The Emperor of All Maladies

by Siddhartha Mukherjee

  When Clauson told her brother about the letter that she had sent, she found him more relieved than annoyed. “It was like an unburdening for him, too,” she recalled. “Einar was a modest man. He had kept to himself because he did not want to brag.” (“I would read in the papers that they had found me someplace,” he said, “and I would smile.”)

  Clauson’s letter was spotted by Karen Cummings, an associate in the Jimmy Fund’s development office, who immediately understood its potential significance. She contacted Clauson, and then reached Gustafson.

  A few weeks later, in January 1998, Cummings arranged to meet Jimmy at a truck stop outside a shopping center in a suburb of Boston. It was six in the morning on a bone-chilling winter day, and Gustafson and his wife piled into Cummings’s warm car. Cummings had brought a tape of Jimmy from 1948 singing his favorite song. She played it:

  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.

  Gustafson listened to his own voice with tears in his eyes. Cummings and Jimmy’s wife sat in the car, their eyes also welling with silent tears.

  Later that month, Cummings drove up to New Sweden, a brutally beautiful town in northern Maine with austere angular houses set against an even more austere landscape. Old-timers in the town also recalled Gustafson’s trips to Boston for chemotherapy. He had hitchhiked to and from Boston in cars and trucks and delivery vans anytime someone from the town had driven up or down the coast; it had taken a village to save a child. As Cummings sat in Gustafson’s kitchen, he crept upstairs and returned with a cardboard box. Wrapped inside was the battered baseball uniform that the Boston Braves had given Jimmy on the night of the Edwards broadcast. Cummings needed no further proof.

  And so it was in May 1998, almost exactly fifty years after he had journeyed from small-town Maine to the Children’s Hospital to meet the odd, formal doctor in a three-piece suit, that Jimmy returned with full fanfare to the Jimmy Fund. His wardmates from the hospital—the Sandler twin with his recalcitrant leukemia engorging his spleen, the blond girl in plaits by the television, little Jenny with leukemia—had long ago been buried in small graves in and around Boston. Gustafson walked into the Jimmy Fund Building,* up the low, long steps to the room where the clockwork train had run through the mountain tunnel. Patients, survivors, nurses, and doctors milled around him. Like a latter-day Rip van Winkle, he found the present unfathomable and unrecognizable. “Everything has changed,” Clauson recalled him saying. “The rooms, the patients, the drugs.” But more than anything, survivorship had changed. “Einar remembered the cancer ward as a place with many curtains,” she continued. “When the children were well, the curtains would be spread open. But they would soon close the curtains, and there would be no child when they were opened again.”

  Here Gustafson was, fifty years later, back in those long hallways with the faded cartoon paintings on the walls, his curtains thrown apart. It is impossible to know whether Jimmy had survived because of surgery, or chemotherapy, or because his cancer had been inherently benign in its behavior. But the facts of his medical history are irrelevant; his return was symbolic. Jimmy had unwittingly been picked to become the icon of the child with cancer. But Einar Gustafson, now sixty-three years old, had returned as the icon of a man beyond cancer.

  The Italian memoirist Primo Levi, who survived a concentration camp and then navigated his way through a blasted Germany to his native Turin, often remarked that among the most fatal qualities of the camp was its ability to erase the idea of a life outside and beyond itself. A person’s past and his present were annihilated as a matter of course—to be in the camps was to abnegate history, identity, and personality—but it was the erasure of the future that was the most chilling. With that annihilation, Levi wrote, came a moral and spiritual death that perpetuated the status quo of imprisonment. If no life existed beyond the camp, then the distorted logic by which the camp operated became life as usual.

  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. The daily life of a patient becomes so intensely preoccupied with his or her illness that the world fades away. Every last morsel of energy is spent tending the disease. “How to overcome him became my obsession,” the journalist Max Lerner wrote of the lymphoma in his spleen. “If it was to be a combat then I had to engage it with everything I had—knowledge and guile, ways covert as well as overt.”

