Oncothermia: Principles and Practices

Transcription

1 Oncothermia: Principles and Practices

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3 Andras Szasz Nora Szasz Oliver Szasz Oncothermia: Principles and Practices 123

4 Andras Szasz Department of Biotechnics Faculty of Engineering St. Istvan University PaterK.u Godollo Hungary Nora Szasz McKinsey & Co. Park Plaza Boston MA, USA Oliver Szasz Oncotherm Inc. Ibolya u Paty Hungary SzaszOliver@oncotherm.org ISBN e-isbn DOI / Springer Dordrecht Heidelberg London New York Springer Science+Business Media B.V No part of this work 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, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Contents 1 Oncology Treatments and Their Limits Cancer Short History and Efforts to Cure Historical Notes The War Against Cancer Paradigm and Challenges of Oncotherapies Limitations of Oncotherapies The Quest for a Step Forward Medical Challenge of Oncotherapies Ethical Challenge of Oncotherapies The Challenge of Evaluating the Results Hyperthermia Results and Challenges Hyperthermia Approach Definition of Hyperthermia in Oncology Basic Concepts of Oncological Hyperthermia Technical Variations of Hyperthermia in Oncology Effects of Hyperthermia Higher Baseline Temperature Vascular Changes Cellular Membrane Changes Lactic Acid Formation ATP Depletion Altered DNA Replication Enhanced Immune Reaction Pain Reduction Selective Gain of the Heat Resistance Clinical Oncological Hyperthermia Local and Whole-Body Heating Hyperthermia as a Complementary Method Hyperthermia Successes Brain Tumor Treatment by Hyperthermia Pancreas Tumor Treatment by Hyperthermia Lung and Bronchus v

6 vi Contents Hepatocellular Carcinoma and Metastatic Tumors of the Liver Colo-Rectal Tumors Esophagus Head and Neck Localizations Gastric Tumors Breast Tumors Other Localizations Treated by Hyperthermia Hyperthermia Challenges in Oncology Challenge of Selection and Focus The Challenge of Temperature Medical Challenges of Hyperthermia in Oncology Challenge of Quality Control and Dosimetry of Hyperthermia What We Expect? Possible Solution: Oncothermia Thermo-Biophysics Factors of Physiology Heating Biothermodynamics Energy, Heat, and Temperature Energy of the Chemical Bonds and Reactions Energy Sources and Driving Forces Energy and Structure Energetics of Malignant Cells Non-Thermal Effects The Thermodynamic Approach Bioelectrodynamics Basic Interactions The Bioimpedance Non-Thermal Effects The Electrodynamic Approach Non-Thermal Effects Approach of Electric Currents Membrane Effects Stochastic Processes Noises and Signals Resonances Modulation Demodulation Special Field Effects of Biosystems Oncothermia A New Kind of Oncologic Hyperthermia Oncothermia Characteristics Electrochemotherapy (ECT) Concept of Oncothermia Pennes Equation Revised

7 Contents vii Thermal Limit Problem Energy Transfer Through the Body Surface Penetration Depth Arrangement of Electrodes Far from Equilibrium Energy Intake and Temperature Macroscopic Focusing on the Tumor Heating the Extra-Cellular Electrolyte Temperature Gradient and Heat Flow on the Membrane Changes of the Membrane Potential Membrane Damage by Constrained Ion Currents Effect on Cell Cell Connections Oncotherm Comparison Oncothermia Treatment Guidelines Treatment Planning Treatment Consensus Complementary Applications Complementary to Radiotherapy Complementary to Chemotherapy Clinical Toxicity, Safety Oncothermia Case Reports Near-Eye Treatments Brain Cases Gynecology Cases Gastrointestinal Cases Pulmonary Cases Other Cases Evaluation of Oncothermia Studies Evaluation Conditions Evaluation Methods General Overview on a Large Patient s Pool Brain Studies Brain Safety Study (Phase I) Brain Efficacy Study (Phase II) Hungarian Brain Glioma Study Small Prospective, Double-Arm Brain Glioma Study Study of Brain Gliomas with Local Clinical Responses Brain Glioma Study with Relapses Bicentral Brain Glioma Study Oncothermia for Heavily Pretreated and Relapsed Brain Gliomas

8 viii Contents Study of Metastatic Brain Tumors Comparison of Oncothermia Brain Studies Pancreas Studies Pancreas Efficacy Study I Pancreas Efficacy Study II (HTT) Additional Historical Control to HTT Pancreas Study Comparison of Pancreas Efficacy Studies I and II Pancreas Efficacy Study III Pancreas Efficacy Study IV Other Oncothermia Pancreas Studies and Their Comparison Lung Studies Oncothermia Lung Study I Oncothermia Lung Study II Meta-Analysis of Oncothermia Lung Studies Comparison to Historical Control Liver Studies Study of Liver Metastases of Colo-Rectal Origin Study of Advanced Liver Metastases of Colo-Rectal Origin II Comparison Study of Treatment Lines of Colo-Rectal Liver Metastases Study of Platinum Derivatives with Oncothermia for Liver Metastases of Colo-Rectal Origin Study of Liver Metastases of Rectal Origin Study of Liver Metastases of Various Origins Study of Very Advanced Liver Metastases of Various Origins: Comparison of Complementary Therapies Comparison of Studies of Liver Metastases Gynecological (Pelvic) Cancer Study Ovary Study Uterine Corpus Cancer Uterine Cervix Comparison of Oncothermia in Pelvic Gynecology Breast Study Esophagus Study Esophagus Study I Esophagus Study II Stomach Study Colo-Rectal Studies Pre-Operative Oncothermia for Rectum Carcinoma Colo-Rectal Carcinoma Study

