The Emperor of All Maladies

by Siddhartha Mukherjee

  But surgeons had no interest in getting help from anyone—least of all chemotherapists. By the mid-1960s, as radical surgery became increasingly embattled, most breast surgeons had begun to view chemotherapists as estranged rivals that could not be trusted with anything, least of all improving surgical outcomes. And since surgeons largely dominated the field of breast cancer (and saw all the patients upon diagnosis), Carbone could not ramp up his trial because he could barely recruit any patients. “Except for an occasional woman who underwent a mastectomy at the NCI . . . the study never got off the ground,” Carbone recalled.

  But Carbone found an alternative. Shunned by surgeons, he now turned to the surgeon who had shunned his own compatriots—Bernie Fisher, the man caught in the controversial swirl of testing radical breast surgery. Fisher was instantly interested in Carbone’s idea. Indeed, Fisher had been trying to run a trial along similar lines—combining chemotherapy with surgical mastectomy. But even Fisher could pick only one fight at a time. With his own trial, the NSABP-04 (the trial to test radical surgery versus nonradical surgery) barely limping along, he could hardly convince surgeons to join a trial to combine chemo and surgery in breast cancer.

  An Italian team came to the rescue. In 1972, as the NCI was scouring the nation for a site where “adjuvant chemotherapy” after surgery could be tested, the oncologist Gianni Bonadonna came to Bethesda to visit the institute. Suave, personable, and sophisticated, impeccably dressed in custom-cut Milanese suits, Bonadonna made an instant impression at the NCI. He learned from DeVita, Canellos, and Carbone that they had been testing combinations of drugs to treat advanced breast cancer and had found a concoction that would likely work: Cytoxan (a cousin of nitrogen mustard), methotrexate (a variant of Farber’s aminopterin), and fluorouracil (an inhibitor of DNA synthesis). The regimen, called CMF, could be tolerated with relatively minimal side effects, yet was active enough in combination to thwart microscopic tumors—an ideal combination to be used as an adjuvant in breast cancer.

  Bonadonna worked at a large cancer center in Milan called the Istituto Tumori, where he had a close friendship with the chief breast surgeon, Umberto Veronesi. Convinced by Carbone (who was still struggling to get a similar trial launched in America), Bonadonna and Veronesi, the only surgeon-chemotherapist pair seemingly on talking terms with each other, proposed a large randomized trial to study chemotherapy after breast surgery for early-stage breast cancer. They were immediately awarded the contract for the NCI trial.

  The irony of that award could hardly have escaped the researchers at the institute. In America, the landscape of cancer medicine had become so deeply gashed by internal rifts that the most important NCI-sponsored trial of cytotoxic chemotherapy to be launched after the announcement of the War on Cancer had to be relocated to a foreign country.

  Bonadonna began his trial in the summer of 1973. By the early winter that year, he had randomized nearly four hundred women to the trial—half to no treatment and half to treatment with CMF. Veronesi was a crucial supporter, but there was still little interest from other breast surgeons. “The surgeons were not just skeptical,” Bonadonna recalled. “They were hostile. [They] did not want to know. At the time there were very few chemotherapists, and they were not rated highly, and the attitude among surgeons was ‘chemotherapists deliver drugs in advanced disease [while] surgeons operate and we have complete remission for the entire life of the patient. . . . Surgeons rarely saw their patients again, and I think they didn’t want to hear about how many patients were being failed by surgery alone. It was a matter of prestige.’”

  On an overcast morning in the winter of 1975, Bonadonna flew to Brussels to present his results at a conference of European oncologists. The trial had just finished its second year. But the two groups, Bonadonna reported, had clearly parted ways. Nearly half the women treated with no therapy had relapsed. In contrast, only a third of the women treated with the adjuvant regimen had relapsed. Adjuvant chemotherapy had prevented breast cancer relapses in about one in every six treated women.

