The Emperor of All Maladies

by Siddhartha Mukherjee

  In August 1924, Keynes examined a patient with breast cancer, a thin, emaciated woman of forty-seven with an ulcerated malignant lump in her breast. In Baltimore or in New York, such a patient would immediately have been whisked off for radical surgery. But Keynes was concerned about his patient’s constitutional frailty. Rather than reaching indiscriminately for a radical procedure (which would likely have killed her at the operating table), he opted for a much more conservative strategy. Noting that radiation therapists, such as Emil Grubbe, had demonstrated the efficacy of X-rays in treating breast cancer, Keynes buried fifty milligrams of radium in her breast to irradiate her tumor and monitored her to observe the effect, hoping, at best, to palliate her symptoms. Surprisingly, he found a marked improvement. “The ulcer rapidly heal[ed],” he wrote, “and the whole mass [became] smaller, softer and less fixed.” Her mass reduced so rapidly, Keynes thought he might be able to perform a rather minimal, nonradical surgery on her to completely remove it.

  Emboldened by his success, between 1924 and 1928, Keynes attempted other variations on the same strategy. The most successful of these permutations, he found, involved a careful mixture of surgery and radiation, both at relatively small doses. He removed the malignant lumps locally with a minor operation (i.e., without resorting to radical or ultraradical surgery). He followed the surgery with radiation to the breast. There was no stripping of nodes, no cracking or excavation of clavicles, no extirpations that stretched into six or eight hours. Nothing was radical, yet, in case after case, Keynes and his colleagues found that their cancer recurrence rate was at least comparable to those obtained in New York or Baltimore—achieved without grinding patients through the terrifying crucible of radical surgery.

  In 1927, in a rather technical report to his department, Keynes reviewed his experience combining local surgery with radiation. For some cases of breast cancer, he wrote, with characteristic understatement, the “extension of [the] operation beyond a local removal might sometimes be unnecessary.” Everything about Keynes’s sentence was carefully, strategically, almost surgically constructed. Its implication was enormous. If local surgery resulted in the same outcome as radical surgery, then the centrifugal theory had to be reconsidered. Keynes had slyly declared war on radical surgery, even if he had done so by pricking it with a pin-size lancet.

  But Halsted’s followers in America laughed away Keynes’s efforts. They retaliated, by giving his operation a nickname: the lumpectomy. The name was like a low-minded joke, a cartoon surgery in which a white-coated doctor pulls out a body part and calls it a “lump.” Keynes’s theory and operation were largely ignored by American surgeons. He gained fame briefly in Europe as a pioneer of blood transfusions during the First World War, but his challenge to radical surgery was quietly buried.

  Keynes would have remained conveniently forgotten by American surgeons except for a fateful series of events. In 1953, a colleague of Keynes’s, on sabbatical from St. Bart’s at the Cleveland Clinic in Ohio, gave a lecture on the history of breast cancer, focusing on Keynes’s observations on minimal surgery for the breast. In the audience that evening was a young surgeon named George Barney Crile. Crile and Keynes had never met, but they shared old intellectual debts. Crile’s father, George Crile Sr., had pioneered the use of blood transfusions in America and written a widely read textbook on the subject. During the First World War, Keynes had learned to transfuse blood in sterilized, cone-shaped glass vessels—an apparatus devised, in part, by the elder Dr. Crile.

  Political revolutions, the writer Amitav Ghosh writes, 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. But a surgical revolution must emanate from within surgery’s inner sanctum—for surgery is a profession intrinsically sealed to outsiders. To even enter the operating theater, one must be soused in soap and water, and surgical tradition. To change surgery, one must be a surgeon.

  The Criles, father and son, were quintessential surgical insiders. The elder Crile, an early proponent of radical surgery, was a contemporary of Halsted’s. The younger had learned the radical mastectomy from students of Halsted himself. The Criles were steeped in Halstedian tradition, upholding the very pole staffs of radical surgery for generations. But like Keynes in London, Crile Jr. was beginning to have his own doubts about the radical mastectomy. Animal studies performed in mice (by Skipper in Alabama, among others) had revealed that tumors implanted in animals did not behave as Halsted might have imagined. When a large tumor was grown in one site, microscopic metastatic deposits from it often skipped over the local nodes and appeared in faraway places such as the liver and the spleen. Cancer didn’t move centrifugally by whirling through larger and larger ordered spirals; its spread was more erratic and unpredictable. As Crile pored through Keynes’s data, the old patterns suddenly began to make sense: Hadn’t Halsted also observed that patients had died four or five years after radical surgery from “occult” metastasis? Could breast cancer in these patients also have metastasized to faraway organs even before radical surgery?