  For Carla, in the midst of the worst phase of her chemotherapy, the day-to-day rituals of survival utterly blotted out any thought of survivorship in the long run. When I asked a woman with a rare form of muscle sarcoma about her life outside the hospital, she told me that she spent her days and nights scouring the Internet for news about the disease. “I am in the hospital,” she said, “even when I am outside the hospital.” The poet Jason Shinder wrote, “Cancer is a tremendous opportunity to have your face pressed right up against the glass of your mortality.” But what patients see through the glass is not a world outside cancer, but a world taken over by it—cancer reflected endlessly around them like a hall of mirrors.

  I was not immune to this compulsive preoccupation either. In the summer of 2005, as my fellowship hurtled to its end, I experienced perhaps the singularly transformative event of my life: the birth of my daughter. Glowing, beautiful, and cherubic, Leela was born on a warm night at Massachusetts General Hospital, then swaddled in blankets and brought to the newborn unit on the fourteenth floor. The unit is directly across from the cancer ward. (The apposition of the two is hardly a coincidence. As a medical procedure, childbirth is least likely to involve infectious complications and is thus the safest neighbor to a chemotherapy ward, where any infection can turn into a lethal rampage. As in so much in medicine, the juxtaposition between the two wards is purely functional and yet just as purely profound.)

  I would like to see myself at my wife’s side awaiting the miraculous moment of my daughter’s birth as most fathers do. But in truth I was gowned and gloved like a surgeon, with a blue, sterile sheet spread out in front of me, and a long syringe in my hands, poised to harvest the maroon gush of blood cells from the umbilical cord. When I cut that cord, part of me was the father, but the other part an oncologist. Umbilical blood contains one of the richest known sources of blood-forming stem cells—cells that can be stored away in cryobanks and used for a bone marrow transplant to treat leukemia in the future, an intensely precious resource often flushed down a sink in hospitals after childbirth.

  The midwives rolled their eyes; the obstetrician, an old friend, asked jokingly if I ever stopped thinking about work. But I was too far steeped in the study of blood to ignore my instincts. In the bone-marrow-transplant rooms across that very hallway were patients for whom I had scoured tissue banks across the nation for one or two pints of these stem cells that might save their lives. Even in this most life-affirming of moments, the shadows of malignancy—and death—were forever lurking on my psyche.

  But not everything was involuting into death. Something transformative was also happening in the fellows’ clinics in the summer of 2005: many of my patients, whose faces had so fixedly been pressed up against the glass of their mortality, began to glimpse an afterlife beyond cancer. February, as I said before, had marked the midpoint of an abysmal descent. Cancer had reached its full, lethal bloom that month. Nearly every week had brought news of a mounting toll, culminating chillingly with Steve Harmon’s arrival in the emergency room and his devastating spiral into death thereafter. Some days I dreaded walking by the fax machines outside my office, where a pile of death certificates would be waiting for my signature.

  But then, like a poisonous tide receding, the bad news ebbed. The nightly phone calls from the hospitals or from ERs and hospice units around Boston bringing news of yet another death (“I’m calling to let you know that your patient ar
rived here this evening with dizziness and difficulty breathing”) suddenly ceased. It was as if the veil of death had lifted—and survivors had emerged from underneath.

  Ben Orman had been definitively cured of Hodgkin’s lymphoma. It had not been an effortless voyage. His blood counts had dropped calamitously during the midcycle of chemotherapy. For a few weeks it had appeared that the lymphoma had ceased responding—a poor prognostic sign portending a therapy-resistant, fatal variant of the disease. But in the end the mass in his neck, and the larger archipelago of masses in his chest, had all melted away, leaving just minor remnants of scar tissue. The formality of his demeanor had visibly relaxed. When I last saw him in the summer of 2005, he spoke about moving away from Boston to Los Angeles to join a law firm. He assured me that he would visit to follow up, but I wasn’t convinced. Orman epitomized the afterlife of cancer—eager to forget the clinic and its bleak rituals, like a bad trip to a foreign country.

