The worst part, perhaps, I kept for last. Acute lymphoblastic leukemia has an ugly propensity for hiding in the brain. The intravenous chemotherapy that we would give Carla, no matter how potent, simply couldn't break into the cisterns and ventricles that bathed her brain. The blood-brain barrier essentially made the brain into a "sanctuary" (an unfortunate word, implying that your own body could be abetting the cancer) for the leukemia cells. To send drugs directly into that sanctuary, the medicines would need to be injected directly into Carla's spinal fluid, through a series of spinal taps. Whole-brain radiation treatment--highly penetrant X-rays dosed directly through her skull--would also be used prophylactically against leukemia growth in her brain. And there would be even more chemotherapy to follow, spanning over two years, to "maintain" the remission if we achieved it.
Induction. Intensification. Maintenance. Cure. An arrow in pencil connecting the four points on a blank piece of paper. Carla nodded.
When I went through the avalanche of chemotherapy drugs that would be used over the next two years to treat her, she repeated the names softly after me under her breath, like a child discovering a new tongue twister: "Cyclophosphamide, cytarabine, prednisone, asparaginase, Adriamycin, thioguanine, vincristine, 6-mercaptopurine, methotrexate."
"The butcher shop"
Randomised screening trials are bothersome. It takes ages to come to an answer, and these need to be large-scale projects to be able to answer the questions. [But . . .] there is no second-best option.
--H. J. de Koning,
Annals of Oncology, 2003
The best [doctors] seem to have a sixth sense about disease. They feel its presence, know it to be there, perceive its gravity before any intellectual process can define, catalog, and put it into words. Patients sense this about such a physician as well: that he is attentive, alert, ready; that he cares. No student of medicine should miss observing such an encounter. Of all the moments in medicine, this one is most filled with drama, with feeling, with history.
--Michael LaCombe,
Annals of Internal Medicine, 1993
It was in Bethesda, at the very institute that had been likened to a suburban golfing club in the 1940s, that the new arsenal of oncology was deployed on living patients.
In April 1955, in the midst of a humid spring in Maryland, a freshly recruited researcher at the National Cancer Institute named Emil Freireich walked up to his new office in the redbrick Clinical Center Building and found, to his exasperation, that his name had been misspelled on the door, with the last five letters lopped off. The plate on the door read EMIL FREI, MD. "My first thought, of course, was: Isn't it typical of the government?"
It wasn't a misspelling. When Freireich entered the office, he confronted a tall, thin young man who identified himself as Emil Frei. Freireich's office, with the name correctly spelled, was next door.
Their names notwithstanding, the two Emils were vastly different characters. Freireich--just thirty-five years old and fresh out of a hematology fellowship at Boston University--was flamboyant, hot-tempered, and adventurous. He spoke quickly, often explosively, with a booming voice followed often by an even more expressive boom of laughter. He had been a medical intern at the fast-paced "Ward 55" of the Cook County Hospital in Chicago--and such a nuisance to the authorities that he had been released from his contract earlier than usual. In Boston, Freireich had worked with Chester Keefer, one of Minot's colleagues who had subsequently spearheaded the production of penicillin during World War II. Antibiotics, folic acid, vitamins, and antifolates were stitched into Freireich's soul. He admired Farber intensely--not just the meticulous, academic scientist, but the irreverent, impulsive, larger-than-life Farber who could antagonize his enemies as quickly as he could seduce his benefactors. "I have never seen Freireich in a moderate mood," Frei would later say.
If Freireich had been a character in a film, he would have needed a cinematic foil, a Laurel to his Hardy or a Felix to his Oscar. The tall, thin man who confronted him at the door at the NCI that afternoon was that foil. Where Freireich was brusque and flamboyant, impulsive to a fault, and passionate about every detail, Frei was cool, composed, and cautious, a poised negotiator who preferred to work backstage. Emil Frei--known to most of his colleagues by his nickname, Tom--had been an art student in St. Louis in the thirties. He had attended medical school almost as an afterthought in the late 1940s, served in the navy in the Korean War, and returned to St. Louis as a resident in medicine. He was charming, soft-spoken, and careful--a man of few, chosen words. To watch him manage critically ill children and their testy, nervous parents was to watch a champion swimmer glide through water--so adept in the art that he made artistry vanish.
