ORLANDO-Results from the European Cooperative Trial in Operable Breast Cancer (ECTO) show that the addition of paclitaxel(Drug information on paclitaxel) to a commonly used breast cancer chemotherapy regimen improved time to progression without increasing toxicities, Luca Gianni, MD, reported at the American Society of Clinical Oncology 41st Annual Meeting (abstract 513). "ECTO is the first study to show therapeutic benefit from adjuvant paclitaxel by directly comparing two regimens of identical duration and similar tolerability," said Dr. Gianni, Istituto Nazionale Tumori, Milan, Italy.
Prior studies have proven the effectiveness of doxorubicin(Drug information on doxorubicin) (Adriamycin) followed by cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) (CMF) in treating high-risk breast cancer, and have shown that paclitaxel and doxorubicin (AT) followed by CMF prior to surgery is well tolerated.
ECTO was designed to test whether adding paclitaxel to doxorubicin followed by CMF improved efficacy and whether primary systemic therapy produced a better result than adjuvant therapy. Researchers randomized 1,355 patients (1,324 evaluable for chemotherapy) with tumors larger than 2 cm to one of three treatment arms. Almost 90% of patients completed the plan of care.
In the first cohort, 444 women received surgery followed by standard therapy (A→CMF): doxorubicin, 75 mg/m2, IV bolus every 3 weeks for four cycles, followed by cyclophosphamide, 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 IV on days 1 and 8, every 4 weeks for four cycles.
The 432 patients in the second cohort had surgery followed by AT→CMF: paclitaxel (Taxol) 200 mg/m2 IV over 3 hours and doxorubicin 60 mg/m2 every 3 weeks for four cycles followed by CMF, as previously outlined. The third cohort of 448 women received AT→CMF, in the doses already described, prior to surgery. All women took tamoxifen(Drug information on tamoxifen) 20 mg daily for 5 years and received radiation therapy as indicated. Endpoints were disease-free and overall survival. Cardiac status was monitored, and pathological responses were determined. Patients were followed every 6 months for the first 2 years, then annually.
"Results at 5 years of follow-up indicate freedom from progression is better for women who received the paclitaxel-containing regimen, with a hazard ratio [HR] of 0.66 and a P value of .01," Dr. Gianni said. In the second planned analysis to determine if giving the paclitaxel-containing regimen prior to surgery was better than adjuvant therapy, the data showed freedom from progression was the same in the two treatment arms. Freedom from progression increased significantly among the primary systemic chemotherapy patients who achieved a pathologic complete response, 89% vs 75% in those who did not obtain a pathologic complete response (HR 2.80, P = .006). "Pathological complete response is an independent variable for predicting efficacy," Dr. Gianni said.
There was no significant difference in risk of local recurrence between women who received conservative therapy and those who underwent a radical mastectomy, independently of administration of chemotherapy before or after surgery.
At 5 years, 87% of the women receiving the traditional therapy were still alive, as were 91% of women who received the adjuvant paclitaxel-containing regimen and 90% of those patients receiving the paclitaxel-containing regimen prior to surgery. "Overall survival shows that there is no significant difference at 5 years," Dr. Gianni said. "However, there is a trend toward improved overall survival in the patients who received the doxorubicin/paclitaxel combination."
The investigators saw no dramatic difference in left ventricular ejection fraction (LVEF) in the traditional vs paclitaxel groups during therapy or follow-up. A minority of patients experienced an LVEF below normal limits or more than 20% of the basal value. Dr. Gianni found no significant difference between the treatment arms. "Cardiac tolerability so far ranks AT→CMF among the safest anthracycline-containing regimens for early breast cancer," he said.
Dr. Gianni concluded that adjuvant AT→CMF significantly prolongs freedom from progression, compared with A→CMF, in patients with operable breast cancer, and at 5 years, efficacy of adjuvant vs primary AT→CMF is similar.
"This study clearly demonstrates that adding paclitaxel to doxorubicin in the context of sequential treatment is superior in terms of event-free survival," said Gabriel N. Hortobagyi, MD, of M.D. Anderson Cancer Center, during the discussion. He cautioned, however, that this trial with fewer than 500 patients in each arm, may have been underpowered for some questions it sought to answer.
