Lung Cancer Treatment [1 ed.] 9781620819197, 9781613241318

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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Lung Cancer Treatment, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Lung Cancer Treatment, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS

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LUNG CANCER TREATMENT

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

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CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS Additional books in this series can be found on Nova’s website under the Series tab.

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CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LUNG CANCER TREATMENT

BRANDON S. WEST AND

DONNA R. STANLEY EDITORS

Nova Science Publishers, Inc. New York Lung Cancer Treatment, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

Copyright ©2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Lung cancer treatment / editors, Brandon S. West and Donna R. Stanley. p. ; cm. Includes bibliographical references and index. ISBN 978-1-62081-919-7 (E-Book) 1. Lungs--Cancer--Treatment. I. West, Brandon S. II. Stanley, Donna R. [DNLM: 1. Lung Neoplasms--therapy. WF 658] RC280.L8L85 2011 616.99'424--dc22 2011008469

Published by Nova Science Publishers, Inc.† New York Lung Cancer Treatment, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

Contents vii 

Preface

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Chapter I

Epidermal Growth Factor Tyrosine Kinase Inhibitors in the Management of Advanced Stage Non-Small Cell Lung Cancer Ross A. Soo and Tony Mok 

Chapter II

Lung Cancer Brachytherapy Janusz Skowronek 

Chapter III

Update Chemotherapy Schedule in the Treatment of Lung Cancer V. Scotti, V. Di Cataldo, C. Franzese, I. Desideri, G. Zei, M. Loi and G. Biti 

Chapter IV

Treatment of Small Cell Lung Cancer Jairam Krishnamurthy, Tsewang Tashi, Wilson Gonsalves and Apar Kishor Ganti 

Chapter V

Volumetric Modulated Arc Therapy in the Treatment of Lung Cancer Merina Ahmed and Maria Hawkins 

Chapter VI

Future Individualized Therapy for Lung Cancer in Post-Genomic Era Shih-Hsin Hsiao, Yiju Hung, Ming-Chih Yu, Kuan-Jen Bai and H. Eugene Liu 

Index Lung Cancer Treatment, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

1  43 

87

111 

125 

137 

149

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Preface Lung cancer is one of the leading causes of death worldwide with the majority of patients suffering from advanced unresectable or metastatic nonsmall cell lung cancer. Despite the advances in palliative chemotherapy, the survival rate for patients with this advanced disease treated with chemotherapy remains poor. In this new book, the authors present topical research in the study of lung cancer treatments including epidermal growth factor tyrosine kinase inhibitors, in the management of advanced stage non-small cell lung cancer; lung cancer brachytherapy; volumetric modulated arc therapy and future individualized therapy for lung cancer in post-genomic era. Chapter I – The epidermal growth factor receptor (EGFR) is an attractive anti-cancer target in non-small cell lung cancer. The small-molecule agents such as erlotinib and gefitinib that selectively inhibit the intracellular tyrosine kinase activity of EGFR have been extensively studied. Multiple randomized trials have evaluated the role of EGFR tyrosine kinase inhibitors in advanced stage non-small cell lung cancer, initially as monotherapy in the pre-treated setting, and subsequently in combination with cytotoxic chemotherapy. More recently, EGFR tyrosine kinase inhibitors has been used as a monotherapy in the first line setting, especially in selected patient population or as maintenance therapy following first line chemotherapy. Whilst most of these trials showed positive results, the greatest effect of EGFR tyrosine kinase inhibitors was seen in particular in patients with specific clinical characteristics and more recently in those with somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.

