panel).

out a median lobe), the AUA guideline additionally recommends laser enucleation procedures and GreenLight Vaporisation (PVP). The AUA guideline still recommends TUMT based on the literature. However, TUMT is clinically no longer relevant. For Thulium Laser Enucleation of the Prostate (ThuLEP), which is explicitly recommended by the AUA regardless of size, it applies that the evidence is worse than for HoLEP, i.e. fewer and qualitatively worse performed RCT! z Anticoagulation

z PV  30 mL

Prostate volume

Can stop anticoagulation/ antiplatelet therapy

yes

Can have surgery under anaesthesia?

no

no

> 80 mL

30 – 80 mL

TUIP (1) TURP

TUIP (1) Lase enucleation Bipolar enucleation Laser vaporisation PU lift

Open prostatectomy (1) HoLEP (1) Biploar enucleation (1) Laser vaporisation Thulium enucleation TURP

Laser vaporisation(1) Laser enucleation

PU lift

. Fig. 20.9  Flowchart for the surgical treatment of BPH, EAU-Guideline. (From Gravas S et al. 2021)

20

laser and enucleation with the Tm:YAG laser or Ho:YAG laser. The literature is still weak—only a few retrospective studies are available. The same procedures are recommended by the AUA—no statements are

made regarding the handling of the different anticoagulants (platelet aggregation inhibitors, NOAC, vitamin K antagonists). The DGU guideline does not comment on this.

205 Guidelines

20

SURGICAL THERAPY Assessment of Large Prostate (>80-150cc) or • Simple Prostatectomy Prostate Size via (Open, Laparoscopic, imaging or cystoscopy Very Large Prostate (>150 cc) Robotic) • HoLEP • ThuLEP Average • TUMT • RWT1 Prostate • TURP • HoLEP (30-80 cc) • PVP • TUVP • WVTT3 • PUL2 • ThuLEP Small Prostate (150 mg/d (1.7 mmol/l), 5 HDL concentration i.S. 130/80 mm Hg and/or 5 Fasting glucose concentration i.S. >110 mg/dl (6.1 mmol/l).

209 Prevention of Benign Prostatic Syndrome

In animal experiments, the autonomous overactivity leads to the development of a (histological) BPH and high-fat diet or obesity, diabetes mellitus and arterial hypertension to BPE and LUTS or to overactive bladder (Golomb et al. 2000; Rahman et al. 2007). Animal experiments also showed that the long-term increase of serum glucose concentration leads to apoptosis of particularly parasympathetic nerve cells and thus causes an imbalance to the sympathetic nerve tone (Cellek et al. 1999). In epidemiological studies, a significantly larger prostate and a faster prostate growth were demonstrated in men who were also affected by obesity, hyperlipidemia, diabetes mellitus type II or arterial hypertension (Gacci et al. 2015). Men with a BMI >35 kg/m2 have a 3.5-fold increased risk of developing BPS than men with a BMI 1.6 µg/l).

21

In case of repeated occurrence of urinary retention, there is usually the need for prostate surgery. Since the vast majority of symptomatic patients with BPH in Germany receive an α1-blocker, the intake of an α1-blocker cannot prevent urinary retention (McConnell et al. 2003). The prostate volume has been increasing continuously since the α1-blocker era forthe indication of TURP (in Japan on average 28.3 cm3 in the period from 1987 to 1990 compared to 61.5 cm3 in the period 2003 to 2006 [Takeuchi et al. 2009]). The morbidity and mortality of TURP are directly dependent on the resection weight (Reich et al. 2008). Therefore, more men will probably develop urinary retention in the future without the knowledge or application of information on secondary prevention and the affected ones will also suffer more perior postoperative complications. Measures for secondary prevention should prevent or slow down BPS progression and thus avoid complications in the lower or upper urinary tract. While no data are available for anticholinergics or phosphodiesterase-5 inhibitors regarding prevention, the following measures for secondary prevention in BPS are known: Measures for secondary prevention in BPS 5 Phytopharmaceuticals 5 α1-adrenoceptor antagonists (α1-blockers) 5 5α-reductase inhibitors 5 Combination therapy with α1-blockers and 5α-reductase inhibitors

z Phytopharmaceuticals

The only study addressing study on the longterm intake of plant extracts showed that the subjective and objective disease progression over 15 years could be prevented by the continuous intake of Serenoa repens (extract of

212

M. Oelke

the saw palmetto) in a daily dosage of once 320 mg (Vinarov et al. 2019). z α1-adrenoceptor ckers)

antagonists

(α1-blo-

The long-term intake (>12 months) of an α1-blocker (Doxazosin or Tamsulosin) was evaluated in numerous studies (McConnell et al. 2003; Narayan et al. 2003; Roehrborn et al. 2010). A five-year open-label study with Tamsulosin, after one-year placebo-controlled treatment, showed a consistent effect of the α1-blocker on LUTS with significant reduction of the total IPSS and the sub-scores for bladder storage and bladder emptying symptoms (Narayan et al. 2003). The MTOPS study, a 54-month, placebo-controlled study comparing the efficacy of Doxazosin, Finasteride or the combination of drugs, also showed a significant effect of the α1-blocker on LUTS over the entire observation period (McConnell et al. 2003); the symptomatic progression inhibition of Doxazosin was significantly more pronounced than that of placebo or Finasteride. The CombAT study (Combination of Avodart and Tamsulosin), in which Tamsulosin versus Dutasteride or the combination of drugs was tested over 48 months, included older patients (average 66 years) with larger prostates (average ca. 55 cm3) or higher PSA concentration (average ca. 4 µg/l) than the MTOPS study (age 62.6 years, prostate volume 36 cm3, PSA 2.4 µg/l) and thus patients who had a higher probability of progression due to these inclusion criteria, showed for the α1-blocker a reduction of LUTS over the entire observation period, even if the effectiveness of Tamsulosin seems to decrease over time compared to Dutasteride (from 15-month treatment time) (Roehrborn et al. 2010). The (mathematical) simulation of the IPSS over a 48 month period showed in Tamsulosin-treated men a stronger symptom reduction compared to untreated patients (D’Agate et al. 2020). The effect was, however, dependent on the initial symptom

21

severity (mild – moderate – severe) and the speed of the calculated disease progression in 10,238 study participants (. Fig. 21.1). z 5α-reductase inhibitors

Dutasterideor finasteride are the best studied drugs for secondary prevention of BPH. The regular intake of a 5α-reductase inhibitor for at least 12 months leads to an average reduction of prostate volume (BPE) by about 15– 28% and a decrease of the serum PSA concentration by about 50% (Gravas and Oelke 2010). Although 5α-reductase inhibitors reduce LUTS only slowly and the symptomatic improvement is superior to placebo therapy only after 6–12 months, the efficacy with regard to the inhibition of symptomatic progression over observation periods of up to 54 months (4.5 years) is proven (McConnell et al. 2003). Compared to α1-blockers, the inhibition of symptomatic progression with 5α-reductase inhibitors is less pronounced in unselected patients. The CombAT study, which examined men with a high risk of progression, showed that in this patient group, the intake of dutasteride for 48 months leads to a stronger symptom reduction than the single treatment with tamsulosin (numerically superior from the 18th month of treatment) (Roehrborn et al. 2010). The influence of 5α-reductase inhibitors on BOO is not yet conclusively clarified. The available data suggest, however, that finasteride significantly and clinically relevantly reduces the degree of BOO (Tammela and Kontturi 1995). > Only 5α-reductase inhibitors can significantly reduce the frequency of urinary retention and the need for prostate surgery.

Under finasteride, compared to placebo, the probability of urinary retention is reduced by 57% after 24 months and by 68% after 54 months, while the probability of prostate surgery within the same observation period is reduced by 34 to 64% (McConnell et al. 2003; Andersen et al. 1997). Studies on dutasteride yielded similar results. The long-

213 Prevention of Benign Prostatic Syndrome

No treatment Tamsulosin monotherapy

Disease progression rate

Disease progresssion rate (DISP, day-1)

2.5% percentile

25% percentile

50% percentile

21

75% percentile

97.5% percentile

mild (IPSS 0-7) moderate (IPSS 8-19) heavy (IPSS 20-35)

Time [months] . Fig. 21.1  Development of symptoms (IPSS) with the α1-blockerTamsulosin (once daily 0.4 mg) vs. no treatment in mild LUTS (upper row), moderate LUTS (middle row) and severe LUTS (lower row) at baseline depending on different disease progression rates (from left to right: 2.5% percentile = slow progression to 97.5% percentile = fast progression). (Modified from D’Agate et al. 2020). (Red = IPSS development without treatment; line = means, red area = 95% prediction interval; blue = IPSS development with Tamsulosin; line = means, blue area = 95% prediction interval)

est study with dutasteride to date, the CombAT study with an observation period of 48 months, resulted in acute urinary retention in a total of 16.2% of patients with tamsulosin, but only 6.6% of patients treated with dutasteride (Roehrborn et al. 2010). Compared to doxazosin, the preventive effect of finasteride is detectable from the 4th year of treatment (MTOPS study) and of tamsulosin to dutasteride from the 8th month of treatment (CombAT study). The larger the prostate volume or the PSA concentration at the start of treatment, the stronger the re-

duction of risk of progression was found (McConnell et al. 2003; Marks et al. 2006; Boyle et al. 1996). z Combination therapy with α1-blockers and 5α-reductase inhibitors

The simultaneous intake of an α1-blocker (Doxazosin or Tamsulosin) and a 5α-reductase inhibitor (Dutasterideor Finasteride) leads to a stronger reduction of LUTS than the intake of the single drugs after more than 12 months, while the reduction of prostate volume remains at the level of the

214

M. Oelke

5α-reductase inhibitor monotherapy (McConnell et al. 2003; Roehrborn et al. 2010). In the MTOPS study, the IPSS was reduced by 4.9 points with placebo, by 6.6 with Doxazosin, by 5.6 with Finasteride and by 7.4 points with the drug combination after 48 months (significantly compared to baseline and placebo for all active therapies, drug combination significantly superior to monotherapy). In the CombAT study, the IPSS was reduced by 3.8 with Tamsulosin, by 5.3 with Dutasteride and by 6.3 with the drug combination (combination vs. single substances each p With the drug combination of Tamsulosin +Dutasteride, the risk of urinary retention is reduced by 67.6% and the need for prostate surgery by 70.6% compared to Tamsulosin monotherapy (Roehrborn et al. 2010).

The combination of drugs is particularly beneficial for men with a prostate size >40 cm3. The (mathematical) simulation showed the lowest probability of urinary retention or the need for prostate surgery for the period of 48 months when using the drug

21

combination Tamsulosin +Dutasteride from the start of therapy or after 1–3 months and the highest probability for Tamsulosin monotherapy. The later Dutasteride was added to Tamsulosin, the lower was the protective effect of the drug combination (. Fig. 21.3) (D’Agate et al. 2021). 21.4  Conclusions

Measures for prevention seem to be reasonable for diseases that occur frequently, lead to a reduction in quality of life, are progressive and potentially associated with complications (Di Silverio et al. 2004). BPH or BPS meets these criteria. 5 Measuresfor primary prevention aim to prevent BPH and the development of one or more components of BPS (BPE, BOO or LUTS) before they become clinically apparent. Primary preventive measures include a healthy lifestyle with plenty of physical activity, the consumption of a lot of vegetables (especially tomatoes), moderate intake of alcohol and the use of 5α-reductase inhibitors, avoiding overweight and the consumption of fatty foods. 5 Measuresfor secondary prevention aim to prevent the progression of BPS and BPS-specific complications. Measures for secondary prevention are reasonable for those men who have an increased risk of disease progression; these are especially older men with larger prostates (>40 cm3) or a  higher serum  PSA concentration (>1.6 µg/l). – With α1-blockers, LUTS are reduced in long term, but not the frequency of urinary retention or the need for prostate surgery prevented. – 5α-reductase inhibitors as monotherapy can reduce the symptomatic progression, the acute urinary retention and the need for prostate surgery, but

215 Prevention of Benign Prostatic Syndrome

21

No treatment Combinaon therapy (tamsulosin + dutasteride)

No treatment Combinaon therapy (tamsulosin + dutasteride)

Time [months]

. Fig. 21.2  Development of the IPSS (top) or the IPSS difference compared to baseline (bottom) with the drug combination (Tamsulosin 0.4 mg + Dutasteride 0.5 mg) vs. no treatment depending on the IPSS at study start (from left to right: IPSS 8 to IPSS 30). (Modified from D’Agate et al. 2020). (Red = IPSS development without treatment; line = mean values, red area = 95% prediction interval; blue = IPSS development with the drug combination; line = mean values, blue area = 95% prediction interval)

the combination of drugs from α1-blocker and 5α-reductase inhibitor is significantly more effective in inhibiting the progression of LUTS, urinary retention and the need for prostate surgery than monotherapy . The data

suggest that all symptomatic BPS patients with increased tendency of progression should be treated early with the combination of drugs: i.e. α1-blockers and 5α-reductase inhibitors.

21 TAM-DUT CT

Cumulative incidence (urinary retention or need for prostate surgery).

Tamsutosm non-responders to TAM-OUT CT at 6 months Tamsutosm non-responders to TAM-OUT CT at 12 months

Time [months]

Tamsulosin non-responders to TAM-DUT CT at 1 month Tamsulosin non-responders to TAM-DUT CT at 3 months

Tamsulosin non-responders to TAM-DUT CT at 24 months.

Start with tamsulosin + dutasteride combination

Start with tamsulosin, plus dutasteride after 1 month.

Start with tamsulosin, additionally dutasteride after 3 months

Start with tamsulosin, plus dutasteride after 6 months.

