by Mary Roach
Sara looked ghastly, Morris told me. "She was so short of breath. It was uncomfortable to watch. I still remember the attending"—the oncologist who admitted her for the pneumonia treatment. "He was actually kind of rattled about the whole case, and for him to be rattled is saying something."
After her parents arrived, Morris talked with them, too, and when they were finished Sara and her family agreed on a plan. The medical team would continue the antibiotics. But if things got worse they would not put her on a breathing machine. They also let him call the palliative-care team to visit. The team prescribed a small dose of morphine, which immediately eased her breathing. Her family saw how much her suffering diminished, and suddenly they didn't want any more suffering. The next morning they were the ones to hold back the medical team.
"They wanted to put a catheter in her, do this other stuff to her," her mother, Dawn, told me. "I said, 'No. You aren't going to do anything to her.' I didn't care if she wet her bed. They wanted to do lab tests, blood-pressure measurements, finger sticks. I was very uninterested in their bookkeeping. I went over to see the head nurse and told them to stop."
In the previous three months, almost nothing we'd done to Sara—none of our chemotherapy and scans and tests and radiation—had likely achieved anything except to make her worse. She may well have lived longer without any of it. At least she was spared at the very end.
That day Sara fell into unconsciousness as her body continued to fail. Through the next night, Rich recalled, "there was this awful groaning." There is no prettifying death. "Whether it was with inhaling or exhaling, I don't remember, but it was horrible, horrible, horrible to listen to."
Her father and her sister still thought that she might rally. But when the others had stepped out of the room, Rich knelt down weeping beside Sara and whispered in her ear. "It's okay to let go," he said. "You don't have to fight anymore. I will see you soon."
Later that morning, her breathing changed, slowing. At 9:45 A.M., Rich said, "Sara just kind of startled. She let a long breath out. Then she just stopped."
The Treatment
Malcolm Gladwell
FROM The New Yorker
IN THE WORLD of cancer research, there is something called a Kaplan-Meier curve, which tracks the health of patients in the trial of an experimental drug. In its simplest version, it consists of two lines. The first follows the patients in the "control arm," the second the patients in the "treatment arm." In most cases those two lines are virtually identical. That is the sad fact of cancer research: nine times out of ten, there is no difference in survival between those who were given the new drug and those who were not. But every now and again—after millions of dollars have been spent, and tens of thousands of pages of data collected, and patients followed, and toxicological issues examined, and safety issues resolved, and manufacturing processes fine-tuned—the patients in the treatment arm will live longer than the patients in the control arm, and the two lines on the Kaplan-Meier will start to diverge.
Seven years ago, for example, a team from Genentech presented the results of a colorectal-cancer drug trial at the annual meeting of the American Society of Clinical Oncology—a conference attended by virtually every major cancer researcher in the world. The lead Genentech researcher took the audience through one slide after another— click, click, click—laying out the design and scope of the study until he came to the crucial moment: the Kaplan-Meier. At that point, what he said became irrelevant. The members of the audience saw daylight between the two lines for a patient population in which that almost never happened, and they leaped to their feet and gave him an ovation. Every drug researcher in the world dreams of standing in front of thousands of people at ASCO and clicking on a Kaplan-Meier like that. "It is why we are in this business," Safi Bahcall says. Once he thought that this dream would come true for him. It was in the late summer of 2006, and is among the greatest moments of his life.
Bahcall is the CEO of Synta Pharmaceuticals, a small biotechnology company. It occupies a one-story brick 1970s building outside Boston, just off Route 128, where many of the region's high-tech companies have congregated, and that summer Synta had two compounds in development. One was a cancer drug called elesclomol. The other was an immune modulator called apilimod. Experimental drugs must pass through three phases of testing before they can be considered for government approval. Phase 1 is a small trial to determine at what dose the drug can be taken safely. Phase 2 is a larger trial to figure out if it has therapeutic potential, and Phase 3 is a definitive trial to see if it actually works, usually in comparison with standard treatments. Elesclomol had progressed to Phase 2 for soft-tissue sarcomas and lung cancer and had come up short in both cases. A Phase 2 trial for metastatic melanoma—a deadly form of skin cancer—was also underway. But that was a long shot: nothing ever worked well for melanoma. In the previous thirty-five years, there had been something like seventy large-scale Phase 2 trials for metastatic-melanoma drugs, and if you plotted all the results on a single Kaplan-Meier there wouldn't be much more than a razor's edge of difference between any two of the lines.
