S U P P L E M E N T

7 downloads 332663 Views 2MB Size Report
Application of NCCN Clinical Practice ... Business Development and Marketing ... Application to mail at Periodical Prices is Pending at Cold Spring Harbor, NY, ...
S U P P L E M E N T

Volume 8 Supplement 3

JNCCN

Journal of the National Comprehensive Cancer Network

The Abu Dhabi Declaration: Adapted Application of NCCN Clinical Practice Guidelines in Oncology in the Middle East and North Africa Region The Process of NCCN Guidelines™ Adaptation to the Middle East and North Africa Region Abdul-Rahman Jazieh, Hamdy A. Azim, Joan McClure, and Mohammad Jahanzeb

Also Featuring Modification and Implementation of NCCN Guidelines™ in the Middle East and North Africa Region on: Breast Cancer Omalkhair Abulkhair, Nagi Saghir, Lobna Sedky, et al.

Non–Small Cell Lung Cancer Abdul-Rahman Jazieh, Hanaa Bamefleh, Ahmet Demirkazik, et al.

Colon Cancer The National Comprehensive Cancer Network® (NCCN®) appreciates that supporting companies recognize NCCN®’s need for autonomy in the development of the content of NCCN resources. All NCCN content is produced completely independently. NCCN GuidelinesTM are not intended to promote any specific therapeutic modality. The distribution of this task force report is supported by an educational grant from Roche.

Fikri İçli, Hakan Akbulut, Shouki Bazarbashi, et al.

Prostate Cancer Waleed A. Hassen, Farrok A. Karsan, Farhat Abbas, et al.

Lymphomas Ali Bazarbachi, Hamdy A. Azim, Hussain Alizadeh, et al.

Hepatobiliary Cancers Muhammed Aasim Yusuf, Vinay Kumar Kapoor, Refaat Refaat Kamel, et al.

Palliative Care Omar Shamieh and Abdul-Rahman Jazieh

NCCN.org

JNCCN

Volume 8 Supplement 3 Journal of the National Comprehensive Cancer Network Masthead

Postal and Contact Information

Editorial Editor-in-Chief: Harold J. Burstein, MD, PhD National Comprehensive Cancer Network Senior Director, Professional and Patient Publications: Kimberly A. Callan, MS, ELS Assistant Managing Editor: Kerrin Robinson, MA Editorial Associate: Genevieve Emberger Hartzman, MA National Comprehensive Cancer Network Chairman of the Board: Thomas A. D’Amico, MD Vice Chair of the Board: Samuel M. Silver, MD, PhD Chief Executive Officer: William T. McGivney, PhD Executive Vice President/Chief Operating Officer: Patricia J. Goldsmith Senior VP, Finance/Chief Financial Officer: Lisa Kimbro, CPA, MBA NCCN GuidelinesTM Senior VP, Clinical Information and Publications: Joan S. McClure, MS VP, Clinical Information Operations: Kristina M. Gregory, RN, MSN, OCN Associate Director, Clinical Information: Dorothy A. Shead, MS Guidelines Coordinators: Nicole R. McMillian, MS Mary Dwyer Rosario, MS Oncology Scientists/Sr. Medical Writers: Miranda Hughes, PhD Hema Sundar, PhD Susan J. Moench, PhD Rashmi Kumar, PhD Maria Ho, PhD Administrative Coordinators: Mary Anne Bergman Jean Marie Dougherty Business Development and Marketing VP, U.S. & Global Development: C. Lyn Fitzgerald Senior Manager, Communications and Marketing: Jennifer Tredwell, MBA Advertising Harborside Press Director of Business Development: David Horowitz Publishing and Design Harborside Press Executive Editor: Conor Lynch Editorial Assistant: Sarah McGullam Production Coordinator: Wendy McGullam President: Anthony Cutrone Publisher: John A. Gentile, Jr.

JNCCN (ISSN 1540-1405), the official journal of the National Comprehensive Cancer Network ® (NCCN®), is published 12 times annually by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Application to mail at Periodical Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster: send address changes to JNCCN, c/o Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Recipient: to change your address contact [email protected] or fax 631-692-0905. © National Comprehensive Cancer Network, Inc. 2010. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, ­electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from NCCN. Subscriptions: Prices for yearly subscriptions (12 issues plus supplements) are: Individual: Print only or online only, US $440; Can/Mex + Int’l $545; print and online, US $485; Can/Mex + Int’l $610. Institutional: Print only or online only, US $685; Can/Mex + Int’l $790; print and online, US $750; Can/ Mex + Int’l $865. Single Copy: US $70.00; Can/Mex $85.00; Int’l $95.00. Subscription Inquiries should be directed to Wendy McGullam, Harborside Press, at: 631-692-0800 x303 or [email protected]. Online access is ­available to subscribers through IngentaConnect (www.ingentaconnect.com). Contact Information Editorial Office:  Manuscripts, correspondence, and commentaries to be considered for publication should be sent to Kimberly Callan, Senior Director, Professional and Patient Publications, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Correspondence can also be faxed: 215-690-0283 (attn: JNCCN). Questions about requirements for publication or topic suitability can be directed as above or to Harold J. Burstein, MD, PhD, Editor-in-Chief, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Instructions for authors are published in JNCCN as space allows and can be found on-line at www.nccn. org/jnccn. They can also be requested by calling 215-690-0270 or e-mailing [email protected]. Advertising To purchase advertising space: Contact David Horowitz, Director of Business Development, Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631-692-0805; or ­e-mail [email protected]. To send film or digital ad materials: Ship to Harborside Press, Attn: Wendy McGullam, (JNCCN, Vol ___ Issue ___), 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x303; fax 631-692-0805; or e-mail [email protected]. To send pre-printed inserts: Ship to Publishers Press, Inc., Attn: Tammy Baugh, 13487 South Preston Highway, Lebanon Junction, KY 40150. Production Reprints:  Reprints of individual articles are available. Orders must be for a minimum of 100 copies. Please contact David Horowitz, Director of Business Development, Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631-692-0805; or e­ -mail [email protected]. Permissions For information about photocopying, republishing, reprinting, or adapting material, please go online to www.NCCN.org/about/permissions. Indexing JNCCN is indexed by MEDLINE/PUBMED®, Chemical Abstracts, EMBASE, EmCare, and Scopus. This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper) effective with Volume 1, Issue 1, 2003. JNCCN is a member of the Medscape Publisher’s Circle®, an alliance of leading medical publishers whose content is featured on Medscape (http://www.medscape.com). Medscape is part of the WebMD Medscape Health Network, a leading online healthcare resource for professionals and consumers.

Disclaimer The treatment algorithms presented in JNCCN and its supplements are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual circumstances to determine any patient’s care or treatment. The research ­articles, reviews, and other individually authored papers presented herein are the work of the authors listed. Furthermore, the reader is advised that, except where specifically stated, all of the ideas and opinions expressed in JNCCN are the authors’ own and do not necessarily reflect those of NCCN, the member organizations, the editor, or the publisher. Publication of an advertisement or other product mention in JNCCN should not be construed as an endorsement of the product or the manufacturer’s claims. The information contained in JNCCN is presented for the purpose of educating our readership on cancer treatment and management. The information should not be relied on as complete or accurate, nor should it be relied on to suggest a course of treatment for a particular individual. It should not be used in place of a visit, call, consultation, or the advice of a licensed physician or other qualified health care provider. Patients with health carerelated questions or concerns are advised to contact a physician or other qualified health care provider promptly. Although every attempt has been made to verify that information presented within is complete and ­accurate, the information is provided “AS IS” without warranty, express or implied. NCCN hereby e­ xcludes all implied warranties of merchantability and fitness for a particular use or purpose with respect to the Information. Furthermore, NCCN makes no warranty as to the reliability, accuracy, timeliness, usefulness, adequacy, completeness, or suitability of the information.

JNCCN

Volume 8 Supplement 3 Journal of the National Comprehensive Cancer Network Mission Statement NCCN Member Institutions City of Hope Comprehensive Cancer Center Los Angeles, California Dana-Farber/Brigham and Women’s Cancer Center| Massachusetts General Hospital Cancer Center Boston, Massachusetts Duke Comprehensive Cancer Center Durham, North Carolina Fox Chase Cancer Center Philadelphia, Pennsylvania Huntsman Cancer Institute at the University of Utah Salt Lake City, Utah Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Seattle, Washington The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois Memorial Sloan-Kettering Cancer Center New York, New York H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute Columbus, Ohio Roswell Park Cancer Institute Buffalo, New York Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, Missouri St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute Memphis, Tennessee Stanford Comprehensive Cancer Center Stanford, California University of Alabama at Birmingham Comprehensive Cancer Center Birmingham, Alabama UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan UNMC Eppley Cancer Center at The Nebraska Medical Center Omaha, Nebraska The University of Texas MD Anderson Cancer Center Houston, Texas Vanderbilt-Ingram Cancer Center Nashville, Tennessee For more information, visit www.NCCN.org

JNCCN is dedicated to improving the quality of cancer care locally, nationally, and internationally while enhancing the collaboration between academic medicine and the community physician. JNCCN is further committed to disseminating information across the cancer care continuum by publishing clinical practice guidelines and reporting rigorous outcomes data collected and analyzed by experts from the world’s leading care centers. JNCCN also provides a forum for original research and review papers focusing on clinical and translational research and applications of the NCCN Guidelines in everyday practice, as well as correspondence and commentary.

NCCN 275 Commerce Drive Suite 300 Fort Washington, PA 19034 215–690–0300 www.NCCN.org

About the NCCN The National Comprehensive Cancer Network ® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.NCCN.org.

JNCCN

Volume 8 Supplement 3 Journal of the National Comprehensive Cancer Network

The Abu Dhabi Declaration: Adapted Application of NCCN Clinical Practice Guidelines in Oncology in the Middle East and North Africa Region Featured Articles

S-1 Welcome William T. McGivney, PhD

S-2 Editorial: The Abu Dhabi Declaration: Why the Hustle? Hamdy A. Azim, MD, PhD; Abdul-Rahman Jazieh, MD, MPH; and Mohammad Jahanzeb, MD

S-5 The Process of NCCN Guidelines™ Adaptation to the Middle East and North Africa Region Abdul-Rahman Jazieh, MD, MPH; Hamdy A. Azim, MD, PhD; Joan McClure, MS; and Mohammad Jahanzeb, MD NCCN Guidelines set the standard of cancer care in the United States. Because of wide acceptance of, need for, and interest in standardized treatment practices across the world, NCCN launched initiatives to help international groups adapt these guidelines. This article describes the initiative in the Middle East and North Africa region.

S-8 Modification and Implementation of NCCN Guidelines™ on Breast Cancer in the Middle East and North Africa Region

Omalkhair Abulkhair, MD; Nagi Saghir, MD; Lobna Sedky, MD; Ahmed Saadedin, MD; Heba Elzahwary, MD; Neelam Siddiqui, MD; Mervat Al Saleh, MD; Fady Geara, MD; Nuha Birido, MD; Nadia Al-Eissa, MD; Sana Al Sukhun, MD; Huda Abdulkareem, MD; Menar Mohamed Ayoub, MD; Fawaz Deirawan, MD; Salah Fayaz, MD; Alaa Kandil, MD; Sami Khatib, MD; Mufid El-Mistiri, MD; Dorria Salem, MD; El Siah Hassan Sayd, MD; Mohammed Jaloudi, MD; Mohammad Jahanzeb, MD; and William I. Gradishar, MD Published data from the Middle East and North Africa (MENA) region indicate suboptimal quality of cancer care, while the World Health Organization predicts an increase in cancer cases in developing countries. Major advances in breast cancer management mandate the development of guidelines to improve the quality and efficacy of oncology practice in the MENA region.

S-16 Modification and Implementation of NCCN Guidelines™ on Non–Small Cell Lung Cancer in the Middle East and North Africa Region

Abdul-Rahman Jazieh, MD, MPH; Hanaa Bamefleh, MBchB, FRCPC; Ahmet Demirkazik, MD; Rabab Mohamed Gaafar, MD; Fady B. Geara, MD, PhD; Mansur Javaid, MD, FCCP, FRCP; Jamal Khader, MD; Kian Khodadad, MD; Walid Omar, MD; Ahmed Saadeddin, MD; Hassan Al Sabe, MD; Mohammad Behgam Shadmehr, MD; Amgad El Sherif, MD, FCCP; Najam Uddin, FRCR; Mohammad Jahanzeb, MD; and David Ettinger, MD A lung cancer committee from the Middle East and North Africa region was established to modify the NCCN Guidelines on Lung Cancer, to create a platform for standard care in the region.

S-22 Modification and Implementation of NCCN Guidelines™ on Colon Cancer in the Middle East and North Africa Region

Fikri İçli, MD; Hakan Akbulut, MD; Shouki Bazarbashi, MD; Mehmet Ayhan Kuzu, MD; Mohandas K. Mallath, MD; Kakil Ibrahim Rasul, FRCP Edin; Scott Strong, MD; Aamir Ali Syed, FRCS; Faruk Zorlu, MD; and Paul F. Engstrom, MD Colorectal cancer is less common in the Middle East and South Asia than in western countries, with the rectum the most common primary site, unlike in the United States. Major differences also exist in treatment preferences, as discussed in this article.

S-26 Modification and Implementation of NCCN Guidelines™ on Prostate Cancer in the Middle East and North Africa Region

Waleed A. Hassen, MD; Farrok A. Karsan, MD; Farhat Abbas, MD; Yasar Beduk, MD; Ahmed El-Khodary, MD; Marwan Ghosn, MD, MBA; Jamal Khader, MD; Raja Khauli, MD; Danny M. Rabah, MD; Ali Shamseddine, MD; and Sandy Srinivas, MD The treatment of prostate cancer in the Middle East and North Africa region has numerous challenges. The hope is that this effort to modify the NCCN Guidelines on Prostate Cancer for practical use in the MENA region will improve regional awareness and patient care.

JNCCN

Volume 8 Supplement 3 Journal of the National Comprehensive Cancer Network

Featured Articles

S-29 Modification and Implementation of NCCN Guidelines™ on Lymphomas in the Middle East and North Africa Region

Ali Bazarbachi, MD, PhD; Hamdy A. Azim, MD, PhD; Hussain Alizadeh, MD, PhD; Mahmoud Aljurf, MD; Ibrahim Barista, MD; Naeem A. Chaudhri, MD; Zahira Fahed, MD; Omar A. Fahmy, MD; Ardeshir Ghavamzadeh, MD; Mohamed H. Khalaf, MD; Sami Khatib, MD; Aghiad Kutoubi, MD; Semra Paydas, MD; Hanadi Rafii Elayoubi, MD; Ghazi Zaatari, MD; Hamdy M. Zawam, MD; and Andrew D. Zelenetz, MD, PhD In the Middle East and North Africa (MENA) region, cancer has many epidemiologic and clinical features that are different from those in the rest of the world. A critical need exists for regional guidelines for cancer care, including those for lymphoid malignancies. This article presents the consensus recommendations from lymphoma experts from the MENA region on the NCCN Guidelines on Non-Hodgkin’s Lymphoma.

S-36 Modification and Implementation of NCCN Guidelines™ on Hepatobiliary Cancer in the Middle East and North Africa Region

Muhammed Aasim Yusuf, FRCP Edin; Vinay Kumar Kapoor, MS, FRCS; Refaat Refaat Kamel, FRCS; Ather Kazmi, MRCP, FRCR; Najam Uddin, FRCR; Nehal Masood, MD; and Abdulmajeed Al-Abdulkareem, MD, FRCSC, FACS Hepatocellular cancer incidence is higher in the Middle East and North Africa region than in the West, and hepatitis B and C infections are particularly important. Regional problems discussed in this article include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities, and treatment cost is an ongoing concern.

S-41 Modification and Implementation of NCCN Guidelines™ on Palliative Care in the Middle East and North Africa Region

Omar Shamieh, MD, and Abdul-Rahman Jazieh, MD, MPH Advancing palliative care in the developing countries is essential to improving patient care. Palliative care is in its early stage of evolution in the Middle East and North Africa region, and its practice encounters many challenges and barriers. Adaptation of guidelines must consider the situation and conditions in the targeted region.

S-1

Journal of the National Comprehensive Cancer Network The National Comprehensive Cancer Network (NCCN) and our 21 member institutions are dedicated to improving the care available to patients around the world. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) and the attendant scientific, evaluative process has become the model for the development and communication of clinical recommendations based on evidence review integrated with expert judgment. The NCCN is pleased to extend our scientific, clinical collaboration to thought leaders in the Middle East and North Africa (MENA). The NCCN–MENA Guidelines Congress held in Abu Dhabi, running from April 23 to 26, 2009, brought together leading clinicians to review the NCCN Guidelines and supporting data and to discuss the applicability of the NCCN Guidelines to patients in this part of our world. As always, the clinical discussion highlighted areas for improvement and clarification in the NCCN Guidelines. As Drs. Azim, Jazieh, and Jahanzeb point out in the accompanying introduction, the work has begun and the initial thinking is published is this “Abu Dhabi Declaration.” Much work remains as experts identify issues for study in trials or through other research methods, issues that relate to possible differences in genetic makeup and its expression, differences in the availability of technology across the 16 countries, and other factors. The NCCN thanks our colleagues in the Middle East and North Africa for their willingness to share their knowledge, expertise, and experience as we work to improve cancer care for patients whom we serve.

Welcome

William T. McGivney, PhD William T. McGivney, PhD, is Chief Executive Officer of the NCCN, responsible for the development of strategies and programs to improve the quality of care available to cancer patients. Such programs include the NCCN Clinical Practice Guidelines in Oncology, NCCN Oncology Outcomes Database, NCCN Oncology Research Program, and NCCN Drugs & Biologics Compendium. Strategically, Dr. McGivney is responsible for the growth of NCCN’s influence in the oncology community and for assuring the development of partnerships with managed care companies and employers, the development of NCCN’s health information capabilities, and the expansion of centralized research programs. Before joining NCCN, Dr. McGivney was Director of the Division of Health Care Technology at the American Medical Association and then Vice President for Clinical and Coverage Policy at Aetna Health Plans. While at Aetna, he helped establish the first formal independent outside review process. Dr. McGivney, a recognized expert in coverage policy and in drug and device regulatory policy, was awarded the FDA Commissioner’s Medal of Appreciation in 1989. He has served on numerous national boards and committees including as President of the Board of the Patient Advocate Foundation and National Patient Advocate Foundation and as a member of the UNOS Board of Directors and the Medicare Coverage Advisory Committee.

The ideas and viewpoints expressed in this editorial are those of the author and do not necessarily represent any policy, position, or program of the NCCN.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-2

Editorial

Journal of the National Comprehensive Cancer Network

The Abu Dhabi Declaration: Why the Hustle?

Hamdy A. Azim, MD, PhD Dr. Azim is Professor of Clinical Oncology at Cairo University in Egypt. His interests lie in lymphoma, breast cancer, bone metastases, and translational research, and has published more than 50 papers and 100 abstracts. Dr. Azim is a member of numerous societies, including ASCO and ASH. He sits on several scientific committees and has been an invited speaker to more than 100 regional and international conferences in the Middle East, Europe, United States, and Asia, and has published more than 50 papers and 100 abstracts.

Abdul-Rahman Jazieh, MD, MPH Dr. Abdul-Rahman Jazieh, MD, MPH, is Chairman of the Department of Oncology at the King Abdulaziz Medical City in Riyadh, Kingdom of Saudi Arabia. He is also a Professor at the King Saud bin Abdulaziz University for Health Sciences and a volunteer professor at the University of Cincinnati in Ohio. He is board certified in internal medicine, hematology, and medical oncology.

Over the past decade, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) have emerged as a very useful tool for supporting and improving the quality of decision-making for oncologists worldwide. Considering that approximately 12 million cancer patients were registered by the WHO during 2008 and that the NCCN Web site (www.NCCN.org) attracts more than 150,000 visitors per month, one can conclude that the NCCN Guidelines program has potentially influenced the management of approximately 15% of all cancer patients worldwide. Although this example shows its far-reaching benefit, it also shows that there is plenty of room for expanding its application. A real need exists within the oncology community to have a reliable evidence-based tool to translate the rapidly accumulating scientific research into practical medical decisions that may offer a better and more consistent treatment outcome for patients. The NCCN recently launched the NCCN–Middle East and North Africa (NCCN–MENA) Guidelines Congress in an attempt to provide versions of the original NCCN Guidelines tailored for cancer management in this region. However, one may ask whether it is really important to have a revised set of Guidelines specifically dedicated to a certain geographical region, when the original NCCN guidelines are satisfactory and comprehensive. We believe the answer is “YES” for 3 main reasons: differences in race, genetic, and environmental factors; differences in presenting features and stage; and differences in access to technology and drugs.

