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- Herausgeber: Thieme
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2005
One of every four deaths occurring in the United States today is due to cancer, and the number of diagnoses continues to increase. Fortunately, however, cancer treatments are improving, which means more and more patients are surviving for longer periods. Complementary methods have played an important role in these treatments, showing benefits such as a higher quality of life, reduced instance and severity of the side effects of standard therapy, and a general improvement of the patient's immunological state. Indeed, these methods - from carefully monitored nutrition, exercise, and psychological support to enzyme substitution, phytotherapy, hyperthermia and microbiology therapy - are critical to a treatment's overall success. More than ever, doctors need accurate, up-to-date information about which methods have been proven in scientifically based clinical studies (EBM) to be acceptable for use in conjunction with standard treatment methods. In this unique book, experts ranging across medical disciplines present data on the efficacy of these methods as they are currently being used, the necessary scientific background, and practical advice for introducing them into practice. With illustrations, tables, and detailed descriptions, this book is an ideal reference and an invaluable tool for educating patients about this encouraging aspect of cancer therapy. Throughout, the contributors emphasize the latest scientifically and clinically tested treatments. A useful chart lays out in detail which treatments are applicable for various types of cancers and what effects they have been shown to cause. The word is out about the beneficial qualities of complementary therapies in the treatment of cancer. More physicians are offering it to their patients, and more and more patients are demanding it. You - and your patients - cannot afford to be without this valuable resource.
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Library of Congress Cataloging-in-Publication Data
Grundlagen der Komplementäronkologie. English.Complementary oncology : adjunctive methods in the treatment of cancer / [edited by] Josef Beuth, Ralph W. Moss ; with contributions by Ulrich Abel …
[et al.].
p. ; cm.
Revised translation of the German ed.,published in 2002.
Includes bibliographical references.
ISBN 3-13-137451-9 (alk. paper) – ISBN 1-58890-323-0 (alk. paper)
1. Cancer – Adjuvant treatment. 2. Cancer – Alternative treatment.
[DNLM: 1. Neoplasms–therapy. 2. Complementary Therapies. QZ 266 G889 2005a] I. Beuth, J. II. Moss,Ralph W. III. Abel, Ulrich, 1952- IV. Title.
RC271.A35G7813 2005
616.99’406–dc22
2005008532
This book is an authorized and completely revised translation of the German edition published and copyrighted 2002 by Hippokrates Verlag, Stuttgart, Germany. Title of the German edition: Grundlagen derKomplementäronkologie: Theorie und Praxis.
Translator: Ursula Vielkind, Ph. D., C. Tran., Ontario, Canada.
Cover Images
Tabàr L, Tot T, Dean PB. Breast Cancer—The Art and Science of Early Detection with Mammography, Thieme 2005.
We would like to thank the authors for their kind permission to use these images.
© 2006 Georg Thieme Verlag, Rüdigerstrasse 14, 70469 Stuttgart, Germany http://www.thieme.de Thieme New York, 333 Seventh Avenue, New York, NY 10001 USA http://www.thieme.com
Typesetting by Satzpunkt Ewert GmbH, Bayreuth Printed in Germany by Druckhaus Götz, Ludwigsburg
ISBN 3-13-137451-9 (GTV)
ISBN 1-58890-323-0 (TNY) 1 2 3 4 5 6
Important note:Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatmentand drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book.
Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed. If errors in this work are found after publication, errata will be posted at www.thieme.com on the product description page.
Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.
This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing, preparation of microfilms, and electronic data processing and storage.
Preface
New approaches to curative cancer therapy are being explored and evaluated around the world. For example, great hopes have been placed in the Human Genome Project as well as in advances in the fields of molecular biology, molecular genetics, and immunology.
Searching for new substances of therapeutic importance (e. g., in rain forests and oceans, or by developing new technologies) also seems promising. However, this is a time-consuming and expensive process because it is an indispensable prerequisite that such treatments be scientifically evaluated before they are clinically applied. Currently, the optimization of curative cancer therapy seems to be most possible through the development of interdisciplinary concepts of oncological therapies.
In the United States, the use of tumor-destructive standard therapies (surgery, radiation, and chemotherapy) did not significantly lower cancer mortality over the last 30 years. Despite expensive efforts in both research and therapy in response to President Nixon’s declaration of war against cancer in 1971, the age-adjusted cancer mortality has even increased by about 6 %. Good therapeutic results were achieved only for relatively rare types of tumors (such as lymphoma, leukemia, and testicular tumors). This failure to achieve positive results in the statistically major forms of cancer has spurred the demand for new concepts of treatment and has ushered in the scientific, experimental, and clinical efficacy testing of therapeutic measures used in complementary oncology.
In the United States, as many as 91 % of all cancer patients now use complementary measures, often without the knowledge of the attending oncologist.Their main motives are:
• to actively participate in fighting their disease or promoting their recovery
• to activate the immune system
• to optimize the standard therapy.
These understandable wishes need to be addressed with critical (though favorable) openmindedness, and therapists should get it straight in their minds that active patients in fact profit from the activation of their psychoneuroimmunological system.
As per their definition, therapeutic measures in complementary oncology are not intended to replace approved standard therapies. Hence, they are not “alternative therapies.” Measures in complementary oncology that prove to be important additions to the tumor-destructive therapies simply claim to optimize these standard therapies.
Preliminary data from scientifically based clinical studies have demonstrated the importance of various measures. The benefits to the patients included improvement in their quality of life, reduction of their symptoms and side effects due to standard therapy, and improvement of their immunological state.
In the present book, efficacy-tested measures of complementary medicine are integrated for the first time in a scientific manner into an oncological treatment plan. Due to the organization of the book and its clearly arranged tables it is not only suitable as a handy reference for the practicing oncologist, but it provides an extensive and critical insight into the relevant test results for the scientifically minded oncologist.
Chapters 1 to 7 offer a critical analysis of the current situation in oncology and introduce the reader to tumor immunology. Other chapters deal with study designs and the problems arising when evaluating oncological studies. This part ends with the presentation of the QoL-Recorder, a tool designed to assist in determining the quality of life—a secret aspect behind therapeutic results, which has been neglected until recently.
Chapters 8 to 20 are competent introductions to complementary therapies for which scientifically based data are available from clinical studies (evidence-based medicine [EBM] level 1 [randomized controlled studies] and level 2 [cohort studies]).
In Chapter 21 the integration of these measures into the standard therapy of solid tumors is presented in the form of tables. Here, the duration and the intensity of the treatments are listed for various types of cancer.
Chapter 22 presents many promising concepts of treatment, but it is still too early to integrate them into the treatment plan.
Our thanks go to Angelika M. Findgott for her charming but straight initiation and accomplishment of this project; Ursula Vielkind for her excellent translation; Stefanie Langner and the staff at Thieme International for the opportunity to realize this project. Finally, we wish to thank all authors of this book for their critical stocktaking of complementary oncology.
