Contents I
MEDICAL RADIOLOGY Radiation Oncology
Editors:
L. W. Brady, Philadelphia H.-P. Heilmann, Hamburg M. Molls, Munich
Contents III
J. M. Brown · M. P. Mehta · C. Nieder (Eds.)
Multimodal Concepts for Integration
of Cytotoxic Drugs
With Contributions by
G-One Ahn · K. K. Ang · N. H. Andratschke · M. Bastasch · C. Belka · J. Bourhis · J. M. Brown B. L. D. M. Brücher · T. A. Buchholz · S. Choi · H. Choy · C. H. Crane · W. Dörr · J. Dunst D. B. Evans · J. Fleckenstein · A. Fyles · H. Geinitz · M. R. Gilbert · D. E. Hallahan · Z. Han P. M. Harari · H. Harada · G. Hariri · M. Hiraoka · D. Khuntia · G. Lammering · Z. Liao F. Lordick · K. A. Mason · L. Milas · M. Milosevic · M. P. Mehta · M. Molls · C. Nieder A. Oza · P. W. T. Pisters · D. Riesenbeck · C. Rödel · C. Rübe · J. N. Sarkaria · R. Sauer K. Shibuya · H. D. Thames · A. M. Traynor · G. Varadhachary · R. A. Wolff · A. Zietman F. Zimmermann
Series Editor’s Foreword by
L.W.Brady · H.-P. Heilmann · M. Molls
With 73 Figures in 83 Separate Illustrations, 12 in Color and 73 Tables
123
IV Contents
J. Martin Brown,PhD
Division of Radiation and Cancer Biology Department of Radiation Oncology Stanford School of Medicine 269 Campus Drive
Center for Clinical Science and Research, Rm 1255 Stanford, CA 94305-5152
USA
Minesh P. Mehta, MD Department of Human Oncology
University of Wisconsin Hospital Medical School 600 Highland Ave., K4 312-3684
Madison, WI 53792 USA
Carsten Nieder, MD
Department of Radiation Oncology Klinikum rechts der Isar der Technischen Universität München Ismaninger Strasse 22
81675 München Germany
Medical Radiology · Diagnostic Imaging and Radiation Oncology
Series Editors: A. L. Baert · L. W. Brady · H.-P. Heilmann · M. Molls · K. Sartor Continuation of Handbuch der medizinischen Radiologie
Encyclopedia of Medical Radiology
Library of Congress Control Number: 2005939063
ISBN-10 3-540-25655-5 Springer Berlin Heidelberg New York ISBN-13 978-3-540-25655-7 Springer Berlin Heidelberg New York
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi - cally the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.
Springer is part of Springer Science+Business Media http//www.springer.com
¤ Springer-Verlag Berlin Heidelberg 2006 Printed in Germany
The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every case the user must check such information by consulting the relevant literature.
Medical Editor: Dr. Ute Heilmann, Heidelberg Desk Editor: Ursula N. Davis, Heidelberg Production Editor: Kurt Teichmann, Mauer
Cover-Design and Typesetting: Verlagsservice Teichmann, Mauer Printed on acid-free paper – 21/3151xq – 5 4 3 2 1 0
Contents V
For decades the combination of radiation therapy and chemotherapy have played an increasingly important role in cancer treatment. Progress has been made, but a variety of concepts have failed to achieve the success sought. Basic to the use of combined integrated multimodality treatment is an understanding of the theoretical background of radiation, drugs and, most importantly, the interaction between the two regimens. Even though there are numerous publications on the topic, this volume – Multimodal Concepts for Integration of Cytotoxic Drugs and Radiation Therapy – makes an important niche for itself in clinical management. In the preclinical part of the volume, the necessary background of radiation biology as the basis for combined treatment is given with special reference to specific drugs and delivery techniques. The clinical part summarizes the knowledge to date of successful combined modality treatment for primary brain tumors, brain metastases, head and neck cancers, gastric cancers, lung cancers, breast cancers, anal and rectal tumors, bladder can- cers as well as gynecologic malignancies. Acute and late toxicity is discussed as are special problems related to treating the elderly and patients with co-morbidity. Every oncologist doing combined modality treatment will find this a valuable source of information.
Philadelphia Luther W. Brady
Hamburg Hans-Peter Heilmann
Munich Michael Molls
Foreword
Contents VII
Preface
Over the last century, the curative potential of radiation therapy for solid tumors has increased. Despite these advances there are major challenges to further improvements that result from the complexities of human tumors that are often not simulated in preclinical models.
In clinical practice normal tissue tolerance remains the most important limitation to adequate tumor dose delivery. Doses resulting in high tumor control probability will often cause unacceptable toxicity, a problem related to the width of the therapeutic window.
Major avenues of progress in overcoming this limitation in the last decades have included the introduction of altered fractionation regimens, and technical advances resulting in better target visualization and more conformal dose distribution with steeper dose gra- dients. Illustrative examples of such technologies include stereotactic radiotherapy (and radiosurgery), intensity-modulated treatment, helical tomotherapy, and image-guided radiotherapy. In addition, there is a major new interest in the refinement and evaluation of particle beam therapy.