Differences in Racial, Genetic, and Environmental Factors The NCCN Guidelines have been generated based on high-level evidence provided by large trials conducted mainly in the United States and Europe (hence predominantly enrolling a Western population) with a limited contribution from the rest of the world, including the Middle East. Racial and genetic factors are known to play a vital role in the development of cancer. For example, in Europe, the United States, and Australia, people have a higher risk of developing skin cancer because they have fair skin, a characteristic that is uncommonly witnessed in other regions. Although guidelines for prevention and early detection of skin cancer are needed in these countries, they are of lesser importance in the Middle East.1 Racial and genetic factors are not only relevant in cancer epidemiology but also can have significant influence on treatment strategies because of varying sensitivities to, and metabolism of, different drugs, resulting in a different prioritization of these approaches. For example, studies recently showed that Asian patients with advanced non–small cell lung cancer have a higher incidence of epidermal growth factor receptor (EGFR) mutations, and therefore experienced a greater benefit from treatment with EGFR inhibitors such as gefitinib and erlotinib.2,3 As a result of these findings, these agents were established as first-line therapies for these patients, before platinum-based chemotherapy, unlike in patients with non–small cell lung cancer in Europe and the United States.4 This raises an important question: can the results from large studies conducted mainly in Caucasian patient populations be accurately applied to the nonCaucasian majority in the rest of the world? Of course, the pharmacogenomic preferential benefit of EGFR inhibitors reported in the above-mentioned studies does not necessarily exist in the same magnitude in other races or with other types of anticancer drugs. However, one may assume

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-3

Editorial

The Abu Dhabi Declaration

that certain differences are likely to emerge from the integrated efforts of experts in the region. The same concept may also be applied to the differences in some environmental factors that may also play a role in the process of carcinogenesis and response to treatment. For example, in contrast to the West, where hepatocellular carcinoma (HCC) is less common and mainly secondary to alcoholic hepatitis and hepatitis B virus,7 in many Middle East countries, HCC is one of the most common cancers and usually secondary to hepatitis C virus (HCV).8 In a subgroup analysis of a pivotal sorafenib study, a greater benefit of this drug was seen among patients with HCV-associated HCC. Another example is bladder cancer, which is usually of transitional cell histology in Europe and the United States, but is commonly of squamous cell histology in several countries in the Middle East where schistosomiasis is rampant.9 These differences may limit the applicability of “West-centric” guidelines in the clinical practice of oncology in other regions of the world. These issues presented significant challenges for our diverse team while setting the objectives of the NCCN–MENA project, because the geography of our loosely defined region stretches from the west of Morocco to the eastern part of India. Therefore, the so-called MENA cancer patients according to this geographic definition are in fact a large population of racially and environmentally heterogeneous people among whom one might elicit differences rather than similarities. Still, in the current project of NCCN–MENA, we made a thorough review of the available literature generated from cancer patients in our region, seeking any convincing evidence that may suggest a unique therapeutic feature attributable to racial, genetic, or environmental factors.

Differences in Presenting Features and Stage In the Middle East and in other developing regions of the world, cancer is often diagnosed at a younger age and tends to be of more advanced-stage compared with cases reported among the Western populations.5 For example, in the Middle East, the median age of breast cancer diagnosis is younger 50 years (with 25% of patients < 40 years) compared with older than 60 years in the West. The lack of early detection programs in the Middle East has resulted in most breast cancer and other solid tumors presenting at stages III/IV compared with in Western countries. Taken together, the screening policy adopted in the West would certainly miss early detection of breast cancer in many young women, who represent a good proportion of cases in the region.

Mohammad Jahanzeb, MD, FACP Dr. Jahanzeb is an international lecturer on issues related to breast and lung cancers. He is currently National Director for Quality Improvement in the Aptium Oncology network and a Professor of Medicine at University of Tennessee. He has served as a member of the National Comprehensive Cancer Network (NCCN) Board of Directors, the NCCN Guidelines Steering and Investigators Steering Committees, and the Breast Cancer and Non-Small Cell Lung Cancer Panels. He is currently the Medical Advisor on Global Initiatives. Dr. Jahanzeb is board certified in Internal Medicine with subspecialties in Hematology and Medical Oncology.

Differences in Access to Technology and Drugs The Middle East is composed mostly of developing nations with restricted access to advanced technology and novel agents incorporated in current oncology practice. Cost–benefit analysis studies conducted in the West are difficult to apply to this region because of the differences in health systems among the developing and developed nations. Guidelines taking into account these limitations would help optimize the application of novel strategies to best use the limited resources available. Current NCCN Guidelines are cost-blind and do not address these issues, and therefore fall short in a resource-restricted setting. Despite these limitations, we believe that this project will provide better guidance for oncologists in the MENA region. These regionally targeted projects are likely to stimulate oncologists in the region to not only practice more evidencebased medicine but also conduct local epidemiologic studies and clinical trials to better define the magnitude of the problem and customize solutions for their part of the world. We believe that the MENA region would benefit greatly if they invested in the area of predictive and prognostic biomarkers.10 Expensive and sophisticated

The ideas and viewpoints expressed in this commentary are those of the author and do not necessarily represent any policy, position, or program of the NCCN.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Editorial

S-4

The Abu Dhabi Declaration

technologies can then be channelled to the subsets of patients who are really likely to benefit from them. Finally, we would like to invite all oncologists in the MENA region to provide feedback on the applicability and usefulness of the first edition of NCCN–MENA Guidelines. It is vital to ensure that this project achieves its primary objective: facilitating the decision-making process in the clinic. Our hope is that this serves as an NCCN pilot project, and that similar initiatives are launched in other regions of the world, such as Central and South Africa, Latin America, and beyond, which are underrepresented in clinical trials on which most NCCN Guidelines are based.

References 1. Wheless L, Ruczinski I, Alani RM, et al. The association between skin characteristics and skin cancer prevention behaviors. Cancer Epidemiol Biomarkers Prev 2009;18:2613–2619. 2. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–346. 3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-

small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129– 2139. 4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957. 5. Salim EI, Moore MA, Al-Lawati JA, et al. Cancer epidemiology and control in the Arab world—past, present and future. Asian Pac J Cancer Prev 2009;10:3–16. 6. El Saghir NS, Khalil MK, Eid T, et al. Trends in epidemiology and management of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg 2007;5:225–233. 7. Fasani P, Sangiovanni A, De Fazio C, et al. High prevalence of multinodular hepatocellular carcinoma in patients with cirrhosis attributable to multiple risk factors. Hepatology 1999;29:1704– 1707. 8. Lehman EM, Wilson ML. Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis. Int J Cancer 2009;124:690– 697. 9. Zaghloul MS, Nouh A, Moneer M, et al. Time-trend in epidemiological and pathological features of schistosoma-associated bladder cancer. J Egypt Natl Canc Inst 2008;20:168–174. 10. Azim HA, Azim HA Jr. Review article optimizing the use of her-2/neu targeting agents in breast cancer: a developing nation perspective. J Egypt Natl Canc Inst 2007;19:225–230.

© Journal of the National Comprehensive Cancer Network  |  Volume 7 Supplement 1  |  February 2010

S-5 Supplement

The Process of NCCN Guidelines™ Adaptation to the Middle East and North Africa Region Abdul-Rahman Jazieh, MD, MPH;a Hamdy A. Azim, MD;b Joan McClure, MS;c and Mohamad Jahanzeb, MD;d Riyadh, Kingdom of Saudi Arabia; Cairo, Egypt; Fort Washington, Pennsylvania; and Memphis, Tennessee

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa region, MENA region Abstract The NCCN developed clinical practice guidelines for oncology that set the standard of cancer care in the United States. Because of wide acceptance of, need for, and interest in standardized treatment practices across the world, NCCN launched initiatives to help international groups adapt these guidelines. This article describes the initiative in the Middle East and North Africa (MENA) region. A group of oncology experts and key opinion leaders were assembled into 7 specific committees to develop treatment guidelines for breast cancer, lung cancer, colon cancer, prostate cancer, hepatobiliary cancer, lymphoma, and palliative care. The committees reviewed the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to identify any modifications required for them to be more applicable to the MENA region based on available evidence and regional experience. These modifications were discussed with NCCN experts and summarized for each specific area. The development of these guidelines generated a strong interest in the region to develop more evidencebased practice and create further networking and collaboration. (JNCCN 2010;8[Suppl 3]:S5–S7)

From the aDepartment of Oncology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia; b Department of Oncology, Cairo University, Cairo, Egypt; cNational Comprehensive Cancer Network, Fort Washington, Pennsylvania; and dAptium Oncology, Lynn Cancer Institute, Boca Raton, Florida, and University of Tennessee, Memphis, Tennessee. Drs. Jazieh and Azim and Ms. McClure had disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors. Dr. Jahanzeb has disclosed that he is on the speakers’ bureau for and an advisor for Genentech, Inc. and sanofi-aventis. Correspondence: Abdul-Rahman Jazieh, MD, MPH, Department of Oncology, Mail Code 1777, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. E-mail: [email protected]

The National Comprehensive Cancer Network (NCCN), an alliance of 21 of the leading cancer centers in the United States, has emerged as a leader in setting the standard of care and impacting the practice of oncology in the United States.1–3 NCCN has established more than 45 multidisciplinary, disease-specific committees and panels and developed more than 100 guidelines that are updated annually and well publicized on the NCCN Web site (www.NCCN.org), in JNCCN–The Journal of the National Comprehensive Cancer Network, and at various national and international events.4 The process of developing these guidelines is elaborate and well described, using the expertise of physicians from these leading institutions. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) became a global phenomenon, with various groups and regions around the world expressing interest in adapting these guidelines. In response, NCCN launched outreach programs to share their extensive experience and resources with interested entities. These efforts were translated into regional guidelines in Korea, Japan, and China, and recently the Middle East and North Africa (MENA) region,5 including countries extending from Morocco to India (West–East) and Turkey to Yemen (North–South). The region spans a wide geographic area, has diverse social and economic profiles, and has significant heterogeneity in health care delivery and infrastructure. This diversity is not only across countries but also among regions within the same country. Therefore, the current standard of oncology care also varies greatly within the region. Developing uniform guidelines that will be widely accepted by practicing oncologists in the region may help

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-6

Supplement

Jazieh et al.

close the gap in the region, or at least will help delineate these variations so that a systemic approach to remedy them can be established. Readers should note that the guidelines referenced during this initiative and discussed throughout this document were the 2009 versions. The most recent versions of the NCCN Guidelines are available on the NCCN Web site at www.NCCN.org.

Methods Committee Formations

Seven disease committees were formed for breast cancer, lung cancer, colon can­cer, prostate cancer, hepatocellular carcinoma, lym­phoma, and palliative care. These committees included multidisciplinary expertise from different countries in the MENA region. Each committee comprised a chair and individual members with expertise in that area of oncology care, in addition to a United States–based NCCN expert from the applicable NCCN panel. The NCCN panel member helped explain the process and thoughts behind certain NCCN guideline recommendations and served as an external advisor with whom to discuss certain issues raised by committee members. The panel of committee chairs was led by a regional chair who coordinated the efforts of the whole group centrally. NCCN staff and leadership provided support and advice to the committees based on the NCCN experience. A launch meeting was held at which the objectives and details of the initiative were presented to the committee members. Thereafter, the committees held meetings separately at convenient times and locations, and members corresponded frequently via e-mail. A large regional symposium was held at the conclusion of the first year activities to provide education for the oncologists in the region regarding NCCN guidelines, review the status of care in the MENA region, and finalize the recommendations in person among the committee members, experts in the United States, and NCCN staff.

Adaption Process

The committee members reviewed the 2009 versions of the NCCN guidelines specific to their area of expertise to determine what areas required modification for use in the MENA region. Recommendations to modify an item were requested to be evidencebased and derived from experience and publications relevant to the region, to avoid having substandard guidelines because of the stark variations in health care delivery among these countries. All modifications and suggestions were listed according to the NCCN guidelines flow. The justification and references were put forth using a set format (Table 1). Committee members discussed these suggestions in group meetings and then with the NCCN experts. A final version of the recommendations were compiled and submitted as a manuscript for publication. During the process, committee members were asked to compile a list of potential research projects that they believed important to the region to help fill the gap in knowledge and address vital issues related to cancer care.

Results Each committee developed lists of suggested modifications with justification and references. The status of care of the particular disease in the region was presented in a general meeting, and then the suggestions were discussed with the respective NCCN expert to address any ambiguous or controversial issues. A final version was then drafted and 7 manuscripts were written and submitted for publication. The committee members also identified various research projects required to address certain gaps in knowledge regarding the management of the diseases.

Discussion The NCCN–MENA initiative was an enriching experience and a good learning opportunity that had a positive impact on involved parties and participants. This initiative was the first in the MENA region

Table 1 Template Form for NCCN Guidelines™ Modification for the Middle East and North Africa Page

Setting

Suggested Modifications

Justification

Reference

List page number in NCCN Guidelines

Write specific clinical setting in that page

Suggest modification concisely and clearly

Explain the reason for recommending the modifications

List references especially relevant to the region

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Process of NCCN Guidelines Adaptation to MENA Region

with the goal of creating guidelines for standardizing cancer care across the countries. Although local guidelines for certain diseases are available, collaboration across countries had not previously occurred in the region.6 The credibility and experience of NCCN helped move the process forward, in addition to strong interest from practicing oncologists in the region for improving the standard of care and the realization of the need for a collaborative approach. Having NCCN experience and guidance coupled with the diverse backgrounds and a high level of expertise from the committee members was very complementary and productive. The interaction facilitated the exchange of thoughts and ideas on how to approach certain issues, and the experience was both educational and professionally stimulating. Participants learned first-hand about the process of guidelines adaptation and gained better insight into the process of guideline development. During the process, participants realized that regional evidence is lacking for many of the recommendations, highlighting the need for future studies to address the issue. Therefore, identifying top priority research projects is a step in the right direction. The initiative generated obvious interest and enthusiasm, and the hope is that further actions will materialize in future meetings. However, this initiative encountered challenges related to the diversity of the participants’ backgrounds. Countries in the region have diverse socioeconomic and health care infrastructures, and span a wide geographic area, presenting a logistic challenge in getting members connected for group discussion. This problem was minimized by using electronic communication more frequently and giving each committee chair the flexibility to select the timing and venue of their committee meeting. The entire group, including all the committees, convened in person only once. The diversity in health care practices, resources, and infrastructures (e.g., access to care and medications) also presented challenges to implementation of standardized guidelines.

To maintain NCCN standards, the best available evidence was adopted irrespective of cost-effectiveness or availability of resources. This approach was adopted so that standards were not lowered to meet the situation in deprived areas; the group avoided making “convenience guidelines.” To improve the standard of care, the group decided to include an ideal target and allow each country or even each institution to decide what practice is suitable for them. This initiative was not intended to develop guidelines for countries with limited resources, as had others.7 Notably, many countries in the region are not among those with limited resources.

Conclusions This initiative is still in its infancy. However, as with any large-scale pioneer projects that face many challenges, the positive impact that it will have on the thousands of cancer patients will serve as motivation to the participants who already demonstrated enthusiasm and commitment.

References 1. McGivney WT. The National Comprehensive Cancer Network: present and future directions. Cancer 1998;82(10 Suppl):2057–2060. 2. Winn RJ, Botnick W, Dozier N. The NCCN Guidelines Development Program. Oncology (Williston Park) 1996;10(11 Suppl):23–28. 3. Winn RJ, Botnick WZ. The NCCN Guideline Program: a conceptual framework. Oncology (Williston Park) 1997;11:25–32. 4. Winn RJ. National Comprehensive Cancer Network. Oncology (Williston Park) 2000;14:2626–2630. 5. Jiang ZF, Wang T. An interpretation of the China edition of National Comprehensive Cancer Network (NCCN) clinical practice guideline for breast cancer. Zhonghua Wai Ke Za Zhi 2009;47:485–487 [in Chinese]. 6. Jazieh A. The process of guideline development. Ann Thorac Med 2008;3:60–61. 7. Anderson BO, Yip CH, Smith RA, et al. Guideline implementation for breast healthcare in low-income and middle- income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer 2008;113(8 Suppl):2221–2243.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-7

S-8 Supplement

Modification and Implementation of NCCN GuidelinesTM on Breast Cancer in the Middle East and North Africa Region Omalkhair Abulkhair, MD;a Nagi Saghir, MD;b Lobna Sedky, MD;c Ahmed Saadedin, MD;d Heba Elzahwary, MD;e Neelam Siddiqui, MD;f Mervat Al Saleh, MD;g Fady Geara, MD;h Nuha Birido, MD;i Nadia Al-Eissa, MD;j Sana Al Sukhun, MD;k Huda Abdulkareem, MD;l Menar Mohamed Ayoub, MD;m Fawaz Deirawan, MD;n Salah Fayaz, MD;o Alaa Kandil, MD;p Sami Khatib, MD;q Mufid El-Mistiri, MD;r Dorria Salem, MD;s El Siah Hassan Sayd, MD;t Mohammed Jaloudi, MD;u Mohammad Jahanzeb, MD;u and William I. Gradishar, MD;v Riyadh, Kingdom of Saudi Arabia; Beirut, Lebanon; Giza, Egypt; Cairo, Egypt; Lahore, Pakistan; Kuwait, Kuwait; Khartoum, Sudan; Damman, Kingdom of Saudi Arabia; Amman, Jordan; Damascus, Syria; Alexandria, Egypt; Benghazi, Libya; Al Ain, United Arab Emirates; Memphis, Tennessee; and Chicago, Illinois

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa, breast cancer Abstract Published data from the Middle East and North Africa (MENA) region indicate suboptimal quality of cancer care, while the World Health Organization predicts an increase in cancer cases in developing countries. Major advances in breast cancer management mandate the development of guidelines to improve the quality and efficacy of oncology practice in the MENA region. A Breast Cancer Regional Guidelines Committee was organized and activated, comprising experts from various regional cancer institutions. The multidisciplinary team included 12 medical oncologists, 3 radiation oncologists, 2 radiologists, 2 surgeons, and 1 pathologist. The committee members agreed on adapting the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) From the aDepartment of Oncology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia; bDepartment of Internal Medicine, American University of Beirut, Beirut, Lebanon; c Clinical Oncology Department, Faculty of Medicine, Cairo University, Giza, Egypt; dDepartment of Oncology, Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia; eDepartment of Oncology, National Cancer Institute, Cairo, Egypt; fDepartment of Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan; g Department of Surgery, Kuwait University, Kuwait, Kuwait; hDepartment of Radiation Oncology, American University of Beirut, Beirut, Lebanon; i Department of Surgery, Khartoum Breast Care Center, Khartoum, Sudan; j Department of Radiology, King Fahad Specialist Hospital, Dammam, Kingdom of Saudi Arabia; kDepartment of Oncology/Hematology, University of Jordan, Amman, Jordan; lHematology/Oncology Unit, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia; m Department of Pathology, Cairo University, Cairo, Egypt; nNuclear Medicine Center, National Cancer Institute, Damascus, Syria; oBreast Unit, Kuwait Cancer Center, Kuwait, Kuwait; pDepartment of Clinical Oncology & Nuclear Medicine, Alexandria School of Medicine, Alexandria, Egypt; q Medical Oncology, King Hussein Institute for Biotechnology and

on Breast Cancer for use in the MENA region to achieve common practice standards for treating patients. The members suggested several modifications to the guidelines, especially those related to risk factor profiles. United States–based NCCN experts reviewed these recommendations before final approval. The MENA–NCCN Breast Cancer Guidelines modification process was the first initiative in the development of common practice guidelines in the region. This project may serve as a foundation for the development of evidence-based practice standards, and improve collaborative projects and initiatives. (JNCCN 2010;8[Suppl 3]:S8–S15)

Breast cancer is the most common malignant disease in women, with an increasing incidence worldwide, especially in developing countries such as the Middle East and North Africa (MENA) region.1–3 However, the mortality rate has declined dramatically in developed Cancer, Amman, Jordan; rFaculty of Medicine, Garyounis University, Benghazi, Libya; sDepartment of Radiology, Cairo University, Cairo, Egypt; tDepartment of Oncology, Tawam Hospital, Al Ain, United Arab Emirates; uDepartment of Medical Oncology, Tawam Hospital, Al Ain, United Arab Emirates; vUniversity of Tennessee, Memphis, Tennessee; and w Northwestern University, Chicago, Illinois. Drs. Abulkhair, Saghir, Sedky, Saadedin, Elzahwary, Siddiqui, Al Saleh, Geara, Birido, Al-Eissa, Al Sukhun, Abdulkareem, Ayoub, Deirawan, Fayaz, Kandil, Khatib, El-Mistiri, Salem, Sayd, Jaloudi, and Gradishar have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors. Dr. Jahanzeb has disclosed that he is on the speakers’ bureau and an advisor for GlaxoSmithKline, Genentech, Inc., and sanofi-aventis. Correspondence: Omalkhair Abulkhair, MD, Division of Adult Medical Oncology, Department of Oncology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia. E-mail: [email protected]

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-9

Supplement

Breast Cancer

countries, including the United States, Canada, Australia, and Europe. This reduction could be attributed to the efficacy of mammography in detecting early-stage breast cancer,4,5 and to the introduction of adjuvant systemic therapy.6 All published clinical epidemiologic data on breast cancer in the MENA region are based on hospital-based registries. Nonetheless, most of the regional and national registries are published as an annual report in a booklet format.3,7 Breast cancer represents 14% to 42% of all cancers in Arab women. Age-adjusted standardized incidence rates (ASR) were reported to vary from 9.5 to 50 cases per 100,000 women per year. Median age at presentation is 48 to 52 years, with 50% of cases in women younger than 50 years compared with 25% in developed countries, and 50% of the cases are in women older than 63 years.4,5 Therefore, women in Arab countries seem to present with breast cancer almost 10 years earlier than in the United States and Europe. The ASR for breast cancer has increased in many countries in the region, such as Lebanon (20 in 1996, 46.7 in 1998, and 69 in 2003), Jordan (from 7.6/100,000 women in 1982 to 32.8/100,000 in 1997), Palestine (increased by 93%), and Egypt (up to 49.6). Reports from the Gulf Center for Cancer Registration (GCCR) presented data from 6 Gulf countries: Kingdom of Saudi Arabia (KSA), United Arab Emirates (UAE), Kingdom of Bahrain, Sultanate of Oman, State of Qatar, and State of Kuwait.

