by Sherwin Nuland
The Malevolence of Cancer As early as the days of Hippocrates and even before, the ancient Greek physicians had a clear understanding of the ways in which a malignant growth so often pursues its inexorable determination to destroy life. They gave a very specific name to the hard swellings and ulcerations they so commonly saw in the breast or protruding from the rectum or vagina; they based that name on the evidence of their eyes and fingers. To distinguish them from ordinary swellings, which they called oncos, they used the term karkinos, or "crab," derived, interestingly enough, from an Indo-European root meaning "hard." Oma being a suffix referring to "tumor," karkinoma was used to designate a tumorous growth that was malignant. Centuries later, the Latin word for "crab," cancer, came into common usage. Oncos, meantime, came to be applied to tumors of any kind, which is why we call a cancer specialist an oncologist. Karkinoma was said to be due to the stagnation within the body of an excess of a hypothetical fluid called black bile, or melan cholos (frommelas, "black" and chole, "bile"). Since the Greeks did not dissect the human body, the cancers they saw were ulcerated malignancies of the breast or skin, and those of the rectum and female genital tract which had grown so large that they protruded through body openings. Accordingly, the fanciful explanation was supported by the common observation that cancer patients were indeed melancholy, and for obvious good reason. The origin of karkinos and karkinoma was based, as were so many Greek medical terms, on simple observation and touch. As Galen, the foremost interpreter and codifier of Greek medicine, put it in the second century a.d., the appearance of this creeping, infiltrating stony mass, ulcerated at its center, which he so often saw in the breasts of women, is "just like a crab's legs extending outward from every part of its body." And it is not only the legs that are digging farther and deeper into the flesh of its victim — the center, too, is eroding its way directly through her. The likeness is to an insidious, groping parasite, attached by sharp-clawed tentacles to the decaying surface of its imperiled prey. The clawing extremities ceaselessly extend the periphery of their malign grip, while the loathsome core of the burrowing beast eats silently away at life, able to digest only what it has first decomposed. The process is noiseless; it has no recognizable instant of beginning and it ends only when the despoiler has consumed the final remnants of its host's vital forces. Until after the middle of the nineteenth century, cancer was thought to do its killing by stealth. Its lurking force lay under the cover of hushed darkness, its first sting felt only when murderous infiltration had strangled too much normal tissue to restore the overwhelmed defenses of its host. The perpetrator regurgitated as malignant gangrene the life it had noiselessly chewed up. We know better now, because we have come to recognize a different personality when our old enemy is seen through the microscope of contemporary science. Cancer, far from being a clandestine foe, is in fact berserk with the malicious exuberance of killing. The disease pursues a continuous, uninhibited, circumferential, barn-burning expedition of destructiveness, in which it heeds no rules, follows no commands, and explodes all resistance in a homicidal riot of devastation. Its cells behave like the members of a barbarian horde run amok — leaderless and undirected, but with a single- minded purpose: to plunder everything within reach. This is what medical scientists mean when they use the word autonomy. The form and rate of multiplication of the murderous cells violate every rule of decorum within the living animal whose vital nutrients nourish it only to be destroyed by this enlarging atrocity that has sprung newborn from its own protoplasm. In this sense, cancer is not a parasite. Galen was wrong to call it praeter naturam, "outside of nature." Its first cells are the bastard offspring of unsuspecting parents who ultimately reject them because they are ugly, deformed, and unruly. In the community of living tissues, the uncontrolled mob of misfits that is cancer behaves like a gang of perpetually wilding adolescents. They are the juvenile delinquents of cellular society. Cancer is best viewed as a disease of altered maturation; it is the result of a multistage process of growth and development having gone awry. Under ordinary conditions, normal cells are constantly being replenished as they die, not only by the reproduction of their younger survivors but also by an actively reproducing group of progenitors called stem cells. Stem cells are very immature forms with enormous potential to create new tissue. In order for the progeny of the stem cells to progress to normal maturity, they must pass through a series of steps. As they get closer to full maturity, they lose their ability to proliferate rapidly in proportion to the increase in their ability to perform the functions for which they are intended as grown-ups. A fully mature cell of the intestinal