|A four-inch-long needle was the standard tool used to extract bone marrow from the hips of breast cancer patients— a bruising procedure. The marrow was then reinjected after high doses of chemotherapy had destroyed the patients' natural supply. |
The patient's name was Diane. She was a 28-year-old truck driver with advanced breast cancer, and her tumor was one of the largest that her doctors had seen. It bulged from the upper right quadrant of her right breast and penetrated deep into her ribs, attaching itself to her chest wall. "It was the size of a muskmelon," oncologist William Peters recalls. "It was a terrible circumstance."
Peters was as young as his patient, but he was rising through the ranks of his profession with the unswerving trajectory of a missile. He had been studying cancer since he was 14, when he took a job as a summer intern at Roswell Park Cancer Institute, in his hometown of Buffalo, New York. He had been a triple major at Pennsylvania State University in biochemistry, biophysics, and philosophy, and had both a medical degree and a Ph.D. in human genetics from Columbia University. Now, in 1981, as a faculty member at the world-renowned Dana-Farber Cancer Institute in Boston, he was about to administer what would become one of the most controversial treatments in all of medicine.
Peters began by outlining the experiment for Diane. He wanted to give her extremely high doses of several chemotherapy drugs— doses toxic enough, he believed, to kill her enormous tumor. Unfortunately, the drugs might also kill her. They would certainly wipe out her bone marrow, leaving her vulnerable to infection. To restore her defenses, Peters would extract some marrow from her hipbone before starting the procedure, then inject it back after the chemo treatments. If all went as planned, her marrow cells would find their way back into her bones and rebuild her immune system in a matter of weeks.
The treatment was the brainchild of Emil "Tom" Frei, director of Dana-Farber at the time and a towering figure in the field of cancer research. Like other physicians, Frei had been frustrated by limited success treating advanced breast cancer with chemotherapy. The tumors would respond— and sometimes even disappear— only to come creeping back once the treatment ended. Frei knew that a single dose high enough to kill every last cell might also kill the patient. But he thought that a combination of drugs might be tolerable. Each would have bad side effects— carmustine can harm the lungs; cisplatin can damage the kidneys; both drugs, along with a third, cyclophosphamide, can wipe out the bone marrow. But together they might spread the collateral damage around. "Intuitively, it made sense," says Craig Henderson, a former colleague of Frei and Peters's at Dana-Farber. "If a little chemo is good, more is better."
Combination chemotherapy with a bone marrow transplant, as the technique is called, had cured leukemias and lymphomas, but no one knew if it would work on breast cancer. "We knew the treatment was going to kill some people along the way, to be quite honest, but we knew the disease killed everybody," Peters says. So the possibility of a cure seemed worth the risk. "We were going to swing and go for the ring," he says. "That drove us. You had to believe you were going to pull off something that was going to change history."
Peters scheduled the operating room at the nearby Beth Israel Hospital for a Monday morning. Diane was put under general anesthesia, and Peters began the brutal procedure of plunging a needle through the flesh of her hip into the bone and drawing out aliquots of marrow. Part way through the procedure, the needle broke, leaving its tip embedded in the bone and the rest buried in the thigh muscle. Cursing, Peters frantically searched the operating room for pliers to grasp the hidden needle, but the hospital was not set up for bone marrow work, so there were no pliers to be found. A nurse was sent out of the operating room to fetch a pair.
That evening, Diane was wheeled back to Dana-Farber, where she received chemotherapy. "We were being watched like a hawk," Peters recalls. Other doctors at the hospital were dubious that a woman could withstand such punishing doses of drugs— roughly 10 times the standard dose— but Diane proved them wrong. The chemotherapy wiped out her bone marrow, yet she weathered the other side effects. Meanwhile, the effect on her monstrous tumor seemed nothing short of miraculous. "Within a week, this huge mass, this four- to five-inch mass, disappeared," Peters says. "I mean, you could literally come in every day and watch this thing melt away. Bingo."
