Читать книгу The Emperor of All Maladies - Siddhartha Mukherjee, Siddhartha Mukherjee - Страница 27

An Early Victory

. . . But I do subscribe to the view³²⁵ 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 Li³²⁶ and Roy Hertz, had been experimenting with choriocarcinoma, a cancer of the placenta. Even rarer 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 Longoria³²⁷, 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,”³²⁸ 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.”

Ethel Longoria hung on. At rounds the next morning, she was still alive, breathing slowly but deeply. The bleeding had now abated to the point that a few more doses could be tried. At the end of four rounds of chemotherapy³³⁰, Li and Hertz expected to see minor changes in the size of the tumors. What they found, instead, left them flabbergasted: “The tumor masses disappeared, the chest X-ray improved, and the patient looked normal,” Freireich wrote. The level of choriogonadotropin, the hormone secreted by the cancer cells, rapidly plummeted toward zero. The tumors had actually vanished. No one had ever seen such a response. The X-rays, thought to have been mixed up, were sent down for reexamination. The response was real: a metastatic, solid cancer had vanished with chemotherapy. Jubilant, Li and Hertz rushed to publish³²⁹ their findings.

But there was a glitch in all this—an observation so minor that it could easily have been brushed away. Choriocarcinoma cells secrete a marker, a hormone called choriogonadotropin, a protein that can be measured with an extremely sensitive test in the blood (a variant of this test is used to detect pregnancies). Early in his experiments, Li had decided that he would use that hormone level to track the course of the cancer as it responded to methotrexate. The hcg level, as it was called, would be a surrogate for the cancer, its fingerprint in the blood.

The trouble was, at the end of the scheduled chemotherapy, the hcg level had fallen to an almost negligible value, but to Li’s annoyance, it hadn’t gone all the way to normal. He measured and remeasured it in his laboratory weekly, but it persisted, a pip-squeak of a number that wouldn’t go away.

Li became progressively obsessed with the number. The hormone in the blood, he reasoned, was the fingerprint of cancer, and if it was still present, then the cancer had to be present, too, hiding in the body somewhere even if the visible tumors had disappeared. So, despite every other indication that the tumors had vanished, Li reasoned that his patients had not been fully cured. In the end, he seemed almost to be treating a number rather than a patient; ignoring the added toxicity of additional rounds of the drug, Li doggedly administered dose upon dose until, at last, the hcg level sank to zero.

When the Institutional Board at the NCI got wind of Li’s decision, it responded with fury. These patients were women who had supposedly been “cured” of cancer. Their tumors were invisible, and giving them additional chemotherapy was tantamount to poisoning them with unpredictable doses of highly toxic drugs. Li was already known to be a renegade, an iconoclast. This time, the NCI felt, he had gone too far. In mid-July, the board summoned³³¹ him to a meeting and promptly fired him.

“Li was accused of experimenting on people,”³³² Freireich said. “But of course, all of us were experimenting. Tom [Frei] and Zubrod and the rest of them—we were all experimenters. To not experiment would mean to follow the old rules—to do absolutely nothing. Li wasn’t prepared to sit back and watch and do nothing. So he was fired for acting on his convictions, for doing something.”

Freireich and Li had been medical residents together in Chicago. At the NCI, they had developed a kinship as two outcasts. When Freireich heard about Li’s dismissal³³³, he immediately went over to Li’s house to console him, but Li was inconsolable. In a few months, he huffed off to New York, bound back for Memorial Sloan-Kettering. He never returned to the NCI.

But the story had a final plot twist. As Li had predicted, with several additional doses of methotrexate, the hormone level that he had so compulsively trailed did finally vanish to zero. His patients finished their additional cycles of chemotherapy. Then, slowly, a pattern began to emerge. While the patients who had stopped the drug early inevitably relapsed with cancer, the patients treated on Li’s protocol remained free of disease—even months after the methotrexate had been stopped.

Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished. The hcg level—the hormone secreted by choriocarcinoma—had turned out to be its real fingerprint, its marker. In the decades that followed, trial after trial would prove this principle. But in 1960, oncology was not yet ready for this proposal. Not until several years later did it strike the board that had fired Li so hastily that the patients he had treated with the prolonged maintenance strategy would never relapse. This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.