lining, for example, absorbs nutriments from the cavity of the gut a lot more efficiently than it reproduces; a fully mature thyroid cell is at its best when it secretes hormone, but it is much less inclined to reproduce than it was while younger. The analogy with the social behavior of a whole organism, like us, is inescapable. A tumor cell is one that has somewhere along the way been stopped in its capacity to differentiate, which is the term used by scientists for the process by which cells go through the steps that enable them to reach healthy adulthood. The clump of immature abnormal cells that results from the blocking of differentiation is called a neoplasm, derived from the Greek word for a new growth or formation. In modern times, the word neoplasm is used synonymously with tumor. Those tumors whose cells have been blocked closest to the attainment of the mature state are the least dangerous and are therefore called benign. A benign tumor has retained relatively little of its potential for uncontrolled reproduction — it is well differentiated; under the microscope, it looks a lot like the adult it was close to becoming. It grows slowly, does not invade surrounding tissues or travel to other parts of the body, is often surrounded by a distinct fibrous capsule, and almost never has the capacity to kill its host. A malignant neoplasm — what we call cancer — is a different creature entirely. Some influence or combination of influences, whether genetic, environmental, or otherwise, has acted as the triggering mechanism to interfere so early in the pathway of maturation that the progress of the cells has been stopped at a stage when they still have an infinite capacity to reproduce. Normal stem cells keep trying to produce normal offspring, but their development continues to be arrested. They do not attain a sufficient level of adulthood to do the work they were meant for or to look more than just a little like the grown-up forms they were intended to be. Cancer cells are fixed at an age where they are still too young to have learned the rules of the society in which they live. As with so many immature individuals of all living kinds, everything they do is excessive and uncoordinated with the needs or constraints of their neighbors. Being not completely grown-up, a cancer cell does not engage in some of the more complicated metabolic activities of mature nonmalignant tissue. A cancer cell of the intestine, for example, doesn't help out in digestion as its adult counterpart does; a cancer cell of the lung is uninvolved in the process of respiration; the same is true of almost all other malignancies. Malignant cells concentrate their energies on reproduction rather than in partaking in the missions a tissue must carry out in order for the life of the organism to go on. The bastard offspring of their hyperactive (albeit asexual) "fornicating" are without the resources to do anything but cause trouble and burden the hardworking community around them. Like their progenitors, they are reproductive but not productive. As individuals, they victimize a sedate, conforming society. Cancer cells do not even have the decency to die when they should. All nature recognizes that death is the final step in the process of normal maturation. Malignant cells don't reach that point — their longevity is not finite. What is true of Dr. Hayflick's fibroblasts does not apply to the cellular population of a malignant growth. Cancer cells cultivated in the laboratory exhibit an unlimited capacity to grow and generate new tumors. In the words of my research colleagues, they are "immortalized." The combination of delayed death and uncontrolled birth are malignancy's greatest violations of the natural order of things. These two factors in combination are the main reasons a cancer, unlike normal tissue, continues to enlarge throughout its lifetime. Knowing no rules, cancer is amoral. Knowing no purpose other than to destroy life, cancer is immoral. A cluster of malignant cells is a disorganized autonomous mob of maladjusted adolescents, raging against the society from which it sprang. It is a street gang intent on mayhem If we cannot help its members grow up, anything we can do to arrest them, remove them from our midst, or induce their demise — anything that accomplishes one of those aims — is praiseworthy. There comes a point at which home turf is not enoughs — offshoots of the gang take wing, invade other communities, and, emboldened by their unresisted depredations, wreak havoc on the entire commonwealth of the body. But in the end, there is no victory for cancer. When it kills its victim, it kills itself. A cancer is born with a death wish. Cancer is, in every possible sense, a nonconformist. But, unlike some nonconformist individuals about whom there is much to admire, the nonconforming malignant cell has not a single redeeming feature. It does everything it can not only to disassociate itself from but even to destroy the community of cells that has given it life. As though to make certain that it is not confused with the conformist adult members of its original family, the cancer cell retains