Diane's tumor eventually returned, and she died several months later. But Peters and Frei went on to perform the transplant on 29 more women. Each responded well initially, and three made a full recovery. Over the next two decades, Peters would become the treatment's most tireless advocate, inspiring doctors around the country to try it on their breast cancer patients. Thousands of women would undergo its rigors before the efficacy of high-dose chemotherapy was fully tested, and the treatment would become a flash point for breast-cancer-patient advocates, insurance companies, and the National Cancer Institute. But that was all in the future. In 1981 the doctors at Dana-Farber were still reeling from the excitement of their initial results. "We really thought we were going to solve the cancer problem," Henderson recalls. "Tom Frei sat me down in his office and said, 'We've got a cure for cancer.'"
|The medical chart of a breast cancer patient is an extraordinarily detailed and painful document, listing page after page of treatment and response. When oncologists audited a clinical trial in South Africa and found only the skimpiest of charts, they began to suspect fraud. |
By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley, California, she had learned a thing or two about suing health insurers. Throughout the 1980s Philipson helped AIDS patients in the San Francisco Bay area get reimbursement for medical care and sue their insurers for discrimination and breach of confidentiality. Her specialty was a branch of law that few lawyers had mastered or wanted any part of. The Supreme Court had ruled that patients couldn't ask for punitive damages when suing their health insurers. "There was no pot of gold," Philipson says, "and most people don't have the money to pay you."
Ricki, her client with breast cancer, was a 48-year-old psychologist with a child still in high school. She had been diagnosed three years earlier, in 1988, and had undergone chemotherapy and a mastectomy. Now the cancer was back, and high-dose chemotherapy seemed her only hope. But her insurer, an affiliate of Health Net, one of the largest HMOs in southern California, refused to pay for it.
The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $125,000 and could easily hit $500,000. Drugs alone ran into the tens of thousands of dollars. The patients spent weeks in isolation rooms, shielded from infections and racking up charges as they waited for their bone marrow to take hold and begin churning out new blood cells. Publicly, insurers argued that the treatment was unproven and experimental. Privately, many doctors believe, insurers worried that if they agreed to pay for one experimental procedure, patients would soon be demanding others.
Philipson agreed to represent Ricki but only if she could find evidence that high-dose chemotherapy was an established therapy. Within a week Ricki came back with a stack of scientific articles, including some by William Peters. By then Peters had become something of an evangelist for high-dose chemo, crisscrossing the country to extol the procedure so often that one colleague nicknamed him Elmer Gantry. At scientific gatherings he paced to and fro across the stage, carrying a microphone in one hand and gesturing toward charts and graphs with the other. He appeared on TV shows, including Nightline
and was quoted in dozens of newspaper articles. "This could save more lives than any form of chemotherapy," he told the New Orleans Times-Picayune
Sifting through the scientific papers, Philipson began to believe she had a case. "The way they portrayed it, bone marrow transplant was the best thing since sliced bread," Philipson says. "They were saying this is a cure." At the same time, she learned that high-dose chemotherapy came at a terrible cost. Besides the marrow-extraction process, patients had to endure drugs that destroyed the intestinal lining from mouth to anus, making both swallowing and defecating unbearably painful. Waves of nausea and vomiting alternated with uncontrollable bouts of diarrhea and terrible loneliness. Though they were put in isolation rooms for weeks on end, many picked up infections anyway. One in five women died directly from the treatment. Those who did survive could be left with permanent damage to the heart, kidneys, lungs, liver, and nerves.
Still, the alternative seemed even worse. As late as 1989, women with stage III breast cancer— tumors larger than two inches across and cancer cells that had spread to the lymph nodes— had a 50 to 70 percent chance of relapsing after standard chemotherapy. Those, like Ricki, who progressed to stage IV— when the cancer invades other organs— were almost certain to die. Given the odds, many patients weren't just willing to try a transplant, they were desperate for it.