Start with tamsulosin, plus dutasteride after 12 months.

Start with tamsulosin, plus dutasteride after 24 months.

Tamsulosin only

. Fig. 21.3  Cumulative incidence of urinary retention or need for prostate surgery over a period of 48 months depending on the drug therapy. The drug combination of Tamsulosin 0.4 mg + Dutasteride 0.5 mg from the start of therapy has the lowest probability, while the monotherapy with Tamsulosin over the entire treatment period has the highest probability. The addition of Dutasteride to Tamsulosin after 1 or 3 months is more protective than the later administration (significant from treatment month 6). (Modified from D’Agate et al. 2021). (Lines = means, colored shadows = 95% prediction interval)

Tamsulosin

216 M. Oelke

217 Prevention of Benign Prostatic Syndrome

References Andersen JT, Nickel JC, Marshall VR et al (1997) Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 49:839–845 Andriole GL, Bostwick DG, Brawley OW et al (2010) Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362:1192–1202 Badawy AA, Abdelhafez AA, Abuzeid AM (2012) Finasteride for treatment of refractory hemospermia: prospective placebo-controlled study. Int Urol Nephrol 44:371–375 Berges R (2008) Epidemiologie des benignen Prostatasyndroms. Assoziierte Risiken und Versorgungsdaten bei deutschen Männern über 50. Urologe A 47:141–148 Berges RR, Pientka L, Höfner K et al (2001) Male lower urinary tract symptoms and related health care seeking in Germany. Eur Urol 39:682–687 Boyle P, Gould AL, Roehrborn CG (1996) Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 48:398–405 Cellek S, Rodrigo J, Lobos E et al (1999) Selective nitrergic neurodegeneration in diabetes mellitus – a nitric oxide-dependent phenomenon. Br J Pharmacol 128:1804–1812 D’Agate S, Wilson T, Adalig B et al (2020) Impact of disease progression on individual IPSS trajectories and consequences of immediate versus delayed start of treatment in patients with moderate or severe LUTS associated with BPH. World J Urol 38:463– 472 D’Agate S, Chavan C, Manyak M et al (2021) Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/ BPH patients with moderate-to-severe symptoms at risk of disease progression. World J Urol. 7 https://doi.org/10.1007/s00345-020-03517-0 (Ahead of print) Dahle SE, Chokkalingam AP, Gao YT et al (2002) Body size and serum levels of insulin and leptin in relation to the risk of benign prostatic hyperplasia. J Urol 168:599–604 Dal Maso L, Zucchetto A, Tavani A et al (2006) Lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia. Int J Cancer 118:2632–2635 Di Silverio F, Gentile V, Pastore AL et al (2004) Benign prostatic hyperplasia: what about a campaign for prevention? Urol Int 72:179–188 Durak I, Yilmaz E, Devrim E et al (2003) Consumption of aqueous garlic extract leads to significant im-

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provement in patients with benign prostatic hyperplasia and prostate cancer. Nutr Res 23:199–204 Edinger MS, Koff WJ (2006) Effect of the consumption of tomato paste on plasma prostate-specific antigen levels in patients with benign prostatic hyperplasia. Braz J Med Biol Res 39:1115–1119 ElJalby M, Thomas D, Elterma D, Chughtai B (2019) The effect of diet on BPH, LUTS and ED. World J Urol 37:1001–1005 Gabrilove JL, Levine C, Kirschenbaum A, Droller M (1987) Effect of a GnRH analogue (leuprolide) on benign prostatic hypertrophy. J Clin Endocrinol Metab 64:1331–1333 Gacci M, Corona G, Vignozzi L et al (2015) Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int 115:24– 31 Golomb E, Rosenzweig N, Eilam R, Abramovici A (2000) Spontaneous hyperplasia of the ventral lobe of the prostate in aging genetically hypertensive rats. J Androl 21:58–64 Gravas S, Oelke M (2010) Current status of 5alpha-reductase inhibitors in the management of lower urinary tract symptoms and BPH. Word J Urol 28:9– 15 Hong Y, Lee S, Won S (2019) The preventive effect of metformin on progression of benign prostatic hyperplasia: a nationwide population-based cohort study in Korea. PLoS ONE 14:e0219394 Issa MM, Fenter TC, Black L et al (2006) An assessment of the diagnosed prevalence of diseases in men 50 years or older. Am J Manag Care 12(4 Suppl.):S83–S89 Jakobsen SJ, Guess HA, Panser L et al (1993) A population-based study of health care-seeking behavior for treatment of urinary symptoms. The Olmsted County Study of Urinary Symptoms and Health Status among Men. Arch Fam Med 2:729–735 Kim HS, Bowen P, Chen L et al (2003) Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer 47:40–47 Kristal AR, Arnold KB, Schenk JM et al (2007) Race/ ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the Prostate Cancer Prevention Trial. J Urol 177:1395–1400 Kristal AR, Arnold KB, Schenk JM et al (2008) Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the Prostate Cancer Prevention Trial. Am J Epidemiol 167:925–934 Lacey JV Jr, Deng J, Dosemeci M et al (2001) Prostate cancer, benign prostatic hyperplasia and physical activity in Shanghai China. Int J Epidemiol 30:341– 349

218

M. Oelke

Marks LS, Roehrborn CG, Andriole GL (2006) Prevention of benign prostatic hyperplasia disease. J Urol 176:1299–1306 McConnell JD, Roehrborn CG, Bautista OM et al (2003) The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2387–2398 Mondul AM, Giovannucci E, Platz EA (2020) A prospective study of physical activity, sedentary behaviour, and incidence and progression of lower urinary tract symptoms. J Gen Intern Med 35:2281– 2288 Moul S, McVary KT (2010) Lower urinary tract symptoms, obesity and the metabolic syndrome. Curr Opin Urol 20:7–12 Mühlstädt S, Oelke M (2019) Akuter Harnverhalt bei Männern: Die Wirksamkeit bei Alpha-Blockern beim Katheterauslassversuch nach Harnverhalt. Urologe A 58:680–685 Narayan P, Evans CP, Moon T (2003) Long-term safety and efficacy of tamsulosin for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. J Urol 170:498–502 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2002) Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421 Oelke M, Speakman M, Desgrandchamps F, Mamoulakis C (2015) Acute urinary retention rates in the general male population and in adult men with lower urinary tract symptoms participating in pharmacotherapy trials – a literature review. Urology 86:654–665 Orsini N, RashidKhani B, Andersson SO et al (2006) Long-term physical activity and lower urinary tract symptoms in men. J Urol 176:2546–2550 Park JS, Koo KC, Kim HK et al (2019) Impact of metabolic syndrome-related factors on the development of benign prostatic hyperplasia and lower urinary tract symptoms n Asian population. Medicine (Baltimore) 98:e17635 Parsons JK, Im R (2009) Alcohol consumption is associated with a decreased risk of benign prostatic hyperplasia. J Urol 182:1463–1468 Parsons JK, Carter HB, Partin AW et al (2006) Metabolic factors associated with benign prostatic hyperplasia. J Clin Endocrinol Metab 91:2562–2568 Platz EA, Kawachi I, Rimm EB et al (1998) Physical activity and benign prostatic hyperplasia. Arch Intern Med 158:2349–2356 Rahman NU, Phonsombat S, Bochinski D et al (2007) An animal model to study lower urinary tract

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symptoms and erectile dysfunction: the hyperlipidaemic rat. BJU Int 100:658–663 Rastinehad AR, Ost MC, VanderBrink BA et al (2008) Persistent prostatic hematuria. Nat Clin Pract Urol 5:159–165 Reich O, Gratzke C, Bachmann A et al (2008) Morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. J Urol 180:246–249 Roehrborn CG, Siami P, Barkin J et al (2010) The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT Study. Eur Urol 57:123–131 Roehrborn CG, Nickel JC, Andriole GL et al (2011) Dutasteride improves outcomes of benign prostatic hyperplasia when evaluated for prostate cancer risk reduction: secondary analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial. Urology 78:641–646 Rohrmann S, Smit E, Giovannucci E, Platz EA (2004) Association between serum concentrations of micronutrients and lower urinary tract symptoms in older men in the Third National Health and Nutrition Examination Survey. Urology 64:504–509 Rohrmann S, Smit E, Giovannucci E, Platz EA (2005) Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes 29:310–316 Rohrmann S, Giovannucci E, Willett WC, Platz EA (2007) Fruit and vegetable consumption, intake of micronutrients, and benign prostatic hyperplasia in US men. Am J Clin Nutr 85:523–529 Swain J (1895) Castration for prostatic hypertrophy. Br Med J 1:12–13 Takeuchi M, Masumori N, Tsukamoto T (2009) Contemporary patients with LUTS/BPH requiring prostatectomy have long-term history of treatment with alpha1-blockers and large prostates compared with past cases. Urology 74:606–609 Tammela TL, Kontturi MJ (1995) Long-term effects of finasteride on invasive urodynamics and symptoms in the treatment of patients with bladder outflow obstruction due to benign prostatic hyperplasia. J Urol 154:1466–1469 van Exel NJ, Koopmanschap MA, McDonnell J et al (2006) Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six European countries: report of the TRIUMPH study. Eur Urol 49:92–102 Vinarov AZ, Spivak LG, Platonova DV et al (2019) 15 years’ survey of safety and efficacy of Serenoa repens extract in benign prostatic hyperplasia patients with risk of progression. Urologia 86:17–22

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The Geriatric Patient Peter Olbert Contents 22.1 Introduction and Definitions – 220 22.2 The Importance of Pre-Therapeutic Evaluation: The Geriatric Assessment – 221 22.3 Specifics of the Pharmacological Therapy of BPS in the Geriatric Patient – 222 22.4 Surgical Therapy in Geriatric Patients—Outcomes and Complications – 226 References – 227

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_22

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22.1  Introduction and Definitions z How can the “geriatric patient” be defined?

For geriatrics or geriatric medicine, the literature offers different definitions. The European Union Geriatric Medicine Society (EuGMS) describes geriatric medicine as a special discipline that deals with the physical, mental, functional and social conditions of acute, chronic, rehabilitative and preventive treatment and care in old age and also at the end of life. All descriptions of geriatric medicine are defined primarily by the patient population, which is associated with a high degree of frailty and active multimorbidity, which require a holistic treatment approach (. Table 22.1). Geriatric medicine is not defined by an age limit, but it treats the typical morbidities of older patients and is always multidisciplinary and -professional. The patients are usually over 65 years old; the problems that can be addressed by geriatrics as a special discipline become significantly more frequent in the age group of over 80-year-olds (7 https:// en.wikipedia.org/wiki/Geriatrics) z What role does BPS play in geriatric patients?

Several facts make it necessary to consider the geriatric patient cohort with regard

to the most frequently applied conservative and interventional treatment options (Berges and Oelke 2011): 5 Benign prostatic enlargement and the associated diseases and symptoms increase with age. 5 This implies that elderly, possibly frail, i.e. geriatric patients, enter a medical or surgical therapy with different anatomical and functional conditions of the lower urinary tract (e.g. bladder capacity, detrusor activity, sphincter function). 5 In geriatric patients, comorbidities, but also drug interactions and side effects are expected to be in a different quantity and quality than in younger patients. Moreover, considering the natural course of BPH, one finds that the symptoms and disorders are slowly progressive. Only 2% will develop a urinary retention in a 5-year period, less than 10% will ultimately have to undergo a surgical procedure (Ball et al. 1981). With a low level of suffering and without urgent medical indication (e.g. recurrent infections), it is therefore justified to advise the patient on a conservative approach by lifestyle modification, e.g. 5 Evening fluid restriction 5 Reduction of caffeine and alcohol-containing beverages 5 Optimization of diuretic drugs

. Table 22.1  Age-associated diseases and symptom complexes/syndromes Age-associated

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Diseases

Symptom complexes/syndromes

• Arteriosclerosis and sequelae • Arthrosis • Dementia • Age-related depression • Diabetes mellitus • Cataract • Tumour diseases • Osteoporosis • Parkinson’s disease • Chronic senile rhinitis • Atrial fibrillation

• Intelligence decline due to various forms of dementia • Cognitive impairment with increasing limitation of sensory functions (vision, hearing, touch, taste, balance, thirst sensation) • Instability (stroke sequelae, vertigo) with increasing risk of falling • Urinary or faecal incontinence • Dehydration

221 The Geriatric Patient

After reading this chapter, you will be able to: 5 Identify a geriatric patient based on the relevant definitions as well as the typical associated symptoms and diseases 5 Assess the severity of impairment using the most important geriatric assessments and derive consequences for the planned therapy 5 Classify the charactericstics of the geriatric patient with regard to the expected treatment outcome and the risk of side effects and complications and take them into account in your treatment decisions.