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Brandon S. West and Donna R. Stanley

Chapter II – Lung cancer is the leading cause of cancer death with fiveyear survival rates reaching only 10-12 % during the last 20 years. The lung cancer failure rate remains unacceptably high, despite major advances over the past 40 years in the field of surgery, radiotherapy and chemotherapy. In general, upon diagnosis 25 – 30 % of the NSCLC patients present with tumors confined to the lung (stage I or II) and only 40 – 50 % of them can be resected for cure, 30 % have locally advanced disease (stage III), the remaining 40 – 45 % have distant metastases (stage IV). Local recurrences after external beam radiotherapy (EBRT) occur in 60-70% of patients, and are responsible for 60% of the mortality due to respiratory failure, obstructive pneumonia and sepsis. One of the most distressing symptoms for lung cancer patients is airway obstruction. The most common symptoms in patients suffering from endobronchial tumors are: cough (45 – 75 %), haemoptysis (25 – 35 %), dyspnoea (40 – 60 %) or post obstructive pneumonia (20 - 25%). Lack of improvement in treatment results of lung cancer leads to searching for new methods. Removal of endobronchial obstruction leads to quick improvement of clinical status and Quality of Life (QoL). Brachytherapy is one of the most efficient methods in overcoming difficulties in breathing that is caused by endobronchial obstruction in palliative treatment of tracheal and lung cancer [1-10]. Depending on the location of the lesion in some cases brachytherapy is a treatment of choice. Efforts to relieve this obstructive process are worthwhile, because patients may experience improved QoL in hours or days after treatment. However, many of these patients have a poor performance status and received multiple other therapies. As a result, treatment options are often limited. In most cases brachytherapy has a palliative aim due to advanced clinical stage [11-16]. Speiser and Spratling [16] considered certain factors for palliative treatment, such as: weight loss of more then 10% in the 6 months prior to diagnosis, poor performance status, tumor stage IIIB or IV, or a recurrent disease following prior external beam irradiation. Lack of clear consensus regarding the value of doses used in brachytherapy is the reason why different fraction doses are used in clinical treatment [3,15,17,18]. Due to bad performance status (Zubrod-ECOG-WHO score >2) single high doses ranging from 10 Gy to 15 Gy are being applied [3,17,19,20]. It seems that results in this procedure are similar to whenever doses were given weekly in two or three fractions. A single dose protocol is cost - sparing and more comfortable for patients. On the other hand, weekly repeated treatment enable to have a better local control visualized with the use of bronchoscopy. Brachytherapy plays a limited but specific role in definitive treatment with curative intent in selected cases of early endobronchial disease as well as in

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Preface

ix

the postoperative treatment of small residual peribronchial disease. Because of the close anatomical and clinical similarities lung and tracheal cancer are discussed together. Chapter III – The histological classification of lung cancer is very important from a clinical and prognostic point of view; it has been revised from the World Health Organization (WHO) in 1999 and 2004 [1,2]. The complete WHO classification of lung tumors is shown in figure 1. It divides malignant tumors, benign epithelial tumors, lymphoproliferative tumors, miscellaneous and metastatic tumors. For the aims of this chapter, the most important classification regards two fundamental groups: Non Small Cell Lung Cancer (NSCLC), that include the squamous cell carcinoma, adenocarcinoma and the large cell carcinoma, and Small Cell Lung Cancer (SCLC). Topographically, lung cancer can be classified into hilar or central tumors (70 -75%) as found at the hilum, and parenchymal or periopheral tumors (25-30%), that arise from the bronchi and peripheral bronchioles. Chapter IV – Small cell lung cancer (SCLC) represents approximately 16 percent of all lung cancers and occurs almost exclusively in smokers. Although SCLC is highly responsive to both chemotherapy and radiotherapy (RT), it commonly relapses within months despite treatment. SCLC is highly responsive to multiple chemotherapeutic drugs, and chemotherapy dramatically prolongs survival compared to best supportive care. Randomized trials have shown a survival benefit for combination regimens compared to single agent chemotherapy, and for simultaneous administration of multiple agents as compared to sequential administration of the same agents. While no specific combination has established superiority in the treatment of SCLC, based upon efficacy and toxicity profiles, platinumbased combinations are generally preferred. For patients with limited stage SCLC who are candidates for aggressive therapy, thoracic radiotherapy (RT) administered concurrently with systemic chemotherapy can be used for initial management. For patients with evidence of continuing response at the completion of chemoradiotherapy, prophylactic cranial irradiation is recommended. Second-line chemotherapy may improve survival and quality of life in patients with relapsed or recurrent SCLC, even in patients who do not achieve an objective response. Several single agents and combination regimens have activity in recurrent SCLC. However, the optimal regimen is unclear, and responses generally are short. For patients with relapsed disease and a good performance status, single agent topotecan therapy is recommended. Various