an immature and different appearance and even shape. This characteristic of malignant growth is called anaplasia, from the Greek term meaning "without form." The anaplastic cell gives birth to anaplastic offspring. But try as it may, only an unusual cancer is composed of cells that have changed their appearance completely enough to become unrecognizable as members of their own original tribe. Except in extreme cases, a careful look down the barrel of a microscope at a bit of the diseased tissue will suffice to reveal its ancestral lineage. Thus, a bowel cancer can be identified as what it is because it still has some characteristic features that betray its intestinal origin. Even far away from home, as when the bloodstream has carried its cells to the liver, the cancer's face, almost no matter the degree of anaplasia, will usually give it away. Even cancer, that remorseless renegade that ran away to join the biological equivalent of Murder, Inc., retains some dimly recognizable traits of its old family and its old obligations. The twin characteristics of autonomy and anaplasia define the modern understanding of cancer. Whether they are to be thought of as "ugly, deformed, and unruly" or more academically as "anaplastic" and "autonomous," the cells of a cancer are wicked in ways far beyond what is implied by the scientific connotation of the word malignant. Malevolent, in fact, says it better, because it bears the implication of an element of ill will. The deformity and ugliness of the individual cancer cell are most manifest in the irregularities of its distorted shape. Whereas the appearance of a normal cell in normal tissue differs hardly at all from that of its normal neighbors, the forms and dimensions of the individuals in a cancer's cellular population are usually neither uniform nor orderly. They may bulge, flatten, elongate, round themselves out, or in some other way demonstrate that each is created as though with a mind of its own — it is an independent agent. Cancer is a state in which a breakdown has occurred in the communication and mutual interdependence between cells. That sequence of events noted above has taken place, in which the genetic characteristics of the malignant cell become altered, and everything else about the disease follows from that fact. Some of the environmental, lifestyle, and other causes of the alterations are known, some are being studied, and some are no doubt still unsuspected. Though chaotic in appearance and inconsistent in size, the community of malignant cells is not necessarily always anarchic. In a few forms of cancer, in fact, all individuals are found to choose a specific uniform shape that suits a shared element in their willfulness. Such malignancies exist as though to demonstrate an obstinate refusal to conform to the accustomed disharmony expected of them; their cells reproduce myriads of virtually identical selves, like so many millions upon millions of little poisonous apples, boringly similar to one another but quite different from their tissue of origin. Even the predictability of malignancy's unpredictability is unpredictable. The central structure of the cancer cell, its nucleus, is larger and more prominent than that of mature relatives and is often as misshapen as the cell itself. Its dominance over the protoplasm surrounding it is intensified by the enhanced avidity with which it takes up standard laboratory stains, a characteristic that gives it a darkened, ominous look. The evil-eye nucleus reveals its disordered independence in yet another way: Instead of dividing neatly into two symmetrical halves during the process of reproduction known as mitosis, the chromosomes (the components of the nucleus that carry the DNA) align themselves in bizarre patterns, attempting with varying degrees of success to multiply, figuratively head over heels, without any element of precision or accountability. The rate of mitosis of some cancers is so rapid that a quick look through the microscope will catch many times the number of cells in the act of trying to reproduce as are found in mature normal tissue, and every one of them seems to be doing it in its own haphazard way. Small wonder that the surviving offspring are ill-suited to their surroundings in the ordered, consistent tissue of the organs of which they were originally meant to be a part. So pugnaciously "other" are the new masses of cells, in fact, that they not only invade but also push their law-abiding grown-up neighbors out of the way as they infiltrate and preempt surrounding territory. In a word, cancer is asocial. Having escaped the constraints that govern nonmalignant cells, the newly formed tissues pursue uncontrolled and domineering relationships with their host organs and cannot be made to restrict their encroaching margins to the foci that gave them birth. Unrestrained and patternless growth enables a cancer to force its way into nearby vital structures to engulf them, prevent their functioning, and choke off their vitality. By this means, and by destroying the organs from whose stem cells they are made, the masses of cancer cells kill the gradually sickening