Cancer Today: Origins, Prevention, and Treatment (1984)

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1 Introduction There is a new sense of optimism pervading cancer hospitals and research laboratories. Scientific advances of the past few dec- ades have brought steady increases in the cancer survival rate. It is estimated that nearly 50 percent of all patients diagnosed with cancer in 1984 will be cured (see Figures 1-1, 1-2). A decade ago, the figure was 40 percent. New techniques have been found for early detection and di- agnosis; new therapies are becoming available for treating some of the highly recalcitrant forms of cancer. And in the past few years, molecular biologists have begun to understand the funda- mental nature of the cancer cell. Their work promises to reveal how the disease gets started in its many forms, opening up new possibilities for prevention and treatment. This book describes the This chapter is based on the remarks of Maureen Henderson, University of Washington, and Paul A. Marks, Memorial Sloan-Kettering Cancer Center, at the 1983 annual meeting of the Institute of Medicine. Dr. Henderson served as chairman of the meeting.

CANCER TODAY PERCENT 10 20 30 40 50 60 70 80 90 100 Uterine Cervix Female Breast Prostate Uterine I I I T 1 T 60 Uterine Corpus Kidney Non-Hodgkin's Lymphoma I FIGURE 1-1 Five-year relative survival rates for black patients, 1973-1979. (SOURCE: SEER Program, National Cancer Institute, 1983.)

/NTRODL/C77ON PERCENT 0 10 20 30 40 50 60 70 80 90 100 I I I I I 1 1 I 1 Uterine Corpus • 176 172 48 Melanoma Female Breast Bladder Uterine Cervix Prostate Colon Kidney Rectum Non-Hodgkin's Lymphoma Ovary Brain Stomach Lung Pancreas (ill 2 FIGURE 1-2 Five-year relative survival rates for white patients, 1973-1979. (SOURCE: SEER Program, National Cancer Institute, 1983.) 43

CANCEL TODAY continuing efforts of researchers in a broad spectrum of disciplines to understand and control cancer. Cancer is still a disease of tragic dimensions. One of every four Americans will develop cancer and one in five will die of it, if current incidence and mortality rates remain the same. It is the second largest cause of death in this country, exceeded only by heart disease. In 1984, there will be 870,000 new cases of cancer and 450,000 cancer deaths, approximately 20 percent of all deaths this year (see Table 1-1). Half of all cancer deaths will result from malignancies of the lung, colon and rectum, breast, and pancreas. Lung cancer, which is closely tied to tobacco consumption, alone accounts for over 20 percent of all cancer deaths. Among men, it is the largest cause of cancer death; among women, the second largest (see Figure 1-3). Although the incidence and mortality rates for lung cancer have soared during the last 50 years, the age-adjusted rates for cancers at most other sites have remained steady or declined.1 For some Lung Colon-Rectum 139,000 130,000 121,000 59,000 Breast 116,000 38,000 Prostate 76,000 25,000 Uterus 55,000** 10,000 Urinary Oral 57,000 27,000 19,000 9,000 Pancreas 25,000 23,000 Leukemia 24,000 17,000 Ovary Skin 18,000 18,000*** 12,000 7,000 TABLE 1-1 Estimated New Cases and Deaths for Major Sites of Cancer—1984* Site No. of Cases Deaths *Figures rounded to nearest 1,000. **If carcinoma in situ is included, cases total over 99,000. * "Estimated new cases of nonmelanoma about 400,000. (SOURCE: American Cancer Society, Cancer Facts and Figures 1984.) 1 The actual number of people who develop and die of cancer has increased throughout this period, largely because a major segment of the population is reaching the age when cancers usually develop.

