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 chemotherapy, 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 publish 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 summoned him to a meeting and promptly fired him.
"Li was accused of experimenting on people," 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 dismissal, 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.
Mice and Men
A model is a lie that helps you see the truth.
--Howard Skipper
Min Chiu Li's experience with choriocarcinoma was a philosophical nudge for Frei and Freireich. "Clinical research is a matter of urgency," Freireich argued. For a child with leukemia, even a week's delay meant the difference between life and death. The academic stodginess of the leukemia consortium--its insistence on progressively and systematically testing one drug combination after another--was now driving Freireich progressively and systematically mad. To test three drugs, the group insisted on testing "all of the three possible combinations and then you've got to do all of the four combinations and with different doses and schedules for each." At the rate that the leukemia consortium was moving, he argued, it would take dozens of years before any significant advance in leukemia was made. "The wards were filling up with these terribly sick children. A boy or girl might be brought in with a white cell count of three hundred and be dead overnight. I was the one sent the next morning to speak with the parents. Try explaining Zubrod's strategy of sequential, systematic, and objective trials to a woman whose daughter has just slumped into a coma and died," Freireich recalled.
The permutations of possible drugs and doses were further increased when yet another new anticancer agent was introduced at the Clinical Center in 1960. The newcomer, vincristine, was a poisonous plant-alkaloid that came from the Madagascar periwinkle, a small, weedlike creeper with violet flowers and an entwined, coiled stem. (The name vincristine comes from vinca, the Latin word for "bind.") Vincristine had been discovered in 1958 at the Eli Lilly company through a drug-discovery program that involved grinding up thousands of pounds of plant material and testing the extracts in various biological assays. Although originally intended as an antidiabetic, vincristine at small doses was found to kill leukemia cells. Rapidly growing cells, such as those of leukemia, typically create a skeletal scaffold of proteins (called microtubules) that allows two daughter cells to separate from each other and thereby complete cell division. Vincristine works by binding to the end of these microtubules and then paralyzing the cellular skeleton in its grip--thus, quite literally, evoking the Latin word after which it was originally named.
With vincristine added to the pharmacopoeia, leukemia researchers found themselves facing the paradox of excess: how might one take four independently active drugs--methotrexate, prednisone, 6-MP, and vincristine--and stitch them together into an effective regimen? And since each drug was potentially severely toxic, could one ever find a combination that would kill the leukemia but not kill a child?
Two drugs had already spawned dozens of possibilities; with four drugs, the leukemia consortium would take not fifty, but a hundred and fifty years to finish its trials. David Nathan, then a new recruit at the NCI, recalled the near standstill created by the avalanche of new medicines: "Frei and Freireich were simply taking drugs that were available and adding them together in combinations. . . . The possible combinations, doses, and schedules of four or five drugs were infinite. Researchers could work for years on finding the right combination of drugs and schedules." Zubrod's sequential, systematic, objective trials had reached an impasse. What was needed was quite the opposite of a systematic approach--an intuitive and inspired leap of faith into the deadly abyss of deadly drugs.
A scientist from Alabama, Howard Skipper--a scholarly, soft-spoken man who liked to call himself a "mouse doctor"--provided Frei and Freireich a way out of the impasse. Skipper was an outsider to the NCI. If leukemia was a model form of cancer, then Skipper had been studying the disease by artificially inducing leukemias in animals--in effect, by
building a model of a model. Skipper's model used a mouse cell line called L-1210, a lymphoid leukemia that could be grown in a petri dish. When laboratory mice were injected with these cells, they would acquire the leukemia--a process known as engraftment because it was akin to transferring a piece of normal tissue (a graft) from one animal to another.
Skipper liked to think about cancer not as a disease but as an abstract mathematical entity. In a mouse transplanted with L-1210 cells, the cells divided with nearly obscene fecundity--often twice a day, a rate startling even for cancer cells. A single leukemia cell engrafted into the mouse could thus take off in a terrifying arc of numbers: 1, 4, 16, 64, 256, 1,024, 4,096, 16,384, 65,536, 262,144, 1,048,576 . . . and so forth, all the way to infinity. In sixteen or seventeen days, more than 2 billion daughter cells could grow out of that single cell--more than the entire number of blood cells in the mouse.
Skipper learned that he could halt this effusive cell division by administering chemotherapy to the leukemia-engrafted mouse. By charting the life and death of leukemia cells as they responded to drugs in these mice, Skipper emerged with two pivotal findings. First, he found that chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was. This percentage was a unique, cardinal number particular to every drug. In other words, if you started off with 100,000 leukemia cells in a mouse and administered a drug that killed 99 percent of those cells in a single round, then every round would kill cells in a fractional manner, resulting in fewer and fewer cells after every round of chemotherapy: 100,000 . . . 1,000 . . . 10 . . . and so forth, until the number finally fell to zero after four rounds. Killing leukemia was an iterative process, like halving a monster's body, then halving the half, and halving the remnant half.
Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing. Since different drugs elicited different resistance mechanisms, and produced different toxicities in cancer cells, using drugs in concert dramatically lowered the chance of resistance and increased cell killing. Two drugs were therefore typically better than one, and three drugs better than two. With several drugs and several iterative rounds of chemotherapy in rapid-fire succession, Skipper cured leukemias in his mouse model.
For Frei and Freireich, Skipper's observations had an inevitable, if frightening, conclusion. If human leukemias were like Skipper's mouse leukemias, then children would need to be treated with a regimen containing not one or two, but multiple drugs. Furthermore, a single treatment would not suffice. "Maximal, intermittent, intensive, up-front" chemotherapy would need to be administered with nearly ruthless, inexorable persistence, dose after dose after dose after dose, pushing the outermost limits of tolerability. There would be no stopping, not even after the leukemia cells had apparently disappeared in the blood and the children had apparently been "cured."
