An Army on the March
Now we are an army on the march.
--Sidney Farber in 1963
The next step--the complete cure--is almost sure to follow.
--Kenneth Endicott,
NCI director, 1963
The role of aggressive multiple drug therapy in the quest for long-term survival [in cancer] is far from clear.
--R. Stein, a scientist in 1969
One afternoon in the late summer of 1963, George Canellos, then a senior fellow at the NCI, walked into the Clinical Center to find Tom Frei scribbling furiously on one of the institute's blackboards. Frei, in his long white coat, was making lists of chemicals and drawing arrows. On one side of the board was a list of cytotoxic drugs--Cytoxan, vincristine, procarbazine, methotrexate. On the other side was a list of new cancers that Zubrod and Frei wanted to target: breast, ovarian, lung cancers, lymphomas. Connecting the two halves of the blackboard were chalky lines matching combinations of cytotoxic drugs to cancers. For a moment, it almost looked as if Frei had been deriving mathematical equations: A+B kills C; E+F eliminates G.
The drugs on Frei's list came largely from three sources. Some, such as aminopterin or methotrexate, were the products of inspired guesswork by scientists (Farber had discovered aminopterin by guessing that an antifolate might block the growth of leukemia cells). Others, such as nitrogen mustard or actinomycin D, came from serendipitous sources, such as mustard gas or soil bacteria, found accidentally to kill cancer cells. Yet others, such as 6-MP, came from drug-screening efforts in which thousands of molecules were tested to find the handful that possessed cancer-killing activity.
The notable common feature that linked all these drugs was that they were all rather indiscriminate inhibitors of cellular growth. Nitrogen mustard, for instance, damages DNA and kills nearly all dividing cells; it kills cancer cells somewhat preferentially because cancer cells divide most actively. To design an ideal anticancer drug, one would need to identify a specific molecular target in a cancer cell and create a chemical to attack that target. But the fundamental biology of cancer was so poorly understood that defining such molecular targets was virtually inconceivable in the 1960s. Yet, even lacking such targets, Frei and Freireich had cured leukemia in some children. Even generic cellular poisons, dosed with adequate brio, could thus eventually obliterate cancer.
The bravado of that logic was certainly hypnotic. Vincent DeVita, another fellow at the institute during that time, wrote, "A new breed of cancer investigators in the 1960s had been addressing the generic question of whether or not cytotoxic chemotherapy was ever capable of curing patients with any type of advanced malignancies." For Frei and Zubrod, the only way to answer that "generic question" was to direct the growing armamentarium of combination chemotherapy against another cancer--a solid tumor this time--which would retrace their steps with leukemia. If yet another kind of cancer responded to this strategy, then there could be little doubt that oncology had stumbled upon a generic solution to the generic problem. A cure would then be within reach for all cancers.
But which cancer would be used to test the principle? Like Kaplan, Zubrod, DeVita, and Canellos also focused on Hodgkin's disease--a cancer that lived on the ill-defined cusp between solid and liquid, a stepping-stone between leukemia and, say, lung cancer or breast cancer. At Stanford, Kaplan had already demonstrated that Hodgkin's lymphoma could be staged with exquisite precision and that local disease could be cured with high-dose extended field radiation. Kaplan had solved half the equation: he had used local therapy with radiation to cure localized forms of Hodgkin's disease. If metastatic Hodgkin's disease could be cured by systemic and aggressive combination chemotherapy, then Zubrod's "generic solution" would begin to sound plausible. The equation would be fully solved.
Outspoken, pugnacious, and bold, a child of the rough-and-tumble Yonkers area of New York who had bulldozed his way through college and medical school, Vincent DeVita had come to the NCI in 1963 and fallen into the intoxicating orbit of Zubrod, Frei, and Freireich. The unorthodoxy of their approach--the "maniacs doing cancer research," as he called it--had instantly fascinated him. These were the daredevils of medical research, acrobats devising new drugs that nearly killed patients; these men played chicken with death. "Somebody had to show the skeptics that you could actually cure cancer with the right drugs," he believed. In the early months of 1964, he set out to prove the skeptics wrong.