person after feasting on the nutrients that were to have sustained him Although it begins as a microscopic phenomenon, the process of malignant growth, once properly established, inevitably continues until it can be seen with the naked eye or felt with the exploring hand. For a while, the growing mass may remain too small or confined to produce symptoms, but in time, the cancer's victim will sense that something untoward is happening to him. By that point, the malignancy may have grown so large that it is beyond cure. Particularly in certain solid organs, a cancer may reach considerable size before it makes its host aware of its presence. It was for this reason, of course, that the disease achieved its legendary reputation as a noiseless killer. A kidney, for example, may be found to harbor a perfectly huge growth when it first reveals its advanced state of disease by spilling visible blood into the urine or causing a dull ache in the flank. If an operation is done at that point, the surgeon's efforts will be defeated by the wide extent of involvement of surrounding tissues. The otherwise-symmetrical brown smoothness of the organ will be found to have been eaten away in one large area by an ugly, lobulated protrusion of coarse gray hardness that has forced its way through to the surface, invaded the adjacent fat, and drawn all nearby tissues into it, the misbegotten whole forming one great puckered grotesquerie of bunched-up aggression. Of all the diseases they treat, cancer is the one that surgeons have given the specific designation of "The Enemy." The visible structure and invasiveness of a cancer are only two of its many forms of unruliness. One of the most duplicitous of malignancy's misbehaviors is the way in which it seems to elude the defenses ordinarily mounted by the body against tissue it perceives as not belonging to it. Theoretically at least, cells that have become cancerous should be detectable as foreign or "other" by an intact immune system and then killed, much as is a virus. This actually does happen to an extent; some researchers believe that our tissues are continually making cancers, which are just as continually being destroyed by this kind of mechanism. Clinical malignancies would then develop in those rare instances when the surveillance system fails. An example of support for such a thesis is to be found in the prevalence in people with AIDS of tumors such as lymphoma and Kaposi's sarcoma. Overall, the incidence of malignancies in immunocompromised individuals is some two hundred times that found in the general population, and for Kaposi's the figure is more than twice what it is for the average tumor. One of the most promising fields of today's biomedical research is the study of tumor immunity with a view toward strengthening the body's responses to the antigens that cancers may produce. Although there have been some promising results, the target cells continue, for the most part, to outwit the scientists. Normal cells require a complex mixture of nutrients and growth factors in order to continue functioning and retain viability. Throughout all tissues of the body, they are bathed in a life-giving nutrient soup called extracellular fluid, which is constantly being restored and cleansed by exchanging substances with circulating blood. The blood's plasma, in fact, amounts to one-fifth of the body's extracellular fluid; most of the other four-fifths lies between the cells, and is called interstitial. The interstitial fluid accounts for approximately 15 percent of body weight; if you weigh 150 pounds, your tissues are soaking in 22 pints of the salty stuff. The nineteenth-century French physiologist Claude Bernard introduced the term milieu interieur to name and describe the function of this internal environment in which cells live within us. It is as though the earliest groups of prehistoric cells, when they first began to form complex organisms in the marine depths from which they drew sustenance, brought some of the sea into and around themselves so that they might continue to be nourished by it. Among the unique features of malignant tissues is their reduced dependence on the nutritional and growth factors in the extracellular fluid. Their lessened need for sustenance from the surroundings enables them to grow and invade even those areas beyond optimal supply lines. No matter that each cellular unit can get along with less, the helter-skelter increase in population soon accumulates so many malignant cells that the requirements of the aggregate tend to outstrip whatever supplies are available. As a result, a total tumor mass will often develop an increased demand for nutrition, even though each individual within it may require less than a normal amount of it. If growth is rapid enough, blood supply after a time will be insufficient to restore used-up nutrients, especially because new vessels usually do not appear rapidly enough to keep pace with the needs of the whole expanding tumor. The result is that a portion of an enlarging tumor may die, literally of malnutrition and oxygen lack. It is for this reason that cancers tend to ulcerate and