Josef Beuth, M. D., Cologne, GermanyRalph W. Moss, Ph. D., Lemont, Pennsylvania
List of Contributors
Ulrich Abel, Ph. D.ProfessorUniversity of HeidelbergHeidelberg, Germany
Arndt Büssing, M. D.University of Witten/HerdeckeDepartment of Applied ImmunologyHerdecke, Germany
E. Dieter Hager, M. D., Ph. D.Director of BioMed-Clinicfor Complementary OncologyBad Bergzabern, Germany
Heide JenikRudolf van LeendertInstitute of Scientific Evaluation ofNaturopathic MethodsUniversity of Cologne,Cologne, Germany
Karl Friedrich Klippel, M. D.ProfessorGeneral Hospital Celle,Celle, Germany
Kedar N. Prasad, Ph. D.Antioxidant Research InstitutePremier Micronutrient CorporationNovato, CA, USA
Dieter Prätzel-Wolters, ProfessorHagen Knaf, Ph. D.Patrick Lang, Ph. D.Fraunhofer-Institute for TechnoandBusiness ArithmeticsKaiserslautern, Germany
Volker Rusch, Ph. D.Institute of Integrative BiologyHerborn, Germany
Volker Schirrmacher, Ph. D.ProfessorGerman Cancer Research Centre HeidelbergTumorimmunologyHeidelberg, Germany
Berthold Schneider,Dr. phil. Nat.ProfessorMedical University HanoverInstitute of BiometricsHanover, Germany
G. N. Schrauzer, M. D.ProfessorBiological Trace ElementResearch InstituteChula Vista, CA,USA
Jörg Sigle, M. D.Private PracticeFreudenstein, GermanyDepartment of General MedicineUniversity of GöttingenGöttingen, Germany
Gerhard Uhlenbruck, M. D.ProfessorIlse LedvinaInstitute of ImmunobiologyUniversity of CologneCologne, Germany
Kurt S. Zänker, M. D.ProfessorUniversity of Witten/HerdeckeInstitute of ImmunobiologyHerdecke, Germany
List of Abbreviations
α-TS α-tocopherol succinate
ADCC antibody-dependent cellular cytotoxicity
AJCC American Joint Committee on Cancer
APC antigen-presenting cell
ASCO American Society of Clinical Oncology
ASI active specific immunotherapy (for cancer)
ATBC α-tocopherol plus β-carotene
ATRA all-transretinoic acid
ATV autologous tumor vaccine
AVI autovaccine for intestinal tract
AWB Anwendungsbeobachtungen (specific observational studies; a German variant of postmarketing surveillance studies)
BALT bronchus-associated lymphoid tissue
BCG bacillus of Calmette-Guerrin
BfArM Federal Institute for Drugs and Medical Devices
BSC best supportive care
CALGB Cancer and Leukemia Group B
CAM complementary and alternative medicine
CAP catabolite activation protein
CARET β-Carotene and Retinol Efficacy Trial
CDC complement-dependent cytotoxicity
CHART continuous hyperfractionated accelerated radiotherapy
CMF cyclophosphamide, methotrexate, fluorouracil (chemotherapy)
CML chronic myeloid leukemia
CR complete remission
CRF case report forms
CTL cytotoxic lymphocyte
DACH German, Austrian, and Swiss Societies of Nutrition
DC dendritic cells
DGE German Society of Nutrition
DHA dehydroascorbic acid
DHT deep hyperthermia
DNA deoxyribonucleic acid
DRI dietary reference intake
DTH delayed-type hypersensitivity
DTIC 5-(3,3-dimethyl-1-triazeno)-imidazol-4-carboximide (dacarbazine)
EBM evidence-based medicine
EBV Epstein–Barr virus
ECOG Eastern Collaborative Oncology Group
EGCG epigallocatechin gallate
EGF epidermal growth factor
EGFR epidermal growth factor receptor
EMEA European Agency for the Evaluation of Medicinal Products
FDA Food and Drug Administration
FGF fibroblast growth factor
FKJ fine-needle catheter jejunostomy
GAC germ-free animal characteristics
Gal galactose
GalNAc N-acetyl-D-galactosamine
GCP good clinical practices (placebo controlled, prospective randomized, double-blind multicenter study)
GEP good epidemiological practices
GM-CSF granulocyte–macrophage colonystimulating factor
GSH-Px glutathione peroxidase
HAA heterocyclic aromatic amines
HADS Hospital Anxiety and Depression Scale
HAMA human antimouse antibody
HBP hepatic binding protein
HL hepatic lectin
HLA human lymphocyte antigen
HRQOL health-related quality of life
HSP heat shock protein
ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
ICHP intracavitary hyperthermic perfusion (perfusion hyperthermia)
IHT interstitial hyperthermia
IL interleukin
IMS Institute for Medical Statistics
iNO inducible nitric oxide synthetase
IOM Institute of Medicine
IPHP intraperitoneal hyperthermic perfusion
IplHP intrapleural hyperthermic perfusion
IRA infrared-A radiation
IRB Institutional Review Board
ISGNAS International Study Group of New Antimicrobial Strategies
ITT intention-to-treat analysis
IVHP intravesicular hyperthermic perfusion
JNCI Journal of the National Cancer Institute
LAK lymphokine-activated killer cell
LCL lymphoblastoid cell line
LHT local hyperthermia
LPS lipopolysaccharide
MAC microflora-associated characteristics
Mab monoclonal antibody
MALT mucosa-associated lymphoid tissue
MCP-1 monocyte chemotactic protein 1
MFH magnetic fluid hyperthermia
MHC major histocompatibility complex
Mn-SOD manganese superoxide dismutase
MSKCC Memorial Sloan-Kettering Cancer Center
NAC N-acetylcysteine
NANA N-acetylneuraminic acid
NB neuroblastoma
NCI National Cancer Institute
NCS national consumption study
NDV Newcastle disease virus
NK natural killer cell
NOD/SCID onobese diabetic/severe combined immunodeficiency disorder (mice)
NSCLC non-small cell lung carcinoma
OS overall survival
PAC polycyclic aromatic carbohydrates
PBL peripheral blood lymphocytes
PDGF platelet-derived growth factor
PDQ Physician’s Data Query
PDTC pyrrolidine dithiocarbamate
PEG percutaneous endoscopic gastrostomy
PEJ percutaneous endoscopic jejunostomy
PH–GSH–Px phospholipid–hydroperoxide–glutathione peroxidase
PHS Physicians Health Study
PHT perfusion hyperthermia
PLAP placental alkaline phosphatase
PR partial remission
PSA prostate-specific antigen
PSMA prostate-specific membrane antigen
PUG percutaneous ultrasonographic gastrostomy
QALYs quality-adjusted life years
QLQ Quality of Life Questionnaire
QoL quality of life
RCT randomized controlled trial
RDA recommended dietary (or daily) allowance
RHT regional hyperthermia
RSV respiratory syncytial virus
SAQLI Calgary Sleep Apnea Quality of Life Index
SCLC small-cell lung cancer
SD stable disease
SEREX serological analysis of antigens by recombinant expression cloning
SHT superficial hyperthermia
SHBG sex hormone-binding protein
SOP standard operating procedure
STH somatotrophic hormone (somatotropin)
TA tumor antigen
TAA tumor-associated antigen
TATA tumor-associated transplantation antigen
TCA tumor cell activity
TCR T-cell receptor
TGF-β transforming growth factorβ
TIMP tissue inhibitor of metalloproteinase
TLR Toll-like receptor
TNF-α tumor necrosis factorα
UICC International Union Against Cancer
VEGF vascular endothelial growth factor
VIL vaccine infiltrating lymphocyte
VLP viruslike particles
WBHT whole-body hyperthermia
wIRA water-filtered infrared A radiation
Contents
Preface
List of Contributors
List of Abbreviations
Current Issues in the Treatment of Cancer
1 Introduction to Complementary Medicine in Oncology
Introduction
Overview of Methods
Nutrition Advice
Exercise, Physical Activity
Psycho-oncological Support
Substitution of Essential Minerals and Vitamins
Enzyme Substitution
Phytotherapy
Thymic Peptide Therapy
Probiotic Therapy
Blockade of Adhesion Molecules
Hyperthermia
Fringe Methods
Conclusion
References
2 The Conventional Treatment of Cancer: The Case of Non-Small Cell Lung Cancer
Introduction
What Are the Characteristics of a Successful Clinical Trial?
