The Emperor of All Maladies

by Siddhartha Mukherjee

  The NCI, as a whole, watched tensely—for its life, too, was on the line. “I did little things,” Freireich wrote. “Maybe I could make them more comfortable, give them a little aspirin, lower their temperatures, get them a blanket.” Thrown into the uncertain front lines of cancer medicine, juggling the most toxic and futuristic combinations of drugs, the NCI doctors fell back to their oldest principles. They provided comfort. They nurtured. They focused on caregiving and support. They fluffed pillows.

  At the end of three excruciating weeks, a few of Freireich’s patients somehow pulled through. Then, unexpectedly—at a time when it was almost unbearable to look for it—there was a payoff. The normal bone marrow cells began to recover gradually, but the leukemia went into remission. The bone marrow biopsies came back one after another—all without leukemia cells. Red blood cells and white blood cells and platelets sprouted up in an otherwise scorched field of bone marrow. But the leukemia did not return. Another set of biopsies, weeks later, confirmed the finding. Not a single leukemia cell was visible under the microscope. This—after near-complete devastation—was a remission so deep that it exceeded the expectations of everyone at the NCI.

  A few weeks later, the NCI team drummed up enough courage to try VAMP on yet another small cohort of patients. Once again, after the nearly catastrophic dip in counts—“like a drop from a cliff with a thread tied to your ankles,” as one researcher remembered it—the bone marrow recovered and the leukemia vanished. A few days later, the bone marrow began to regenerate, and Freireich performed a hesitant biopsy to look at the cells. The leukemia had vanished again. What it had left behind was full of promise: normal cobblestones of blood cells growing back in the marrow.

  By 1962, Frei and Freireich had treated six patients with several doses of VAMP. Remissions were reliable and durable. The Clinical Center was now filled with the familiar chatter of children in wigs and scarves who had survived two or three seasons of chemotherapy—a strikingly anomalous phenomenon in the history of leukemia. Critics were slowly turning into converts. Other clinical centers around the nation joined Frei and Freireich’s experimental regimen. The patient “is amazingly recovered,” a hematologist in Boston treating an eleven-year-old wrote in 1964. Astonishment slowly gave way to buoyancy. Even William Dameshek, the opinionated Harvard-trained hematologist and one of the most prominent early opponents of VAMP, wrote, “The mood among pediatric oncologists changed virtually overnight from one of ‘compassionate fatalism’ to one of ‘aggressive optimism.’”

  The optimism was potent, but short-lived. In September 1963, not long after Frei and Freireich had returned from one of those triumphant conferences celebrating the unexpected success of VAMP, a few children in remission came back to the clinic with minor complaints: a headache, a seizure, an occasional tingling of a nerve in the face.

  “Some of us didn’t make much of it at first,” a hematologist recalled. “We imagined the symptoms would go away.” But Freireich, who had studied the spread of leukemia cells in the body for nearly a decade, knew that these were headaches that would not go away. By October, there were more children back at the clinic, this time with numbness, tingling, headaches, seizures, and facial paralysis. Frei and Freireich were both getting nervous.

  In the 1880s, Virchow had observed that leukemia cells could occasionally colonize the brain. To investigate the possibility of a brain invasion by cancer cells, Frei and Freireich looked directly at the spinal fluid using a spinal tap, a method to withdraw a few milliliters of fluid from the spinal canal using a thin, straight needle. The fluid, a straw-colored liquid that circulates in direct connection with the brain, is a surrogate for examining the brain.

  In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself.

  But there is another moment of discovery—its antithesis—that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone. A patient’s CT scan shows a relapsed lymphoma. A cell once killed by a drug begins to grow back. A child returns to the NCI with a headache.

  What Frei and Freireich discovered in the spinal fluid left them cold: leukemia cells were growing explosively in the spinal fluid by the millions, colonizing the brain. The headaches and the numbness were early signs of much more profound devastations to come. In the months that followed, one by one, all the children came back to the institute with a spectrum of neurological complaints—headaches, tinglings, abstract speckles of light—then slumped into coma. Bone marrow biopsies were clean. No cancer was found in the body. But the leukemia cells had invaded the nervous system, causing a quick, unexpected demise.

  It was a consequence of the body’s own defense system subverting cancer treatment. 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. The leukemia, sensing an opportunity in that sanctuary, had furtively climbed in, colonizing the one place that is fundamentally unreachable by chemotherapy. The children died one after the other—felled by virtue of the adaptation designed to protect them.

  Frei and Freireich were hit hard by those relapses. For a clinical scientist, a trial is like a child, a deeply personal investment. To watch this sort of intense, intimate enterprise fold up and die is to suffer the loss of a child. One leukemia doctor wrote, “I know the patients, I know their brothers and sisters, I know their dogs and cats by name. . . . The pain is that a lot of love affairs end.”

  After seven exhilarating and intensive trials, the love affair at the NCI had indeed ended. The brain relapses after VAMP seemed to push morale at the institute to the breaking point. Frei, who had so furiously tried to keep VAMP alive through its most trying stages—twelve months of manipulating, coaxing, and wheedling—now found himself drained of his last stores of energy. Even the indefatigable Freireich was beginning to lose steam. He felt a growing hostility from others at the institute. At the peak of his career, he, too, felt tired of the interminable institutional scuffles that had once invigorated him.

