Adding Sequential Docetaxel to Adjuvant E→CMF Marginally Improves DFS in Early Breast Cancer Patients

ATLANTA—Results of the multicenter Italian phase III Taxit 216 trial show marginally better disease-free survival (DFS) with the addition of sequential docetaxel (Taxotere) to standard epirubicin→CMF (cyclophosphamide/methotrexate/fluorouracil) as adjuvant treatment for high-risk early breast cancer, with acceptable toxicity.

Angelo R. Bianco, MD, reported the results at the American Society of Clinical Oncology 42nd Annual Meeting (abstract LBA520). Dr. Bianco, of University Federico II, Naples, Italy, presented the data on behalf of the Taxit 216 Study Group.

"Docetaxel is among the most active drugs for the treatment of advanced breast cancer and has recently shown efficacy in the adjuvant setting," Dr. Bianco commented. "This trial was aimed at comparing the efficacy and tolerability of a sequential regimen containing docetaxel to a standard anthracycline-based regimen as adjuvant therapy in node-positive early breast cancer."

The investigators randomized 972 node-positive patients to one of two arms:

• Arm A: E→CMF (epirubicin 120 mg/m² IV on day 1 every 21 days for four cycles, followed by cyclophosphamide 600 mg/m² IV, methotrexate 40 mg/m² IV, and fluorouracil 600 mg/m² IV on days 1 and 8 every 28 days for four cycles)

• Arm B: E→T→CMF (with docetaxel 100 mg/m² IV on day 1 every 21 days for four cycles after the fourth cycle of E and before the first cycle of CMF)

Colony-stimulating factors were used "according to the doctor's judgment," Dr. Bianco said.

Patients were stratified by center, lymph node involvement (1 to 3, 4 to 9, more than 10), estrogen-receptor status (negative/positive/unknown), and menopausal status (pre/post). At the completion of treatment, patients were followed every 3 months for the first 2 years, every 6 months for years 3 to 5, and every 12 months for years 6 to 10. The primary endpoint was disease-free survival; secondary endpoints were tolerability and overall survival (OS).

Dr. Bianco said that the study protocol originally had three treatment arms, the third of which combined dose-dense epirubicin, dose-dense docetaxel, and high-dose combination chemotherapy. He explained that after 25 patients had been randomized to this arm, it was closed to enrollment at the request of the study sponsor, Sanofi-Aventis. "I think this was due to budget, since toxicity was acceptable," Dr. Bianco said.

At a median follow-up of 53.6 months, Dr. Bianco reported that there were no significant differences in either disease-free survival or overall survival between the two treatment groups, with P values of .0846 and .0877 for DFS and OS, respectively.

Adjusted Disease-Free Survival

After adjustment by predefined balancing factors (estrogen-receptor, nodal, and menopausal status), there was a marginally significant advantage in disease-free survival for the docetaxel arm, Dr. Bianco reported. The hazard ratio (HR) was 0.787 (95% CI: 0.614-1.008; P = .0576), he said.

Adjusted overall survival for arm B showed an HR of 0.724 (95% CI: 0.504-1.039, P = .0797).

The researchers concluded that sequential E→T→CMF yields a borderline significant (21%) improvement in risk of relapse and a nonsignificant 28% improvement in risk of death, compared with E→CMF, while also causing more febrile neutropenia and more grade 3-4 nonhematologic toxicities.

Dr. Bianco noted that "the cumulative incidence of nonhematologic adverse events remains, however, clinically acceptable (less than 4.5% of patients)."