History of Clinical Trials
Surgery as a Cancer Therapy
Radiation as a Cancer Therapy
Chemotherapy as a Cancer Therapy
The Conventional Treatment of Non-Small Cell Lung Cancer
The Surgical Treatment of Non-Small Cell Lung Cancer
Stage I NSCLC
Stage II NSCLC
Stage III NSCLC
Stage IV NSCLC
Iressa
Psychosocial Impact of Placebo and “Nocebo” in Advanced NSCLC
Recurrences of Stage IV NSCLC
Conclusions
Comparisons with CAM
References
3 Tumor Immunology
Introduction
Identifiable Tumor Antigens
Effector Cells and Mechanisms of Antitumor Immunity
Recognition of Danger Signals by Toll-Like Receptors and DC Activation
Concomitant Immunity, Generation of Memory Cells, and Tumor Immune Escape
Looking Ahead
References
4 Introduction to Medical Biometry
Introduction
The Setting of Therapeutic Research in Oncology
Special Features of Research in Cancer Treatment
Problems of Conducting Studies in Complementary Oncology
Primary Outcome Measures in Therapeutic Trials in Oncology
Survival Time and Quality of Life
The Problem of Secondary Efficacy Parameters
Evaluation of Efficacy
Objectives and Types of Trials
The Problem of Comparability
Randomization and Feasibility of Randomization
Implementation of Therapeutic Trials
Choice of Outcome Measures
The Intention-to-Treat Principle
Avoidance of Inflation of False-Positive Results
References
5 Expert Systems in Complementary Oncology
Introduction
Mathematical Contribution to Diagnosis and Therapy
What is an Expert System?
Uses in Medicine
Fuzzy Logic
Fuzzy set
Linguistic Variables
Fuzzy Rules
Fuzzy Implication
Fuzzy-Logical Operations
Combination
Example: Interpretation of Regulation Thermograms
Regulation Thermography
Fuzzy Modeling of Expert Knowledge
Design of an Expert System for Regulation Thermography
Creating a Body of Rules
Automatic Generation of Rules/ Hypotheses
Neuronal Networks
References
6 Observational Studies on Drugs Efficacy
Introduction
Therapeutic Efficacy and Proof of Efficacy
Controlled Clinical Trials
Cohort Studies
Study Design
Concept for Evaluation
Example of a Cohort Study in Oncology
Summary
Addendum: Basic Terminology of Probability and Statistics
References
7 Electronically Supported Outcome Measurement
Introduction
Basic Methodological Considerations
Evidence-Based Medicine
Efficacy and Benefit
Prolonged Survival, Historical Controls, Screening
Spontaneous Course of Disease and Motivation
Applicability of Study Results
Routine Care-Based Research
Quality of Life Measurement
Health-Related Quality of Life
Self-Assessment vs. Proxy Rating
Questionnaire Development
Costs of Quality of Life Measurement
Preconditions of Quality of Life Measurement
Adequate Setting
Paper-Based vs. Electronic Outcome Measurement
Technical Possibilities
Requirements for an Ideal Tool
The QL-Recorder
Pre-Configured Software Packages with Electronic Questionnaires
Non-Technical Requirements
Research Questions
Staff Training
Process Management and Tight Feedback
Data Protection
Application Examples
References
8 Cancer and Nutrition
Introduction
Carcinogens and Cocarcinogens in the Food
Dietary Components Effective in Prevention
Antioxidants
Clinical Studies
Dietary Recommendations for the Prevention of Cancer
The Role of Nutrition in Cancer Treatment
Cancer Cachexia and Anorexia
Determination of the Nutritional State
Nutritional Recommendations for Cancer Patients
Preoperative Nutrition Therapy
Postoperative Nutrition Therapy
Adjuvant Nutrition Therapy
Benefits of Nutritional Consultation—Conclusions
References
9 Exercise in Cancer Prevention and Follow-up
Introduction
Effect of Exercise
Clinical Examinations
Organization of Sport Groups
Entrance Examination
Preparation
Exemplary Exercise Units
Contraindications and Application Restrictions
Exercise for the Cancer Patient Outside of Specialized Types of Sport
Water Gymnastics
Swimming
Aqua-Jogging
Gymnastics
Ball Games
Racket Games
Martial Arts
Tai Chi
Winter Sports
Hiking
Walking
Long-Distance Running
References
10 Psycho-oncology
Introduction
The Term “Health”
The Cancer Diagnosis as Psychological Trauma
Coping Mechanisms and Defense Mechanisms
Clinical Studies
Cancer Personality
Cancer Biography
Stress and Cancer
Psychosomatic Strain in Cancer
Tumor Activation
Psychotherapeutic Aspects in Oncology
Effective Factors in Psycho-oncology Therapy
Subjective Disease Concept
The Patient–Doctor Relationship in Oncology
Treatment Planning
Points of Emphasis in the Physician’s Conducting of Conversation and the Conversational Setting
Questioning Techniques
Conversation Techniques
The Power of the Word
References
11 Biological Basis for Using High Dose Multiple Antioxidants as an Adjunct to Radiotherapy, Chemotherapy, and Experimental Cancer Therapies
Introduction
Antioxidants
Definition of Types of Antioxidants and Their Doses
Conceptual Framework of Hypotheses
Effect in Experimental Analysis
Experimental Basis of Our Hypothesis
High Doses of Dietary Antioxidants Enhance the Effect of Irradiation on Cancer Cells
High Doses of Dietary Antioxidants Enhance the Effect of Chemotherapeutic Agents on Cancer Cells
Efficacy of Individual Antioxidants in Combination with Hyperthermia
Effect of Individual Antioxidant Vitamins in Combination with Certain Biological Response Modifiers
Antioxidants Selectively Protect Normal Cells against Damage Produced by Radiation and Chemotherapeutic Agents
Mechanisms of Action of Dietary Antioxidant-Induced Enhancement of Radiotherapy and Chemotherapy
Modification of Radiation Damage by Endogenous Antioxidants
Experimental Basis of the Other Hypothesis
Proposed Doses of Micronutrients To Be Used as an Adjunct to Radiation Therapy and/or Chemotherapy
References
12 Selenium in Oncology
Introduction
Selenium in Cancer Prevention
Epidemiological and Case–Control Studies
Effects of Selenium-Antagonistic Elements
Cancer Prevention Trials with Selenium
Mechanisms of Anticarcinogenic Action
Effects of Selenium Deficiency on Gene Expression
Antimutagenic and Antiviral Effects
