The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

In Aleksandr Solzhenitsyn’s novel Cancer Ward, Pavel Nikolayevich Rusanov, a youthful Russian in his midforties, discovers that he has a tumor in his neck and is immediately whisked away into a cancer ward in some nameless hospital in the frigid north. The diagnosis of cancer—not the disease, but the mere stigma of its presence—becomes a death sentence for Rusanov.

To be diagnosed with cancer, Rusanov discovers, is to enter a borderless medical gulag, a state even more invasive and paralyzing than the one that he has left behind.

colleague, freshly out of his fellowship, pulled me aside on my first week to offer some advice. “It’s called an immersive training program,” he said, lowering his voice. “But by immersive, they really mean drowning. Don’t let it work its way into everything you do. Have a life outside the hospital. You’ll need it, or you’ll get swallowed.” But it was impossible not to be swallowed.

I had a novice’s hunger for history, but also a novice’s inability to envision it.

The isolation and rage of a thirty-six-year-old woman with stage III breast cancer had ancient echoes in Atossa, the Persian queen who swaddled her diseased breast in cloth to hide it and then, in a fit of nihilistic and prescient fury, possibly had a slave cut it off with a knife.

Cancer is built into our genomes:

Unable to find a unifying explanation for it, and seeking a name for this condition, Virchow ultimately settled for weisses Blut—white blood—no more than a literal description of the millions of white cells he had seen under his microscope. In 1847, he changed the name to the more academic-sounding “leukemia”—from leukos, the Greek word for “white.”

The humility of the name (and the underlying humility about his understanding of cause) epitomized Virchow’s approach to medicine.

Leukemia was a malignant proliferation of white cells in the blood. It was cancer in a molten, liquid form.

The life expectancy of Americans rose from forty-seven to sixty-eight in half a century, a greater leap in longevity than had been achieved over several previous centuries. The sweeping victories of postwar medicine illustrated the potent and transformative capacity of science and technology in American life.

Cancer is an expansionist disease; it invades through tissues, sets up colonies in hostile landscapes, seeking “sanctuary” in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively—at times, as if teaching us how to survive. To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are. This image—of cancer as our desperate, malevolent, contemporary doppelgänger—is so haunting because it is at least partly true.

Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.

it is under these clarifying headlamps of an ancient surgeon that cancer first emerges as a distinct disease. Describing case forty-five, Imhotep advises, “If you examine [a case] having bulging masses on [the] breast and you find that they have spread over his breast; if you place your hand upon [the] breast [and] find them to be cool, there being no fever at all therein when your hand feels him; they have no granulations, contain no fluid, give rise to no liquid discharge, yet they feel protuberant to your touch, you should say concerning him: ‘This is a case of bulging masses I have to contend with.… Bulging tumors of the breast mean the existence of swellings on the breast, large, spreading, and hard; touching them is like touching a ball of wrappings, or they may be compared to the unripe hemat fruit, which is hard and cool to the touch.’”

Aufderheide isn’t the only paleopathologist to have found cancers in mummified specimens. (Bone tumors, because they form hardened and calcified tissue, are vastly more likely to survive over centuries and are best preserved.) “There are other cancers found in mummies where the malignant tissue has been preserved. The oldest of these is an abdominal cancer from Dakhleh in Egypt from about four hundred AD,” he said. In other cases, paleopathologists have not found the actual tumors, but rather signs left by the tumors in the body. Some skeletons were riddled with tiny holes created by cancer in the skull or the shoulder bones, all arising from metastatic skin or breast cancer. In 1914, a team of archaeologists found a two-thousand-year old Egyptian mummy in the Alexandrian catacombs with a tumor invading the pelvic bone. Louis Leakey, the anthropologist who dug up some of the earliest known human skeletons, also discovered a jawbone dating from two million years ago from a nearby site that carried the signs of a peculiar form of lymphoma found endemically in southeastern Africa (although the origin of that tumor was never confirmed pathologically). If that finding does represent an ancient mark of malignancy, then cancer, far from being a “modern” disease, is one of the oldest diseases ever seen in a human specimen—quite possibly the oldest.