22.2  The Importance of Pre-

Therapeutic Evaluation: The Geriatric Assessment

For the estimation of important, age-related factors in the elderly patient such as immobility, incontinence, fall risk, cognition, polypharmacy and social networking, various screening and assessment tools are available. However, there is no uniform procedure or recommendation for the use of a specific instrument to assess peri- and postoperative problems and complications, neither on a national nor on an international level. Generally, screening instruments are shorter and simpler structured and should serve to identify the patients who should undergo a comprehensive geriatric assessment. The focus is on the structured and standardized recording of the (instrumental) activities of daily living – (I)ADL: (In-

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strumental) Activities of Daily Living—, which are impaired with a high prevalence (7–30% or 12–77%) in elderly patients who undergo surgery, for example, for a solid tumor disease. A correlation with perioperative complications exists only for the IADL assessment, none of the two tools allows an estimation of the postoperative mortality risk. The recording and quantification of mobility, for example by the simple to perform “Timed up and go” test, shows a significant correlation with the occurrence of postoperative complications and the 1-year mortality (Robinson et al. 2013b) in the geriatric patient population. An interesting aspect for the pre-interventional risk assessment in elderly and multimorbid patients is the introduction of the concept of “frailty” or the “frailty” syndrome. It can be generally defined as the decreasing adaptability to external and internal stress factors (stressors), which can vary greatly in quality and quantity. Across the different definitions, it can be assumed that about 30–60% of the older patients who have to undergo surgery are classified as “frail”. It seems possible, in this way, to identify, for example, patients at risk preoperatively by classifying them as “prefrail” or “frail”, to take precautions or to adapt the therapeutic approach. For cardiac and colorectal surgery, a significant association between the degree of frailty and the occurrence of complications, the length of stay and the 30-day readmission rate was demonstrated (Robinson et al. 2013a). “Frailty” seems to be a better and more stable predictor of postoperative complications than classical prognostic factors such as age and ASA score (ASA =American Society of Anesthesiologists) (Watt et al. 2018).

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22.3  Specifics of the

Pharmacological Therapy of BPS in the Geriatric Patient

The pharmacological therapy of lower urinary tract symptoms (LUTS) in the older man, which are in most cases directly or indirectly caused by the prostate (-enlargement), has meanwhile become an integral part. As a first choice treatment modality or also—especially in the comorbid geriatric patient—as an alternative to surgery, mainly 5 substance groups with excellent evidence are used as monotherapy or as a combination therapy. The therapeutic goal is the relief of both obstructive and irritative symptoms. The focus of the following remarks is on the side effects and interactions of the substance classes and their consequences for the use in geriatric patients. Here, both directly age-related changes of pharmacodynamics and pharmacokinetics (. Table 22.2) and the phenomenon of polypharmacy, which increases with age, have to be considered. Polypharmacy is defined by the German Society for General Medicine as the simultaneous intake of 5 or more medications. It can be assumed that more than 40% of the over 65-year-olds are affected. As a rule, polypharmacy is a consequence of existing multimorbidity, i.e. the

presence of 3 or more diseases. The problem is further complicated by the combination therapy of individual diseases with several medications (e.g. arterial hypertension or diabetes mellitus type II) (Masnoon et al. 2017). Men with therapy-requiring BPS are usually over 65 and at least half of them report comorbidities (Michel et al. 1998). z Alpha-1-adrenoceptor antagonists (alpha-blockers)

Alpha-blockers effectively reduce the tone of the smooth muscle at the bladder neck and in the prostate, by blocking the effect of endogenously released noradrenaline. Because of their good effect on both obstructive and irritative symptoms of BPS, they are often the first choice of drug therapy; alpha-blockers have no effect on prostate enlargement and other histological-anatomical changes underlying BPS. Today, alpha-1 A-receptor active substances (e.g. tamsulosin, silodosin) with delayed release of the active substance are used. Their slightly better tolerability and at the same time the typical spectrum of side effects of the substance class can be explained by the receptor distribution of the alpha-1 receptor subtypes. While the alpha-1 A-receptors are almost exclusively located in the lower urinary tract (bladder neck, prostate), the alpha-2 B-receptors

. Table 22.2  Causes and consequences of the age-related altered tissue distribution of medications

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Age-related characteristic

Pharmacokinetic effect

Potential effect on drug dosing

Increased body fat percentage

Distribution volume of lipophilic drugs increased

Extended half-life of fat-soluble drugs Toxicity ↑

Lean body mass decreased, total body water content reduced

Distribution volume of hydrophilic drugs decreased

Increased plasma concentration Toxicity ↑

Water accumulation at the site of infection (edema, ascites)

Decreased concentration of hydrophilic drugs at the infection site

Inadequate dosing

Malnutrition, proteinuria with consecutive hypoalbuminemia

Increased concentration of free active substance in plasma

Toxicity ↑

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223 The Geriatric Patient

are the predominant receptor type on the smooth vascular muscle cells. Vasodilation is the reason for the most important side effects such as dizziness, orthostatic hypotension and syncope, which can lead to falls and fractures especially in elderly patients. Uroselective preparations such as tamsulosin and silodosin have the least effect on blood pressure and a lower risk of vascular side effects (Chapple et al. 2011; Djavan et al. 2004). Ejaculatory disorders up to retrograde ejaculation are another important side effect, which has to be explained to the older, sexually active patient, even if the topic of “desire for children” is usually of secondary importance here. The association of alpha-blockers (especially tamsulosin) with the “floppy iris syndrome”, which can lead to complications during cataract surgery, should also be taken into account. This problem affects the geriatric patient population quite a bit. Interactions or an enhancement of the effect in connection with the intake of other medications mainly affects untreated and treated hypertensive patients. Approximately 25% of men over 60 suffer from both, BPS related symptoms and arterial hypertension, this number increases with increasing age. The exact interactions of alpha-blockers with each individual antihypertensive med-

ication or combination therapy cannot be discussed in the context of this chapter. > However, non-selective alpha-1 blockers should only be considered for normotensive patients without blood pressure medication. In almost all other cases, preference should be given to alpha-1 A-selective preparations (. Table 22.3).

z Anticholinergics antagonists)

(muscarinic

receptor

Anticholinergics are mainly used in BPS when LUTS are present that affect the storage phase of the bladder, i.e. pollakisuria, nocturia, imperative urgency up to urge incontinence. The different approved preparations do not differ significantly, depending on the receptor specificity for the muscarinic receptors M1-5. However, there are considerable differences in the spectrum of side effects with significant relevance for the indication in geriatric patients. Common side effects of anticholinergics The most common side effects include, often in combination: 5 Dry mouth (up to 16%) 5 Constipation (up to 4%) 5 Dizziness (up to 5%)

. Table 22.3  Indication for alpha-blocker therapy depending on pre-existing blood pressure medication (modified after (Chu et al. 2021)) Hypertensive

Normotensive

Blood pressure medication: no

• Start of blood pressure adjustment • Treatment of BPS with uroselective alpha-1 blockers • Non-selective alpha-1 blockers should not be used for combined first line therapy of BPS and arterial hypertension

• Uroselective and non-selective alpha-1 blockers are possible options for the treatment of BPS

Blood pressure medication: yes

• Adjust antihypertensive medication + uroselective alpha-1 blockers • Maintain antihypertensive medication, add non-selective alpha-1 blocker

• Uroselective alpha-1 blockers are preferable to non-selective preparations

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5 Bladder emptying disorder with residual urine (up to 2%), especially in patients with pre-existing obstructive symptoms or detrusor underactivity 5 Accommodation disorder and increased intraocular pressure, especially in narrow-angle glaucoma 5 Tachycardia 5 Mental confusion and deterioration of cognitive function

It should be noted that in the older, polypharmaceutically burdened patient numerous drugs are frequently prescribed with anticholinergic effects, e.g. among many others: 5 H1-antihistamines 5 Anti-Parkinson drugs 5 Spasmolytics 5 Antiemetics 5 Antipsychotics (chlorpromazine, flu­ phenazine, clozapine) and tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, nortriptyline) > Meanwhile, a connection between the sum of the ingested anticholinergic substances („anticholinergic burden“) and the occurrence and severity of dementia and delirium has been established (Egberts et al. 2021; Gray et al. 2015).

A minimization of side effects and interactions, especially in the geriatric patient, can be achieved by choosing a preparation with high specificity for the M3 receptor, which is mainly responsible for the anticholinergic effect on the smooth detrusor muscle (e.g. solifenacin) or the administration of trospium chloride, which cannot cross the blood-brain barrier, so that at least the central nervous side effects are eliminated. In principle, an anticholinergic therapy without clinically relevant side effects is hardly

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possible, the therapy discontinuation rate is therefore high (approx. 2/3 after 1 year). The indication for a treatment with this substance class is particularly critical in the geriatric patient. z 5-alpha-reductase inhibitors (5-ARI)

5-ARIs inhibit the conversion of testosterone to dihydrotestosterone by the enzyme 5-alpha-reductase, thereby inducing an apoptosis of prostate epithelial cells and an atrophy of the prostate tissue. There are 2 approved representatives of the substance class: 5 Finasteride, which is specific for the 5-alpha-reductase type 2, which accounts for 90% of the enzyme content in the prostate 5 Dutasteride, which acts on the 5-alpha-reductase type 1 and 2, in which type 1 is the predominant enzyme outside the prostate and occurs, for example, in the skin or the liver. In meta-analyses, no differences in efficacy and safety of the preparations could be shown. The therapy with 5-ARI in patients with moderate to severe LUTS and a gland volume >40 ml could reduce the prostate volume (20%), the symptoms and the risk of urinary retention (57%) and of a surgical therapy of BPH (55%) (Roehrborn et al. 1999). In addition to the typical antiandrogenic side effects, such as erectile dysfunction, loss of libido or sensation of tension of the breast gland, there are scientific hints for an increase in mood swings and anxiety disorders. A connection with cardiovascular events could not be proven so far, unlike the androgen deprivation therapy in prostate cancer (Loke et al. 2013; Skeldon et al. 2017). > Especially in elderly patients, who want to avoid a surgical intervention, 5-ARIs thus appear as an effective and safe therapy option.

225 The Geriatric Patient

z β-3-adrenoceptor agonists (B3A)

Mirabegron, the currently only approved β-3-adrenoceptor agonist, binds to the corresponding receptors of the smooth detrusor muscle and thus causes relaxation during the storage phase; the number of urgency episodes and the micturition frequency can be significantly reduced, the functional bladder capacity increased (Khullar et al. 2013; Tubaro et al. 2017). Mirabegron does not affect the contraction force of the detrusor during micturition, the risk of residual urine formation or acute urinary retention which is low compared to the anticholinergic therapy principle. In patients with cardiovascular comorbidities, Mirabegron showed no increased risk for corresponding toxicities. The EAU guideline recommends Mirabegron as firstline therapy for patients with moderate to severe, predominantly storage phase-related LUTS due to its favorable safety and tolerability profile (Lee and Kuo 2018; Makhani et al. 2020). The safety of the preparation could also be shown for elderly patients (Lee and Kuo 2018; Makhani et al. 2020). In case of a glomerular filtration rate Mirabegron is therefore not recommended for insufficiently controlled hypertension, as well as for severe renal or hepatic dysfunction. Considering these limitations, Mirabegron represents an effective and safe therapy option also for geriatric BPS patients with predominantly irritative micturition symptoms.

z Phosphodiesterase-5 inhibitors (PDE-5-I)

The long-acting PDE-5-I Tadalafil was tested in BPS/LUTS in numerous randomized controlled trials against placebo or α-blocker (Sebastianelli et  al. 2020).

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The mechanism of action is still unclear. An improvement of the IPSS score is consistent across virtually all studies, the results on urinary flow and post-void residual urine are contradictory. The study cohorts mostly included younger patients with mild to moderate LUTS (Gravas et al. 2021). A meta-analysis showed no positive effect vs. placebo in patients >75 years (Oelke et al. 2017). The safety profile is generally favorable. Due to interactions with severe to uncontrolled hypotension, there is a contraindication against PDE-5 intake in patients who take nitrates, nicorandil or also the non-selective α-1-blockers doxazosin and terazosin; as well as for patients with unstable angina pectoris, recent myocardial infarction or stroke, and severe heart, kidney or liver failure; the indication in the geriatric patient population is therefore critical. Taking into account the mentioned contraindications, Tadalafil is recommended by the EAU guideline 2021 for men with mild to moderate LUTS with or without erectile dysfunction based on the current literature (Gravas et al. 2021). According to a meta-regression analysis, younger men with low body mass index seem to benefit the most (Gacci et al. 2012). z Phytotherapeutics

One should not forget the numerous available plant-based preparations among the conservative treatment approaches for BPS. These preparations are usually extracts from Serenoa repens (saw palmetto), which are then used as a single substance or in combination with other ingredients of plant origin (often pumpkin seed or nettle root, but many others) are used. The active components of the relevant preparations include, among others, phytosterols, beta-sitosterol, fatty acids and lectins. In  vitro, mainly anti-inflammatory, anti-androgenic, anti-proliferative and estrogen-like effects could be demonstrated. Receptors (e.g. alpha-adrenoceptors,

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muscarinic receptors) and enzymes (5-alpha-reductase) relevant for the pathophysiology are inhibited. The in vivo effects are complex and often only incompletely understood (Cicero et al. 2019). Meanwhile, there is an acceptable evidence base—also from randomized, placebo-controlled studies—that justifies a trial of therapy with these phytotherapeutics, especially in cases of moderately pronounced symptoms, in the first line of therapy, possibly also in combination with an alpha-blocker. In various structured reviews and meta-analyses of these studies, it could be shown that the treatment with Serenoa-based preparations is often not significantly inferior to pharmacotherapy, but in many cases superior to placebo treatment (Tacklind et al. 2012; Vela-Navarrete et al. 2018). > The special appeal of phytotherapeutics in geriatric, polypharmaceutically burdened patients lies of course in the lack of side effects. These are, apart from individual intolerances and rare, gastroinestinal complaints ( In conclusion, there are more alternatives available today for high risk patients or those who cannot discontinue anticoagulation than just TUR-P or HoLEP. These have to be discussed individually with the patient, also taking into account possibly poorer functional results or higher retreatment rates (Bortnick et al. 2020).