The Putative Role of the Thioredoxin Reductases
Effect on DNA Methylation
Oncogene Inactivation
Selenium in Cancer Chemotherapy
Reduction of Side Effects of Chemotherapeutic Agents
Current Therapeutic Selenite Dosage Recommendations
Anti-Inflammatory Effects
Diminution of Drug Resistance
Radioprotective Effects
Immunoprotective Effects
Sodium Selenite in the Management of Secondary Lymphedema
Lymphedema of the Arm
Lymphedema in the Head–Neck Area
Sodium Selenite in the Maintenance of Brain Tumor Patients
Answers to Some Frequently Asked Questions
Germany’s Selenium Status and the Recommended Daily Selenium Intake
Optimal Selenium Intakes for Cancer Prevention
Therapeutic and Nutritional Forms of Selenium
Incompatibility of Vitamin C with Sodium Selenite
Upper Safe, Permissible, and Toxic Dosages
References
13 Proteolytic Enzymes
Introduction
Pharmacological Examinations
Experimental Studies
Clinical Studies
Plasmacytoma
Breast Cancer
Colorectal Cancer
Summary
References
14 Lectin-Standardized Mistletoe Extracts
Origin of the Mistletoe Extract Therapy
Mechanism of Action and the Application of Mistletoe Extracts in Medicine
Experimental Studies
Clinical Studies
General Remarks
Special Applications
Summary
Outlook
References
15 Mistletoe Extracts from the Anthroposophical Point of View
Introduction
Mistletoe Extracts
Experimental Studies
Cytotoxicity
Immunomodulation
Clinical Studies
Immunomodulation
Quality of Life
Summary
16 Thymic Peptides
General Remarks
Total Thymic Extracts (Complex Mixtures)
Thymic Peptides
Standardized Thymic Peptide Mixtures
Experimental Studies
Clinical Studies
Summary
Outlook
References
17 Probiotic Therapy
Introduction
Man and Microbes
Gnotobiology
Microbial Populations
Pathogenic Microbes
Antibiosis
Probiotic Therapy
Microorganisms Used
Autovaccines
Indications and Forms of Administration.
Extent and Duration
Side Effects
Clinical Application
Malignant Diseases
References
18 Blockade of Adhesion Molecules
Lectins and Tumor Metastasis
Experimental Blockade of Liver Lectins
Clinical Studies
Summary
References
19 Tumor Vaccination and Antibody-Mediated Immunotherapy
Introduction
Tumor Vaccines and Active Specific Immunotherapy (ASI)
Clinical Studies
Monoclonal Antibodies and Passive Immunotherapy
Clinical Studies
Outlook
References
20 Hyperthermia
General Remarks
Hyperthermia Combined with Radiation Therapy or Chemotherapy
Generation of Hyperthermia
Clinical Application
Local Hyperthermia
Regional Hyperthermia
Hyperthermic Perfusion
Transurethral Hyperthermia
Whole Body Hyperthermia
Hyperthermia Centers
References
21 Applied Complementary Oncology
22 Advances in Oncology—From Research to Application
Introduction
New Approaches
High-Dose Chemotherapy
Treatment Optimization Studies
Cancer Treatment Based on Target Structures
Inhibition of Angiogenesis
Gene Therapy: Prospects
Differentiation Inducers
Phytoestrogens, Polyphenols, and Nutrition
Cancer Prevention
Comorbidity
Outlook
References
Index
Current Issues in the Treatment of Cancer
Since the main causes of death were first considered in medicine, cardiovascular disease has proven to be the leading cause, with cancer in second place. Each year since these statistics have been taken, the number of deaths from cancer has remained the same, while the number of deaths resulting from cardiovascular disease has decreased. In 2001 over half a million people died of cancer in the U. S. (see Fig. 1). It is estimated today that in just a few years from now the death toll from cancer will exceed that from cardiovascular disease.
The dramatic decline in deaths from heart disease can easily be attributed to modern technological and social improvements made to our lives in the past century: the availability of hospital services with intensive care units, roads and transportation allowing rapid response to cardiac attacks, communication systems, and, indeed, better understanding and medical surgical and pharmacological care for heart conditions.
The situation is very different where cancer is concerned. Although we have all these improvements, the number of cancer incidences has exceeded the anticipated growth and age of the population. The number of deaths has remained the same, which means that many people who have cancer may not necessarily die as a result. However, this does not represent an improvement in cancer cure rates, though we have succeeded in some cases such as with childhood leukemia and lymphoma. People do not die from cancer because we have improved their treatments in order to allow a delay in recurrence. In addition, most people facing cancer are older and have other complicating conditions that may result in their death. For estimated cancer deaths by specific sites refer to Figure 2.
Fig. 1
Fig. 2
The probability of men who live to be 80 years of age getting cancer is 1 in 2, while for women it is 1 in 3, with mainly prostate cancer increasing the probability for men. The overall risk of death resulting from cancer varies significantly according to cancer sites and ethnicity. Overall, African Americans have an 11 % higher risk of dying from cancer than Whites.
A further interesting observation is that cancer rates are much higher in the developed countries than in developing or third-world countries. A particularly confusing case is that of breast cancer. Breast cancer rates in Western countries are up to 15 times higher than in Africa and up to 5 times higher than in China and Japan. It has been observed that breast cancer incidence rates of second generation daughters of East Asian immigrants to the U.S. equals that of the general population. This observation suggests that it is not the genetic make up of the East Asians that provide protective benefit to breast cancer but rather environmental factors or life style. It has been suspected that the Asian diet is associated with the reduced risk. Since industrialization has rapidly taken place in China the breast cancer rates in the cities have increased dramatically.