Philipson's job was to prove that Ricki's insurer was obliged contractually to pay for the procedure. She bombarded the company with scientific papers and statements from breast cancer specialists who claimed that transplants were an accepted medical practice. She sent letters demanding proof that the company had properly reviewed Ricki's case. Ricki, meanwhile, paid to have her bone marrow harvested. "We were working against the clock," Philipson says. "If her tumors got too big, she couldn't have the treatment."
In the end the insurer agreed to pay, prompting more women to come to Philipson with the same problem. She won three more cases over the next two years. Then, in 1993, she assisted in a trial that threw open the legal floodgates. That year, a lawyer named Mark Hiepler sued Health Net on behalf of his sister, Nelene Fox, who had died of breast cancer while trying to persuade the company to cover a transplant. A loophole in the law allowed Hiepler to sue for damages. Health Net decided to fight.
Philipson told Hiepler to comb through the company's records for evidence that their decision was capricious. They soon discovered that the Health Net physician who denied Fox coverage had been promised a bonus at the end of the year if the insurer kept down costs. "It sounded terrible," Philipson recalls. "The defense attorney says: 'It's no different from John Deere or any other American company.' The jury comes back and says, 'The hell it isn't different. John Deere makes tractors, and you decide on people's lives.'" The jury awarded the Fox family $89 million in damages, a record judgment against an insurer. Health Net appealed and then settled out of court for an undisclosed sum.
Within a year of the Health Net judgment, women were filing suit against insurers in record numbers. The strategy was always the same. The plaintiffs argued that high-dose chemotherapy was accepted practice, and transplant doctors backed them up on the witness stand. The most persuasive evidence came from a study that Peters himself had published in 1993. In it he compared the results of his high-dose cases with those of patients who had received standard doses of chemotherapy elsewhere. Approximately 70 percent of Peters's patients were cancer-free 48 months after treatment; among women who had received standard treatment, only 35 percent were cancer-free. "That paper drove the field," Craig Henderson says. "Every transplanter, every cancer doctor, had a copy."
By then Peters had left Dana-Farber to build a transplant program at Duke University Medical Center. As more and more doctors began trying their hand at transplants, hopeful stories began to appear in the media. In nearly every case, the dying patient was cast as a victim of both her breast cancer and her greedy insurance company. Women were in a "desperate struggle to buy more time," as the Dayton Daily News
put it. Soon advocacy groups like the Susan G. Komen Foundation, which sponsors the annual Race for the Cure, took up the cause. With the help of doctors like Peters, groups lobbied state and federal legislatures to mandate coverage.
In 1993 Peters spoke to members of Congress at a luncheon. Paul Goldberg, editor of The Cancer Letter,
later described the scene: "Peters said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' " Then he asked the 70 or so breast cancer patients he had brought to the lunch to stand up. Turning back to his audience, Peters announced that at least half of the women would be dead had they not undergone his lifesaving treatment. "'As you look at a woman across the table from you,' he said, 'ask yourself: Is the price of this woman's life worth the price of a luxury car?'"
|A bone marrow biopsy is no longer than a match, yet it symbolized survival to breast cancer patients. "They came to us in great shape" says one transplanter. "These were young women with kids, and they were desperate."|
The real question was not the worth of a woman's life but whether or not high-dose chemotherapy was saving lives. But the answer no longer seemed to matter once the insurance money began to flow. In the mid-1980s, fewer than 100 bone marrow transplants a year were performed on breast cancer patients. By 1994 the number had jumped to around 4,000. The treatment was a rare source of profit for hospitals in the 1990s, when they were being squeezed financially by HMOs.
