Posted: February 22, 2006
NEW YORK (Reuters Health) - Docetaxel is more effective than vinorelbine when administered prior to fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy in improving recurrence-free survival in women with early breast cancer, according to the results of a prospective study conducted in Finland. Moreover, among the subset of women whose tumors overexpress HER2/neu (ErbB2), adding treatment with the monoclonal antibody trastuzumab (Herceptin, Roche) prior to cardiotoxic FEC therapy improves outcomes without damaging the heart, the investigators report in the New England Journal of Medicine for February 23.
Dr. Heikki Joensuu, from Helsinki University Central Hospital, and colleagues enrolled 1010 women with axillary-node-positive or high-risk node-negative breast cancer in their phase III, open label trial.
Patients were randomly assigned to treatment with docetaxel (Taxotere, Sanofi-Aventis) 100 mg per square meter of body-surface area on day 1 of three 21-day cycles, decreased to 80 mg per square meter if necessary for toxicity (n = 502), or vinorelbine (Navelbine, Pierre Fabre) 25 mg per square meter on days 1, 8 and 15 of three 21 day cycles (n = 508).
Once the initial experimental treatment was completed, patients were treated with FEC on day 1 of at least three 21-day cycles. Patients with estrogen-receptor- or progesterone-receptor-positive tumors were also treated with tamoxifen 20 mg per day for up to 5 years, and radiation was administered for women who had breast-conserving surgery.
At 3 years, recurrence-free survival was 91.3% in the docetaxel group versus 86.4% in the vinorelbine group (hazard ratio for recurrence or death, 0.58, p = 0.005). Overall survival was not significantly different between the two groups.
The researchers also randomized half of the 232 women with HER2/neu-expressing tumors to receive trastuzumab. The first dose of trastuzumab was 4 mg/kg, and 2 mg/kg thereafter, administered weekly for 9 weeks, to be infused prior to docetaxel or vinorelbine. No trastuzumab was administered during FEC treatment.
Recurrence-free survival was 89.3% in the trastuzumab group versus 77.6% in the no trastuzumab group (HR 0.42, p = 0.01).
Previous studies have demonstrated that trastuzumab can cause heart failure or a decrease in left ventricular ejection fraction. In the current study, none of those treated with trastuzumab developed heart failure, and they actually had slightly better maintenance of left ventricular ejection fraction than those not given the antibody.
In a related Perspective article, Dr. Kenneth R. Chien, from Harvard Medical School in Boston, explains that anthracyclines promote cardiotoxicity in the absence of ErbB2 protein. Therefore, trastuzumab's reduction in ErbB2 opens the way for anthracyclines to induce their cardiotoxic effects.
By administering trastuzumab prior to FEC, he continues, "the therapeutic effect of trastuzumab in ErbB2-positive breast cancer was completely dissociated from its modifying effect on anthracycline-induced cardiotoxic effects."
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