  The news was so unexpected that it was greeted by a stunned silence in the auditorium. Bonadonna’s presentation had shaken the terra firma of cancer chemotherapy. It was only on the flight back to Milan, ten thousand feet above the earth, that Bonadonna was finally inundated with questions about his trial by other researchers on his flight.

  Gianni Bonadonna’s remarkable Milanese trial left a question almost begging to be answered. If adjuvant CMF chemotherapy could decrease relapses in women with early-stage breast cancer, then might adjuvant tamoxifen—the other active breast cancer drug established by Cole’s group—also decrease relapses in women with localized ER-positive breast cancer after surgery? Had Moya Cole been right about her instinct in treating early-stage breast cancer with antiestrogen therapy?

  This was a question that Bernie Fisher, although embroiled in several other trials, could not resist trying to answer. In January 1977, five years after Cole had published her results on tamoxifen in metastatic cancer, Fisher recruited 1,891 women with estrogen receptor–positive (ER-positive) breast cancer that had spread only to the axillary nodes. He treated half with adjuvant tamoxifen and the other half with no tamoxifen. By 1981, the two groups had deviated sharply. Treatment with tamoxifen after surgery reduced cancer relapse rates by nearly 50 percent. The effect was particularly pronounced among women above fifty years old—a group most resistant to standard chemotherapy regimens and most likely to relapse with 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.

  By the early 1980s, brave new paradigms of treatment had thus arisen out of the ashes of old paradigms. Halsted’s fantasy of attacking early-stage cancers was reborn as adjuvant therapy. Ehrlich’s “magic bullet” for cancer was reincarnated as antihormone therapy for breast and prostate cancer.

  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. In the end, often after decades of remission, chemotherapy-resistant and hormone-resistant cancers grew despite the prior interventions, flinging aside the equilibrium established during the treatment.

  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. Breast or prostate cancers came in an array of forms, each with unique biological behaviors. The heterogeneity was genetic: in breast cancer, for instance, some variants responded to hormonal treatment, while others were hormone-unresponsive. And the heterogeneity was anatomic: some cancers were localized to the breast when detected, while others had a propensity to spread to distant organs.

  Second, understanding that heterogeneity was of deep consequence. “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 dis
carded as having no benefit.

  This nuanced understanding of cancer underscored by these trials had a sobering effect on cancer medicine. As Frank Rauscher, the director of the NCI, put it in 1985, “We were all more naive a decade ago. We hoped that a single application of drugs would result in a dramatic benefit. We now understand it’s much more complicated than that. People are optimistic but we’re not expecting home runs. Right now, people would be happy with a series of singles or doubles.”

  Yet the metaphorical potency of battling and obliterating cancer relatively indiscriminately (“one cause, one cure”) still gripped oncology. Adjuvant chemotherapy and hormonal therapy were like truces declared in the battle—signs, merely, that a more aggressive attack was necessary. 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. Pumped up with self-confidence, bristling with conceit, and hypnotized by the potency of medicine, oncologists pushed their patients—and their discipline—to the brink of disaster. “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.

  “More is more,” a patient’s daughter told me curtly. (I had suggested to her delicately that for some patients with cancer, “Less might be more.”) The patient was an elderly Italian woman with liver cancer that had metastasized widely throughout her abdomen. She had come to the Massachusetts General Hospital seeking chemotherapy, surgery, or radiation—if possible, all three. She spoke halting, heavily accented English, often pausing between her words to catch her breath. Her skin had a yellow-gray tinge—a tinge, I was worried, that would bloom into a bright jaundice if the tumor obstructed her bile duct fully and her blood began to fill up with bile pigments. Exhausted, she drifted in and out of sleep even while I was examining her. I asked her to hold the palms of her hands straight upward, as if halting traffic, looking for signs of a subtle flapping motion that often predates liver failure. Thankfully, there was no tremor, but the abdomen had a dull, full sound of fluid building up inside it, likely full of malignant cells.

  The daughter was a physician, and she watched me with intense, hawklike eyes while I finished the exam. 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. The daughter wanted the best possible care for her mother—the best doctors, the best room with the best view of Beacon Hill, and the best, strongest, and toughest medicine that privilege and money could buy.

