The Emperor of All Maladies

by Siddhartha Mukherjee

Prostate cancer represents a full third of all cancer incidence in men—sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.

“Cancer is not necessarily autonomous548 and intrinsically self-perpetuating,” Huggins wrote. “Its growth can be sustained and propagated549 by hormonal function in the host.” 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.

Cells that expressed the estrogen receptor could bind tamoxifen, and the drug, an estrogen antagonist, shut off estrogen responsiveness, thus choking the cells’ growth. But ER-negative cells lacked the receptor for the drug and thus were insensitive to it. The schema had a satisfying simplicity. For the first time in the history of cancer, a drug, its target, and a cancer cell had been conjoined by a core molecular logic.

To describe this form of treatment, Carbone and his team used the word adjuvant, from the Latin phrase “to help.” Adjuvant chemotherapy, Carbone conjectured, could be the surgeon’s little helper. It would eradicate microscopic deposits of cancer left behind after surgery, thus extirpating any remnant reservoirs of malignancy in the body in early breast cancer—in essence, completing the Herculean cancer-cleansing task that Halsted had set for himself.

“Know thine enemy” runs the adage, and Fisher’s and Bonadonna’s trials had shown that it was essential to “know” the cancer as intimately as possible before rushing to treat it. The meticulous separation of breast cancer into distinct stages, for instance, was a crucial prerequisite to the success of Bonadonna’s study: early-stage breast cancer could not be treated like late-stage breast cancer. The meticulous separation of ER-positive and ER-negative cancers was crucial to Fisher’s study: if tamoxifen had indiscriminately been tested on ER-negative breast cancer, the drug would have been discarded as having no benefit.

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. Writing about pain relief, a Boston surgeon thus reasoned in the 1950s: “If there is persistent pain576 which cannot be relieved by direct surgical attack on the pathological lesion itself . . . , relief can be obtained only by surgical interruption of sensory pathways.” The only alternative to surgery was more surgery—fire to fight fire. Pain-relieving opiate drugs such as morphine or fentanyl were deliberately denied.

“The resistance to providing palliative care to patients,”579 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.”

Saunders refused to recognize this enterprise as pitted “against” cancer. “The provision of . . . terminal care580,” 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.” This, too, then, was knowing the enemy.

Pott’s observation extended the work of the Paduan physician Bernardino Ramazzini. In 1713, Ramazzini had published604 a monumental work—De Morbis Artificum Diatriba—that had documented dozens of diseases that clustered around particular occupations. Ramazzini called these diseases morbis artificum—man-made diseases. Soot cancer, Pott claimed, was one such morbis artificum—only in this case, a man-made disease for which the inciting agent could be identified. Although Pott lacked the vocabulary to describe it as such, he had discovered a carcinogen.

Second, if a foreign substance was truly the cause, then cancer was potentially preventable. There was no need to purge the body of fluids. Since the illness was man-made, its solution could also be man-made. Remove the carcinogen—and cancer would stop appearing.

But political winds changed. By the late eighteenth century, the embarrassing plight of London’s climbing-boys was publicly exposed, and social reformers in England sought to create laws to regulate the occupation. In 1788, the Chimney Sweepers Act608 was passed in Parliament, preventing master sweeps from employing children under eight (children over eight were allowed to be apprenticed). In 1834, the age was raised to fourteen, and in 1840 to sixteen years. By 1875, the use of young climbing-boys was fully forbidden and the profession vigorously policed to prevent infractions. Pott did not live to see the changes—he contracted pneumonia and died in 1788—but the man-made epidemic of scrotal cancer among sweeps vanished over several decades.

Like a virus, too, the cigarette mutated, adapting itself to diverse contexts. In the Soviet gulags, it became an informal currency; among English suffragettes, a symbol of rebellion; among American suburbanites, of rugged machismo, among disaffected youth, of generational rift. In the turbulent century between 1850 and 1950, the world offered conflict, atomization, and disorientation. The cigarette offered its equal and opposite salve: camaraderie, a sense of belonging, and the familiarity of habits. If cancer is the quintessential product of modernity, then so, too, is its principal preventable cause: tobacco.

