The Emperor of All Maladies

by Siddhartha Mukherjee

In 1919, a pair of American pathologists220, 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 autopsies revealed what the Krumbhaars had noted earlier. In the men and women who had initially survived the bombing but succumbed later to injuries, white blood cells had virtually vanished in their blood, and the bone marrow was scorched and depleted. The gas had specifically targeted bone marrow cells—a grotesque molecular parody of Ehrlich’s healing chemicals.

Goodman and Gilman weren’t interested226 in the “vesicant” properties of mustard gas—its capacity to burn skin and membranes. They were captivated by the Krumbhaar effect—the gas’s capacity to decimate white blood cells. Could this effect, or some etiolated cousin of it, be harnessed in a controlled setting, in a hospital, in tiny, monitored doses, to target malignant white cells?

Burchenal and Murphy were astonished by the speedy remissions produced by 6-MP. Leukemia cells flickered and vanished in the bone marrow and the blood, often within a few days of treatment. But, like the remissions in Boston, these were disappointingly temporary, lasting only a few weeks. As with Farber’s anti-folates, there was only a fleeting glimpse of a cure.

Perhaps he had stumbled upon an even more provocative principle—that cancer could be cured by chemicals alone.

Scientists often study the past as obsessively as historians because few other professions depend so acutely on it. Every experiment is a conversation with a prior experiment, every new theory a refutation of the old. Farber, too, studied the past compulsively—and the episode that pivotally fascinated him was the story of the national polio campaign.

If Farber’s antifolates were his first discovery in oncology, then this critical truth was his second. It set off a seismic transformation in his career that would far outstrip his transformation from a pathologist to a leukemia doctor. This second transformation—from a clinician into an advocate for cancer research—reflected the transformation of cancer itself. The emergence of cancer from its basement into the glaring light of publicity would change the trajectory of this story. It is a metamorphosis that lies at the heart of this book.

Etymologically, patient means sufferer244. It is not suffering as such that is most deeply feared but suffering that degrades. —Susan Sontag, Illness as Metaphor

It was Disney World fused with Cancerland.

Farber needed a means to stimulate and fund the effort to find even more powerful antileukemia drugs. “We are pushing ahead as fast as possible,” he wrote in another letter—but it was not quite fast enough for him. The money that he had raised255 in Boston “has dwindled to a disturbingly small amount,” he noted. He needed a larger drive, a larger platform, and perhaps a larger vision for cancer. He had outgrown the house that Jimmy had built.

Perhaps there is only one cardinal sin256: impatience. Because of impatience we were driven out of Paradise, because of impatience we cannot return. —Franz Kafka

“If a toothpaste . . .266 deserved advertising at the rate of two or three or four million dollars a year,” Mary Lasker reasoned, “then research against diseases maiming and crippling people in the United States and in the rest of the world deserved hundreds of millions of dollars.

The death of a man291 is like the fall of a mighty nation That had valiant armies, captains, and prophets, And wealthy ports and ships all over the seas But now it will not relieve any besieged city It will not enter into an alliance —Czeslaw Milosz, “The Fall”

Oliver Heaviside, an English mathematician from the 1920s, once wrote jokingly about a scientist musing at a dinner table, “Should I refuse my dinner302 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?

Although combination X-ray and chemotherapy did not always produce long-term cures, Wilms’ tumor was the first metastatic solid tumor to respond to chemotherapy. Farber had achieved his long-sought leap from the world of liquid cancers to solid tumors.

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.”

The best [doctors] seem to have a sixth sense311 about disease. They feel its presence, know it to be there, perceive its gravity before any intellectual process can define, catalog, and put it into words. Patients sense this about such a physician as well: that he is attentive, alert, ready; that he cares. No student of medicine should miss observing such an encounter. Of all the moments in medicine, this one is most filled with drama, with feeling, with history. —Michael LaCombe, Annals of Internal Medicine,

By the winter of 1962, the compass of leukemia medicine pointed unfailingly in one direction. If two drugs were better than one, and if three better than two, then what if four antileukemia drugs could be given together—in combination, as with TB?

Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished. The hcg level—the hormone secreted by choriocarcinoma—had turned out to be its real fingerprint, its marker.

This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.

Killing leukemia was an iterative process, like halving a monster’s body, then halving the half, and halving the remnant half.

If we didn’t kill the tumor343, we killed the patient. —William Moloney on the early days of chemotherapy

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.

But the story of leukemia—the story of cancer—isn’t the story of doctors who struggle and survive, moving from one institution to another. It is the story of patients who struggle and survive, moving from one embankment of illness to another. 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 Farber’s leukemia had occupied the hazy border between liquid and solid tumors, then Hodgkin’s disease inhabited yet another strange borderland: a local disease on the verge of transforming into a systemic one—Halsted’s vision of cancer on its way to becoming Galen’s.

But hadn’t Halsted wagered on the same horse and lost? Hadn’t radical surgery become entangled in the same logic—carving out larger and larger areas for treatment—and then spiraled downward? Why did Kaplan succeed where others had failed?

First, because Kaplan meticulously restricted radiotherapy to patients with early-stage disease. He went to exhaustive lengths to stage patients before unleashing radiation on them. By strictly narrowing the group of patients treated, Kaplan markedly increased the likelihood of his success.

And second, he succeeded because he had picked the right disease. Hodgkin’s was, for the most part, a regional illness. “Fundamental to all attempts at curative treatment379 of Hodgkin’s disease,” one reviewer commented memorably in the New England Journal of Medicine in 1968, “is the assum...

Early-stage, local cancers, Kaplan realized, were often inherently different from widely spread, metastatic cancers—even within the same form of cancer. A hundred instances of Hodgkin’s disease, even though pathologically classified as the same entity, were a hundred variants around a common theme. Cancers possessed temperaments, personalities—behaviors.

The notable common feature that linked all these drugs was that they were all rather indiscriminate inhibitors of cellular growth.

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.

The treatment lasted up to two and a half years; it involved multiple exposures to radiation, scores of blood tests, dozens of spinal taps, and multiple intravenous drugs—a strategy so precise and demanding that one journal refused to publish it, concerned that it was impossible to even dose it and monitor it correctly393 without killing several patients in the trials. Even at St. Jude’s, the regimen was considered so overwhelmingly toxic that the trial was assigned to relatively junior physicians under Pinkel’s supervision because the senior researchers, knowing its risks394, did not want to run it. Pinkel called it “total therapy.” As fellows, we called it “total hell.”

These observations had led to a theory called the somatic mutation hypothesis of cancer. The somatic theory of cancer argued that environmental carcinogens such as soot or radium somehow permanently altered the structure of the cell and thus caused cancer. But the precise nature of the alteration was unknown. Clearly, soot, paraffin, and radium possessed the capacity to alter a cell in some fundamental way to generate a malignant cell. But how could such a diverse range of insults all converge on the same pathological insult? Perhaps a more systematic explanation was missing—a deeper, more fundamental theory of carcinogenesis.

The agent responsible for carrying the cancer, Rous concluded, was not a cell or an environmental carcinogen, but some tiny particle lurking within a cell. The particle was so small that it could easily pass through most filters and keep producing cancer in animals. The only biological particle that had these properties was a virus. His virus was later called Rous sarcoma virus, or RSV for short.

In her letters, Mary Lasker began428 to refer to a programmatic War on Cancer as the conquest of “inner space” (as opposed to “outer space”), instantly unifying the two projects. The moon landing thus marked a turning point in the life cycle of the cancer crusade. In the past, the Laskerites had concentrated much of their efforts on political lobbying in Washington. When advertisements or posters had been pitched directly to the public, they had been mainly educational. The Laskerites had preferred to maneuver backstage, preferring political advocacy to public advocacy.

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.