The first test of intensive combination chemotherapy for advanced-stage Hodgkin's disease, led by DeVita, combined four drugs--methotrexate, vincristine (also called Oncovin), nitrogen mustard, and prednisone, a highly toxic cocktail called MOMP. Only fourteen patients were treated. All suffered the predictable consequences of combination chemotherapy; all were hospitalized and confined in isolation chambers to prevent infections during the life-threatening drop in blood counts. As expected, the regimen was sharply criticized at the NCI; this, again, was a quantum leap into a deadly world of mixed poisons. But Frei intervened, silencing the critics and allowing the program to continue.
In 1964, DeVita modified the regimen further. Methotrexate was substituted with a more powerful agent, procarbazine, and the duration of treatment was lengthened from two and a half months to six months. With a team of young, like-minded fellows at the NCI, DeVita began to enroll patients with advanced Hodgkin's disease in a trial of this new cocktail, called MOPP. Like lymphoblastic leukemia, Hodgkin's disease is a rare illness, but the researchers did not need to look hard to find patients. Advanced Hodgkin's disease, often accompanied by the spectral B symptoms, was uniformly fatal. Young men and women (the disease typically strikes men and women in their twenties and thirties) were often referred to the NCI as hopeless cases--and therefore ideal experimental subjects. In just three years, DeVita and Canellos thus accumulated cases at a furious clip, forty-three patients in all. Nine had been blasted with increasing fields of radiation, a la Kaplan, and still progressed inexorably to disseminated, widely metastatic disease. Others had been treated with an ad hoc mix of single agents. None had shown any durable response to prior drugs.
So, like the younger band of leukemics that had gone before them, a fresh new cohort appeared at the institute every two weeks, occupying the plastic chairs of the Clinical Center, lining up for the government-issued cookies and awaiting the terrifying onslaught of the experimental drugs. The youngest was twelve, not even a teenager yet, with lymphoma cells packed in her lungs and liver. A thirteen-year-old boy had Hodgkin's in his pleural cavity; malignant fluid had compressed itself into the lining between his chest wall and lung and made it hard to breathe. The oldest was a sixty-nine-year-old woman with Hodgkin's disease choking off the entrance to her intestine.
If the terror of VAMP was death by infection--children slumped on ventilators with no white blood cells to speak of and bacteria streaming in their blood--then the terror of MOPP was more visceral: death by nausea. The nausea that accompanied the therapy was devastating. It appeared suddenly, then abated just as suddenly, almost capable of snapping the mind shut with its intensity. Many of the patients on the protocol were flown in from nearby cities every fortnight. The trip back home, with the drugs lurching in the blood and the plane lurching in the air, was, for many, a nightmare even worse than their disease.
The nausea was merely a harbinger. As DeVita charged ahead with combination chemotherapy, more complex and novel devastations were revealed. Chemotherapy caused permanent sterility in men and some women. The annihilation of the immune system by the cytotoxic drugs allowed peculiar infections to sprout up: the first adult case of a rare form of pneumonia, caused by an organism, Pneumocystis carinii (PCP), was observed in a patient receiving MOPP (the same pneumonia, arising spontaneously in immune-compromised gay men in 1981, would auger the arrival of the HIV epidemic in America). Perhaps the most disturbing side effect of chemotherapy would emerge nearly a decade later. Several young men and women, cured of Hodgkin's disease, would relapse with a second cancer--typically
an aggressive, drug-resistant leukemia--caused by the prior treatment with MOPP chemotherapy. As with radiation, cytotoxic chemotherapy would thus turn out to be a double-edged sword: cancer-curing on one hand, and cancer-causing on the other.
But the evidently grim litany of side effects notwithstanding, even early in the course of treatment, there was payoff. In many of the young men and women, the palpable, swollen lymph nodes dissolved in weeks. A twelve-year-old boy from Illinois had been so ravaged by Hodgkin's that his weight had sunk to fifty pounds; within three months of treatment, he gained nearly half his body weight and shot up two feet in height. In others, the stranglehold of Hodgkin's disease loosened on the organs. Pleural effusions gradually cleared and the nodes in the gut disappeared. As the months passed, it was clear that combination chemo had struck gold once again. At the end of half a year, thirty-five of the forty-three patients had achieved a complete remission. The MOPP trial did not have a control group, but one was not needed to discern the effect. The response and remission rate were unprecedented for advanced Hodgkin's disease. The success would continue in the long-term: more than half the initial cohort of patients would be cured.
