Four landmark studies of ultra-high-dose chemotherapy followed by bone-marrow transplants for women with advanced breast cancer aren't expected to provide compelling evidence that the treatments are more effective than conventional chemotherapy, according to people familiar with early drafts. But the studies are likely to spark a firestorm of controversy.
The aggressive chemotherapy-transplant treatment has become a kind of Holy Grail for women whose cancer has spread beyond the breast. Doctors, patients and insurers have been eagerly awaiting the studies' results, hoping they would help settle more than 10 years of debate over whether the treatment is worth the expense and risk to patients. Early findings are set to be made public April 15 -- a month earlier than originally planned, because of growing public pressure.Although the studies are considered the most definitive to date, they also are expected to meet with criticism that they are flawed, outdated or ambiguous.
"Believers (in the high-dose therapy) will figure out how to make the (results) positive," says John Durant, executive vice president of the American Society of Clinical Oncology. "Disbelievers will figure out how to make them negative. And the honest skeptics will want more data."
Among the flaws is timeliness, according to doctors familiar with the studies. Begun nearly a decade ago, some include drug-dosing strategies that have since been upgraded and transplant methods that were more dangerous than current techniques. Over the years, the studies began to use the newer methods, but some doctors believe the results will still skew negatively.
One large, federally funded trial -- sponsored by the National Cancer Institute and designed to provide statistical proof of a fairly large benefit -- is expected to show no clear-cut benefit at all for women with the most serious form of the disease, according to the people familiar with the study. The findings of another NCI-funded study are almost certain to be attacked because they are based on a drug regimen most doctors don't follow. That study and two others, from South Africa and Sweden, are expected to produce conflicting results.
None of the investigators in the two U.S. trials are publicly discussing details of their results. They and the authors of the two foreign studies are under orders from the clinical-oncology society to refrain from talking about the findings until they are released, partly because the preliminary results may change somewhat as the data are compiled and analyzed.
Some top cancer specialists are raising doubts about how useful the studies will be. Dr. Durant, who has described them as "antique," says the studies took far too long to complete. Over the past 10 years, thousands of women have undergone transplants outside the government trials, and doctors have made great advances in reducing the risks. Indeed, a decade ago, as many as 15 percent to 20 percent of women who got bone-marrow transplants died from the effects of the procedure; today, the death rate has dropped to about 1 percent to 5 percent, oncologists say.
Some cancer specialists who doubt the therapy's value say the studies' inconclusive results confirm suspicions that too many women are receiving the transplants outside of rigorous clinical trials, where the treatment's efficacy can be best evaluated against that of conventional cancer therapy.
Indeed, some cancer doctors say they have been refusing to provide the therapy unless patients agree to participate in randomized trials. Such tests, considered the gold standard of scientific proof, randomly divide patients into two groups to determine whether an experimental therapy is better than existing care.
"We feel the (therapy) should only be given in the context of research, not as proven care," says Robert Livingston, an oncologist at University of Washington School of Medicine, in Seattle. Some cancer centers, such as Memorial Sloan-Kettering, in New York, don't currently perform the treatment at all, and provided it only as part of one of the federal trials.
The ambiguous results may give insurers new ammunition in their fight to stop covering the costly procedure. Last year, more than 6,000 women had bone-marrow transplants, at a cost of $50,000 to $150,000 each. Facing lawsuits, lobbying by advocacy groups and legislative mandates, most insurance plans cover the treatment.
The prospect that many doctors and insurers will abandon bone-marrow transplants troubles cancer specialists who believe the treatment is effective for some patients. Richard Champlin, chairman of the blood-and-marrow transplantation department at University of Texas-MD Anderson Cancer Center in Houston, says that of an initial group of about 100 women with metastatic breast cancer who received bone-marrow transplants at the center more than a decade ago, 10 are still alive.
"We believe most of them would have died had they not received a transplant," Dr. Champlin says. Among women with such advanced breast cancer who receive conventional, lower-dose chemotherapy, even fewer survive for five years; many live only another one or two years, Dr. Champlin says.
Bone-marrow transplants were initially used to treat certain types of blood cancer, such as leukemia. They were first tried on patients with very advanced breast cancer in the mid-1980s as a way of delivering much-higher-than-normal doses of cancer-killing drugs. Superhigh doses, aimed at killing resistant cancer cells, can also kill a patient, by destroying the disease-fighting immune system. Doctors try to minimize the risk of death by first harvesting patients' bone marrow (or, as the procedure is done today, stem cells directly from the bloodstream) before giving them the drugs and then reinjecting the cells later.
Several early studies of the procedure had promising results, suggesting that as many as 20 percent of women with the most advanced form of breast cancer could survive for five years after getting a transplant. Other studies, of women whose cancer was less advanced, had even better results. But critics have charged that some of the positive results attributed to the transplant probably were a result of doctors' offering the procedure only to healthier patients, who had a better shot at survival anyway.
Indeed, a small, randomized study from the Netherlands published last year in the journal Lancet found that bone-marrow transplants offered no survival benefit to women whose cancer had spread to their lymph nodes, compared with those who received conventional chemotherapy. William Peters, president of the Barbara Ann Karmanos Cancer Institute in Detroit, who led one of the four unreleased studies, says his research will provide important new information but cautions, "No single study answers all the questions." Dr. Peters declined to discuss results of his trial in detail. The institute, in a statement on its Web site, says, "At least one of the studies shows that bone marrow transplant is effective in treating breast cancer."
Dr. Peters's study, which tests the therapy in 874 women whose cancer had spread to nearby lymph nodes, compared high-dose therapy with lower doses of the same drugs -- a regimen few doctors use as part of conventional treatment, preferring to use lower doses of different medicines.
Edward Stadtmauer, director of the bone-marrow transplant program at the University of Pennsylvania Medical Center and head of the other U.S. study, examined the therapy in 553 women with metastatic disease. Some people familiar with the study say it will show no significant benefit to bone-marrow transplants.
Dr. Jeffrey Abrams, coordinator of breast-cancer-treatment studies for the National Cancer Institute, says Dr. Stadtmauer's study wasn't big enough to provide a statistical conclusion for a small benefit from the transplant treatment; such a conclusion would have required a study involving many more patients. As bone-marrow transplants have become much safer over the years, even a very small benefit could be important to patients facing a grim prognosis on conventional therapy. Dr. Abrams says two additional federal, randomized trials of bone-marrow transplants for breast cancer are under way.