Radiation Therapy for Genitourinary Malignancies: A Practical and Technical Guide (Practical Guides in Radiation Oncology) 3030651363, 9783030651367

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Practical Guides in Radiation Oncology Series Editors: Nancy Y. Lee · Jiade J. Lu

Abhishek A. Solanki Ronald C. Chen Editors

Radiation Therapy for Genitourinary Malignancies A Practical and Technical Guide

Practical Guides in Radiation Oncology Series Editors: Nancy Y. Lee Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York, NY, USA Jiade J. Lu Department of Radiation Oncology Shanghai Proton and Heavy Ion Center Shanghai, China

The series Practical Guides in Radiation Oncology is designed to assist radiation oncology residents and practicing radiation oncologists in the application of current techniques in radiation oncology and day-to-day management in clinical practice, i.e., treatment planning. Individual volumes offer clear guidance on contouring in different cancers and present treatment recommendations, including with regard to advanced options such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). Each volume addresses one particular area of practice and is edited by experts with an outstanding international reputation. Readers will find the series to be an ideal source of up-to-date information on when to apply the various available technologies and how to perform safe treatment planning. More information about this series at http://www.springer.com/series/13580

Abhishek A. Solanki  •  Ronald C. Chen Editors

Radiation Therapy for Genitourinary Malignancies A Practical and Technical Guide

Editors Abhishek A. Solanki Department of Radiation Oncology Loyola University Chicago Maywood, IL USA

Ronald C. Chen Department of Radiation Oncology University of Kansas Medical Center Kansas City, KS USA

ISSN 2522-5715     ISSN 2522-5723 (electronic) Practical Guides in Radiation Oncology ISBN 978-3-030-65136-7    ISBN 978-3-030-65137-4 (eBook) https://doi.org/10.1007/978-3-030-65137-4 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved 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 Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Dr. Solanki dedicates this book to his family—his parents Ashok, Rashmi, Manilal, and Bhanuben; his siblings Pooja and Aalap; his wife Charmi; and his daughters Esha and Riya. A more loving, supportive, and inspiring family has never existed and he is thankful for them every day. Dr. Chen would like to dedicate this book to his parents, Kehpin Chen and Sheaufeng Lo, whose love and many sacrifices facilitated his opportunities in life.

Preface

Radiation therapy, and radiation oncologists, have long played a key role in the management of genitourinary malignancies. We believe that this role is even more critical today than it has been in the past. In the last decade, there have been several “disruptive” phenomena that have drastically advanced and expanded the use of radiation therapy for genitourinary malignancies. First, multiple new approaches to the delivery of radiotherapy have been incorporated into the standard care for men with prostate cancer, including moderate and ultra-hypofractionated external beam radiotherapy and proton therapy. These modalities have the potential to improve the therapeutic index and convenience of radiation therapy, but require expertise in the unique considerations and complexities of the nuances of treatment planning and delivery. Second, there has been a decline in the use of brachytherapy for prostate cancer, at least partially due to clinicians not feeling comfortable with performing the procedures and treatment delivery. Brachytherapy is a valuable tool available to the radiation oncologist, and many clinicians seek the opportunity to expand brachytherapy programs at their institutions. These clinicians may benefit from an improved understanding of the fundamentals of treatment. Third, the role of ablative radiotherapy in metastatic prostate cancer continues to grow with every academic conference and publication. These are new frontiers for the radiation oncologist, and along with this comes new strategies for the optimal delivery of radiotherapy in this setting. Few resources exist to help guide the details of radiotherapy delivery in this setting. Finally, the role of radiotherapy has historically been limited at most centers in the curative management of several other genitourinary malignancies, such as bladder, kidney, and penile cancer. However, due to several recent and ongoing high-­ profile international clinical trials and consortiums, the role of radiation therapy has been solidified in these malignancies. It is crucial for clinicians to understand the ideal approaches for delivery of radiotherapy in these cases. Our goal in developing this textbook was to create a single resource where radiation oncologists and trainees who want to develop expertise in the care of patients with genitourinary malignancies could easily turn to as a reference and learning tool. We assembled a team of authors who were internationally renowned leaders in the clinical care of patients with these malignancies and frequently had helped create the standards of care that are used today. We asked the authors to focus less on vii