Even Kaplan, not an early believer in chemotherapy, was astonished. "Some of the patients with advanced disease have now survived relapse free," he wrote. "The advent of multiple-drug chemotherapy has dramatically changed the prognosis of patients with previously untreated stage III or stage IV Hodgkin's disease."
In May 1968, as the MOPP trial was ascending to its unexpected crescendo, there was equally unexpected news in the world of lymphoblastic leukemia.
Frei and Freireich's VAMP regimen had trailed off at a strange and bleak point. Combination chemo had cured most of the children of leukemia in their blood and bone marrow, but the cancer had explosively relapsed in the brain. In the months following VAMP in 1962, most of these children had hobbled back to the clinic with seemingly innocuous neurological complaints and then spiraled furiously toward their deaths just a week or two afterward. VAMP, once widely touted as the institute's success story, had turned, instead, into its progressive nightmare. Of the fifteen patients treated on the initial protocol, only two still survived. At the NCI, the ambition and bravado that had spurred the original studies was rapidly tipping toward a colder reality. Perhaps Farber's critics had been right. Perhaps lymphoblastic leukemia was a disease that could, at best, be sent into a flickering remission, but never cured. Perhaps palliative care was the best option after all.
But having tasted the success of high-dose chemotherapy, many oncologists could not scale back their optimism: What if even VAMP had not been intensive enough? What if a chemotherapy regimen could be muscled up further, pushed closer to the brink of tolerability?
The leader of this gladiatorial camp was a protege of Farber's, a thirty-six-year-old oncologist, Donald Pinkel, who had been recruited from Boston to start a leukemia program in Memphis, Tennessee.* In many ways, Memphis was the antipode of Boston. Convulsing with bitter racial tensions and rock-and-roll music--gyrating between the gold and pink of the Graceland mansion in its south and the starkly segregated black neighborhoods in its north--Memphis was turbulent, unpredictable, colorful, perennially warm, and, medically speaking, virtually a no-man's-land. Pinkel's new hospital, called St. Jude's (named, aptly enough, after the patron saint of lost causes), rose like a marooned concrete starfish out of a concrete parking lot on a barren field. In 1961, when Pinkel arrived, the hospital was barely functional, with "no track record, uncertain finances, an unfinished building, no employees or faculty."
Still, Pinkel got a chemotherapy ward up and running, with nurses, residents, and fellows trained in administering the toxic, mercurial drugs. And flung far from the epicenters of leukemia research in New York and Boston, Pinkel's team was determined to outdo every other leukemia trial--the edge outmoding the center--to push the logic of high-dose combination chemotherapy to its extreme. Pinkel thus hammered away in trial after trial, edging his way toward the outer limit of tolerability. And Pinkel and his collaborators emerged with four crucial innovations to the prior regimens.+
First, Pinkel reasoned that while combinations of drugs were necessary to induce remissions, combinations were insufficient in themselves. Perhaps one needed combinations of combinations--six, seven, or even eight different chemical poisons mixed and matched together for maximum effect.
Second, since the nervous system relapses had likely occurred because even these highly potent chemicals could not breach the blood-brain barrier, perhaps one needed to instill chemotherapy directly into the nervous system by injecting it into the fluid that bathes the spinal cord.
Third, perhaps even that instillation was not enough. Since X-rays could penetrate the brain regardless of the blood-brain barrier, perhaps one needed to add high-dose radiation to the skull to kill residual cells in the brain.
And finally, as Min Chiu Li had seen with choriocarcinoma, perhaps one needed to continue chemotherapy not just for weeks and months as Frei and Freireich had done, but for month after month, stretching into two or even three years.