  The flaw in the logic began to crystallize. If the tumor was locally confined to start with, Crile argued, then it would be adequately removed by local surgery and radiation, and manically stripping away extra nodes and muscles could add no possible benefit. In contrast, if breast cancer had already spread outside the breast, then surgery would be useless anyway, and more aggressive surgery would simply be more aggressively useless. Breast cancer, Crile realized, was either an inherently localized disease—thus curable by a smaller mastectomy—or an inherently systemic disease—thus incurable even by the most exhaustive surgery.

  Crile soon gave up on the radical mastectomy altogether and, instead, began to operate in a manner similar to Keynes’s, using a limited surgical approach (Crile called it the “simple mastectomy”). Over about six years, he found that his “simple” operation was remarkably similar to Keynes’s lumpectomy+radiation combination in its impact: the survival rate of patients treated with either form of local surgery tended to be no different from that of those treated historically with the radical mastectomy. Separated by an ocean and forty years of clinical practice, both Keynes and Crile had seemingly stumbled on the same clinical truth.

  But was it a truth? Keynes had had no means to prove it. Until the 1930s, clinical trials had typically been designed to prove positive results: treatment A was better than treatment B, or drug X superior to drug Y. But to prove a negative result—that radical surgery was no better than conventional surgery—one needed a new set of statistical measures.

  The invention of that measure would have a profound influence on the history of oncology, a branch of medicine particularly suffused with hope (and thus particularly prone to unsubstantiated claims of success). In 1928, four years after Keynes had begun his lumpectomies in London, two statisticians, Jerzy Neyman and Egon Pearson, provided a systematic method to evaluate a negative statistical claim. To measure the confidence in a negative claim, Neyman and Pearson invoked a statistical concept called power. “Power” in simplistic terms, is a measure of the ability of a test or trial to reject a hypothesis. Intuitively, Neyman and Pearson reasoned that a scientist’s capacity to reject a hypothesis depends most critically on how intensively he has tested the hypothesis—and thus, on the number of samples that have independently been tested. If one compares five radical mastectomies against five conventional mastectomies and finds no difference in outcome, it is hard to make a significant conclusion about the result. But if a thousand cases of each produce precisely identical outcomes, then one can make a strong claim about a lack of benefit.

  Right there, buried inside that dependence, lies one of the strangest pitfalls of medicine. For any trial to be adequately “powered,” it needs to recruit an adequate number of patients. But to recruit patients, a trialist has to convince doctors to participate in the t
rial—and yet these doctors are often precisely those who have the least interest in having a theory rejected or disproved. For breast cancer, a discipline immersed in the legacy of the radical surgery, these conflicts were particularly charged. No breast cancer trial, for instance, could have proceeded without the explicit blessing and participation of larger-than-life surgeons such as Haagensen and Urban. Yet these surgeons, all enraptured intellectual descendants of Halsted, were the least likely to sponsor a trial that might dispute the theory that they had so passionately advocated for decades. When critics wondered whether Haagensen had been biased in his evaluation by selecting only his best cases, he challenged surgeons to replicate his astounding success using their own alternative methods: “Go thou and do likewise.”

  Thus even Crile—a full forty years after Keynes’s discovery—couldn’t run a trial to dispute Halsted’s mastectomy. 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. 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.

  It took a Philadelphia surgeon named Bernard Fisher to cut through that knot of surgical tradition. Fisher was brackish, ambitious, dogged, and feisty—a man built after Halsted’s image. He had trained at the University of Pittsburgh, a place just as steeped in the glorious Halstedian tradition of radical surgery as the hospitals of New York and Baltimore. But he came from a younger generation of surgeons—a generation with enough critical distance from Halsted to be able to challenge the discipline without undermining its own sense of credibility. Like Crile and Keynes, he, too, had lost faith in the centrifugal theory of cancer. The more he revisited Keynes’s and Crile’s data, the more Fisher was convinced that radical mastectomy had no basis in biological reality. The truth, he suspected, was quite the opposite. “It has become apparent that the tangled web of threads on the wrong side of the tapestry really represented a beautiful design when examined properly, a meaningful pattern, a hypothesis . . . diametrically opposite to those considered to be ‘halstedian,’” Fisher wrote.

  The only way to turn the upside-down tapestry of Halstedian theory around was to run a controlled clinical trial to test the radical mastectomy against the simple mastectomy and lumpectomy+radiation. But Fisher also knew that resistance would be fierce to any such trial. Holed away in their operating rooms, their slip-covered feet dug into the very roots of radical surgery, most academic surgeons were least likely to cooperate.

  But another person in that operating room was stirring awake: the long-silent, etherized body lying at the far end of the scalpel—the cancer patient. By the late 1960s, the relationship between doctors and patients had begun to shift dramatically. 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. Thalidomide, prescribed widely to control pregnancy-associated “hysteria” and “anxiety,” was hastily withdrawn from the market in 1961 because of its propensity to cause severe fetal malformations. In Texas, Jane Roe (a pseudonym) sued the state for blocking her ability to abort her fetus at a medical clinic—launching the Roe v. Wade case on abortion and highlighting the complex nexus between the state, medical authority, and women’s bodies. 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. “Refuse to submit to a radical mastectomy,” Crile exhorted his patients in 1973.