Freireich and Frei were now ready to take their pivotal and intuitive leap into the abyss. The next regimen they would try would be a combination of all four drugs: vincristine, amethopterin, mercaptopurine, and prednisone. The regimen would be known by a new acronym, with each letter standing for one of the drugs: VAMP.
The name had many intended and unintended resonances. Vamp is a word that means to improvise or patch up, to cobble something together from bits and pieces that might crumble apart any second. It can mean a seductress--one who promises but does not deliver. It also refers to the front of a boot, the part that carries the full brunt of force during a kick.
VAMP
Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing.
--Voltaire
If we didn't kill the tumor, we killed the patient.
--William Moloney on the early days
of chemotherapy
VAMP--high-dose, life-threatening, four-drug combination therapy for leukemia--might have made obvious sense to Skipper, Frei, and Freireich, but to many of their colleagues, it was a terrifying notion, an abomination. Freireich finally approached Zubrod with his idea: "I wanted to treat them with full doses of vincristine and amethopterin, combined with the 6-MP and prednisone." The ands in the sentence were italicized to catch Zubrod's attention.
Zubrod was stunned. "It is the dose that makes a poison," runs the old adage in medicine: all medicines were poisons in one form or another merely diluted to an appropriate dose. But chemotherapy was poison even at the correct dose.* A child with leukemia was already stretched to the brittle limits of survival, hanging on to life by a bare physiological thread. People at the NCI would often casually talk of chemotherapy as the "poison of the month." If four poisons of the month were simultaneously pumped daily into a three- or six-year-old child, there was virtually no guarantee that he or she could survive even the first dose of this regimen, let alone survive week after week after week.
When Frei and Freireich presented their preliminary plan for VAMP at a national meeting on blood cancers, the audience balked. Farber, for one, favored giving one drug at a time and adding the second only after relapse and so forth, following the leukemia consortium's slow but steady method of adding drugs carefully and sequentially. "Oh, boy," Freireich recalled, "it was a terrible, catastrophic showdown. We were laughed at and then called insane, incompetent, and cruel." With limited patients and hundreds of drugs and combinations to try, every new leukemia trial had to wind its way through a complex approval process through the leukemia group. Frei and Freireich, it was felt, were making an unauthorized quantum leap. The group refused to sponsor VAMP--at least not until the many other trials had been completed.
But Frei wrangled a last-minute compromise: VAMP would be studied independently at the NCI, outside the purview of the ALGB. "The idea was preposterous," Freireich recalled. "To run the trial, we would need to split with the ALGB, the very group that we had been so instrumental in founding." Zubrod wasn't pleased with the compromise: it was a break from his cherished "cooperative" model. Worse still, if VAMP failed, it would be a political nightmare for him. "If the children had died, we'd be accused of experimenting on people at this federal installation of the National Cancer Institute," Freireich acknowledged. Everyone knew it was chancy territory. Embroiled in controversy, even if he had resolved it as best he could, Frei resigned as the chair of the ALGB. Years later, Freireich acknowledged the risks involved: "We could have killed all of those kids."
The VAMP trial was finally launched in 1961. Almost instantly, it seemed like an abysmal mistake--precisely the sort of nightmare that Zubrod had been trying to avoid.
The first children to be treated "were already terribly, terribly ill," Freireich recalled. "We started VAMP, and by the end of the week, many of them were infinitely worse than before. It was a disaster." The four-drug chemo regimen raged through the body and wiped out all the normal cells. Some children slumped into near coma and were hooked to respirators. Freireich, desperate to save them, visited his patients obsessively in their hospital beds. "You can imagine the tension," he wrote. "I could just hear people saying, 'I told you so, this girl or boy is going to die.'" He hovered in the wards, pestering the staff with questions and suggestions. His paternal, possessive instincts were aroused: "These were my kids. I really tried to take care of them."
The NCI, as a whole, watched tensely--for its life, too, was on the line. "I did little things," Freireich wrote. "Maybe I could make them more comfortable, give them a little aspirin, lower their temperatures, get them a blanket." Thrown into the uncertain front lines of cancer medicine, juggling the most toxic and futuristic combinations of drugs, the NCI doctors fell back to their oldest principles. They provided comfort. They nurtured. They focused on caregiving and support. They fluffed pillows.
At the end of three excruciating weeks, a few of Freireich's patients somehow pulled through. Then, unexpectedly--at a time when it was almost unbearable to look for it--there was a payoff. The norm
al bone marrow cells began to recover gradually, but the leukemia went into remission. The bone marrow biopsies came back one after another--all without leukemia cells. Red blood cells and white blood cells and platelets sprouted up in an otherwise scorched field of bone marrow. But the leukemia did not return. Another set of biopsies, weeks later, confirmed the finding. Not a single leukemia cell was visible under the microscope. This--after near-complete devastation--was a remission so deep that it exceeded the expectations of everyone at the NCI.
A few weeks later, the NCI team drummed up enough courage to try VAMP on yet another small cohort of patients. Once again, after the nearly catastrophic dip in counts--"like a drop from a cliff with a thread tied to your ankles," as one researcher remembered it--the bone marrow recovered and the leukemia vanished. A few days later, the bone marrow began to regenerate, and Freireich performed a hesitant biopsy to look at the cells. The leukemia had vanished again. What it had left behind was full of promise: normal cobblestones of blood cells growing back in the marrow.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 17