The GCCR data showed that breast cancer was the most common cancer in the GCCR states from January 1998 to December 2005, with 8349 breast cancers registered from all GCCR states, accounting for 11.6% of all malignancies and 23.2% of all female cancers. The overall breast cancer ASR for all GCCR states was 18.2 per 100,000 population. Although Bahrain reported the highest incidence of breast cancer, it was the pioneer in establishing a National Screening Program for detecting breast cancer at a very early stage. The ASR per 100,000 women was 53.4 for Bahrain, followed by Qatar (48.2), Kuwait (46.6), UAE (22.8), Oman (17.5), and KSA (14.8;8 Figure 1). Although these rates are low compared with those in developed countries, they are rising and expected to reach levels similar to those in Western countries. Many factors can attribute to this rise, including improvement in health care with subsequent prolonged life expectancy, delayed age of marriage and first pregnancy, and decline in breast feeding. Recent socioeconomic changes have resulted in a sedentary modified lifestyle, such as increased prevalence of tobacco use, decreased physical activity, and unhealthy diet consisting of fatty fast food. Advanced disease is commonly seen at diagnosis, whereas ductal carcinoma in situ (DCIS) represents fewer than 5% of the cases.3,7,8 (Figure 2). Factors contributing to late presentations include decreased awareness, lack of knowledge, and social factors such as shyness, fear of divorce stigma, and low index of

60

ASR per 100,000

50 40 30 20 10 0 KSA

Oman

UAE

Kuwait

Qatar

Bahrain

GCC

Figure 1  Age standardized incidence rate (ASR) of female breast cancer in the Gulf Cooperation Council States, 1998–2005. Abbreviations: GCC, Gulf Cooperation Council; KSA, Kingdom of Saudi Arabia; UAE, United Arab Emirates. From Al-Madouj AN, Al-Zahrani AS. Eight-year cancer incidence among nationals of the GCC states: 1998–2005. Gulf Center for Cancer Registration, 2005. Available at: http://www.sgh.org.sa/PDF/cancer%201998-2005.pdf. Accessed June 8, 2010.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

S-10

Supplement

Abulkhair et al.

suspicion by primary physicians.9 Two publications from Saudi Arabia and Lebanon reported that young age at presentation (> 35–39 years) was associated with poor prognosis10,11 (Figure 3). Health care standards vary among different areas within the region, and the quality of care depends on many factors, including where the patient lives and how long it takes for the patient to reach the cancer center and undergo treatment. Although a wide range of breast cancer treatment approaches are available in the MENA region, primary prevention is still rarely practiced and secondary prevention (i.e., screening and early detection) is applied sporadically in many countries that lack regular inspection strategies, quality control, and licensing for screening centers. A few national screening programs were initiated in the past 2 to 3 years in Bahrain, Egypt, KSA, and Kuwait. However, efforts should be made to study detection rates, screen-initiated testing, biopsies results, and outcomes.10,11 One small retrospective single-institution study in Qasseem, KSA showed that the quality of care provided to breast cancer patients did not meet international standards, possibly because of nonavailability of some resources, the absence of local guidelines, and small sample size.12 Radiation therapy centers in the region are scarce and mostly available in major cities, and many young women do not undergo breast-conserving surgery

11.4

20.9

20.7

47.0 Localized

Distant

Regional NOS

Unknown

Figure 2  Stage distribution of breast cancer, 1998–2005. From Al-Madouj AN, Al-Zahrani AS. Eight-year cancer incidence among nationals of the GCC states: 1998–2005. Gulf Center for Cancer Registration, 2005. Available at: http:// www.sgh.org.sa/PDF/cancer%201998-2005.pdf. Accessed June 8, 2010.

because of lack of access to radiotherapy facilities (Table 1). Furthermore, a multidisciplinary approach is applied only in major cancer centers. In general, there is a marked deficiency in supportive care systems, trained social workers, health educators, and plastic surgeons to perform breast reconstruction. Based on international studies, adjuvant therapy includes chemotherapy, targeted therapy with trastuzumab, and hormonal therapy.13–15 In countries with limited resources, anthracyclines and taxanes are the 1.00

1.0

0.8

0.75

0.6

DFS

Cumulative Survival

Breast Cancer

0.5

Age > 40 Age ≤ 40

35–49 above 50 below 35 35–49-censored above 50-censored below 35-censored

0.2

0.50

0.25

P = .035

0.0

0.00 0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

0.0

2.5

5.0

Follow Up Time (Years)

7.5

10.0

12.5

15.0

Years

Figure 3  Relation of young age to worse prognosis in breast cancer. Abbreviation: DFS, disease-free survival. From El Saghir NS, Seoud M, Khalil MK, et al. Effects of young age at presentation on survival in breast cancer. BMC Cancer 2006;6:194; and Elkum N, Dermime S, Ajarim D, et al. Being 40 or younger is an independent risk factor for relapse in operable breast cancer patients: the Saudi Arabia experience. BMC Cancer 2007;7:222.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

17.5

S-11

Supplement

Breast Cancer

Table 1 Radiation Therapy Centers in the Arab Countries Compared With United States (Equivalent in Population Numbers) Countries

Population

Radiation Treatment Centers

Radiation Oncologists

Radiation Technologists

Arab

301,227,000

87*

325

490

United States

298,213,000

1875

3068

5155

*Source: International Atomic Energy Agency IAEA 2007 (www.iaea.org) Adapted and updated from El Saghir NS, Khalil MK, Eid T, et al. Trends in epidemiology and mangament of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg 2007;5:225–233.

most commonly used drugs, either in combination or sequentially, according to the recommendations of the Breast Health Global Initiative (BHGI).16 However, locally advanced breast cancer is treated with neoadjuvant chemotherapy, mainly an anthracycline/taxane-based regimen, to improve breast conservation rates and increase complete pathologic remission.17,18 In HER2-positive tumors, chemotherapy with targeted trastuzumab yields higher rates of clinical and pathologic remissions.19 Evidence shows that patients with less residual disease or who experience complete pathologic response tend to have better survival.20 However, preoperative therapy in early-stage breast cancer requires availability of adequate radiologic and pathologic evaluation is limited in some MENA region countries.21 With many major advances in breast cancer therapy and the WHO expectation of an increase in cancer cases in developing countries, a pressing need exists for the MENA region to develop guidelines for breast cancer management. This explains the interest in participating in NCCN Guidelines development to improve the quality of oncology practice in the region.

Material and Methods The global need for comprehensive and evidencebased guidelines has encouraged the NCCN administration to expand their experience to include other regions such as China, Japan, and, recently, the MENA region. In November 2008, the MENA Breast Cancer Regional Guidelines Committee (BCRGC) was organized and activated. The members are prominent experts representing various regional cancer institutions, and included 12 medical oncologists, 3 radiation oncologists, 2 radiologists, 2 surgeons, and 1 pathologist. The committee members reviewed the 2009

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Breast Cancer and suggested modifications suitable to the region. These modifications were discussed among the group members and with a United States–based NCCN expert to establish the final version.

Results After a series of meetings, members of the BCRGC reached agreement on a few modifications to the guidelines based on the state of breast cancer care in the region. These suggestions, which were presented during the second NCCN–MENA conference held in Abu Dhabi from April 23 to 26, 2009, emphasized 5 major modifications: • Diagnosis at age younger than 40 years should be considered an independent risk factor of poor prognosis. • Staging workup for stage IIB breast cancer should include bone scan and CT of the chest and abdomen as the standard of care, not optional. • For DCIS, lumpectomy without radiation is not considered acceptable because of risk for recurrence. • Adjuvant radiotherapy for locoregional stages I and IIA should be given after systemic chemotherapy. • Several clinical research plans were suggested to prioritize a database bank for breast malignancies in the MENA region.

Specific Recommended Modifications The committee recommended several modifications to the 2009 NCCN Guidelines on Breast Cancer for use in the MENA region.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

S-12

Supplement

Abulkhair et al.

DCIS

Invasive Breast Cancer

Radiation Therapy

Workup

Recommendations: Delete lumpectomy without radiation. Justification: Patients who undergo lumpectomy without radiation have been shown to have a high risk for relapse.22–24 Margin Status

Recommendations: Hospitals should have guidelines for the assessment of margins. Surgeons should ink specimen margins to enable pathologists to provide better assessment. Justification: Most hospitals in the MENA region do not have written policies for handling of specimen and inking of margins. Inking allows evaluation of negativity and distance between tumor and margins. Primary Status

Recommendations: Sentinel lymph node biopsy is recommended for large DCIS (> 3 cm) and highgrade and extensive in situ disease. Justification: Large and high-grade DCIS may harbor invasive disease. The recommendation for performing sentinel lymph node biopsy is based on the tumor size and pathologic characteristics rather than type of surgery. The type of surgery chosen (mastectomy vs. lumpectomy) may be based on tumor size but not always (e.g., may be patient choice based on risk factors). Genetic Counseling for High-Risk Women

Recommendations: Setup for infrastructure, genetic counselors, and nurses is encouraged and should be prepared along with laws to protect women and families with positive hereditary factors from discrimination at jobs and regarding insurance, particularly health insurance policies. Justification: These important elements for genetic counseling are not currently available in the region, but are very crucial components of a proper genetic counseling process. Adjuvant Tamoxifen (Surveillance/Follow-up)

Recommendations: Treatment with adjuvant tamoxifen during surveillance and follow-up should be considered a category 1 recommendation. Justification: In contrast to the findings reported by NSABP B-24, other studies have shown no benefit associated with adjuvant tamoxifen in patients with DCIS.25,26

Recommendations: Staging workup should be standard for stage IIA or IIB disease and not optional. Justification: In clinical practice, physicians in the MENA region encounter many patients with metastasis and node-negative stage IIA/IIB disease. Adjuvant Therapy: Locoregional Treatment of Clinical Stage I, IIA, or IIB Disease or T3, N1, M0

Recommendations: Recommendation should read “postchemotherapy radiation” rather than “consider postchemotherapy radiation.” Justification: Postchemotherapy radiation is indicated because of risk for recurrence.27 Systemic Adjuvant Treatment: Hormone Receptor–Positive/HER2-Positive Disease

Recommendations: Patient age younger than 40 years should be considered a risk factor. Justification: Young age (< 40 years) has been shown to be an independent factor for poor prognosis.10,11,28 Systemic Adjuvant Treatment: Hormone Receptor–Positive/HER2-Negative Disease

Recommendations: Adjuvant chemotherapy should be recommended for patients younger than 40 years. Furthermore, adjuvant chemotherapy is recommended for moderately/poorly differentiated tumors, and particularly in young patients with poorly differentiated tumors. Trastuzumab is given for HERpositive tumors. Justification: Young age carries worse prognosis by itself, especially if 21-gene reverse transcription-polymerase chain reaction (RT-PCR) assay is not performed.10,11,28 For patients with poorly differentiated tumors, young age was added as a criterion to emphasize the need for aggressive therapy. According to 2 studies in MENA region, young age was a contributing factor for poor prognosis in patients with breast cancer.10,11 Referral to Adjuvant Hormonal Therapy and Chemotherapy

Recommendations: Guidelines should specify that patients should undergo adjuvant chemotherapy followed by adjuvant hormonal therapy.29 Justification: The recommendation becomes clearer when it states that chemotherapy should be followed by hormonal therapy. These therapies are not given concurrently because hormonal therapy decreases the effects of chemotherapy.29

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Breast Cancer

21-Gene RT-PCR

Recommendations: When recommending 21-gene RT-PCR assay, specify “when available.” Justification: Specifying “when available” is important because this procedure is listed as a category 2B recommendation. The specimen must be shipped overseas and the process is very costly. It may be more important to have pathologists become more familiar and reliable in reporting readily available proliferation indices, such as mitotic counts and Ki67.30 Tumor Size Less Than 1 cm

Recommendations: Guidelines should be modified to recommend that young women with ERpositive breast cancer should always be given adjuvant tamoxifen hormonal therapy. Justification: The committee suggested adding adjuvant hormonal therapy, specifying that young patients should always be given tamoxifen. Young age is a poor prognostic factor and a large percentage of patients in the MENA region are young (< 50 years) and very young (< 35 years). T1a

Recommendations: The committee suggested not recommending adjuvant therapy except in the footnote. Justification: The committee suggested adding adjuvant hormonal therapy, specifying that young patients should always be given tamoxifen. Young age is a poor prognostic factor and large percentage of patients in MENA region are young (< 50 years) and very young (< 35 years).7 Estrogren Receptor–Positive/HER2-Negative Disease

Justification: Young age alone is an independent factor associated with a worse prognosis.10,11,28 Up to 50% of patients with breast cancer in the MENA countries are younger than 50 years. Systemic Adjuvant Treatment: Favorable Histopathologies

Recommendations: Adjuvant endocrine therapy should be given for tumors less than 1 to 2.9 cm. Tumors 1 cm or smaller should be given no adjuvant therapy, and tumors 1 cm or greater should be treated with endocrine therapy. Justification: No evidence exists for not giving adjuvant endocrine therapy to patients with tumors 1 to 2.9 cm. Therefore, hormonal therapy is recommended for all women with hormone receptor– positive tumors. Preoperative Chemotherapy Guideline: Workup

Recommendations: Complete staging should be performed (chest/abdominal CT, bone scan) for stage IIA/IIB disease even if laboratory tests are normal or patients are asymptomatic. Justification: In the committee members’ clinical experience, metastatic disease is discovered not commonly in these patients. Locally Advanced Invasive Breast Cancer: Noninflammatory

Recommendations: Full staging should be performed (chest/abdominal CT, bone scan), even in the absence of symptoms or the presence of normal laboratory tests. Justification: In the committee members’ clinical experience, metastatic disease is discovered frequently in these patients.

Recommendations: Adjuvant hormonal therapy should be given alone with tamoxifen plus leuteinizing hormone–releasing hormone (LHRA) with zoledronic acid, at least in patients with node-negative disease. Justification: Results of the ABCSG-12 study showed 94% survival in patients treated with hormonal therapy alone.31

Surveillance/Follow-Up

Systemic Adjuvant Treatment: Hormone Receptor–Negative/HER2-Negative Disease

Recommendations: The committee members suggest adding “consider checking 25-hydroxy vitamin D levels.” Justification: Insufficient and deficient vitamin D levels have been associated with poorer outcome among women with breast cancer in Canada.32 Aromatase inhibitors can cause secondary osteopenia and osteopo-

Recommendations: Adjuvant chemotherapy should be recommended for patients younger than 40 years, including those with stage IIB disease. Furthermore, chemotherapy should be recommended for patients with T1b, especially young women.

Recommendations: A history and physical examination should be performed every 3 months for the first 2 years, then every 4 to 6 months for 3 years, and then annually. Justification: Patients have a high recurrence rate in the first 2 years. Surveillance

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

S-13

S-14

Supplement

Abulkhair et al.

rosis in postmenopausal women. Because of traditional dress codes, a large number of women in the MENA region do not get enough exposure to sunlight, and studies have shown that despite living in sunny countries, women may have vitamin D deficiency because of poor exposure to sunlight. Vitamin D levels should be checked and may need to be corrected.32,33

Phyllodes Tumor Phyllodes Tumor Recurrence: Treatment

Recommendations: Mastectomy is recommended rather than re-excision. Justification: Whole organ resection is the best option in case of recurrence.

Recurrent or Initial Workup for Stage IV

Recommendations: Rebiopsy at recurrence is recommended. Justification: This recommendation is made to confirm the diagnosis and tumor pathologic profile (estrogen receptor, progesterone receptor, and HER2 status). Systemic Treatment of Recurrent or Stage IV Disease

Recommendations: The committee recommends administering adjuvant radiation therapy to supraclavicular lymph nodes. The committee also prefers the term visceral disease over visceral crisis and would rather classify treatment for asymptomatic visceral disease based on either presence of minimal visceral disease with a long disease-free interval or presence of visceral disease, young age, multiple disease sites, and a short disease-free interval. Therefore, the treatment nodes would appear as:

Conclusions The process of reviewing the NCCN Breast Cancer Guidelines and discussing their applicability in the MENA region was a unique and productive experience. As a result, the key opinion leaders in the breast cancer field in the MENA region were able to provide their input and clinical recommendations that might be more practical in daily use. Furthermore, the committee members highlighted the deficiencies in the standards of oncology practice and the urgent need for a common database, and provided potential research ideas. This experience is evidence of the interest in and possibility of establishing a multidisciplinary working group, comprising representatives from different countries, to improve cancer care in the MENA region.

References

Asymptomatic visceral disease

Long disease-free interval, minimal visceral disease (endocrine therapy if not refractory)

Visceral, young age, multiple site, short diseasefree interval (chemotherapy)

Justification: Radiation volumes for recurrence should include all regional lymphatic basins. The modified terminology was preferred because visceral disease is understood as disease involving visceral organs such as liver and lungs. The treatment classification was proposed because the presence of visceral disease with young age, multiple sites of disease, and short disease-free intervals is an indication for chemotherapy.

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 57:43–66. 2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality and prevalence across five continents defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2005;24:2137–2150. 3. Kingdom of Saudi Arabia Ministry of Health National Cancer Registry. Cancer incidence report Saudi Arabia. Available at: http://www.scr.org.sa. Accessed March 31, 2010. 4. Ries LA, Melbert D, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD. Available at: http//seer.cancer.govt/cst/1975-2004, based on November 2006 SEER data submission, posted to the SEER Web site, 2007. 5. Jemal A, Ward E, Thun MJ. Recent trends in breast cancer incidence rates by age and tumor characteristics among US women. Breast Cancer Res 2007;9:R28. 6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365:1684–1717. 7. El Saghir NS, Khalil MK, Eid T, et al. Trends in epidemiology and management of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg 2007;5:225–233.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Breast Cancer 8. Gulf Center for Cancer Registration, 2005. Gulf Center for Cancer Registration, 2005. Available at: http://www.sgh.org.sa/PDF/ cancer%201998-2005.pdf. Accessed March 31, 2010. 9. Lamyian M, Hydarnia A, Ahmadi F, et al. Barriers to and factors facilitating breast cancer screening among Iranian women: a qualitative study. East Mediterr Health J 2007;13:1160–1169. 0. Elkum N, Dermime S, Ajarim D, et al. Being 40 or younger is 1 an independent risk factor for relapse in operable breast cancer patients: the Saudi Arabia experience. BMC Cancer 2007;7:222. 1 1. El Saghir NS, Seoud M, Khalil MK, et al. Effects of young age at presentation on survival in breast cancer. BMC Cancer 2006;6:194. 1 2. Akhtar SS, Nadrah HM. Assessment of the quality of breast cancer care: a single institutional study from Saudi Arabia. Int J Qual Health Care 2005;17:301–305. 1 3. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133– 1144. Erratum in: Ann Oncol 2007;18:1917. 1 4. El Saghir NS, Hatoum H, Shamseddeen W, Shamseddine AI. Prediction of prognosis and survival in early stage breast cancer using the lymph node ratio of involved lymph nodes to the total number of removed lymph nodes from the axilla [abstract]. Presented at 2007 Breast Cancer Symposium; September 7–8, 2007; San Francisco, California. Abstract 70. 1 5. Carlson RW, Allred DC, Anderson BO, et al. NCCN clinical practice guidelines in oncology: breast cancer. Version 1, 2009. The most recent version is available at: www.NCCN.org. Accessed September 20, 2008. 1 6. Anderson BO, Yip CH, Smith RA, et al. Guideline implementation for breast healthcare in low and middle income countries: overview of the breast health global initiative summit 2007. Cancer 2008;113(8 Suppl):2221–2242. 1 7. Mauri D, Pavlidis N, Ionnidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97:188–194. 1 8. Wolmark N. Preoperative chemotherapy, NSABP protocols B-18 and B-27: an update. Available at: http://ctep.cancer.gov/ highlights/docs/wolmark.pdf. Accessed March 31, 2010. 1 9. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathological complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676– 3685. 20. Escobar PF, Patrick R, Rybicki L, et al. Clinical predictors with residual breast disease after primary induction chemotherapy [abstract]. J Clin Oncol 2004;22(Suppl 1):Abstract 688. 21. El Saghir NS, Eniu A, Carlson RW, et al. Locally advanced breast cancer: treatment guidelines with particular attention to low- and middle-income countries. Cancer 2008;113(8 Suppl):2315–2324. 2 2. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 2006;24:1031–1036.