That left apilimod. In animal studies and early clinical trials for autoimmune disorders, it seemed promising. But when Synta went to Phase 2 with a trial for psoriasis, the results were underwhelming. "It was ugly," Bahcall says. "We had lung cancer fail, sarcoma next, and then psoriasis. We had one more trial left, which was for Crohn's disease. I remember my biostats guy coming into my office, saying, 'I've got some good news and some bad news. The good news is that apilimod is safe. We have the data. No toxicity. The bad news is that it's not effective.' It was heartbreaking."
Bahcall is a boyish man in his early forties, with a round face and dark, curly hair. He was sitting at the dining-room table in his sparsely furnished apartment in Manhattan, overlooking the Hudson River. Behind him a bicycle was leaning against a bare wall, giving the room a post-college feel. Both his parents were astrophysicists, and he, too, was trained as a physicist, before leaving academia for the business world. He grew up in the realm of the abstract and the theoretical—with theorems and calculations and precise measurements. But drug development was different, and when he spoke about the failure of apilimod there was a slight catch in his voice.
Bahcall started to talk about one of the first patients ever treated with elesclomol: a twenty-four-year-old African American man. He'd had Kaposi's sarcoma; tumors covered his lower torso. He'd been at Beth Israel Deaconess Medical Center in Boston, and Bahcall had flown up to see him. On a Monday in January 2003, Bahcall sat by his bed and they talked. The patient was just out of college. He had an IV in his arm. You went to the hospital and you sat next to some kid whose only wish was not to die, and it was impossible not to get emotionally involved. In physics, failure was disappointing. In drug development, failure was heartbreaking. Elesclomol wasn't much help against Kaposi's sarcoma. And now apilimod didn't work for Crohn's. "I mean, we'd done charity work for the Crohn's & Colitis Foundation," Bahcall went on. "I have relatives and friends with Crohn's disease, personal experience with Crohn's disease. We had Crohn's patients come in and talk in meetings and tell their stories. We'd raised money for five years from investors. I felt terrible. Here we were with our lead drug, and it had failed. It was the end of the line."
That summer of 2006, in one painful meeting after another, Synta began to downsize. "It was a Wednesday," Bahcall said. "We were around a table, and we were talking about pruning the budget and how we're going to contain costs, one in a series of tough discussions, and I noticed my chief medical officer, Eric Jacobson, at the end of the table, kind of looking a little unusually perky for one of those kinds of discussions." After the meeting, Bahcall pulled Jacobson over: "Is something up?" Jacobson nodded. Half an hour before the meeting, he'd received some news. It was about the melanoma trial for elesclomol, the study everyone had given up on. "The consultant said she had never seen data this good," Jacobson told him.
Bahcall called back the management
team for a special meeting. He gave the floor to Jacobson. "Eric was, like, 'Well, you know we've got this melanoma trial,'" Bahcall began, "and it took a moment to jog people's memories, because we'd all been so focused on Crohn's disease and the psoriasis trials. And Eric said, 'Well, we got the results. The drug worked! It was a positive trial!'" One person slammed the table, stood up, and hollered. Others peppered Eric with questions. "Eric said, 'Well, the group analyzing the data is trying to disprove it, and they can't disprove it.' And he said, 'The consultant handed me the data on Wednesday morning, and she said it was boinking good.' And everyone said, 'What?' Because Eric is the sweetest guy, who never swears. A bad word cannot cross his lips. Everyone started yelling, 'What? What? What did she say, Eric? Eric! Eric! Say it! Say it!'"