The person responsible for bringing the two Emils to Bethesda was Gordon Zubrod, the new director of the NCI's Clinical Center. Intellectual, deliberate, and imposing, a clinician and scientist known for his regal composure, Zubrod had arrived at the NIH having spent nearly a decade developing antimalaria drugs during World War II, an experience that would deeply influence his early interests in clinical trials for cancer.
Zubrod's particular interest was children's leukemia--the cancer that Farber had plunged into the very forefront of clinical investigation. But to contend with leukemia, Zubrod knew, was to contend with its fieriness and brittleness, its moody, volcanic unpredictability. Drugs could be tested, but first, the children needed to be kept alive. A quintessential delegator--an "Eisenhower" of cancer research, as Freireich once called him--Zubrod quickly conscripted two young doctors to maintain the front lines of the wards: Freireich and Frei, fresh from their respective fellowships in Boston and St. Louis. Frei drove cross-country in a beat-up old Studebaker to join Zubrod. Freireich came just a few weeks later, in a ramshackle Oldsmobile containing all his belongings, his pregnant wife, and his nine-month-old daughter.
It could easily have been a formula for disaster--but it worked. Right from the start, the two Emils found that they shared a unique synergy. Their collaboration was symbolic of a deep intellectual divide that ran through the front lines of oncology: the rift between overmoderated caution and bold experimentation. Each time Freireich pushed too hard on one end of the experimental fulcrum--often bringing himself and his patients to the brink of disaster--Frei pushed back to ensure that the novel, quixotic, and often deeply toxic therapies were mitigated by caution. Frei and Freireich's battles soon became emblematic of the tussles within the NCI. "Frei's job," one researcher recalled, "in those days was to keep Freireich from getting in trouble."
Zubrod had his own schemes to keep leukemia research out of trouble. As new drugs, combinations, and trials proliferated, Zubrod worried that institutions would be caught at cross-purposes, squabbling over patients and protocols when they should really be battling cancer. Burchenal in New York, Farber in Boston, James Holland at Roswell Park, and the two Emils at the NCI were all chomping at the bit to launch clinical trials. And since ALL was a rare disease, every patient was a precious resource for a leukemia trial. To avert conflicts, Zubrod proposed that a "consortium" of researchers be created to share patients, trials, data, and knowledge.
The proposal changed the field. "Zubrod's cooperative group model galvanized cancer medicine," Robert Mayer (who would later become the chair of one of these groups) recalls. "For the first time, an academic oncologist felt as if he had a community. The cancer doctor was not the outcast anymore, not the man who prescribed poisons from some underground chamber in the hospital." The first group meeting, chaired by Farber, was a resounding success. The researchers agreed to proceed with a series of common trials, called protocols, as soon as possible.
Zubrod next set about organizing the process by which trials could be run. Cancer trials, he argued, had thus far been embarrassingly chaotic and disorganized. Oncologists needed to emulate the best trials in medicine. And to learn how to run objective, unbiased, state-of-the-art clinical trials, they would need to study the history of the development of antibiotics.
In the 1940s, as new antibiotics had begun to appear on the horizon, physicians had encountered an important quandary: how might one objectively test the efficacy of any novel drug? At the Medical Research Council in Britain, the question had taken on a particularly urgent and rancorous note. The discovery of streptomycin, a new antimicrobial drug in the early forties, had set off a flurry of optimism that tuberculosis could be cured. Streptomycin killed tuberculosis-causing mycobacteria in petri dishes, but its efficacy in humans was unknown. The drug was in critically short supply, with doctors parrying to use even a few milligrams of it to treat a variety of other infections. To ration streptomycin, an objective experiment to determine its efficacy in human tuberculosis was needed.
But what sort of experiment? An English statistician named Bradford Hill (a former victim of TB himself) proposed an extraordinary solution. Hill began by recognizing that doctors, of all people, could not be entrusted to perform such an experiment without inherent biases. Every biological experiment requires a "control" arm--untreated subjects against whom the efficacy of a treatment can be judged. But left to their own devices, doctors were inevitably likely (even if unconsciously so) to select certain types of patients upfront, then judge the effects of a drug on this highly skewed population using subjective criteria, piling bias on top of bias.