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targeted therapies, cancer vaccines, and novel cytotoxic agents are currently being evaluated for their role in SCLC. Chapter V – The concept of intensity modulated arc therapy (IMAT) was introduced as early as 1995 by Yu et al as an alternative to intensity modulated radiotherapy (IMRT) or tomotherapy [1] but was not adopted by the radiotherapy community at large. Lately developments in the linear accelerator’s technology have facilitated the capability to simultaneously vary the gantry speed, multi-leaf collimator leaf positions and dose rate during single or multi-arc treatments thus providing a superior form of IMAT known as volumetric arc therapy (VMAT). This has led to a resurgence of interest in arc therapy in certain tumour sites one of which is lung cancer. This chapter aims to provide a comprehensive review of this technique of radiotherapy planning, its advantages and limitations, and the comparisons to other forms of conformal planning in the radical treatment of lung cancer. Chapter VI – Since lung cancer is often diagnosed at advanced stages, patients usually require systemic therapy, such as chemotherapy or targeted agents, to control their disease. In the past, patients are treated in a trial-anderror fashion. Now with the advances in genomic sequencing, the application of mutation screening particularly in epidermal growth factor receptor (EGFR) and K-ras to predict the response to targeted agents has gradually become a routine practice. In addition, multiple biomarkers have been identified to correlate not only the response but also the side effects of cancer treatment. However, translating the new information into the care of lung cancer has yet been fully realized. To accomplish the goal of individualized therapy, we need a comprehensive approach to integrate current individual genomic information into our clinical practice in the post-genomic era. In this chapter, we review current development in the integration of pharmacogenomics, pharmacokinetics and new biomarkers and hope to depict the future of individualized therapy for lung cancer. The integration might allow us to optimize the efficacy of chemotherapy and targeted agents with minimized toxicity, so patients with lung cancer will receive the right agents with the right dose at the right time in the modern post-genomic era.

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In: Lung Cancer Treatment Editors: B.S. West, D.R. Stanley, 1-41

ISBN: 978-1-61324-131-8 © 2011 Nova Science Publishers, Inc.

Chapter I

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Epidermal Growth Factor Tyrosine Kinase Inhibitors in the Management of Advanced Stage Non-Small Cell Lung Cancer Ross A. Soo1,2* and Tony Mok3 1

Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore 2 Cancer Science Institute of Singapore, Singapore 3 State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China

Abstract The epidermal growth factor receptor (EGFR) is an attractive anti-cancer target in non-small cell lung cancer. The small-molecule agents such as erlotinib and gefitinib that selectively inhibit the intracellular tyrosine kinase activity of EGFR have been extensively studied. Multiple randomized trials *

Corresponding author: Ross A Soo, Department of Hematology-Oncology, National University Health System, Email: [email protected]

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have evaluated the role of EGFR tyrosine kinase inhibitors in advanced stage non-small cell lung cancer, initially as monotherapy in the pre-treated setting, and subsequently in combination with cytotoxic chemotherapy. More recently, EGFR tyrosine kinase inhibitors has been used as a monotherapy in the first line setting, especially in selected patient population or as maintenance therapy following first line chemotherapy. Whilst most of these trials showed positive results, the greatest effect of EGFR tyrosine kinase inhibitors was seen in particular in patients with specific clinical characteristics and more recently in those with somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.