INTRODUCTION < oc 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 YEAR FIGURE 1-3 Age-adjusted cancer death rates by site, United States, 193G- 1979. (SOURCE: American Cancer Society, Cancer Facts and Figures 1984.) cancers, this reflects a drop in the incidence, or the number of new cancer cases; for others, the striking improvements in the cure rate for certain cancers. Cancer takes many forms, striking different types of cells in diverse parts of the body. Each cancer runs its own distinctive course. For instance, although cancer usually appears as a tumor— a visible mass of cancer cells—in leukemia the malignant cells largely remain dispersed throughout the body in the blood and bone marrow. All of these cancers, however, share the same fundamental prop- erties. Cancer is a breakdown of the orderly process of cell growth and differentiation. It seems to begin with a change in a single cell, presumably a mutation in that cell's genetic apparatus. This change transforms the cell profoundly; it begins to divide without restraint, failing to differentiate into its mature form. Eventually, this altered cell will give rise to billions of other aberrant cells,

CANCER TODAY cancer cells, that invade and destroy nearby tissues. As the colony grows, some of these cells will break off, or metastasize, and be carried by the blood or lymph stream to remote parts of the body where they will invade other tissues as well. The first section of this report describes some of the phenomenal strides of the past decade in determining the biological basis of cancer. Specifically, it recounts the discovery of cancer genes and the preliminary insights this research has provided into the genetic and biochemical changes that give rise to cancer. On another front, researchers have been seeking the external factors that cause or contribute to cancer. The role of some agents, including radiation, certain occupational or environmental chem- icals, and tobacco, are well documented. New studies discussed in the second section suggest that diet and nutrition may also be responsible for a significant portion—as much as 30 percent—of all cancers in the United States, which opens up new possibilities for prevention. The work under way in molecular biology laboratories here and abroad promises to profoundly alter approaches to cancer treat- ment and prevention. In the near term, however, the major ad- vances in cancer survival will probably come from improvements in conventional cancer drugs developed over the past three dec- ades, according to Paul A. Marks, president of Memorial Sloan- Kettering Cancer Center. Eventually, the recent discoveries in molecular biology should contribute to the development of a whole new order of chemotherapeutic agents. The final section of this report describes progress and potential in the treatment of cancer, as well as new approaches to ameliorating the devastating psy- chological effects of the disease. The Biology of Cancer In the early 1970s, cancer research was galvanized by the dis- covery of oncogenes, specific genes that can trigger a cell's un- bridled growth. Since that time, close to 30 of these cancer genes have been isolated from both human and animal cells. In laboratory experiments, the activity of a single one of them is often sufficient to transform normal cells to cancer cells.

INTRODUCTION In the past few years, molecular biologists have been able to decipher the genetic code of these cancer genes. To their surprise, they found that the oncogenes are remarkably similar, if not iden- tical, to benign genes that are normally present within the cell. It now appears that each cell contains certain normal genes that when activated or altered in some way can start the cell on the path to cancer. Many cancer researchers suspect that all agents of cancer— radiation, chemicals, and viruses—act upon these genes, some- how releasing their malignant potential. Investigators have already identified several mechanisms that activate these genes, transforming them from an innocuous to a malignant state. More such mechanisms will undoubtedly be dis- covered. One of the greatest challenges to cancer biologists in the coming years will be to determine how the oncogenes differ from normal genes, and where and how they act in the cell to induce cancer. Like other genes, an oncogene directs the synthesis of a protein, which in turn performs some specific biochemical activity within the cell. The key to understanding cancer would seem to lie in these oncogene proteins, for it is their activity that renders the cell malignant. In the past few years, molecular biologists have begun to identify and study some of these cancer proteins, gaining the first glimpses into the biochemical activities that induce cancer. The evidence to date is tantalizing: it suggests that cancer may arise from a very subtle distortion of normal cellular processes. This work is just beginning; many questions remain. It is still not clear whether oncogenes are involved in all or just some can- cers. Nor is it known how they fit into the overall scheme of carcinogenesis, which in humans is a complex process involving many discrete steps and often taking 20 years. While the activation of an oncogene may be a necessary part of this process, it is not sufficent to induce human cancer. If the past few years are any indication, answers to some of these questions may be available in the coming months and years. It is impossible to predict, however, which lines of research will prove the most fruitful. The discoveries that have revealed on- cogenes to date have come from a convergence of some surpris- ingly disparate research pursuits.