The treatment protocol that emerged from these guiding principles could only be described as, as one of Pinkel's colleagues called it, "an all-out combat." To start with, the standard antileukemic drugs were given in rapid-fire succession. Then, at defined intervals, methotrexate was injected into the spinal canal using a spinal tap. The brain was irradiated with high doses of X-rays. Then, chemotherapy was bolstered even further with higher doses of drugs and alternating intervals, "in maximum tolerated doses." Antibiotics and transfusions were usually needed, often in succession, often for weeks on end. The treatment lasted up to two and a half years; it involved multiple exposures to radiation, scores of blood tests, dozens of spinal taps, and multiple intravenous drugs--a strategy so precise and demanding that one journal refused to publish it, concerned that it was impossible to even dose it and monitor it correctly without killing several patients in the trials. Even at St. Jude's, the regimen was considered so overwhelmingly toxic that the trial was assigned to relatively junior physicians under Pinkel's supervision because the senior researchers, knowing its risks, did not want to run it. Pinkel called it "total therapy."
As fellows, we called it "total hell."
Carla Reed entered this form of hell in the summer of 2004. Chemotherapy and radiation came back-to-back, one dark tide after another. Some days she got home in the evening (her children already in bed, her husband waiting with dinner) only to turn around and come back the next morning. She lost sleep, her hair, and her appetite and then something more important and ineffable--her animus, her drive, her will. She walked around the hospital like a zombie, shuffling in small steps from the blue vinyl couch in the infusion room to the water dispenser in the central corridor, then back to the couch in those evenly measured steps. "The radiation treatment was the last straw," she recalled. "Lying on the treatment table as still as death, with the mask on my face, I often wondered whether I would even wake up." Even her mother, who had flown in and out of Boston regularly during Carla's first month of treatment, retreated to her own house in Florida, red-eyed and exhausted.
Carla withdrew even more deeply into her own world. Her melancholy hardened into something impenetrable, a carapace, and she pulled into it instinctually, shutting everything out. She lost her friends. During her first few visits, I noticed that she often brought a cheerful young woman as a companion. One morning, I noticed that the friend was missing.
"No company today?" I asked.
Carla looked away and shrugged her shoulders. "We had a falling-out." There was something steely, mechanical in her voice. "She needed to be needed, and I just couldn't fulfill that demand. Not now."
I found myself, embarrassingly enough, sympathizing with the missing friend. As Carla's doctor, I needed to be needed as well, to be acknowledged, even as a peripheral participant in her battle. But Carla had barely any emotional energy for her own recuperation--and certainl
y none to spare for the needs of others. For her, the struggle with leukemia had become so deeply personalized, so interiorized, that the rest of us were ghostly onlookers in the periphery: we were the zombies walking outside her head. Her clinic visits began and ended with awkward pauses. Walking across the hospital in the morning to draw yet another bone marrow biopsy, with the wintry light crosshatching the rooms, I felt a certain dread descend on me, a heaviness that bordered on sympathy but never quite achieved it.
Test came after test. Seven months into her course, Carla had now visited the clinic sixty-six times, had had fifty-eight blood tests, seven spinal taps, and several bone marrow biopsies. One writer, a former nurse, described the typical course of "total therapy" in terms of the tests involved: "From the time of his diagnosis, Eric's illness had lasted 628 days. He had spent one quarter of these days either in a hospital bed or visiting the doctors. He had received more than eight hundred blood tests, numerous spinal and bone marrow taps, 30 X-rays, 120 biochemical tests, and more than two hundred transfusions. No fewer than twenty doctors--hematologists, pulmonologists, neurologists, surgeons, specialists and so on--were involved in his treatment, not including the psychologist and a dozen nurses."
How Pinkel and his team convinced four- and six-year-olds in Memphis to complete that typical routine remains a mystery in its own right. But he did. In July 1968, the St. Jude's team published its preliminary data on the results of the most advanced iteration of total therapy. (Pinkel's team would run eight consecutive trials between 1968 and 1979, each adding another modification to the regimen.) This particular trial, an early variant, was nonrandomized and small, a single hospital's experience with a single cohort of patients. But despite all the caveats, the result was electrifying. The Memphis team had treated thirty-one patients in all. Twenty-seven of them had attained a full remission. The median time to relapse (the time between diagnosis and relapse, a measure of the efficacy of treatment) had stretched out to nearly five years--more than twenty times the longest remissions achieved by most of Farber's first patients.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 20