23. Kerlikowske K, Molinaro A, Cha I, et al. Characteristics associated with recurrence among women with ductal carcinoma in situ treated by lumpectomy. J Natl Cancer Inst 2003;95:1692–1702. 24. Wagner LI, Wang M, Miller K, et al. Health-related quality of life among patients with metastatic breast cancer receiving paclitaxel versus paclitaxel plus bevacizumab: results from the Eastern Cooperative Oncology Group (ECOG) study E2100 [abstract]. Breast Cancer Res Treat 2006;100(Suppl 1):Abstract 5078. 25. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000. 26. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia and New Zealand: randomized controlled trial. Lancet 2003;362:95–102. 27. Guarneri V, Piacentini F, Frassoldati A, et al. A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Presented at the 31st Annual San Antonio Breast Cancer Symposium; December 10–14, 2008; San Antonio, Texas. 28. Peppercorn J, Partridge AH. Breast cancer in young women: a new color or a different shade of pink? J Clin Oncol 2008;26:3303– 3305. 29. Albain K, Barlow W, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, nodepositive, ER-positive breast cancer (S8814, INT0100). Presented at 30th Annual San Antonio Breast Cancer Symposium; December 13–16, 2007; San Antonio, Texas. 30. Ellis MJ, Luo J, Tao Y, et al. Tumor Ki67 proliferation index within 4 weeks of initiating neoadjuvant endocrine therapy for early identification of non-responders. Presented at 32nd Annual San Antonio Breast Cancer Symposium; December 9–12, 2009; San Antonio, Texas. 31. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in postmenopausal breast cancer. N Engl J Med 2009;360:2367. 32. Goodwin P. Toronto researcher reveals vitamin D deficiency associated with breast cancer [media release]. Toronto: The Samuel Lunenfeld Research Institute of Mount Sinai Hospital, May 15, 2008. 33. El-Rassi R, Baliki G, El-Hajj Fulheihan G. Vitamin D status in Middle East and Africa. [International Osteoporosis Foundation Web site]. Available at: http://www.iofbonehealth.org/download/ osteofound/filemanager/health_professionals/pdf/Vitamin-Dreports/Vitamin_D-MEast_Africa.pdf. Accessed March 31, 2010.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

S-15

S-16 Supplement

Modification and Implementation of NCCN Guidelines™ on Non–Small Cell Lung Cancer in the Middle East and North Africa Region Abdul-Rahman Jazieh, MD, MPH;a Hanaa Bamefleh, MBchB, FRCPC;b Ahmet Demirkazik, MD;c Rabab Mohamed Gaafar, MD;d Fady B. Geara, MD, PhD;e Mansur Javaid, MD, FCCP, FRCP;f Jamal Khader, MD;g Kian Khodadad, MD;h Walid Omar, MD;i Ahmed Saadeddin, MD;j Hassan Al Sabe, MD;k Mohammad Behgam Shadmehr, MD;l Amgad El Sherif, MD, FCCP;m Najam Uddin, FRCR;n Mohammad Jahanzeb, MD;o and David Ettinger, MD;p Riyadh, Kingdom of Saudi Arabia; Ankara, Turkey; Cairo, Egypt; Beirut, Lebanon; Lahore, Pakistan; Amman, Jordan; Tehran, Iran; Damascus, Syria; Al Ain, United Arab Emirates; Memphis, Tennessee; and Baltimore, Maryland

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa, lung cancer Abstract A lung cancer committee from the Middle East and North Africa (MENA) region was established to modify the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non–Small Cell Lung Cancer to create a platform for standard care in the region. The committee comprised different experts in thoracic oncology from the region, including the disciplines of medical and clinical oncology, radiation oncology, thoracic surgery, pulmonary medicine, radiology, and pathology. The committee reviewed version 2 of the 2009 NCCN Guidelines on Non–Small Cell Lung Cancer and identified recommendations requiring modification for the region using published evidence and relevant experience. These sug-

From the aDepartment of Oncology and bPathology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia; c Section of Medical Oncology, Ankara University, Cebeci Hastaneleri, Ankara, Turkey; dDepartment of Medical Oncology, National Cancer Institute, Cairo, Egypt; eRadiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon; fPulmonary & Critical Care, Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan; gRadiation Oncology, King Hussein Cancer Center, Amman, Jordan; hThoracic Oncology Section, National Institute of Tuberculosis and Lung Disease, Tehran, Iran; iNuclear Medicine Unit, National Cancer Institute, Faculty of Medicine, Cairo, Egypt; j Department of Oncology, Riyadh Military Hospital, Riyadh, Kingdom of Saudi Arabia; kAl Bieruni Cancer Hospital, Damascus, Syria; lDepartment of Surgery, National Institute of Tuberculosis and Lung Disease, Tehran, Iran; m Cardiothoracic Surgery, Tawam Hospital, Al Ain, United Arab Emirates; n Department of Radiology, Shaukat Khanum Memorial Cancer Hospital

gested modifications were discussed among the group and with a United States–based NCCN expert for approval. The recommended modifications, with justification and references, were categorized based on the NCCN Guidelines flow. This article describes these recommended modifications. The process of adapting the first NCCNbased guidelines in the region is a step toward helping to improve lung cancer care in the region and encouraging networking and collaboration. (JNCCN 2010;8[Suppl 3]:S16–S21)

Lung cancer is the leading cancer worldwide; not only

in incidence but also in cancer-related death, with approximately 1.2 million cases diagnosed worldwide and 18% of cancer deaths related to lung cancer.1,2 In the United States, lung cancer kills more people than the 3 most common cancers, namely breast, prostate, and co& Research Center, Lahore, Pakistan; oUniversity of Tennessee, Memphis, Tennessee; and nThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. Drs. Jazieh, Bamefleh, Demirkazik, Gaafar, Geara, Javaid, Khader, Khodadad, Omar, Saadeddin, Al Sabe, Shadmeht, El Sherif, and Uddin have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors. Dr. Jahanzeb has disclosed that he is an advisory board member, member of the speakers’ bureau, or consultant for Genentech, Inc.; sanofi-aventis; and GlaxoSmithKline. Dr. Ettinger has disclosed that he is a consultant for Eli Lilly and Company; Genentech, Inc.; and Pfizer Inc. Correspondence: Abdul Rahman Jazieh, MD, MPH, Department of Oncology (Mail Code 1777), P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. E-mail: [email protected]

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Non–Small Cell Lung Cancer

lon. However, the lung cancer epidemic is not limited to developed countries. Developing countries are also seeing an increased lung cancer burden because of the increased prevalence of the main risk factor: tobacco use.3,4 Lung cancer varies in incidence and mortality among countries, but in Western Asian countries it is ranked number 1, and was number 3 in North African countries.5 It is number 1 in cancer incidence in 7 of 13 Arab countries.6 Furthermore, available data indicate that lung cancer is on the rise in many countries and that its health toll will mirror, and even may exceed, that of Western countries if tobacco control is not properly addressed. For example, in the Kingdom of Saudi Arabia, lung cancer is the third most common cancer in men and twelfth in women, with an age standardized rate of 6.1 per 100,000 and 1.9 per 100,000, respectively. Its incidence increased by 57% between 2001 and 2005,7 and was approximately 40% in Jordan around the same period. In Egypt, lung cancer is the fourth most common cancer in men and ninth in women. According to the Gharbia Cancer registry, it represents 7.4% of all male and 2.7% of female malignancies. The Egyptian National Cancer Institute data shows that the frequency of lung cancer was not different between 2001 and 2006.8

Current Status of Lung Cancer Care in the Middle East and North Africa Region The Middle East and North Africa (MENA) region is diverse in many aspects, especially in economic background and health care infrastructure. Even within the same country, disparities may be present in health care resources and services. Therefore, no absolute universal statement can be made about health care in the region, although some common findings are descriptive of the status of lung cancer care in general. The cancer care issues can be categorized into 5 areas that are related to the principles of oncology care:9 cancer diagnosis, proper staging, offering curative treatment whenever possible, offering palliative and supportive care when cure is not attainable, and participation in clinical research. Confirming Diagnosis

Bronchoscopy and CT scan–guided biopsies are available only in tertiary centers in major cities,

making tissue specimens difficult to obtain, although they are possible in most countries. The laboratories in the regions are equipped for straightforward procedures, such as classic immunohistochemical staining, but generally are not ready for more sophisticated tests, such as molecular studies for customization of therapy (e.g., epidermal growth factor receptor [EGFR] mutation analysis). Staging

Proper staging of lung cancer is essential for management and prognosis, which may require invasive procedures or imaging studies. In the MENA region, mediastinoscopy is not used as frequently as indicated because of lack of expertise, interest, or agreement on its value. CT scanning is generally available, more so than MRI. However, PET scans are scarce because many countries do not have any machines, some have only one, and few have more than one. Therefore, PET scanning is not widely accessible. Offering Curative Treatment

Providing curative treatment often requires a multimodality approach. However, multidisciplinary teams and tumor boards are not widely used and there is shortage of properly trained thoracic surgeons in the region. Regarding treatment, adjuvant chemotherapy is not standard practice across the region, and many logistical challenges make concurrent chemotherapy and radiotherapy difficult to offer in some settings, including the fact that a shortage exists of adequate radiotherapy machines and expertise. Palliative Treatment

Systemic Therapy: The MENA region has issues related to access to care, in that tertiary centers may not accept patients with metastatic cancer, instead directing resources toward curable cancers. Furthermore, access to routine chemotherapy is limited in many countries and is even more so for biologic agents. Some tertiary centers do not have new biologic and targeted therapies for economic and financial reasons. Symptom Management: The MENA region has a clear shortage of trained palliative care physicians and support staff, in addition to lack of proper facilities. Access to pain medications such as morphine is also challenging.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-17

S-18

Supplement

Jazieh et al.

Participation in Research

Like other developing countries, participation in research in the region is limited to major centers in some countries and plagued with many challenges, such as lack of research culture, infrastructure, expertise, and funding.10 The Importance of Lung Cancer Guidelines

Although the described limitations and variations may represent challenges to creating uniform guidelines, they are actually strong reasons to attempt to establish these guidelines in effort to close the oncology practice gap in the region. Identifying these limitations and variables is the first step toward addressing them.

Methodology As a part of the initiative to adapt the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non–Small Cell Lung Cancer11 to the MENA region, a lung cancer guidelines committee was formed. The committee comprises various experts in thoracic oncology, including medical and clinical oncology, radiation oncology, pulmonology medicine, thoracic surgery, radiology, and pathology. The committee convened twice and corresponded frequently electronically. They reviewed the second version of the 2009 NCCN Guidelines thoroughly, identified items requiring modification for the region, and considered justification and references. Adherence to NCCN Guidelines principles and structure was required, with emphasis on the same categories of evidence and consensus as justification for adopting a modification. A summary of the suggested modifications was then discussed thoroughly with the NCCN experts to reach an agreement on the recommendations and understand the mechanism and rationale of some of the United States guidelines recommendations. Furthermore, the committee members were asked to identify a priority list of research projects for the region. This article summarizes these recommendations.

Recommended Modifications The committee recommended the following modifications to the second version of the 2009 NCCN Guidelines on Non–Small Cell Lung Cancer for the MENA region.

Initial Evaluation: Chemistry Profile

Recommendations: The committee suggested specifying the tests constituting the chemistry profile, including at least calcium, albumin, alkaline phosphatase, lactate dehydrogenase, renal function, and liver function tests such as total bilirubin, alanine aminotransferase, and aspartate aminotransferase. Justifications: To prevent requesting unnecessary laboratory tests and to emphasize obtaining valuable laboratory tests that may have an impact on prognosis, may reflect the presence of distant metastases, or might impact treatment choice. Clinical Stage IIIB, T4 (Pleural or Pericardial Effusion)

Recommendations: The term malignant should be placed before pleural or pericardial effusion for stage IIIB, T4. Justifications: All pleural/pericardial effusions are not necessarily malignant, and only malignant fluids meet the criteria for T4, although this stage will be reclassified as stage IV in the seventh edition of the TNM staging system.12 Pretreatment Evaluation: Stage I (Peripheral T2, N0 and Central T1–2, N0) and Stage II (T1–2, N1)

Recommendations: Add endoscopic and endobronchial ultrasound procedures to the list of workup procedures. Justifications: These techniques can be alternative procedures for evaluation of mediastinal lymph nodes, in addition to other mentioned procedures and/or imaging.13–18 Adjuvant Treatment, Stage IB, T2, N0, Margin Negative (R0)

Recommendations: For the treatment option of chemotherapy, adding “especially for tumor size T ≥ 4 cm” is recommended. Justifications: Based on updated results of CALGB 9633, patients with tumors 4 cm or larger will benefit from chemotherapy,19 although many of these cases will be reclassified as stage II in the seventh version of the TNM staging system. Adjuvant Treatment, Stage IIIA, T1–2, N2, Margin Negative (R0)

Recommendations: The committee suggested changing the recommendation for “Chemotherapy + mediastinal RT” to “chemotherapy +/– mediastinal RT” as a category 2B recommendation. Justification: The committee questioned whether ad-

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Non–Small Cell Lung Cancer

juvant mediastinal radiotherapy (RT) is necessary for all patients at this stage after mediastinal lymph node dissection (not sampling), and suggested that perhaps only high-risk groups should be considered for adjuvant mediastinal RT for multilevel involvement of mediastinal lymph nodes or extracapsular spread, or for inadequate lymph node dissection. Adjuvant RT

Recommendations: Do not include recommendation of chemoradiation for N1 disease with adverse factors (category 3) Justification: Studies have shown that postoperative RT is detrimental in N1 disease.20 All Stages of Positive Margins (R1, R2)

Recommendations: For all stages of positive margins, the committee suggested adding “If resection is not possible” after recommendation for chemoradiotherapy. For stage IA, committee suggested adding “if chemoradiotherapy is not feasible” after RT, followed by chemotherapy. Justification: All residual disease that is not resectable should be practically treated like unresectable stage III, with concurrent chemoradiotherapy as the preferred modality. Initial Treatment: Superior Sulcus Tumor T3–4, N0–1

Recommendations: The committee suggested adding surgery alone as an initial modality (category 3 recommendation). Justification: This NCCN recommendation is based on a phase II study that did not compare chemoradiation followed by surgery with surgery alone and does not eliminate surgery as a valid initial treatment option for resectable disease.21 Initial Treatment: Chest Wall, Proximal Airway, or Mediastinum, T3–4, N0–1

Recommendations: The committee suggested adding an option for unresectable tumors, with initial treatment as concurrent chemoradiotherapy + chemotherapy. Justification: In some cases in this stage, the initial workup determines that the tumor is not completely resectable. In these cases, the preferred treatment could be a multimodality option of chemoRT followed by chemotherapy and preclude an unnecessary operation. According to the current NCCN algorithm all of these patients must undergo surgery.

Initial Treatment: T1-2, N2 Nodes Positive, Negative for M1 Disease

Recommendations: The committed suggested adding “especially responders” after “surgery” for patients with no progression. Justification: Patients responding to treatment are more likely to benefit from surgery more than those with stable disease. Performance Status 3 and 4

Recommendations: The committee suggests separating recommendations for performance stage (PS) 3 and 4, with erlotinib or single-agent chemotherapy (category 2B) recommended for PS 3 and palliative care for PS 4. Justification: Because erlotinib has activity in previously treated patients with PS 3, it probably will have some benefits as first-line treatment. Committee members had encouraging experience with singleagent erlotinib in these patients.22 Therapy for Recurrence and Metastases: Cycle 1

Recommendations: The committee suggested deleting “tumor response evaluation” after cycle 1, and adding a footnote after cycle 2 stating “if symptoms suggestive of disease progression, evaluation can be done after 1 cycle”. Justification: No strong evidence exists for performing response evaluation after one cycle; however, this will save patients with symptoms suggesting disease progression from undergoing further treatment that will prove futile. Therapy for Recurrence and Metastases: 4–6 Cycles (Total)

Recommendations: The committee suggested deleting “or until disease progression (category 2B),” changing the recommendation to “4 cycles for stable disease and up to 6 cycles for responders,” and adding “(category 2B) or docetaxel for all histology” after squamous histology. Justification: No evidence shows benefit of therapy beyond 4 to 6 cycles of the same chemotherapy,23 and new evidence shows maintenance with premetrexed (for nonsquamous carcinoma) and docetaxel.24,25 Performance Status 0–2 and 3–4

Recommendations: The committee recommended that erlotinib be considered in patients with PS 0 through 3 after first progression. They also suggested separating PS 3 from PS 4, with the recommendation to give erlotinib to patients with PS 3 if not given previously, and

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-19

S-20

Supplement

Jazieh et al.

offering palliative care to patients with PS 4. Justification: The BR21 study,22 which showed a survival benefit associated with erolotinib, included some patients with PS 3, and the committee members reported similar results based on personal experience. Principles of Surgical Resection

Recommendations: The committee suggested adding a bullet stating that “Chemotherapy and radiation therapy are recommended to start between 4–6 weeks postoperatively, if patient recovered from surgery.” Justification: This recommendation was made to assure full recovery from surgery and avoid unnecessary delays. Principles of Radiation Therapy

Recommendations: The committee recommends adding “Gross tumor volume can be reduced to postchemotherapy volume if there was reexpansion of the lung” after the first sentence of the bullet beginning “In patients who receive induction chemotherapy, attempts should be made to obtain a baseline planning CT prior to induction chemotherapy.” Justification: This modification was recommended to decrease irradiation to expanded normal lung tissue and minimize lung toxicity. Recommendations: The committee suggested modifying the radiation doses as follows: • Extracapsular nodal extension or microscopic positive margins: 50 Gy • Gross residual tumor: 66 Gy • Definitive RT: 70 Gy • Definitive RT with concurrent chemotherapy: 60–66 Gy Justification: Data do not favor high doses for postoperative RT; they do not show a dose–response relationship for RT in lung cancer except for hyperfractionation (which is uncommonly used currently). However, RT with concurrent chemotherapy using 66 Gy has shown very good median survival. Systemic Therapy for Advanced or Metastatic Disease

First-Line Therapy: Recommendations: The committee suggested changing the statement that systemic chemotherapy is not indicated in patients with PS 3 or 4 to “patients with PS 3 may benefit from singleagent erlotinib. Single-agent chemotherapy can be used in selected cases.” Second-Line Therapy: Recommendations: The com-

mittee recommended adding a new bullet stating “Gefinitib was shown to be noninferior to docetaxel in second-line therapy.”26

Future Research Ideas for MENA Region During the discussion among committee members, many information gaps were identified that can be addressed through future research projects. The following is a short list of projects the committee members indentified as important: • Epidemiology data collection on incidence, subtypes, and treatment patterns (registry) • Early detection/screening studies to address what is the best recommendation • PET scan studies to determine best use of this technology relevant to the region • Radiotherapy: !! Stereotactic radio-surgery in lung cancer management such as inoperable disease !! Role of radiotherapy in N1 disease !! Role of prophylactic cranial irradiation in certain setting of stage III non–small cell lung cancer • Molecular studies, such as ERCC1, RRM1, EGFR, and Kras, in terms of their prevalence and use in clinical research and practice (pharmacogenomic studies) • Validate phase III data from Western countries in MENA population, in simple multisite studies to assure the capabilities to do research as a group/network

Conclusions MENA–NCCN Lung Cancer Guidelines development was a very enriching experience to participants through providing in-depth exposure to the extensive NCCN experience. Furthermore, it helped develop the first regional guidelines and encouraged networking. It also helped highlight the major gaps in practice evidence in the region, allowing the committee to propose future research ideas. Future refinement of these guidelines to incorporate emerging evidences and regional experiences is being planned.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Non–Small Cell Lung Cancer

References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108. 2. Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003:123;21S–49S. 3. Proctor RN. Tobacco and the global lung cancer epidemic. Nat Rev Cancer 2001;1:82–86. 4. Cooley ME, Kaiser LR, Abrahm JL, Giarelli E. The silent epidemic: tobacco and the evolution of lung cancer and its treatment. Cancer Invest 2001:19:739–751. 5. International Agency for Research on Cancer. The GLOBOCAN 2002 Database. Available at: http://www-dep.iarc.fr/globocan/ database.htm. Accessed March 31, 2010. 6. Salim EI, Moore MA, Al-Lawati JA, et.al. Cancer epidemiology and control in the Arab world—past, present and future. Asian Pac J Cancer Prev 2009;10:3–16. 7. National Cancer Registry, Saudi Arabia. Available at: http:// bportal.kfshrc.edu.sa. Accessed March 31, 2010. 8. National Cancer Institute: Egypt. Cairo Registry, 2006. Available at: www.nci.edu.eg. 9. Jazieh AR. The principles of oncology care: back to basics. Am J Clin Oncol 2009;32:330–331. 10. Sumathipala A, Siribaddana S, Patel V. Under-representation of developing countries in the research literature: ethical issues arising from a survey of five leading medical journals. BMC Med Ethics 2004;5:E5.

16. Herth FJ, Rabe KF, Gasparini S. Transbronchial and transoesophageal (ultrasound-guided) needle aspirations for the analysis of mediastinal lesions. Eur Respir J 2006;28:1264–1275. 17. El-Bayoumi E, Silvestri GA. Bronchoscopy for the diagnosis and staging of lung cancer. Semin Respir Crit Care Med 2008;29:261– 270. 18. Alberts WM; American College of Chest Physicians. Diagnosis and management of lung cancer executive summary: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:1S–19S. 19. Strauss GM, Herndon JE II, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043–5051. 20. Dautzenberg B, Arriagada R, Chammard AB, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Group d’Etude et de Traitement des Cancers Bronchiques. Cancer 1999;86:195–196. 21. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of the Southwest Oncology Group trial 9416 (Intergroup trial 0160). J Thorac Cardiovasc Surg 2001;121:472–483. 22. Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small cell cancer. N Engl J Med 2005;353:123–132.

11. Ettinger DS, Akerley W, Bepler G, et al. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version 2, 2009. The most recent version is available at: www.NCCN.org. Accessed September 20, 2008.

23. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV nonsmall-cell-lung cancer. J Clin Oncol 2002;20:1335–1343.

12. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4–9.

24. Ciuleanu T, Brodowicz T, Belani C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care: a randomised, double-blind, phase III study. Lancet 2009:374:1432– 1440.