CANCER TODAY Investigators were led to human oncogenes by the study of tumor viruses found in experimental animals. Many of the insights into the activation and function of these genes have come from yet other fields. For instance, some 30 years ago Barbara Mc- Clintock first proposed that genes are not static or permanently fixed on the chromosome. Rather, her studies of the corn plant suggested that genes might be capable of moving from place to place on the same chromosome, or even of jumping from chro- mosome to chromosome, thereby altering the expression of nearby genes. Over the past few years, some basic researchers studying the genetics of the human immune system have revealed how McClintock's process of DNA rearrangement might serve to ac- tivate an oncogene, at least in one type of cancer. Although McClintock and others were doing work relevant to understanding cancer decades ago, the technology needed to con- firm their ideas and tie them to the disease process has been avail- able only for the past 10 years or so. Without recombinant DNA and other genetic technologies, most recent research in molecular biology could not have proceeded. It is these technologies that have enabled researchers for the first time to isolate and study a single gene from among the tens of thousands contained in a human cell. The next three chapters of this report describe the discovery of oncogenes and the continuing efforts to determine their function. For those readers who do not choose to dwell long on the intri- cacies of cancer genes, Chapter 2 should suffice to convey both the excitement and the potential of this new field. For those who want a more detailed understanding of the molecular basis of can- cer, Chapters 3 and 4 attempt to provide it in accessible language. Diet and Cancer Even before the discovery of oncogenes, it was thought that cancer, at least in some of its manifestations, was the product of the interaction of genes and the environment. Certain agents, such as ultraviolet and ionizing radiation, some chemicals, and some viruses, can initiate cancer, presumably by causing a genetic mu- tation. From recent work, it is tempting to think that the mutation 8

INTRODUCTION occurs on an oncogene. Still other external or environmental agents can promote or facilitate the process of carcinogenesis without actually inducing it. There is now widespread agreement that roughly 85 percent of all cancers are caused by broad environmental factors, including lifestyle patterns. The rest, presumably, have a hereditary basis, or else arise from spontaneous metabolic events. Identifying the environmental factors in cancer, however, has not been easy. At this stage, viruses appear to play only a minor role in human cancers. Occupational chemicals are thought to be responsible for 4 percent of all cancers; environmental chemicals for an estimated 2 percent. Tobacco is by far the largest documented cause of can- cer, accounting for roughly 30 percent of all cancers in lungs and some other sites. Recently, epidemiological studies similar to those that uncov- ered an association between smoking and cancer have detected a link between the foods that people eat and the cancers that afflict them. Overall, dietary factors are thought to be responsible for another 30 percent of the cancer incidence in the United States, which could mean that a substantial portion of those cancers may be preventable. With a few exceptions, the studies have not turned up specific culprits—certain foods or constitutents of foods that cause cancer. Nor does the major problem appear to be food additives or con- taminants. Rather, as described in Chapter 5, cancer risk is asso- ciated with certain broad dietary patterns and the consumption of major nutrients. Specifically, a diet high in fats and fatty meats seems to carry a risk of cancer. Salt-cured, salt-pickled, and highly spiced foods are also suspect. On the other hand, the consumption of high-fiber grains, vegetables, and fruits seems to protect against cancer. In short, cancer risk appears to be a matter of dietary choice, of the balance and proportion of nutrients in the diet, as well as of methods of food preparation. The case against diet is still circumstantial. These epidemiol- ogical studies have revealed broad associations, not causality. Fur- ther laboratory and clinical studies are necessary to determine ex- actly how diet contributes to cancer. For instance, the specific dietary constituents that may be responsible for observed carcin-

CANCER TODAY ogenic or protective effects are not known, nor are their mecha- nisms of action. Nonetheless, several federal agencies have decided that the weight of evidence is strong enough to suggest that the public modify its eating habits in accordance with the findings of these studies. This is not to imply that a modification in diet would elicit a reduction in cancer incidence similar to the one that would result if smoking were eliminated. Studies to date have made it abun- dantly clear that the relationship of diet to cancer is exceedingly complex. The risk factors in diet cannot simply be eliminated; some of the dietary constitutents that seem to pose greatest cancer risk are essential human nutrients. In addition, as described in Chapter 6, it has become increasingly clear from another line of inquiry that natural mutagens and car- cinogens are ubiquitous throughout the human diet, occurring in common vegetables, fruits, meats, nuts, and beverages. Con- versely, some natural substances, such as the precursor of vitamin A and the mineral selenium, appear to be anticarcinogens, capable of preventing the process of malignant transformation in labora- tory studies. At this stage, the potency of most of the natural carcinogens and the magnitude of risk they pose to human health have not been determined, nor is it known if and how they might interact with anticarcinogens in the diet. What does seem clear, however, is that it will not be possible to specify a risk-free diet. Cancer researchers generally agree that adoption of a low-risk diet should help to prevent some cancers. The exact benefit to be gained, however, cannot be predicted until the biological mech- anisms underlying the association between diet and cancer are better understood. Chapter 7 discusses the implications of these new findings for the federal approach to cancer prevention. Traditionally, the gov- ernment has acted through its regulatory policies to minimize human exposure to harmful substances in foods. It has set stand- ards for food additives and natural contaminants, as well as for pesticide residues and other industrial chemicals that might enter the food supply. Now that foods themselves, not the substances added to them, appear to pose the greatest cancer risk, this reg- 10