  And refuse they did. Rachel Carson, the author of Silent Spring and a close friend of Crile’s, refused a radical mastectomy (in retrospect, she was right: her cancer had already spread to her bones and radical surgery would have been pointless). Betty Rollin and Rose Kushner also refused and soon joined Carson in challenging radical surgeons. Rollin and Kushner—both marvelous writers: provocative, down-to-earth, no-nonsense, witty—were particularly adept at challenging the bloated orthodoxy of surgery. They flooded newspapers and magazines with editorials and letters and appeared (often uninvited) at medical and surgical conferences, where they fearlessly heckled surgeons about their data and the fact that the radical mastectomy had never been put to a test. “Happily for women,” Kushner wrote, “. . . surgical custom is changing.” It was as if the young woman in Halsted’s famous etching—the patient that he had been so “loathe to disfigure”—had woken up from her gurney and begun to ask why, despite his “loathing,” the cancer surgeon was so keen to disfigure her.

  In 1967, bolstered by the activism of patients and the public attention swirling around breast cancer, Fisher became the new chair of the National Surgical Adjuvant Breast and Bowel Project (NSABP), a consortium of academic hospitals modeled self-consciously after Zubrod’s leukemia group that would run large-scale trials in breast cancer. Four years later, the NSABP proposed to test the operation using a systematic, randomized trial. It was, coincidentally, the eightieth “anniversary” of Halsted’s original description of the radical mastectomy. The implicit, nearly devotional faith in a theory of cancer was finally to be put to a 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.”

  It took Fisher a full ten years to actually gather that data. Recruiting patients for his study was an uphill task. “To get a woman to participate in a clinical trial where she was going to have her breast off or have her breast not taken off, that was a pretty difficult thing to do. Not like testing Drug A versus Drug B,” he recalled.

  If patients were reluctant, surgeons were almost impossibly so. Immersed in the traditions of radical surgery, many American surgeons put up such formidable barriers to patient recruitment that Canadian surgeons and their patients were added to complete the study. The trial recruited 1,765 patients in thirty-four centers in the United States and Canada. Patients were randomized into three groups: one treated with the radical mastectomy, the second with simple mastectomy, and the third with surgery followed by radiation. Even with all forces in gear, it still took years to recruit adequate numbers. Crippled by forces within surgery itself, the NSABP-04 trial barely hobbled to its end.

  In 1981, the results of the trial were finally made public. The rates of breast cancer recurrence, relapse, death, and distant cancer metastasis were statistically identical among all three groups. The group treated with the radical mastectomy had paid heavily in morbidity, but accrued no benefits in survival, recurrence, or mortality.

  Between 1891 and 1981, in the nearly one hundred years of the radical mastectomy, an estimated five hundred thousand women underwent the procedure to “extirpate” cancer. Many chose the procedure. Many were forced into it. Many others did not even realize that it was a choice. Many were permanently disfigured; many perceived the surgery as a benediction; many suffered its punishing penalties bravely, hoping that they had treated their cancer as aggressively and as definitively as possible. Halsted’s “cancer storehouse” grew far beyond its original walls at Hopkins. His ideas entered oncology, then permeated its vocabulary, then its psychology, its ethos, and its self-image. When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today.

 
“The smiling oncologist”

  Few doctors in this country seem to be involved with the non-life-threatening side effects of cancer therapy. . . . In the United States, baldness, nausea and vomiting, diarrhea, clogged veins, financial problems, broken marriages, disturbed children, loss of libido, loss of self-esteem, and body image are nurses’ turf.

  —Rose Kushner

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

  —Hegel

  The ominous toppling of radical surgery off its pedestal may have given cancer chemotherapists some pause for reckoning. But they had their own fantasy of radicalism to fulfill, their own radical arsenal to launch against cancer. Surgery, the traditional battle-ax against cancer, was considered too primitive, too indiscriminate, and too weary. A “large-scale chemotherapeutic attack,” as one doctor put it, was needed to obliterate cancer.

  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,” 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.

  The journalist Stewart Alsop was confined to one such ward at the NIH in 1973 for the treatment of a rare and unidentifiable blood cancer. Crossing its threshold, he encountered a sanitized vision of hell. “Wandering about the NIH clinical center, in the corridors or in the elevator, one comes occasionally on a human monster, on a living nightmare, on a face or body hideously deformed,” he wrote. Patients, even disguised in “civilian” clothes, could still be identified by the orange tinge that chemotherapy left on their skin, underneath which lurked the unique pallor of cancer-related anemia. The space was limbolike, with no simple means of egress—no exit. In the glass-paneled sanatorium where patients walked for leisure, Alsop recalled, the windows were covered in heavy wire mesh to prevent the men and women confined in the wards from jumping off the banisters and committing suicide.