The formal presentation of preliminary results from five high-dose chemotherapy clinical trials for breast cancer brought an anti-climactic close to a subject that attracted a flurry of media attention earlier this year. It also opened the door for debate among the scientific community on what should be done next.
Four of the five studies presented in Atlanta at the 35th Annual Meeting of the American Society of Clinical Oncology in May showed no benefit in survival for women with breast cancer receiving high-dose therapy over those who received standard therapy (see related story). The fifth study, conducted in South Africa, showed that the high-dose chemotherapy arm had fewer deaths and a lower rate of relapse.
ASCO released the abstracts from the five trials in April as a result of significant public interest in the results. "The decision [to release the data] was made after very careful consideration with the leadership from the National Cancer Institute, ASCO, the cooperative groups, and members of the advocacy groups," said William Gradishar, M.D., of Northwestern University Medical School, Chicago, who moderated a press conference on the trials' results, "The decision was to circumvent the probability that inaccurate information would be released and disseminated causing concern to patients prior to this meeting."
There are substantial differences among the five trials. Three were for women at high risk of recurrence; two were for metastatic breast cancer. All trials used different regimens of standard and high-dose chemotherapy. The largest study randomized 783 patients; the smallest, 61. One researcher presented results with a median follow-up of 5 years; another had data on patients tracked for a median of 23.7 months. Two trials were conducted in the United States, one in France, one in South Africa, and one in Scandinavia.
High Toxicity
One concern arising from the preliminary results is the toxicity-related deaths that occurred in the trials. In the Cancer and Leukemia Group B study, 29 women in the HDC group died as a result of toxicities from chemotherapy, two women died in the Scandinavian study, and there were no deaths in the South Africa study from toxicity-related causes. In all three of these studies, there were no deaths in the standard-dose groups from toxicity-related causes.
Gabriel N. Hortobagyi, M.D., of the University of Texas M. D. Anderson Cancer Center, Houston, said in a discussion of the abstracts that while results on the small increase of time-to-progression in the high-dose arms is encouraging, the therapy is not useful if toxicity-related deaths increase.
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Scientists also discussed a theory for why the South Africa study found a benefit for HDC while the others showed no benefit. The South Africa study, led by Werner Bezwoda, M.D., at the University of Witwatersrand Medical School in Johannesburg, treated one group of women with high-dose chemotherapy without first administering standard chemotherapy.
"We were giving the most effective treatment first," Bezwoda said.
This may suggest that the standard treatment makes cancer cells resistant to further therapy, according to Nelson Chao, M.D., of Duke University Medical Center. As a result, Chao said, "we will probably see a national study developed in the United States to test high-dose therapy alone."
There are four trials examining HDC in metastatic breast cancer in Europe; however, the trials have not yet reached their accrual targets. In the meantime, the consensus remains that HDC does not clearly improve survival or time to progression.
"There's still room for discussion between patients and physicians about what they think is the best treatment," said Edward Stadtmauer, M.D., of the University of Pennsylvania Cancer Center. "The assumption is that now these treatments are equal."
Patients should consider the pros and cons of HDC in extensive conversation with their doctors, and consider enrolling in a clinical trial, said William Peters, M.D., of the Barbara Ann Karmanos Cancer Institute, Detroit, Mich.
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"Patients involved in clinical trials are better off than patients treated off-study." Peters pointed out that in the CALGB study the survival rate for both groups the women on high dose chemotherapy and those on standard therapy was 20% better than patients who are not enrolled in a clinical trial. Some of this could be due to patient selection.
Further Analysis
All panelists and discussants concurred that the preliminary data needs to be further analyzed, and that the development of more clinical trials is essential in testing the efficacy of high-dose treatment. There is currently only one clinical trial accruing patients in the United States for high-dose therapy. The study, conducted by the Southwest Oncology Group, is for primary breast cancer patients with four to nine positive axillary lymph nodes. More than 500 patients have been enrolled with an expected final accrual of 1,000 patients by the year 2001.
"Science is not done by the New York Times or NBC News," Peters said. "Important new studies need to be conducted to understand the role of this therapy in treating women with breast cancer."
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