Our intuitive acuity about statistical correlations, like the acuity of the human eye, performs best at the margins. When rare events are superposed against rare events, the association between them can be striking. Pott, for instance, had discovered the link between scrotal cancer and chimney sweeping because chimney sweeping (the profession) and scrotal cancer (the disease) were both uncommon enough that the juxtaposition of the two stood out starkly like a lunar eclipse—two unusual occurrences in precise overlap.

If nearly all men smoked, and only some of them developed cancer, then how might one tease apart the statistical link between one and the other?

Even surgeons, who encountered lung cancer most frequently, could no longer perceive any link. In the 1920s, when Evarts Graham, the renowned surgeon in St. Louis who had pioneered the pneumonectomy (the resection of the lung to remove tumors), was asked whether tobacco smoking had caused the increased incidence of lung cancer, he countered dismissively, “So has the use of nylon stockings.”620

Tobacco, like the nylon stockings of cancer epidemiology, thus vanished from the view of preventive medicine. And with its medical hazards largely hidden, cigarette usage grew even more briskly, rising at a dizzying rate throughout the western hemisphere. By the time the cigarette returned to visibility as arguably the world’s most lethal carrier of carcinogens, it would be far too late. The lung cancer epidemic would be in full spate, and the world wou...

Wars generally stimulate two industries, ammunition and cigarettes, and indeed both the World Wars had potently stimulated the already bloated tobacco industry. Cigarette sales had climbed640 to stratospheric heights in the mid-1940s and continued to climb in the ’50s. In a gargantuan replay of 1864, as tobacco-addicted soldiers returned to civilian life, they brought even more public visibility to their addiction.

“A causal relationship between heavy cigarette smoking and cancer of the lung is stronger than for the efficacy of vaccination against smallpox, which is only statistical.”

On February 14, with his condition deteriorating weekly, Graham wrote to his friend and collaborator the surgeon Alton Ochsner: “Perhaps you have heard that657 I have recently been a patient at Barnes Hospital because of bilateral bronchogenic carcinoma which sneaked up on me like a thief in the night. . . . You know I quit smoking more than five years ago, but the trouble is that I smoked for 50 years.”

“The obstinacy of [policymakers],” he wrote, “compels one to conclude that it is their own addiction . . . which blinds them. They have eyes to see, but see not because of their inability or unwillingness to give up smoking. All of this leads to the question . . . are the radio and the television to be permitted to continue carrying the advertising material of the cigarette industry? Isn’t it time that the official guardian of the people’s health, the United States Public Health Service, at least make a statement of warning?”

Politicians were far more protective of the narrow interests of tobacco than of the broad interest of public health. Tobacco makers need not have bothered inventing protective filters, Drew wrote drily: Congress had turned out to be “the best filter yet.”

Banzhaf was lounging at home during the Thanksgiving holiday of 1966 (watching the omnipresent cigarette ads) when his mind raced to an obscure legal clause. In 1949, Congress had issued the “fairness doctrine,” which held that public broadcast media had to allow “fair” airtime to opposing viewpoints on controversial issues. (Congress had reasoned that since the broadcast media used a public resource—airwaves—they should reciprocate by performing a public function, by providing balanced information on controversial issues.) The doctrine was little known and little used. But Banzhaf began to wonder whether it could be applied to cigarette advertising. The FTC had attacked the disingenuousness of the tobacco industry’s advertising efforts. Could a parallel strategy be used to attack the disproportionality of its media presence?

“The advertisements in question679 clearly promote the use of a particular cigarette as attractive and enjoyable. Indeed, they understandably have no other purpose. We believe that a station which presents such advertisements has the duty of informing its audience of the other side of this controversial issue of public importance—that, however enjoyable, such smoking may be a hazard to the smoker’s health.”

Banzhaf chose to go to trial anyway. Dragged into court in 1968, he squared off against “a squadron of the best-paid lawyers in the country,680 row after row of them in pinstripe suits and cuff links”—and, to the utter shock of the tobacco industry, won his case.

The industry tried to mount an aggressive countercampaign. An unpublicized internal report drawn up in 1969 to respond to the looming threat of the FCC advertising ban concluded, “Doubt is our product,681 since it is the best means of competing with the ‘body of fact.’ ” But antismoking advocates had also learned the tricks of the trade; if tobacco sellers had “doubt” to sow into public minds, then tobacco opponents had something just as visceral: fear—in particular, fear of the ultimate illness. A barrage of antismoking commercials appeared on television. In 1968, a worn and skeletal-looking William Talman682, a veteran actor and former smoker, announced in a prime-time advertisement that he was dying from lung cancer. Narcotized on painkilling medicines, his words slurring, Talman nonetheless had a clear message for the public: “If you do smoke—quit. Don’t be a loser.”