“A radical change happened to the perception441 of the object of horror” in the 1970s, a progression from the external to the internal. In the 1950s, in the throes of the Cold War, Americans were preoccupied with the fear of annihilation from the outside: from bombs and warheads, from poisoned water reservoirs, communist armies, and invaders from outer space. The threat to society was perceived as external. Horror movies—the thermometers of anxiety in popular culture—featured alien invasions, parasitic occupations of the brain, and body snatching: It Came from Outer Space or The Man from Planet X. But by the early 1970s, the locus of anxiety—the “object of horror,” as Salecl describes it—had dramatically shifted from the outside to the inside. The rot, the horror—the biological decay and its concomitant spiritual decay—was now relocated within the corpus of society and, by extension, within the body of man. American society was still threatened, but this time, the threat came from inside. The names of horror films reflected the switch: The Exorcist; They Came from Within.

Cancer epitomized this internal horror. It was the ultimate emergence of the enemy from within—a marauding cell that crawled out of one’s own body and occupied it from the inside, an internal alien. The “Big Bomb,” a columnist wrote442, was replaced by “the Big C”:

“Congratulations, Carla,” I said. “You are in a full remission.”

Oft expectation fails476, and most oft there Where most it promises; and oft it hits Where hope is coldest, and despair most sits —William Shakespeare, All’s Well That Ends Well

“I do not despair of carcinoma being cured486 somewhere in the future, but this blessed achievement will, I believe, never be wrought by the knife of the surgeon.”

Political revolutions, the writer Amitav Ghosh writes494, often occur in the courtyards of palaces, in spaces on the cusp of power, located neither outside nor inside. Scientific revolutions, in contrast, typically occur in basements, in buried-away places removed from mainstream corridors of thought.

Crile found himself pitted against his own department, against friends and colleagues. The very doctors that he would need to recruit to run such a trial were fervently, often viciously, opposed to it. “Power,” in the colloquial sense of the word, thus collided with “power” in the statistical sense. The surgeons who had so painstakingly created the world of radical surgery had absolutely no incentive to revolutionize it.

And it is solely by risking life513 that freedom is obtained.

Every battle needs its iconic battleground, and if one physical place epitomized the cancer wars of the late 1970s, it was the chemotherapy ward. It was “our trench and our bunker,”515 a chemotherapist recalls, a space marked indelibly in the history of cancer. To enter the ward was to acquire automatic citizenship—as Susan Sontag might have put it—into the kingdom of the ill.

Cisplatin had chemically attacked DNA with its reactive molecular arms, cross-linking and damaging the molecule irreparably, forcing cells to arrest their division.

Cisplatin was touted as the epic chemotherapeutic product of the late 1970s, the quintessential example of how curing cancer involved pushing patients nearly to the brink of death. By 1978, cisplatin-based chemotherapy was the new vogue in cancer pharmacology; every conceivable combination was being tested on thousands of patients across America. The lemon-yellow chemical dripping through intravenous lines was as ubiquitous in the cancer wards as the patients clutching their nausea basins afterward.

“When doctors say that the side effects are tolerable541 or acceptable, they are talking about life-threatening things,” she wrote. “But if you just vomit so hard that you break the blood vessels in your eyes . . . they don’t consider that even mentionable. And they certainly don’t care if you’re bald.” She wrote sarcastically, “The smiling oncologist does not know whether his patients vomit or not.”

The language of suffering had parted, with the “smiling oncologist” on one side and his patients on the other. In Edson’s Wit—a work not kind to the medical profession—a young oncologist, drunk with the arrogance of power, personifies the divide as he spouts out lists of nonsensical drugs and combinations while his patient, the English professor, watches with mute terror and fury: “Hexamethophosphacil with Vinplatin to potentiate.543 Hex at three hundred mg per meter squared. Vin at one hundred. Today is cycle two, day three. Both cycles at the full dose.”

It is said that if you know your enemies544 and know yourself, you will not be imperiled in a hundred battles; if you do not know your enemies but do know yourself, you will win one and lose one; if you do not know your enemies nor yourself, you will be imperiled in every single battle. —Sun Tzu