  Katherine Fitz could also see a life beyond cancer. For Fitz, with the lung tumor wrapped ominously around her bronchus, the biggest hurdle had been the local control of her cancer. The mass had been excised in an incredibly meticulous surgery; she had then finished adjuvant chemotherapy and radiation. Nearly twelve months after the surgery, there was no sign of a local relapse. Nor was there any sign of the woman who had come to the clinic several months earlier, nearly folded over in fear. Tumor out, chemotherapy done, radiation behind her, Fitz’s effervescence poured out of every spigot of her soul. At times, watching her personality emerge as if through a nozzle, it seemed abundantly clear why the Greeks had thought of disease as pathological blockades of humors.

  Carla returned to see me in July 2005, bringing pictures of her three growing children. She refused to let another doctor perform her bone marrow biopsy, so I walked over from the lab on a warm morning to perform the procedure. She looked relieved when she saw me, greeting me with her anxious half-smile. We had developed a ritualistic relationship; who was I to desecrate a lucky ritual? The biopsy revealed no leukemia in the bone marrow. Her remission, for now, was still intact.

  I have chosen these cases not because they were “miraculous” but because of precisely the opposite reason. They represent a routine spectrum of survivors—Hodgkin’s disease cured with multidrug chemotherapy; locally advanced lung cancer controlled with surgery, chemotherapy, and radiation; lymphoblastic leukemia in a prolonged remission after intensive chemotherapy. To me, these were miracles enough. It is an old complaint about the practice of medicine that it inures you to the idea of death. But when medicine inures you to the idea of life, to survival, then it has failed utterly. The novelist Thomas Wolfe, recalling a lifelong struggle with illness, wrote in his last letter, “I’ve made a long voyage and been to a strange country, and I’ve seen the dark man very close.” I had not made the journey myself, and I had only seen the darkness reflected in the eyes of others. But surely, it was the most sublime moment of my clinical life to have watched that voyage in reverse, to encounter men and women returning from the strange country—to see them so very close, clambering back.

  Incremental advances can add up to transformative changes. In 2005, an avalanche of papers cascading through the scientific literature converged on a remarkably consistent message—the national physiognomy of cancer had subtly but fundamentally changed. The mortality for nearly every major form of cancer—lung, breast, colon, and prostate—had continuously dropped for fifteen straight years. There had been no single, drastic turn but rather a steady and powerful attrition: mortality had declined by about 1 percent every year. The rate might sound modest, but its cumulative effect was remarkable: between 1990 and 2005, the cancer-specific death rate had dropped nearly 15 percent, a decline unprecedented in the history of the disease. The empire of cancer was still indubitably vast—more than half a million American men and women died of cancer in 2005—but it was losing power, fraying at its borders.

  What precipitated this steady decline? There was no single answer but rather a multitude. For lung cancer, the driver of decline was primarily prevention—a slow attrition in smoking sparked off by the Doll-Hill and Wynder-Graham studies, fueled by the surgeon general’s report, and brought to its full boil by a combination of political activism (the FTC action on warning labels), inventive litigation (the Banzhaf and Cipollone cases), medical advocacy, and countermarketing (the antitobacco advertisements).

  For colon and cervical cancer, the declines were almost certainly due to the successes of secondary prevention—cancer screening. Colon cancers were detected at earlier and earlier stages in their evolution, often in the premalignant state, and treated with relatively minor surgeries. Cervical cancer screening using Papanicolaou’s smearing technique was being offered at primary-care centers throughout the nation, and as with colon cancer, premalignant lesions were excised using relatively minor surgeries.

  For leukemia, lymphoma, and testicular cancer, in contrast, the declining numbers reflected the successes of chemotherapeutic treatment. In childhood ALL, cure rates of 80 percent were routinely being achieved. Hodgkin’s disease was similarly curable, and so, too, were some large-cell aggressive lymphomas. Indeed, for Hodgkin’s disease, testicular cancer, and childhood leukemias, the burning question was not how much chemotherapy was curative, but how little: trials were addressing whether milder and less toxic doses of drugs, scaled back from the original protocols, could achieve equivalent cure rates.