Just as age alone is not a criterion for classifying a patient as “geriatric”, it should not be the decision criterion for or against a specific surgical procedure in BPS patients. There is no data basis for this. More valid parameters may be the need for care and/or a pre-existing permanent catheter. In a large study of over 2869 nursing home patients with an average age of 80.9 years who underwent TUR-P and were already preoperatively provided with a permanent

22

catheter, it was shown that about 30% died within the first 12 postoperative months. Of the non-deceased patients, 95% had a permanent catheter again during this period (Suskind et al. 2017). In general, the functional outcome after TUR-P seems to depend mainly on geriatric factors affecting the general condition, multimorbidity and care status. The indication must therefore be reconsidered individually for each patient. The newer, so-called minimally invasive procedures, such as 5 Rezüm® (water vapor injection) 5 Prostate artery embolization 5 UroLift® 5 iTIND® (temporary prostate stent implantation) have the appeal, regarding the “old and frail” population, that no general or regional anesthesia is necessary for cooperative patients. Data that show with good evidence that these technologies lead to the desired functional outcomes in exactly these patients, who would benefit from an operation in local anesthesia, for example 5 the liberation from the permanent catheter 5 an improvement of the functional micturition parameters and ultimately 5 an increase of the quality of life are not available to the author’s knowledge, but are naturally also difficult to collect.

References Anonymous 7 https://wikipedia.org/wiki/geriatrie Ball AJ, Feneley RC, Abrams PH (1981) The natural history of untreated „prostatism“. Br J Urol 53:613–616 Berges R, Oelke M (2011) Age-stratified normal values for prostate volume, PSA, maximum urinary flow rate, IPSS, and other LUTS/BPH indicators in the German male community-dwelling population aged 50 years or older. World J Urol 29:171–178 Bortnick E, Brown C (2020) Modern best practice in the management of benign prostatic hyperplasia in the elderly. Ther Adv Urol 12:1–11

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Chapple CR, Montorsi F, Tammela TL et al (2011) Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol 59:342– 352 Chu PSK, Leung CLH, Cheung MH et al (2021) Hong Kong Geriatrics Society and Hong Kong Urological Association consensus on personalised management of male lower urinary tract symptoms in the era of multiple co-morbidities and polypharmacy. Hong Kong Med J 27:127–139 Cicero AFG, Allkanjari O, Busetto GM et al (2019) Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. Arch Ital Urol Androl 91 Colau A, Lucet JC, Rufat P et al (2001) Incidence and risk factors of bacteriuria after transurethral resection of the prostate. Eur Urol 39:272–276 De Lucia C, Femminella GD, Rengo G et al (2013) Risk of acute myocardial infarction after transurethral resection of prostate in elderly. BMC Surg 13(Suppl 2):S35 Djavan B, Chapple C, Milani S et al (2004) State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 64:1081–1088 Egberts A, Moreno-Gonzalez R, Alan H et al (2021) Anticholinergic drug burden and delirium: a systematic review. J Am Med Dir Assoc 22(65– 73):e64 Gacci M, Corona G, Salvi M et al (2012) A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 61:994–1003 Gravas SCJN, Gacci M, Gratzke C, Herrmann TRW, Mamoulakis C, Rieken M, Speakman MJ, Tikkinen KAO (2021) EAU-Guidelines on management of non-neurogenic ,male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO). EAU Guidelines. European Association of Urology Gray SL, Anderson ML, Dublin S et al (2015) Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175:401–407 Hwang EC, Jung SI, Kwon DD et al (2014) A prospective Korean multicenter study for infectious complications in patients undergoing prostate surgery: risk factors and efficacy of antibiotic prophylaxis. J Korean Med Sci 29:1271–1277

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Khullar V, Amarenco G, Angulo JC et al (2013) Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol 63:283– 295 Kikuchi M, Kameyama K, Yasuda M et al (2016) Postoperative infectious complications in patients undergoing holmium laser enucleation of the prostate: Risk factors and microbiological analysis. Int J Urol 23:791–796 Kirollos MM (1997) Length of postoperative hospital stay after transurethral resection of the prostate. Ann R Coll Surg Engl 79:284–288 Kirollos MM, Campbell N (1997) Factors influencing blood loss in transurethral resection of the prostate (TURP): auditing TURP. Br J Urol 80:111– 115 Lee YK, Kuo HC (2018) Safety and therapeutic efficacy of mirabegron 25 mg in older patients with overactive bladder and multiple comorbidities. Geriatr Gerontol Int 18:1330–1333 Loke YK, Ho R, Smith M et al (2013) Systematic review evaluating cardiovascular events of the 5-alpha reductase inhibitor - Dutasteride. J Clin Pharm Ther 38:405–415 Makhani A, Thake M, Gibson W (2020) Mirabegron in the treatment of overactive bladder: safety and efficacy in the very elderly patient. Clin Interv Aging 15:575–581 Martin SA, Haren MT, Marshall VR et al (2011) Prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling Australian men. World J Urol 29:179–184 Masnoon N, Shakib S, Kalisch-Ellett L et al (2017) What is polypharmacy? A systematic review of definitions. BMC Geriatr 17:230 Miano R, De Nunzio C, Asimakopoulos AD et al (2008) Treatment options for benign prostatic hyperplasia in older men. Med Sci Monit 14:RA94– R102 Michel MC, Mehlburger L, Bressel HU et al (1998) Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does co-morbidity alter tolerability? J Urol 160:784–791 Nakahira J, Sawai T, Fujiwara A et al (2014) Transurethral resection syndrome in elderly patients: a retrospective observational study. BMC Anesthesiol 14:30 Oelke M, Wagg A, Takita Y et al (2017) Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged >/=75 years: integrated analyses of pooled data from multinational, randomized, placebo-controlled clinical studies. BJU Int 119:793–803

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Robinson TN, Wu DS, Pointer L et al (2013a) Simple frailty score predicts postoperative complications across surgical specialties. Am J Surg 206:544–550 Robinson TN, Wu DS, Sauaia A et al (2013b) Slower walking speed forecasts increased postoperative morbidity and 1-year mortality across surgical specialties. Ann Surg 258:582–588; discussion 588–590 Roehrborn CG, Boyle P, Bergner D et al (1999) Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 54:662–669 Schneidewind L, Kranz J, Schlager D et al (2017) Mulitcenter study on antibiotic prophylaxis, infectious complications and risk assessment in TUR-P. Cent European J Urol 70:112–117 Sebastianelli A, Spatafora P, Morselli S et al (2020) Tadalafil alone or in combination with tamsulosin for the management for LUTS/BPH and ED. Curr Urol Rep 21:56 Skeldon SC, Macdonald EM, Law MR et al (2017) The cardiovascular safety of dutasteride. J Urol 197:1309–1314

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Suskind AM, Walter LC, Zhao S et al (2017) Functional outcomes after transurethral resection of the prostate in nursing home residents. J Am Geriatr Soc 65:699–703 Tacklind J, Macdonald R, Rutks I et al (2012) Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 12:CD001423 Tubaro A, Batista JE, Nitti VW et al (2017) Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol 9:137–154 Vela-Navarrete R, Alcaraz A, Rodriguez-Antolin A et al (2018) Efficacy and safety of a hexanic extract of Serenoa repens (Permixon((R)) ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/ BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. BJU Int 122:1049–1065 Watt J, Tricco AC, Talbot-Hamon C et al (2018) Identifying older adults at risk of harm following elective surgery: a systematic review and meta-analysis. BMC Med 16:2

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Controversies in Conser­ vative and Surgical BPS Therapy Christopher Netsch and Andreas J. Gross Contents 23.1  Does the Normal-Sized Prostate Correspond to A Chestnut, is it 20 g in Size? – 234 23.2 Is there a Bladder Outlet Obstruction (BOO) in Case of a Large Prostate? – 234 23.3 Are Bladder Trabeculae Composed of Hypertrophied Muscle and are they Signs of Bladder Outlet Obstruction (BOO)? – 234 23.4 What are Bladder Diverticula and Bladder Pseudodiverticula? – 235 23.5 Is Urethrocystoscopy Suitable for the Diagnosis of Bladder Outlet Obstruction (BOO)? – 235 23.6 Does BPS Progress in Stages? – 236 23.7 Is Residual Urine Formation Caused by Bladder Outlet Obstruction? – 236 23.8 Does Residual Urine (RU) Lead to Urinary Tract Infections (UTIs)? – 237 23.9 Does RU Lead to Urinary Retention? – 237 23.10 Does RU Formation Lead to Renal Dysfunction? – 238

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_23

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23.11 Can Drugs Reduce Bladder Outlet Obstruction (BOO)? – 238 23.12 “Transurethral Enucleation Procedures take too Long Time. For Open Simple Prostatectomy (OSP) I just need 40 min” – 239 23.13 Is Resection to the Prostate Capsule Essential for an Optimal Result of TUR-P? – 239 23.14 What is Meant by Long-Term Data in Surgical BPS Therapy? – 240 23.15 Is a Histology Necessary After the Surgical Treatment of BPS? – 240 23.16 Can I Perform a HoLEP with the Thulium Laser? – 241 23.17 Are the Clinical (Long-Term) Data for GreenLight Vaporisation of the Prostate (PVP), Aquabeam®, iTind®, Rezum® and Urolift® convincing? – 241 23.18 Is it Possible to Treat a 150-g Prostate by TUR-P? – 242 23.19 Is the Learning Curve (LC) of (Laser) Enucleation of the Prostate Longer than that of TUR-P? – 243 23.20 We Perform Robotic-Assisted Simple Prostatectomy (RASP) Because Patients are Incontinent and Bleed After Transurethral Enucleation – 244 23.21 “The GreenLight Laser Is Not Suitable for BPS Surgery. Finally, You Have To Take the Loop.” Is a Surgical (Laser) Procedure for the Treatment of BPS Unreasonable, Because Finally One Takes a Loop for Coagulation? – 244

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23.22 We Perform Transurethral (Laser) Enucleation of the Prostate in Prostates larger than 60 g, Below that  TUR-P Because of Training the Residents. We Perform Open Simple Prostatectomy Because of Training the Residents – 245 23.23 Are more Patients Incontinent After Laser Surgery of the Prostate than After TUR-P? – 245 23.24 Do Patients Develop more Urge Symptoms After Laser Surgery of the Prostate than After TUR-P and Open Simple Prostatectomy (OSP)? – 246 23.25 Do have New-Minimally Invasive Procedures such as Aquabeam®, Rezum® or Urolift® No Serious Complications? – 247 References – 249

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 C. Netsch and A. J. Gross (eds.), Benign Prostate Syndrome, https://doi.org/10.1007/978-3-662-67057-6_23

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23.1  Does the Normal-Sized

Prostate Correspond to A Chestnut, is it 20 g in Size?

Chestnuts do not have a uniform size, but vary considerably in dimensions, weight and the different chestnut species. The prostate volume (PV) of a man after puberty corresponds more to a pigeon egg (22.3 cm3) than to a chestnut. The prostate, however, has the shape of a chestnut: heartshaped with a concave dorsal surface. The indication of the prostate weight of 20 g is based on average values, which were determined by a meta-analysis of autopsy studies (>1000 patients) (Berry SJ et al. 1984). The analysis of the individual studies reveals the enormous range of the weight: For example, in one study, prostates without evidence of a BPS had weights between 8 and 40 g (Swyer GI 1944). Also, in studies of young healthy adult men with transrectal ultrasound (TRUS), the average PV was 23.0 cm3 (range: 11.3-39.1 cm3) (Jakobson H et al. 1988). Consequently, the normal-sized prostate has an average weight (volume) of about 20 g (cm3), but can vary greatly from this reference value individually. In young healthy adult men, PVs between 8 and 40 cm3 are considered physiological. A clear prostate enlargement is present when the prostate has the dimensions of a golf ball (approx. 40 cm3) or exceeds them. The PV determined by digital rectal examination or TRUS is based on length measurements. The volume estimation is done by multiplying 3 length specifications (width [cm] x length [cm] x depth [cm] x 0.52), resulting in the volume (cm3). According to the international system of units, a volume indication could also be given in milliliters (ml) (1 cm3 = 1 ml), but only if it is a liquid. Therefore, cm3 is the correct unit for the PV after DRE or TRUS

and “g” is the correct unit for the weighted prostate tissue after prostate operations. 23.2  Is there a Bladder Outlet

Obstruction (BOO) in Case of a Large Prostate?

Although the probability of a BOO increases with increasing prostate volume (PV), the diagnosis of a prostate enlargement is not a reliable indicator of the presence of a BOO. Rosier et al. investigated the relationship between PV and BOO: While a severe (Schäfer grade 5/6) BOO was already present in 11% and a mild BOO in 50% of cases with PV between 20 and 40 cm3 (Schäfer grade 2-4), even patients with a PV between 60 and 80 cm3 had no BOO in approx. 15% and patients with PV >100 cm3 in approx. 10% (Rosier and Rosette 1995).The sensitivityand specificity for the presence of a BOO for PV ≥ 40 cm3 is only 49% and 32%, respectively. A study from Korea confirmed the results: Even with a PV > 80cm3, a BOO is present in only 83% of cases (Kang M et al. 2016). The PV therefore has no reliable relationship to the BOO or the degree of BOO. A BOO can only be detected by a urodynamic examination or sonographic detrusor thickness measurement. 23.3  Are Bladder Trabeculae

Composed of Hypertrophied Muscle and are they Signs of Bladder Outlet Obstruction (BOO)?

Bladder trabeculae are histologically composed of deposits of collagenous and elastic fibers in the mucosa/submucosa of the bladder wall (Gosling JA et al. and

235 Controversies in Conservative and Surgical BPS Therapy

Dixon 1980). These are not caused by increased detrusor pressure during micturition (BOO), but by unknown mechanisms in detrusor overactivity (DO) (Abrahams PH et al. 1976). However, the probability of DO also increases with increasing BOO degree (Detrusor overactivity without BOO in 51% → in severe BOO in 83%) (Oelke M et al. 2008). In some patients, the bladder trabeculation is an expression of a DO caused by BOO, but in individual cases, the reliable prediction for a BOO in the presence or absence of bladder trabeculation is not possible.