bleed, sometimes producing thick, slimy deposits of necrotic tissue (from the Greek nekrosis, meaning "becoming dead") within their centers or at the periphery. Until mastectomy became a common operation less than a hundred years ago, the most dreaded complication of breast malignancy was not death but the fetid running sores it produced as a hapless woman's chest wall was digested away. This is precisely why the ancients referred to karkinoma as the "stinking death." In the late eighteenth century, Giovanni Morgagni, the author of a landmark text of pathological anatomy, said of the cancer he saw in his patients and at their autopsies that it was "a very filthy disease." Even in relatively recent times, when much more was known, malignant tumors continued to be viewed as repugnant sources of self-loathing and decay, a humiliating abomination to be concealed behind euphemisms and lies. Many are the stories of women with breast cancer who withdrew from friends, secluded themselves at home, and lived their final months as recluses, sometimes even from their own families. As recently as the period of my training, just over thirty years ago, I saw a few such women who had finally been prevailed upon to come to the clinic because their situations had become intolerable. Of the several reasons we still hesitate to utter the word cancer in the presence of a patient or family assaulted by it, the residual heritage of its odious connections is the one most difficult for our generation to expunge. Not enough that a rapidly growing cancer may so infiltrate a solid organ like the liver or kidney that insufficient tissue remains to perform the organ's functions effectively; not enough that it may obstruct a hollow structure like the intestinal tract and make adequate nourishment impossible; not enough that even a small mass of it can destroy a vital center without which life functions cannot go on, as some brain tumors do; not enough that it erodes small blood vessels or ulcerates sufficiently to result gradually in severe anemia, as it often does in the stomach or colon; not enough that its very bulk sometimes interferes with the drainage of bacteria-laden effluents and induces pneumonia and respiratory insufficiency, which are common causes of death in lung cancer; not enough that a malignancy has several ways by which it can starve its host into malnutrition — a cancer has still other ways to kill. Those just mentioned refer, after all, only to potentially lethal consequences of encroachment by the primary tumor itself, without its ever having left the organ where it first arose. These are the kinds of damage cancer does in its own neighborhood. But it has an additional way of killing that takes it out of the category of localized disease and permits it to attack a wide assortment of tissues far from its origin. That mechanism has been given the name metastasis. Meta is a Greek preposition meaning "beyond" or "away from," and stasis connotes "position" or "placing." Introduced as early as the Hippocratic writings to indicate a change away from one form of fever to another, metastasis later came to be applied specifically to migration of bits of tumor. In modern times, this one word, metastasis, has come to articulate the defining feature of malignancy — cancer is a neoplasm that has the potential to go beyond its home and travel to some other place. A metastasis is, in effect, a transplant of a sample of the primary tumor to another structure or even a distant part of the body. Cancer's ability to metastasize is both its hallmark and its most menacing characteristic. If a malignant tumor did not have the ability to travel, surgeons would be able to cure all but those that involve vital structures, which cannot be removed without compromising life. In order to travel, the tumor must erode through the wall of a blood vessel or lymph channel, and then some of its cells must become detached and pass into the flowing stream. Either individually or clumped into an embolus, the cells are then carried to some other tissue, where they implant and grow. Determined by the route of blood or lymph flow as well as other still-unclear factors, various cancers have a predilection to be deposited in certain specific organs. For example, a breast cancer is most likely to metastasize to bone marrow, lungs, liver, and, of course, the lymph nodes in the armpit, or axilla. A cancer of the prostate commonly travels to bone. Bones, in fact, along with the liver and kidney, are the most common sites for metastatic deposits, regardless of the malignancy's organ of origin. In order to take root in a distant location, tumor cells need to be hardy enough to resist destruction while on their journey. The simple mechanical dangers of traveling through the jolting circulation complicate the possibility of being killed by the host's immune system during the course of the passage. If they survive the voyage, the cells must then establish a new home and be provided a reliable source of nutrition. This means a priori that the transplanted bit of cancer cannot create a viable colony on the newly reached distant shore unless