Table Of ContentAntiturnor
Drug-Radiation
Interactions
Editors
Bridget T. Hill, Ph.D., F.R.S.C., F.I. Biol.
Head
Laboratory of Cellular Chemotherapy
Imperial Cancer Research Fund Laboratories
London, England
Angela S. Bellamy, Ph.D.
Department of Neurochemistry
Institute of Neurology
London, England
Boca Raton London New York
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Library of Congress Cataloging-in-Publication Data
Antitumor drug-radiation interactions.
Includes bibliographies and index.
ISBN 0-8493-4620-7
1. Cancer--Adjuvant therapy. 2. Cancer--Chemotherapy. 3. Cancer--Radiotherapy. 4. Antineoplastic
agents.
I. Hill, Bridget T. II. Bellamy, Angela S.
[DNLM: 1. Combined Modality Therapy. 2. Neoplasms--drug therapy. 3. Neoplasms--radiotherapy.
QZ266 A6293]
C271.A35A57 1990 616.99’406 89-9850
A Library of Congress record exists under LC control number: 89009850
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contact.
ISBN 13: 978-1-315-89061-6 (hbk)
ISBN 13: 978-1-351-06971-7 (ebk)
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CRC Press Web site at http://www.crcpress.com
This book is a timely reminder of the continuing potential of chemotherapy and radio-
therapy to improve the prognosis of many different cancers. However optimistic we may
be about the clinical application of recent advances in basic sciences, such as molecular
biology, these studies have yet to be translated into significant clinical benefit. It remains
a fact that most of the progress in the control and treatment of cancer has been made by the
more intelligent use of therapeutic methods that have been available for some time. Certain
laboratory studies using tissue culture techniques have, however, led to real improvements
in the treatment of human cancer. Thus, the direct application of certain principles of stem
cell kinetics derived from animal models to clinical cancer chemotherapy enables intensive
drug treatment to be given to patients with far fewer side effects than in the past and also
enables it to be integrated more safely in combined treatment with radiation therapy. These
tissue culture studies also formed the experimental rationale for the development of very
high dose methotrexate therapy now extensively used, for example, in the improved treatment
of osteogenic sarcoma. It is encouraging to note in a number of the chapters that clinical
trials have been set up based on certain data derived from laboratory studies, e.g., the
improved therapeutic results that can be achieved combining 5-fluorouracil and radiation
therapy in a more logical manner. It seems probable that many past therapeutic protocols
using combined chemotherapy and radiation may not have used these modalities optimally
and that different strategies of sequencing and doses may be appropriate for different tumors.
Certainly the received dose intensity of some past chemotherapy protocols has been too low,
largely because of an exaggerated fear of side effects, most of which can be prevented.
Suboptimal therapy produces suboptimal results and we should not allow the fact that
inadequate therapy has been given in the past to prevent us from attempting adequate therapy
in the future.
The work described herein is encouraging and important. It shows that fixed opinions
about the roles of chemotherapy and radiation in the treatment of malignant diseases are
premature and that the use of these modalities more judiciously combined may well continue
to improve the treatment of certain cancers in the future as they have in the past. It may
well be that such an approach will result in further increases in cure rates and include some
cancers in which only temporary responses are being achieved at present. As Howard Skipper
has said, "We cannot afford to sit and wait for the promise of tomorrow so long as stepwise
progress can be made with tools at hand today." This book contains a wealth of information
which will be of value to all those concerned with the treatment of cancer in the immediate
future.
L. A. Price
United Kingdom Representative
Scientific Council
New York Chemotherapy Foundation
PREFACE
Surgery, with or without radiotherapy, is still generally considered as the standard
primary therapy for many advanced common "solid" tumors. While these local therapies
have undoubtedly cured a proportion of these patients, their efficacies have rarely been
established by randornized, controlled clinical trials. Furthermore, in spite of such local
therapy, the majority of patients presenting with advanced tumors continue to die with
systemic disease. The potential contribution of chemotherapy toward increasing the overall
cure rate has, of course, been appreciated since the early 1960s. Unfortunately, many studies
aimed at determining its effectiveness in combination with local treatments have employed
inadequate or compromised drug scheduling. This was based on the mistaken belief that the
combined modality approach would automatically result in unacceptable enhanced normal
tissue toxicities, and the firm conviction that no modifications in the surgical procedure or
radiotherapy planning could be entertained. We should, therefore, not be too disappointed
that results of these initial studies frequently failed to provide clear evidence of advantage
for this combined modality approach. Gradually, however, the critical importance of drug
concentrations and scheduling has been appreciated, fist in experimental laboratory studies
and now in clinical practice. We are thus no longer surprised when inadequate chemotherapy,
used either as a single modality or in combination with local therapies, yields inadequate
results.