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. Document after document revealed frantic struggles within the industry to conceal risks, often leaving even its own employees feeling morally queasy.

Lampooned in court as a weak-willed, ill-informed, and dim-witted addict unaware of the “obvious” dangers of tobacco, Rose Cipollone nonetheless turned into a heroic icon of a cancer victim battling her disease—even from her grave.

During World War Two, hundreds of tons of mustard gas were released on the Bari harbor in Italy during an air raid. The gas decimated normal white blood cells in the body, leading pharmacologists to fantasize about using a similar chemical to kill cancers of white blood cells. Chemotherapy—chemical warfare on cancer cells—was inspired, literally, by war.

In the 1990s, Barbara Bradfield was among the first women to be treated with a drug, Herceptin, that specifically attacks breast cancer cells. She is the longest survivor of that treatment, with no hint of her cancer remaining.

By granting relative protection from future legal action, by restricting cigarette advertising, and by allowing its signatory companies to fix prices, the agreement provides a virtual monopoly to the companies that have signed the MSA. Small independent manufacturers dare not enter or compete in the business, leaving big tobacco to become even bigger tobacco. The influx of annual settlement payments from cigarette makers creates “client-states” that depend on this money to fund escalating medical costs. Indeed, the real cost of the agreement is borne by addicted smokers who now pay more for cigarettes, and then pay with their lives.

Nor has the MSA signaled the death of the industry in a more global sense; beleaguered in America, the Marlboro Man has simply sought out new Marlboro countries. With their markets and profits dwindling and their legal costs mounting, cigarette manufacturers have increasingly targeted developing countries as new markets, and the number of smokers in many of these nations has risen accordingly. Tobacco smoking is now a major preventable cause705 of death in both India and China. Richard Peto, an epidemiologist at Oxford706 and a close collaborator of Richard Doll’s (until Doll’s death in 2005), recently estimated that the number of smoking-related deaths among adults in India would rise to 1 million per year in the 2010s and continue to rise in the next decade. In China, lung cancer is already707 the leading cause of death, attributable to smoking in men.

In a recent editorial in the British Medical Journal,711 Stanton Glantz, an epidemiologist at the University of California, San Francisco, described this as yet another catastrophe in the making: “Multinational cigarette companies act as a vector that spreads disease and death throughout the world. This is largely because the tobacco industry uses its wealth to influence politicians to create a favourable environment to promote smoking. The industry does so by minimising restrictions on advertising and promotion and by preventing effective public policies for tobacco control such as high taxes, strong graphic warning labels on packets, smoke-free workplaces and public places, aggressive countermarketing media campaigns, and advertising bans. Unlike mosquitoes, another vector of worldwide disease, the tobacco companies quickly transfer the information and strategies they learn in one part of the world to others.”

It is difficult for me to convey the range and depth of devastation that I witnessed in the cancer wards that could be directly attributed to cigarette smoking. An ebullient, immaculately dressed young advertising executive who first started smoking to calm his nerves had to have his jawbone sliced off to remove an invasive tongue cancer. A grandmother who taught her grandchildren to smoke and then shared cigarettes with them was diagnosed with esophageal cancer. A priest with terminal lung cancer swore that smoking was the only vice that he had never been able to overcome. Even as these patients were paying the ultimate price for their habit, the depth of denial in some of them remained astonishing; many of my patients continued to smoke, often furtively, during their treatment for cancer (I could smell the acrid whiff of tobacco on their clothes as they signed the consent forms for chemotherapy).

A surgeon who practiced in Britain in the seventies—a time when lung cancer incidence was ascending to its macabre peak—recalled his first nights in the wards when patients awoke from their cancer operations and then walked like zombies through the corridors begging the nurses for cigarettes.

Yet despite the evident seriousness of this addiction and its long-term consequences, tobacco consumption continues relatively unfettered even today. Smoking rates, having plateaued for decades, have begun to rise again in certain demographic pockets, and lackluster antismoking campaigns have lost their grip on public imagination. The disjunction between the threat and the response is widening. 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 pub...