13. Herth F, Becker HD, Ernst A. Conventional vs endobronchial ultrasound-guided transbronchial needle aspiration: a randomized trial. Chest 2004;125:322–325. 14. Herth FJ, Eberhardt R, Vilmann P. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006;61:795–798.

25. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009;27;591–598.

15. Herth FJ, Ernst A, Eberhardt R. Endobronchial ultrasoundguided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur Respir J 2006;28:910–914.

26. Maruyama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol 2008;26:4244–4252.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-21

S-22 Supplement

Modification and Implementation of NCCN Guidelines™ on Colon Cancer in the Middle East and North Africa Region Fikri İçli, MD;a Hakan Akbulut, MD;a Shouki Bazarbashi, MD;b Mehmet Ayhan Kuzu, MD;c Mohandas K. Mallath, MD;d Kakil Ibrahim Rasul, FRCP Edin;e Scott Strong, MD;f Aamir Ali Syed, FRCS;g Faruk Zorlu, MD;h and Paul F. Engstrom, MD;i Ankara, Turkey; Riyadh, Kingdom of Saudi Arabia; Mumbai, India; Doha, Qatar; Abu Dhabi, United Arab Emirates; Lahore, Pakistan; and Philadelphia, Pennsylvania

Key Words NCCN Clinical Practice Guidelines in Oncology NCCN Guidelines, Middle East and North Africa, colorectal cancer, colon cancer Abstract Colorectal cancer is less common in the Middle East and South Asia than in western countries, with the rectum the most common primary site, unlike in the United States. A project was planned to address various local issues regarding the management of common cancers, including colorectal cancer, and to adapt the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to the Middle East and North Africa (MENA) region. A survey of oncologists in this geographic area showed that the management practices and issues regarding colorectal cancer are similar to those presented in the NCCN Colorectal Cancer Guidelines. However, 2 major differences exist: most oncologists in the MENA region prefer chest radiograph over CT in pretreatment workup, and almost 50% of

From aAnkara University Medical School, Ankara, Turkey; b Section of Medical Oncology, King Faisal Specialist and Research Centre, Riyadh, Kingdom of Saudi Arabia; CUniversity of Ankara, Department of Surgery, Ankara, Turkey; dTata Memorial Center, Mumbai, India; eHamad Medical Corporation, Al-Amal Hospital, Doha, Qatar; fSheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates; gShaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; hHacettepe University Medical School, Ankara, Turkey; and iFox Chase Cancer Center, Philadelphia, Pennsylvania. Drs. İçli, Akbulut, Bazarbashi, Kuzu, Rasul, Strong, Syed, and Zorlu have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors. Dr. Mallath has disclosed that he has received research funding from GlaxoSmithKline, Amgen Inc., Merck & Co., Inc., and Pfizer Inc. Dr. Engstrom has disclosed that he is an advisory board member for Novartis Pharmaceuticals Corporation. Correspondence: Fikri İçli, MD, Department of Medical Oncology, Ankara University School of Medicine, Cebeci Hastanesi, Dikimevi, Ankara 06590, Turkey. E-mail: [email protected]

them prefer to use cetuximab in the first-line treatment of patients with the wild-type KRAS gene. The committee, comprising 9 oncologists from different countries, proposed 4 modifications to the 2009 version of the NCCN Colorectal Cancer Guidelines for use in the MENA region, relating to 1) short-course preoperative radiotherapy, 2) dose of capecitabine, 3) stereotactic radiotherapy for liver metastasis, and 4) qualification of surgeons performing colorectal surgery. The modification of NCCN Colorectal Cancer Guidelines for use in the MENA region represents a step toward creating a uniform practice in the region based on evidence and local experience. (JNCCN 2010;8[Suppl 3]:S22–S25)

Colorectal cancer is less common in the Middle East and

South Asia region than in the United States (Table 1). However, it is among the 10 most common cancer types in all the countries.1 The age-standardized incidence rate is below 10 per 100,000 in most countries in this region, and ranges between 10 to 40 per 100,000 in a few countries such as Turkey, Qatar, Kuwait, and Israel.1 In a study from Turkey, one third of patients were younger than 50 years, and the rectum was the most common site of occurrence (42.5%), followed by the sigmoid colon (23.2%).2 The epidemiologic features are similar in India.3 However, in a study from Qatar, the descending and sigmoid colon were the most common sites.4 Although the management of colorectal cancer should ideally be based on evidence-based medicine, standardized practices do not exist in other parts of the world. The social, cultural, and economic differences among the countries may be responsible for this lack of standard management. The paucity of local randomized trials from the

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Colon Cancer

Table 1 Colorectal Cancer Age Standardized Rate per 100,000 Population Country

Men

Women

Egypt

6.3

4.3

Lebanon

5.5

4.2

Syria

8.0

5.1

Qatar

31.7

7.7

Kuwait

15.0

14.5

United Arab Emirates

5.8

6.3

Kingdom of Saudi Arabia

8.3

6.3

Pakistan

7.8

5.2

India

4.7

3.2

Israel

40.6

32.7

Turkey

19.7

11.9

Data from Borchana et al.5

region adds to the difficulty in following new developments and innovations. However, the need for guidelines that are compatible with evidence-based medicine and social, cultural, and economic realities of the MENA region cannot be denied. The NCCN–MENA project was established to address this need.

Methods and Results The colorectal cancer committee comprised 9 members from 6 different countries who collected the data and participated in the deliberations. A survey with 11 questions related to the management of colorectal cancer was prepared and sent to all members to determine the patterns of care and compatibility with the 2009 version of the NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org). The survey was distributed to 24 well-known gastrointestinal oncologists in Turkey, and personal opinions were obtained from members in Qatar, United Arab Emirates, and India; Table 2 summarizes the results. Answers from most oncologists in Turkey and committee members from other countries were generally in accordance with the NCCN Guidelines, except those related to questions number 1 and 10. According to the results, 69% did not perform routine chest CT before surgery for all patients with colon cancer. With regard to first-line chemotherapy for metastatic colorectal cancer, 47% of those surveyed preferred to use cetuximab in addition to chemother-

apy as first-line treatment in patients with wild-type KRAS tumors. Committee members met on March 8, 2009, in Istanbul to discuss the survey results and other issues, including proposals for adapting the NCCN guidelines to the MENA region. The proposals accepted by the majority were prepared for presentation at a congress in the United Arab Emirates.

Proposed Modifications Proposal 1

Short-course preoperative radiotherapy (SCRT) may be an alternative for long-course preoperative radiotherapy (LCRT) or chemoradiotherapy in operable rectal cancer with smaller tumors (< T4). Rationale

Preoperative SCRT was found to reduce the local recurrence in rectal cancer when compared with surgery alone.5 In a large randomized trial, the Dutch Colorectal Cancer Group showed a significant reduction of local recurrence risk with SCRT followed by total mesorectal excision (TME) compared with TME alone.6 Significant improvement was observed for rectal lesions 5 cm or smaller and those larger than 5 cm. Another small randomized study from Bulgaria suggests that although SCRT is less effective than conventional radiotherapy in reducing local tumor recurrences in the lower third of the rectum and for advanced rectal cancer (T4 and N2), it is equally as effective in treating other occurrences.7 A Polish study comparing preoperative SCRT with chemoradiation showed similar survival, local control, and late toxicity for both treatments at 4 years.8 Another review of the 2 randomized trials on 396 patients showed that SCRT may be as effective as conventional radiotherapy/chemoradiation.9 A recent retrospective analysis of clinical outcome in 520 Danish patients with rectal cancer also confirmed the efficacy of SCRT.10 Furthermore, a survival benefit was observed for SCRT in the Swedish Rectal Cancer Trial.11 In conclusion, the evidence favors preoperative SCRT as an alternative to conventional preoperative radiotherapy/chemoradiation in operable rectal cancer. Proposal 2

Dose of capecitabine may be lower than 1000 mg/m2

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-23

S-24

Supplement

İçli et al.

Table 2 Questionnaire Related to the Management of Colorectal Cancer and the Results Questions

Most Relevant Answers

1. Do you recommend routine chest CT before surgery in patients with resectable colorectal cancer?

• No: 69%

2. What is your choice for adjuvant chemotherapy of patients with T3N0M0 colon cancer (no high-risk factors)?

• Observation: 53 % • Mayo regimen: 23.5%

3. What do you prefer for adjuvant chemotherapy in patients with T3N0M0 rectal cancer?

• Mayo regimen: 57%

4. What do you prefer for adjuvant chemotherapy of patients with T1–4/N1–2/M0 rectal cancer?

• FOLFOX: 72%

5. Do you recommend routine PET scan in the surveillance of patients with stage T3/4N0M0 colon cancer?

• No: 100%

6. What is your choice for neoadjuvant treatment of patients with synchronous resectable liver only or lung-only metastases?

• FOLFIRI or FOLFOX or CapeOX: 41% • Chemotherapy + bevacizumab: 47%

7. What is your choice for adjuvant treatment of patients with synchronous resectable liver only or lung-only metastases after surgery?

• FOLFIRI or FOLFOX or CapeOX: 39% • Chemotherapy + bevacizumab: 31%

8. Do you add bevacizumab to the active chemotherapy (FOLFIRI/ FOLFOX/CapeOx) in patients with unresectable liver only or lung-only metastases?

• Yes: 86%

9. What is your choice of first-line treatment in patients with unresectable metastatic colorectal cancer who are not candidates for any future surgical treatment?

• FOLFIRI or FOLFOX or CapeOX + bevacizumab: 75%

10. What is your choice of first-line treatment in patients with unresectable metastatic colorectal cancer with wild-type KRAS gene?

• Chemotherapy + bevacizumab: 37% • Chemotherapy + cetuximab: 47%

11. What is your choice of first-line treatment in patients with metastases who cannot tolerate intensive treatment?

• Continuous-infusion 5-FU or capecitabine: 26% • Continuous-infusion 5-FU or capecitabine + bevacizumab: 36% • Continuous-infusion 5-FU or capecitabine + cetuximab if wild-type KRAS gene: 26%

Abbreviations: 5-FU, fluorouracil; CapeOX, capecitabine and oxaliplatin; FOLFIRI, leucovorin, fluorouracil, and irinotecan; FOLFOX, leucovorin, fluorouracil, and oxaliplatin; Mayo regimen, fluorouracil and leucovorin.

twice daily. Rationale

Many patients in this region are unable to tolerate recommended higher dosages because of severe hand–foot syndrome or diarrhea (based on personal experience of the committee). This could be related to high folate intake in the diet or issues related to food hygiene. The committee proposed a prospective trial be conducted to find the optimal dose for the patients in the region. Proposal 3

Stereotactic radiation for liver metastasis could be an alternative. Rationale

Resection is the standard of care for treating liver metastasis in colorectal cancer. However, more than 80% of patients have unresectable disease. Several studies have shown the efficacy of stereotactic body

radiation therapy as an alternative to radiofrequency ablation in treating this condition.12–15 A phase I/ II study showed that it is also safe and effective for treating grade 1 to 3 metastasis.16 Proposal 4

Operations should be performed by surgeons experienced in colorectal surgery and TME, and the surgeries should occur at centers conducting more than 50 surgeries per year. Rationale

The surgeon is an independent factor for outcome in colorectal surgery. The outcome was also related to surgical caseload and training/teaching activities.17 Because of the lower incidence of colorectal cancer, a dilution of cases between centers occurs in some countries. Some patients managed by general surgeons are found to lack TME for rectal cancer or adequate lymph node dissection. Although no specific

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Colon Cancer

caseload number has been established for surgeons, the committee recommended that colorectal surgery should be performed at centers performing at least 50 operations per year.

Conclusions This multinational project is the first in the region with the goal of establishing standard management of colorectal cancer. The recommendations are based on evidence in the literature and personal experiences that must be tested in prospective randomized studies. Continuation of this scientific cooperation between NCCN and the MENA countries may improve quality of care for patients with colorectal cancer in the region.

6. Kapıteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–646. 7. Klenova A, Georgiev R, Kurtev P, Kurteva G. Short versus conventional preoperative radiotherapy of rectal cancer: indications. J BUON 2007;12:227–232. 8. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Longterm results of a randomized trial comparing preoperative shortcourse radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215–1223. 9. Sajid MS, Siddiqui MR, Kianifard B, Baig MK. Short-course versus long-course neoadjuvant radiotherapy for lower rectal cancer: a systematic review. Ir J Med Sci 2010; in press. 10. Jensen LH, Altaf R, Harling H, et al. Clinical outcome in 520 consecutive Danish rectal cancer patients treated with short course preoperative radiotherapy. Eur J Surg Oncol 2009;36:237–243. 11. Siegel R, Burock S, Wernecke KD, et al. Preoperative shortcourse radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society. BMC Cancer 2009;9:50. 12. Mendez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase I-II study. Acta Oncol 2006;45:831–837.

References 1. Barchana M, Ibrahim AS, Mikhail N, et al. MOS Epidemiology Group Special report: cancer incidence in Mediterranean populations. Mediterranean Oncology Society Web site. Available at: http://www.mosepi.org. Accessed March 31, 2010. 2. Eser SY. Cancer incidence in Turkey. In: Tuncer M, ed. Cancer Control in Turkey. Ankara, Turkey: The Ministry of Health of Turkey; 2007:17–44. 3. Mohandas KM, Desai DC. Epidemiology of digestive tract cancers in India. Indian J Gastroenterol 1999:18:118–121. 4. Rasul KI,  Awidi AS,  Mubarak AA,  Al-Homsi UM. Study of colorectal cancer in Qatar. Saudi Med J 2001;22:705–707. 5. Goldberg PA, Nicholls RJ, Porter NH, et al. Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer 1994:30A:1602–1606.

13. Kim MS, Kang JK, Cho CK, et al. Three-fraction stereotactic body radiation therapy for isolated liver recurrence from colorectal cancer. Tumori 2009;95:449–454. 14. Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer 2009;45:2947– 2959. 15. Fuss M, Thomas CR Jr. Stereotactic body radiation therapy: an ablative treatment option for primary and secondary liver tumors. Ann Surg Oncol 2004;11:130–138. 16. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multiinstitutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol 2009;27:1572–1578. 17. Renzulli P, Laffer UT. Learning curve: the surgeon as a prognostic factor in colorectal cancer surgery. Recent Results Cancer Res 2005;165:86–104.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-25

S-26 Supplement

Modification and Implementation of NCCN GuidelinesTM on Prostate Cancer in the Middle East and North Africa Region Waleed A. Hassen, MD;a,b Farrok A. Karsan, MD;c Farhat Abbas, MD;d Yasar Beduk, MD;e Ahmed El-Khodary, MD;f Marwan Ghosn, MD, MBA;g Jamal Khader, MD;h Raja Khauli, MD;i Danny M. Rabah, MD;j Ali Shamseddine, MD;k Sandy Srinivas, MD;l Bethesda, Maryland; Al Ain, United Arab Emirates; Karachi, Pakistan; Ankara Turkey; Kuwait City, Kuwait; Beirut, Lebanon; Amman, Jordan; Riyadh, Kingdom of Saudi Arabia; and Stanford, California

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa, prostate cancer Abstract A prostate cancer committee was established to modify the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Prostate Cancer for adaptation and implementation in the Middle East and North Africa (MENA) region. The objective was to enhance the multidisciplinary approach to the treatment of prostate cancer. The committee, comprising regional experts in the fields of urologic, medical, and radiation oncology, reviewed the 2009 version of the NCCN Guidelines on Prostate Cancer and suggested modifications based on the unique needs of the regions determined through published evidence and local expertise. The committee identified several areas in the NCCN Guidelines that they believed required modification, which are presented in this article. The treatment of

From the aDepartment of Urology, Johns Hopkins Medical Institutions, Bethesda, Maryland; bDepartment of Urology, Tawam Hospital, Al Ain, United Arab Emirates; cDepartment of Radiation Oncology, Aga Khan University Hospital, Karachi, Pakistan; d Department of Urology, Aga Khan University Hospital, Karachi, Pakistan; eDepartment of Urology, Ankara University, Ankara, Turkey; fDepartment of Oncology, Kuwait Cancer Control Center, Kuwait City, Kuwait; gDepartment of Urology, Hotel Dieu Hospital, Beirut, Lebanon; hDepartment of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan; iDepartment of Urology, American University of Beirut, Beirut, Lebanon; jDivision of Urology, Department of Surgery, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; kDepartment of HematologyOncology, American University of Beirut, Beirut, Lebanon; and l Stanford University School of Medicine, Stanford, California. The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors. Correspondence: Waleed A. Hassen, MD, Department of Urology, Tawam Hospital, P.O. Box 15258, Al Ain, United Arab Emirates. E-mail: [email protected]

prostate cancer in the MENA region has numerous challenges. The hope is that this effort to modify the NCCN Guidelines on Prostate Cancer for practical use in the MENA region will improve regional awareness and patient care. (JNCCN 2010;8[Suppl 3]:S26–S28)

Prostate cancer is a significant source of morbidity and

mortality in the West, and remains the second leading cause of death from a solid malignancy in men in the United States.1 However, its effect on populations in the Middle East and North Africa (MENA) region is not completely known. A prostate cancer committee was established to modify the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Prostate Cancer for adaptation and implementation in the MENA region. The objective was to enhance the multidisciplinary approach to the treatment of prostate cancer. The committee, comprising regional experts in the fields of urologic, medical, and radiation oncology, reviewed the 2009 version of the NCCN Guidelines on Prostate Cancer and suggested modifications based on the unique needs of the region determined through published evidence and local expertise. The committee identified several areas in the NCCN Guidelines that they believed required modification, which are presented in this article. The treatment of prostate cancer in the MENA region has numerous challenges. The hope is that this effort to modify the NCCN Guidelines on Prostate Cancer for practical use in the MENA region will improve regional awareness and patient care.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Prostate Cancer

The Region

Diagnosis and Staging

For the purposes of this section, the MENA region refers to Afghanistan, Algeria, Armenia, Egypt, Ethiopia, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Oman, Pakistan, Qatar, Kingdom of Saudi Arabia (KSA), Somalia, Sudan, Syria, Tunis, Turkey, United Arab Emirates (UAE), and Yemen. This collection of countries is obviously extremely heterogeneous in terms of economic resources and health care infrastructure. Although generalizations are difficult, some pertinent issues and challenges are broadly applicable to this region.

Because PSA screening is not routine in the MENA region, patients tend to present with more advanced disease. A general lack of primary care exists in the health systems of the region, which represents a challenge to timely diagnosis. Transrectal sonography is not routinely available except in regional centers, and experience with transrectal sonographic biopsy of the prostate also seems to be limited to regional centers. Similarly, experience with the pathologic diagnosis of prostate cancer (including the nuances of grading) is also limited to referral centers. Although CT and nuclear bone scans are generally available, MRI has more limited availability.

Incidence Although the exact incidence of prostate cancer in the MENA region is unknown, the reported incidence is approximately 5.8 cases per 100,000, with a mortality rate of 4.9 cases per 100,000.2 The accuracy of these data is not clear, however, because they are derived from unweighted averages from other regions. In general, prostate-specific antigen (PSA) screening is not routine, and therefore whether the lower incidence rate is secondary to the absence of screening or from a truly lower prevalence in the population is unknown. Smaller regional cancer databases, however, suggest that the true impact of this disease may be more significant than generally perceived. Young3 reported on regional cancer databases from 8 countries in the MENA region (Jordan, Egypt, Bahrain, KSA, Kuwait, Qatar, Oman, and UAE), and found that prostate cancer ranked among the top 4 malignancies in terms of frequency in 5 countries.3 Shamseddine et al.4 reported that prostate cancer represented the most frequently reported malignancy in Lebanese men. In general it is the committee’s perception that most patients present with late-stage disease because of the lack of PSA screening. It is also important to consider that the MENA region population is approximately 750 million.5 Because 65% of the population is currently younger than 30 years, even if the incidence of prostate cancer is lower than that of the West, the scope of the problem will only become more significant over the next 20 years as the population ages and presumably has access to improved medical care.

Treatment The definitive and palliative treatment of prostate cancer has multiple regional challenges. Definitive treatment typically involves either surgery or radiotherapy, and experience in the management of this disease is generally lacking. A brief poll of urologists, for example, found that awareness of the existence of NCCN Guidelines on Prostate Cancer varied between 5% and 86%. Adequate experience in the surgical management of prostate cancer has been shown to improve outcomes.6 A lack of surgical experience in the localized management of prostate cancer generally exists, even in referral centers, and radiation therapy has similar issues. According to the International Atomic Energy Agency (IAEA), only 93 machines are capable of delivering greater than 10 mV of energy in a region of 730 million people.7 More importantly, 70 machines are clustered in 3 countries (Turkey, Egypt, and KSA), leaving 23 machines to service the needs of 19 countries. Only 30 of 93 machines are capable of delivering CT dosimetry and planning. Furthermore, the costs of neoadjuvant hormonal therapy in combination with radiation therapy are also challenging, and experience with brachytherapy is limited. Similar issues arise when addressing the management of advanced disease. Although the cost of hormonal ablation is prohibitive, bilateral orchiectomy is a viable option and available. Access to systemic chemotherapy is limited, palliative care specialists are few, and the availability of narcotics tends to be limited.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-27

S-28

Supplement

Hassen et al.

