Treating Breast Cancer Patients with a Stem Cell Transplant: What Now?

Since May, 1999 when several researchers reported no statistically significant survival benefit for women who underwent a stem cell transplant to cure their breast cancer, the news has been full of stories questioning the role of high-dose chemotherapy and stem cell transplant (HDC/SCT) in the treatment of breast cancer. Interest among patients in pursuing this treatment has declined, and enrollment in breast cancer clinical trials testing the effectiveness of HDC/SCT has dropped markedly.

Do these reports, however, prove that HDC/SCT does not benefit patients with breast cancer? No, says Karen Antman MD, Cancer Center Director at Columbia University in New York, who believes that some of the media have not properly explained the status of the research. At a March, 2000 meeting of the American Society of Blood & Marrow Transplantation, Dr. Antman summarized the results of the 10 breast cancer studies published thus far, and clarified what can currently be concluded from them.

Sorting Through the Data

Drawing meaningful conclusions from the 10 studies published thus far is complicated by a number of factors, said Antman.

The first problem is the size or the “power” of the studies. Only three of the 10 studies randomized 200 or more women to receive HDC/SCT versus another treatment. “Studies that randomize small numbers of patients are not powerful enough to detect a significant difference in outcomes, even if one exists,” said Antman.

The second problem is that patient follow-up on the studies has been relatively short. Often, differences in survival do not become big enough to be statistically significant until eight or ten years after treatment, said Antman. “We need to wait for the data to mature before drawing definitive conclusions.”

A third problem is how high-dose chemotherapy is defined. Some studies that have been described by the media as a comparison of high-dose chemotherapy to low-dose chemotherapy actually compared two groups of patients that both received much higher than standard dosages of chemotherapy, she said.

The Metastatic Studies

Four of the studies looked at the use of HDC/SCT to treat women with metastatic breast cancer—cancer that has spread to the lymph nodes, liver, lungs, bone marrow or brain. The largest, the Philadelphia study, was first presented at a meeting of the American Society of Clinical Oncology (ASCO) in May, 1999 and published in final form this Spring. Of 553 patients enrolled in the study, 199 were randomized to receive either HDC/SCT, or up to 24 months of conventional-dose chemotherapy. The study found no survival advantage for either group.

The fact that more than half the women enrolled in this study were not randomized is troubling, said Antman. Although some patients did not respond to chemotherapy and were not eligible for randomization, about 100 patients dropped out of the study after their initial round of chemotherapy. “When such a high proportion of study candidates refuse randomization, it can bias the results,” Antman said.

“It’s also important to note that women on the ‘low-dose’ chemotherapy arm of this study actually got more chemotherapy than those on the ‘high-dose’ chemotherapy arm of the study,” said Antman. “Women on the low-dosage arm received up to 24 months of chemotherapy, and most got more than twice as much chemotherapy over time as the women on the high-dosage arm. “Given that outcomes were equivalent for both groups, some women may prefer to get one round of high-dose chemotherapy rather than monthly doses of chemotherapy for as long as 24 months.”

The second largest study for which results are available is the Duke study. In this trial, 98 patients who were in complete remission following conventional-dose chemotherapy were randomized to receive either HDC/SCT or no further therapy. Disease-free survival was significantly higher for patients treated with HDC/SCT.

Patients who did not initially receive HDC/SCT, but later relapsed, were then offered HDC/SCT. When measuring survival, they fared slightly better than those who underwent immediate HDC/SCT.

The third largest study is a South African trial that found a significant survival advantage for patients who underwent HDC/SCT. However, one of the study’s authors, Werner Bezwoda, was found to have misrepresented data on a different HDC/SCT study. The metastatic breast cancer study is currently being audited to see if it has the same deficiencies as the discredited study.

The smallest trial was a French study that randomized 61 patients to receive either HDC/SCT, or ongoing conventional-dose chemotherapy. The median survival time for patients who received conventional-dose chemotherapy was 18 months, while those who received HDC/SCT survived more than twice as long—a median of 42 months. “While not statistically significant, because of the small number of patients enrolled, this is certainly medically significant,” said Antman.

Adjuvant Studies

The remaining six studies explored the use of HDC/SCT to treat patients with high risk stage II or stage III breast cancer—cancer that was highly likely to progress.

The largest, a Dutch study, randomized 885 patients with four or more involved lymph nodes to receive either five cycles of standard-dose chemotherapy, or four cycles of standard-dose chemotherapy followed by HDC/SCT. At the May, 2000 ASCO meeting, the study authors reported results for the first 200 women enrolled in the study who were followed a median of seven years.

The women who were randomized to the receive HDC/SCT fared significantly better both in terms of disease-free survival (77 percent for the high-dose group vs. 62 percent for the low-dose group) and overall survival (89 percent vs. 79 percent). There is currently a trend favoring HDC/SCT for the entire study of 885 patients, but it is too early to tell whether the trend will be confirmed in the final analysis, said Antman.

The second largest study, the American Intergroup study, randomized 785 patients to receive HDC/SCT, or intermediate-dose chemotherapy and no transplant. The study was designed to detect a 14 percent difference in survival between the two groups of patients at a median follow-up of five years. The five-year follow-up point has not yet been reached, and there is no difference in survival at this time.

There was a higher rate of early deaths due to treatment-related complications on the transplant arm, but there has been a lower relapse rate on the transplant arm as well. There is a trend favoring the transplant arm for disease-free survival, said Antman. “It’s too early to draw any conclusions about this trial, but if current trends continue, there will ultimately be a significant difference that favors the transplant arm.”

The third largest study, a Scandinavian trial, randomized 525 patients to receive either three cycles of conventional-dose chemotherapy, followed by a transplant, or nine cycles of increasing dosages of chemotherapy with injections of growth factors to help blood cells grow. “This study compared two different high-dose chemotherapy regimens, not high-dose chemotherapy versus standard-dose chemotherapy,” said Antman.

Follow-up of patients on this study has been short—about two years—and thus far no differences in survival or relapse rates have been observed between the two groups. “One major problem is a high incidence of acute myeloid leukemia and myelodysplasia among patients who were not on the transplant arm of the study,” said Antman.

The fourth study is the South African study, which has recently been discredited. Two other studies—a Dutch study and one at MD Anderson Cancer Center—which involved fewer than 100 patients each have shown no statistically significant differences between patients treated with conventional-dose chemotherapy and those treated with HDC/SCT. “These two studies are each too small to reliably detect even a 30 percent difference between the conventional and high-dose groups, let alone smaller differences,” Antman said.

Too Soon to Tell

The fact that results from many of these studies are not yet ready for final analysis has not stopped the media from a rush to judgment, said Antman. “The public deserves a more careful analysis of this data. It takes time for the data to mature to the point where you can draw meaningful conclusions.”

“The good news is that results from at least five more studies will be available in the next two to four years,” noted Antman. “These were moderately-sized studies that randomized between 300 and nearly 900 patients. Once the data from these studies mature, we will finally be able to begin drawing some reliable conclusions about the role of high-dose chemotherapy and stem cell transplant in the treatment of breast cancer.”

A Closer Look at the 10 Studies