It was in the time of Hippocrates, around 400 BC, that a word for cancer first appeared in the medical literature: karkinos, from the Greek word for “crab.” The tumor, with its clutch of swollen blood vessels around it, reminded Hippocrates of a crab dug in the sand with its legs spread in a circle. The image was peculiar (few cancers truly resemble crabs), but also vivid.

Another Greek word would intersect with the history of cancer—onkos, a word used occasionally to describe tumors, from which the discipline of oncology would take its modern name. Onkos was the Greek term for a mass or a load, or more commonly a burden; cancer was imagined as a burden carried by the body. In Greek theater, the same word, onkos, would be used to denote a tragic mask that was often “burdened” with an unwieldy conical weight on its head to denote the psychic load carried by its wearer.

Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis.

In 1828, a Berlin scientist named Friedrich Wöhler had sparked a metaphysical storm in science by boiling ammonium cyanate, a plain, inorganic salt, and creating urea, a chemical typically produced by the kidneys. The Wöhler experiment—seemingly trivial—had enormous implications. Urea was a “natural” chemical, while its precursor was an inorganic salt. That a chemical produced by natural organisms could be derived so easily in a flask threatened to overturn the entire conception of living organisms: for centuries, the chemistry of living organisms was thought to be imbued with some mystical property, a vital essence that could not be duplicated in a laboratory—a theory called vitalism. Wöhler’s experiment demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals—a beaker with arms, legs, eyes, brain, and soul. With vitalism dead, the extension of this logic to medicine was inevitable.

The acute, short-term effects of nitrogen mustard—the respiratory complications, the burnt skin, the blisters, the blindness—were so amply monstrous that its long-term effects were overlooked. In 1919, a pair of American pathologists, Edward and Helen Krumbhaar, analyzed the effects of the Ypres bombing on the few men who had survived it. They found that the survivors had an unusual condition of the bone marrow. The normal blood-forming cells had dried up; the bone marrow, in a bizarre mimicry of the scorched and blasted battlefield, was markedly depleted. The men were anemic and needed transfusions of blood, often up to once a month. They were prone to infections. Their white cell counts often hovered persistently below normal. In a world less preoccupied with other horrors, this news might have caused a small sensation among cancer doctors. Although evidently poisonous, this chemical had, after all, targeted the bone marrow and wiped out only certain populations of cells—a chemical with specific affinity. But Europe was full of horror stories in 1919, and this seemed no more remarkable than any other. The Krumbhaars published their paper in a second-tier medical journal and it was quickly forgotten in the amnesia of war.

The wartime chemists went back to their labs to devise new chemicals for other battles, and the inheritors of Ehrlich’s legacy went hunting elsewhere for his specific chemicals. They were looking for a magic bullet that would rid the body of cancer, not a toxic gas that would leave its victims half-dead, blind, blistered, and permanently anemic. That their bullet would eventually appear out of that very chemical weapon seemed like a perversion of specific affinity, a ghoulish distortion of Ehrlich’s dream.

Looking frantically through the patient lists, Farber and Koster found a single child healthy enough to carry the message—a lanky, cherubic, blue-eyed, blond child named Einar Gustafson, who did not have leukemia but was being treated for a rare kind of lymphoma in his intestines. Gustafson was quiet and serious, a precociously self-assured boy from New Sweden, Maine. His grandparents were Swedish immigrants, and he lived on a potato farm and attended a single-room schoolhouse. In the late summer of 1947, just after blueberry season, he had complained of a gnawing, wrenching pain in his stomach. Doctors in Lewiston, suspecting appendicitis, had operated on his appendix, but found the lymphoma instead.

Einar Gustafson, though, was a mouthful of a name. Farber and Koster, in a flash of inspiration, rechristened him Jimmy.