Hill's proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By "randomizing" patients to each arm, any doctors' biases in patient assignment would be dispelled. Neutrality would be enforced--and thus a hypothesis could be strictly tested.
Hill's randomized trial was a success. The streptomycin arm of the trial clearly showed an improved response over the placebo arm, enshrining the antibiotic as a new anti-TB drug. But perhaps more important, it was Hill's methodological invention that was permanently enshrined. For medical scientists, the randomized trial became the most stringent means to evaluate the efficacy of any intervention in the most unbiased manner.
Zubrod was inspired by these early antimicrobial trials. He had used these principles in the late 1940s to test antimalarials, and he proposed using them to lay down the principles by which the NCI would test its new protocols. The NCI's trials would be systematic: every trial would test a crucial piece of logic or hypothesis and produce yes and no answers. The trials would be sequential: the lessons of one trial would lead to the next and so forth--a relentless march of progress until leukemia had been cured. The trials would be objective, randomized if possible, with clear, unbiased criteria to assign patients and measure responses.
Trial methodology was not the only powerful lesson that Zubrod, Frei, and Freireich learned from the antimicrobial world. "The analogy of drug resistance to antibiotics was given deep thought," Freireich remembered. As Farber and Burchenal had discovered to their chagrin in Boston and New York, leukemia treated with a single drug would inevitably grow resistant to the drug, resulting in the flickering, transient responses followed by the devastating relapses.
The situation was reminiscent of TB. Like cancer cells, mycobacteria--the germs that cause tuberculosis--also became resistant to antibiotics if the drugs were used singly. Bacteria that survived a single-drug regimen divided, mutated, and acquired drug resistance, thus making that original drug useless. To thwart this resistance, doctors treating TB had used a blitzkrieg of antibiotics--two or three used together like a dense pharmaceutical blanket meant to smother all cell division and stave off bacterial resistance, thus extinguishing the infection as definitively as possible.
But could two or three drugs be tested simultaneously against cancer--or would the toxicities be so forbidding that they would instantly kill patients? As Freireich, Frei, and Zubrod studied the growing list of antileukemia drugs, the notion of combining drugs emerged with growing clarity: toxicities notwithstanding, annihilating leukemia might involve using a combination of two or more drugs.
The first protocol was launched to test different doses of Farber's methotrexate combined with Burchenal's 6-MP, the two most active antileukemia drugs. Three hospitals agreed to join: the NCI, Roswell Park, and the Children's Hospital in Buffalo, New York. The aims of the trial were kept intentionally simple. One group would be treated with intensive methotrexate dosing, while the other group would be treated with milder and less intensive dosing. Eighty-four patients enrolled. On arrival day, parents of the children were handed white envelopes with the randomized assignment sealed inside.
Despite the multiple centers and the many egos involved, the trial ran surprisingly smoothly. Toxicities multiplied; the two-drug regimen was barely tolerable. But the intensive group fared better, with longer and more durable responses. The regimen, though, was far from a cure: even the intensively treated children soon relapsed and died by the end of one year.
Protocol I set an important precedent. Zubrod's and Farber's cherished model of a cancer cooperative group was finally in action. Dozens of doctors, nurses, and patients in three independent hospitals had yoked themselves to follow a single formula to treat a group of patients--and each one, suspending its own idiosyncrasies, had followed the instructions perfectly. "This work is one of the first comparative studies in the chemotherapy of malignant neoplastic disease," Frei noted. In a world of ad hoc, often desperate strategies, conformity had finally come to cancer.
In the winter of 1957, the leukemia group launched yet another modification to the first experiment. This time, one group received a combined regimen, while the other two groups were given one drug each. And with the question even more starkly demarcated, the pattern of responses was even clearer. Given alone, either of the drugs performed poorly, with a response rate between 15 and 20 percent. But when methotrexate and 6-MP were administered together, the remission rate jumped to 45 percent.