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23.5  Is Urethrocystoscopy

Suitable for the Diagnosis of Bladder Outlet Obstruction (BOO)?

The optical assessment of the lower urinary tract is a very unreliable method for BOO assessment (El Din KE et al. 1996). Thus, a patient without relevant occlusion of the prostatic urethra has a BOO probability of already 18%, but with strong occlusion only of 56% (. Fig. 23.1a/b). Similarly, the assessment of the degree of trabeculation of the bladder mucosa is unreliable. While a

23.4  What are Bladder

Diverticula and Bladder Pseudodiverticula?

A true diverticulum consists in the pathological-anatomical sense of all wall layers, i.e. mucosa, detrusor and adventitia; in contrast, the wall of a pseudodiverticulum consists only of mucosa. Therefore, most supposed bladder diverticula are actually pseudodiverticula and vice versa the small bladder wall protrusions are true diverticula. There is no solid evidence for the assumption that the entire bladder wall (diverticulum) or only the mucosa (pseudodiverticulum) is pushed outwards through gaps in the bladder wall by increased detrusor pressure during micturition in BOO (Oelke M et al. 2012). Only a retrospective comparison (24 patients with pseudodiverticula vs. 67 patients without pseudodiverticula) showed that significant differences existed in the groups among others regarding the BOO degree (Adot Zurbano JM et al. 2005). This study showed that patients with pseudodiverticula have increased micturition pressures, but does not prove that the increased pressures caused the pseudodiverticula.

. Fig. 23.1  Cystoscopic classification of bladder trabeculation in 4 grades (upper half of the picture, grade 0 = smooth bladder mucosa without signs of trabeculation → grade 3 = strong trabeculation with formation of bladder diverticula) and classification of the occlusion degree of the prostatic urethra in 3 grades (lower half of the picture; grade 1=slightly prominent lateral lobes with patent urethra → grade 3=prominent lateral lobes, which touch each other in the midline and cannot be flushed open with the irrigation jet of the cystoscope.

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bladder without trabeculation (trabeculation degree 0) has a probability of BOO of 18%, a bladder with strong trabeculation (trabeculation degree 3) has one of 78% (. Fig. 23.1a/b).

No BOO

borderline BOO

BOO

23.6  Does BPS Progress in Stages?

Outdated classifications (Vahlensieck, Alken) assume that a chronological sequence of anatomical and pathophysiological changes in the lower urinary tract exists in BPS. Such a staging of BPS has not been established internationally due to lack of evidence. There are no fixed relationships between BPE and BOO (Bosch JL et al. 1995), BPE and LUTS (Bosch JL et al. 1995; Girman CJ et al. 1995) as well as BOO and LUTS (Barry MJ et al. 1993; El Din KE et al. 1996; Ko DS et al. 1995; Yalla SV et al. 1995). Therefore, the view described by Hald (1989) has prevailed internationally (. Fig. 23.2, Hald T 1989). This view assumes that all components of BPS can occur alone or in (all conceivable) combinations and patients must be classified individually with regard to BPE, BOO and LUTS: One change cannot automatically be referred to another. Furthermore, the Hald rings imply that each component or component combination must be treated specifically (. Fig. 23.3). 23.7  Is Residual Urine Formation

Caused by Bladder Outlet Obstruction?

Normal values Targeted studies on residual urine (RU) in asymptomatic men >50 years (without taking medications that affect bladder function) have shown that a small amount of RU is normal. On average, these values were age-independent and ranged between

Trabe gully degree of the hambladder mucous membrane

No BOO

borderline BOO

BOO

Degree of occlusion of the prosta c urethra

. Fig. 23.2  a Probability of BOO with different degrees of trabeculation of the bladder mucosa. With increasing bladder trabeculation, the probability of BOO increases (grade 0 = 18% → grade 3 = 78%). However, the degree of trabeculation does not allow reliable conclusions about the presence of BOO in the individual patient. b Probability of BOO with different degrees of occlusion of the prostatic urethra. With increasing occlusion degree, the probability of BOO increases (grade 1 = 18% → grade 3 = 56%). However, the diagnostic performance for BOO assessment is low and does not allow reliable conclusions about the presence of BOO in the individual patient

22 and 39 ml, with a maximum of 57 ml (Berges R and Oelke M 2011). Pathophysiology The causes of RU formation are diverse. The most common cause is postulated to be mechanical BOO due to BPE, which, however, only applies to about half of the BPS patients (Oelke M et al. 2008). More significant is the genesis of RU by detrusor underactivity (DUA), which is often underestimated as a cause of BPS. The causes of DUA are diverse and not yet fully un-

237 Controversies in Conservative and Surgical BPS Therapy

. Fig. 23.3  Schematic representation of the relationships between the 3 main components of BPS (LUTS lower urinary tract symptoms, BPE benign prostatic enlargement, BOO bladder outlet obstruction) (Modified after Hald T 1989; Girman et al. 1995). The socalled Hald rings illustrate that there are no fixed relationships between the main components of BPS and LUTS, BPE and BOO can occur individually or in various combinations. For this reason, the individual main components must also be analyzed separately, since the presence or absence of one component does not automatically imply the presence or absence of another component

derstood. Anatomically caused RU occurs in pseudodiverticula or reflux due to the “trickling” of urine into the bladder after the end of micturition. Residual urine and BOO There is only a weak correlation between RU and BOO. There is also only a weak association between RU, strength of LUTS and PV (Barry MJ et al. 1993; Bosch JL et al. 1995). The presence or absence of BOO cannot be confirmed or ruled out by the amount of RU measured. RU and detrusor underactivity (DUA)? The prevalence of DUA is reported to be 9–48% and occurs in men and women with approximately equal frequency (Osman NI et al. 2014). DUA is thus hardly explainable

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by the presence of BOO and rather related to age-related changes of the detrusor, diabetes mellitus, degenerative changes of the central or peripheral nervous system, neurological diseases etc. RH >300 ml, which is referred to as chronic retention in the English literature, is more indicative of DUA than of BOO (Abrahams PH and Griffiths 1979). If a TUR-P is performed in DUA, a worse outcome than in BOO is to be expected (Anderson JB and Grant JB 1991; Van De Beek et al. 1992). In a long-term observation of patients with DUA (without evidence of BOO) >10 years after TUR-P, these showed no benefits of surgery compared to untreated patients and even had a higher rate of RH >300 ml (Thomas AW et al. 2004). 23.8  Does Residual Urine (RU)

Lead to Urinary Tract Infections (UTIs)?

The assumption that RU is associated with an increased rate of UTIs is controversial. In geriatric patients, RU does not seem to be associated with bacteriuria, incontinence, immobility, cognitive impairment or neurological diseases (Barabas G and Molstad S 2005; Omli R et al. 2008). In 225 asymptomatic men (mean age 66 years), a higher rate of bacteriuria was found with increasing RU. The threshold of RU at which the occurrence of a UTI is likely could not be determined (Brookman-May S et al. 2010). In men with BPS, only a weak correlation between RU and UTI was demonstrated (Bruskewitz RC et al. 1982). 23.9  Does RU Lead to Urinary

Retention?

In the 4-armed MTOPS study on the pharmacological mono- and combination therapy of BPH, the analysis of the patients

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treated with placebo after 4 years showed no higher incidence of acute urinary retention depending on larger or smaller RU before therapy initiation (Crawford ED et al. 2006). Depending on the RU, only an increase in the global progression of BPH (symptoms and probability of invasive therapy) was observed. In another study, 156 patients with urinary retention were urodynamically examined for the presence of BOO. 5 days after urine drainage by means of a catheter, the RU in patients with BOO was even lower than in those without BOO (Rom M et al. 2013). However, there is a good correlation between RU and age (Kaplan SA et al. 2008). In men with BOO, only age and larger PV were predictive of urinary retention (Thomas AW et al. 2005). 23.10  Does RU Formation Lead

to Renal Dysfunction?

A literature review on the relationship between BPH and renal insufficiency showed that RU >300 ml were associated with an increased rate of renal insufficiency, but additional factors influencing renal function such as arterial hypertension, UTI and reduced bladder distensibility (low compliance) were identified (Rule AD et al. 2005). The authors concluded that there is no direct relationship between RU alone and renal insufficiency. A further study confirms this result (Hong SK et al. 2010): In 5.9% of the patients, an increase in the serum creatinine concentration was detected, which was associated with poorer uroflow, hypertension and/or diabetes mellitus. A correlation between RU alone and renal insufficiency could not be demonstrated.

23.11  Can Drugs Reduce Bladder

Outlet Obstruction (BOO)?

The basis for the possibility that BPH drugs could reduce BOO is the concept of the dynamic and static component of the obstruction (Donker PJ et al. 1972; Furuya S et al. 1982). The dynamic component is defined by an increase in tension of the prostatic muscle and the static component by an increase in tissue due to BPH/BPE. Based on this, the idea developed that α-blockers could cause a relaxation of the prostatic muscle and thus a reduction of the dynamic obstruction by inhibiting the intraprostatic α1-receptors and 5α-reductase inhibitors could cause a reduction of the PV and thus a reduction of the static BOO by inhibiting the conversion of testosterone into dihydrotestosterone. A meta-analysis of the influence of placebo and all drugs currently used in the therapy of BPH on the urodynamics of BOO from 147 original publications shows: Only α-blockers reduce the most important parameter Pdet.Qmax for the urodynamic quantification of BOO by an average of –12.9 cm H2O. A more recent meta-analysis finds similar values with –11.39 cm H2O (Fusco F et al. 2016). The BOO reduction is thus marginal and clinically not relevant, a deobstruction does not occur. The reduction of Pdet.Qmax with anticholinergics is explained by the (slight) decrease in detrusor contractility and not by the influence on the BOO. z Surgical therapy of BPH

Even if it is hard for experienced surgeons to accept: Progress does not stop at ­operative medicine! Questioning one’s own skills should ideally be inherent in every

239 Controversies in Conservative and Surgical BPS Therapy

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surgeon - especially if one has established a procedure, learned an intervention laboriously and mastered the procedure. A new surgical procedure always questions one’s own skills. There are 3 ways to deal with it. 1. Deal seriously with the procedure (the ideal) 2. Ignore it (be satisfied with what one can do) 3. Discredit new things by targeted misinformation (because one does not have access to the technique or has established the old/competing technique).

compared BipolEP with OSP, OSP was significantly faster (121 vs. 102 min, PV 127 vs. 118 ml). In summary, the above statement can be refuted, since a) operative times of 40 min for OSP cannot be proven by literature and b) transurethral enucleation procedures are not always slower than OSP. However, higher morbidity, longer catheterization times and longer hospital stay are well documented for OSP compared to transurethral enucleation procedures (Cornu JN et al. 2015).

In the following section we discuss common questions/statements that are repeatedly asked/asserted in connection with the operative BPH therapy.

23.13  Is Resection to the Prostate

23.12  “Transurethral Enucleation

Procedures take too Long Time. For Open Simple Prostatectomy (OSP) I just need 40 min”

In a prospective multicenter evaluation of 902 patients who underwent OSP, the preoperative PV was 96 ml on average. In 81 min, an average of 84.8 g was removed (Gratzke et al. 2007). Adam et al. retrospectively analyzed 201 patients who received OSP. The mean operative time was 85.3 min with a PV of 90.3 g (Adam et al. 2004). In contrast, a prospective analysis of 266 patients with a median PV of 100 cm3, who underwent transurethral thulium vapoenucleation of the prostate (ThuVEP), documented a median operative time of 75 min (Gross et al. 2013). In 3 prospective randomized studies that compared bipolar enucleation of the prostate (BipolEP) with OSP, no differences were found regarding the operative times (Geavlete B et al. 2014; Ou R et al. 2013; Rao M et al. 2013). Only in a randomized controlled trial (RCT) by Chen et al., who

Capsule Essential for an Optimal Result of TUR-P?

This question cannot be answered unequivocally, because the endpoint “optimal” is not defined. What is “optimal”? A sufficient improvement of micturition in the immediate perioperative course or 1, 2, 3 or 5 years after surgery? Few urge complaints? A low re-intervention rate after 5 or 10 years? Mauermeyer (1981) had characterized the thesis that TUR-P should correspond to OSP in terms of resection volume, i.e. the complete removal of the transitional zone to the “surgical capsule” (Mauermeyer 1981). For PV ≤30 cm3, the efficiency of monopolar or holmium incision of the prostate without any ablation of tissue is well documented comparable with TUR-P (Elkoushy MA et al. 2015; Lourenco T et al. 2010). In contrast, a meta-analysis showed a higher re-OP rate after TUIP than after TUR-P (18.4% vs. 7.2%) (Lourenco T et al. 2010). A correlation between the relative ratio of resected tissue to total weight of the prostate and subjective and objective TUR-P outcomes could not be demonstrated. Antunes et al. resected different PV in 88 patients and compared resection volumes50% (n = 22) (Antunes AA et al. 2009). Three months

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after TUR-P, there were no differences in IPSS or quality of life. In the immediate postoperative course, the amount of removed tissue does not seem to make a difference on the improvement of micturition. Conversely, 8 years after OSP (n = 2452 patients), a significantly lower rate of secondary procedures compared to TUR-P (n = 20,671 patients) was shown (9.5 vs. 14.7%) (Madersbacher S et al. 2005). This can only be explained by the complete removal of the transitional zone with OSP. 23.14  What is Meant by Long-

Term Data in Surgical BPS Therapy?

