Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741

TLDR

The trial compared sequential versus concurrent adjuvant chemotherapy and dose‑dense versus conventional schedules in women with axillary node‑positive breast cancer to evaluate disease‑free and overall survival and toxicity. Two hundred five patients were randomized to one of four regimens: sequential doxorubicin, paclitaxel, cyclophosphamide every 3 weeks; the same sequence every 2 weeks with filgrastim; concurrent doxorubicin‑cyclophosphamide followed by paclitaxel every 3 weeks; or the concurrent schedule every 2 weeks with filgrastim. Dose‑dense therapy reduced relapse or death (RR 0.74) and improved overall survival (RR 0.69), yielding 4‑year DFS of 82% versus 75% for conventional regimens, with no difference between concurrent and sequential schedules and less severe neutropenia.

Abstract

Purpose: Using a 2 × 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node–positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. Patients and Methods: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A × 4 (doses) → T × 4 → C × 4 with doses every 3 weeks, (II) sequential A × 4 → T × 4 → C × 4 every 2 weeks with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks, or (IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim. Results: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P = .010), and OS (RR = 0.69; P = .013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. Conclusion: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.