Fig. 3
This may lead us to the conclusion that industrial pollution is the primary cause of breast cancer. However, this is an oversimplified conclusion, and studies attempting to determine industrial pollutants (such as petrochemicals, pesticides and herbicides, electromagnetic fields, microwave emissions, etc.) as a cause were unsuccessful in showing them to be a conclusive cause of the initiation or promotion of breast cancer. Two examples of industrialization have been implicated. As cancer is a disease mostly encountered as we age, the fact that we live much longer than people did just a century ago increases our risk. In addition, for the first time in history in the developed world we have too much food. A significant increase in overall body mass index has been observed in almost all countries. In Japan protein consumption has increased 6 times over since the 1970’s, which resulted in an average 6 in (25 cm) increase in height over the previous generation. Similar trends occurred in the U. S. and Europe earlier in the 20th century.
So why would the good things that come with industrialization result in an increase in cancer incidence and death? Cancer is a disease of uncontrolled cell growth. Cell growth is mediated by a complex signaling system mediated by many innate processes. Cell growth is needed for growth, development, procreation, and repair. The cells are therefore susceptible to messages that regulate all these processes. As a result of evolution, the body has adapted to respond to a variety of both internal and external signals. For example, the amount and type of nutrients made available through ingestion facilitates the growth and development of an individual. After the body reaches a certain level of maturity and size, an internal system of hormones regulates the growth and maturity of reproductive ability. Both examples indicate how cell growth may be mediated but in fact set a complex coordinated signaling inside each individual cell that results in its replication (the mitotic process). Cancer occurs when the controls on the processes that regulate the growth and death of cells within the cell are damaged. The cell can lose control in one of four main ways; growth is either promoted or simply not halted, or death is inhibited or simply not initiated. There are genes and proteins within the cell that are responsible for each of these processes. They can change their behavior unexpectedly. This is called mutation. It is currently thought that for a cell to become cancerous it needs to acquire at least four different hits, or particular mutations. Many controls involved in the regulation of growth have to become damaged for the cell to become out of control.
Following this process of initiation or carcinogenesis there must be a way for these cells to continue growing. A supportive environment is required to promote growth; also, ways for the cells to expand, infiltrate surrounding areas, and then break free from their original location to move, lodge, and grow elsewhere. This is a process we call metastasis.
Unfortunately, when we try to isolate the potential genes and proteins involved in the process there are too many of them. They are not easy to target with therapy and, when mutated, they cannot easily be repaired. In addition, each cancer case is different. Despite much effort to understand and target therapies, the pharmaceutical and biotechnology industry has failed to produce more than a handful of useful therapies. Most of the successful targeted therapies are only applicable to specific cases, yet they provide great hope for people. As an example of this, we have been aware of the association between estrogen inhibition and breast cancer recurrence for more than a century. Until the late 1980’s, when the estrogen antagonist, tamoxifen, became available, all we could offer to women with breast cancer was oopherectomy, and this only to pre-menopausal women, who represent only a small proportion of women with breast cancer. Later we learned that the efficacy of tamoxifen was further subject to the expression level of the estrogen receptor in the woman’s tumor, and only 60 % have sufficient expression of this protein. This highlights the fact that not all breast cancers are alike and that not all breast cancers require a similar mechanism to promote their growth.
This leads us to the current issue in hand. When and why should patients use a complimentary therapy for the treatment of their cancer? The definition that authors use for this book is that complementary treatment is used to aid or help the current existing therapies employed by standard oncology practice and should not attempt to cure or be used as alternatives to accepted therapies. There are very few cancers where chemotherapy, radiation, hormonal therapy, and immunotherapy such as cytokines or monoclonal antibodies are not used to compliment surgery and so are not viable independent treatments for cancer. They are most commonly used as adjuvants or as palliative treatment in the case of advanced disease. Therefore, the purpose of the suggested treatments is to enhance the effect of the standard therapies, reduce their side effects and toxicities, and potentially improve functions that can improve clinical and survival outcomes. The following question then arises: What is the burden of proof required in order to use any such therapy to be accepted by the general medical community? Another question raised by the contributors is aimed at challenging the current definition of treatment efficacy for any particular cancer: Are the standards employed by clinical trials for the treatment of cancer relevant for a patient’s life, survival, or the disease? I think the reader will find the chapters in this book informative and detailed. I also think the challenge is real and we may have to rethink our standards for both the treatment and for future evaluation of the treatment of cancer.
Isaac Cohen, O. M. D., L. Ac.Chief Scientific OfficerBionovo, Inc., Emeryville, CaliforniaGuest ScientistUniversity of California, San FranciscoMt. Zion, Comprehensive Cancer Center andDepartment of Ob/Gyn, Center for ReproductiveEndocrinology
1 Introduction to Complementary Medicine in Oncology
Joseph Beuth
Introduction
New developments of complementary medicine in oncology have emerged out of a general disappointment with the results of more traditional treatment options. Despite innovative approaches toward tumor destruction, including surgery, chemotherapy, or radiotherapy, cancer mortality rates have not been reduced in the United States or other industrialized countries in the past twenty years. The age-adjusted mortality rates have even increased by about 6 %. Notable treatment success has only been achieved in rare cancers (such as leukemia, lymphomas, and testicular carcinoma) (3).
Global analyses conducted independently by Abel (1) and Moss (16) dampened the optimism associated with chemotherapy for advanced carcinomas, especially when “responses” (temporary tumor shrinkages) are used as a measure of therapeutic success.
These authors urged the medical establishment to think about new therapeutic strategies. While conventional oncology still promoted the application of high-dose chemotherapy, which can only be survived through measures of intensive clinical care, some less toxic complementary approaches underwent scientific and clinical trials.
The effectiveness of high-dose chemotherapy of epithelial tumors (e. g., breast cancer) still remains to be proved (15). The use of chemotherapy for advanced tumors does not result in significant survival outcomes (1, 16). A statement made by the drug administration in Germany, about unconventional alternatives with respect to aggressive tumor treatment, should be mentioned: “The practice of drug therapy as the main pillar of treatment offered in medicine by all industrialized nations is based on the scientific acknowledgement of certain laws (drug-receptor interactions, dose-response relationships, demonstrated effects on the disturbed regulation of biochemical and psycho-physiological processes) and on the testing of these medicines according to internationally accepted clinical-pharmacological and biometric methods.” (7)
The consistent application of this statement should result in an ethical consensus and lead to the following set of requirements:
• Scientific study and evaluation (proof of efficacy) of all therapeutic concepts
• Limitation to diagnostics and therapeutics with proved efficacy and their inclusion into health insurance plans
• Development of a comprehensive plan for adequate prevention, prophylaxis, diagnosis, therapy, and follow-up of cancer
While the importance of tumor prevention has moved into the forefront of public consciousness, due to intense awareness campaigns by the cancer societies of various nations, the areas that include diagnosis, therapy, and follow-up need to catch up. Widespread passive follow-up ought to be replaced with an active treatment plan tailored to the respective indications of the patient's disease. In order to reach this goal, oncologists should aim to expand on proved complementary medicinal approaches and optimize the timing of therapy. Particularly the induction of immune suppression (11, 13), the surgery-induced spread of metastases (10), as well as the impairment of quality of life (9, 13) due to the use of traditional therapies can be compensated by a timely combination with complementary medicinal approaches.
