The War on Cancer (eBook)

ACKNOWLEDGEMENTS 7
TABLE OF CONTENTS 11
INTRODUCTION 16
PART I CANCER STATISTICS: SOME FACTS 19
Chapter 1 ASSESSING THE MAGNITUDE OF THE PROBLEM 20
1. CANCER STATISTICS 21
1.1 How are statistics collected? 21
1.2 How statistics are reported and what they mean 22
1.3 Cancer incidence and mortality in the United States, 2004 22
1.4 Individual probability of developing and dying of cancer in the US 25
2. CANCER PREVALENCE IN THE US, 2000 26
3. HISTORICAL TRENDS: INCIDENCE, MORTALITY AND SURVIVAL, 1950- 2000 27
3.1 Incidence and mortality 27
3.2 Survival statistics 30
Chapter 2 THE PROBLEM IS GROWING, NOT GOING AWAY 34
PART II What is cancer? 38
Chapter 3 CANCER THROUGH THE AGES 40
1. FROM ANCIENT EGYPT TO GREECE AND ROME 41
2. THE MIDDLE AGES: BYZANTIUM, THE MUSLIMS, AND THE PRE- RENAISSANCE 42
3. FROM THE RENAISSANCE TO WORLD WAR II 43
Chapter 4 OUR CURRENT UNDERSTANDING 52
1. THE GENETIC BASIS OF CANCER 52
1.1 First the basics 52
2. HOW DOES CANCER ARISE? 68
2.1 First the basics 68
2.2 More details 69
3. HOW DOES CANCER SPREAD? 73
3.1 Local invasiveness 73
3.2 Metastases 74
PART III HOW IS CANCER TREATED? 77
Chapter 5 THE CANCER CELL-KILL PARADIGM AND ITS COROLLARIES 78
Chapter 6 CHEMOTHERAPY DRUGS 84
1. HISTORICAL BACKGROUND: MUSTARD GAS 84
2. FIFTY YEARS OF ANTI-CANCER DRUG DISCOVERY: THE ROLE OF SERENDIPITY AND TRIAL & ERROR
3. FORTY YEARS OF ATTEMPTS TO OVERCOME CANCER DRUG INEFFICACY 89
Chapter 7 TREATMENT OUTCOMES: DISMAL BY ANY STANDARD 100
PART IV WHY DOES THIS SYSTEM PERSIST? 107
Chapter 8 THE ROLE OF THE NATIONAL CANCER INSTITUTE 109
1. HISTORICAL BACKGROUND 109
3. CANCER CENTERS PROGRAM 114
4. COOPERATIVE TRIALS STRUCTURE 114
Chapter 9 PUBLICATIONS: THE FACTS AND NOTHING BUT THE FACTS? 124
Chapter 10 FROM THE DOCTORS' PERSPECTIVE 130
1. PHYSICIANS' QUALIFICATIONS 130
1.1 Training and board certification 130
1.2 Continuing Medical Education 132
2. FACTORS THAT DICTATE CANCER TREATMENT 134
2.1 The imperatives of "standard of care" 135
2.2 Financial incentives or “the chemotherapy concession” 137
Chapter 11 FROM THE PATIENTS' PERSPECTIVE 142
1. PATIENTS' PERCEPTIONS AND EXPECTATIONS 142
1.2 Disclosure in the community setting 146
2. FACING HARD CHOICES 149
2.1 When to withhold or withdraw treatment 150
2.2 Managing patients with refractory cancers 153
PART V WHERE DO WE GO FROM HERE ? 158
Chapter 12 A VISION FOR THE FUTURE 160
1. CANCER PREVENTION 161
1.1 Tobacco 163
1.2 Cancer viruses 167
2. CANCER SCREENING 170
2.1 Prostate cancer 172
2.2 Breast cancer 175
3. WHEN PREVENTION AND SCREENING FAIL: A NEW CANCER TREATMENT PARADIGM 179
3.1 The bcr/abl fusion gene: a prototypic molecular target 181
3.2 The genome and proteome as bases for anti-cancer drugs 184
Chapter 13 SHIFTING FROM THE CELL-KILL PARADIGM TO PHARMACOGENOMICS 186
1. A BLUEPRINT FOR FUTURE CLINICAL CANCER RESEARCH 187
2. A BLUEPRINT FOR FUTURE PATIENT MANAGEMENT: PROPORTIONAL AND COMPASSIONATE 191
CONCLUSIONS 196
REFERENCES 199
GLOSSARY 224
INDEX 236

