Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology)

Abstract

Purpose: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy.

Method: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS).

Results: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group.

Conclusion: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100.

Trial registration: ClinicalTrials.gov: NCT00087178.

Keywords: Anthracyclines; Duration of therapy; Node-negative breast cancer.

Conflict of interest statement

Conflict of interest Charles E. Geyer, Jr.—Grants, non-financial support and other from Genentech/Roche, Daiichi/Sankyo, and AstraZeneca, during the conduct of the study, and personal fees from Exact Sciences and Athenex, outside the submitted work. Priya Rastogi: Genentech/Roche—Unpaid advisory boards, travel, accommodations; Lilly—Travel, accommodations; Astra/Zeneca— Travel, accommodations. Johnathan Polikoff – Consultant, Natera. Louise Provencher: Consulting or Advisory Role: Lilly, Pfizer, Roche, Novartis; Research Funding: Pfizer, Roche, Novartis, Merck, GlaxoSmithKline, Odonate Therapeutics Sandra M. Swain: Personal Fees for consulting/advisory services/nonpromotional speaking: Astra-Zeneca, Athenex, Daiichi-Sankyo, Genentech/Roche, Exact Sciences (Genomic Health), Eli Lilly and Company, Bejing Medical Award Association, Merck, Natera, Molecular Templates, Silverback Therapeutics; Non-financial support (i.e., travel, accommodations, and/or food & beverage); Genentech/Roche: Research support (to institution): Genentech/Roche, Kailos Genetics; Other support: AstraZeneca (member, independent data monitoring committee) and Genentech/Roche (third-party writing assistance). Eleftherios P. Mamounas: Genentech/Roche, Exact Sciences: Consultant (Advisory Board) and Speaker’s Bureau. Biotheranostics, Daiichi Sankyo, Puma Biotechnology, Merck: Consultant (Advisory Board).

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Figure 1.

CONSORT diagram. AC, doxorubicin and cyclophosphamide; FEC-100, 5-fluorouracil, epirubicin and cyclophosphamide.

Figure 2.

Kaplan-Meier estimates of disease-free survival. AC, doxorubicin and cyclophosphamide; FEC-100, 5-fluorouracil, epirubicin and cyclophosphamide.

Figure 2.

Kaplan-Meier estimates of disease-free survival. AC, doxorubicin and cyclophosphamide; FEC-100, 5-fluorouracil, epirubicin and cyclophosphamide.

Figure 2.

Kaplan-Meier estimates of disease-free survival. AC, doxorubicin and cyclophosphamide; FEC-100, 5-fluorouracil, epirubicin and cyclophosphamide.