Overview of Methods
Complementary medicine should primarily be seen as an addition or enhancement of current standard treatment options in oncology. It is to be differentiated from “alternative medicine,” which seeks to find replacements for conventional toxic approaches. Although complementary and alternative medicines are grouped together in the popular acronym “CAM,” they are in fact quite different in their aims. Since many alternative treatments are still poorly documented, equating the two could lead to a misguided and undeserved rejection of all complementary medicine.
That many of the methods discussed in this book can complement standard treatment has been proved in clinical trials that have shown an increase in the quality of life, as well as in total survival time. Biometrically secured and prospectively randomized data are presented for these approaches, for the most part from placebo-controlled clinical trials and cohort trials according to Good Epidemiological Practice (GEP), which will be described shortly (Table 1.1).
Nutrition Advice
The National Cancer Institute of the United States attributes about 35 % of all types of cancer to malnutrition (5, 17). The potential for prevention of cancer is thus large, and general nutrition guidelines for primary and secondary prevention are of much value (according to the German Society of Nutrition [DGE] and the American Institute for Cancer Research).
Once cancer becomes apparent, success of therapy, or the healing process, is decisively determined by the patient's nutritional state. Fundamentally, a specific advisory for the patient's optimized nutrition is of great importance at this point, since malnutrition and cachexia can have a significant effect on the quality and duration of life. Malnutrition increases cancer mortality by about 30% (17), and cachexia worsens the prognosis of disease significantly, since it is associated with reduced response to treatment, more complications, and therefore prolonged hospitalization.
Exercise, Physical Activity
Focused gymnastics, moderate exercise (of longer duration), or physical activity has proved beneficial in the prevention and follow-up of cancer (2, 21). This has led to:
• Improvement in bodily functions, including regeneration of previous abilities (for example, restitution of shoulder-arm-joint mobility after cancer-destructive therapy for breast cancer).
• Activation/modulation of hormones and immune system responses and positive influence on mood, sensitivity to pain and quality of life through the release of neuropeptides (e.g., β-endorphins).
• Result in psychological stabilization through social contacts (sense of belonging to a team or group).
Psycho-Oncological Support
Psychotherapeutic measures should be an integral part of any immediate treatment or rehabilitation of today's cancer patient. It is widely known that handicaps may lead to psychosomatic diseases and that these can be relieved or even cured with appropriate psychological aid or therapeutic modalities.
In addition, psychotherapeutic measures are indicated for dealing with disease in the following types of problems and symptoms:
• Emotional disturbances, such as fear and depression
• Conflicts within a relationship or family
• Impairment in social behavior
• Social withdrawal tendencies
• Psychological impairment with physical decline and deterioration
• Problems in accepting the disease
• Discrepancies between therapeutic expectancy and actual treatment options
• Inadequate behavior toward disease
Psychotherapy is an integral part of acute and rehabilitative treatment in oncology.
Substitution of Essential Minerals and Vitamins
The cancer patient has an increased requirement for essential micronutrients that are rarely adequately supplied even through a wholesome and balanced diet. This especially holds true before or during tumor-destructive therapy, since the need for micronutrients in these phases is increased due to side effects such as reduced appetite, nausea, vomiting, diarrhea, and perspiration.
It has been demonstrated that a deficit in micronutrients (vitamins and minerals) results in a reduced tolerance of current standard cancer therapy.
The role of micronutrients in the primary and secondary prevention of cancer is multifunctional. Vitamins and minerals inhibit the activation of cancer-causing substances as well as inflammatory processes. Other micronutrients can prevent the reuptake of cancer-inducing substances into the cell and protect cellular DNA by disabling the adhesion of cancerous compounds (2, 17).
The indication-specific substitution with essential micronutrients (combination of balanced vitamins and minerals) as a prevention of cancer as well as a compensation of therapy-induced nutritive deficits has proved beneficial in intervention studies and controlled clinical trials.
Enzyme Substitution
A standard combination of proteolytic enzymes (papain, trypsin, chymotrypsin) resulted in a reduction of disease and therapy-induced symptoms, depending on the stage of disease progression as well as the type of cancer (results were noticeable in patients with plasmacytoma, colorectal cancer, and breast cancer). Additionally, an increase in quality of life, survival time and regression intervals, or metastasis-free intervals was noticed (4). Treatment with proteolytic enzymes that are adapted to the respective stage and type of cancer, may enhance standard therapy and now qualifies as evidence-based medicine.
Phytotherapy
Treatment with mistletoe extract as the prototype of phytotherapy is the most common complementary procedure in Central European oncology. According to a questionnaire, more than 80% of all German cancer patients use some form of complementary therapy (62% use mistletoe extracts) (20). Patients give the following reasons for complementary use of mistletoe extracts:
• Involvement of patients themselves in the process of cure and coping with disease
• Optimization of standard therapy
• Reduction in side effects of standard therapy
• Augmentation of patient's immune system
• Desire for a holistic approach of therapy
• Wish to not leave any option untried
Current medical therapy with mistletoe extracts is performed using standardized lectin extracts. Preclinical research using mistletoe extracts or its defined components (lectins, viscotoxins, polysaccharides, vesicles) are far advanced. The following results have been noticed:
• Immune modulation
• Cytotoxicity
• Induction of apoptosis
• Stabilization of DNA
• Antitumor effect
• Anti-infectious effect
Initial controlled trials showed stage-specific effects in certain cancers (breast carcinoma, colorectal carcinoma, glioblastoma): reduction in side effects with simultaneous improvement in quality of life and reproducible immune system regeneration using mistletoe extract therapy (8, 9,12, 13). Also, an effect on survival was noticed using standardized mistletoe therapy in an intervention trial.
Mistletoe therapy has proved useful in controlled clinical trials performed by the author and others. One should keep in mind the stage and type of cancer, since clinical trials have shown that mistletoe therapy has no advantage, for example, in patients with epithelial cancer of the throat (19). Systemic diseases (leukemia, lymphoma) are a contraindication for immunotherapies with mistletoe extracts.
Thymic Peptide Therapy
Standardized thymic peptide preparations (i. e., biochemically defined fractions of thymic peptides, such as thymosin α-1, thymopentin, thymic humoral factor) are applied to stimulate the immune system (e. g., in the event of immune suppression following standard therapy). Experimental and preclinical effects have been demonstrated for these substances (including the modulation, stimulation, or restoration of immune cells, and antitumor, antimetastasic, or antiviral activity). In addition following application, there are well-documented observations that demonstrate a positive influence on the immune system and the quality of life (such as the reduction in the side effects of tumor-aggressive therapeutic measures) (14).
At this point, it should be mentioned, however, that mere observational studies do not result in definitive proof of efficacy.
Despite many clinical studies, it yet remains to be proved whether treatment with thymic peptides can effectively prevent relapse and metastasis and thereby prolong survival time. All trials showed certain weaknesses and deficits and have not met the criteria of scientific standards. The initial trials that were non-GCP-compliant were promising (14) and still need to demonstrate proof of efficacy in current GCP-compliant multicenter studies.