  The elderly woman, meanwhile, would hardly tolerate even the mildest drug. Her liver had not failed yet but was on the verge of doing so, and subtle signs suggested her kidneys were barely functioning. I suggested that we try a palliative drug, perhaps a single chemotherapeutic agent that might just ameliorate her symptoms rather than pushing for a tougher regimen to try to cure an incurable disease.

  The daughter looked at me as if I were mad. “I came here to get treatment, not consolations about hospice,” she finally said, glowering with fury.

  I promised to reconsider by asking more experienced doctors to weigh in. Perhaps I had been too hasty in my caution. But in a few weeks, I learned that she and her daughter had found another doctor, presumably someone who had acquiesced more readily to their demands. I do not know whether the elderly woman died from cancer or its cure.

  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.

  It was a fitful and uncomfortable lesson. Palliative care, the branch of medicine that focuses on symptom relief and comfort, had been perceived as the antimatter of cancer therapy, the negative to its positive, an admission of failure to its rhetoric of success. 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 pain 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. “If surgery is withheld,” the writer continued, “the sufferer is doomed to opiate addiction, physical deterioration or even suicide”—an ironic consideration, since Halsted himself, while devising his theory of radical surgery, had swiveled between his twin addictions to cocaine and morphine.

  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. Its founder was Cecily Saunders, a former nurse who had retrained as a physician in England. In the late 1940s, Saunders had tended to a Jewish refugee from Warsaw dying of cancer in London. The man had left Saunders his life savings—£500—with a desire to be “a window in [her] home.” As Saunders entered and explored the forsaken cancer wards of London’s East End in the fifties, she began to decipher that cryptic request in a more visceral sense: she encountered terminally ill patients denied dignity, pain relief, and often even basic medical care—their lives confined, sometimes literally, to rooms without windows. These “hopeless” cases, Saunders found, had become the pariahs of oncology, unable to find any place in its rhetoric of battle and victory, and thus pushed, like useless, wounded soldiers, out of sight and mind.

  Saunders responded to this by inventing, or rather resurrecting, a counterdiscipline—palliative medicine. (She avoided the phrase palliative care because care, she wrote, “is a soft word” that would never win respectability in the medical world.) 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. And she would physically remove the dying from the oncology wards: in 1967, she created a hospice in London to care specifically for the terminally ill and dying, evocatively naming it St. Christopher’s—not after the patron saint of death, but after the patron saint of travelers.

  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.”

  Providing end-of-life care required a colossal act of reimagination and reinvention. Trials on pain and pain relief—trials executed with no less rigor or precision than those launched to test novel drugs and surgical protocols—toppled several dogmas about pain and revealed new and unexpected foundational principles. Opiates, used liberally and compassionately on cancer patients, did not cause addiction, deterioration, and suicide; instead, they relieved the punishing cycle of anxiety, pain, and despair. New antinausea drugs were deployed that vastly improved the lives of patients on chemotherapy. 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.”

  This, too, then, was knowing the enemy.

  Counting Cancer

  We must learn to count the living with that same particular attention with which we number the dead.

  —Audre Lorde

  Counting is the religion of this generation. It is its hope and its salvation.

  —Gertrude Stein

  In November 1985, with oncology caught at a pivotal crossroads between the sobering realities of the present and the hype of past promises, a Harvard biologist named John Cairns resurrected the task of measuring progress in the War on Cancer.

  The word resurrection implies a burial, and since the Fortune article of 1937, composite assessments of the War on Cancer had virtually been buried—oddly, in an overwhelming excess of information. Every minor footfall and every infinitesimal step had been so obsessively reported in the media that it had become nearly impossible to discern the trajectory of the field as a whole. In part, Cairns was reacting to the overgranularity of the view from the prior decade. He wanted to pull away from the details and offer a bird’s-eye view. Were patients with cancer surviving longer in general? Had the enormous investments in the War on Cancer since 1971 translated into tangible clinical achievements?