it is capable of stimulating the growth of tiny new blood vessels to supply its needs. So difficult is it to satisfy all of these requirements that very few of the migrating cells ever do manage to colonize some far-flung site. When tumor cells are experimentally injected into mice, only one-tenth of 1 percent survive beyond twenty- four hours; it is estimated that only one of each 100,000 cells entering the bloodstream lives to reach another organ, and a far smaller proportion successfully implant themselves. Were it not for obstacles such as these, massive numbers of metastases would appear as soon as a cancer becomes sufficiently large to shed many cells into the circulation. By the twin forces of local invasion and distant metastasis, a cancer gradually interferes with the functioning of the various tissues of the body. Tubular organs are obstructed, metabolic processes are inhibited, blood vessels are eroded sufficiently to cause minor and sometimes major bleeding, vital centers are destroyed, and delicate biochemical balances are deranged. In time, a point is reached at which life can no longer be sustained. In addition, there are less direct ways for cancer to take its toll on those in whom its growth is unchecked, and they are usually the result of the debilitation, poor nutrition, and susceptibility to infection that come with the malignant process. Nutritional depletion is so common that a term has been devised to designate its effects: cancer cachexia. Cachexia is derived from two Greek words meaning "bad condition," which is exactly the situation in which advanced cancer patients find themselves. It is characterized by weakness, poor appetite, alterations in metabolism, and wasting of muscle and other tissues. Actually, cancer cachexia is sometimes present even in people whose disease is still localized and relatively small, so it is clear that factors account for it other than a tumor's gobbling up of its host's resources. Though a tumor is capable of depriving its host of some essential nutrients, the concept of parasitizing may be, in fact, a simplistic way of looking at far more complicated causes of its ability to deplete resources. Changes in taste perception, for example, and local tumor effects such as obstruction and swallowing problems sometimes contribute to inadequate intake, as do chemotherapy and X-ray treatment. Numerous studies of people with malignancies reveal various kinds of abnormalities in the utilization of carbohydrates, fats, and proteins, the causes of which are uncertain. Some tumors even seem capable of increasing a patient's expenditure of energy, thereby contributing to the inability to maintain weight. To add to the problem, certain malignancies and even some of the host's own white blood cells (monocytes) have been shown to release a substance appropriately given the name cachectin, which decreases appetite by direct action on the brain's feeding center. Cachectin is not the only such agent. It is likely that tumors of all sorts are capable of secreting various hormonelike substances which produce generalized effects on nutrition, immunity, and other vital functions that until recently were attributed to the parasitizing effects of the growth itself. Malnutrition causes problems far beyond weight loss and exhaustion. The healthy body adapts to ordinary starvation by using fats as its main energy source, but this process is not effective in cancer, with the result that protein must be utilized. Not only does this and the lessened food intake cause muscle wasting; the decreased protein levels contribute to the dysfunction of organs and enzyme systems, and may significantly affect the immune response. There is evidence that one of the substances released by tumor cells further depresses immunity. Although this may, at least theoretically, enhance cancer growth, that untoward effect seems much less important than the fact that depressed immunocompetence, especially when magnified by chemotherapy and radiation, increases susceptibility to infection. Pneumonia and abscesses, along with urinary and other infections, are frequently the immediate causes of death of cancer patients, and sepsis is their common terminal event. The profound weakness of severe cachexia does not permit effective coughing and respiration, increasing the chances of pneumonia and the inhalation of vomitus. The final hours are sometimes accompanied by those deep, gurgling respirations that are one of the forms of the death rattle, quite distinct from the agonal bark of a James McCarty. Near the end, a decreased volume of circulating blood and extracellular fluid not infrequently leads to a gradual decrease in blood pressure. Even if this does not proceed to shock, it may cause organs such as the liver or kidney to fail because of chronic lack of sufficient nutrients and oxygen, although they are not directly involved with tumor. Since many people with cancer are in an older age group, the various forms of depletion often induce stroke, myocardial infarction, or heart failure. Of course, the presence of a generalized disease of metabolism, like diabetes, complicates