INTRODUCTION ulatory approach no longer appears sufficient, although it is cer- tainly a vital element of any food safety policy. Indeed, the most effective strategy for preventing cancer may simply be to provide information that will help consumers make intelligent dietary de- cisions, giving them an increasing share of the responsibility for their own protection. Cancer Medicine The impressive gains in cancer survival of the past three decades stem in large part from advances in chemotherapy. When the effort to develop cancer drugs and appropriate therapeutic regimens began in the 1940s, investigators had few clues into the nature of carcin- ogenesis and thus little rational basis for testing one compound over another. Trial and error played a substantial part in early chemo- therapy research, as described in Chapter 8. From 1955 to 1975, some 40,000 compounds were screened each year in hope of finding a few capable of killing cancer cells. Once those compounds were detected, clinical investigators tried them in various doses and combinations until they found the most effective regimen. Some 30 chemotherapeutic agents are now available, most of them developed beween 1940 and 1965. Their use has brought a dramatic reversal in the prognosis for some types of cancer. For instance, in 1955 virtually every child afflicted with acute lym- phocytic leukemia died of the disease, usually within a few months of diagnosis. Today the cure rate is 58 percent. Despite these dramatic successes, chemotherapy has several lim- itations. One is the ease with which cancer cells can become re- sistant to many of these drugs, rendering them ineffective. Another is the extreme toxicity of certain cancer drugs. Chemotherapeutic agents work by killing cancer cells, and they invariably kill some normal cells as well. The cells in the intestinal mucosa, bone mar- row, and hair follicles are the most vulnerable to attack, which explains the common side effects of nausea, vomiting, and hair loss. Perhaps more important, none of the existing agents is totally effective against the most prevalent form of cancer, the carcino- 11

CANCER TODAY mas, or malignancies of the epithelial tissues, which develop in the head, neck, breast, lung, bowel, and other organs. The search for new antitumor agents is continuing, as are efforts to increase the effectiveness or reduce the side effects of existing drugs. For the future, advances in molecular biology—both in the understanding of the nature of cancerous transformation and in the refinement of genetic engineering techniques—offer novel ap- proaches to chemotherapy. As mentioned earlier, toxicity is a problem because it has not been possible to target a cytotoxic drug exclusively to cancer cells. The new genetic technologies may change that. Tumor cells bear distinctive antigens, or proteins, on their surface. Investigators are now trying to develop very specific antibodies, known as mono- clonal antibodies, that will interact with only those tumor antigens. Conceivably, these antibodies could be used to deliver a cancer drug to that cell and that cell alone. Genetic technologies may also provide methods of arresting cancer without relying on cytotoxic drugs. One approach under study would enlist the aid of some of the substances, such as interferon and growth factors, that cells produce to regulate their growth and provide defense against disease. It may also be possible to manipulate the immune system so that it is better able to fight off cancer. Eventually, it may even prove feasible to turn off oncogenes and halt the process of carcinogenesis, or perhaps to somehow interfere with the oncogene protein product. Early Detection The chances of successful treatment are greatly enhanced if the cancer is discovered at an early stage, before it has invaded adjacent tissues. One factor in the increasing cure rate has been the intro- duction of techniques for the early detection of cancer. For in- stance, the widespread adoption of the "Pap smear" has been credited with a 50 percent decline in the death rate from cervical cancer in the United States. According to Paul Marks, new tech- niques for diagnosing tumors at early stages may offer the greatest near-term potential for improving the ability to treat common cancers. 12