Another way of achieving better tumor control rates, both within the target volume and potentially also at microscopic distant sites, is by combining ionizing radiation with cytotoxic chemotherapy. Besides simple additive cell kill without added local toxicity and spatial cooperation, several other mechanisms can lead to increased efficacy. These mecha- nisms depend on drug type and concentration, drug target, metabolism, timing of admin- istration, microenvironmental and genetic factors, etc. The principles of such combined modality approaches have been defined in appropriate models and successfully transferred through translational research into clinical practice. In several common solid tumor types, landmark clinical studies have clearly demonstrated the benefit of combined modality treatment. The number of patients undergoing such treatment has been increasing steadily for the last two decades.
Clinical optimization of combination regimens is ongoing but with tremendous chal- lenges, related to the development and incorporation of new compounds, especially the so-called “molecularly targeted” agents that interfere with important signal transduction pathways, angiogenesis, tumor microenvironment, etc. The challenge can be illustrated very well by modeling glioblastoma multiforme as an example; three common pathways are believed to confer a proliferative advantage and resistance to apoptotic death in this disease, including dramatic oversecretion of VEGF which drives angiogenesis, EGFR over- expression/activation which drives proliferation, and PTEN deletions, which drive anti- apoptotic properties. Over 40 targeted drugs now exist to block these pathways at one or more points, and if selected for combination with radiotherapy in various permutations and combinations, over 4000 possible therapeutic regimens could be developed for testing purposes. This clearly poses an enormous challenge in terms of understanding the biology, and conducting well thought out research.
VIII Contents
Every clinician and researcher involved in development and optimization of innova- tive combined modality approaches, or in treating patients will find valuable information about the principles of such treatment and the effects of the various compounds in this volume. The comprehensive clinical chapters focus on results of recent studies and provide data pertinent to everyday practice with regard to dosing, toxicities and supportive care.
Special emphasis is also placed on treatment of elderly patients, given the demographics in most developed countries. In the future, combined modality treatment will undergo fur- ther substantial refinement, and will continue to play an important role in the treatment of solid tumors. Such refinement includes better response evaluation and prediction and better tailoring of regimens to an individual patient.
Stanford J. Martin Brown
Madison Minesh P. Mehta
Munich Carsten Nieder
Contents IX
Preclinical Part. . . 1
1 Biological Basis of Combined Radio- and Chemotherapy
Claus Belka, Carsten Nieder and Michael Molls . . . 3 2 Combinations of Antimetabolites and Ionizing Radiation
Hiroshi Harada, Keiko Shibuya, and Masahiro Hiraoka. . . 19 3 Combinations of Taxanes and Ionizing Radiation
Luka Milas, Kathryn A. Mason, Zhongxing Liao and Kian K. Ang . . . 35 4 Combinations of Topoisomerase Inhibitors and Ionizing Radiation . . . 53
Michael Bastasch and Hak Choy
5 Combinations of Hypoxia-Targeting Compounds and Radiation-Activated Prodrugs with Ionizing Radiation
G-One Ahn and J. Martin Brown . . . 67 6 Combinations of Platinum Compounds and Ionizing Radiation
Carsten Nieder and Florian Lordick . . . 93 7 Combinations of Cytotoxic Drugs, Ionizing Radiation and
Angiogenesis Inhibitors
Carsten Nieder and Nicolaus H. Andratschke . . . 103 8 Combinations of Cytotoxic Drugs, Ionizing Radiation and EGFR Inhibitors
Guido Lammering . . . 115 9 Combinations of Cytotoxic Drugs, Ionizing Radiation and
Mammalian Target of Rapamycin (mTOR) Inhibitors
Jann N. Sarkaria . . . 127 10 Combinations of Ionizing Radiation and Other Sensitizing Agents
Minesh P. Mehta . . . 139 11 Radiotherapy and Tumor-Targeted Drug Delivery
Zhaozhong Han, Ghazal Hariri and Dennis E. Hallahan. . . 151
Contents
X Contents
Clinical Part . . . 163
12 Applications in Malignant Brain Tumors
Carsten Nieder and Mark R. Gilbert . . . 165 13 Applications in Head and Neck Cancer
Deepak Khuntia, Anne M. Traynor, Paul M. Harari and Jean Bourhis . . . 187 14 Applications in Esophageal and Gastric Cancer
Frank Zimmermann and Björn L. D. M. Brücher . . . 197 15 Novel Chemoradiation in Localized Pancreatic Cancer: Clinical Studies
Christopher H. Crane, Gauri Varadhachary, Peter W. T. Pisters,
Douglas B. Evans, and Robert A. Wolff . . . 215 16 Applications in Lung Cancer
Jochen Fleckenstein and Christian Rübe . . . 231 17 Integration of Radiation Therapy and Systemic Therapy for Breast Cancer
Seungtaek Choi, Howard D. Thames, and Thomas A. Buchholz. . . 251 18 Applications in Rectal and Anal Cancer
Claus Rödel and Rolf Sauer. . . 267 19 Concomitant Radiation and Chemotherapy in Muscle-Invasive Bladder Cancer
Jürgen Dunst, Claus Rödel, and Anthony Zietman. . . 285 20 Applications to Gynecological Cancers
Anthony W. Fyles, Michael Milosevic and Amit Oza. . . 303 21 Early and Late Treatment-Induced Toxicity
Wolfgang Dörr, Dorothea Riesenbeck, and Carsten Nieder . . . 317 22 Feasibility of Combined Chemo- and Radiation Treatment in
Elderly/Comorbid Patients
Hans Geinitz . . . 333 Subject Index . . . 341 List of Contributors . . . 345