the problems enormously. Thus far, only those cancers have been mentioned that begin as tumors originally localized to a specific organ or tissue. A smaller group of malignant diseases have a more generalized distribution from the very beginning, or arise in multiple sites of a particular kind of tissue, specifically the blood and lymph systems. Leukemia, for example, is a cancer of the tissues responsible for the production of white blood cells, and lymphoma is a malignancy of lymph glands and similar structures. Patients with leukemia and lymphoma are particularly prone to infection, and it is a leading cause of death in those malignancies. One of the common forms of lymphoma is Hodgkin's disease. I cannot mention Hodgkin's disease without calling attention to a remarkable accomplishment that is in many ways exemplary of the biomedical achievements of the last third of the twentieth century Thirty years ago, virtually every patient with Hodgkin's disease died of it, unless claimed by something else in the several-year interval between diagnosis and the terminal phase. Since then, improved understanding of the way in which the disease distributes itself in the lymph glands, and its responsiveness to appropriate programs of chemotherapy and supervoltage X-ray, have resulted in five-year disease-free survival of approximately 70 percent, which is as high as 95 percent for patients whose disease is discovered when its extent is still limited; recurrence rates after this period are low and decrease with each year. Not only Hodgkin's disease but lymphomas in general are now among the most curable of all cancers. The changed outlook for people with lymphoma is only one example of extraordinary progress in treating cancer. Another is childhood leukemia. Four out of five children with this disease have a form of it called acute lymphoblastic leukemia, previously fatal in every case; today, the five-year rate of continuous remission of acute lymphoblastic leukemia is 60 percent, and most of these youngsters will be cured. Although there have thus far been only a few other success stories of the sheer magnitude of these two, the general trend in the campaign against cancer is favorable enough to justify cautious optimism. Basic research, new ways of interpreting the clinical phenomena of disease, innovative applications of pharmacology and the physical sciences, and the willingness of informed patients to enroll in large-scale trials of promising treatments are among the reasons for the vast changes over the past few decades. In the year I was born, 1930, only one in five people diagnosed with cancer survived five years. By the 1940s, the figure was one in four. The effect of modern biomedicine's research capacity began to make itself felt in the 1960s, when the proportion of survivors reached one in three. At the present time, 40 percent of all cancer patients are alive five years after diagnosis; making proper statistical allowances for those who die of some unrelated cause, such as heart disease or stroke, 50 percent survive at least that long. It is well known that those who reach the five-year milestone free of disease face greatly decreased odds of eventual recurrence of their malignancy. Virtually all of the progress has been made possible by a combination of earlier diagnosis and the improved treatment resulting from the factors listed in the preceding paragraph. Improved treatment and the possibility of success of the constantly appearing innovative approaches to advanced disease bring hope to today's cancer patient. Paradoxically, and sometimes tragically, that kind of hope is the very thing that has led to some of the most error-fraught dilemmas that patients and their doctors are compelled to face today. My clinical career encompasses a period during which a realistic expectation first began to be felt in the scientific community that malignant disease would prove amenable to treatment based on an understanding of cellular biology rather than the ages-old oversimplifications of surgery. As more was learned about the cancer cell, new and increasingly effective ways were developed to combat its unchecked ravages. With the optimism born of therapeutic successes came a determined cockiness that sometimes goes beyond reason; it finds expression in the philosophy that treatment must be pursued until futility can be proven, or at least proven to the satisfaction of the physician. The boundaries of medical futility, however, have never been clear, and it may be too much to expect that they ever will be. It is perhaps for this reason that there has arisen the conviction among doctors — more than a mere conviction, it is nowadays felt by many to be a responsibility — that should error occur in the treatment of a patient, it must always be on the side of doing more rather than less. Doing more is likely to serve the doctor's needs rather than the patient's. The very success of his esoteric therapeutics too often leads the physician to believe he can do what is beyond his doing and save those who, left to their own unhindered judgment, would choose not to be subjected to his saving.