Effective combinations of antitumor drugs and radiation offer the possibility not only
of increasing the cure rate, but also of leading to less mutilating surgery and hence an
improved quality of life. We consider that data from experimental laboratory studies can
provide leads for improving clinical treatment programmes. In 1984 we published two major
review articles describing antitumor drug-radiation interactions and since then there has been
considerable research into this topic. Therefore, in this volume we have asked a number of
investigators to review the interactions between clinically effective antitumor drugs and
radiation. The aims were to highlight the most effective laboratory-based schedules for
achieving definite therapeutic benefit, to discuss the mechanisms of interactions, and to
summarize clinical evaluations of these combinations.
After reviewing the chapters in this volume it is particularly encouraging to realize that
detailed mechanistic studies are already underway for most of the combinations, and in spite
of the initial disappointing clinical data, encouraging results are now available from large
randomized studies in breast cancer, anal cancer, and certain head and neck tumors. This
has provided the impetus for carefully designed clinical trials in other selected tumor types.
In addition, consideration is now being given to the possibility of including other agents in
the combinations, e.g., certain hormonal agents, interferons, differentiating-inducinga gents,
and even drug-targeted monoclonal antibodies. It therefore appears that continued evaluations
at the cellular, molecular, and clinical levels may provide further leads as to how future
therapies may be more effectively optimized.
Bridget T. Hill
Angela S. Bellamy
Bridget T. Hill, Ph.D., is Head of the Cellular Chemotherapy Laboratory at the Imperial
Cancer Research Fund Laboratories in London, England and is an Honorary Senior Lecturer
at the Institute of Urology, University College and Middlesex School of Medicine of Uni-
versity College London.
Dr. Hill obtained a First Class Joint Honours degree in Chemistry and Zoology in 1965
and a Ph.D. in Biochemistry in 1968 from the University of London. She was made a Fellow
of the Royal Society of Chemistry in 1975 and a Fellow of the Institute of Biology in 1979.
She is also a member of both the American and the British Associations for Cancer Research,
the American Society of Clinical Oncology, the European Cell Culture Society, the Bio-
chemical Society, and the EORTC Clonogenic Assay Screening Group.
Dr. Hill's postgraduate studies in the area of cancer chemotherapy were carried out
initially at the Chester Beatty Research Institute in London, England and then, as a recipient
of a Ludwig Travel Award, first in Dr. Renato Baserga's Department at Temple University
Medical School in Philadelphia, and subsequently in Dr. J. H. Goldie's Laboratory at St.
Michael's Hospital and the University of Toronto. On her return to England in 1974, Dr.
Hill joined the staff of the Imperial Cancer Research Fund and in 1977 was appointed to
her present position as Head of the Cellular Chemotherapy Laboratory.
Dr. Hill's main research interests have centered on aspects of cell proliferation and cell
cycle kinetics, as they relate to the design of safer and more effective clinical cancer
chemotherapy programs and, more recently, on antitumor drug resistance and drug-radiation
interactions. She is the author of over 200 articles on these and related topics.
Angela S. Bellamy ,M . A.(Cantab.), Ph.D., is now the Product Development Manager
for Gower Medical Publishing, London, England.
Dr. Bellamy obtained an Honours degree in Natural Sciences, specializing in pharma-
cology, from the University of Cambridge in 1979, and received her Ph.D. in biochemistry
from the University of London in 1982. She camed out her postgraduate research at the
Imperial Cancer Research Fund Laboratories in London from 1979 to 1982. These studies
indicated favorable in vitro interactions between X-irradiation and certain antitumor drugs
in human tumor cell lines. This work provided useful background and specific data for an
ongoing clinical trial at the Royal Marsden Hospital in London, in which combination
chemotherapy was administered before radiotherapy in the management of advanced head
and neck cancer.
For her postdoctoral studies Dr. Bellamy joined the Department of Neurochemistry at
the Institute of Neurology in London in 1982, investigating the neuroimrnunology of multiple
sclerosis. During a sabbatical period in Hong Kong from 1985 to 1987 she worked as a
medical writer for a publishing company, and was the scientific adviser to a media campaign
in Southeast Asia to increase the coverage of hepatitis B vaccination.
ACKNOWLEDGMENTS
Many of the ideas and concepts discussed in the overview chapters have resulted from
discussions and correspondence with a number of investigators, to whom we would like to
express our appreciation: Dr. L. A. Price, London, U. K.; Dr. J. H. Goldie, Vancouver,
Canada; Dr. V. Ling, Toronto, Canada; Dr. H. E. Skipper, Birmingham, AL, U.S.; and
Dr. W. B. Looney, Charlottesville, VA, U.S.
We would as well like to thank Miss Gwyneth Jones for her skilled secretarial assistance
in preparation of this volume and acknowledge the support of the Imperial Cancer Research
Fund in this venture.
CONTRIBUTORS
Harry Bartelink, Ph.D. Cai Grau, M.D.