More than a century after Tocqueville toured the States, as Farber sought to transform the landscape of cancer, he instinctively grasped the truth behind Tocqueville’s observation. If visionary changes were best forged by groups of private citizens forming societies, then Farber needed such a coalition to launch a national attack on cancer.

Oliver Heaviside, an English mathematician from the 1920s, once wrote jokingly about a scientist musing at a dinner table, “Should I refuse my dinner because I don’t understand the digestive system?” To Heaviside’s question, Farber might have added his own: should I refuse to attack cancer because I have not solved its basic cellular mechanisms?

Cancer, he insisted, was a total disease—an illness that gripped patients not just physically, but psychically, socially, and emotionally. Only a multipronged, multidisciplinary attack would stand any chance of battling this disease. He called the concept “total care.”

When Carla’s children stopped by, in masks and gloves, she wept quietly, turning her face toward the window. For Carla, the physical isolation of those days became a barely concealed metaphor for a much deeper, fiercer loneliness, a psychological quarantine even more achingly painful than her actual confinement. “In those first two weeks, I withdrew into a different person,” she said. “What went into the room and what came out were two different people.

The permutations of possible drugs and doses were further increased when yet another new anticancer agent was introduced at the Clinical Center in 1960. The newcomer, vincristine, was a poisonous plant-alkaloid that came from the Madagascar periwinkle, a small, weedlike creeper with violet flowers and an entwined, coiled stem.

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.

“I don’t know why I deserved the illness in the first place, but then I don’t know why I deserved to be cured. Leukemia is like that. It mystifies you. It changes your life.”

The lump in his neck, whatever it was, would doubtless vanish in time as well. But it grew instead, imperceptibly at first, then more assertively, turning from grape-size to prune-size in about a month. He could feel it on the shallow dip of his collarbone. Worried, Orman went to the walk-in clinic of the hospital, almost apologetic about his complaints. The triage nurse scribbled in her notes: “Lump in his neck”—and added a question mark at the end of the sentence. With that sentence, Orman entered the unfamiliar world of oncology—swallowed, like his own lump, into the bizarre, cavitary universe of cancer. The doors of the hospital opened and closed behind him. A doctor in a blue scrub suit stepped through the curtains and ran her hands up and down his neck. He had blood tests and X-rays in rapid succession, followed by CT scans and more examinations. The scans revealed that the lump in the neck was merely the tip of a much deeper iceberg of lumps. Beneath that sentinel mass, a chain of masses coiled from his neck down into his chest, culminating in a fist-size tumor just behind his sternum. Large masses located in the anterior chest, as medical students learn, come in four T’s, almost like a macabre nursery rhyme for cancer: thyroid cancer, thymoma, teratoma, and terrible lymphoma. Orman’s problem—given his age and the matted, dense appearance of the lumps—was almost certainly the last of these, a lymphoma—cancer of the lymph glands.

Carla had barely any emotional energy for her own recuperation—and certainly none to spare for the needs of others. For her, the struggle with leukemia had become so deeply personalized, so interiorized, that the rest of us were ghostly onlookers in the periphery: we were the zombies walking outside her head. Her clinic visits began and ended with awkward pauses.

“Cancer may be infectious,” a Life magazine cover piece asserted in 1962. Rous received hundreds of letters from anxious men and women asking about exposures to cancer-causing bacteria or viruses. Speculation soon inched toward hysteria and fear. If cancer was infectious, some wondered, why not quarantine patients to prevent its spread?