  In the winter of 1963, Frei left for a position at the MD Anderson Cancer Center in Houston, Texas. The trials were temporarily put on hold (although they would eventually be resurrected in Texas). Freireich soon left the NCI to join Frei in Houston. The fragile ecosystem that had sustained Freireich, Frei, and Zubrod dissolved in a few months.

  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 the history of medicine is told through the stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients.

  I said that all the children had relapsed and died—but this is not quite true. A few, a small handful, for mysterious reasons, never relapsed with leukemia in the central nervous system. At the NCI and the few other hospitals brave enough to try VAMP, about 5 percent of the treated children finished their yearlong journey. They remained in remission not just for weeks or months, but for years. They came back, year after year, and sat nervously in waiting rooms at trial centers all around the nation. Their voices deepened. Their hair grew back. Biopsy after biopsy was performed. And there was no visible
sign of cancer.

  On a summer afternoon, I drove through western Maine to the small town of Waterboro. Against the foggy, overcast sky, the landscape was spectacular, with ancient pine and birch forests tipping into crystalline lakes. On the far edge of the town, I turned onto a dirt road leading away from the water. At the end of the road, surrounded by deep pine forests, was a tiny clapboard house. A fifty-six-year-old woman in a blue T-shirt answered the door. It had taken me seventeen months and innumerable phone calls, questions, interviews, and references to track her down. One afternoon, scouring the Internet, I had found a lead. I remember dialing the number, excited beyond words, and waiting for interminable rings before a woman answered. I had fixed up an appointment to meet her that week and driven rather recklessly to Maine to keep it. When I arrived, I realized that I was twenty minutes early.

  I cannot remember what I said, or struggled to say, as a measure of introduction. But I felt awestruck. Standing before me against the door, smiling nervously, was one of the survivors of that original VAMP cohort cured of childhood leukemia.

  The basement was flooded and the couch was growing mildew, so we sat outdoors in the shadows of the trees in a screened tent with deerflies and mosquitoes buzzing outside. The woman—Ella, I’ll call her—had collected a pile of medical records and photographs for me to look through. As she handed them over, I sensed a shiver running through her body, as if even today, forty-five years after her ordeal, the memory haunts her viscerally.

  Ella was diagnosed with leukemia in June 1964, about eighteen months after VAMP was first used at the NCI. She was eleven years old. In the photographs taken before her diagnosis, she was a typical preteen with bangs and braces. In the photograph taken just six months later (after chemotherapy), she was transformed—bald, sheet-white from anemia, and severely underweight, collapsed on a wheelchair and unable to walk.

  Ella was treated with VAMP. (Her oncologists in Boston, having heard of the spectacular responses at the NCI, had rather bravely chosen to treat her—off trial—with the four-drug regimen.) It had seemed like a cataclysm at first. The high doses of vincristine caused such severe collateral nerve damage that she was left with a permanent burning sensation in her legs and fingers. Prednisone made her delirious. The nurses, unable to deal with a strong-willed, deranged preteen wandering through the corridors of the hospital screaming and howling at night, restrained her by tying her arms with ropes to the bedposts. Confined to her bed, she often crouched in a fetal position, her muscles wasting away, the neuropathy worsening. At twelve years of age, she became addicted to morphine, which was prescribed for her pain. (She “detoxed” herself by sheer force of will, she said, by “lasting it out through the spasms of withdrawal.”) Her lower lip is still bruised from the time she bit herself in those awful months while waiting out the hour for the next dose of morphine.

  Yet, remarkably, the main thing she remembers is the overwhelming feeling of being spared. “I feel as if I slipped through,” she told me, arranging the records back into their envelopes. She looked away, as if to swat an imaginary fly, and I could see her eyes welling up with tears. She had met several other children with leukemia in the hospital wards; none had survived. “I don’t know why I deserved the illness in the first place, but then I don’t know why I deserved to be cured. Leukemia is like that. It mystifies you. It changes your life.” My mind briefly flashed to the Chiribaya mummy, to Atossa, to Halsted’s young woman awaiting her mastectomy.

  Sidney Farber never met Ella, but he encountered patients just like her—long-term survivors of VAMP. In 1964, the year that Ella began her chemotherapy, he triumphantly brought photographs of a few such patients to Washington as a sort of show-and-tell for Congress, living proof that chemotherapy could cure cancer. The path was now becoming increasingly clear to him. Cancer research needed an additional thrust: more money, more research, more publicity, and a directed trajectory toward a cure. His testimony before Congress thus acquired a nearly devotional, messianic fervor. After the photographs and his testimony, one observer recalled, any further proof was “anticlimactic and unnecessary.” Farber was now ready to leap out from the realm of leukemia into the vastly more common real cancers. “We are attempting to develop chemicals which might affect otherwise incurable tumors of the breast, the ovary, the uterus, the lung, the kidney, the intestine, and highly malignant tumors of the skin, such as the black cancer, or melanoma,” he wrote. The cure of even one such solid cancer in adults, Farber knew, would singularly revolutionize oncology. It would provide the most concrete proof that this was a winnable war.