Then the business got better. New drugs, called growth factors, came on the market in 1991, making transplants a little less risky and shortening a woman's stay in the isolation ward. They stimulated the growth of bone marrow to the point at which marrow stem cells could be harvested from the blood rather than extracted from the hip. Better yet, they helped the marrow regrow once the cells were returned to the woman's body. By 1995 less than 10 percent of patients were dying outright from the treatment, and a typical transplant, billed at $80,000 to $100,000, cost a hospital less than $60,000. Under Peters, Duke University Hospital's breast cancer transplant program took in as much as $14 million a year in revenue. It wasn't long before hospitals large and small were converting entire wards into transplant units. Many turned to Response Oncology, a company based in Memphis, Tennessee, that franchised bone marrow transplants. Company trainers would arrive at a hospital and, in two days, teach nurses and oncologists how to do the procedure. The company also helped hospitals build transplant wings and handle their insurance claims.
As procedures became more sophisticated, Henderson says, "Transplanters became gods at hospitals." They took a patient to the brink of death and then snatched her back at the last moment. Some began treating ovarian cancer with high-dose chemotherapy, too, although there was no evidence that it improved a patient's odds. Others subjected women with smaller, less-advanced breast tumors to high-dose chemo. Even Peters told colleagues that he was going to begin transplanting in patients with advanced prostate cancer. The doctors were silent until one pointed out that advanced prostate cancer rarely responds to chemotherapy, no matter how high the dose.
By then Philipson had taken a hard look at her clients' longevity. First, Ricki died in 1993, after winning her lawsuit, surviving the transplant, and keeping her cancer at bay for nearly two years. Then another former client died, and another. Philipson had helped five women receive bone marrow transplants over the years, and she was familiar with a dozen more. Every single one of them was dead.
Philipson wasn't the only one to notice a problem. Craig Henderson had long insisted that more testing was necessary. He knew that Peters's seminal 1993 paper, which compared high-dose chemotherapy with standard treatment, wasn't proof that the new treatment saved more lives. Peters's subjects were carefully selected to withstand the treatment. Because they were healthier than most breast cancer patients to begin with, they might have done just as well on conventional therapy.
But most doctors had little training in statistics or the design of clinical trials. They took Peters's paper as proof that his treatment worked. When Henderson warned them against accepting it as an article of faith, they mostly ignored him.
Ironically, one of the few to recognize the need for more testing was Peters. He knew that only a controlled, randomized clinical trial could provide definitive proof that the treatment worked. He persuaded the National Cancer Institute to fund a lengthy trial that would eventually involve more than 1,000 women. Patients would be eligible if their breast cancer had not yet metastasized but was likely to recur after surgery. Each woman would be assigned randomly to one of two treatments: Half would receive a moderately high dose of chemotherapy and no more. The other half would get an additional, even higher dose of chemotherapy and then a stem-cell transplant.
The trouble was, by the time Peters had organized his trial, few women wanted to participate. Joining the trial meant running the risk of not getting high-dose chemo, and many had read newspaper accounts that convinced them that the treatment was their only chance for survival. Their doctors often agreed. At the University of California at San Francisco, where Henderson would become head of oncology, one transplanter pulled out a copy of Peters's 1993 paper. "I don't see how with these data it's even ethical to do a randomized trial," he said.
The randomized trial ended up taking nearly a decade to complete— twice as long as it should have. In 1999, when the results were presented at the annual meeting of the American Society of Clinical Oncology, along with those from four other, smaller clinical trials, they were inconclusive at best. Three found no significant benefit in high-dose chemotherapy and transplant over conventional treatment. Peters's trial showed that women who received a transplant were a little more likely to stay free of cancer than women who received conventional therapy. But any survival advantage was wiped out by the fact that they were also more likely to die from the treatment.
"It's too early to draw conclusions," Peters told colleagues and reporters. The data were preliminary, he pointed out, and the fifth trial, by the South African oncologist Werner Bezwoda, had proved very encouraging. Bezwoda's experiment was small— only 154 patients— but the results were spectacular: Of 75 women who received high-dose chemo and a transplant, only 19 relapsed and eight died. Of 79 women who received conventional treatment, 52 suffered relapses and 28 died.