/NTRODUCT/ON Researchers are now studying techniques to enable the detection of minute tumors and even microscopic metastases in inaccessible parts of the body. Although this work is not covered in this report, it deserves mention here because of its vast potential for improving cancer treatment and survival. Such techniques would be useful not only in the early detection of cancer, but also as diagnostic devices to determine how far the cancer has spread, or to monitor the patient's response to therapy and warn of any recurrence at an early stage. Genetic engineering technology makes possible the large-scale production of specific cancer antibodies, which can also be used in diagnosis. Labeled with a radioactive tag, these antibodies can search out minute tumors or dispersed cancer cells. The new imaging techniques also show considerable promise for detecting tumors in inaccessible sites. The CAT scan, or com- puterized axial tomograph, involves the use of a computer to reconstruct X-ray data into images of plane sections of the body. Nuclear magnetic resonance, or NMR, which uses magnetic fields to produce a cross-sectional image of the body, has the added advantage of sparing the patient exposure to potentially harmful X rays. The Psychological Effects of Cancer Until recently, most clinical research has focused on methods to detect and treat cancer—surgery to cut away the tumor, drugs and radiation to shrink or destroy it. Yet there has also been a growing realization that to effectively treat cancer, the clinician must understand not only the physical course of the disease, but its effects on the psyche as well. The past decade has seen the emergence of psychosocial research on cancer care, which seeks to understand and mitigate the psychological and social conse- quences of cancer (Chapter 9). Investigators have found, for example, that advances in cancer treatment have spawned an entirely new set of issues, those of the cured cancer patient. These cancer survivors, as they are called, face medical, psychological, and social problems during the tran- sition back to an active, healthy life. For one, their future health 13

CANCER TODAY is uncertain: they are at risk of developing a secondary malignancy or they may suffer consequences from chemotherapy or radiation therapy, such as damage to reproductive organs. Little is known about the long-term effects of these traumatic therapies. Investi- gations are now under way to determine the extent of these and other physical problems, as well as the psychological scars that may linger after the symptoms of the disease have disappeared. Similarly, at some time during or after treatment, all patients experience bouts of emotional turmoil—anger, depression, anx- iety, and above all, fear. For some patients, the distress can be debilitating, warranting psychiatric intervention of some kind. Yet all too often the turmoil and depression have been considered an inevitable consequence of cancer, as have the stresses on the family and the medical staff, and little has been done to alleviate them. Psychosocial researchers are now beginning to assess the effec- tiveness of psychotropic drugs and counseling for cancer patients. Others are studying the psychological and social problems con- fronting the family and medical staff. One of the most obvious expressions of the increased concern for the emotional as well as physical well-being of cancer patients is the emergence of the hospice movement in the United States. The first U.S. hospice, a center for treatment of terminally ill patients, was established in 1974; now over 1,000 institutions throughout the country offer hospice care. Hospices focus on emo- tional support and relief of pain, rather than on intensive, continual medical interventions that may serve to prolong life by a few days or weeks. Families and friends play a major role in patient care; indeed, the patient often remains at home throughout the illness. The first major study comparing hospice with conventional care is summarized in Chapter 10. This study, mandated by Congress, turned up distinct differences in the type of medical and social services a patient is likely to receive in each system, concluding that each apparently has distinct advantages for certain types of patients. Implications For several decades, clinical investigators have been quietly working at improving the lot of the cancer patient. They have 14

/NTKODt/CT/ON developed better diagnostic techniques; drugs with fewer side ef- fects; less disfiguring forms of surgery; safer, more effective uses of radiation; and new types of care for those patients who will ultimately succumb to cancer. During this time, epidemiologists have identified some of the external factors that cause or contribute to cancer. And most re- cently, molecular biologists have begun to understand how the disease is initiated within the cell. The implication of this massive research effort, says Paul Marks, is not that cancer will fade away in the next few years, or even decades. Indeed, he adds, the discovery of oncogenes suggests that cancer may be an integral part of living, the result of the interaction of our genes with the environment. Certainly, an understanding of the fundamental nature of carcinogenesis will transform the nature of clinical care. But it will not yield a magic bullet to cure the disease, nor a vaccine to prevent it. Cancer will not be erad- icated like smallpox or polio. Rather, what seems likely to emerge are new approaches to early diagnosis of cancers and new tech- niques to treat them, providing steady gains in our ability to cure and, more important, to prevent cancer. 15