The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing. —Voltaire

“It is the dose that makes a poison,” runs the old adage in medicine: all medicines were poisons in one form or another merely diluted to an appropriate dose. But chemotherapy was poison even at the correct dose.*

In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself. But there is another moment of discovery—its antithesis—that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone.

It was a consequence of the body’s own defense system subverting cancer treatment. The brain and spinal cord are insulated by a tight cellular seal called the blood-brain barrier that prevents foreign chemicals from easily getting into the brain. It is an ancient biological system that has evolved to keep poisons from reaching the brain. But the same system had likely also kept VAMP out of the nervous system, creating a natural “sanctuary” for cancer within the body. The leukemia had grown out in that sanctuary, colonizing the one place that is fundamentally unreachable by chemotherapy. The children died one after the other—felled by virtue of the adaptation designed to protect them.

Resilience, inventiveness, and survivorship—qualities often ascribed to great physicians—are reflected qualities, emanating first from those who struggle with illness and only then mirrored by those who treat them. If the history of medicine is told through the stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients.

The high doses of vincristine caused such severe collateral nerve damage that she was left with a permanent burning sensation in her legs and fingers. Prednisone made her delirious. The nurses, unable to deal with a strong-willed, deranged preteen wandering through the corridors of the hospital screaming and howling at night, restrained her by tying her arms with ropes to the bedposts. Confined to her bed, she often crouched in a fetal position, her muscles wasting away, the neuropathy worsening. At twelve years of age, she became addicted to morphine, which was prescribed for her pain.

cavitary

It was, I suspected, not the first time that a patient had consoled a doctor about the ineffectuality of his discipline.

The job’s most inventive academic perk, perhaps, was his new title: the Curator of the Museum and the Inspector of the Dead.

Instead of trying to tailor the disease to fit his medicine, Kaplan learned to tailor his medicine to fit the right disease. This simple principle—the meticulous matching of a particular therapy to a particular form and stage of cancer—would eventually be given its due merit in cancer therapy.

To design an ideal anticancer drug, one would need to identify a specific molecular target in a cancer cell and create a chemical to attack that target. But the fundamental biology of cancer was so poorly understood that defining such molecular targets was virtually inconceivable in the 1960s.

When a disease insinuates itself so potently into the imagination of an era, it is often because it impinges on an anxiety latent within that imagination. AIDS loomed so large on the 1980s in part because this was a generation inherently haunted by its sexuality and freedom; SARS set off a panic about global spread and contagion at a time when globalism and social contagion were issues simmering nervously in the West. Every era casts illness in its own image. Society, like the ultimate psychosomatic patient, matches its medical afflictions to its psychological crises; when a disease touches such a visceral chord, it is often because that chord is already resonating.

Cancer is the obsession of people who sense that disaster may not be a purposeful instrument of public policy but a matter of accidental, random carelessness.”

The hierarchical practice of medicine, its internal culture, its rituals of practice (“The Gospel[s] of the Surgical Profession,” as Crile mockingly called it), were ideally arranged to resist change and to perpetuate orthodoxy.

Medicine, once considered virtually infallible in its judgment, was turning out to have deep fallibilities—flaws that appeared to cluster pointedly around issues of women’s health.

Political feminism, in short, was birthing medical feminism—and the fact that one of the most common and most disfiguring operations performed on women’s bodies had never been formally tested in a trial stood out as even more starkly disturbing to a new generation of women.

Cisplatin was unforgettable in more than one sense. The drug provoked an unremitting nausea, a queasiness of such penetrating force and quality that had rarely been encountered in the history of medicine: on average, patients treated with the drug vomited twelve times a day.

To attack a cancer cell specifically, one needed to begin by identifying its biological behavior, its genetic makeup, and its unique vulnerabilities. The search for magic bullets needed to begin with an understanding of cancer’s magical targets.

The link between the growth-sustenance of normal cells and of cancer cells was much closer than previously imagined: cancer could be fed and nurtured by our own bodies.

“We shall so poison the atmosphere of the first act,” the biologist James Watson warned about the future of cancer in 1977, “that no one of decency shall want to see the play through to the end.”

She was devoted to her mother, with the reversed—and twice as fierce—maternal instinct that marks the poignant moment of midlife when the roles of mother and daughter begin to switch.

If oncologists could not bring themselves to provide care for their terminally ill patients, she would leverage other specialists—psychiatrists, anesthesiologists, geriatricians, physical therapists, and neurologists—to help patients die painlessly and gracefully.

In the history of medicine, no significant disease had ever been eradicated by a treatment-related program alone.