When approaching the surgical BPS literature, one finds contradictory information on the definition of “long-term data”. These are relevant when comparing new procedures with the standard procedures, TUR-P and OSP. For these procedures, data with a follow-up of up to 20 years are available. So what are long-term data? Krambeck et al. called 12-month data long-term data in their analysis of HoLEP data (Krambeck A et al. 2010), while others referred to a mean follow-up of 16.9 months (Kuo RL et al. 2003), 24 months (Bruyere F et al. 2010), 36 months (Elzayat EA et al. and Elhilali 2006; Te AE et al. 2006; Elmansy HM et al. 2010), 41 months (Varkarakis I et al. 2004) or 60 months (Ruszat R et al. 2008) as long-term data. Consequently, there is a confusion regarding the term “long-term data”. When interpreting data, attention must also be paid to the rate of those who were available at follow-up (drop outs). However, in order to classify the long-term success of a BPS therapy, the long-term follow-up is crucial, in addition to the quality of the study design, in order to assess the reintervention rate of the respective procedures. Or, in other words: A high drop-out rate

can ­dilute the long-term results positively or negatively, because either only those who have no micturition problems attend the (long-term) follow-up examinations, or only those who have micturition problems. 23.15  Is a Histology Necessary

After the Surgical Treatment of BPS?

Bach et al. performed a retrospective analysis of 154 patients with biopsy-confirmed prostate cancer (PCa) who underwent TUR-P before HIFU therapy. The average PSA value was 9.8 ng/dL, the PV was 32 ml and the resection weight was 18 g. A PCa was found in only 54% of the patients (Bach T et al. 2008). Consequently, the value of a histology in TUR-P with biopsy-confirmed PCa is equivalent to a coin toss. Herlemann et al. retrospectively examined the oncological parameters before and after HoLEP (n = 289) and TUR-P (n = 229). The prevalence of incidental PCa (iPCa) was 15 and 17% after HoLEP and TUR-P, respectively. In a multiple logistic regression analysis, age and PSA density were identified as independent predictors for the detection of an iPCa (Herlemann A et al. 2017). Elkoushy et al. found in a retrospective analysis of a HoLEP series of 1242 patients an iPCa in 70 patients (5.64%). Patients with iPCa had a higher preoperative PSA and a higher total PSA density. Patient age and the preoperative total PSA density were independent predictors for an iPCa after HoLEP. In patients with iPCa, the overall survival was 72.8% after 5 and 63.5% after 10 years, with only 7 (11.7%) patients with iPCa receiving active therapy (Elkoushy et al. 2015a,b). What are the conclusions? 1. A transurethral histology does not replace an adequate preoperative PCa diagnosis (e.g. PSA, MRI, fusion biopsy) 2. Even in the case of an iPCa

241 Controversies in Conservative and Surgical BPS Therapy

diagnosis, the long-term survival is good (Elkoushy MA et al. 2015). 23.16  Can I Perform a HoLEP

with the Thulium Laser?

In principle, all transurethral enucleation procedures of the prostate are based on the work of Hiraoka et al. and Peter Gilling (Hiraoka and Akimoto 1989; Gilling P et al. 1998): Either the tip of the resectoscope is used to bluntly separate the prostate adenoma from the surgical pseudocapsule followed by a coagulation of bleeding vessels with the respective energy source, or the energy source is continuously applied to the enucleation layer between adenoma and surgical pseudocapsule. The physical-technical properties of thulium lasers (Tm:YAG and thulium fiber laser) are similar to those of the Ho:YAG laser. While the Ho:YAG laser has a wavelength of 2100 nm and a tissue penetration depth (i.e. coagulation zone) of 0.4 mm, the wavelength of the thulium laser varies depending on the model between 1940 and 2013 nm, with a tissue penetration depth of 0.2 mm. The target chromophore of the thulium and the holmium laser is water; the wavelengths of the thulium and the holmium laser are close to the absorption maximum of water. The main difference between holmium and thulium lasers is the kind of the energy delivery: While the Ho:YAG laser is a so-called pulsed laser, the thulium laser can deliver the energy continuously (so-called “continuous wave”) (Bach T et al. 2012). What does this mean for practice? 1. The individual laser pulses (gas bubble at the tip of the laser fiber) of the holmium laser lead to a spreading of the layer between adenoma and pseudocapsule. A HoLEP works very well - but the layer has to be found. A vaporization or resection of the prostate with the

23

­ olmium:YAG laser is ineffective up to h impossible (Bach T et al. 2012). 2. The continuous laser radiation of the thulium laser results in a high energy density, which leads to a rapid vaporization (evaporation) of water and (water-containing) tissue. Due to the high vaporization component during resection and enucleation with the thulium laser, the acronyms ThuVaRP (Thulium VapoResection of the prostate) and ThuVEP (Thulium VapoEnucleation of the prostate) were introduced (Bach T et al. 2010). The continuous energy delivery of thulium lasers allows a maximum hemostasis and coagulation. Smooth cut surfaces are created with high tissue vaporization (so-called vaporization) and low tissue penetration. This technical-physical difference, the “cw” energy delivery, may represent an advantage in learning the enucleation technique with the thulium laser: The cw energy delivery allows an uncomplicated correction of the enucleation layer or an easy switch from the VapoEnucleation to VapoResection or to a pure vaporization technique. In summary, the same result is achieved with the thulium or holmium enucleation of the prostate: a complete removal of the adenoma from the pseudocapsule of the prostate - but the surgical technique differs. 23.17  Are the Clinical (Long-

Term) Data for GreenLight Vaporisation of the Prostate (PVP), Aquabeam®, iTind®, Rezum® and Urolift® convincing?

All the mentioned procedures have in common that the evidence is based on excellently done, RCT. The study objectives are

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achieved by appropriate patient selection and definition of the study endpoints. A major weakness of these studies is the lack of independence: The studies were funded by the manufacturers, the list of conflicts of interest of the involved physicians is accordingly long. Exemplarily, studies on PVP and Aquablation are presented here: 1. The 2-year results of the so far only RCT (GOLIATH study) between mono- and bipolar TUR-P and PVP with the 180-W laser in patients with a PV up to 80 ml showed a non-inferiority of PVP with the 180-W laser with regard to IPSS improvement - but also no superiority over TUR-P (i.e. no advantage). Furthermore, the improvement of Qmax, the reduction of postvoid residual urine (PVR), the reduction of PV, the PSA drop as well as quality of life questionnaires were comparable (Thomas JA et al. 2016). A more meaningful endpoint to compare both procedures would have been the reintervention rate after 5 years. Moreover, this RCT represents a highly selected patient population: 16 patients were enrolled per month in a total of 29 centres. 2. In the WATER study, 181 patients with a PV between 30 and 80 ml and an IPSS  ≥12 were included and randomised in a 2:1 ratio to Aquablation or TUR-P. The primary efficacy endpoint of the study was the change in IPSS from baseline to 6 months postoperatively. Of course, besides the primary, all secondary endpoints were achieved. Also 3 years postoperatively, excellent results were published. Aquablation was not inferior to TUR-P. Remarkably, despite of a low PSA reduction in both study arms an excellent micturition improvement and a low reintervention rate was found (Gilling P et al. 2020): In particular, the reintervention rate in the TUR-P arm was lower than in

c­ omparable TUR-P series. Interestingly, all Aquablation procedures were accompanied by company proctors. 3. Also for Rezum® (McVary KT et al. 2021), Urolift® (Roehrborn CG et al. 2017) and iTind® (De Nuncio C et al. 2020) there are studies with excellent results, but with the mentioned limitations (conflicts of interest, sponsoring by the manufacturers).

23.18  Is it Possible to Treat

a 150-g Prostate by TUR-P?

TUR-P is the standard procedure for the surgical therapy of BPS. Long-term data documented the effectiveness of the method. The good long-term results are contrasted by the perioperative morbidity of the procedure. In a multicenter study of over 10,000 patients, it was shown that the perioperative complication risk increases with increasing prostate resection weight: With more than 60 g of resected prostate tissue, a significant increase in the transfusion rate (9.5% vs. 2%), immediate reintervention rate (9.8% vs. 5.2%), TUR syndrome (3% vs. 1.2%) and mortality rate (0.71% vs. 0.09%) was observed compared to a resection weight 300 g) in patients on oral anticoagulants. In fact, in the largest prospective multicenter series (n = 487), the median PV was 110 ml and the resection weight was 75 g (Autorino R et al.

2015), a PV many urologists would still perform a TUR-P. While the ­perioperative morbidity, the postoperative incontinence is well documented for EEP, this is not the case for RASP. Only in a retrospective comparative study was the transient incontinence after HoLEP higher than after RASP (8.9% vs. 1.2%), but after 6 months no longer detectable in both groups (Umari P et al. 2017). The transfusion rates seem to be comparable after RASP, if performed by experts, to EEP. Nevertheless, catheter and hospital stay are shorter after HoLEP than after RASP (John H et al. 2021). The tendency to perform RASP seems to be driven by the expertise and availability of the technique according to the authors of the chapter: Excellent robotic surgeons can rarely perform an EEP at a similar expert level as a RASP … so which technique will they probably offer?

23.21  “The GreenLight Laser

Is Not Suitable for BPS Surgery. Finally, You Have To Take the Loop.” Is a Surgical (Laser) Procedure for the Treatment of BPS Unreasonable, Because Finally One Takes a Loop for Coagulation?

This question cannot be answered with literature, because the literature does not provide standardized information on this issue. Renowned HoLEP surgeons state that they “always” have a loop on the operating table. In the HoLEP and EEP literature, this is sparsely stated. Therefore, the “estimated figure” for the use of a loop for final coagulation/apical resection of the prostate is probably much higher for EEP procedures. On the other hand, for PVP and

245 Controversies in Conservative and Surgical BPS Therapy

for publications on aquablation therapy of the prostate, it is precisely stated in what percentage coagulation or resection was ­ performed. Can one now infer from the use of a loop whether a procedure is suitable for BPS surgery or not? A negative, positive effect or the percentage of using a loop has not been published at least for HoLEP. 23.22  We Perform Transurethral

(Laser) Enucleation of the Prostate in Prostates larger than 60 g, Below that TUR-P Because of Training the Residents. We Perform Open Simple Prostatectomy Because of Training the Residents

There are good arguments for the former statement, which can be supported by literature. TUR-P is the standard procedure in the surgical therapy of BPH. Longterm data document the effectiveness of the method. The perioperative complication risk increases with increasing prostate resection weight (Reich O et al. 2008). For smaller PV, this plays only a minor role. Therefore, TUR-P is recommended in the current EAU guidelines up to 80 ml PV (Gravas S et al. 2016). Minimally-invasive (laser) procedures are not available everywhere. For smaller PV the differences between the procedures are not so evident, so that teaching TUR-P is reasonable. In addition, the pseudocapsule of the prostate is not so strongly developed in smaller PV and the enucleation therefore often proves more difficult than in PV between 60 and 100 ml. For the second statement, however, there are few arguments: The perioperative morbidity of the OSP is considerable: Gratzke and colleagues analyzed the

23

data of 902 patients who received an OSP (Gratzke C et al. 2007) and found a high perioperative morbidity (transfusion rate 7.5%, mean hospital stay 11.9 days, morbidity 17.3%, mortality 0.2%). Newer data from Gilfrich and colleagues confirmed the results of the study (Gilfrich C et al. 2016). They analyzed the data of 95,577 patients from the period 2008-2013 who received a surgical therapy of LUTS. They found a high perioperative morbidity (mortality: 0.51%, transfusion: 14.49%, complication rate; 24.42%). Compared to aser vaporization, TUR-P and laser enucleation of the prostate, OSP had the highest perioperative morbidity (Gilfrich C et al. 2021): In summary, OSP is an effective procedure with a not up-to-date perioperative morbidity. Moreover, the surgery of large PV in BPH is an elective procedure. Alternative surgical methods such as the EEP are available, which question the performance of an OSP in Germany in 2021. Basically, the question arises, what should be learned during training of the residents. An OSP seems to be outdated according to the authors of the chapter. The training argument is often put forward. However, the „training“ argument means that for training reasons also open stone surgery (open nephrolithotomy for staghorn stones, ureterotomy for distal stones) should be taught, TUR-P should be performed without a camera and a nephrostomy insertion should be done by incision for teaching reasons........ 23.23  Are more Patients

Incontinent After Laser Surgery of the Prostate than After TUR-P?

In a RCT that compared HoLEP with OSP, the transient stress incontinence was 2.4% and 2.5% respectively after 3 months and

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subsided after 1 year. In contrast, 34.1% and 38.6% (p = 0.2) of the patients after HoLEP and OSP showed a transient urge incontinence. After one year, the urge incontinence rate dropped to 5.4% in the HoLEP and 8.5% (p = 0.03) in the OSP arm (Naspro et al. 2006) and was thus significantly higher after OSP. Ahyai and colleagues performed a meta-analysis of transurethral procedures for the treatment of BPH in 2010 to compare the perioperative morbidity and the postoperative success. In the pooled data analysis, the rate of postoperative stress incontinence for PVP was 0%, 0.6% for TUR-P and 0.9% for HoLEP (Ahyai et al. 2010). In a prospective multicenter study, all patients who received a surgical therapy for BPH between 2011 and 2014 were recorded from 5 Hamburg departments. A total of 2648 patients (TUR-P: n = 798, PVP: n = 468, ThuVEP: n = 1382) were included. A de novo incontinence was found in 1.7%: 2.1% after PVP, 1.6% after TUR-P and 1.5% after ThuVEP (Bach T et al. 2016). In the GOLIATH study, a multicenter non-inferiority RCT that compared the 180 W XPS GreenLight PVP (n = 136) with mono- or bipolar TUR-P (n = 133), the immediate postoperative incontinence rate was 11.8% after PVP and 4.5% after TUR-P. 12 months postoperatively, the incontinence rate was 2.9% and 3% after PVP and TUR-P respectively (Bachmann A et al. 2015). In summary, patients who received treatment for BPH with the common laser systems (holmium, thulium, greenlight laser) did not develop incontinence more often than after TUR-P or OSP.

