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Transplants for Breast Cancer: New Data Results from five large clinical trials that tested the effectiveness of high dose chemotherapy and stem cell transplant (HDC/SCT) to treat breast cancer were released April 15th by the American Society of Clinical Oncology (ASCO) and the National Cancer Institute (NCI). The studies, which involved more than 1,700 women treated for breast cancer between 1990 and 1997, compared HDC/SCT to standard chemotherapy, or to standard chemotherapy with various enhancements. Patients with High Risk Breast Cancer Three of the studies, which took place in the US, Scandinavia and South Africa, enrolled women with primary breast cancer who had a high risk of recurrence, but whose disease had not spread beyond the breast and axillary lymph nodes (under the arm).
The US study involved 783 women, the Scandinavian trial enrolled 525 women, and the South African trial included 154 women. In all three studies, women were randomly assigned to receive HDC/SCT or lower dose chemotherapy. The US and Scandinavian studies found no survival difference between the HDC/SCT and lower-dose groups. However, the US study found fewer recurrences of breast cancer among patients treated with HDC/SCT. These results are preliminary and may change with longer patient follow-up, caution officials at the National Cancer Institute. The progress of patients who participated in the US trial has only been followed a median of 37 months.1 Women who participated in the Scandinavian trial have been followed a median of 20.2 months. Survival and recurrence rates for women who participated in the US study will be reviewed again in 2001, says Bill Peters MD, who headed the study. A third study from South Africa reported a significant survival advantage for patients treated with HDC/SCT. After more than five years of follow-up, investigators reported significantly fewer deaths in the transplant group (17 percent) than in the standard therapy group (35 percent). The study also found that 25 percent of women in the transplant group had a recurrence of the disease, as compared to 66 percent of the women treated with standard chemotherapy.
The South African study differed from the US and Scandinavian studies in several respects. Patients in the transplant group were given a novel combination of chemotherapy that is not widely used in the US—high dose Cytoxan, Mitroxantrone and VP-16. Patients in the South African trial did not receive a preliminary round of lower-dose chemotherapy before undergoing HDC/SCT, as did the women on the US and Scandinavian trials. “The chemotherapy agents used in this trial… and the particular approach employed by the South Africans may be responsible for the positive results,” said Richard Klausner MD, director of the National Cancer Institute. It should be noted that NONE of these studies found standard CAF chemotherapy (Cytoxan, Adriamycin and 5-FU) equivalent or superior to more intensive treatments, said Bill Peters MD during a teleconference with patient advocates, sponsored by the Susan G. Komen Breast Cancer Foundation. The only study that directly compared standard CAF therapy to HDC/SCT (the South African study) found the high-dose treatment to be superior, he said. The US and Scandinavian trials compared HDC/SCT to more intensive regimens of chemotherapy than CAF. Complete data about toxic side effects associated with the various treatments are not yet available. However, the US trial reported 29 treatment-related deaths in the HDC/SCT group and none in the other group. The Scandinavian study had two treatment-related deaths in the transplant group, and eight treatment-related cases of acute myelogenous leukemia/myelodysplasia in the non-transplant group. Others have also reported secondary cancers arising from the same combination of lower-dose chemotherapy used in the Scandinavian trial, says the National Cancer Institute. Metastatic Breast Cancer Two other studies compared HDC/SCT to several rounds of lower dose chemotherapy for women with metastatic breast cancer. Metastatic breast cancer is advanced breast cancer that has spread beyond the breast and neighboring lymph nodes. One study, conducted in the US, randomized 199 women who responded to an initial round of chemotherapy to receive either HDC/SCT or lower dose “maintenance” chemotherapy. The study found no difference in survival between the two groups. There was one treatment-related death among patients treated with HDC/SCT and none among patients treated with conventional dose chemotherapy. The second study from France involved 61 women with metastatic breast cancer who responded to an initial round of chemotherapy. After five years of follow-up, there was no statistically significant difference in survival or disease recurrence between the two groups. However, those in the transplant group relapsed later than those treated with conventional chemotherapy, suggesting a better quality of life (no treatment for a longer period of time) with transplant versus conventional chemotherapy. The data from the French study must be viewed with caution, however, says the National Cancer Institute, due to the smaller number of patients studied. “Although the results of these two studies do not demonstrate a significant improvement in survival with HDC/SCT versus standard dose therapy, an earlier randomized South African study published in 1995 showed a convincing difference,” says Stephanie Williams MD, a transplant physician involved in HDC/SCT research. A fourth randomized study from the Netherlands found no survival advantage for patients treated with HDC/SCT after an additional round of chemotherapy. Both this and the South African study should be considered when interpreting results of trials comparing HDC/SCT to more conventional chemotherapy, says the National Cancer Institute. Interpreting the Data “Given the preliminary nature of the data, the conflicting 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,” said the American Society of Clinical Oncologists in a statement that accompanied release of the trial results. The investigators who headed the US, Scandinavian and South African studies will present their data at the ASCO annual meeting in May. The session will be available live on ASCO’s website (http://www.asco.org). “We expect that there will be lively debate and even disagreement among physicians about the implication of these findings” says Robert Wittes MD, director of NCI’s Division of Cancer Treatment and Diagnosis. “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. Others will be more impressed with the limitations of the present trials and will be eager to continue studying different high-dose combinations.” “For example, these studies represent treatment programs that were designed 5-10 years ago,” says Stephanie Williams MD. “None of the chemotherapeutic regimens contained newer more active agents for breast cancer such as the taxanes (taxol and taxotere). Further Investigation Additional studies of HDC/SCT for breast cancer are underway. “Several active clinical trials are investigating whether purging tumor cells from the stem cell product will reduce the incidence of relapse after transplant,” says Stephanie Williams MD. “Others will look at ways to manipulate the patient’s immune system after transplant to produce an anti-tumor effect to eradicate remaining disease.” It’s important that patients participate in clinical trials studying HDC/SCT says Richard Klausner MD of the NCI. “The five trials [reported April 15th] took nine years to yield these preliminary data because it took so long to enroll the required number of patients. Greater participation by physicians and patients in clinical trials would speed answers, not only to crucial questions concerning high-dose chemotherapy with transplants, but other cancer treatments as well.” An estimated 12,000 women in the US have been treated with HDC/SCT during the 1990s. Fewer than 1,000 were enrolled in clinical trials. |
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