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academic discussions of the literature, and more on practical recommendations that could guide day-to-day practice—allowing clinicians to deliver advanced and high-­ quality radiotherapy to patients with genitourinary malignancies they would encounter in clinic. We hope you find this textbook to be a valuable tool in helping to improve the care of your patients with genitourinary malignancies, and hope you enjoy reading it as much as we enjoyed developing it. We want to thank the contributors of the book for their expertise and commitment to the success of this book. Maywood, IL, USA Kansas City, KS, USA 

Abhishek A. Solanki Ronald C. Chen

Contents

Part I Prostate Cancer 1 The Management of Prostate Cancer������������������������������������������������������   3 Robert T. Dess, William C. Jackson, and Daniel E. Spratt 2 Imaging in Prostate Cancer����������������������������������������������������������������������  25 Joel R. Wilkie, Aradhana M. Venkatesan, Vrinda Narayana, Patrick Hurley, and Patrick W. McLaughlin 3 Androgen Deprivation Therapy for Patients with Intact Prostates Undergoing Radiation Therapy����������������������������������������������������������������  63 Edward Christopher Dee and Paul L. Nguyen 4 Conventional and Moderately Hypofractionated Radiation Therapy for Prostate Cancer��������������������������������������������������������������������  91 Ethan M. Steele, Todd R. Mereniuk, and Jordan A. Holmes 5 Low Dose Rate Brachytherapy: Uses and Advanced MRI Techniques in Prostate Cancer ���������������������������������������������������������������� 105 Ibrahim Abu-Gheida, Amy C. Moreno, Chad Tang, Rajat Kudchadker, Jihong Wang, and Steven J. Frank 6 High Dose Rate Prostate Brachytherapy ������������������������������������������������ 127 Alexander A. Harris, Kyle Stang, Matthew M. Harkenrider, Mitchell Kamrava, Derrick Lock, Gerard Morton, Michael L. Mysz, Timothy Showalter, Anthony C. Wong, and Abhishek A. Solanki 7 Ultra-hypofractionated Radiotherapy (Stereotactic Body Radiotherapy)������������������������������������������������������������ 153 Michael C. Repka, Edina Wang, Nima Aghdam, Siyuan Lei, Abdul Rashid, Simeng Suy, Seth Blacksburg, and Sean P. Collins 8 Proton Therapy for the Treatment of Prostate Cancer�������������������������� 169 Adam C. Mueller and Thomas J. Pugh 9 Postoperative Radiotherapy for Prostate Cancer ���������������������������������� 189 Tru-Khang T. Dinh, Meghan W. Macomber, and Timur Mitin

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10 Radiotherapy for Oligometastatic Prostate Cancer������������������������������� 209 John W. Shumway and Trevor J. Royce Part II Non-prostate Genitourinary Malignancies 11 Bladder Cancer Radiotherapy������������������������������������������������������������������ 225 Sameer Jhavar, Gabriel Axelrud, and Jason A. Efstathiou 12 Testicular Cancer Radiotherapy�������������������������������������������������������������� 255 Amandeep R. Mahal and James B. Yu 13 Radiation Therapy for Renal Cell Carcinoma���������������������������������������� 301 William Grubb, Simon Lo, Rodney Ellis, Alexander Louie, Bin Teh, and Shankar Siva 14 Rare Genitourinary Malignancies (Penile, Urethral, Renal Pelvis, and Ureteral Cancers)�������������������������������������������������������� 313 Anna M. Torgeson and Jonathan D. Tward

Part I Prostate Cancer

1

The Management of Prostate Cancer Robert T. Dess, William C. Jackson, and Daniel E. Spratt

Contents 1.1  Epidemiology 1.2  Anatomy and Physiology 1.3  Pathology 1.4  Diagnosis 1.5  Staging and Risk Groupings 1.6  Management of Intact Prostate Cancer 1.7  Post-prostatectomy Radiation Therapy 1.8  Treatment of Metastatic Prostate Cancer 1.9  Technological Advancements in Radiotherapy 1.10  Focus on Patient Reported Quality of Life 1.11  Follow-Up and Survivorship References