Perhaps doctors should keep transplanting after all.
At least one member of the audience was skeptical. Raymond Weiss, an oncologist in Washington, D.C., had been to South Africa on vacation earlier that year and had met some of Bezwoda's colleagues. What he heard was troubling. "We don't think he has follow-up on his patients," they said. "A lot of them go back to rural areas and die, and nobody knows it."
Soon after Bezwoda's results were announced at the meeting, Weiss and fellow oncologist Roy Beberidge helped organize an audit of the South African's research. At first, Bezwoda agreed to cooperate, provided only four people came and only for two days. The audit was set for January 2000, but as the date approached, Bezwoda changed his mind. Then he relented, and Weiss's team flew to Johannesburg.
Bezwoda now said that only 151 patients had participated in the trial, not 154, yet he had charts for only 62. The other 89 charts were in a room jumbled together with those of thousands of other patients, the team was told. The records on hand contained only sketchy information: Stacked one on top of the other, all 62 of them were only seven inches tall. "I got out a ruler and measured it," Weiss says. "That's about the thickness of the chart of one U.S. transplant patient."
In the morning the Americans sat down and read through the charts— twice. Many of the records bore unsigned, handwritten entries— a breach of standards in a clinical trial. There was no evidence that Bezwoda had randomly assigned patients to receive either high-dose or standard chemotherapy. In fact, there were no records showing that any patients had received the standard treatment.
Weiss and the other Americans were stunned. When they confronted Bezwoda the next day, he denied any wrongdoing. Uncertain what to do next, the Americans returned home. But three days later he sent a letter to his department at the university, admitting he had a committed a "serious breach of scientific honesty and integrity." The results of the study, he wrote, had been "a misrepresentation." The letter was forwarded to the American Society of Clinical Oncology, which sent out an advisory to members and a press release announcing the fraud. Bezwoda now claims that his work wasn't fraudulent after all. But after Weiss led an audit of another Bezwoda trial, the society issued a statement declaring that the South African's results "should not be used as the basis for the treatment of any patient."
The warning came too late for four women in Seattle. In 1998 two researchers at the University of Washington had begun a trial to test Bezwoda's special high-dose regimen for women with metastatic breast cancer. They had copied Bezwoda's published formula faithfully, administering it to six patients, all under the age of 50. Two of the four died of congestive heart failure a few months after their treatment. One patient lived with acute cardiac damage until she succumbed to breast cancer. The fourth patient is still alive; she has heart problems brought on by the chemotherapy. The researchers stopped the study.
|Marrow is reinjected after chemotherapy and finds its way back to the bones. "Transplants represent the triumph of hope over experience," says Fran Visco, president of the National Breast Cancer Coalition. "We should have known whether this works years ago."|
Most oncologists now agree that high-dose chemotherapy is simply the wrong treatment for breast cancer. Chemotherapy works by killing cells when they're dividing, so the faster cancer cells divide, the harder they're hit. Blood cancers— some leukemias and lymphomas— grow rapidly and so are acutely vulnerable. But breast cancer cells reproduce more slowly and tend to be far more resistant to cancer drugs. No matter how many breast cancer cells are killed, at least a few survive, and they keep dividing after the chemotherapy ends.
The slow pace of most breast cancers also helps explain why transplanters were so optimistic. Breast tumors can take years to reappear after treatment, but the transplanters were used to leukemia, which tends to come roaring back in a matter of months. If they found no evidence of breast cancer after a year and a half— the usual waiting period for blood cancers— they assumed a patient was cured, or at least in long-term remission. Yet the cancer was often lurking in the background, gathering its forces for another, more devastating appearance.