  * Since most of the early anticancer drugs were cytotoxic—cell-killing—the threshold between a therapeutic (cancer-killing) dose and a toxic dose was extremely narrow. Many of the drugs had to be very carefully dosed to avoid the unwarranted but inextricably linked toxicity.

  An Anatomist’s Tumor

  It took plain old courage to be a chemotherapist in the 1960s and certainly the courage of the conviction that cancer would eventually succumb to drugs.

  —Vincent DeVita, National Cancer Institute

  investigator (and eventually NCI director)

  On a chilly February morning in 2004, a twenty-four-year-old athlete, Ben Orman, discovered a lump in his neck. He was in his apartment, reading the newspaper, when, running his hand absentmindedly past his face, his fingers brushed against a small swelling. The lump was about the size of a small dried grape. If he took a deep breath, he could swallow it back into the cavity of his chest. He dismissed it. It was a lump, he reasoned, and athletes were used to lumps: calluses, swollen knees, boils, bumps, bruises coming and going with no remembered cause. He returned to his newspaper and worry vanished from his mind. The lump in his neck, whatever it was, would doubtless vanish in time as well.

  But it grew instead, imperceptibly at first, then more assertively, turning from grape-size to prune-size in about a month. He could feel it on the shallow dip of his collarbone. Worried, Orman went to the walk-in clinic of the hospital, almost apologetic about his complaints. The triage nurse scribbled in her notes: “Lump in his neck”—and added a question mark at the end of the sentence.

  With that sentence, Orman entered the unfamiliar world of oncology—swallowed, like his own lump, into the bizarre, cavitary universe of cancer. The doors of the hospital opened and closed behind him. A doctor in a blue scrub suit stepped through the curtains and ran her hands up and down his neck. He had blood tests and X-rays in rapid succession, followed by CT scans and more examinations. The scans revealed that the lump in the neck was merely the tip of a much deeper iceberg of lumps. Beneath that sentinel mass, a chain of masses coiled from his neck down into his chest, culminating in a fist-size tumor just behind his sternum. Large masses located in the anterior chest, as medical students learn, come in four T’s, almost like a macabre nursery rhyme for cancer: thyroid cancer, thymoma, teratoma, and terrible lymphoma. Orman’s problem—given his age and the matted, dense appearance of the lumps—was almost certainly the last of these, a lymphoma—cancer of the lymph glands.

  I saw Ben Orman nearly two months after that visit to the hospital. He was sitting in the waiting room, reading a book (he read fiercely, athletically, almost competitively, often finishing one novel a week, as if in a race). In the eight weeks since his ER visit, he had undergone a PET scan, a visit with a surgeon, and a biopsy of the neck lump. As suspected, the mass was a lymphoma, a relatively rare variant called Hodgkin’s disease.

  More news followed: the scans revealed that Orman’s cancer was confined entirely to one side of his upper torso. And he had none of the ghostly B symptoms—weight loss, fever, chills, or night sweats—that occasionally accompany Hodgkin’s disease. In a staging system that ran from I to IV (with an A or B added to denote the absence or presence of the occult symptoms), he fell into stage IIA—relatively early in the progression of the disease. It was somber news, but of all the patients shuttling in and out of the waiting room that morning, Orman arg
uably carried the most benign prognosis. With an intensive course of chemotherapy, it was more than likely—85 percent likely—that he would be cured.

  “By intensive,” I told him, “I mean several months, perhaps even stretching out to half a year. The drugs will be given in cycles, and there will have to be visits in between to check blood counts.” Every three weeks, just as his counts recovered, the whole cycle would begin all over again—Sisyphus on chemotherapy.

  He would lose his hair with the first cycle. He would almost certainly become permanently infertile. There might be life-threatening infections during the times when his white counts would bottom out nearly to zero. Most ominously, the chemo might cause a second cancer in the future. He nodded. I watched the thought pick up velocity in his brain, until it had reached its full impact.

  “It’s going to be a long haul. A marathon,” I stammered apologetically, groping for an analogy. “But we’ll get to the end.”

  He nodded again silently, as if he already knew.

  On a Wednesday morning, not long after my meeting with Orman, I took a shuttle across Boston to see my patients at the Dana-Farber Cancer Institute. Most of us called the institute simply “the Farber.” Large already in life, Sidney Farber had become even larger in death: the eponymous Farber was now a sprawling sixteen-story labyrinth of concrete crammed full of scientists and physicians, a comprehensive lab-cum-clinic-cum-pharmacy-cum-chemotherapy-unit. There were 2,934 employees, dozens of conference rooms, scores of laboratories, a laundry unit, four banks of elevators, and multiple libraries. The site of the original basement lab had long been dwarfed by the massive complex of buildings around it. Like a vast, overbuilt, and overwrought medieval temple, the Farber had long swallowed its shrine.