Table Of ContentHyperthermia
and Cancer
Hyperthermia
and Cancer
George M. Hahn
Stanford University School of Medicine
Stanford California
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Hahn, George M., 1926-
Hyperthermia and cancer.
Includes bibliographical references and index.
1. Cancer - Treatment. 2. Thermotherapy. 3. Heat - Physiological effect. l. Title.
[DNLM: 1. Fever therapy. 2. Neoplasms-Therapy. QZ 266 H148h]
RC271.T5H33 1982 616.99'40632 82-12368
lSBN-I3: 978-1-4684-4195-6 e-ISBN-13: 978-1-4684-4193-2
DOl: 10.1007/978-1-4684-4193-2
© 1982 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1982
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Dedicated to the memory of
DAVID HAHN: 1950-1962
Preface
Hyperthermia as a tool for the treatment of malignant disease is rapidly
becoming a clinical reality. In this book I am attempting to summarize
the known biological and physical underpinnings that have led to this
development. I also present a compilation of existing clinical results,
limited as these are. My aim is to provide oncologists and other physicians
with up-to-date information on this modality, which is both new and old,
as well as to make available to biologists, physicists and engineers sum
maries of currently available information on specific areas of hyperthermic
research.
Many people have helped me with this book. Specifically, thanks are
due to Drs. William Dewey, Jean Dutreix, Peter Fessenden, Gloria Li,
and Jane Marmor. Their suggestions have been invaluable. I hope that
not too many errors and omissions have crept into the volume, but in any
case, for these I have only myself to blame. I also wish to express my
appreciation to David Betten and Marie Graham for their help.
Most of this material was written while I was on sabbatical leave on
the shores of Lake Atitlan in Guatemala. There I enjoyed the hospitality
of a gracious, friendly, and proud people who deserve better than fate
seems to have in store for them.
George M. Hahn
vii
Contents
Chapter 1. Introduction: Historical and General Comments ............. 1
Chapter 2. Mammalian Cell Survival Responses after Exposure to
Elevated Temperatures ....................................... 7
2.1. Introduction .......................................................... 7
2.2. Heat Sensitivity of Mammalian Cells: Definition .................. 8
2.3. Assays ................................................................ 9
2.4. Survival of Cells Exposed to Single Heat Treatments ........... 12
2.4.1. Stable Heat-Resistant Variants ............................. 16
2.4.2. Stable Heat-Sensitive Variants ............................. 19
2.4.3. Sensitivities of Normal and Malignant Cells .............. 20
2.4.4. Influence of Ploidy, Cell Density, and Cell Cycle on
Heat Sensitivity ............................................. 23
2.5. Modifications of Heat Responses .................................. 25
2.5.1. Modification by Changes in pH ............................ 27
2.5.2. Nutrients ..................................................... 30
2.5.3. Protective Agents ........................................... 35
2.6. Survival of Cells Exposed to Multiple Heat Treatments ......... 36
2.6.1. Recovery Phenomena ....................................... 38
2.6.2. Thermotolerance ............................................ 41
2.7. Summation .......................................................... 53
Chapter 3. Thermal Enhancement of the Actions of
Anticancer Agents ............................................ 55
3.1. Introduction ......................................................... 55
3.2. Thermal Enhancement of Radiation Sensitivity .................. 56
3.2.1. Upper Limit of Heat Sensitization ......................... 57
3.2.2. The Survival Surface ....................................... 58
ix
x CONTENTS
3.2.3. X-Ray Sensitivity and Thermosensitization of
Thermotolerant Cells ....................................... 59
3.2.4. Thermal Enhancement of the X-Ray Response of
Normal and Malignant Cells ............................... 62
3.2.5. Oxygen Enhancement Ratios .............................. 63
3.2.6. Hyperthermia and High LET Radiations .................. 64
3.2.7. Sequencing and Timing ..................................... 65
3.2.8. Hyperthermia, Radiation, and the Cell Cycle ............. 66
3.2.9. Proliferation Kinetics ....................................... 69
3.2.10. Recovery Phenomena: X Irradiation and Heat .......... 72
3.3. Enhancement by Hyperthermia of Drug Cytotoxicity ............ 74
3.3.1. Classification of Interactions ............................... 76
3.3.2. Technical Aspects of Drug Studies In Vitro .............. 76
3.3.3. Drugs Showing No Threshold Effects ..................... 77
3.3.4. Drugs Showing Marked Threshold Effects ................ 80
3.3.5. Thermosensitizers ........................................... 80
3.3.6. Modification of Drug-Heat Interactions ................... 83
3.3.7. Negative Studies ............................................ 84
3.4. Summary ............................................................ 85
Chapter 4. Mechanisms of Heat Action .................................. 87
4.1. Introduction ......................................................... 87
4.2. Heat Death of Cells ................................................. 87
4.2.1. Definition of Heat Dose .................................... 87
4.2.2. A Nonspecific Model of Heat Inactivation ................ 90
4.2.3. Macromolecules as Heat "Targets" ....................... 95
4.2.4. Cellular Organelles as Heat "Targets" ................... 100
4.2.5. Thermotolerance ........................................... 115
4.3. Heat-Enhanced X-Ray Cytotoxicity .............................. 119
4.4. Drug Cytotoxicities at Elevated Temperatures .................. 125
4.4.1. Alkylating Agents .......................................... 125
4.4.2. Bleomycin and Adriamycin ............................... 127
4.4.3. Cis-Diamminedichloroplatinum(Il) ........................ 127
4.5. Summary ........................................................... 127
Chapter 5. Responses of Murine Tumors and Normal Tissues ....... 131
5.1. Introduction ........................................................ 131
5.1.1. Model Systems ............................................. 132
5.2. Responses of Murine Tumors to Hyperthermia Alone .......... 134
5.2.1. Methodology of Heating Murine Tumors ................ 134
5.2.2. Tumor Cures and Survival of Tumor Cells .............. 136
CONTENTS xi
5.2.3. Effects of Different Heating Modalities .................. 142
5.2.4. Modulation of Glucose Blood Levels ..................... 143