Bahcall contacted Synta's board of directors. Two days later he sent out a company-wide e-mail saying that there would be a meeting that afternoon. At four o'clock, all 130 employees trooped into the building's lobby. Jacobson stood up. "So the lights go down," Bahcall continued. "Clinical guys, when they present data, tend to do it in a very bottom-up way: this is the disease population, this is the treatment, and this is the drug, and this is what was randomized, and this is the demographic, and this is the patient pool, and this is who had toenail fungus, and this is who was Jewish. They go on and on and on, and all anyone wants is, Show us the fucking Kaplan-Meier! Finally he said, 'All right, now we can get to the efficacy.' It gets really silent in the room. He clicks the slide. The two lines separate out beautifully—and a gasp goes out, across a hundred and thirty people. Eric starts to continue, and one person goes like this"—Bahcall started clapping slowly—"and then a couple of people joined in, and then soon the whole room is just going like this—clap, clap, clap. There were tears. We all realized that our lives had changed, the lives of patients had changed, the way of treating the disease had changed. In that moment, everyone realized that this little company of a hundred and thirty people had a chance to win. We had a drug that worked, in a disease where nothing worked. That was the single most moving five minutes of all my years at Synta."
In the winter of 1955, a young doctor named Emil Freireich arrived at the National Cancer Institute in Bethesda, Maryland. He had been drafted into the army and had been sent to fulfill his military obligation in the public-health service. He went to see Gordon Zubrod, then the clinical director for the NCI and later one of the major figures in cancer research. "I said, 'I'm a hematologist,'" Freireich recalls. "He said, 'I've got a good idea for you. Cure leukemia.' It was a military assignment." From that assignment came the first great breakthrough in the war against cancer.
Freireich's focus was on the commonest form of childhood leukemia—acute lymphoblastic leukemia (ALL). The diagnosis was a death sentence. "The children would come in bleeding," Freireich says. "They'd have infections. They would be in pain. Median survival was about eight weeks, and everyone was dead within the year." At the time three drugs were known to be useful against ALL. One was methotrexate, which, the pediatric pathologist Sidney Farber had shown seven years earlier, could push the disease into remission. Corticosteroids and 6-mercaptopurine (6-MP) had since proved useful. But even though methotrexate and 6-MP could kill a lot of cancer cells, they couldn't kill them all, and those that survived would regroup and adjust and multiply and return with a vengeance. "These remissions were all temporary—two or three months," Freireich, who now directs the adult-leukemia research program at the M. D. Anderson Cancer Center in Houston, says. "The authorities in hematology didn't even want to use them in children. They felt it just prolonged the agony, made them suffer, and gave them side effects. That was the landscape."
In those years the medical world had made great strides against tuberculosis, and treating TB ran into the same problem as treating cancer: if doctors went after it with one drug, the bacteria eventually developed resistance. Their solution was to use multiple drugs simultaneously that worked in very different ways. Freireich wondered about applying that model to leukemia. Methotrexate worked by disrupting folic-acid uptake, which was crucial in the division of cells; 6-MP shut down the synthesis of purine, which was also critical in cell division. Putting the two together would be like hitting the cancer with a left hook and a right hook. Working with a group that eventually included Tom Frei, of the NCI, and James Holland, of the Roswell Park Cancer Institute in Buffalo, Freireich started treating ALL patients with methotrexate and 6-MP in combination, each at two-thirds its regular dose to keep side effects in check. The remissions grew more frequent. Freireich then added the steroid prednisone, which worked by a mechanism different from that of either 6-MP or methotrexate; he could give it at full dose and not worry about the side effects getting out of control. Now he had a left hook, a right hook, and an uppercut.
"So things are looking good," Freireich went on. "But still everyone dies. The remissions are short. And then out of the blue came the gift from heaven"—another drug, derived from periwinkle, that had been discovered by Irving Johnson, a researcher at Eli Lilly. "In order to get two milligrams of drug, it took something like two train-car loads of periwinkle," Freireich said. "It was expensive. But Johnson was persistent." Lilly offered the new drug to Freireich. "Johnson had done work in mice, and he showed me the results. I said, 'Gee whiz, I've got ten kids on the ward dying. I'll give it to them tomorrow.' So I went to Zubrod. He said, 'I don't think it's a good idea.' But I said, 'These kids are dying. What's the difference?' He said, 'Okay, I'll let you do a few children.' The response rate was fifty-five percent. The kids jumped out of bed." The drug was called vincristine, and by itself it was no wonder drug. Like the others, it worked only for a while. But the good news was that it had a unique mechanism of action—it interfered with cell division by binding to what is called the spindle protein—and its side effects were different from those of the other drugs. "So I sat down at my desk one day and I thought, Gee, if I can give 6-MP and meth at two-thirds dose and prednisone at full dose and vincristine has different limiting toxicities, I bet I can give a full dose of that, too. So I devised a trial where we would give all four in combination." The trial was called VAMP. It was a left hook, a right hook, an uppercut, and a jab, and the hope was that if you hit leukemia with that barrage it would never get up off the canvas.
