The Emperor of All Maladies: A Biography of Cancer (24 page)

In the winter of 1956, after a prolonged and bruising battle, Sonja’s son, three-year-old David Goldstein, died of metastatic Wilms’ tumor at the Jimmy Fund clinic, having spent the last few hours of his life delirious and
whimpering under an oxygen mask. Sonja Goldstein left the hospital carrying her own brown paper bag containing the remains of her child.

But Farber was unfazed. The arsenal of cancer chemotherapy, having been empty for centuries, had filled up with new drugs. The possibilities thrown open by these discoveries were enormous: permutations and combinations of medicines, variations in doses and schedules, trials containing two-, three-, and four-drug regimens. There was, at least in principle, the capacity to re-treat cancer with one drug if another had failed, or to try one combination followed by another. This, Farber kept telling himself with hypnotic conviction, was not the “
finish.
” This was just the beginning of an all-out attack.

In her hospital bed on the fourteenth floor, Carla Reed was still in “isolation”—trapped in a cool, sterile room where even the molecules of air arrived filtered through dozens of sieves. The smell of antiseptic soap pervaded her clothes. A television occasionally flickered on and off. Food came on a tray labeled with brave, optimistic names—Chunky Potato Salad or Chicken Kiev—but everything tasted as if it had been boiled and seared almost to obliteration. (It had been; the food had to be sterilized before it could enter the room.) Carla’s husband, a computer engineer, came in every afternoon to sit by her bed. Ginny, her mother, spent the days rocking mechanically in a chair, exactly as I had found her the first morning. When Carla’s children stopped by, in masks and gloves, she wept quietly, turning her face toward the window.

For Carla, the physical isolation of those days became a barely concealed metaphor for a much deeper, fiercer loneliness, a psychological quarantine even more achingly painful than her actual confinement. “In those first two weeks, I withdrew into a different person,” she said. “What went into the room and what came out were two different people.

“I thought over and over again about my chances of surviving through all this. Thirty percent. I would repeat that number to myself at night. Not even a third. I would stay up at night looking up at the ceiling and think: What
is
thirty percent? What happens thirty percent of the time? I am thirty years 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 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.