NEWS

High-Dose Chemo For Breast Cancer: Does It Still Have a Chance?

Caroline McNeil

A year after the appearance of negative data on high-dose chemotherapy with bone marrow transplant for breast cancer, patients and physicians seem to be eschewing high-dose regimens with the same fervor they once pursued them. Accrual to ongoing transplant trials has slowed dramatically, and there are reports that its use outside of trials has dropped as well.

But such extreme pessimism is not warranted, according to breast cancer experts at the May meeting of the American Society of Clinical Oncology in New Orleans. Many believe that the pendulum has now swung too far in the negative direction. "Until 1999 expectations were unreasonably high," said Sjoerd Rodenhuis, M.D., of the Netherlands Cancer Institute, Amsterdam. "Since then they have been unreasonably low."

In truth, the answers are not in, said Gabriel Hortobagyi, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston. Hortobagyi reviewed the status of high-dose chemotherapy in a special media session on clinical trials, noting that many people have concluded that high-dose regimens do not work based on the trials presented at ASCO last year. "This is simply not correct," he said.



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Dr. Gabriel Hortobagyi

 
High-dose chemotherapy with bone marrow or stem cell transplant became the focus of high hopes when small, single-institution (phase II) trials suggested that it could produce major gains in survival among high-risk, node-positive and metastatic patients. Doubts set in last year when preliminary findings from four randomized phase III trials failed to confirm the phase II results. The bad news got even worse in February, when a fifth randomized study, a small South African trial and the only one with positive data, turned out to be fraudulent.

No Answers Yet

The problem is that neither the phase II studies nor the randomized trials reported so far give the answers, said George Sledge, M.D., of the University of Indiana, who moderated a session on controversies in breast cancer therapy. The phase II data looked good when compared with survival rates for treatments developed earlier, but such historical controls can be deceptive, Sledge said.

For example, phase II trials may involve selection bias. Patients who meet the eligibility criteria for these trials often would do better than those who do not meet the criteria, regardless of treatment. In addition, diagnosis and staging techniques change over time. In trials particularly, very careful staging can result in upstaging—i.e., patients who may have been diagnosed with an earlier stage are found to actually have a higher stage of disease. Upstaging improves outcomes of both groups, Sledge noted.

If the phase II trials did not deserve the faith put in them, the phase III results do not justify the complete loss of confidence that seems to have occurred since the ASCO meeting in 1999. The data reported last year, in addition to being preliminary, had various limitations. For instance, two of the trials—the French and the U.S. Eastern Cooperative Oncology Group studies—were too small to show any but a very large difference between the high-dose and control arms, Sledge said.

What the preliminary findings from these trials do suggest is that transplant may not produce large, dramatic differences in survival. "We probably won’t have a home run," said NCI’s Jeff Abrams, M.D. "But we may see important incremental gains in survival in subgroups of women, comparable to what we see with other new treatments."

Promising Results

A glimmer of hope comes with very early data from the Netherlands Working Party on Autotransplantation in Solid Tumors (NWAST). In New Orleans, the Netherlands Cancer Institute’s Rodenhuis reported on 284 patients out of the 880 enrolled. The women were 55 years old or younger and had undergone mastectomy or lumpectomy for breast cancer. Patients in this group had no distant metastases and at least four tumor-positive nodes.

In this small cohort, the 3-year survival rate in the high-dose arm was 77% compared with 62% for the standard-dose arm. Overall survival was 89% versus 79%. In both cases, the difference was statistically significant.

This trial includes women with as few as four involved lymph nodes, bolstering hope that high-dose chemotherapy will turn out to have some benefit in this subset. More data should be available in mid-2002, Rodenhuis said, including analyses of response and survival data by number of nodes.

Patients with as few as four positive nodes are also eligible for the largest U.S. trial now under way. SWOG 9623 is comparing high-dose chemotherapy with transplant to intensive, sequential chemotherapy with granulocyte-colony stimulating factor to support white blood cell production.

Investigators now worry that questions about high-dose chemotherapy may never be resolved. Accrual to ongoing trials has dropped sharply in the past year. SWOG principal investigator Scott Bearman, M.D., of the University of Colorado, Denver, said that accrual to SWOG 9623 had been flat since the negative reports following the ASCO presentations a year ago.

Elsewhere, transplant for breast cancer has also fallen. Statistics for 1999 are not yet available, but transplant center physicians say that referrals have dropped since last year.

The message at this year’s ASCO meeting was that such wholesale negative attitudes are no more realistic than was the earlier pro-transplant bias among many physicians and patients.

Transplants should not be performed outside of clinical trials, said Hortobagyi, Sledge, and others. "But it is just as inappropriate to be totally negative about transplant as it was to be wildly positive," Hortobagyi said. "It continues to be a good idea until proven otherwise."



             
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