Epirubicin Associated With Prolonged Survival in the Neoadjuvant Setting for Breast Cancer

CANTON, Ohio—Neoadjuvant breast cancer therapy research has revealed that “epirubicin has good activity in the neoadjuvant setting and was associated with prolonged survival in four studies, although this remains to be confirmed,” Terry Mamounas, MD, stated. Dr. Mamounas, Medical Director at Aultman Memorial Hospital in Canton, Ohio, spoke at the clinical investigators’ workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.

“Neoadjuvant therapy demonstrates quickly the in vivo sensitivity of new agents and allows assessment of surrogate biomarkers such as clinical and pathological complete response (CR),” Dr. Mamounas said. He offered several reasons why epirubicin (Ellence) is an attractive candidate for neoadjuvant breast cancer treatment:

• the anthracyclines are very active in breast cancer;
• the dose of epirubicin can be intensified; and
• epirubicin is easier to combine with other agents, especially the taxanes, than are other anthracyclines.

In a study sponsored by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), 448 patients were randomized to epirubicin/cyclophosphamide (Cytoxan) (EC) with granulocyte colony stimulating factor (G-CSF) or to standard CEF (cyclophosphamide, epirubicin, 5-fluorouracil [5-FU]). The intensified EC regimen yielded no improvement in CR rates, Dr. Mamounas reported, and no differences in relapse-free survival or in overall survival at a median follow-up of 30 months. Other studies, however, did show benefits of epirubicin.

Breast-Conserving Surgery

Dr. Mamounas referred to a report by Gianni Bonadonna, MD, and colleagues from Italy at the American Society of Clinical Oncology (ASCO) annual meeting that neoadjuvant treatment with single-agent epirubicin permitted effective down-staging of many tumors and permitted more women to undergo breast-conserving surgery. The 4-year results from that trial showed a 68% overall response rate with single-agent epirubicin. According to Dr. Mamounas, this is comparable to results with the standard doxorubicin (Adriamycin)/cyclophosphamide (AC) regimen. Sixty-seven percent of patients were able to undergo breast-conserving surgery.

“This trial shows that we have to make very sure our margins are negative in surgery after neoadjuvant therapy,” Dr. Mamounas said. The risk of ipsilateral relapse was 13.9% in patients with positive margins and 2.9% in those with negative margins (P = .008).

A French phase II trial compared FEC-100 (5-FU 50 mg/m², cyclophosphamide 500 mg/m², plus epirubicin 100 mg/m²) with epirubicin/docetaxel (Taxotere) (ED) as neoadjuvant regimens. Forty-eight patients in each group were evaluable for toxicity. Grade 3-4 neutropenia was more common in the ED group, Dr. Mamounas reported, but was generally brief and manageable with growth factors. There were no instances of congestive heart failure (CHF) in the ED group and 3 in the FEC group.

Overall response rates and pathological response in the lymph nodes were similar. The objective response rate was 81% with ED vs 55% with FEC-100, but Dr. Mamounas warned that this was a small phase II trial and needs to be confirmed in larger randomized studies.

Weekly neoadjuvant ED has also been studied in a phase I trial in 23 patients. Patients were treated with 30 mg/m² of epirubicin and 35 mg/m² of docetaxel once weekly. The overall response rate was 88%, Dr. Mamounas said, and 56% of patients had sufficient tumor shrinkage to permit breast-conserving surgery.

Infusional Therapy

Infusional epirubicin/cisplatin/5-FU (ECisF) has been compared to AC in a phase III trial in 426 patients. Dr. Mamounas reported that the clinical response rate was very encouraging at a median follow-up of 30 months, but “whether this means anything needs to be seen.’’

Patients on the infusional therapy experienced greater toxocity and required more treatment delays and dosage reductions. ‘‘Clearly, this is a tough regimen to use in the neoadjuvant setting,’’ Dr. Mamounas said.

The influence of cancer susceptibility genes is increasingly coming into play in designing breast cancer therapy, and Dr. Mamounas discussed a trial of the response to neoadjuvant FEC-50 (with epirubicin 50 mg/m²) vs FEC-100 in women with HER2/neu-positive breast cancer. ‘‘The conclusion was that if you are HER2/neu positive, you should get the higher dose regimen,’’ he stated.