9 Contents ix 4.17 Bone Studies Refractory Bone Metastases Complementary to Radiotherapy Monotherapy for Advanced Bone Metastases Osteosarcoma Study Kidney Study Head and Neck Study Urinary Bladder Malignancies Soft-Tissue Malignancies Prostate Study Oncothermia Perspectives Appendixes Acknowledgment References Index

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11 Objective of the Book Oncothermia is a treatment modality for malignant tumor diseases. Cancer has been a permanent fear of human kind since ancient times. It was incurable, fatal and from ancient times we have been in a continuous war against these malignant diseases. Despite all our sustained efforts to cure cancer this has not become a reality yet. Hyperthermia is an ancient treatment. The fire (Sun) had symbolic significance in ancient human cultures, so heat delivery was naturally at the top of curative possibilities. Ancient heat-delivery methods were of course ineffective, but modern electromagnetic heating techniques were able to renew this methodology. Heating up the whole body or a part or local volume began to rapidly develop in modern oncotherapeutic practices. Selective energy absorption has several favorable physiological and cellular effects promoting direct and indirect tumor destruction without notable toxicity. Its main success lies in its complementary applications. Oncological hyperthermia is an ideal combination therapy; it provides synergies with most of the conventional treatment modalities, boosts their efficacy, and helps in desensitizing previously non-effective treatments. Hyperthermia in oncology has been debated in an increasing number of books and high-ranking clinical publications. Contrary to its long history, the state of oncological hyperthermia today is similar to that of therapies in their infancy. Like many early-stage therapies, it lacks adequate treatment experience and long-range, comprehensive statistics that can help us optimize its use for all indications. Nevertheless, we will present a wealth of information about the mechanisms and effects of hyperthermia in oncology, showing the clinical efficacy in a wide range of malignancies. This relatively simple, physical-physiological method has a phoenix-like history with some bright successes and many deep disappointments. What we have in hand? Is it a brilliant, miraculous, non-toxic treatment or a quackery of some charlatans? In our present book we try to answer these questions too. Oncothermia employs many modern scientific achievements in order to assure and enhance the clinical success of hyperthermia in oncology. Oncothermia is a certain further development of hyperthermia. Of course it also cannot offer a miracle; it is only a new weapon to be applied. Oncothermia uses many natural processes to xi

12 xii Objective of the Book reach the curative effect, initializing and supporting the complex human system to make a successful defense against cancer and promote the probable cure or at least the palliative treatment. To explain oncothermia, we present updated scientific results, complex approaches using the state-of-art in biophysics and medicine. We use a wide range of inter-disciplinary facilities: from physics we employ thermodynamics, statistical mechanics, quantum mechanics, electrodynamics together with biophysics achievements in fractal physiology, stress adaptation, cellular signaling, and add a huge technical arsenal including the radiofrequency technique, impedance control, and antenna fitting. There are a great number of books, published to date, devoted to the efficacy and power of hyperthermia in oncology [1 19]. The method is a part of the universal and well-accepted oncology knowledge [20] discussed in detail in large text-books of radiology/radiotherapy [21] and general oncology [22] also. We would like to demonstrate the force and perspectives of oncothermia, as a highly specialized hyperthermia in clinical oncology. Our aim is to prove the ability of oncothermia to be a candidate to become a widely accepted modality of standard cancer care. We would like to show the proofs and challenges of oncothermia applications, to provide the presently available data and summarize the knowledge on the topic. We concentrate mainly on local/regional hyperthermia with its non-invasive electromagnetic applications, so whole-body hyperthermia and the RF-ablation techniques will not receive much attention and neither will ultrasound or other heating techniques. We would like to show a new paradigm for oncological thermal treatment and give its perspectives for the future. The rich reference list and discussions of hot topics will help specialists both in labs and clinical practices to use the book as a handy reference. For the numerous questions that could be addressed you may find answers in this book to the following: Hyperthermia has a long history in oncology however, it has no acceptance. Why? Oncologic hyperthermia has a large number of publications but the results are often contradictory. Why? Huge investigation efforts are made in hyperthermia in oncology worldwide yet there is no complete understanding of the underlying mechanism. Why? Hyperthermia has many convicted enthusiastic oncology practitioners using contradictory explanations. Why? There are several possible microscopic effects that could be used to control the hyperthermia process but only the temperature is used generally. Why? Hyperthermia is basically nontoxic and widely compatible with other oncotherapies but it is less recognized than much more toxic treatments. Why? What is against the active use of hyperthermia in oncology? Has hyperthermia a future in oncology at all?

13 Objective of the Book xiii After these questions obviously one more arises: what do we have in hand? We would like to offer the physical effects of oncothermia, and present the results, which could make harmonizing the disciplines easier, exploring the heart of oncological hyperthermia as an inter-disciplinary topic. The aim of this book is to point out the challenges, set the right questions (starting with the apparent contradiction between the oldest method in cancer treatment being at the same time the youngest method in modern oncology), and try to generate the right answers. The open questions need further investigation and we strive to motivate the kind reader. In summary: we propose a change of paradigm for hyperthermia in oncology. The old paradigm, the conventional, classical hyperthermia, (we use further the term hyperthermia ), while the proposed new paradigm is referred to as oncothermia. This book is an invitation to share the challenge of the new method, share the excitement of applying a new effective treatment, and share enjoyment in the results.