1.1

   3    5    5    6    7  10  13  15  16  16  17  18

Epidemiology

Prostate cancer is the most common cancer diagnosed in men in the United States with over 165,000 new cases per year [1]. Worldwide over 1.2 million men are diagnosed with prostate cancer. Although the majority of men will not die from their disease, prostate cancer remains the second leading cause of cancer death in the United States [1]. In 2015, there were an estimated 3,120,000 men alive in the United States with prostate cancer [2]. Furthermore, given the high incidence, long natural history, and frequent treatment-related morbidity, prostate cancer remains the most common cause of cancer associated years lived with disability worldwide [3]. R. T. Dess · W. C. Jackson · D. E. Spratt (*) Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2021 A. A. Solanki, R. C. Chen (eds.), Radiation Therapy for Genitourinary Malignancies, Practical Guides in Radiation Oncology, https://doi.org/10.1007/978-3-030-65137-4_1

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R. T. Dess et al.

The median age of diagnosis is 66 years old, and the largest risk factor is age. Autopsy studies have shown that ~10% of men in their 20s and >25% of men in their 40s can harbor prostate cancer [4, 5]. With increasing age, beyond 80 years, the majority of men will harbor some form of prostate cancer, most commonly indolent low grade disease [5]. In contrast, men under 45 years old rarely are diagnosed with prostate cancer, comprising only 0.5% of all new cases [1]. The majority of men who die from prostate cancer are >75 years old, with only approximately 10% of deaths from prostate cancer occurring in men under 65 years old. Prostate cancer is diagnosed 1.7-fold more often in black than white men in the United States [1]. This is despite the known social disparities that exist in the United States between black and white men, where black men undergo less PSA screening, have less insurance, and are less likely to have a primary care physician [6]. Thus, the difference in new cases would likely be even larger if these social disparities were minimized. Additionally, black men have a 2.2-fold greater likelihood of dying of prostate cancer than white men [1]. The difference in mortality appears to largely be driven by social factors as well, including being diagnosed at a later stage of disease, receiving less guideline concordant treatment, and receipt of heterogeneous follow-up and monitoring. In contrast, Asian-Americans are nearly half as likely to be diagnosed with prostate cancer as white men and are more than twofold less likely to die from prostate cancer [7]. Other risk factors beyond age and race include a Western diet and obesity [8]. There is mixed evidence regarding the impact of diabetes on the development of prostate cancer, as well as the impact of diabetic medications on prostate cancer aggressiveness [9, 10]. By reducing circulating dihydrotestosterone (DHT), 5-alpha reductase inhibitors decrease the development and diagnosis of prostate cancer, but there is debate whether men who take these medications develop more aggressive prostate cancer [11, 12]. Approximately one in ten men with prostate cancer have a hereditary or underlying genetic risk for the development of prostate cancer [13]. Similar to breast cancer, mutations in multiple DNA damage repair genes, such as BRCA2, are associated with an increased predisposition for the development of prostate cancer [14]. There are now established recommendations for germline screening in men newly diagnosed with prostate cancer that are predominately guided based on family history and stage of their prostate cancer (Table 1.1) [15]. Table 1.1  ISUP grade groups

Gleason score 6 3 + 4 = 7 4 + 3 = 7 8 9–10

ISUP grade group 1 2 3 4 5

1  The Management of Prostate Cancer

1.2

5

Anatomy and Physiology

The prostate, which is part of the male reproductive system, is a small exocrine gland of approximately 30 cc in size located within the true pelvis. The primary function of the prostate gland is to secrete fluid that is combined with the spermatozoa from the seminal vesicles to constitute the majority of the semen contents. This secretion is known to facilitate sperm motility and survival. The prostate is regulated by testosterone and DHT. The urethra passes through the prostate. The bladder sits superior to the prostate with the prostatic base approximating the bladder neck. The rectum is posterior to the prostate and seminal vesicles. The pubic symphysis is anterior to the prostate. The gland is responsible for production of the majority of the contents of the male ejaculate, which is stored in the connecting seminal vesicles. The prostate is commonly divided based on zonal anatomy into three zones: peripheral zone, central zone, and the transitional zone. Additionally, although rarely a site of prostate cancer, the anterior aspect of the prospect is comprised by fibromuscular stroma. Prostate cancer mostly commonly resides within the peripheral zone, which makes up ~70% of the prostate gland. The peripheral zone abuts the anterior rectal wall and is most easily accessible via trans-rectal ultrasound guided biopsy and digital rectal examination. The central zone covers 25% of the prostate gland and contains approximately one-third of the ducts that secrete fluid that helps create semen. It is cone-shaped and is located at the base of the prostate adjacent to the seminal vesicles. The transition zone comprises the remaining 5% of the prostate and surrounds the urethra. The prostate gland is enclosed by a fibrous tissue layer and is named as the prostate capsule. Although most cancer resides in the peripheral zone, other prostatic zones may harbor prostate cancer at a lesser frequency and are not routinely sampled with a standard templated biopsy.

