Longer Chemo for Breast Cancer More Effective

(MedPage Today) -- A sequential form of adjuvant chemotherapy for early-stage breast cancer outperformed two shorter regimens in some -- but not all -- outcomes in a major clinical trial, researchers said.

In a randomized trial of 5,351 women with operable, node-positive breast cancers, the so-called sequential-ACT regimen yielded improved disease-free survival after eight years of follow-up compared with patients on two other regimens.

It also improved overall survival compared with doxorubicin-docetaxel but not concurrent ACT, according to Sandra Swain, MD, of Washington Hospital Center in the District of Columbia, and colleagues.

But regardless of regimen, women who developed at least six months of amenorrhea during the chemotherapy had better overall survival, Swain and colleagues said in the June 3 issue of the New England Journal of Medicine.

The findings come from the National Surgical Adjuvant Breast and Bowel Project B-30 trial, which randomized patients to three treatment schedules:

• Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (Cytoxan) for four cycles -- the concurrent ACT regimen (n=1784)
• Concurrent doxorubicin and docetaxel for four cycles (n=1784)
• And doxorubicin and cyclophosphamide for four cycles, followed by four cycles of docetaxel -- the sequential ACT regimen (n=1783)

Some details of the study were presented in 2008 at the San Antonio Breast Cancer Symposium. (See SABCS: Mixed Results for Sequential Versus Concurrent Therapy for Breast Cancer)

While the results in the B-30 study appear clear-cut, Swain and colleagues noted, a similar European study -- by the Breast Cancer International Research Group -- found little difference between the sequential and concurrent regimens.

Taken together, the researchers said, the two studies taken together suggest that the key factor is the cumulative dose of docetaxel. In the U.S. study, the cumulative dose of the drug was 400 milligrams per square meter in the sequential arm -- higher than that used in either of the other arms but similar to the amount in both arms of the European trial.

The hypothesis of the study was that the short course of ACT would be superior to the sequential regimen on the basis of a hoped-for synergistic effect, according to Matthew Ellis, PhD, of Washington University School of Medicine in St. Louis.

But the results support the opposite conclusion and current clinical practice, Ellis wrote in an accompanying editorial. "The sequential-ACT regimen in this trial, or its paclitaxel-based equivalents, is standard therapy for node-positive disease."

But the general conclusion -- that longer chemo is better than shorter -- doesn't hold up, he said, since many sequential regimens now employed are "dose-dense" and thus offer the same levels of medication in a shorter course.

In the B-30 trial, dose reductions to minimize toxicity were needed to make the two concurrent regimens feasible. "It is hard to escape the conclusion that the inferior results," Ellis said, "were mainly due to the significant dose reductions."

The analysis showed:

• The eight-year overall survival was 17% better in the sequential-ACT group than in the doxorubicin-docetaxel group -- the hazard ratio for death was 0.83, which was significant at P=0.03.
• Overall survival tended to be improved over the concurrent-ACT group, but not significantly -- the hazard ratio was 0.86, but the significance value was P=0.09.
• The concurrent regimens had similar overall survival.
• Eight-year disease-free survival was 74% in the sequential-ACT group, compared to 69% in both of the other groups. The hazard ratio for recurrence, a second malignant condition, or death was 0.80 for the doxorubicin-docetaxel regimen and 0.83 for the concurrent-ACT group. Significance values were P=0.001 and P=0.01, respectively.

For the menstrual subanalysis, data was available for 2,343 patients, 97% of the premenopausal women in the study, the researchers said.

For those women, overall and disease-free survival was improved if they had no menses for at least six months during the first 24 months of follow-up. The relative risks were 0.76 and 0.70, respectively, with significance values of P=0.04 and P<0.001.

The results were consistent regardless of treatment, Swain and colleagues said.

During the chemotherapy, 65% of patients in the sequential-ACT group reported grade 3 or 4 adverse events, compared with 45% in the doxorubicin-docetaxel group and 48% in the concurrent-ACT group, they said.

In his editorial, Ellis also pointed out that "an overall survival advantage of 4 percentage points is only a modest gain in exchange for increasing the dose of chemotherapy agents, doubling the duration of therapy, and markedly increasing acute toxicity. It is therefore hard to escape the conclusion that this trial marks the end of the road for generic studies of combinations of anthracycline, taxane, and cyclophosphamide."

The study was supported by the Public Health Service, the National Cancer Institute, the NIH, the Department of Health and Human Services, and sanofi-aventis.

Swain reported financial links, either personally or institutionally, with Rhône-Poulenc-Rhorer, sanofi-aventis, Bristol-Myers Squibb, the Susan G. Komen for the Cure Foundation, Living in Pink, Safeway, Eisai, GlaxoSmithKline, Pfizer, Onyx, Novartis, Roche, Abraxis, BiPar, and Wyeth.

Ellis reported financial links with Bristol-Myers Squibb, sanofi-aventis, Novartis, Pfizer, AstraZeneca, Abraxis, and GlaxoSmithKline.

Primary source: New England Journal of Medicine Source reference: Swain SM, et al "Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer" N Engl J Med 2010; 362: 2053-65.Additional source: New England Journal of MedicineSource reference: Ellis M "Taxane-based chemotherapy for node-positive breast cancer -- Take-home lessons" N Engl J Med 2010; 362: 2122-24.

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