In a phase III trial (SWOG S0221) reported in the Journal of Clinical Oncology, George T. Budd, MD, of Taussig Cancer Center, Cleveland Clinic, and colleagues found no difference in disease-free survival among four different combinations of continuous or every-other-week doxorubicin/cyclophosphamide (AC) and weekly or every-2-week paclitaxel in patients with node-positive or high-risk node-negative breast cancer.¹ Both the AC comparison and the paclitaxel comparison were halted for futility at interim analyses. In the current analysis, a difference in overall survival was observed among regimens, and subgroup analysis suggested benefit of every-2-week AC and every-2-week paclitaxel among patients with hormone receptor–negative/HER2-negative disease.

Study Details

This 2 × 2 factorial design trial tested two hypotheses: (1) that a novel continuous schedule of AC was superior to six cycles of AC once every 2 weeks; and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks.

The first randomization compared intravenous doxorubicin at 60 mg/m² on day 1, intravenous cyclophosphamide at 600 mg/m² on day 1, and subcutaneous pegfilgrastim (Neulasta) at 6 mg on day 2 every 2 weeks vs intravenous doxorubicin at 24 mg/m² once per week, oral cyclophosphamide at 60 mg/ m² once daily, and subcutaneous filgrastim ­(Neupogen) at 5 µg/kg rounded to the nearer of 300 or 480 µg once daily (except on the days of intravenous drug administration).

The second randomization was subsequent intravenous paclitaxel at 175 mg/m² on day 1 once every 2 weeks and subcutaneous pegfilgrastim at 6 mg on day 2 every 2 weeks for six cycles vs intravenous paclitaxel 80 mg/m² once per week for 12 weeks.

Between December 2003 and November 2010, 2,716 patients were randomly assigned to receive AC every 2 weeks for six cycles plus paclitaxel every 2 weeks for six cycles (n = 678), AC weekly for 15 weeks plus paclitaxel every 2 weeks for six cycles (n = 693), AC every 2 weeks for six cycles plus paclitaxel weekly for 12 weeks (n = 697), or AC weekly for 15 weeks plus paclitaxel weekly for 12 weeks (n = 648). The primary endpoint was disease-free survival.

Futility Boundaries Crossed

The futility boundary was crossed for the AC comparison at the first interim analysis in September 2010. Accrual was suspended in November 2010, and the trial was reopened in December 2010, with all patients assigned to four cycles of AC every 2 weeks and randomly assigned to receive the two paclitaxel schedules (total, 578 additional patients). The futility boundary for the paclitaxel comparison was crossed at the third interim analysis in September 2012.  

Evidence of Interaction

The current analysis included outcomes through October 2013. No significant interaction of the AC and paclitaxel factors was found in the interim analyses. However, after a median follow-up of 6 years, a significant interaction developed between the two randomization factors (P = .024 for disease-free survival, P = .010 for overall survival) among the 2,716 originally randomized patients, which precluded interpretation of the two factors separately.

Survival Results

Comparison of all four groups simultaneously showed no difference in disease-free survival (P = .11). Compared with the AC every-2-week/paclitaxel every-2-week group, hazard ratios were 1.32 (95% confidence interval [CI] = 1.04–1.68) for continuous AC/paclitaxel every 2 weeks, 1.24 (95% CI = 0.98–1.59) for AC every 2 weeks/weekly paclitaxel, and 1.12 (95% CI = 0.87–1.44) for continuous AC/weekly paclitaxel.  

Comparison of all four groups showed a significant difference in overall survival (P = .040), with the highest overall survival reported in the every-2-week AC and every-2-week paclitaxel group; compared with this group, hazard ratios were 1.44 (95% CI = 1.08–1.93) for continuous AC/paclitaxel every 2 weeks, 1.46 (95% CI = 1.09–1.95) for AC every 2 weeks/weekly paclitaxel, and 1.24 (95% CI = 0.91–1.68) for continuous AC/weekly paclitaxel.

Subset Analysis

Unplanned subset analyses to investigate the possible interaction between the AC and paclitaxel schedules suggested that the observed difference in overall survival was confined to patients with hormone receptor–negative/HER2-negative tumors (P = .067), with no evidence of difference in patients with hormone receptor–positive/HER2-negative tumors (P = .90) or HER2-positive tumors (P = .40).

Toxicity

Grade 3 or 4 leukopenia occurred in 20% of patients during treatment with AC every 2 weeks and 15% of patients during treatment with continuous AC; grade 3 or 4 neutropenia occurred in 26% and 23%, respectively; and grade 3 or 4 febrile neutropenia occurred in 6% and 2%, respectively. Grade 3 or 4 leukopenia (7% vs 1%) and neutropenia (12% vs 2%) were more common during treatment with weekly paclitaxel vs every-2-week paclitaxel, but rates of febrile neutropenia were similar (0.1% vs 0.2%).

Grade 3 or 4 allergic reactions (1.4% vs 0.5%), musculoskeletal pain (11% vs 3%), and neurologic toxicity (17% vs 10%) were more common during every-2-week paclitaxel. Deaths due to toxicity during paclitaxel given every 2 weeks were due to heart failure after AC every 2 weeks in one patient, pneumonitis in one patient, and unclear/multifactorial factors in two patients. Deaths due to toxicity during treatment with weekly paclitaxel were caused by heart failure after AC every 2 weeks in one patient and pneumonitis in two patients.

All planned AC treatment was completed by 88% of patients receiving AC every 2 weeks and by 83% of those receiving continuous AC (P < .001), with 7.9% vs 11% (P = .006) stopping AC early due to adverse events.

The investigators concluded: “Patients achieved a similar disease-free survival with any of these regimens. Our study suggests the hypothesis that patients with hormone receptor–negative/HER2-negative high-risk breast cancers may have improved outcome when treated with the once-every-2-week regimen, and we recommend that this hypothesis be investigated in other studies.” ■

Disclosure: This study was supported by the National Cancer Institute, the Canadian Cancer Society Research Institute, and Amgen. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.