Department of Radiotherapy Research Associate
Netherlands Cancer Institute Department of Experimental Clinical
Amsterdam, Netherlands Oncology
Danish Cancer Society
Adrian C. Begg, Ph.D. Aarhus, Denmark
Senior Research Scientist
Department of Experimental Therapy Bridget T. Hill, Ph.D.
Netherlands Cancer Institute Head
Amsterdam. Netherlands Department of Cellular Chomotherapy
ICRF Laboratories
Angela S. Bellamy, Ph.D. London, England
Department of Neurochemistry
Institute of Neurology
London, England Harold A. Hopkins, Ph.D.
Associate Research Professor
James A. Belli, M.D. Division of Radiobiology and Biophysics
Professor and Chairman University of Virginia Health Sciences
Department of Radiation Therapy Center
The University of Texas Medical Branch Charlottesville, Virginia
Galveston, Texas
Wiliam B. Looney, M.D., Ph.D.
John E. Byfield, M.D., Ph.D.
Professor and Director
Associate Director
Division of Radiobiology and Biophysics
Kern Regional Cancer Center
University of Virginia Health Sciences
Bakersfield, California
Center
Charlottesville, Virginia
W. De Neve, M.D.
Resident
Department of Radiotherapy Marc M. Mareel, M.D.
Vrye University of Brussels Professor
Brussels, Belgium Department of Radiotherapy and Nuclear
Medicine
Luc Dewit, Ph.D. University Hospital
Radiotherapist Ghent, Belgium
Department of Radiotherapy
Netherlands Cancer Institute
Jens Overgaard, M.D.
Amsterdam, Netherlands
Head
Department of Experimental Clinical
Willem Distelmans, M.D.
Oncology
Head
Danish Cancer Society
Laboratory of Oncology
Aarhus , Denmark
Janssen Research Foundation
Beerse, Belgium
Sara Rockwell, Ph.D.
Evan B. Douple, Ph.D. Professor
Professor Department of Therapeutic Radiology
Department of Medicine Comprehensive Cancer Center
Dartmouth Medical School Yale University School of Medicine
Hanover, New Hampshire New Haven, Connecticut
Nicola S. Russell, B.M., B.S. Fiona A. Stewart, Ph.D.
Department of Radiotherapy Senior Research Scientist
Netherlands Cancer Institute Department of Experimental Therapy
Amsterdam, Netherlands Netherlands Cancer Institute
Amsterdam, Netherlands
Man C. Sartorelli, Ph.D.
Professor and Director
Guy Storme, M.D.
Department of Pharmacology
Head
Comprehensive Cancer Center
Department of Radiotherapy
Yale University School of Medicine
Oncology Center VUB
New Haven, Connecticut
Brussels, Belgium
Dietmar W. Siemann, Ph.D.
Director Hans von der Maase, M.D., Ph.D.
Experimental Therapeutics Division Department of Oncology
University of Rochester Cancer Center Herlev University Hospital
Rochester, New York Herlev, Denmark
TABLE OF CONTENTS
Chapter 1
Fundamental Concepts Associated with Combining Cytotoxic Drugs and X-Irradiation . . 1
Angela S. Bellamy
Chapter 2
Radiation Damage Interaction with Actinomycin D and Adriamycin ....................2 3
James A. Belli
Chapter 3
Interactions between Bleomycin and X-Irradiation ......................................5 3
Jens Overgaard and Cai Grau
Chapter 4
Interactions between Cyclophosphamide and Radiation.. ................................ 69
Harold A. Hopkins and William B. Looney
Chapter 5
Useful Interactions between 5-Fluorouracil and Radiation in Man: 5-Fluorouracil as a
Radiosensitizer ..........................................................................8 7
John E. Byfield
Chapter 6
Interactions between Microtubule Inhibitors and Ionizing Radiation.. ..................1 07
Guy Storme, W. Distelmans, W. De Neve, and M. Mareel
Chapter 7
Interactions between Mitomycin C and Radiation ......................................1 25
Sara Rockwell and Alan C Sartorelli
Chapter 8
Interactions between Nitrosoureas and X-Irradiation.. ..................................1 41
Dietmar W. Siemann
Chapter 9
Interactions between Cisplatin and Radiation in Experimental Rodent Tumors and
Normal Tissues. ........................................................................ l53
Adrian C. Begg, F. A. Stewart, L. Dewit, and H. Bartelink
Chapter 10
Interactions between Platinum Coordination Complexes and Radiation. ................1 7 1
Evan B. Douple
Chapter 11
Experimental Drug-Radiation Interactions in Critical Normal Tissues ..................1 9 1
Hans von der Maase
Chapter 12
In Vitro Drug-Radiation Interactions using Fractionated X-Irradiation Regimens ...... .207
Bridget T. Hill
