Paclitaxel Administered Weekly Doubles Pathologic Complete Response in Noninflammatory Operable Breast Cancer

HOUSTON—Weekly paclitaxel (Taxol) as part of a primary systemic chemotherapy regimen for operable breast cancer improves pathologic complete remission rates when compared with every 3-week paclitaxel therapy, according to results of a prospective phase III trial (ASCO abstract 135).

"When you administer paclitaxel weekly, pathologic complete response is double that of the usual protocol in which it is given every 3 weeks," said lead author Marjorie C. Green, MD, assistant professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "If we believe that pathologic complete response translates into improved survival based upon the results of studies such as B18, then the data are very exciting for our patients. The weekly regimen may be better but those results should be validated," she told ONI.

Paclitaxel has significant antitumor activity in patients with metastatic breast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy. Although pathologic complete response, defined as the absence of invasive cancer in the breast and lymph nodes, portends a good prognosis following treatment, correlation with survival and clinical outcome is still incomplete.

Randomized by Nodal Status

Previous studies suggest that patients who achieve a pathologic complete response after primary systemic chemotherapy have better survival than do similarly staged patients who have residual disease following primary systemic chemotherapy.

To determine if different schedules or dose densities of paclitaxel improve pathologic complete response rates or reduce toxicity, 258 patients with operable noninflammatory breast cancer (T1-3, N0-1, M0) were randomized by nodal status to receive either weekly or every-3-week regimens of paclitaxel as primary systemic chemotherapy.

Subsequently, all patients received combination therapy with FAC (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan, Neosar] every 3 weeks for four cycles, followed by locoregional and hormonal therapy as appropriate. Patient groups were generally well balanced in terms of demographic and clinical variables including tumor size.

Paclitaxel dose varied depending on lymph node status, and was 80 mg/m²/wk for 12 weeks in node-negative patients, and was 150 mg/m²/wk for 3 weeks followed by a 1-week break for four cycles in node-positive patients. Initial attempts to give node-positive patients 175 mg/m²/wk proved to be too toxic.

The standard paclitaxel regimen was 225 mg/m² given as a 24-hour continuous infusion every 3 weeks for four cycles. This regimen was associated with increased febrile neutropenia relative to the weekly regimen. After completion of chemotherapy, treatment-related neuropathy regressed in most patients.

Response Rates Vary

Clinical response occurred in 86% of patients in both regimens. Clinical complete response occurred in 43% of those receiving paclitaxel every 3 weeks and 54% of those on weekly paclitaxel.

In patients treated with weekly paclitaxel, pathologic complete response occurred in 29% of node-positive patients and in 28% of node-negative patients. Among patients treated with paclitaxel every 3 weeks, 15% of node-positive patients and of node-negative patients achieved pathologic complete response, with statistical significance of P < .01 favoring the weekly schedule.

Comparing the two treatment regimens, 28% of patients treated with weekly paclitaxel but only 15% of patients receiving paclitaxel every 3 weeks had a pathologic complete response (P < .01).

Weekly administration of paclitaxel practically doubles response relative to the every-3-week schedule. Although the mechanism of how the weekly schedule improves outcome is still unclear, Dr. Green suggests that antiangiogenesis or intervention at a key point in the cell cycle may be involved.

"Will the pathological CR translate to a clinical benefit and maintenance of a disease-free state? More validative studies may be needed," Dr. Green said.