The next chemotherapy protocol, launched just two years later in 1959, ventured into even riskier territory. Patients were treated with two drugs to send them into complete remission. Then half the group received several months of additional drugs, while the other group was given a placebo. Once again, the pattern was consistent. The more aggressively treated group had longer and more durable responses.
Trial by trial, the group crept forward, like a spring uncoiling to its end. In just six pivotal years, the leukemia study group had slowly worked itself to giving patients not one or two, but four chemotherapy drugs, often in succession. By the winter of 1962, the compass of leukemia medicine pointed unfailingly in one direction. If two drugs were better than one, and if three better than two, then what if four antileukemia drugs could be given together--in combination, as with TB?
Both Frei and Freireich sensed that this was the inevitable culmination of the NCI's trials. But even if they knew it subconsciously, they tiptoed around the notion for months. "The resistance would be fierce," Freireich knew. The leukemia ward was already being called a "butcher shop" by others at the NCI. "The idea of treating children with three or four highly cytotoxic drugs was considered cruel and insane," Freireich said. "Even Zubrod could not convince the consortium to try it. No one wanted to turn the NCI into a National Institute of Butchery."
An Early Victory
. . . But I do subscribe to the view that words have very powerful texts and subtexts. "War" has truly a unique status, "war" has a very special meaning. It means putting young men and women in situations where they might get killed or grievously wounded. It's inappropriate to retain that metaphor for a scholarly activity in these times of actual war. The NIH is a community of scholars focused on generating knowledge to improve the public health. That's a great activity. That's not a war.
--Samuel Broder, NCI director
In the midst of this nervy deliberation about the use of four-drug combination therapy, Frei and Freireich received an enormously exciting piece of news. Just a few doors down from Freireich's office at the NCI, two researchers, Min Chiu Li and Roy Hertz, had been experimenting with choriocarcinoma, a cancer of the placenta. Even ra
rer than leukemia, choriocarcinoma often grows out of the placental tissue surrounding an abnormal pregnancy, then metastasizes rapidly and fatally into the lung and the brain. When it occurs, choriocarcinoma is thus a double tragedy: an abnormal pregnancy compounded by a lethal malignancy, birth tipped into death.
If cancer chemotherapists were generally considered outsiders by the medical community in the 1950s, then Min Chiu Li was an outsider even among outsiders. He had come to the United States from Mukden University in China, then spent a brief stint at the Memorial Hospital in New York. In a scramble to dodge the draft during the Korean War, he had finagled a two-year position in Hertz's service as an assistant obstetrician. He was interested in research (or at least feigned interest), but Li was considered an intellectual fugitive, unable to commit to any one question or plan. His current plan was to lie low in Bethesda until the war blew over.
But what had started off as a decoy fellowship for Li turned, within a single evening in August 1956, into a full-time obsession. On call late one evening, he tried to medically stabilize a woman with metastatic choriocarcinoma. The tumor was in its advanced stages and bled so profusely that the patient died in front of Li's eyes in three hours. Li had heard of Farber's antifolates. Almost instinctually, he had made a link between the rapidly dividing leukemia cells in the bone marrow of the children in Boston and the rapidly dividing placental cells in the women in Bethesda. Antifolates had never been tried in this disease, but if the drugs could stop aggressive leukemias from growing--even if temporarily--might they not at least partially relieve the eruptions of choriocarcinoma?
Li did not have to wait long. A few weeks after the first case, another patient, a young woman called Ethel Longoria, was just as terrifyingly ill as the first patient. Her tumors, growing in grapelike clusters in her lungs, had begun to bleed into the linings of her lungs--so fast that it had become nearly impossible to keep up with the blood loss. "She was bleeding so rapidly," a hematologist recalled, "that we thought we might transfuse her back with her own blood. So [the doctors] scrambled around and set up tubes to collect the blood that she had bled and put it right back into her, like an internal pump." (The solution bore the quintessential mark of the NCI. Transfusing a person with blood leaking out from her own tumor would have been considered extraordinary, even repulsive, elsewhere, but at the NCI, this strategy--any strategy--was par for the course.) "They stabilized her and then started antifolates. After the first dose, when the doctors left for the night, they didn't expect that they'd find her in rounds the next morning. At the NCI, you didn't expect. You just waited and watched and took surprises as they came."
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 16
