Six chemotherapy cycles failed to improve outcomes in node-negative breast cancer

SAN ANTONIO — Patients with node-negative breast cancer who received six cycles of 5-fluorouracil, epirubicin and cyclophosphamide experienced similar DFS and OS as patients who received four cycles of doxorubicin and cyclophosphamide, according to results of a phase 3 study presented at the San Antonio Breast Cancer Symposium.

“[In the MA-5 trial, the NCIC Clinical Trials Group] administered a dose-intensified epirubicin program, and the RFS and OS results were encouraging,” Charles Edward Geyer, Jr., MD, FACP, associate director for clinical research at Virginia Commonwealth University Massey Cancer Center, said during his presentation. “Additionally, the French Adjuvant Study Group around that time had also evaluated their standard adjuvant regimen of FEC-50 and had shown that six cycles of therapy were more effective than three. So, at that time, we had two separate trials looking at different epirubicin schedules, both of which had seemed to be positive. It seemed reasonable at that time to compare [doxorubicin and cyclophosphamide] with one of those regimens. Since we were going to conclude the study in node-negative patients and include post-menopausal women, we chose the FEC-100 [chemotherapy regimen] because of its improved toxicity profile.”

Charles Edward Geyer

Geyer and colleaguesevaluated data from 2,722 patients who had node-negative disease. Forty percent of the population were aged younger than 50 years, 68% had undergone lumpectomy and 65% had hormone-positive disease.

Researchers randomly assigned half of the patients to FEC-100, which consisted of six cycles of 500 mg/m² 5-fluorourcil, 100 mg/m² epirubicin and 500 mg/m² cyclophosphamide. The other half of patients received AC chemotherapy, which consisted of four cycles of 60 mg/m² doxorubicin (Adriamycin, Pharmacia & Upjohn) and 600 mg/m²cyclophosphamide.

The original analysis also included further randomization to one of the chemotherapy arms with or without celecoxib (Celebrex, GD Searle); however, this analysis was terminated in 2004 due to concerns for cardiovascular disease with COX-2 inhibitors.

Median follow-up was 82.8 months.

Overall, the AC and FEC-100 arms conferred similar rates of 8-year DFS (82.3% vs. 82.1%). First events on the AC and FEC-100 arms included distant recurrence (4.8% vs. 4.6%), local recurrence (3.5% vs. 3.8%) and second primary disease (4.9% vs. 4.7%).

“The number of patients developing a second primary as a first event was matched by the number developing distance recurrence, so this is a patient population that is becoming increasing difficult to study in adjuvant trials,” Geyer said.

Eight-year OS also was comparable among patients who received AC and FEC-100 (91.2% vs. 92%) chemotherapy.

FEC-100 chemotherapy was associated with greater rates of grade 3 to grade 4 fatigue (8.45% vs. 3.55%), febrile neutropenia (9.42% vs. 3.7%) and thrombocytopenia (4.41% vs. 0.74%). Two patients on the AC arm and five on the FEC-100 arm died from toxicities.

“[Six cycles of] FEC-100 did not improve the primary endpoint of DFS or our secondary endpoint of OS relative to [four cycles of] AC,” Geyer said. “Toxicities were increased with the FEC-100, which wasn’t unexpected because it did administer additional cycles of therapy compared with AC. Overall, the results do not support the use of six cycles of anthracycline-based regimens in node-negative breast cancer.”

For more information:

Samuel JA. Abstract#: S3-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.

Disclosure: The study was funded in part by the NCI and Pharmacia & Upjohn Co. The researchers report consultant roles with and travel compensation from Celgene, Eisai, Genomic Health, Pfizer and Roche/Genentech.