The first patient treated under the experimental regimen was a young girl. Freireich started her off with a dose that turned out to be too high, and she almost died. She was put on antibiotics and a respirator. Freireich saw her eight times a day, sitting at her bedside. She pulled through the chemo-induced crisis, only to die later of an infection. But Freireich was learning. He tinkered with his protocol and started again, with Patient No. 2. Her name was Janice. She was fifteen, and her recovery was nothing short of miraculous. So was the recovery of the next patient and the next and the next, until nearly every child was in remission, without need of antibiotics or transfusions. In 1965 Frei and Freireich published one of the most famous articles in the history of oncology, "Progress and Perspective in the Chemotherapy of Acute Leukemia," in Advances in Chemotherapy. Almost three decades later, a perfectly healthy Janice graced the cover of the journal Cancer Research.
What happened with ALL was a formative experience for an entire generation of cancer fighters. VAMP proved that medicine didn't need a magic bullet—a superdrug that could stop all cancer in its tracks. A drug that worked a little bit could be combined with another that worked a little bit and another that worked a little bit, and, as long as all three worked in different ways and had different side effects, the combination could turn out to be spectacular. To be valuable, a cancer drug didn't have to be especially effective on its own; it just had to be novel in the way it acted. And from the beginning, this was what caused so much excitement about elesclomol.
Safi Bahcall's partner in the founding of Synta was a cell biologist at Harvard Medical School named Lan Bo Chen. Chen, who is in his mid-sixties, was born in Taiwan. He is a mischievous man with short-cropped
straight black hair and various quirks—including a willingness to say whatever is on his mind, a skepticism about all things Japanese (the Japanese occupied Taiwan during the war, after all), and a keen interest in the marital prospects of his unattached coworkers. Bahcall, who is Jewish, describes him affectionately as "the best and worst parts of a Jewish father and the best and worst parts of a Jewish mother rolled into one." (Sample e-mail from Chen: "Safi is in Israel. Hope he finds wife.")
Drug hunters like Chen fall into one of two broad schools. The first school, that of "rational design," believes in starting with the disease and working backward—designing a customized solution based on the characteristics of the problem. Herceptin, one of the most important of the new generation of breast-cancer drugs, is a good example. It was based on genetic detective work showing that about a quarter of all breast cancers were caused by the overproduction of a protein called HER2. HER2 kept causing cells to divide and divide, and scientists set about designing a drug to turn HER2 off. The result is a drug that improved survival in 25 percent of patients with advanced breast cancer. (When Herceptin's Kaplan-Meier was shown at ASCO, there was stunned silence.) But working backward to a solution requires a precise understanding of the problem, and cancer remains so mysterious and complex that in most cases scientists don't have that precise understanding. Or they think they do, and then, after they turn off one mechanism, they discover that the tumor has other deadly tricks in reserve.
The other approach is to start with a drug candidate and then hunt for diseases that it might attack. This strategy, known as "mass screening," doesn't involve a theory. Instead, it involves a random search for matches between treatments and diseases. This was the school to which Chen belonged. In fact, he felt that the main problem with mass screening was that it wasn't mass enough. There were countless companies outside the drug business—from industrial research labs to photography giants like Kodak and Fujifilm—that had millions of chemicals sitting in their vaults. Yet most of these chemicals had never been tested to see if they had potential as drugs. Chen couldn't understand why. If the goal of drug discovery was novelty, shouldn't the hunt for new drugs go as far and wide as possible?