Five breast cancer trials show discouraging results

An aggressive therapy, which oncologists hoped would be effective in treating high-risk primary breast cancer and metastatic breast cancer, failed to outperform treatment with standard, lower-dose therapies in four out of five large-scale, randomized, controlled clinical trials conducted around the world.

Researchers in the United States, France, Sweden and South Africa compared the clinical outcomes of treating breast cancer patients with high-dose chemotherapy and bone marrow transplants or peripheral blood stem cell support versus treating them with lower-dose chemotherapy without transplants. Of the five trials, only the South African trial indicated a significant outcome in favor of the high-dose chemotherapy with bone marrow transplant or peripheral blood stem cell support therapy.

"The hypothesis going into these trials, our hope, was that the more aggressive approach would prove clearly superior to standard therapy," said Richard Klausner, M.D., director of the National Cancer Institute, which sponsored the two trials held in the United States. "But based upon these studies, high-dose therapy has not yet been shown to be superior to lower-dose treatment."

Results of the studies, which were significant because they reflected the first large-scale scientific trials to study the effects of high-dose chemotherapy, were released by the American Society of Clinical Oncologists in mid-April.

Treatment background

High-dose chemotherapy is chemotherapy that is administered in doses five to 30 times greater than standard dose.

Because the dosage of chemotherapy is so high, it destroys bone marrow, and patients must receive bone marrow transplants or peripheral blood stem cell support to avoid dying from the treatment.

Previous studies have proven that high-dose chemotherapy is highly effective in overcoming drug resistance and eradicating certain cancers such as leukemia and lymphomas. Results of the five recent breast cancer treatment trials do not contradict that evidence. However, oncologists have been administering the therapy to very high-risk breast cancer patients based on the evidence of its efficacy in the other patient groups as well as on small-scale feasibility studies.

Since the therapy became technologically feasible in the mid-1980s, more than 12,000 women with breast cancer in the United States have undergone bone marrow transplantation, according to the American Society of Clinical Oncologists. The women were provided the therapy - and their insurers often paid for it - in spite of the lack of clinical evidence to justify it.

These most recent study results, however, raise the question of whether or not the therapy is worth the expense or the risk - a question researchers quickly addressed.

Is the therapy worth it?

"Some may consider the matter settled, at least for these particular patient groups, and will no longer consider high-dose chemotherapy with transplants worthy of further testing," said Robert Wittes, M.D., the director of the National Cancer Institute's Division of Cancer Treatment and Diagnosis. "Others will be more impressed with the limitations of the present trials and will be eager to continue studying different high-dose combinations."

The National Cancer Institute indicated that it favors conducting more phase III studies of the high-dose chemotherapy in breast cancer treatment, especially in patient groups that were not included in the five studies.

Susan Braun, president of the Susan B. Komen Breast Cancer Foundation, an organization that has been influential in raising funds and public awareness for breast cancer research, responded to the report: "The results of these studies in no way suggest that this matter is settled. The length of follow-up on these studies is still relatively short, and additional data analyses need to be completed."

The Komen Foundation, she added, will continue to encourage breast cancer patients who are considering high-dose chemotherapy to consult with their oncologists and "seek an unbiased second opinion when warranted."

Braun also responded to the suggestion that health care insurers might refuse to cover the treatment as a result of the four negative study findings: "It would be irresponsible for any insurance carrier to change its policies based on these studies. In fact, these studies should encourage insurance carriers to support ongoing clinical trials in order to obtain more definitive data on the effectiveness of this and other treatments, as well as to ensure standard-of-care coverage."

The American Society of Clinical Oncologists took a cautious stance in its reactions to the studies, releasing the following statement: "Given the preliminary nature of the data, the conflicting initial results and the specific differences in the study designs, it is not yet possible to draw definitive conclusions about the role of high-dose chemotherapy in breast cancer."

Of particular interest is why the South African researchers found such different results. In a study of 153 patients with breast cancer that had spread to 10 or more auxilliary lymph nodes, researchers saw increased survival rates and lower relapse rates in the 75 women in the high-dose group than in the 79 women in the standard-dose group. After more than five years of follow-up, the researchers reported that 66% of women in the standard-dose group had relapsed but only 25% of women in the high-dose group did the same; meanwhile, 35% of the standard-dose group died, compared with only 17% of patients in the high-dose group.

"The chemotherapy agents used in this trial were different from those in the other trials, and the particular approach employed by the South Africans may be responsible for the positive results," said Klausner, the director of the National Cancer Institute. The South African researchers used cyclophosphamide, mitoxantrone and VP16.

The reports from the other trials, one of which studied 783 patients, showed nearly equivalent results in mortality and relapse for the two treatment groups. More information about the studies is posted on the American Society of Clinical Oncologist's Web site, www.asco.org and on the National Cancer Institute's Web site, www.nci.nih.gov. PR