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Back To Vidyya Will High-Dose Chemotherapy For Breast Cancer Continue?


Trial Fraud Exposed, Treatments Called Unfounded And Breast Cancer Treatment Left In Limbo


Over the past 20 years, more than 15,000 women with breast cancer have been treated with an arduous yet largely unproven procedure - high doses of chemotherapy followed by blood cell transplants (cells are removed from the patient before chemotherapy) to replace bone marrow damaged by the chemotherapy.

In the early 1990s, after a few encouraging preliminary reports, breast cancer patients and advocates began demanding the treatment. Some state legislatures responded by mandating that insurance companies pay for the lengthy procedure, which can cost up to $100,000 per case, much more than conventional treatments. By mid-decade, more people were receiving high-dose chemotherapy with transplants for breast cancer than for any other cancer.

But two recently published studies show that high doses of chemotherapy are no more effective than standard chemotherapy for women with advanced or high-risk breast cancer. And results from a third study -- which was originally positive for the high-dose treatment -- have been discounted after the lead South African researcher admitted serious fraud.

These developments leave the practice of high-dose chemotherapy for breast cancer in limbo. The American Society of Clinical Oncology recommends that women receive the treatment only if part of a "high-quality" clinical trial. Editorials in the March 18, 2000 The Lancet and the April 13, 2000 New England Journal of Medicine (NEJM) make the same argument. Researchers at the National Cancer Institute (NCI) have long supported this approach and NCI has sponsored four large national trials; three of these have completed enrollment and one is still ongoing.

These scientific sentiments have been echoed by one of the nation's largest insurers, Aetna/U.S. Healthcare, which in February announced that it will pay for high-dose chemotherapy plus transplants only for patients enrolled in federally-sponsored clinical trials. The company previously reimbursed expenses for women who were not in clinical trials.

The vast majority of women who received the high-dose regimens have not participated in clinical trials, which are required to rigorously test new cancer treatments. Results from well-conducted, carefully monitored randomized trials are urgently needed to figure out which breast cancer patients, if any, may benefit from high-dose therapy plus transplants, says Jeff Abrams, M.D., a breast cancer researcher at NCI.


Current Recommendations


Newly Published Studies

  • Stadtmauer study (on NEJM Web site)
  • Hortobagyi study (Abstract from National Library of Medicine's PubMed database)

    The early studies of high-dose chemotherapy plus transplant for breast cancer that caused so much attention were not randomized. That is, they did not compare patients who received the new treatment to patients who received standard treatment. The two new studies, one published in the NEJM, led by Edward Stadtmauer, M.D., University of Pennsylvania Cancer Center; the other in the Journal of the National Cancer Institute (JNCI) from Gabriel Hortobagyi, M.D. at the University of Texas M.D. Anderson Cancer Center, were randomized, meaning that they provide a truer measure of the treatment's effectiveness.

    The Stadtmauer study enrolled 553 patients who had metastatic (spreading to other organs) breast cancer. All of the patients received four to six cycles of standard chemotherapy. The patients whose disease responded were then randomized; eighty-nine received the standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) and 110 the high-dose chemotherapy (cyclophosphamide, carboplatin, and thiotepa) plus transplant.

    After following both groups for an average of three years, the researchers report no significant difference in overall survival times - 32 percent of the high-dose group and 38 percent of the conventional chemotherapy group were alive at three years post-treatment. There also was no difference in the time it took for the disease to worsen - about 9 months post-treatment for each group. In addition, infection, vomiting, diarrhea, and other side effects were much more common in the high-dose group.

    While the final study was smaller than originally planned, the authors state that there were still enough patients to detect even a small (6 month) survival time advantage. They conclude that they do not recommend high-dose chemotherapy for women with metastatic breast cancer.

    The second study, from Hortobagyi, reached a similar conclusion for 78 patients with less severe breast cancer - cancer that had spread to the lymph nodes near the breast, but not to other organs. (This type of breast cancer is often called "high risk" because patients often relapse after surgery or chemotherapy.)

    The three-year survival rate for the group receiving high-dose chemotherapy was 58 percent, compared to 77 percent for the standard chemotherapy group. Relapse-free survival rates were 48 percent and 62 percent respectively. Again, there were more severe side effects in the high-dose group. These results lead the authors to succinctly report that "high-dose chemotherapy is not indicated outside a clinical trial."

    However, the Hortobagyi study was "much too small to detect even moderate differences" in survival times. That means that the study should not be considered definitive and that additional, larger studies are needed.

    Ongoing Trials

    While results from recent studies are discouraging for those who had hopes for high-dose chemotherapy for breast cancer, several larger studies need to be completed or analyzed before the treatment is completely discounted, says Abrams.

    Preliminary findings of one of these trials (a study of 800 women with high-risk breast cancer), were presented at the 1999 meeting of the American Society of Clinical Oncology. Headed by William Peters, M.D., Ph.D., director of the Barbara Ann Karmanos Cancer Institute in Detroit, the study is comparing women who receive high doses of cyclophosphamide, cisplatin and BCNU, followed by transplants, with women who receive "intermediate" doses of the same drugs without transplants.

    Although early results show no difference in survival, patients receiving the high-dose therapy have about a 68 percent chance of being alive without breast cancer at three years, compared with a 64 percent chance for those receiving the intermediate-dose therapy. While the patients need to be followed for a few more years before any conclusions can be drawn, the early results provide encouragement for completion of ongoing trials.

    The largest of these studies is designed to enroll 1000 patients at 100 centers nationwide. Women may be eligible if they have had breast surgery and have four to nine lymph nodes with cancer. Another study, based in Seattle, is looking at a different chemotherapy regimen in women with both high-risk and metastatic breast cancer. Other studies are ongoing in Australia, France, and Scotland.

    A full list of current trials, with links to more information on patient eligibility criteria, is available on cancerTrials.

    References

    "Where next with stem-cell-supported high-dose therapy for breast cancer?" J. Bergh, The Lancet, March 18, 2000, p. 944. [Text of editorial on The Lancet Web site]

    "High-dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer," M. Lippman, The New England Journal of Medicine, April 13, 2000, p. 1119. [Text of editorial on NEJM Web site]

    "Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer," E. A. Stadtmauer, et al., The New England Journal of Medicine, April 13, 2000, p. 1069. [Text of article on NEJM Web site]

    "Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast cancer," G.N. Hortobagyi, et al., Journal of the National Cancer Institute, Feb. 2, 2000, pp. 225-233. [Abstract of article from National Library of Medicine's PubMed database]



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Editor: Susan K. Boyer, RN
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