1.3

Pathology

1.3.1 Histology Based on the 2016 World Health Organization classification of tumors of the prostate, there are over ten types of prostate cancer, with multiple histologic variants of each tumor type [16]. The most common histologic type of prostate cancer is acinar adenocarcinoma. Other types include ductal adenocarcinoma, urothelial carcinoma, squamous neoplasms, basal cell carcinoma, mesenchymal tumors, hematopoetic tumors, and neuroendrocrine tumors. Acinar adenocarcinomas, as most prostate adenocarcinomas do, typically express PSA and PSMA and have a functional androgen receptor (AR) present. There are numerous acinar variants of

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unclear significance, including atrophic, pseudohyperplastic, microcystic, foamy, mucinous, signet-ring, pleomorphic giant cell, and sarcomatoid. Another common type of prostate cancer is intraductal carcinoma, a distinct entity from ductal adenocarcinoma [17], which is present in ~17% of radical prostatectomy cases but only 3% of needle biopsies. It is associated with a worse prognosis, BRCA2 mutations, PTEN loss, loss of heterozygosity of TP53 or RB1, and SChLAP1 dysregulation. Neuroendocrine tumors are a rare type of prostate cancers that are binned into four groups: adenocarcinoma with neuroendocrine differentiation, well-­ differentiated neuroendocrine tumor (carcinoid tumor), small cell, and large cell neuroendocrine tumors [16, 18]. Pure small cell or neuroendocrine prostate cancers are uncommon and are associated with very poor outcomes [19]. This entity should be distinguished from treatment-induced neuroendocrine prostate cancer after years of androgen-deprivation therapy. Pure small cell prostate cancer often has lost either or both PSA and PSMA expression and has over expressed neuroendocrine markers, such as chromogranin and synaptophysin.

1.3.2 Prostate Adenocarcinoma Grading Prostate adenocarcinoma is graded conventionally using the Gleason grading system, which most recently has been converted into the 2014 International Society of Urologic Pathology (ISUP) grade groupings (grade 1–5) shown in Table 1.1 [20, 21]. Grade groups are based on the histologic architectural pattern observed and are assigned based on the most common and second most common pattern seen. The higher the grade group, the worse the prognosis and higher risk for the development of metastatic disease.

1.4

Diagnosis

The diagnosis of prostate cancer must be made by tissue confirmation. The most common reason for undergoing a prostate biopsy is due to a rising PSA.  Although there are age adjusted PSA thresholds, simplified National Comprehensive Cancer Network (NCCN) guidelines typically recommend that if a man has a PSA ≥3  ng/mL this should prompt further testing based on a patients age [22]. This includes ruling out benign causes of a PSA rise such as infection. This also should prompt a digital rectal exam to determine if a palpable abnormality can be felt or if there is increased pain on prostate exam indicative of prostatitis. The PSA should be repeated to determine if it remains elevated. Based on the PSA, DRE findings, and estimated PSA density, one should determine the patient’s pretest probability of harboring clinically significant cancer. There are multiple available blood and urine-based assays that can help improve the pretest probability of detecting clinically significant cancer [23]. While not recommended for routine