Chapter 4
OUR CURRENT UNDERSTANDING (p. 37-38)

1. THE GENETIC BASIS OF CANCER

1.1 First the basics

Cancer is not one disease but an assortment of over 200 diverse diseases that can arise from all tissues and organs. For example, cancers arising from blood cells are called leukemias; those arising from organ tissues such as the liver or the lungs are called solid tumors. More than one type of cancer can originate from an organ or tissue, as is the case of Lymphomas, a group of malignancies of the lymphatic system, encompassing more than 20 related cancers, depending on the classification used ^69,70.

Cancers can exhibit slow growth patterns compatible with long and symptom-free survival, such as indolent lymphomas or chronic lymphocytic leukemia ^71,72, or can quickly progress causing symptoms and death in only a few months, as is the case of acute myelocytic leukemia and pancreatic cancer ⁷³. Likewise, some cancers quickly spread distally from the site of origin, such as colon, prostate, and lung cancer that often reach liver, bone, and brain, respectively. Others tend to invade locally as is the case of head and neck cancers.

Yet, despite their heterogeneous origin, distinct clinical features, and vastly different course and outcome, the underlying genetic processes leading to their development, growth, and dissemination are similar. The master blueprint that determines the structure and function of all organisms, including man, is called the "genome". Each of the approximately 30 trillion cells that make a human being contains a copy of the entire genome and its approximately 30,000 "genes", neatly packaged in 46 microscopic units called "chromosomes" found bundled in the cell "nucleus".

Genes are deoxyribonucleic acid (DNA) sequences that contain the code for cells to produce proteins, which are the signals that control the structure and function of each cell, of each organ, and ultimately of the entire organism. These cell-produced, cell-targeted protein signals are at the center of the interdependent relationship that characterizes both the harmonious function of normal cells, and the aberrant behavior of cancer cells. Thus, the genome can be thought of as the book of life where chromosomes are chapters and genes are the carefully crafted sentences made of precise words spelled with "nucleotide bases", all sequentially arranged on the DNA molecule.

During the process of cell division and of human reproduction the entire genome must be duplicated and passed from cell to cell and from parent to offspring. While this process is prodigiously accurate, "spelling" errors do occur. Minor alterations are corrected by "DNA repair" genes. Major errors activate "gate-keeper" genes that block cell replication and force the cell to commit suicide ("apoptosis"). The role of DNA repair and gate-keeper genes is to ensure genomic integrity as cells advance through their replication cycle ("cell cycle"). However, occasional non-lethal alterations escape detection, repair, or blockade and are transmitted from a replicating cell to its daughter cells.

Transmitted alterations of DNA sequences outside of genes, called "polymorphism", are neither beneficial nor harmful to the cell or the host. Conversely, transmitted alterations within gene sequences, called "mutations", are responsible for approximately 4,000 human diseases, including cancer. When mutations affect an egg or a sperm, they can be transmitted to future generations, resulting in familial predisposition to diseases such as hemophilia, and to some cancers such as retinoblastoma. At present, the genetic fingerprints of most cancers are not known mainly because insensitive detection techniques of the pre-genomic era uncovered mostly structural chromosomal abnormalities visible by light microscopy that are seldom disease-specific. While diagnostically and prognostically valuable in the clinical setting, such gross abnormalities seldom provide insight into the genetic defects responsible for the development, growth, and dissemination of cancer.