If the “cancer germ” had infected one space most acutely, it was the imagination of the public—and, equally, the imagination of researchers.

test. “The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,” Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”

Bernard Fisher

This pattern was repeated with tiresome regularity for many forms of cancer. In metastatic lung cancer, for instance, combination chemotherapy was found to increase survival by three or four months; in colon cancer, by less than six months; in breast, by about twelve. (I do not mean to belittle the impact of twelve or thirteen months of survival. One extra year can carry a lifetime of meaning for a man or woman condemned to death from cancer. But it took a particularly fanatical form of zeal to refuse to recognize that this was far from a “cure.”) Between 1984 and 1985, at the midpoint of the most aggressive expansion of chemotherapy, nearly six thousand articles were published on the subject in medical journals. Not a single article reported a new strategy for the definitive cure of an advanced solid tumor by means of combination chemotherapy alone.

aggressive, metastatic breast cancer. Three years later, in ’85, when Fisher reanalyzed the deviating curves of relapse and survival, the effect of tamoxifen treatment was even more dramatic. Among the five-hundred-odd women older than fifty assigned to each group, tamoxifen had prevented fifty-five relapses and deaths. Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects.

Neither method of treatment professed to be a complete cure. Adjuvant therapy and hormonal therapy typically did not obliterate cancer. Hormonal therapy produced prolonged remissions that could stretch into years or even decades. Adjuvant therapy was mainly a cleansing method to purge the body of residual cancer cells; it lengthened survival, but many patients eventually relapsed.

But although these alternatives did not offer definitive cures, several important principles of cancer biology and cancer therapy were firmly cemented in these powerful trials. First, as Kaplan had found with Hodgkin’s disease, these trials again clearly etched the message that cancer was enormously heterogeneous.

Second, understanding that heterogeneity was of deep consequence.

The allure of deploying a full armamentarium of cytotoxic drugs—of driving the body to the edge of death to rid it of its malignant innards—was still irresistible. So cancer medicine charged on, even if it meant relinquishing sanctity, sanity, or safety.

“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.” For many cancer patients caught in the first act, there was little choice but to see the poisonous play to its end.

Yet a third voice of dissent arose in oncology in the 1980s, although this voice had skirted the peripheries of cancer for several centuries. As trial after trial of chemotherapy and surgery failed to chisel down the mortality rate for advanced cancers, a generation of surgeons and chemotherapists, unable to cure patients, began to learn (or relearn) the art of caring for patients.

The word palliate comes from the Latin palliare, “to cloak”—and providing pain relief was perceived as cloaking the essence of the illness, smothering symptoms rather than attacking disease.

The movement to restore sanity and sanctity to the end-of-life care of cancer patients emerged, predictably, not from cure-obsessed America but from Europe.

It would take a full decade for Saunders’s movement to travel to America and penetrate its optimism-fortified oncology wards. “The resistance to providing palliative care to patients,” a ward nurse recalls, “was so deep that doctors would not even look us in the eye when we recommended that they stop their efforts to save lives and start saving dignity instead… doctors were allergic to the smell of death. Death meant failure, defeat—their death, the death of medicine, the death of oncology.”

The first hospice in the United States was launched at Yale–New Haven Hospital in 1974. By the early 1980s, hospices for cancer patients built on Saunders’s model had sprouted up worldwide—most prominently in Britain, where nearly two hundred hospice centers were operating by the end of that decade. Saunders refused to recognize this enterprise as pitted “against” cancer. “The provision of… terminal care,” she wrote, “should not be thought of as a separate and essentially negative part of the attack on cancer. This is not merely the phase of defeat, hard to contemplate and unrewarding to carry out. In many ways its principles are fundamentally the same as those which underlie all other stages of care and treatment, although its rewards are different.”

The grand tally, generously speaking, amounted to about 35,000 to 40,000 lives per year. That number was to be contrasted with the annual incidence of cancer in 1985—448 new cancer cases diagnosed for every 100,000 Americans, or about 1 million every year—and the mortality from cancer in 1985—211 deaths for every 100,000, or 500,000 deaths every year. In short, even with relatively liberal estimates about lives saved, less than one in twenty patients diagnosed with cancer in America, and less than one in ten of the total number of patients who would die of cancer, had benefited from the advances in therapy and screening.

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.

chemicals to create a catalog of chemicals that increased the mutation rate—mutagens. And as he populated his catalog, he made a seminal observation: chemicals that scored as mutagens in his test tended to be carcinogens as well.

“All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”