From the moment Peters first administered high-dose chemotherapy until the first clinical trials were concluded, nearly 20 years passed. During that time, hundreds of physicians practiced the unproven treatment. An estimated 30,000 breast cancer patients suffered through high-dose chemotherapy, only a fraction of them as part of a clinical trial. All told, the nation spent around $3 billion paying for it, while an estimated 4,000 to 9,000 women died not from their cancer but from the treatment.
"Nobody got cured," Philipson says of her clients. "I put them through litigation when they were dying. Then if I won, they got to have a bone marrow transplant. You can't raise your head, you are so sick, and it's so horrible and so hard, and you don't have time to say good-bye to the people you love. I had to decide for myself whether I was going to take these cases anymore, and I decided not to. It was a cure that didn't work."
William Peters rarely visits the oncology ward anymore. Now in his early fifties, he recently stepped down as CEO of the Barbara Ann Karmanos Cancer Institute in Detroit to become an administrator and staff oncologist. But he still has his sunny corner office in a brand new building. "I designed the interiors myself," he says, gesturing at the bright, abstract pattern of the carpet. Short and dapper, with small, soft hands, a quick wit, and a manner that veers between Marcus Welby and a salesman, Peters can fill a room with energy. When asked if he deserves some of the blame for how events turned out, he seems genuinely baffled. "My interest was to get patients on the randomized trials," he says. Besides, he adds, "transplants may still work."
Pulling a fountain pen from his shirt pocket, Peters flips over a scientific paper and quickly sketches out a series of graphs. One axis represents time, the other the number of women surviving cancer. He has reanalyzed the results of his clinical trial, he says, and found what seem to be positive results for women under 50. "It's incredible data," he says. "I still believe [transplanting] is of great value. It is a stepping-stone to finding cures for people who have not been cured before."
One gets the sense that Peters has delivered a version of this polished and heartfelt speech before— perhaps to donors, reporters, and prospective patients. There are several die-hard transplanters around the country who still believe, as Peters does, and who are still giving transplants to breast cancer patients. But most of their colleagues are no longer swayed by the transplanters' arguments. Jeffrey Abrams, an oncologist and senior investigator at the National Cancer Institute, says Peters's new interpretation "doesn't prove anything." High doses of chemotherapy put young women into early menopause, and that alone reduces the chances that their breast cancer will return. There are ways to trigger early menopause without nearly killing the patient.
High-dose chemotherapy arrived at a pivotal moment in the history of breast cancer, when breast-cancer-patient advocates had recently learned to flex their political muscle. Yet 20th-century American medicine often values innovation at the expense of caution, and its history is littered with other poorly proven treatments— from frontal lobotomy to radical mastectomy. "The system should have insisted on sound medical evidence before it became a widespread therapy," Abrams says. "We should have relied on the science and proved to ourselves that this really was a better way to treat women. It is more toxic [than standard therapy]; it is more expensive. If it's only going to be as good as standard therapy, then it's not an advance. The system failed."
These days, with earlier diagnosis and new drugs such as tamoxifen, the hopelessness that breast cancer brought in the 1970s and 1980s seems a distant memory. But patients and doctors are still swayed by the ancient medical dictum that says desperate diseases may require desperate cures. Patients with no other hope will always be willing to try a miracle cure— no matter how barbaric the costs and uncertain the odds. "A lot of it had to do with psychology," says Marilyn McGregor, a breast cancer survivor and activist in San Francisco. "Women, especially younger women with children, will do anything to save their lives, so they did not hear the statistics. Or they made their bargains with God that they would go through this treatment if only they could be allowed to live. They just wanted to believe." —Additional reporting by Sheila Kaplan
For more about William Peters and the Karmanos Cancer Institute, see www.karmanos.org
To learn about breast cancer treatment policies and options, see the National Cancer Institute's Breast Cancer Web site (www.cancer.gov/cancer_information/cancer_type/breast
) or visit the National Breast Cancer Coalition advocacy group's home page (www.natlbcc.org/bin/index.htm