Recommendations Based on these challenges, the committee recommended the following modifications to the NCCN Guidelines on Prostate Cancer. Staging Workup

tion, the committee suggests the daily use of diethylstilbestrol in low doses (1–3 mg) in combination with warfarin as an affordable second-line alternative. Diethylstilbestrol has been shown to result in PSA declines in up to 42% of patients with rising PSA.8

Staging with CT/MRI seems restrictive for stage 1 to 2, which limits these imaging modalities to those patients with a 20% or more probability of lymph node involvement. Given that expertise in treatment is limited, a diagnosis of metastatic disease would potentially avoid needless definitive intervention. Therefore, the committee believed that a cutoff of 10% would be more appropriate.

Principles of Radiation Therapy

Expected Patient Survival

The treatment of prostate cancer in the MENA region is a challenge and numerous obstacles hinder the delivery of what would be deemed appropriate care in the West. Although the incidence of prostate cancer seems to be less than in the West, the true incidence probably is at least partially understated. Physician awareness of appropriate treatment guidelines may not be sufficient; the hope is that this initial effort in tailoring guidelines to the region will lead to improved patient care.

Life expectancy estimates from data obtained in the developed world may not be representative of the MENA region. Morbidity and mortality from the same illness may be more severe because of genetic factors, access to health care facilities, and availability of technology, socioeconomics, and education. Barring the availability of country-specific life expectancy tables, the committee recommends a combination of factors, including performance status, comorbid conditions, disease stage, and physician judgment based on local experience. Initial Therapy

Although data show that a certain percentage of patients with locally advanced disease (T3b–T4) may be treated with surgery, the availability of surgical expertise for treating this patient population is extremely limited. Surgery is not recommended as an option, except in the rare institutions with a high level of surgical expertise. Primary Salvage Therapy

Because experience with cryotherapy or brachytherapy is extremely limited, the management of postradiation recurrence with either of these modalities should be restricted to a research setting. Systemic Salvage Therapy

As stated in the NCCN guidelines, the clinical benefit of antiandrogens in hormone-refractory disease is limited. Given that the cost of these medications is prohibitive for a significant segment of the popula-

Although the NCCN guidelines do not mention high–dose-rate brachytherapy in the principles of radiation therapy, the committee believes that guidelines for the use of this technology should be incorporated.

Summary

References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–249. 2. Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer Statistics, 2002. CA Cancer J Clin 2005;55:74–108. 3. Young JL. Cancer incidence in the Middle East and Gulf Cooperation Council countries. Presented at the Middle East Cancer Consortium Steering Committee Meeting; January 20, 2003; Lyon, France. 4. Shamseddine A, Sibai AM, Gehchan N, et al. Cancer incidence in postwar Lebanon: findings from the first national population-based registry, 1998. Ann Epidemiol 2004;14:663–668. 5. Unicef Regional Statistics, 2009. 6. Bianco FJ Jr, Riedel ER, Begg CB, et al. Variations among high volume surgeons in the rate of complications after radical prostatectomy: further evidence that technique matters. J Urol 2005;173:2099–2103. 7. International Atomic Energy Agency. Directory of Radiotherapy Centres. Available at: http://www-naweb.iaea.org/nahu/dirac/ default.asp. Accessed March 31, 2010. 8. Smith DC, Redman BG, Flaherty LE, et al. A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 1998;52:257–260.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-29 Supplement

Modification and Implementation of NCCN GuidelinesTM on Lymphomas in the Middle East and North Africa Region Ali Bazarbachi, MD, PhD;a Hamdy A. Azim, MD, PhD;b Hussain Alizadeh, MD, PhD;c Mahmoud Aljurf, MD;d Ibrahim Barista, MD;e Naeem A. Chaudhri, MD;d Zahira Fahed, MD;g Omar A. Fahmy, MD;b Ardeshir Ghavamzadeh, MD;g Mohamed H. Khalaf, MD;h Sami Khatib, MD;i Aghiad Kutoubi, MD;j Semra Paydas, MD;k Hanadi Rafii Elayoubi, MD;l Ghazi Zaatari, MD;m Hamdy M. Zawam, MD;b and Andrew D. Zelenetz, MD, PhD;n Beirut, Lebanon; Cairo, Egypt; Al Ain, United Arab Emirates; Riyadh, Kingdom of Saudi Arabia; Ankara, Turkey; Damascus, Syria; Tehran, Iran; Amman, Jordan; Adana, Turkey; Doha, Qatar; and New York, New York

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa, lymphoma, non-Hodgkin’s lymphoma, Hodgkin lymphoma Abstract In the Middle East and North Africa (MENA) region, cancer has many epidemiologic and clinical features that are different from those in the rest of the world. Additionally, the region has a relatively young population and large disparities in the availability of resources at diagnostic and treatment levels. A critical need exists for regional guidelines on cancer care, including those for lymphoid malignancies. A panel of lymphoma experts from MENA reviewed the 2009 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non-Hodgkin’s Lymphoma and Hodgkin Lymphoma and suggested modifications for the region that were discussed with the United States NCCN Lymphoma Panels. This article presents the consensus recommendations. (JNCCN 2010;8[Suppl 3]:S29–S35)

From the aDepartment of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; bCairo University, Cairo, Egypt; c Tawam Hospital/Johns Hopkins, Al Ain, UAE; dSection of Hematology/ Hematopoietic Stem Cell Transplant, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia; eDepartment of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey; fHematology and Medical Oncology, Al Bairouni University Hospital for Cancer, Damascus, Syria; gTehran University of Medical Sciences, Tehran, Iran; hDepartment of Hematology and Bone Marrow Transplantation, Maadi Armed Forces Medical Compound, Cairo, Egypt; i King Hussein Institute for Biotechnology and Cancer, Amman, Jordan; j Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut, Lebanon; kDepartment of Oncology, Faculty of Medicine, Cukurova University, Adana, Turkey; lAl Amal Hospital, Doha, Qatar; mDepartment of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon; and nDivision

Overview

In the Middle East and North Africa (MENA) region,

cancer has many epidemiologic and clinical features that are different from those in the rest of the world. Additionally, the region has a relatively young population and large disparities in the availability of resources at diagnostic and treatment levels. A critical need exists for regional guidelines on cancer care, including those for lymphoid malignancies. A panel of lymphoma experts from MENA reviewed the 2009 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non-Hodgkin’s Lymphoma and the 2008 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hodgkin Lymphoma (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) and suggested

of Hematology/Oncology, Department of Medicine, Memorial SloanKettering Cancer Center, New York, New York. Drs. Bazarbachi, Azim, Alizadeh, Aljurf, Barista, Chaudhri, Fahed, Fahmy, Ghavamzadeh, Khalaf, Khatib, Kutoubi, Paydas, Elayoubi, Zaatari and Zawam have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors. Dr. Zelenetz has disclosed that he receives research support from Abbott Laboratories; Cephalon, Inc.; GlaxoSmithKline; Allos Pharmaceuticals; Glouster Pharmaceuticals; Roche; and Seattle Genetics. He is an advisory board member for Bristol-Myers Squibb Company; Cephalon, Inc.; Eli Lilly and Company; Genentech, Inc.; GlaxoSmithKline; and Allos Pharmaceuticals. He is also a consultant for Genentech, Inc.; GlaxoSmithKline; Cancer Genetics; and sanofi-aventis U.S. Correspondence: Ali Bazarbachi, MD, PhD, Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 1136044, Beirut, Lebanon. E-mail: [email protected]

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-30

Supplement

Bazarbachi et al.

modifications for the region that were discussed with the United States NCCN Non-Hodgkin’s Lymphoma Panel. This article presents the consensus recommendations. For Hodgkin lymphoma, if PET-CT scan is not available, Gallium scan or biopsy is recommended to evaluate for residual disease. In mantle cell lymphoma, rituximab and a high-dose cytarabine–containing regimen such as DHAP (dexamethasone, cisplatin, cytarabine) were added to the first-line options. In diffuse large B-cell lymphoma, the dose-dense, dense-intense RACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen was added as an acceptable alternative to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in patients younger than 60 years. In Burkitt’s lymphoma, the LMB (B-cell non-Hodgkin’s lymphoma and B-cell acute lymphoblastic leukemia) protocol was added as an acceptable alternative and rituximab use was recommended for all CD20-positive tumors. In cutaneous lymphomas, human T-cell lymphotropic virus type 1 (HTLV-1) serology was recommended, particularly for patients from endemic areas. Finally, the panel formulated new recommendations for the diagnosis, workup, and management of HTLV-1–associated adult T-cell leukemia/lymphoma (ATL). In the acute, chronic, and smoldering forms of ATL, antiviral therapy using the combination of zidovudine and interferon (IFN)-α is recommended. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended in patients with acute ATL who do not experience a complete remission. In ATL lymphoma, first-line chemotherapy followed by allogeneic HSCT is recommended. In the MENA region, these suggested modifications should encourage the use of the NCCN guidelines for treating patients with lymphoma. At the global level, they represent an important addition to the NCCN guidelines by providing recommendations for the management of patients with ATL.

Background Malignant lymphomas constitute a sizeable percentage of human cancers, and recent epidemiologic data suggest a worldwide increase in incidence (approximately 30% in the past 5 years),1,2 which may be caused by environmental factors, including increased pesticide use, and the emergence of infectious diseases, such as hepatitis C virus infections. These malig-

nant lymphomas represent a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. Most non-Hodgkin lymphoma (NHL) cases are of B-cell origin; however, histologic subtypes may vary in different parts of the world. Prognosis depends on histologic type, stage, age, and treatment. In addition, tumor environment (e.g., immune and stromal infiltration), presence of infectious agents associated with lymphomagenesis, and molecular events involved in cell proliferation, differentiation, and apoptosis are emerging as new prognostic factors that eventually may be used for targeted therapies. Hodgkin lymphoma is characterized by a very good prognosis and a significant cure rate with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-type chemotherapy.3 However, targeted therapy either alone or in combination with chemotherapy has significantly improved the prognosis of NHL of B-cell origin, particularly with the use of rituximab, an anti-CD20 monoclonal antibody.4,5 Diffuse large B-cell lymphoma (DLBCL) is a distinct histologic type within B-cell NHL characterized by large tumor cells and aggressive clinical behavior. This subtype accounts for approximately 30% to 40% of adult NHL.6 Regional specificities in the incidence of lymphomas have been reported with a significantly lower incidence of follicular lymphoma and chronic lymphocytic leukemia, and a significantly higher incidence of T-cell lymphomas in Asian countries compared with Europe and North America.7–9 A high incidence of Epstein-Barr virus–associated lymphomas has been reported in some Middle East countries.10,11 In addition, HTLV-1–associated ATL is endemic in some Middle East regions.12,13 Finally, management of malignant lymphomas in developing countries is variable and largely depends on the availability of diagnostic and therapeutic resources, such as immunohistochemistry and molecular techniques, PET-CT scan, and expensive targeted therapies.

Methods The NCCN–MENA project was launched during a preparatory meeting held in Abu Dhabi, United Arab Emirates on November 9, 2008, involving NCCN members and chairpersons of the different

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Lymphoma

guidelines panels. The goal was to adapt the NCCN guidelines to the region. The chair of the NCCN Lymphoma Panel, in consultation with the chairman of the NCCN–MENA project and chairpersons of other groups, nominated lymphoma experts from multiple specialties, including hematology, medical oncology, radiation oncology, pathology, and diagnostic radiology, join the NCCN–MENA guideline committee. These individuals were contacted by email and agreed to participate. All members were emailed the 2008 version of the NCCN Guidelines on Non-Hodgkin’s Lymphomas and the 2009 version of the NCCN Guidelines on Hodgkin Lymphoma and asked to communicate their suggested modifications. Several members sent their suggested modifications to the whole group. The regional lymphoma group met in Beirut, Lebanon on February 21, 2009, to discuss the suggested modifications. Consensus recommendations were made, including specific modifications to the existing NCCN recommendations and new recommendations for ATL management because none were present in the 2009 version of the NCCN Guidelines on Non-Hodgkin’s Lymphomas. The chair compiled these modifications and forwarded them to the chair of the NCCN Non-Hodgkin’s Lymphomas Panel in the United States, and then the comments of the NCCN panel were e-mailed to the MENA lymphoma committee. Subsequently suggested MENA modifications were presented at the Abu Dhabi meeting in April 2009; consensus recommendations were then established at a special lymphoma committee meeting attended by several MENA lymphoma committee members and the chair of the NCCN panel. These recommendations were then discussed and finalized by the NCCN panel in June 2009.

Hodgkin Lymphoma Background

The current NCCN treatment algorithm for Hodgkin lymphoma is based on PET-CT findings. However, this modality is not available or accessible everywhere. A small survey of the groups’ practices showed that Gallium scan is more widely available and accessible in the MENA region. Imaging with Gallium requires several days, but there is no need to wait after the end of treatment. A baseline scan is also required.

Some studies14 indicate no statistical difference between the imaging methods. However, most studies indicate that PET is superior to Gallium scan in terms of sensitivity for activity and site detection, and also has a slightly higher specificity. Suggested Modification

• If PET-CT is not available, Gallium scan is recommended. • If Gallium scan is not available, a biopsy of the residual disease is recommended. • If Gallium scan is positive, a biopsy is recommended. • If Gallium scan is negative, the group recommends following the NCCN guidelines for negative PET-CT scan.

Mantle Cell Lymphoma Background

Several reports show that high-dose cytarabine is an effective chemotherapeutic agent in mantle cell lymphoma. For example, the protocol involving RDHAP (dexamethasone, cisplatin, high-dose cytarabine, rituximab) followed by autologous stem cell transplant (ASCT)15 for previously untreated younger patients (< 65 years) is a very affordable and rather effective regimen, with 3-year overall and event-free survival rates of 75% and 76%, respectively, based on an intent-to-treat analysis. Suggested Modification

The group recommended that suggested first-line treatment regimens include a rituximab and highdose cytarabine–containing regimen, such as DHAP, with a corresponding footnote indicating that highdose chemotherapy and ASCT should be given after high-dose cytarabine.

DLBCL Background

Multiple studies have shown that advances in treatment can improve the outcome of patients with DLBCL, and that the standard CHOP regimen is not sufficient as first-line chemotherapy to cure many patients. The first improvement was reported in 2 randomized studies, which showed the superiority of a dose-dense and -intense regimen, ACVBP

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-31

S-32

Supplement

Bazarbachi et al.

(doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone), over CHOP.16,17 This regimen is now widely used in several countries in Europe and the MENA region. The second improvement was the increased survival achieved with the addition of rituximab to combination chemotherapy.18,19 Suggested Modification

The group recommended adding R-ACVBP as an acceptable alternative to R-CHOP.

Burkitt’s Lymphoma Background

Excellent results are reported in young adults treated with the pediatric LMB protocol.20,21 The second improvement was the increased survival achieved with the addition of rituximab to combination chemotherapy.18,19 Furthermore, rituximab significantly improves outcome in patients with CD20-positive Burkitt’s lymphoma. Suggested Modification

The group suggested that the LMB protocol be added as an acceptable alternative to the current NCCN Guidelines for Burkitt’s Lymphoma (CODOX-M or HyperCVAD), and that rituximab use be considered for all tumors that are CD20-positive.

T-Cell Lymphomas ATL

Background: ATL is an aggressive malignancy of mature activated CD4-positive CD25-positive T cells associated with a retrovirus-designated HTLVI.22 Endemic areas include Japan, the Caribbean, intertropical Africa, Brazil, Eastern Europe (Romania), and the Middle East (particularly Iran).23,24 The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into 4 categories: acute, lymphoma, chronic, and smoldering types (Table 1).25 The chronic and smoldering subtypes are considered indolent, but eventually have poor long-term survival. Patients with aggressive ATL (acute and lymphoma types) generally have a very poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, or frequent infectious complications from

a profound T-cell immunodeficiency.22,26,27 Numerous small phase II studies using zidovudine (AZT) and IFN-α have shown responses in patients with ATL.28–31 High doses of both agents were used: 6 to 9 million units of IFN-α in combination with daily divided AZT doses of 800 to 1000 mg/d. However, only patients with wild-type p53 and low IFN regulatory factor 4 expression seem to exhibit long-term responses to AZT/IFN therapy.32,33 The results of a recent worldwide meta-analysis on the use of AZT/ IFN for treating ATL indicate a significant survival advantage in acute, chronic, and smoldering-type ATL, but not in lymphoma ATL.34 The recently published proposal from the International Consensus Meeting recommended a strategy for treating ATL.35 Suggested Modification: Diagnosis: In all patients with leukemic manifestations, ATL is usually diagnosed based on the presence of 5% or more abnormal T lymphocytes in peripheral blood according to morphology and flow cytometry. In those without leukemic manifestations, it is diagnosed based on a finding of T-cell lymphoma on biopsy of involved organs. Additionally, HTLV-1 seropositivity is mandatory for ATL diagnosis. Clonal integration of HTLV-1 provirus should be performed in most cases and is mandatory in atypical cases. Workup: The group recommended that workup for ATL include the following: • CBC and blood smear: lymphocytosis (absolute lymphocyte count > 4000) in acute and chronic subtypes. Typical ATL cells (“flower cells”) have markedly polylobated nuclei with homogeneous and condensed chromatin, small or absent nucleoli, and agranular and basophilic cytoplasm, but multiple morphologic variations can be encountered. • Flow cytometry on peripheral blood: mature Tcell phenotype. Minimum panel: CD3, CD4, CD7, CD8, and CD25. Usually CD4-positive cells with expression of CD2, CD5, CD25, CD45RO, CD29, T-cell receptor–αβ, and HLADR. Most cases are CD7-negative and CD26negative with low CD3 expression. Rare cases are CD8-positive or CD4/CD8-double positive or CD4/CD8-double negative. • HTLV-I serology: positive (enzyme-linked immunosorbent assay and Western blot). • Molecular analysis: monoclonal integration of

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-33

Supplement

Lymphoma

Table 1 Adult T-Cell Leukemia/Lymphoma Subtype According to Shimoyama Classification Healthy Carrier

Smoldering ATL

Chronic ATL

Acute ATL

ATL Lymphoma

HTLV-I serology

+

+

+

+

+

Clonal integration of provirus

– (blood)

+ (blood)

+ (blood)

+ (blood)

+ (lymph nodes)

Lymphocyte count

Normal

Normal

Elevated

Elevated

Normal

Abnormal cells

< 5%

> 5%

> 5%

> 5%

< 1%

Hypercalcemia







+

+

LDH level

Normal

< 1.5 N

2N

>2N

Skin or lung involvement



+

+

+

+

Bone marrow or spleen involvement





+

+

+

Bone, gastrointestinal, or central nervous system involvement







+

+

Abbreviations: ATL, adult T-cell leukemia/lymphoma; HTLV-1, human T-cell lymphotropic virus type 1; LDH, lactate dehydrogenase.

HTLV-I provirus (Southern blot or inverted polymerase chain reaction). • Bone marrow aspirate and biopsy: generally not required to make the diagnosis. However, bone marrow involvement is an independent poor prognostic factor. • Radiologic imaging: CT scans of neck, thorax, abdomen, and pelvis. Skeletal survey in symptomatic patients. • Gastrointestinal evaluation: upper gastrointestinal endoscopy (frequent gastrointestinal involvement). • Central nervous system evaluation: CT scan, MRI, and/or lumbar puncture in all patients with acute or lymphoma subtypes or in those with neurologic manifestations. • Biopsy of lymph nodes (excisional), skin biopsy, gastrointestinal tract biopsy, or bone marrow biopsy is required if the diagnosis is not established based on molecular assay of peripheral blood (for histology and molecular analyses of HTLV-I provirus integration), or to rule out an underlying infection (e.g., tuberculosis, histoplasmosis, toxoplasmosis). • Chemistry: electrolyte, blood urea nitrogen, creatinine, serum calcium, and serum lactate dehydrogenase (LDH) levels. • Stool examination for parasites. Treatment of Chronic/Smoldering ATL: The group recommends treatment for all patients with chronic/smoldering ATL. Recent results from a Japanese study show poor outcome for patients treated with a “watch and wait” strategy or chemotherapy.36

The group recommended that treatment include the following: • Initial therapy outside clinical trials: AZT (1 g/d orally) and IFN-α (6–10 million units per day). A recent worldwide meta-analysis showed this regimen resulted in 100% long-term survival.34 • Response evaluation: complete remission is defined by normalization of lymphocytosis (if present) and LDH level (if elevated), with disappearance of all clinical manifestations (particularly skin involvement and lymphadenopathy). However, persistence of fewer than 5% flower cells on peripheral smear is allowed. • Almost all patients with chronic or smoldering ATL should experience response to AZT/IFN. Outside clinical trials, treatment should never be interrupted in these patients. Response is usually obtained within 1 to 2 months. If no response is seen at 2 months, treatment should be discontinued. In patients who experience progression with life-threatening manifestations, treatment can be discontinued before 2 months. • Very few patients with chronic/smoldering ATL will not experience response or will experience progression after AZT/IFN. For these patients, chemotherapy is recommended (CHOP is the most used regimen, although one randomized study showed that Japanese LSG15 [vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP); doxorubicin, ranimustine, and prednisone (AMP); and vindesine, etoposide, carboplatin, and prednisone (VECP)] is superior to CHOP).37

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-34

Supplement

Bazarbachi et al.

