Sequential treatment for early-stage breast cancer more effective

Sequential doxorubicin, cyclophosphamide, docetaxel had the best outcomes for OS and PFS in women with early breast cancer.

Results of the National Surgical Adjuvant Breast and Bowel Project B-30 trial indicate that the use of sequential doxorubicin plus cyclophosphamide followed by docetaxel — or sequential ACT — improved DFS in patients with early-stage breast cancer compared with the use of concurrent ACT. In addition, sequential ACT also improved OS in these patients compared with doxorubicin/docetaxel.

The results of the randomized, multicenter phase-3 trial were published recently in The New England Journal of Medicine, and originally presented at the 2008 San Antonio Breast Cancer Symposium.

“In absolute terms, sequential ACT was approximately five percentage points better for eight-year disease-free survival and approximately four percentage points better for overall survival,” Matthew Ellis, MB, BChir, PhD, from the division of oncology, department of medicine, Washington University School of Medicine, St. Louis, wrote in an accompanying editorial. “The results provide support for current practice, since the sequential-ACT regimen in this trial, or its paclitaxel-based equivalents, is standard therapy for node-positive disease.”

In the trial, 5,264 women with operable, node-positive, early-stage breast cancer were assigned one of three treatment regimens: four cycles of sequential ACT (n=1,753), four cycles of doxorubicin and docetaxel (n=1,753), or concurrent ACT (n=1,758). The median follow-up was 73 months.

There were 803 deaths among the intention-to-treat population. Patients treated with sequential ACT had an eight-year OS of 83% compared with 79% for patients treated with doxorubicin-docetaxel (P=.03) and 79% for patients treated with concurrent ACT (P=.09).

When the researchers examined DFS, they found that patients treated with sequential ACT had a eight-year DFS of 74%. This was a statistically significant improvement in DFS compared with doxorubicin-docetaxel (69%) and concurrent ACT (69%).

In addition, regardless of treatment group, women with amenorrhea for six months or longer had improved OS and DFS compared with women without amenorrhea.

Despite the results, the trial is complicated by the inclusion of women with HER-2–positive tumors, wrote Ellis.

“These patients would not currently be eligible for treatment with any of the non-trastuzumab-based regimens investigated in this trial, and so this study is irrelevant for this important subgroup,” Ellis wrote. “Complicating matters, HER-2 status is a positive predictor for the benefit of both taxane and anthracycline therapy. It is therefore hard to know whether the HER-2–negative population (and most particularly the large group of patients with ER-positive, HER-2–negative tumors, which may be relatively taxane-resistant) would benefit from the modest advantages associated with the increased drug doses and more prolonged treatment in the sequential-ACT regimen.”

“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,” he concluded.

Ellis M. N Engl J Med. 2010;3622122-2124.

Swain SM. N Engl J Med. 2010;362:2053-2065.