The Emperor of All Maladies. Siddhartha Mukherjee
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old—about thirty percent of ninety. If someone gave me thirty percent odds in a game, would I take the odds?”
The morning after Carla had arrived at the hospital, I walked into her room with sheaves of paper. They were consent forms for chemotherapy that would allow us to instantly start pumping poisons into her body to kill cancer cells.
Chemotherapy would come in three phases. The first phase would last about a month. The drugs—given in rapid-fire succession—would hopefully send the leukemia into a sustained remission. They would certainly kill her normal white blood cells as well. Her white cell count would drop in free fall, all the way to zero. For a few critical days, she would inhabit one of the most vulnerable states that modern medicine can produce: a body with no immune system, defenseless against the environment around it.
If the leukemia did go into remission, then we would “consolidate” and intensify that remission over several months. That would mean more chemotherapy, but at lower doses, given over longer intervals. She would be able to leave the hospital and return home, coming back every week for more chemotherapy. Consolidation and intensification would last for eight additional weeks, perhaps longer.
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.”
Randomised screening trials are bothersome310. 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 sense311 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 Freireich312 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,”313 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 director314 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 later315, 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