The measurement of illness, Breslow was arguing, is an inherently subjective activity: it inevitably ends up being a measure of ourselves.

The idea of preventive medicine is faintly un-American. It means, first, recognizing that the enemy is us.

Tobacco was the economic lifeblood of Southern states, and the industry had bribed politicians and funded campaigns so extensively over the years that negative political action was inconceivable.

“Statistics,” the journalist Paul Brodeur once wrote, “are human beings with the tears wiped off,” and thus far the antitobacco campaign had offered plenty of statistics, but with the human victims of tobacco somehow effaced.

But what mattered was not how much Rose Cipollone knew about tobacco risks; what mattered was what cigarette makers knew, and how much of the cancer risk they had revealed to consumers such as Rose.

Many of the cigarette makers had not only known about the cancer risks of tobacco and the potent addictive properties of nicotine, but had also actively tried to quash internal research that proved it.

Pyrrhic victory.

old sins have long shadows,

It remains an astonishing, disturbing fact that in America—a nation where nearly every new drug is subjected to rigorous scrutiny as a potential carcinogen, and even the bare hint of a substance’s link to cancer ignites a firestorm of public hysteria and media anxiety—one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store for a few dollars.

Papanicolaou had extended his technique to human patients. (His wife, Maria, in surely one of the more grisly displays of conjugal fortitude, reportedly allowed herself to be tested by cervical smears every day.)

The Pap smear had, in effect, pushed the clock of cancer detection forward by nearly two decades, and changed the spectrum of cervical cancer from predominantly incurable to predominantly curable.

In cancer, where both overdiagnosis and underdiagnosis come at high costs, finding that exquisite balance is often impossible. We want every cancer test to operate with perfect specificity and sensitivity. But the technologies for screening are not perfect. Screening tests thus routinely fail because they cannot even cross this preliminary hurdle—the rate of over- or underdiagnosis is unacceptably high.

The solution to this seeming paradox—called lead-time bias—is immediately obvious. Using survival as an end point for a screening test is flawed because early detection pushes the clock of diagnosis backward. Hope’s tumor and Prudence’s tumor possess exactly identical biological behavior. But since doctors detected Hope’s tumor earlier, it seems, falsely, that she lived longer and that the screening test was beneficial.

So our test must now cross an additional hurdle: it must improve mortality, not survival. The only appropriate way to judge whether Hope’s test was truly beneficial is to ask whether Hope lived longer regardless of the time of her diagnosis.

Only a test capable of meeting all these criteria—proving mortality benefit in a genuinely randomized setting with an acceptable over- and underdiagnosis rate—can be judged a success.

“Suspicion, like beauty, lies in the eye of the beholder,” one of the trial’s chief investigators countered.

A mammogram, it turns out, is not a particularly good tool for detecting early breast cancer. Its false-positive and false-negative rates make it far from an ideal screening test. But the fatal flaw in mammography lies in that these rates are not absolute: they depend on age. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit. For women between forty and fifty years, though, the incidence of breast cancer sinks to a point that a “mass” detected on a mammogram, more often than not, turns out to be a false positive.

Seeing a “small” tumor and extracting it from the body does not guarantee our freedom from cancer—a fact that we still struggle to believe.

If every dividing cell in the body needed to be obliterated to rid it of cancer, then so be it. It was a conviction that would draw oncology into its darkest hour.

“If a man die,” William Carlos Williams once wrote, “it is because death / has first possessed his imagination.”

It was easy to repossess imagination with false promises; much harder to do so with nuanced truths.

It was all masterfully done, a graded movement toward reconciliation with death, but a movement nonetheless—statistics without stasis.

Ars longa, vita brevis. The art of medicine is long, Hippocrates tells us, “and life is short; opportunity fleeting; the experiment perilous; judgment flawed.”

If cancer, as Sontag had once argued, was perceived as the product of spoiled germ, of biological mutability gone wild, then AIDS was the result of contaminated germ, of social mutability gone wild: men unmoored from the usual conventions of society, metastasizing from coast to coast on airplanes, carrying disease and devastation within them.

Symptomatic of this intransigence was the process by which the FDA evaluated and approved lifesaving drugs for AIDS, a process that Kramer characterized as terminally lazy and terminally slow.

It is in vain to speak of cures, or think of remedies, until such time as we have considered of the causes… cures must be imperfect, lame, and to no purpose, wherein the causes have not first been searched. —Robert Burton, The Anatomy of Melancholy, 1893

perhaps src, the precursor to the cancer-causing gene, was endogenous to the cell. Perhaps viral src had evolved out of cellular src.