  Perhaps most symbolically, the decline in breast cancer mortality epitomized the cumulative and collaborative nature of these victories—and the importance of attacking cancer using multiple independent prongs. Between 1990 and 2005, breast cancer mortality had dwindled an unprecedented 24 percent. Three interventions had potentially driven down the breast cancer death rate—mammography (screening to catch early breast cancer and thereby prevent invasive breast cancer), surgery, and adjuvant chemotherapy (chemotherapy after surgery to remove remnant cancer cells). Donald Berry, a statistician in Houston, Texas, set out to answer a controversial question: How much had mammography and chemotherapy independently contributed to survival? Whose victory was this—a victory of prevention or of therapeutic intervention?*

  Berry’s answer was a long-due emollient to a field beset by squabbles between the advocates of prevention and the proponents of chemotherapy. When Berry assessed the effect of each intervention independently using statistical models, it was a satisfying tie: both cancer prevention and chemotherapy had diminished breast cancer mortality equally—12 percent for mammography and 12 percent for chemotherapy, adding up to the observed 24 percent reduction in mortality. “No one,” as Berry said, paraphrasing the Bible, “had labored in vain.”

  These were all deep, audacious, and meaningful victories borne on the backs of deep and meaningful labors. But, in truth, they were the victories of another generation—the results of discoveries made in the fifties and sixties. The core conceptual advances from which these treatment strategies arose predated nearly all the significant work on the cell biology of cancer. In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world—of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. Mary Lasker had once searched for an epochal shift in cancer. But the shift that had occurred seemed to belong to another epoch.

  Mary Lasker died of heart failure in 1994 in her carefully curated home in Connecticut—having removed herself physically from the bristling epicenters of cancer research and policymaking in Washington, New York, and Boston. She was ninety-three years old. Her life had nearly spanned the most transformative and turbulent century of biomedical science. Her potent e
bullience had dimmed in her last decade. She spoke rarely about the achievements (or disappointments) of the War on Cancer. But she had expected cancer medicine to have achieved more during her lifetime—to have taken a more assertive step toward Farber’s “universal cure” for cancer and marked a more definitive victory in the war. The complexity, the tenacity—the sheer magisterial force of cancer—had made even its most committed and resolute opponent seem circumspect and humbled.

  In 1994, a few months after Lasker’s death, the cancer geneticist Ed Harlow captured both the agony and the ecstasy of the era. At the end of a weeklong conference at the Cold Spring Harbor Laboratory in New York pervaded by a giddy sense of anticipation about the spectacular achievements of cancer biology, Harlow delivered a sobering assessment: “Our knowledge of . . . molecular defects in cancer has come from a dedicated twenty years of the best molecular biology research. Yet this information does not translate to any effective treatments nor to any understanding of why many of the current treatments succeed or why others fail. It is a frustrating time.”

  More than a decade later, I could sense the same frustration in the clinic at Mass General. One afternoon, I watched Tom Lynch, the lung cancer clinician, masterfully encapsulate carcinogenesis, cancer genetics, and chemotherapy for a new patient, a middle-aged woman with bronchoalveolar cell cancer. She was a professor of history with a grave manner and a sharp, darting mind. He sat across from her, scribbling a picture as he spoke. The cells in her bronchus, he began, had acquired mutations in their genes that had allowed them to grow autonomously and uncontrollably. They had formed a local tumor. Their propensity was to acquire further mutations that might allow them to migrate, to invade tissues, to metastasize. Chemotherapy with Carboplatin and Taxol (two standard chemotherapy drugs), augmented with radiation, would kill the cells and perhaps prevent them from migrating to other organs to seed metastases. In the best-case scenario, the cells carrying the mutated genes would die, and her cancer would be cured.