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Introduction Lung cancer is one of the leading causes of death worldwide with the majority of patients presenting with advanced unresectable or metastatic nonsmall cell lung cancer (NSCLC). Despite the advances in palliative chemotherapy, the survival for patients with advanced disease treated with chemotherapy remains poor with a median survival of 8-10 months [1]. The development of the specific molecular-targeted therapeutic agents has provided more treatment options to prolong survival. One such molecular target is the epidermal growth factor receptor (EGFR). The EGFR is an attractive target for various antitumor strategies including small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity and antiEGFR monoclonal antibody that inhibit extracellular ligand-induced phosphorylation and receptor degradation [2]. This review will further discuss on the role of EGFR tyrosine inhibitors (TKIs) as well as the multikinase EGFR inhibitors in the management of advanced stage NSCLC.

EGFR Pathway in NSCLC The epidermal growth factor, a member of the human epidermal growth factor receptor (HER) family, is a transmembrane glycoprotein that consists of three main components: an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain [3]. The

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EGFR signaling pathway plays a pivotal role in carcinogenesis. Dimerization of the EGFR occurs after stimulation by a ligand such as epidermal growth factor, transforming growth factor-alpha, epiregulin and amphiregulin, results in autophosphorylation and downstream activation of a number of cell signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3’ kinase (PI3K)–AKT pathway, and the STAT pathway. This leads to increased cell proliferation, inhibition of apoptosis, increased invasion and metastasis [2]. The overexpression of EGFR occurs in approximately 60% of metastatic NSCLC cases and is associated with poorer prognosis [4]. Given the importance of EGFR in lung cancer, therapies targeting the EGFR have been developed. EGFR TKIs inhibit the intracellular tyrosine kinase domain of the EGFR and therefore block the signal transduction pathways implicated in the proliferation and survival of cancer cells.

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Clinical Pharmacology of GEFITINIB and ERLOTINIB The small-molecule EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, are orally active low molecular weight compound (40-600kD) that reversibly compete with ATP to bind to the intracellular catalytic domain of EGFR. This leads to inhibition of autophosphorylation and subsequent downstream inhibition of RAS-RAF-MEK-MAPK (gene transcription, cell cycle progression, and cell proliferation) and PI3K-Akt pathway (antiapoptotic and prosurvival) [3, 5]. The bioavailability of a single dose of erlotinib 150mg is about 60% and peak plasma levels occur 4 hours after dosing. Bioavailability is increased to almost 100% with food. Erlotinib is 93% protein bound to albumin and α-1 acid glycoprotein and the volume of distribution is approximately 232 liters. The half-life after a single dose is 36 hours and it is metabolized mainly by CYP3A4 and to a lesser extent by CYP1A2 and CYP1A1. No significant relationships of clearance to patient age, body weight, or gender has been reported whilst smokers had a 24% higher rate of erlotinib clearance [6]. As the metabolism of erlotinib is via CYP3A4, drugs known to affect CYP3A4 activity should be recognised. Inducers of CYP3A4 such as rifampicin may require an increase in erlotinib dose whilst CYP3A4 inhibitors such as ketoconazole or fluconazole may require a reduction in erlotinib dose [6]. The

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cerebrospinal fluid (CSF) concentration of erlotinib has been described recently. The CSF concentration of erlotinib and its active metabolite, OSI420, was In a small study of 4 NSCLC patients with brain metastases treated with erlotinib 150mg daily, the mean + SD CSF penetration rates of erlotinib and OSI-420 were 5.1% + 1.9% and 5.8% + 3.6% respectively [7]. The CSF concentrations of erlotinib exceeded the median IC50 of erlotinib in cell lines harboring EGFR WT. After a single-dose administration of gefitinib, peak plasma levels occur within 3–7 hours and bioavailability is about 60%. It is 91% bound to human plasma proteins, mainly serum albumin and α1-acid glycoprotein. Gefitinib also undergoes extensive CYP3A-mediated metabolism [8]. Studies have shown the concomitant administration of rifampicin was associated with a reduced mean AUC of gefitinib by 83% whilst concomitant administration of itraconazole with gefitinib increased mean gefitinib AUC by 78% [9].