Probiotic Therapy
The secretory immune system of the gastrointestinal tract is considered part of the humoral immune system (MALT - mucosa-associated lymphoid tissue). Also part of this system are the mucosa of the respiratory tract (BALT - bronchial-associated lymphoid tissue), the mucosa of the urogenital tract, and the mammary glands. It has been proved experimentally that the physiological function of the immune system is closely related to the mucosal microflora. This is the underlying principle upon which the outcome of microbiological (probiotic) therapy rests.
Probiotics (e. g., Propionobacterium species, Lactobacillus species, Enterococcus species, Bifidobacterium species) belong to the physiological microflora of the body and have shown to be efficient immune modulators in clinical and experimental trials (11).
Blockade of Adhesion Molecules
A specific adhesion mechanism of hepatocytes and tumor cells has been observed through clinical studies of tissue and tumor cells. Experimental in-vitro trials, as well as in-vivo studies (using murine tumor models), have proved that metastasis in the liver is initiated through galactoside-specific binding of hepatic lectins to the terminal galactose on tumor cell receptors.
The blockade of liver lectins resulted in a numerically significant reduction of liver metastases in two experimental murine models. This well-documented fundamental mechanism presents the opportunity of blocking liver lectins through galactoglycoconjugates during the perioperative time period, when the tumor cells reach the circulation.
Three controlled clinical trials have shown that by blocking liver lectins through perioperative galactose infusions, the adhesion of tumor cells and the development of liver metastases have significantly been reduced in patients with colorectal or gastric cancer (10). A validation study has to further prove the value of this promising complementary therapeutic strategy.
Hyperthermia
Hyperthermia is based on external physical heat application and can be categorized according to its focus and extent of expansion into:
• Whole body hyperthermia: treatment of advanced-stage cancer
• Deep hyperthermia: treatment of localized cancer, for example, of internal organs or bones
• Superficial hyperthermia: treatment of skin cancer/metastases
• Perfusion hyperthermia: treatment of cancerous/metastatic invasion of hollow organs
• Interstitial thermography/hyperthermia: treatment of regional cancer
A combination of hyperthermia with standard or immune therapies is expected to result in additive and synergistic effects. Hyperthermia (in combination with chemotherapy/radiotherapy) is currently being subjected to scientific testing worldwide. It is absolutely vital to perform evaluations of this therapeutic measure without preconceived notions. Hyperthermia has been used for many centuries as a tumor-reductive therapy. Although there are many clinical trials (PubMed cites 400 references to randomized controlled trials), there is still a lack of definitive clinical results. The first controlled clinical studies have been promising and all seem to point to hyperthermia as a complementary treatment measure that enhances standard tumor-destructive therapies.
All of the aforementioned therapeutic approaches are currently being evaluated further, and exaggerated claims are unwarranted. Since proof of efficacy for specific tumor types and stages is measured separately, additional studies must be completed so that defined complementary medicinal concepts may be integrated into evidence-based oncology.
Occasional discrediting of complementary procedures as scientifically unfounded is the result of inappropriate equation with unsound fringe methods. Relevant complementary oncology procedures are currently being studied in standardized GCP/GEP-compliant trials for efficacy, which serves to safeguard the patient. The studies are, in addition, visibly positioned in the guidelines of specialty groups to improve quality assurance.
Fringe Methods
It is imperative to beware of unsound therapeutic and diagnostic measures that have not undergone any scientific testing for efficacy, but are sometimes erroneously associated with scientifically proved complementary medicine. These procedures are being intensely advertised (internet, television, tabloids) and wrongly suggest the following after application:
• Reduction in tumor growth and mass
• Slowing of growth of metastases
• Prolongation of survival time
• They are the sole beneficial treatment modality after all other options have failed
• Delay of the necessity of chemotherapy
• Intensified chemotherapy and radiotherapy effectiveness
Although we should always remain open to new concepts, such procedures are usually not based on sound scientific principles and may ultimately prove life-threatening for the patient (if he or she delays possibly curative measures).
Table 1.2Examples of diagnostic and therapeutic procedures that have not been sufficiently evaluated
Promotion can take the shape of directly advertising a doctor's practice to the public. Since this is still looked at with considerable suspicion, there is also a strong undercurrent of indirect and masked promotion, with the worrisome result that doctors are guided less and less by conscientious check on the quality of their actions according to an ethical standpoint. It is not surprising that self-proclaimed expertise and financial remuneration of ambitious individuals, as well as irresponsible and exaggerated advertisement of scientifically unsound and insufficiently evaluated (and usually costly) therapeutic and diagnostic procedures are more and more commonly seen in medical practice.
In addition, this especially holds true for all specialties in which chronically diseased and fearful patients must be managed just as well as they are in the field of oncology. It has become common for self-proclaimed “specialists” in their area of expertise to abuse public health organizations and self-help groups by giving presentations and slide shows in an attempt to acquire patients. One has also seen the growth of disreputable clinics, practices, laboratories, and unproved diagnostic and therapeutic procedures with promises of a cure.
The chronically ill cancer patient is often ridden with survival fears in addition to sacrificing quality of life. Although many such patients have become self-educated “experts” on their own disease, others are at the mercy of their attending doctors. This leaves the door open for considerable abuse with recommendations for diagnostics and medications with no proven effectiveness or safety.
Conclusion
Complementary procedures in medicine are currently widely debated by the scientific community, because the required scientific proof of effectiveness for most of the therapeutic approaches has not yet been met with definite results. In the past years, basic research and clinical evaluation of defined complementary therapeutic concepts in oncology have been intensified in an attempt to integrate these procedures into evidence-based medicine.
According to definition, scientifically based therapies of complementary medicine cannot replace the much studied conventional tumor-destructive therapies (operation, chemotherapy, and radiotherapy) and are thus not to be seen as “alternative therapy.” Complementary approaches in oncology that are advised as additional therapy to standard tumor-destructive therapy claim to optimize this therapy. The first data emerging from scientifically sound clinical trials prove that defined complementary procedures are beneficial for the patient.
References
1. Abel U: Chemotherapie fortgeschrittener Karzinome. Stuttgart, Germany: Hippokrates Verlag; 1995.
2. Arnold von Versen B: Der Einsatz von Mikronährstoffen bei Tumorerkrankungen und zur Tumorprävention. Dtsch Z Onkol. 2001; 33:19–29.
3. Bailar JC, Gornik HL: Cancer undefeated. N Engl J Med. 1997; 336:1569–1574.
4. Beuth J, Ost B, Pakdaman A, et al.: Impact of complementary oral enzyme application on the postoperative treatment results of breast cancer patients–results of an epidemiological mulitcentre retrolective cohort study. Cancer Chemother Pharmacol. 2001; 47:53–62.