1  The Management of Prostate Cancer

7

use for the detection of prostate cancer by the NCCN, these tests can be useful for increasing the specificity of cancer detection or aiding in decision making regarding the need for additional biopsies in men with an initial negative biopsy. There are several commercially available assays. The Prostate Health Index combines total PSA, free PSA, and p2PSA to improve the sensitivity of detecting prostate cancer and is FDA-approved for use in men with serum PSA values between 4 and 10 ng/ mL [24]. The Progensa PCA3 test which combines PCA3 and PSA mRNA has FDA approval for use in men with an elevated PSA and a previously negative biopsy [25]. Tests available to predict the likelihood of observing a Gleason score of 7 or higher on biopsy include the 4Kscore [26], which measures free PSA, total PSA, human kallikrein 2, and intact PSA, as well as the Mi-Prostate score [27], which combines serum PSA and post-DRE urine expression of PCA3 and the TMPRSS2:ERG fusion mRNA. In addition to blood and urine-based biomarkers, recently multiple randomized controlled trials have shown that multiparametic MRI can significantly improve the detection of clinically significant cancer while reducing unnecessary biopsies and the detection of low grade cancers [28, 29]. However, there is significant heterogeneity in the inter-reader reliability using the current PI-RADS version 2, even among experts [30]. Other factors that increase the likelihood of harboring cancer are PSA density, strong family history, African-American race, or known familial cancer mutation (e.g., BRCA2). Once a patient has a sufficiently high pretest probability, they should undergo a transrectal ultrasound-guided sextant biopsy with at least 12 templated cores. If an MRI were already performed, several systems are available to enhance the yield and accuracy of the biopsy by performing MRI-targeted biopsies to any regions of interest. Importantly, the templated and targeted biopsies should both be performed as MRI-targeted biopsy alone may miss 10% of clinically significant cancers when the templated systematic biopsies are omitted [31]. Other methods for the diagnosis of prostate cancer are incidental. These most commonly include detection of prostate cancer during a trans-urethral resection of the prostate or cystoprostatectomy.

1.5

Staging and Risk Groupings

Once a histologic diagnosis of prostate cancer is made, a full staging workup is appropriate based on the patient’s stage and NCCN risk group [32]. Nearly all cancers of the human body are staged using the American Joint Committee on Cancer (AJCC) 8th edition. However, for prostate cancer, these stage groupings are rarely utilized for multiple reasons. First and foremost, the prostate cancer stage grouping system is one of the few that is based not from specific outcomes data but rather expert consensus. Second, national guidelines and most clinical trials use NCCN risk groups [33] to bin patients into similar prognostic groups. However, the basic TNM staging used in the AJCC staging system is a critical component to determining a patient’s NCCN risk group.

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The three most important clinicopathologic prognostic factors that comprise both the AJCC stage groupings and NCCN risk groups are a patient’s pre-treatment PSA, ISUP Grade group, and TNM stage. Cancers can be first divided into localized, locally advanced, node positive, and metastatic [32]. Within localized and locally advanced prostate cancer, NCCN subdivides them into six risk groups: very low, low, favorable intermediate, unfavorable intermediate, high, and very high. This expanded NCCN classification has evolved from the original D’Amico risk groups of low, intermediate, and high [34], which are still used by many today. The current AJCC 8th edition staging and the 2018 NCCN risk groups are shown in Tables 1.2, 1.3 and 1.4. Table 1.2  AJCC 8th Edition TNM Definitions Primary tumor: clinical (cT) Primary tumor: pathologic (pT) T1—clinically inapparent tumor neither palpable nor visible by imaging  T1a—incidental histologic finding in 5% or less of tissue resected  T1b—incidental histologic finding in more than 5% of tissue resected  T1c—identified by needle biopsy (e.g., because of elevated PSA) T2—palpable and confined within prostate T2—organ confined  T2a—involves one half of one side or less  T2b—involves more than one half of one side but not both sides  T2c—involves both sides T3—extraprostatic extension T3—extraprostatic tumor that is not fixed or does not invade adjacent structures  T3a—extracapsular extension (unilateral or  T3a—extraprostatic extension or bilateral) microscopic invasion of bladder neck  T3b—invades seminal vesicles  T3b—invades seminal vesicle(s) T4—fixed or invades adjacent structures other T4—fixed or invades adjacent structures other than seminal vesicles: bladder, external than seminal vesicles: bladder, external sphincter, rectum, levator muscles, and/or sphincter, rectum, levator muscles, and/or pelvic wall pelvic wall Regional lymph nodes N0—none N1—yes Regional lymph nodes: pelvic, hypogastric, obturator, iliac (internal, external), sacral Distant lymph nodes: aortic, common iliac, inguinal (deep), inguinal (superficial, femoral), supraclavicular, cervical, scalene, retroperitoneal Distant metastases (clinical or pathologic) M0—none M1a—non-regional lymph nodes M1b—bone M1c—other sites

Node positive Metastatic

>20 >20

10–20

Unfavorable

High Very high