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Phase I/II Trials pf GEFITINIB Phase I trials of patients with a range of solid tumors known to have high expression of EGFR have shown gefitinib to be well tolerated, with the commonest adverse events being rash, diarrhea, nausea, anorexia, and asthenia [10-13]. The maximum tolerated dose was 700 mg daily and subsequently the lowest dose chosen for phase II clinical trials was 250 mg daily. The alternative dose of 500 mg daily was selected as the highest tolerated dose by most patients. In two randomized phase II studies, the Iressa Dose Evaluation in Advanced Lung Cancer, IDEAL 1 and 2, patients with pre-treated NSCLC were randomized to gefitinib at 250 mg or 500 mg daily. In IDEAL-1 where patients had received one or two lines of chemotherapy, a similar response rate of 18.4% and 19% was seen at gefitinib 250mg and 500mg daily, respectively. In addition, the disease control rate (54.4% versus 51.4%), progression-free survival (2.7 months versus 2.8 months), median overall survival (7.6 months versus 8 months), and 1-year survival (35% versus 29%) were also similar. Subset analysis showed that Japanese patients had a better response rate compared to non-Japanese (27.5% versus 10.4%; p = 0.002) [14]. In IDEAL-2, a multicentre US study, patients with advanced NSCLC previously treated with two or more regimens, including a platinum agent and docetaxel were randomised to gefitinib at 250mg or 500mg daily. The

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response rate was 12% versus 10%, and the median survival was 7 versus 6 months for 250 mg and 500 mg daily, respectively [15]. Treatment was well tolerated in both IDEAL-1 and -2, with skin rash the most common side effect. The 250mg daily was selected for further trials as the efficacy was similar between the two doses and as grade 3-4 toxicity was more frequent in patients receiving 500 mg daily. Clinical predictors for response were Japanese patients, women, adenocarcinoma histology, never smokers, and good performance status.

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Clinical and Genomic Predictive Markers for EGFR TKI Whilst EGFR TKIs displayed some activity in unselected patients with NSCLC, differences in response rates were observed in certain patient subgroups. Retrospective analysis suggests clinical characteristics such as female gender, adenocarcinoma histology, Asian ethnicity and a history of never/ light smoking were associated with increased response to EGFR TKIs. An association between somatic activating mutations in exon 18-21 of EGFR (commonly exon 19 deletions and L858R point mutation in exon 21) and EGFR TKI sensitivity was reported by several investigators [16-18] and that these mutations are present predominantly in patients with the clinical features mentioned previously [19]. Other molecular determinants of EGFR TKIs response include EGFR gene copy number detected by fluorescence in situ hybridization (FISH) [20]. The activating mutations of the EGFR gene are commonly found in exons 18 through 21 of the TK domain with deletions in exon 19 and the point mutation of L858R comprising about 90% of all EGFR activating mutations, [21, 22]. The majority of EGFR TKI-sensitizing mutations are in-frame deletions in exon 19; usually involving the amino-acid residues leucine-747 to glutamic acid-749, and account for about 44% of all EGFR TK mutations. The predominant single-point mutation involves exon 21, which substitutes an arginine for a leucine at codon 858 (L858R) and accounts for about 41% of all EGFR TK activating mutations. Other less common activating mutations include a glycine-719 (G719) change to serine, alanine or cysteine (4% of all EGFR TK activating mutations), missense mutations (6% of EGFR mutations), in-frame duplications and/or insertions in exon 20 (5% of EGFR

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TK activating mutations) and rarely mutations such as V765A and T783A (