5.2.5. Factors Governing Variability of Tumor Responses .... 146
5.3. Normal Tissue Responses to Heat. ............................... 147
5.3.1. Skin ......................................................... 149
5.3.2. Cartilage .................................................... 151
5.3.3. Other Tissues ............................................... 153
5.3.4. Discussion .................................................. 154
5.4. Responses of Tumor and Normal Tissue to Combinations of
Heat and X-Ray .................................................... 154
5.4.1. Effects on Tumors ......................................... 154
5.4.2. Effects on Normal Tissue: Therapeutic Gain Factors ... 156
5.5. Responses of Tumors to Combinations of Heat and Drugs ..... 163
5.5.1. Alkylating Agents .......................................... 164
5.5.2. Antitumor Antibiotics ...................................... 165
5.5.3. Nitrosoureas ................................................ 167
5.5.4. Platinum Compounds ...................................... 167
5.5.5. Electron Affinic Compounds .............................. 168
5.5.6. Lidocaine ................................................... 169
5.6. Do Tumor Cells Die in the Same Manner In Vivo as They Do
In Vitro? ........................................................... 170
5.6.1. The Role of Immune Responses .......................... 172
5.6.2. Effect of Hyperthermia on Spread and Growth of
Metastases .................................................. 174
5.7. Summary ........................................................... 176
Chapter 6. Technical Aspects of Hyperthermia ........................ 179
6.1. Introduction ........................................................ 179
6.2. Localized Heating ....................... , ......................... 182
6.2.1. System Requirements ...................................... 182
6.2.2. Blood Flow in Normal Tissue and in Tumors ........... 184
6.2.3. Methods of Local Heating ................................. 191
6.3. Regional Heating ................................................... 208
6.3.1. Perfusion with Extracorporeally Heated Blood .......... 208
6.3.2. Other Techniques .......................................... 209
6.4. Whole-Body Heating .............................................. 209
6.4.1. "Pettigrew" Technique .................................... 210
6.4.2. "Blanket" Technique ...................................... 210
6.4.3. Heating Cabinet ............................................ 211
6.4.4. Perfusion with Extracorporeally Heated Blood .......... 211
6.4.5. Discussion of Whole-Body Heating Techniques ......... 212
6.5. Possible Adverse Aspects of Heating ............................ 2 I 3
6.5.1. Dangers Associated with High Temperatures ............ 2 I3
6.5.2. Dangers Associated with Methods of Induction of
Hyperthermia ............................................... 214
6.6. Measurement of Temperatures .................................... 215
6.6.1. Invasive Techniques ....................................... 2 I 6
6.6.2. Noninvasive Techniques .................................. 221
6.7. Summary ........................................................... 224
Chapter 7. Effects of Hyperthermia Against Spontaneous Cancers 227
7.1. Introduction ........................................................ 227
7.2. Historical Background ............................................. 228
7.3. Cancers in Out-Bred Animal Populations ........................ 228
7.4. Human Cancers: Heat Alone ..................................... 233
7.4.1. Whole-Body Heating ...................................... 233
7.4.2. Regional Heating ........................................... 236
7.4.3. Heating of Isolated Lesions ............................... 238
7.4.4. Discussion .................................................. 242
7.5. Human Cancer: Heat Plus Irradiation ............................ 243
7.5.1. Tumor Responses .......................................... 243
7.5.2. Discussion .................................................. 250
7.6. Human Cancers: Heat Plus Drugs ................................ 251
7.7. Conclusion .......................................................... 253
7.8. Summary ........................................................... 254
References .............................................................. 257
Index ..................................................................... 281
1
Introduction
Historical and General Comments
Hundreds of years ago, the Greek physician Parmenides said that given
the means to induce fevers he would be able to cure all illnesses. Pre
sumably he meant to include cancer, since malignancies were described
in early Greek literature. The effects of elevated temperatures on human
physiological functions and, in particular, on the healing process have
fascinated clinicians and researchers for many years. Hippocrates de
scribed in detail many febrile diseases and commented extensively on the
beneficial role of fever. A Roman, Celsus, catalogued the clinical symp
toms of inflammation and noticed their association with fevers.
Today, the induction of elevated temperatures (hyperthermia), either
locally or over the whole body, has become quite feasible. Whether or
not this is a realization of Parmenides's wish is somewhat questionable.
Fever is a unique form of hyperthermia in that it is not associated with
the failure of a thermal regulatory system but rather with a change in the
"set point," i.e., the temperature about which regulation is exerted. This
is true not only in humans but also in a wide range of animals. The point
is perhaps most graphically illustrated in a fascinating set of experiments
involving a poikilotherm, the desert iguana, Disposaurus dorsalis (Kluger
et al., 1973). These animals were placed in a box in which a thermal
gradient had been established by heating one end of the container and
cooling the opposite end. The "normal" iguanas consistently settled in
one temperature zone. This very primitive regulation, their own motion,
established the set point for normal lizards. The reptiles were then injected
with a known reptilian pathogen (e.g., Pasteurella hemolytica). They
promptly moved to a warmer zone, thus inducing a "fever." After further
injection with appropriate doses of sodium salicylate, which is a well
known antipyretic agent, the iguanas returned to the cooler location. In
these experiments, the movement of the animal was a direct, visual dem
onstration of the change in "set point" of their thermal regulatory system.
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