Treatment of Acute ATL: • Recommended initial therapy outside clinical trials: AZT (1g/d orally) and IFN-α (6–10 million units per day). This strategy is associated with an improved survival rate compared with first-line chemotherapy in worldwide meta-analysis. High doses of both agents are needed for at least 1 month. Dose reduction for hematotoxicity is allowed starting from month 2. • Response evaluation: complete remission is defined by normalization of lymphocytosis (if present) and the LDH level (if elevated), with disappearance of all clinical manifestations and tumor sites. However, persistence of less than 5% flower cells on peripheral smear is allowed. • Outside clinical trials, treatment should never be interrupted in patients experiencing response. Response is obtained within 1 to 2 months. If no response is achieved at 2 months, AZT/IFN should be discontinued. In patients experiencing progression with life-threatening manifestations, treatment can be discontinued before 2 months. • Alternative first-line option and for patients who do not experience respond or will experience progression after AZT/IFN: inclusion in clinical trials or chemotherapy (CHOP is the most used regimen, although one randomized study showed that Japanese LSG15 [VCAP, AMP, and VECP] is superior to CHOP).37 Data are weak for monoclonal antibodies (anti-CD52 or -CD25). • Young patients with a human leukocyte antigen (HLA)–identical donor should be referred for allogeneic HSCT (myeloablative or reducedintensity conditioning) except those who experience complete response on AZT/IFN (80% long-term survival is expected). • Antimicrobial prophylaxis: trimethoprim-sulfamethoxazole (Bactrim) and strongyloidosis prophylaxis is recommended. • Central nervous system prophylaxis: intrathecal chemotherapy is recommended (methotrexate, cytarabine, and corticosteroids). Treatment of ATL Lymphoma: • AZT/IFN is not effective in these patients (inferior outcome compared with chemotherapy). Chemotherapy is more effective in ATL lymphoma than in acute ATL. • Recommended first-line therapy: inclusion in clinical trials or chemotherapy (CHOP is the

most used regimen, although one randomized study showed that Japanese LSG15 [VCAP, AMP, and VECP] is superior to CHOP).37 Data are weak for monoclonal antibodies (anti-CD52 or -CD25). • Young patients with an HLA–identical donor should be referred for allogeneic HSCT (myeloablative or reduced-intensity conditioning). • Antimicrobial prophylaxis: trimethoprim-sulfamethoxazole (Bactrim) and strongyloidosis prophylaxis is recommended. • Central nervous system prophylaxis: intrathecal chemotherapy is recommended (methotrexate, cytarabine, and corticosteroids).

Cutaneous T-Cell Lymphomas Background

Many patients with smoldering ATL can be misdiagnosed with mycosis fungoides or Sézary syndrome if HTLV-I serology is not requested. Suggested modification

• The group recommends including HTLV-I serology as part of the workup, particularly if the patient is from an endemic area.

Conclusions In the MENA region, these suggested modifications should encourage the use of the NCCN guidelines for treating patients with lymphoma. At the global level, they represent an important addition to the NCCN guidelines by providing recommendations for managing patients with ATL.

References 1. Eltom MA, Jemal A, Mbulaiteye SM, et al. Trends in Kaposi’s sarcoma and non-Hodgkin’s lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst 2002;94:1204–1210. 2. Grulich AE, Vajdic CM. The epidemiology of non-Hodgkin lymphoma. Pathology 2005;37:409–419. 3. Evens AM, Hutchings M, Diehl V. Treatment of Hodgkin lymphoma: the past, present, and future. Nat Clin Pract Oncol 2008;5:543–556. 4. Sonet A, Bosly A. Rituximab and chemotherapy in diffuse large B-cell lymphoma. Expert Rev Anticancer Ther 2009;9:719–726. 5. Leonard JP, Martin P, Barrientos J, Elstrom R. Targeted treatment and new agents in diffuse large B-cell lymphoma. Semin Hematol 2008;45(3 Suppl 2):S11–16.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Lymphoma 6. Armitage JO, Weisenburger DD. New approach to classifying nonHodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 1998;16:2780–2795. 7. Gross SA, Zhu X, Bao L, et al. A prospective study of 728 cases of non-Hodgkin lymphoma from a single laboratory in Shanghai, China. Int J Hematol 2008;88:165–173. 8. Shih LY, Liang DC. Non-Hodgkin’s lymphomas in Asia. Hematol Oncol Clin North Am 1991;5:983–1001. 9. Intragumtornchai T, Wannakrairoj P, Chaimongkol B, et al. NonHodgkin’s lymphomas in Thailand. A retrospective pathologic and clinical analysis of 1391 cases. Cancer 1996;78:1813–1819. 10. Vasef MA, Ubaidat MA, Khalidi HS, et al. Association between Epstein-Barr virus and classic Hodgkin lymphoma in Jordan: a comparative study with Epstein-Barr virus-associated Hodgkin lymphoma in North America. South Med J 2004;97:273–277. 11. Al-Salam S, John A, Daoud S, et al. Expression of Epstein-Barr virus in Hodgkin lymphoma in a population of United Arab Emirates nationals. Leuk Lymphoma 2008;49:1769–1777. 12. Sidi Y, Meytes D, Shohat B, et al. Adult T-cell lymphoma in Israeli patients of Iranian origin. Cancer 1990;65:590–593. 13. Kchour G, Tarhini M, Sharifi N, et al. Increased microvessel density in involved organs from patients with HTLV-I associated adult T cell leukemia lymphoma. Leuk Lymphoma 2008;49:265–270. 14. Fruchart C, Reman O, Le Stang N, et al. Prognostic value of early 18 fluorodeoxyglucose positron emission tomography and gallium-67 scintigraphy in aggressive lymphoma: a prospective comparative study. Leuk Lymphoma 2006;47:2547–2557. 15. de Guibert S, Jaccard A, Bernard M, et al. Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma. Haematologica 2006;91:425–426. 16. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005;352:1197–1205. 17. Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 2003;102:4284–4289. 18. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242. 19. Gisselbrecht C, Fitoussi O, Belhadj K, et al. Survival impact of rituximab combined to ACVBP (R-ACVBP) in 209 poor risk diffuse large B-cell lymphoma (DLBCL) patients treated with upfront high-dose consolidative autotransplantation (HDC): a GELA phase II study [abstract]. Blood 2008;112:286. Abstract 771. 20. Patte C, Philip T, Rodary C, et al. High survival rate in advancedstage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol 1991;9:123–132. 21. Diviné M, Casassus P, Koscielny S, et al. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol 2005;16:1928–1935.

22. Bazarbachi A, Ghez D, Lepelletier Y, et al. New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol 2004;5:664– 672. 23. Kaplan J, Khabbaz R. The epidemiology of human T-lymphotropic virus type I and II. Medical Virol 1993;3:137–148. 24. Gessain A. Epidemiology of HTLV-1 and associated diseases. Human T-cell lymphotropic virus type 1. In: Höllsberg P, Hafler DA, eds. Human T-Cell Lymphotropic Virus Type I. Chichester, UK: John Willey & Sons Ltd; 1996:33–64. 25. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 1991;79:428– 437. 26. Shimoyama M. Treatment of patients with adult T-cell leukemialymphoma: an overview. In: Takatsuki K, Hinuma Y, Yoshida M, eds. Advances in Adult T-Cell Leukemia and HTLV-I Research. Tokyo: Japan Scientific Societies Press; 1992:43–56. 27. Hermine O, Wattel E, Gessain A, Bazarbachi A. Adult T-cell leukaemia: a review of established and new treatments. BioDrugs 1998;10:447–462. 28. Gill PS, Harrington W Jr, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995;332:1744–1748. 29. Hermine O, Bouscary D, Gessain A, et al. Brief report: treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa. N Engl J Med 1995;332:1749–1751. 30. Bazarbachi A, Hermine O. Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13(Suppl 1):S186–S190. 31. Kchour G, Tarhini M, Kooshyar MM, et al. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood 2009;113:6528–6532. 32. Datta A, Bellon M, Sinha-Datta U, et al. Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence. Blood 2006;108:1021–1029. 33. Ramos JC, Ruiz P Jr, Ratner L, et al. IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood 2007;109:3060–3068. 34. Bazarbachi A, Plumelle Y, Ramos JC, et al. A worldwide metaanalysis on the use of zidovudine and interferon-alpha in adult T-cell leukemia/lymphoma: improved survival in the leukemic subtypes. J Clin Oncol 2010; in press. 35. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemialymphoma: a proposal from an international consensus meeting. J Clin Oncol 2009;27:453–459. 36. Takasaki Y, Iwanaga M, Imaizumi Y, et al. Long-term study of indolent adult T-cell leukemia-lymphoma (ATL). Blood 2010; in press. 37. Tsukasaki K, Utsunomiya A, Fukuda H, et al. VCAP-AMPVECP compared with biweekly CHOP for adult T-cell leukemialymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 2007;25:5458–5464.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-35

S-36 Supplement

Modification and Implementation of NCCN Guidelines™ on Hepatobiliary Cancers in the Middle East and North Africa Region Muhammed Aasim Yusuf, FRCP Edin;a Vinay Kumar Kapoor, MS, FRCS;b Refaat Refaat Kamel, FRCS;c Ather Kazmi, MRCP, FRCR;d Najam Uddin, FRCR;e Nehal Masood, MD;f and Abdulmajeed Al-Abdulkareem, MD, FRCSC, FACS;g Lahore, Pakistan; Lucknow, India; Cairo, Egypt; Karachi, Pakistan; and Riyadh, Kingdom of Saudi Arabia

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa region, MENA region, hepatobiliary cancer, cancer Abstract The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers address hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Hepatocellular cancer incidence is higher in the Middle East and North Africa (MENA) region than in the West, and hepatitis B and C infections are particularly important; the incidence of gallbladder cancer is among the highest in the world. Regional problems include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities. Furthermore, costs associated with molecular and targeted therapies are an increasing concern. A committee was formed, consisting of leading specialists and decision-makers from the region, with each member being tasked to suggest modifications to the existing guidelines based on review of the literature and consultations

From the aDepartment of Gastroenterology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; b Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; cHepatobiliary Surgery & Liver Transplantation, Ein Shams University, Cairo, Egypt; dClinical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; eInterventional Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; fMedical Oncology, Aga Khan University Hospital, Karachi, Pakistan; and gDepartment of Hepatobiliary Sciences and Liver Transplantation, King Abdul Aziz Medical City, King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia. The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors. Correspondence: Muhammed Aasim Yusuf, FRCP Edin, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. E-mail: [email protected]

with local colleagues. This committee met as a group, and then continued to discuss and debate the suggested modifications electronically. Several recommendations were finalized after vigorous debate. The final approved recommendations were then presented in April 2009 to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval. This project represents an effort to modify and implement the NCCN Guidelines on Hepatobiliary Cancers in the MENA region, while taking into consideration local differences in patient and disease characteristics. The hope is that this will form the basis of future local, regional, and international cooperation in guideline development and research. (JNCCN 2010;8[Suppl 3]:S36–S40)

The 2009 version of the NCCN Clinical Practice Guide-

lines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN. org) addresses 4 main tumor groups: hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. The incidence of hepatocellular cancer seems to be significantly higher in the Middle East and North Africa (MENA) region than in the West. The age-standardized incidence rate is 12.8 per 100,000 population in Egypt,1 8 per 100,000 in Pakistan,2 and 4.2 per 100,000 in Saudi Arabia,3 compared with 2.5 per 100,000 in the United States.4 The region also shares some unique regional risk factors. Hepatitis B and C infections seem to be particularly important. A predominance of hepatitis B virus surface antigen is seen in patients with hepatocellular

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Hepatobiliary Cancer

cancer from most Asian, African, and Latin American countries; hepatitis C predominates in Japan, Pakistan, Mongolia, and Egypt.5 Although the MENA region is not homogeneous, most countries represented in the committee have some common issues, albeit to a variable extent. These include delay in diagnosis, often from an absence of screening programs in those infected with hepatitis B or C, and a shortage of trained staff required for diagnosis and treatment, including gastroenterologists/hepatologists, radiologists, hepatobiliary surgeons, and oncologists. Furthermore, insufficient or, in some cases, nonexistent liver transplant facilities are a serious limitation to treatment for some patients. Pakistan, with a population of more than 170 million, has no liver transplant program. India has 3 centers, performing a total of 550 transplants annually. Egypt has 10 centers, with 150 to 200 transplants performed per year, whereas Saudi Arabia has 3 centers, performing 120 transplants annually. The costs associated with diagnosis and treatment are an increasing concern in an age of molecular and targeted therapies. Sorafenib for treating hepatocellular carcinoma, for example, is too expensive to be used by most eligible patients in many countries. It is currently recommended primarily in patients with Child’s A disease, precluding its use in most patients in the MENA region. Additionally, the modest benefit in survival improvement means that both patients and physicians question the cost/benefit analysis. Shortage of trained staff is a major problem in many countries in the region. Interventional radiologists are a rare species in many countries. Currently, only 4 centers in Pakistan offer transarterial chemoembolization, with each performing fewer than 500 procedures per year, for an estimated 15,000 new cases per year. A dearth of surgical expertise for liver resection and transplantation exists across the region. Therefore, numerous challenges exist in the region. A large number of patients have hepatitis B and C infections, suggesting a huge tumor load in the future. Patients present at an advanced stage, with poor background liver function in up to half, thus precluding many treatment options. A culture of cooperation between different specialties is often lacking, with multidisciplinary care the exception rather than the norm. This results in squandering of research opportunities and lack of progress at the local, national, and regional levels.

Typical Journey of a Patient With Hepatocellular Carcinoma in Pakistan Abdominal pain leads to investigation, and usually the discovery of hepatitis C infection. Abdominal imaging, usually with ultrasonography, leads to the finding of a mass or masses in the liver. Most patients will have access to biphasic CT scanning, usually at a referral center or in the private sector. However, up to 85% may be unsuitable for treatment based on extent of disease or poor liver function. The remainder are offered various treatments, but cost issues often limit patient acceptance, especially for sorafenib, which only 1 in 8 patients will accept at Shaukat Khanum Memorial Cancer Hospital in Lahore. In a single-center experience in Pakistan,2 586 patients were diagnosed with hepatocellular cancer over a 10-year period. Most presented with large, multifocal tumors (mean cross-sectional diameter, 8 cm). Background liver function, assessed according to Child-Pugh status, was poor (B to C) in 46%. Median survival after diagnosis was 10.5 months, with 1-, 3-, and 5-year survival rates of 45%, 20%, and 10%, respectively (Figure 1). Regarding gall bladder cancer, the highest incidence rates worldwide were reported for women in Delhi, India (21.5/100,000); South Karachi, Pakistan (13.8/100,000); and Quito, Ecuador (12.9/100,000).6 Risk factors for gallbladder cancer include gallstones, particularly those associated with chronic cholecystitis; calcified (porcelain) gallbladder; gallbladder polyps; typhoid carrier; obesity; multiparity; and chronic infection with Helicobacter bilis and H pylori.6,7 Gallstone disease has been shown to start at a younger age in Northern India and Kashmir.8 Decreasing biliary tract cancer mortality worldwide reflects more widespread and earlier adoption of cholecystectomy. However, in many high-risk areas, including Pakistan and India, access to gallbladder surgery remains patchy and inadequate.9

Methods After the successful development of regional NCCN guidelines for Korea and China, a committee was formulated in November 2008 to begin developing regional guidelines for the MENA region. The committee also had major representation from South Asia. The initial group consisted of the various committee chairs. Each committee chair then began identifying

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-37

S-38

Supplement

Yusuf et al. 1.0 .9 .8

Cumulative Survival

.7 .6 Median survival time: 10.5 months

.5 .4 .3 .2 .1 0

0

12

24

36

48

60

72

84

96

108

Months

Figure 1  Overall survival of patients with hepatocellular carcinoma. From Yusuf MA, Badar F, Meerza F, et al. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:273; with permission.

and inviting leading specialists and decision-makers from the region to participate. Each member was asked to suggest modifications to the existing guidelines, based on review of the literature and after consultations with local colleagues. The committee met in Dubai in January 2009 to discuss and debate the various suggested modifications. Further modifications followed, with most discussion and changes occurring by email. All members were required to provide references from the literature for any modifications to be approved. The committee then met again, on the sidelines of the NCCN–MENA meeting in Abu Dhabi in April 2009, to finalize the presentation and recommendations. These were then presented to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval.

Recommended Modifications Table of Contents

The committee suggested adding “The NCCN believes that all cancer patients should be managed by a multidisciplinary team, and preferably in a specialist center.” Hepatocellular Carcinoma

Screening: The committee suggested modifying footnote “b” to read “Imaging of those with elevated AFP [alpha-fetoprotein] should be with CT/MR,

and not with ultrasound scan [USS]. If CT/MR is normal, then follow-up imaging will be with USS.”10 This recommendation was made because contrastenhanced ultrasound scan is not widely available in the MENA region. Diagnosis: The committee suggested amending “biopsy” to read “FNAC/biopsy” and adding a footnote stating that “FNAC appropriate if cytopathology expertise available.” The rationale for this recommendation is that fine-needle aspiration (FNA) may be easier and safer and requires less monitoring. Furthermore, it may be associated with fewer complications and is often less expensive than liver biopsy. Workup: The committee recommended amending footnote “g” to read “assess liver reserve using combination of Child-Pugh score, estimation of residual liver volume, and assessment of portal hypertension (e.g., varices, splenomegaly, thrombocytopenia, and measurement of portal vein pressure, where available).”10–12 The committee believed that these additional modalities helped to more appropriately select patients who would be suitable for surgery, particularly resection. The committee also suggested adding a footnote after “AFP” stating “AFP > 1000 is suggestive of microvascular invasion in tumors > 5 cm. These patients are not suitable for transplantation.”13 Surgical Assessment: The committee suggested replacing “Child’s A, B” with “Child’s A” because they believed that this was more in agreement with the American Association for the Study of Liver Disease (AASLD) guidelines, which state that “Patients who have a single lesion can be offered surgical resection if they are noncirrhotic or have cirrhosis but still have well-preserved liver function, normal bilirubin, and hepatic vein pressure gradient < 10 mm Hg.”10 The committee believed that those with poorer liver function (i.e., patients with Child’s B) probably should be considered for transplantation rather than resection. For transplant candidates, the committee suggested adding a footnote stating “Ablation techniques can be considered in selected patients waiting for a transplant, especially when the waiting time is more than 6 months.”10,14 The committee also suggested adding a footnote stating “Patients originally deemed unsuitable for transplant may be reconsidered for transplant after ablative therapies.”15 Unresectable Clinical Presentation: The commit-

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

Supplement

Hepatobiliary Cancer

tee recommended changing footnote “r,” dealing with the use of sorafenib, from “There are limited safety data available for patients with Child-Pugh class B. Use with extreme caution in patients with elevated bilirubin levels” to read “There are limited safety data available for patients with Child-Pugh class B and dosing is uncertain. Extreme caution is required and participation in clinical trials is recommended.” The committee members believed that data were insufficient to recommend anything more than this. Gallbladder

For workup of jaundiced patients, the committee suggested changing “cholangiography” to “ERCP/PTC + biliary drainage (+ biopsy if possible) if obstruction confirmed.” The committee members believed that magnetic resonance cholangiopancreatography was less likely to be useful in jaundiced patients, because many or most would also require a biliary drainage procedure. The committee also believed that “biliary drainage” should be removed from the primary treatment column, because this should be performed normally during the diagnostic workup. Intrahepatic Cholangiocarcinoma

Although not disagreeing with resection as a possible treatment for intrahepatic cholangiocarcinoma, the committee believed it important to add a footnote stating that “There is no level 1 data with regard to the value of hepatic resection in this situation.” Extrahepatic Cholangiocarcinoma

In workup, the committee suggested changing “cholangiography” to “ERCP/PTC + biliary drainage (+ biopsy if possible) if obstruction confirmed.” The committee also believed that “biliary drainage” should be removed from the primary treatment column, because this should be performed normally during the diagnostic workup. For “Resected, negative margin (R0), negative regional nodes,” the committee recommended removing the chemotherapy option because they believed the benefit of adjuvant chemotherapy remains unproven, and the only randomized trial examining this did not show any benefit in treating cholangiocarcinoma.16 The committee also recommended that the chemotherapy + radiation therapy (XRT) option be removed because of conflicting data regarding adjuvant chemoradiation. No ran-

domized trials specifically address this treatment, and most retrospective series consisted of a mix of R0 and R1 tumors. No clear evidence shows that adjuvant chemoradiation “improves” outcomes in patients with R0 cancers. The committee believed it reasonable to leave “Observe or clinical trial” as the only 2 available options.

Conclusions This initiative represents the first effort in the MENA region to implement transnational guidelines, with content based on the NCCN guidelines but modified to take into consideration local differences in patient and disease characteristics. Every effort was made to recommend modifications based on the literature or, at the minimum, best practice in the region, and backed by expert opinion. This project could form the basis of future cooperation, not only in guideline development and modification, but also in research. It became painfully obvious to all involved in this effort that little local research data was available on which to base suggested modifications. This finding highlighted the need for regional cooperation and the development of research protocols to study these common diseases in the MENA region. Great disparity exists within the MENA region in terms of patients and resources, but many similarities are also present. The committee members hope to revisit this subject at regular intervals, and look forward to when all cancer care in this region follows treatment guidelines derived from robust local data.

Acknowledgments The following also contributed to the process of guideline formulation and revision, as members of the NCCN–MENA Hepatobiliary Guidelines Review Committee: Khalid Omer Abdullah, King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia; Hassan Jaafar, Tawam Hospital, AlAin, United Arab Emirates; Kakil Ibrahim Rasul, Hamad Medical Corporation, Doha, Qatar; Suayib Yalcin, Hacettepe University Institute of Oncology, Ankara, Turkey; and Abdel-Rahman El-Zayadi, Ain Shams University, Cairo, Egypt.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-39

S-40

Supplement

Yusuf et al.