As with Pott and scrotal cancer, the statistical confluence of a rare profession and a rare tumor swiftly identified the causal agent in this cancer: exposure to asbestos.

How could DES, asbestos, radiation, hepatitis virus, and a stomach bacterium all converge on the same pathological state, although in different populations and in different organs? The list of cancer-causing agents seemed to get—as another swallower of unknown potions might have put it—“curiouser and curiouser.”

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.

Mammography, as Salomon called his technique, languished in neglect. It was hardly missed: in a world obsessed with radical surgery, since small or large masses in the breast were treated with precisely the same gargantuan operation, screening for small lesions made little sense.

Egan, like Papanicolaou, cast himself more as an immaculate craftsman than a scientist—a photographer, really, who was taking photographs of cancer using X-rays, the most penetrating form of light. He tinkered with films, angles, positions, and exposures, until, as one observer put it, “trabeculae as thin as a spider’s web”752 in the breast could be seen in the images. But could cancer be caught in that “spider’s web” of shadows, trapped early enough to prevent its spread? Egan’s mammograms could now detect tumors as small as a few millimeters, about the size of a grain of barley. But would screening women to detect such early tumors and extricating the tumors surgically save lives?

But the discovery had to come from the bottom up—from the cancer cell to its therapy. “As the decade ended,” Bruce Chabner781, former director of the NCI’s Division of Cancer Treatment, recalled, “it was as if the whole discipline of oncology, both prevention and cure, had bumped up against a fundamental limitation of knowledge. We were trying to combat cancer without understanding the cancer cell, which was like launching rockets without understanding the internal combustion engine.”

An anxious woman with stage III breast cancer needs her imagination to be repossessed before she will accept chemotherapy that will likely extend her life. A seventy-six-year-old man attempting another round of aggressive experimental chemotherapy for a fatal, drug-resistant leukemia needs his imagination to be reconciled to the reality that his disease cannot be treated. Ars longa, vita brevis. The art of medicine is long, Hippocrates tells us, “and life is short; opportunity fleeting; the experiment perilous; judgment flawed.”

For cancer therapeutics, the mid and late 1980s were extraordinarily cruel years, mixing promise with disappointment, and resilience with despair. As physician-writer Abraham Verghese wrote, “To say this was a time of unreal787 and unparalleled confidence, bordering on conceit, in the Western medical world is to understate things. . . . When the outcome of treatment was not good, it was because the host was aged, the protoplasm frail, or the patient had presented too late—never because medical science was impotent.

To test this theory, Frei hoped to launch one of the most ambitious trials in the history of chemotherapy. With his ear for catchy acronyms, Frei christened the protocol the Solid Tumor Autologous Marrow Program—or STAMP.

In an essay titled A View from the Front Line, Jencks described her experience with cancer as like being woken up midflight on a jumbo jet and then thrown out with a parachute into a foreign landscape without a map: “There you are, the future patient,854 quietly progressing with other passengers toward a distant destination when, astonishingly (Why me?) a large hole opens in the floor next to you. People in white coats appear, help you into a parachute and—no time to think—out you go. “You descend. You hit the ground. . . . But where is the enemy? What is the enemy? What is it up to? . . . No road. No compass. No map. No training. Is there something you should know and don’t?

An era of oncology was coming to a close. Already, the field had turned away from its fiery adolescence, its entrancement with universal solutions and radical cures, and was grappling with fundamental questions about cancer. What were the underlying principles that governed the root behavior of a particular form of cancer? What was common to all cancers, and what made breast cancer different from lung or prostate cancer? Might those common pathways, or differences for that matter, establish new road maps to cure and prevent cancer?

“With holistic clarity of mechanism,937 cancer prognosis and treatment will become a rational science, unrecognizable by current practitioners.” Having wandered in the darkness for decades, scientists had finally reached a clearing in their understanding of cancer. Medicine’s task was to continue that journey toward a new therapeutic attack.

Have you met Jimmy941? . . . Jimmy is any one of thousands of children with leukemia or any other form of cancer, from the nation or from around the world. —Pamphlet for the Jimmy Fund, 1963

Take me out to the ball game, Take me out with the crowd. Buy me some peanuts and Cracker Jack, I don’t care if I never get back.

Cancer is not a concentration camp, but it shares the quality of annihilation: it negates the possibility of life outside and beyond itself; it subsumes all living.