23.24  Do Patients Develop more

Urge Symptoms After Laser Surgery of the Prostate than After TUR-P and Open Simple Prostatectomy (OSP)?

In a RCT by Naspro et al. from 2006, HoLEP was compared with OSP. Transient urge incontinence occurred in 34.1% and 38.1% of patients after HoLEP and OSP, respectively, without differences between the procedures. After 1 year, the urge incontinence rate after OSP was higher than after HoLEP (8.5 vs. 5.4%). Dysuria occurred after both procedures transiently (68.2 vs. 41%) and after one year (10.8 vs. 8.5%) more frequently after HoLEP than after OPE (Naspro et al. 2006). Montorsi et al. conducted a RCT and compared TUR-P with HoLEP. Here, dysuria occurred in 58.9% of patients after HoLEP and in 29.5% after TUR-P. A transient urge incontinence was found in 44% and 38.6% after HoLEP and TUR-P, respectively (Montorsi F et al. 2004). In the already mentioned GOLIATH study, the immediate postoperative rate of voiding symptoms (irritative symptoms, pain, mild pain) was 18.4% after PVP and 18% after TUR-P without differences between the procedures (Bachmann A et al. 2015). Ahyai and colleagues performed a systematic review of minimally-invasive therapies for BPH in 2010. Transient dysuria rates of 0.8% (0-22%) for M-TUR-P, 0% for B-TUR-P, 2.9% (0-12%) for bipolar prostate vaporization, 1.2% (0-10%) for

23

247 Controversies in Conservative and Surgical BPS Therapy

HoLEP and 8.5% (0-22%) for PVP are reported. Urge symptoms of 2.2% (0-38%) for M-TUR-P, 0.2% (0-2%) for bipolar TUR-P, 0% for bipolar prostate vaporization, 5.6% (0-44%) for HoLEP and 0% for Greenlight vaporization are reported (Ahyai S et al. 2010). In summary, it can be stated that the picture is not as clear as assumed. Even after TUR-P and OSP, urge symptoms and urge incontinence occur more frequently than previously thought. 23.25  Do have New-Minimally

Invasive Procedures such as Aquabeam®, Rezum® or Urolift® No Serious Complications?

For the so-called “minimally-invasive surgical therapies”, the MIST procedures for the treatment of BPH, there are excellent RCTs such as the WATER-I study (Aquablation vs. TUR-P, Gilling P et al. 2020), the L.I.F.T. study (Urolift vs. Sham procedure, Roehrborn CG et al. 2017) or 5-year data for Rezum® (Rezum® vs. Sham procedure, McVary KT et al. 2021). The occurrence of complications was low in these studies. To assess the occurrence of complications of these procedures, Weiss et al. evaluated data from the Food and Drug Administration (FDA, US agency for ­

food and drug safety): the so-called FDA Manufacturer and User Facility Device (MAUDE) database. In this online database, all complications of surgical procedures are reported, partly mandatory, partly voluntary (Weiss et al. 2021). Weiss and colleagues evaluated the data for Rezum®, Urolift® and the TUR-P for the period 01/2015 to 12/2019. Complications were rated in severity from 1 (simple, no deviation from postop. course) to 4 (severe, life-threatening). The study came to surprising results. In fact, life-threatening events and bleeding complications were reported more frequently for Urolift® and Rezum® than for the TUR-P (. Tab. 23.1,23.2).Bleeding complications were the most common reported complications after Urolift® and Rezum® (Weiss et al. 2021). Kaplan-Marans and colleagues conducted a similar search using the MAUDE database (Kaplan-Marans et  al. 2021). They analyzed reported Aquablation, Urolift®- and Rezum®-complications for the period from 01/2015 to 07/2020. The following complications were recorded for the procedures (. Tab. 23.3): In summary, even minimally-invasive procedures of the prostate, the so-called MIST therapies, are not completely free of complications. Patients should be fully informed about the occurrence of complications, even with the so-called MIST procedures.

. Tab. 23.1  Postoperative complications grade 1–4. (After Weiss et al. 2021) TUR-P (n = 214)

Urolift® (n = 83)

Rezum® (n = 112)

Total (n = 408)

Grade 1

114 (53.3%)

13 (15.7%)

35 (31.3%)

161 (39.5%)

Grade 2

87 (40.7%)

28 (33.7%)

66 (58.9%)

181 (44.4%)

Grade 3

10 (4.7%)

26 (31.3%)

7 (6.3%)

43 (10.5%)

Grade 4

3 (1.4%)

16 (19.3%)

4 (3.6%)

23 (5.6%)

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C. Netsch and A. J. Gross

. Tab. 23.2  Types of complications. (According to Weiss et al. 2021) TUR-P (n = 214)

Urolift® (n = 83)

Rezum® (n = 112)

UTI

0

12

13

Sepsis

0

7

2

Infection

Abscess

0

0

1

Necrotizing fasciitis

0

1

0

7

8

14

Bleeding Hematuria (without clots) Hematuria (with clots)

0

9

5

Blood transfusion

1

19

0

Retroperitoneal/pelvic hematoma

0

16

0

Operative intervention required

0

17

4

Pain

7

11

28

LUTS

5

20

37

Sexual dysfunction

1

0

10

Cardiovascular events

0

5

2

Death

3

6

1

. Tab. 23.3  Types of complications. (After Kaplan-Marans et al. 2021) Complications

Urolift® n = 132 (%)

Aquablation n = 102 (%)

Rezum® n = 157 (%)

Hematuria

21 (16 %)

38 (37 %)

24 (15 %)

Blood transfusion

21 (16 %)

32 (31 %)

1 (1 %)

Tamponade removal/irrigation

11 (8 %)

25 (25 %)

6 (4 %)

Retroperitoneal/pelvic hematoma

13 (10 %)

0 (0 %)

0 (0 %)

Arterial embolization

1 (1 %)

1 (1 %)

0 (0 %)

Percutaneous drainage

1 (1 %)

0 (0 %)

0 (0 %)

Laparotomy

3 (2 %)

2 (2 %)

0 (0 %)

Hydrocele infection or epididymitis

0 (0 %)

0 (0 %)

5 (3 %)

Rectal perforation

0 (0 %)

4 (4 %)

0 (0 %) (Continued)

249 Controversies in Conservative and Surgical BPS Therapy

23

. Tab. 23.3  Continued Complications

Urolift® n = 132 (%)

Aquablation n = 102 (%)

Rezum® n = 157 (%)

Percutaneous nephrostomy

1 (1 %)

0 (0 %)

0 (0 %)

DJ catheter

3 (2 %)

0 (0 %)

0 (0 %)

Stone removal

2 (2 %)

0 (0 %)

0 (0 %)

Prostate capsule perforation

0 (0 %)

2 (2 %)

0 (0 %)

Bladder perforation

1 (1 %)

0 (0 %)

1 (1 %)

Orchiectomy

1 (1 %)

0 (0 %)

0 (0 %)

Embolism, thrombosis Implant removal Late problems due to Implant

0 (0 %) 16 (12 %) 9 (7 %)

1 (1 %)

0 (0 %)

References Abrams PH, Roylance J, Feneley RC (1976) Excretion urography in the investigation of prostatism. Br J Urol 48:681–684 Abrams PH, Griffiths DJ (1979) The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 51:129–134 Adam C, Hofstetter A, Deubner J et al (2004) Retropubic transvesical prostatectomy for significant prostatic enlargement must remain a standard part of urology training. Scand J Urol Nephrol 38:472–476 Adot Zurbano JM, Salinas Casado J, Metal D (2005) Urodynamics of the bladder diverticulum in the adult male. Arch Esp Urol 58:641–649 Ahyai SA, Gilling P, Kaplan SA, Kuntz RM, Madersbacher S, Montorsi F, Speakman MJ, Stief CG (2010) Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol 58:384–397 Anderson JB, Grant JB (1991) Postoperative retention of urine: a prospective urodynamic study. BMJ302:894–896 Antunes AA, Srougi M, Coelho RF et al (2009) Transurethral resection of the prostate for the treatmentof lower urinary tract symptomsrelated to benign prostatichyperplasia: howmuch should be resected? Int Braz JUrol 35:683–689 (discussion 689–691) Autorino R, Zargar H, Mariano MB et al (2015) Perioperative outcomes of robotic and laparoscopic simple prostatectomy: a European-American multi-institutional analysis. Eur Urol 68:86–94

Berges RR, Pientka L, Höfner K et al (2001) Male lower urinary tract symptoms and related health care seeking in Germany. EurUrol 39:682–687 Bach T, Geavlete B, Pfeiffer D, Wendt-Nordahl G, Michel MS, Gross A (2008) TURP in patients with Biopsy-Proven prostate cancer: sensitivity for cancer detection. Urology 73:100–104. 7 https:// doi.org/10.1016/j.urology.2008.06.047 Bach T, Muschter R, Sroka R et al (2012) Laser treatment of benign prostatic obstruction: basics and physical differences. Eur Urol 61:317–325 Bach T, Xia SJ, Yang Y et al (2010) Thulium: YAG 2 mum cw laser prostatectomy: where do we stand? World J Urol 28:163–168 Bach T, Wölbling F, Gross AJ, Netsch C, Tauber S, Pottek T, Wülfing C, Brunken C (2016) Prospective assessment of perioperative course in 2648 patients after surgical treatment of benign prostatic obstruction. World J Urol 35:285–292. 7 https://doi. org/10.1007/s00345-016-1866-7 Epub 2016 Jun 4 Bachmann A, Tubaro A, Barber N, d’Ancona F, Muir G, Witzsch U, Grimm MO, Benejam J, Stolzenburg JU, Riddick A, Pahernik S, Roelink H, Ameye F, Saussine C, Bruyère F, Loidl W, Larner T, Gogoi NK, Hindley R, Muschter R, Thorpe A, Shrotri N, Graham S, Hamann M, Miller K, Schostak M, Capitán C, Knispel H, Thomas JA, Bachmann A et al (2015) A European multicenter randomized noninferiority trial comparing 180 W GreenLight XPS laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the GOLIATH study. J Urol. 2015 Feb;193(2):570–578

250

23

C. Netsch and A. J. Gross

Barabas G, Molstad S (2005) No association between elevated post-void residual volume and bacteriuria in residents of nursing homes. Scand J PrimHealthCare 23:52–56 Berges R, Oelke M (2011) Age-stratified normal values for prostate volume, PSA, maximum urinary flow rate, IPSS, and other LUTS/BPH indicators in the German male community-dwelling population aged 50 years or older. World JUrol 29:171–178 Barry MJ, Cockett AT, Holtgrewe HL et al (1993) Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 150:351–358 Berry SJ, Coffey DS, Walsh PC et al (1984) The development of human benign prostatic hyperplasia with age. J Urol 132:474–479 Bosch JL, Kranse R, Van Mastrigt R et al (1995a) Reasons for the weak correlation between prostate volume and urethral resistance parameters in patients with prostatism. J Urol 153:689–693 Bosch JL, Hop WC, Kirkels WJ et al (1995b) The International Prostate Symptom Score in a community-based sample of men between 55 and 74 years of age: prevalence and correlation of symptomswith age, prostate volume, flow rate and residual urine volume. Br J Urol 75:622–630 Brookman-May S, Burger M, Hoschke B et al (2010) Association between residual urinary volume and urinary tract infection: prospective trial in 225male patients. Urologe A 49:1163–1168 Bruce A, Krishan A, Sadiq S, Ehsanullah SA, Khashaba S, Bruce A et al (2021) Safety and efficacy of bipolar transurethral resection of the prostate vs monopolar transurethral resection of prostate in the treatment of moderate-large volume prostatichyperplasia: a systematic review and meta-analysis. J Endourol 35(5):663–673 Bruskewitz RC, Iversen P, Madsen PO (1982) Value of postvoid residual urine determination in evaluation of prostatism. Urology 20:602–604 Bruyere F, Puichaud A, Pereira H et al (2010) Influence of photoselective vaporization of the prostate on sexual function: results of a prospective analysis of 149 patients with long-term follow-up. Eur Urol 2010(58):207–211 Crawford ED, Wilson SS, Mcconnell JD et al (2006) Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 175:1422–1426 (discussion1426–1427) Chen S, Zhu L, Cai J et al (2014) Plasmakinetic enucleation of the prostate compared with open prostatectomy for prostates larger than 100 grams: a randomized noninferiority controlled trial with long-term results at 6 years. Eur Urol 66:284–291

