VAMP

Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing.

—Voltaire

If we didn’t kill the tumor, we killed the patient.

—William Moloney on the early days
of chemotherapy

VAMP—high-dose, life-threatening, four-drug combination therapy for leukemia—might have made obvious sense to Skipper, Frei, and Freireich, but to many of their colleagues, it was a terrifying notion, an abomination. Freireich finally approached Zubrod with his idea: “I wanted to treat them with full doses of vincristine and amethopterin, combined with the 6-MP and prednisone.” The ands in the sentence were italicized to catch Zubrod’s attention.

Zubrod was stunned. “It is the dose that makes a poison,” runs the old adage in medicine: all medicines were poisons in one form or another merely diluted to an appropriate dose. But chemotherapy was poison even at the correct dose.^* A child with leukemia was already stretched to the brittle limits of survival, hanging on to life by a bare physiological thread. People at the NCI would often casually talk of chemotherapy as the “poison of the month.” If four poisons of the month were simultaneously pumped daily into a three- or six-year-old child, there was virtually no guarantee that he or she could survive even the first dose of this regimen, let alone survive week after week after week.

When Frei and Freireich presented their preliminary plan for VAMP at a national meeting on blood cancers, the audience balked. Farber, for one, favored giving one drug at a time and adding the second only after relapse and so forth, following the leukemia consortium’s slow but steady method of adding drugs carefully and sequentially. “Oh, boy,” Freireich recalled, “it was a terrible, catastrophic showdown. We were laughed at and then called insane, incompetent, and cruel.” With limited patients and hundreds of drugs and combinations to try, every new leukemia trial had to wind its way through a complex approval process through the leukemia group. Frei and Freireich, it was felt, were making an unauthorized quantum leap. The group refused to sponsor VAMP—at least not until the many other trials had been completed.

But Frei wrangled a last-minute compromise: VAMP would be studied independently at the NCI, outside the purview of the ALGB. “The idea was preposterous,” Freireich recalled. “To run the trial, we would need to split with the ALGB, the very group that we had been so instrumental in founding.” Zubrod wasn’t pleased with the compromise: it was a break from his cherished “cooperative” model. Worse still, if VAMP failed, it would be a political nightmare for him. “If the children had died, we’d be accused of experimenting on people at this federal installation of the National Cancer Institute,” Freireich acknowledged. Everyone knew it was chancy territory. Embroiled in controversy, even if he had resolved it as best he could, Frei resigned as the chair of the ALGB. Years later, Freireich acknowledged the risks involved: “We could have killed all of those kids.”

The VAMP trial was finally launched in 1961. Almost instantly, it seemed like an abysmal mistake—precisely the sort of nightmare that Zubrod had been trying to avoid.

The first children to be treated “were already terribly, terribly ill,” Freireich recalled. “We started VAMP, and by the end of the week, many of them were infinitely worse than before. It was a disaster.” The four-drug chemo regimen raged through the body and wiped out all the normal cells. Some children slumped into near coma and were hooked to respirators. Freireich, desperate to save them, visited his patients obsessively in their hospital beds. “You can imagine the tension,” he wrote. “I could just hear people saying, ‘I told you so, this girl or boy is going to die.’” He hovered in the wards, pestering the staff with questions and suggestions. His paternal, possessive instincts were aroused: “These were my kids. I really tried to take care of them.”

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.