References 1. Ibrahim AS. Liver and intrahepatic bile duct cancer. Available at: http://seer.cancer.gov/publications/mecc/mecc_liver.pdf. Accessed March 31, 2010.

9. Randi G, Malvezzi M, Levi F, et al. Epidemiology of biliary tract cancers: an update. Ann Oncol 2009;20:146–159. 10. Bruix, J, Sherman, M. AASLD practice guideline: management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.

2. Yusuf MA, Badar F, Meerza F, et al. Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. Asian Pac J Cancer Prev 2007;8:272–274.

11. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–1440.

3. Kindgom of Saudi Arabia Ministry of Health National Cancer Registry. Cancer incidence report Saudi Arabia 2003. Available at: http://www.kfshrc.edu.sa/oncology/files/NCR2003.pdf. Accessed March 31, 2010.

12. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–1022.

4. Carr BI, ed. Hepatocellular cancer: diagnosis and treatment. Totowa (NJ): Humana Press; 2005. 5. Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer 2007;96:1127–1134. 6. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:1591–1602. 7. Kapoor VK, McMichael AJ. Gallbladder cancer: an ‘Indian’ disease. Natl Med J India 2003;16:209–213. 8. Khuroo MS, Mahajan R, Zargar SA, et al. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kashmir. Gut 1989;30:201–205.

13. Pawlik TM, Delman KA, Vauthey JN, et al. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 2005;11:1086–1092. 14. Llovet JM, Mas X, Aponte JJ, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123–128. 15. Yao FY, Kerlan RK Jr, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819–827. 16. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreatobiliary carcinoma. Cancer 2002;95:1685–1695.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  Juy 2010

S-41 Supplement

Modification and Implementation of NCCN Guidelines™ on Palliative Care in the Middle East and North Africa Region Omar Shamieh, MD, and Abdul-Rahman Jazieh, MD, MPH, Riyadh, Kingdom of Saudi Arabia

Key Words NCCN Clinical Practice Guidelines in Oncology, NCCN Guidelines, Middle East and North Africa, palliative care, cancer Abstract Palliative care is an important component of cancer treatment. Advancing palliative care in the developing countries is essential to improving patient care. The issues limiting its practice must be addressed, especially in light of the initiative to adapt the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to the Middle East and North Africa (MENA) region. Palliative care is in its early stage of evolution in the MENA region, and its practice encounters many challenges and barriers. Adaptation of guidelines should take into consideration the situation and conditions in the targeted region to improve the standard of care to an internationally acceptable level. A group of experts in the MENA region reviewed the literature and collaborated to assess the current status of palliative care and recommend modifications to the NCCN Guidelines based on the unique needs of the region. (JNCCN 2010;8[Suppl 3]:S41–S47)

SAn initiative was launched to adapt several of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to the Middle East and North Africa (MENA) region. Palliative care was one area of cancer treatment selected because of its high level of importance. To better understand how to adapt the From the Department of Oncology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia. The authors have disclosed that they have no financial interests, arrangements, or afiliations with the manufacturers of any products discussed in the article or their competitors. Correspondence: Omar Shamieh, MD, Department of Oncology, King Saud bin Abdulaziz University for Health Sciences, Mail Code 1777, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. E-mail: [email protected]

NCCN Guidelines on Palliative Care in this region, the current status of palliative care had to be assessed. This article addresses the practice of palliative care in the MENA region.

Population and Religion In our review, we evaluated 19 Arab countries of the MENA region, with 12 of these in Asia (Saudi Arabia, Kuwait, Qatar, United Arab Emirates, Bahrain, Oman, Yemen, Iraq, Palestinian Authorities, Jordan, Syria, and Lebanon) and the remainder in Northern Africa (Egypt, Sudan, Libya, Morocco, Tunisia, Algeria, and Djibouti).1,2 The total population of the MENA region exceeds 326 million (Table 1), with Arabic the official and most common language. The predominant religion is Islam, although other religions exist for the native population or expatriates. These countries have a wide heterogeneity of culture, religious practices and adherence, and social issues. Palliative care principles are aligned and applicable to all religions and faiths.3 Although palliative care concepts and practice are more accepted by health care professionals, patients, and families, than in the past, families may tend to withhold, and persuade health care providers to withhold, information from patients, even at end of life. Furthermore, resistance to opioid use by individuals and providers in this region is usually a result of misconceptions and attitude, in addition to religious misinterpretation.4

Economy and Health Care Finance The economic classifications of these countries vary widely, ranging from those that are wealthy to those

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-42

Supplement

Shamieh and Jazieh

Table 1 Cancer Mortality and Opioid Consumption in the Middle East and North Africa Countries Country

Population19

Mortality From Cancer5 (Estimated Cause of Death 2005)

Opioid Consumption 2007 (kg)12

Algeria

33.4 M

19,000

2

Bahrain

0.7 M

370

1

Djibouti

0.5 M

460

NA

Egypt

83 M

42,000

9

Iraq

27.5 M

15,000

NA

Jordan

6M

3700

11

Kuwait

2.5 M

700

11

Lebanon

4M

2600

4

Libya

6M

2700

NA

Morocco

33 M

13,000

9

Oman

3.2 M

1200

2

Palestinian Authority

4M

NA

NA

Qatar

0.9 M

160

1

Saudi Arabia

27.6

12,000

13

Sudan

39 M

22,000

NA

Syria

19 M

5000

NA

Tunisia

10.1 M

6000

20

United Arab Emirates

4.4 M

1200

2

Yemen

22 M

10,000

NA

TOTAL

326.8 M

157,090*

85

Abbreviation: NA, not available. *Cancer mortality exceeds 200,000 accounting for all MENA countries.

with very limited resources. Household incomes, health care expenditure, and human development also vary widely. People tend to migrate from rural to urban areas, increasing the isolation of the rural areas and placing more governmental focus on large cities, resulting in an underserved rural population.3 Health care systems in many countries havelimited resources and low expenditures. The government may provide most cancer care, either partly or fully, to a portion of the population based on available resources and services; however, many countries may not have access to all treatment modalities. In view of this fact and other constraints, many patients are unable to access the system or afford treatment.3 Private cancer care is provided on an out-ofpocket basis rather than through organized insurance, and most countries do not a have a national cancer control program.

Family Model An obvious shift is occurring from the traditional extended family model to a more nuclear, mobile, and isolated family structure. Families and individuals tend to rely more and more on the health care system and hospitals for the care of sick loved ones. This shift has resulted in overuse of health care resources, emergency visits, and in-patient beds for chronic and palliative care needs.3

Cancer Epidemiology Despite the advancement in medical technology and innovative therapeutics and pharmaceutical products, a huge increase in cancer incidence has occurred not only in the MENA region but also worldwide. Cancer ranges from the third to the fifth leading cause of death.5 In 2005, approximately 200,000 cancer deaths occurred in MENA countries, with approximately 60% of deaths in individuals younger

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Palliative Care

than 70 years (Table 1).5 Cancer incidence is underreported in most of these countries, either because of the lack of cancer registries or the absence of effective data collection.

Traditional Cancer Care Model The traditional cancer care model in MENA countries almost follows an older cancer care model, which is marked by delayed patient presentation as a result of late detection, poor access, and late referrals, followed by an active anticancer treatment approach at diagnosis, ending with death or cessation of anticancer therapy. Less attention is paid to pain and symptom management, and poor end-of-life care is available, if at all. Except for a few centers mentioned later, no hospice palliative care model exists in most of these countries. Even in countries in which palliative care service is available, patients tend to be referred to palliative care late in the trajectory of their illness.

Need for Palliative Care The needs of patients with cancer in the MENA region does not differ greatly from those of patients in the rest of the world. Patients diagnosed with cancer have multiple domains of suffering, including physical, social, spiritual, practical, and psychological, as a result of multiple levels of interactions with the disease itself, or with relatives, care providers, health care systems, and the community. Palliative care should start from cancer diagnosis for all patients, regardless of the type or stage, and continue through the cancer journey for both survivors and advanced cases to end-of-life care. Palliative care should be delivered simultaneously with disease-modifying treatment. The need for palliative care increases as the disease progresses, until it is the only focus of care.6 More than 80% of cancer cases are advanced at presentation, making palliative care the only option for patients and highlighting the importance of making palliative care services available for those patients and their families.6 Using the WHO formula6 and multiplying cancer mortality (Table 1)5 by the percentage of advanced cases provides an approximate number of patients in the MENA region needing palliative

care before they die in the given year, which was 160,000 for 2005 (200,000 x 0.8 = 160,000). Similarly, assuming one caregiver is needed per patient with advanced cancer, the number of caregivers can be estimated (> 160,000 in 2005).6

WHO Definition of Palliative Care The WHO defines palliative care7 by noting that palliative care improves quality of life of patients and families facing a life-threatening illness by preventing and relieving suffering through early identification, assessment, and treatment of pain and other physical, psychosocial, and spiritual problems. Palliative care: • Provides relief from pain and other distressing symptoms; • Affirms life and considers dying a normal process; • Intends neither to hasten nor postpone death; • Integrates the psychological and spiritual aspects of patient care; • Offers a support system to help patients live as actively as possible until death; • Offers a support system to help the patient’s family cope during the illness and through bereavement; • Uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated; • Will enhance quality of life and may also positively influence the course of illness; and • Is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes investigations needed to better understand and manage distressing clinical complications.

Current Palliative Care Services Palliative care provision and development varies widely among countries. Based on a pilot study report from the International Observatory on End of Life Care, countries were divided into 4 categories based on the level of hospice and palliative care development. Countries in the first level, or category 1, have no available services for palliative care. Those in the second level, or category 2, are in the capacity-building stage, in which the need for palliative care is recognized and some awareness courses are

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-43

S-44

Supplement

Shamieh and Jazieh

available. Countries in the third category, or level 3, have a local provision, with one or more palliative care programs established. Those in the fourth category, or level 4, have palliative care fully integrated into the health care system.8 None of the MENA countries approached integration. Although some cancer centers in a few countries have succeeded in integrating palliative care into their existing institutions, the program is not developed in the entire country. An increasing number of countries are establishing a localized provision of palliative care, including Egypt, Iraq, Jordan, Morocco, Saudi Arabia, and United Arab Emirates.9 At the time of this report, Qatar, Tunisia, Sudan, and Kuwait started or are starting to implement palliative care services. Countries that have begun implementing various palliative capacity-building activities but have no formal services available are Algeria, Bahrain, Lebanon, Oman, and Palestinian Authority.9 Djibouti, Libya, and Syria have no known palliative care activities. Few countries are privileged to have well-established centers of excellence for comprehensive cancer care, such as the Kingdom of Saudi Arabia.10 Most palliative care services in these countries deliver excellent care to a certain portion of population, but do not offer wider coverage. In addition, palliative care is still not included in the cancer control plan or any national health care policy.

Table 2 Barriers to Palliative Care Provisions in Middle East and North Africa Region Health care professionals

• Negative attitude to caring for the dying patients • Fear of opioids use because of absence of or inadequate training, !!Fear of side effects !!Fear of prosecution • Resources focused on cure and acute care • Perceived sense of failure

Patients and families

• Fear of addiction • Fear of abandoning • Unrealistic hope • Diversity in religious interpretation

Health care system

• Acute care focus dictates the allocation of resources to acute care rather than palliative care • Lack of space and resources for palliative care • Less priority of palliative and end-of-life care in the health care strategy • Scarce long-term and community services

Manpower

• Lack of palliative care expert physicians, nurses, medical social workers, and medical religious advisors • Lack of interdisciplinary teams

Drugs

• Lack of opioids • Very strict opioid prescriptions and dispensing policies • Unavailability of opioids in peripheral centers • Lack of essential medications

Barriers to Palliative Care Provision

Education

Many barriers exist to the availability, access, and provision of palliative care, such as those summarized in Table 2.

• Lack of palliative care education programs and curriculum at all levels of education

Funding

• No funds for education, building programs, or hiring experts

Policy

• Lack of national policies, including those regarding palliative care

Opioid Availability

Pain is underreported and undertreated in most of the world.6 Morphine consumption has been used by the WHO to measure pain control and, ultimately, provision of palliative care.3 According to the International Narcotics Controlling Board report in 2007, the total estimated reported morphine consumption is 84 kg for all MENA countries.11,12 Opioid availability varies across the region. Highest consumption has been reported in Tunisia based on the absolute quantity, total population, and total reported cancer mortality. Barriers to pain control are almost universal, and

include fear of opioids, unavailability of medications, poor access to medication, lack of education, and fear of addiction.13 The amount of morphine needed can be predicted through calculating the estimated need of oral morphine for each patient who died of cancer. Assuming that each patient will require 100 mg/d of oral morphine in the last 3 months of life, an estimated 10 g of oral morphine will be needed per patient. Then, in multiplying this number by the esti-

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Palliative Care

mated number of patients who died of cancer (Table 1; 200,000),14 the predicted need of oral morphine required to control pain in those patients is determined to be approximately 2000 kg. This number is less than 5% of the reported consumption of less than 100 kg. Notably, this estimation does not take into account the other needs for opioids to control pain in cancer survivors, such as non–cancer-related or postoperative pain, further illustrating the huge gap existing between the actual need and the current consumption. One major factor contributing to opioid underuse in the MENA countries is that they are not available. However, simply making opioids available will not solve the problem; a simultaneous and effective educational program is needed for health care workers, patients, families, communities, religious workers, government, and leaders, along with sufficient manpower to develop palliative care initiatives. Another important factor contributing to inadequate pain control is the existence of rigid and strict opioid or narcotic policies (Table 2), which are implemented as a result of fear regarding abuse and misuse. These policies must be revised and made flexible to allow sufficient supply and effective pain control, while at the same time maintaining accountability.11 Years ago, WHO advocated establishing recommendations and guidelines to improve cancer pain control. The recommended strategy is summarized in the following steps:15 • The country should make cancer pain relief a high priority in the form of health care policy. • An educational program should target officials, policy makers, and regulators to increase awareness of the possibility and importance of managing cancer pain. • An educational program should be established to train health care providers to treat cancer pain. • Analgesics, including opioids, should be made available. Education

Palliative care educational opportunities are scarce in MENA countries. Formal palliative care education is minimal. Most palliative care expertise is gained through education in countries with more advanced palliative care programs, such as North America and Europe. An increasing number of sen-

sitization courses are occurring in the MENA countries, such as in Jordan, Egypt, and Saudi Arabia.9 More formal palliative care training in the form of advanced fellowships and well-developed palliative care curricula in medical schools do exist in countries like Saudi Arabia; however, other countries have no educational provision at all. Palliative care education is an integral part of establishing an effective palliative care program. The level of educational needs varies among specialty institutions and communities. Basic palliative care knowledge is essential to all health care providers, regardless of specialty, service, or settings.14 More advanced skills and expert training will be needed for services, with the highest demand in disciplines such as oncology, intensive care, and infectious diseases to ensure implementation of best palliative care practices.14 A palliative care curriculum should be incorporated into undergraduate nursing and medical school education, residency training programs, and highdemanding fellowships such as oncology. Funding

The field of palliative care seems to be a great opportunity for countries with limited resources to provide care for patients while developing the other components of a comprehensive cancer control program, ranging from prevention and early detection to optimal treatment.16 Palliative care should be delivered in a cost-effective manner and can be provided in less-served cities and communities in all countries, not just those with limited resources. However, funding for palliative care is challenging for many reasons, including underrecognition of the importance of this field, resulting in inadequate resource allocation and government support. Existing and evolving programs in countries with limited resources must identify sources of financial support. Establishing a national policy for palliative care might allow governments to take some responsibility for funding. Countries with a disadvantaged financial and economic situation may seek support and funding from community resources, nongovernmental entities, local philanthropist associations, or international organizations, such as the International Association for Hospice and Palliative Care.16

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-45

S-46

Supplement

Shamieh and Jazieh

Recommendations to Improve Palliative Care in MENA Countries Every country should aim to integrate pain relief and palliative care into the mainstream of health care. Pain relief and palliative care should be available to all populations, although this article only focuses on those with cancer. However, palliative care can benefit all patients with advanced illness, including those with HIV, dementia, and organ failure.17 Furthermore, palliative care should be available to patients everywhere, not only those in major cities or tertiary cancer centers. Access to these services should be available to peripheral cities and disadvantaged communities. Initiatives to improve palliative care should include policy development, program implementation, opioid availability, and education.14 Palliative care education should be available to all health care providers, medical and nursing schools, and training programs. The most effective strategy for implementing a palliative care program is a public health initiative that incorporates all levels of the health care system, government leadership, and the community. This approach should benefit not only patients and families but also society as a whole.14

NCCN Guidelines for Palliative Care and Cancer Pain Management The successful implementation of NCCN palliative care and cancer pain management guidelines depends on acceptance of the following principles: • Palliative care is an integral part of effective and comprehensive cancer care. • Palliative care should be introduced as early as the time of diagnosis. • All health care providers, health care leaders, pharmaceutical leaders, government leaders, and religious scholars dealing with patients with cancer must be aware of the importance of palliative care. • Basic palliative care education is needed for all oncologists and cancer care providers at all levels of care, including inpatient, outpatient, and extended care facilities in both private and public sectors.18 • Opioids and essential drugs must be available to manage pain and distressing symptoms. • Cancer and palliative care should be delivered

using an interdisciplinary approach; treatment programs should involve effective multidisciplinary teams to deliver the most comprehensive care.18 Adapting the NCCN guidelines to the MENA region may trigger a systemic evaluation of the status and needs regarding palliative care so that the highest possible standards of care can be implemented.

References 1. League of Arab States. Member Countries. Available at: http:// www.arableagueonline.org/las/index.jsp. Accessed March 31, 2010. 2. UNICEF. Middle East and North Africa. Available at: http://www. unicef.org/infobycountry/northafrica.html. Accessed March 31, 2010. 3. De Lima L, Hamzah E. Socioeconomic, cultural and political issues in palliative care. In: Bruera E, De Lima L, Wenk R, Farr W, eds. Palliative Care in the Developing World: Principles and Practice. Houston: IAHPC Press; 2004:23–38. 4. Al-Shahri M, al-Khanizan A. Palliative care for Muslim patients. J Support Oncol 2005;3:432–436. 5. World Health Organization. WHO Global InfoBase: Data for saving lives. Available at: https://apps.who.int/infobase/report. aspx?rid=126. Accessed March 31, 2010. 6. Cancer Control: Knowledge Into Action: WHO Guide for Effective Programmes: Palliative Care. Available at: http://www.who.int/ cancer/media/FINAL-PalliativeCareModule.pdf. Accessed March 31, 2010. 7. World Health Organization. WHO Definition of Palliative Care. Available at: http://www.who.int/cancer/palliative/definition/en. Accessed March 31, 2010. 8. Wright M, Wood J, Lynch T, Clark D. Mapping levels of palliative care development: a global view. J Pain Symptom Manage 2008;35:469–485. 9. Shamieh O. Building Capacity for Palliative Care at King Abdulaziz Medical City, Riyadh, Saudi Arabia [International Association for Hospice & Palliative Care Web site]. Available at: http://www. hospicecare.com/news/09/03/regional_reports_saudi_arabia_asia. html. Accessed March 31, 2010. 10. Stjernswärd J, Ferris FD, Khleif SN, et al. Jordan palliative care initiative: a WHO Demonstration Project. J Pain Symptom Manage 2007;33:628–633. 11. International Narcotics Control Board. Report of the International Narcotics Control Board for 2008. Available at: http://www.incb. org/pdf/annual-report/2008/en/AR_08_English.pdf. Accessed March 31, 2010. 12. Table XII. Consumption of principal narcotic drugs, 2003–2007, INCB statistical tables Available at: http://www.incb.org/incb/en/ narcotic_drugs_stat_tables.html. Accessed March 31, 2010. 13. Isbister WH, Bonifant J. Implementation of the World Health Organization ‘analgesic ladder’ in Saudi Arabia. Palliat Med 2001;15:135–140. 14. Stjernswärd J, Foley KM, Ferris FD. The public health strategy for palliative care. J Pain Symptom Manage 2007;33:486–493. 15. Joranson D. Availability of Opioids for cancer pain: recent trends, assessment of system barriers. New World Health Organization

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

Supplement

Palliative Care guidelines and the risk of diversion. J Pain Symptom Manage 1993;8:353–360.

hrsa.gov/publications/palliative/palliative_care-who_approach. htm. Accessed March 31, 2010.

16. Callaway M, Foley K, De Lima L, et al. Funding for palliative care programs in developing countries. J Pain Symptom Manage 2007;33:509–513.

18. Ferris F, Bruera E, Cherny N, et al. Palliative cancer care a decade later: accomplishments, the need, next steps—from the American Society of Clinical Oncology. J Clin Oncol 2009;27:3052–3058.

17. Sepulveda C. Palliative care in resource-constrained settings for people living with HIV and other life threatening illnesses: the World Health Organization approach. Available at: http://hab.

19. The World Factbook. Washington, DC: CIA, 2009. Available from at: https://www.cia.gov/library/publications/the-world factbook/ region/region_mde.html. Accessed August 2009.

© Journal of the National Comprehensive Cancer Network  |  Volume 8 Supplement 3  |  July 2010

S-47