Cornu JN, Ahyai S, Bachmann A, de la Rosette J, Gilling P, Gratzke C, McVary K, Novara G, Woo H, Madersbacher S (2015) A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol 67:1066–1096 De Nunzio C, Cantiello F, Fiori C, Crocerossa F, Tognoni P, Amparore D, Baldassarri V, Elbers JR, Sancha FG, Porpiglia F (2020) Urinary and sexual function after treatment with temporary implantable nitinol device (iTind®) in men with LUTS: 6-month interim results of the MT-06-study. World Journal of Urology Donker PJ, Ivanovici F, Noach EL (1972) Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Br JUrol44:180–193 El Din KE, De Wildt MJ, Rosier PF et al (1996) The correlation between urodynamic and cystoscopic findings in elderlymenwith voiding complaints. J Urol 155:1018–1022 Elkoushy MA, Elshal AM, Elhilali MM (2015a) Holmium laser transurethral incision of the prostate: can prostate size predict the long-term outcome? Can Urol Assoc J 9:248–254 Elkoushy MA, Elshal AM, Elkoushy MM et  al (2015b) Incidental prostate cancer diagnosis during holmium laser enucleation: assessment of predictors, survival, and disease progression. Urology 86:552–557 Elmansy HM, Elzayat E, Elhilali MM (2010) Holmium laser ablation versus photoselective vaporization of prostate less than 60 cc: long-term results of a randomized trial. J Urol 184:2023 Elzayat EA, Elhilali MM (2006) Holmium laser enucleation of the prostate (HoLEP): The endourologic alternative to open prostatectomy. Eur Urol 49:87 Enikeev D, Morozov A, Taratkin M, Misrai V, Rijo E, Podoinitsin A, Gabdullina S, Herrmann TRW (2021) Systematic review of the endoscopic enucleation of the prostate learning curve. World J Urol 2021(39):2427–2438 Fraundorfer MR, Gilling PJ (1998). Holmium:YAG laser enucleation of the prostate combined with mechanical morcellation: preliminary results. Eur Urol 33:69–72 Furuya S, Kumamoto Y, Yokoyama E et al (1982) Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol 128:836–839 Furuya S, Furuya R, Ogura H, Araki T, Arita T (2006) A study of 4,031 patients of transurethral resection of the prostate performed by one

251 Controversies in Conservative and Surgical BPS Therapy

v­ surgeon: learning curve, surgical results and postoperative complications. Hinyokika Kiyo 52:609– 614 Fusco F, Palmieri A, Ficarra V et al (2016) alpha1-blockers improve benign prostatic obstruction in men with lower urinary tract symptoms: a systematic review and meta-analysis of urodynamic studies. EurUrol 69:1091–1101 Geavlete B, Stanescu F, Iacoboaie C et al (2013) Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign prostatic hyperplasia cases – a medium term, prospective, randomized comparison. BJU Int 111:793–803 Gilfrich C, Leicht H, Fahlenbrach C, Jeschke E, Popken G, Stolzenburg JU, Weißbach L, Zastrow C, Günster C (2016) Morbidity and mortality after surgery for lower urinary tract symptoms: a study of 95 577 cases from a nationwide German health insurance database. Prostate Cancer Prostatic Dis. 19:406–411 Gilling P, Barber N, Bidair M, Anderson P, Sutton M, Aho T, Kramolowsky E, Thomas A, Cowan B, Kaufman RP, Trainer A, Arther A, Badlani G, Plante M, Desai M, Doumanian L, Te AE, DeGuenther M, Roehrborn C (2020) Three-year outcomes after Aquablation therapy compared to TUR-P: results from a blinded randomized trial. Can J Urol 27:10072–10079 Girman CJ, Jacobsen SJ, Guess HA et al (1995) Natural history of prostatism: relationship among symptoms, prostate volume andpeakurinary flow rate. J Urol 153:1510–1515 Gross AJ, Netsch C, Knipper S, Hölzel J, Bach T (2013) Complications and early postoperative outcome in 1080 patients after thulium vapoenucleation of the prostate: results at a single institution. Eur Urol 63:859–867 Gosling JA, Dixon JS (1980) Structure of trabeculated detrusor smooth muscle in cases of prostatic hypertrophy. Urol Int 35:351–355 Gratzke C, Schlenker B, Seitz M et al (2007) Complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol 177:1419–1422 Gravas S, Bach T, Bachmann A, Drake M, Gacci M, Gratzke C, Madersbacher S, Mamoulakis S, Tikkinen KAO (2016) Guidelines on the management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO) EAU; 7 http://uroweb.org/guideline/treatment-of-non-neurogenicmale-luts/ . Zugegriffen: Mar 2016 Hald T (1989) Urodynamics in benign prostatic hyperplasia: a survey. Prostate Suppl 2:69–77 Herlemann A, Wegner K, Roosen A, Buchner A, Weinhold P, Bachmann A, Stief CG, Gratzke C,

23

Magistro G (2017) „Finding the needle in a haystack“: oncologic evaluation of patients treated for LUTS with holmium laser enucleation of the prostate (HoLEP) versus transurethral resection of the prostate (TURP). World J Urol 35:1777– 1782 Hiraoka Y, Akimoto M (1989) Transurethral enucleation of benign prostatic hyperplasia. J Urol 1989(142):1247–1250 Hong SK, Lee ST, Jeong SJ et al (2010) Chronic kidney disease among men with lower urinary tract symptoms due to benign prostatic hyperplasia. BJUInt 105:1424–1428 Jakobsen H, Torp-Pedersen S, Juul N (1988) Ultrasonic evaluation of age-related human prostatic growth and development of benign prostatic hyperplasia. Scand J Urol Nephrol Suppl 107:26–31 John H, Wagner C, Padevit C, Witt JH (2021a) From open simple to robotic-assisted simple prostatectomy (RASP) for large benign prostate hyperplasia: the time has come. World J Urol John H, Wagner C, Padevit C, Witt JH (2021b) From open simple to robotic-assisted simple prostatectomy (RASP) for large benign prostate hyperplasia: the time has come. World J Urol. 7 https:// doi.org/10.1007/s00345-020-03508-1 Kang M, Kim M, Choo MS et al (2016) Urodynamic features and significant predictors of bladder outlet obstruction in patients with lower urinary tract symptoms/benign prostatic hyperplasia and smallprostate volume. Urology 89:96–102 Kaplan SA, Wein AJ, Staskin DR et al (2008) Urinary retention and post-void residual urine in men: separating truth from tradition. J Urol 180:47–54 Kaplan-Marans E, Martinez M, Wood A, Cochran J, Dubowitch E, Schulman A. Kaplan-Marans E et al (2021) Aquablation, prostatic urethral lift, and transurethral water vapor therapy: a comparison of device related adverse events in a national registry. J Endourol. Jul 27. 7 https://doi. org/10.1089/end.2021.0455 . Online ahead of print Ko DS, Fenster HN, Chambers K et al (1995) The correlation ofmultichannel urodynamic pressureflowstudies and American Urological Association symptom index in the evaluation of benign prostatichyperplasia. J Urol 154:396–398 Krambeck AE, Handa SE, Lingeman JE (2010) Experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. J Urol 183:1105–1109 Kuo RL, Kim SC, Lingeman JE, Paterson RF, Watkins SL, Simmons GR, Steele RE (2003) Holmium laser enucleation of prostate (HoLEP): the Methodist Hospital experience with greater than 75 gram enucleations. J Urol 170:149–152 Lourenco T, Shaw M, Fraser C et al (2010) The clinical effectiveness of transurethral incision of the

252

23

C. Netsch and A. J. Gross

prostate: a systematic review of randomised controlled trials.World J Urol 28:23–32 Madersbacher S, Lackner J, Brössner C, Röhlich M, Stancik I, Willinger M, Schatzl G; Prostate Study Group of the Austrian Society of Urology (2005) Reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. Eur Urol 47:499–504 Mauermayer W (1981) Transurethrale Operationen. Springer, Berlin, Heidelberg, NewYork McVary KT, Gittelman MC, Goldberg KA, Patel K, Shore ND, Levin RM, Pliskin M, Beahrs JR, Prall D, Kaminetsky J, Cowan BE, Cantrill CH, Mynderse LA, Ulchaker JC, Tadros NN, Gange SN, Roehrborn CG (2021). Final 5-Year Outcomes of the Multicenter Randomized Sham-Controlled Trial of Rezum® Water Vapor Thermal Therapy for Treatment of Moderate-To-Severe Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. J Urol: 101097JU0000000000001778 Montorsi F, Naspro R, Salonia A, Suardi N, Briganti A, Zanoni M, Valenti S, Vavassori I, Rigatti P (2004) Holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center, prospective, randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol 172:1926–1929 Naspro R, Suardi N, Salonia A, Scattoni V, Guazzoni G, Colombo R, Cestari A, Briganti A, Mazzoccoli B, Rigatti P, Montorsi F (2006) Holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. Eur Urol 50:563–568 Oelke M, Baard J, Wijkstra H et al (2008) Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol 54:419–426 Oelke M, Kirschner-Hermanns R, Thiruchelvam N et al (2012) Can we identify men who will have complications from benign prostatic obstruction (BPO)? ICI-RS2011.Neurourol Urodyn31:322–326 Oelke M, Bschleipfer T, Höfner K (2019) Fake News BPH - what is really true!. Urologe A 58:271–283. doi: 7 https://doi.org/10.1007/s00120-019-0885-6 Omli R, Skotnes LH, Mykletun A et al (2008) Residual urine as a risk factor for lower urinary tract infection: a 1-year follow-up study in nursing homes. J Am Geriatr Soc 56:871–874 Ou R, Deng X, Yang W (2013) Transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes >80 mL: a prospective randomized study. BJU Int 112:239–245

Osman NI, Chapple CR, Abrams P et al (2014) Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, anddiagnosis. Eur Urol 65:389–398 Rao J-M, Yang J-R, Ren Y-X et al (2013) Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia >80 mL: 12-month follow-up results of a randomized clinical trial. Urology 82:176–181 Reich O, Gratzke C, Bachmann A, Seitz M, Schlenker B, Hermanek P, Lack N, Stief CG, Urology Section of the Bavarian Working Group for Quality Assurance (2008) Morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. J Urol 180:246–249 Roehrborn CG, Barkin J, Gange SN, Shore ND, Giddens JL, Bolton DM, Cowan BE, Cantwell AL, McVary KT, Te AE, Gholami SS, Moseley WG, Chin PT, Dowling WT, Freedman SJ, Incze PF, Coffield KS, Herron S, Rashid P, Rukstalis DB (2017) Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol 24:8802–8813 Rom M, Waldert M, Klingler HC et al (2013) Bladder outlet obstruction in men with acute urinary retention: an urodynamic study. World J Urol 31:1045–1050 Rosier PF, De La Rosette JJ (1995) Is there a correlation between prostate size and bladderoutletobstruction? World J Urol 13:9–13 Rule AD, Lieber MM, Jacobsen SJ (2005) Is benign prostatic hyperplasia a risk factor for chronic renal failure? JUrol173:691–696 Ruszat R, Seitz M, Wyler SF et al (2008) GreenLight laser vaporisation of the prostate: single-center experience and longterm results after 500 procedures. Eur Urol 54:893 Swyer GI (1944) Post-natal growth changes in the humanprostate. J Anat 78:130–145 Te AE, Malloy TR, Stein BS et al (2006) Impact of prostate-specific antigen level and prostate volume as predictors of efficacy in photoselective vaporization prostatectomy: analysis and results of an ongoing prospective multicentre study at 3 years. BJU Int 97:1229 Thomas AW, Cannon A, Bartlett E et al (2004) The natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on the outcome after transurethral resection of the prostatewith a minimum10-year urodynamic follow-up. BJU Int 93:745–750 Thomas AW, Cannon A, Bartlett E et al (2005) The natural history of lower urinary tract

253 Controversies in Conservative and Surgical BPS Therapy

­ ysfunctionin men: minimum 10-year urodynamic d followup of untreated detrusor underactivity. BJU Int96:1295–1300 Thomas JA, Tubaro A, Barber N, d’Ancona F, Muir G, Witzsch U, Grimm MO, Benejam J, Stolzenburg JU, Riddick A, Pahernik S, Roelink H, Ameye F, Saussine C, Bruyere F, Loidl W, Larner T, Gogoi NK, Hindley R, Muschter R, Thorpe A, Shrotri N, Graham S, Hamann M, Miller K, Schostak M, Capitan C, Knispel H, Bachmann A (2016) A multicenter randomized ­ noninferiority trial comparing greenlight-XPS laser vaporization of the prostate and transurethral resection of the prostate for the treatment of benign prostatic obstruction: two-yr outcomes of the GOLIATH study. Eur Urol 69:94–102 Umari P, Fossati N, Gandaglia G et al (2017) Robotic assisted simple prostatectomy versus holmium laser enucleation of the prostate for lower urinary tract symptoms in patients with large volume prostate: a comparative analysis from a high volume center. J Urol 197:1108–1114 Van De Beek C, Rollema HJ, Van Mastrigt R et al (1992) Objective analysis of infravesical obstruction and detrusor contractility; appraisal of the computer program Dx/CLIM and Schäfer nomogram.Neurourol Urodyn1:394–395

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Van Exel NJ, Koopmanschap MA, McDonnell J et al (2006) Medical consumption and costs during a one-year follow-up of patientswith LUTS suggestive of BPH in six europeancountries: report of the TRIUMPH study. Eur Urol 49:92–102 Varkarakis I, Kyriakakis Z, Delis A et al (2004) Longterm results of open transvesical prostatectomy from a contemporary series of patients. Urology 64:306 Yalla SV, SullivanMP, Lecamwasam HS et al (1995) Correlation of American Urological Association symptomindex with obstructive and nonobstructive prostatism. J Urol 153:674–679 (discussion 679–680) Yamaçake KG, Nakano ET, Soares IB, Cordeiro P, Srougi M, Antunes AA,Yamaçake KG et al (2015). Analysis of the learning curve for transurethral resection of the prostate. Is there any influence of musical instrument and video game skills on surgical performance? Turk J Urol; 41:132–7 Weiss JK, Santucci NM, Sajadi KP, Chouhan JD (2021) Post-surgical complications after bladder outlet reducing surgery: an analysis of the FDA Manufacturer and User Facility Device Experience (MAUDE) database. Urology 156:211–215. 7 https://doi.org/10.1016/j.urology.2021.04.030