5. Doll R, Peto R: The causes of cancer. Quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981; 66:1193–1208.
6. Grossarth-Maticek R, Kiene H, Baumgartner SM, et al.: Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Alternative Therapies. 2001; 7:57–78.
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2 The Conventional Treatment of Cancer: The Case of Non-Small Cell Lung Cancer
Ralph W. Moss Ph. D.
Introduction
The purpose of this chapter is to review critically the three main conventional treatments for cancer: surgery, radiotherapy, and chemotherapy. I will illustrate problems involved in assessing their effectiveness by focusing on one kind of malignancy, non-small cell lung cancer (NSCLC). I have chosen lung cancer because it is among the most prevalent causes of cancer death worldwide and NSCLC is overwhelmingly the most common type of cancer at this anatomical site. I shall discuss the effectiveness of the standard methods in the treatment of various stages and substages of the disease.
The central question is whether conventional treatments, singly or in combination, have been proved to be effective and reasonably safe. There are many definitions of effectiveness, which leads to widespread confusion. Some people think effectiveness should be measured by the complete removal en bloc of a growth and its surrounding tissue; by the prevention of local, regional, or distant recurrences; or by the shrinkage of measurable tumor for a prescribed length of time.
My definition of effectiveness, however, hinges on an increase in the median overall survival (OS) of all the patients who are given the treatment.
Ideally, a description of effectiveness involves a comparison with patients who do not receive the treatment in question but receive a placebo or “sham” treatment. The effectiveness of any treatment must also be studied in the context of its long-term impact on the patient’s quality of life (QOL).
The best way of attaining such evidence is through prospective, randomized controlled trials (RCTs). According to the Institute of Medicine (IOM) of the US Academy of Sciences, an RCT is:
“… a formal study carried out according to a prospectively defined protocol. It is intended to discover or verify the safety and effectiveness in human beings of interventions to promote well-being, or to prevent, diagnose, or treat illness … Properly conducted clinical trials are a necessity in health care because very few interventions produce such large or striking results that they can be evaluated by observation alone” (1).
What Are the Characteristics of a Successful Clinical Trial?
According to the IOM:
“To generate the most reliable information, clinical trials require certain design characteristics (particularly assignment of participants to interventions by ‘randomization’) and they must include enough participants to exclude the play of chance as a likely explanation for results. … Regardless of the sophistication and complexity of the design and analysis, the question of whether ‘a’ is better than ‘b’ is the essence of the clinical trial” (1).
Since the end of World War II, clinical trials have been widely used throughout the industrialized world for the testing of new drugs and vaccines. After the well-known thalidomide disaster, and the consequent enhancement of the powers of the US Food and Drug Administration (FDA) in 1962, the US government has required clinical trials before it will allow any new diagnostic procedures or therapeutic agents onto the marketplace. (As I shall explain below, this standard has been eroded in recent years.)
RCTs should be large enough to yield a meaningful result (be adequately powered) and should hopefully involve more than one medical center. The RCT is the “gold standard” of testing. There is a perception among both medical professionals and the lay public that the conventional treatments for cancer (primarily surgery, radiation, and chemotherapy), which are in use worldwide, have been proved through this rigorous scientific process. In fact, the presence or absence of RCTs is supposed to form the boundary line between conventionally proved treatments and those nonconventional treatments that are collectively referred to as conventional and alternative medicine (CAM). Any claims of effectiveness for CAM is routinely met with the rejoinder: “Where are the RCTs to support such approaches?”
The question implies that conventional cancer treatments rest on a solid foundation of successful RCTs and that such trials are the basis for declaring these treatments proved and effective. The purpose of this chapter is to determine whether such claims for conventional cancer treatments can in fact be documented through reference to the standard medical database, Medline.
We immediately confront a problem: the focus of FDA reform in the 1960s was pharmacological agents. But two of these three main anticancer modalities, surgery and radiation, were excluded from the stringent 1962 FDA regulations. In legal parlance, they were grandfathered into US law (i. e. accepted based solely on their prior widescale use). Essentially, no formal approval process was deemed necessary before surgery or radiation therapy was employed as treatments for cancer patients. This exemption covered not just past treatments but future ones as well: cancer surgeons and radiation oncologists were essentially given carte blanche from the US government to introduce new or modified techniques for treating cancer. Other governments followed suit.
Perhaps for that reason, clinical trials of these two older modalities are more limited in number and scope than they are for drug-based therapies. In fact, on a percentage basis, there are approximately three times as many RCTs of cancer chemotherapy as there are for cancer surgery (Table 2.1).
However, despite this legal carte blanche, the scientific requirements of proof obviously remain the same for surgery or radiation as for any other treatment. No treatment can be considered effective until and unless it has been subjected to the highest possible standards of proof. Whenever feasible and ethical, this is the RCT. A World Health Organization publication addresses this question. “Radiotherapy must justify its place in the armamentarium of cancer-fighting technologies. Not only must it constantly be subject to clinical trials evaluating its role, it must also be reviewed in terms of its cost–benefit and utility in the circumstances in which it is used” (61). The same should be said of cancer surgery and chemotherapy.
History of Clinical Trials
The idea of comparing one regimen or treatment directly with another is very old (5,15). There is even reference to an early “clinical trial” in the Old Testament. Daniel and his companions were resolved to eat and drink a purely vegetarian diet. But Babylon’s chief palace official feared that “if you eat something else and end up looking worse than the other young men” the King might be angry. And so Daniel proposed the following test: “For the next ten days,” he said, “let us have only vegetables and water at mealtime. When the ten days are up, compare how we look with the other young men, and decide what to do with us…. Ten days later, Daniel and his friends looked healthier and better than the young men who had been served food from the royal palace” (12).
The foundations of the modern RCT were laid in the nineteenth century. A great French physician, Pierre Charles Alexandre Louis (1787–1872), wrote that “the edifice of medicine reposes entirely upon facts, and that truth cannot be elicited, but from those that have been well and completely observed” (45). Through a statistically driven study, Louis showed that bloodletting (the cornerstone of the conventional medicine of his day) was much less effective for inflammations than had previously been supposed. Louis declared that the rate of death of different patient populations “can only be attributed to the employment, or omission, of bloodletting” (44).
But the development of RCTs primarily came from Great Britain before and after World War Two: Major Greenwood (1880–1949) was an early biostatistician who deplored the sloppy substantiation of the claims of most clinicians. One of his students was Austin Bradford Hill (1897–1991). In 1937, the editors of The Lancet asked Hill to write a series of articles on the proper method of applying statistics to medical questions. These articles were later published as the classic work Principles of Medical Statistics. In their preface, the editors prophetically declared:
“In clinical medicine today there is a growing demand for adequate proof of the efficacy of this or that form of treatment. Often proof can come only by means of a collection of records of clinical trials devised on such a scale and in such a form that statistically reliable conclusions can be drawn from them. However great may be our aversion to figures, we cannot escape the conclusion that the solution of most of the problems of clinical or preventive medicine must ultimately depend on them” (30).
