Relationship of Anthracycline-Free Interval to Outcomes in a Phase 3 Trial of Pegylated Liposomal Doxorubicin Plus Docetaxel Compared with Docetaxel Monotherapy in Patients with Advanced Breast Cancer Treated with Adjuvant Anthracycline.

Abstract Background: An earlier report showed that pegylated liposomal doxorubicin (PLD) + docetaxel (D) improved time to progression (TTP) vs D alone in patients (pts) with advanced breast cancer (ABC) who had relapsed at least 1 year after adjuvant or neoadjuvant anthracycline therapy. (Sparano et al., SABC 2008, #80) This analysis evaluated whether the time between completion of adjuvant anthracycline therapy until relapse impacts overall outcome. We retrospectively examined outcomes in pts with an anthracycline-free (A-F) interval of 1 to 2 years and pts with an A-F of >2 years.Methods: 751 pts were randomly assigned to receive either D 75 mg/m2 (N=373) or PLD 30 mg/m2 followed by D 60 mg/m2 (N=378) every 21 days. Treatment was continued until disease progression or the occurrence of unacceptable toxicity. The primary endpoint was TTP and secondary endpoints included overall survival (OS), progression free survival (PFS), objective response rate (ORR), and safety. Pts were categorized into groups by anthracycline-free interval of 1-2 years or >2 years. Relationship between the interval and outcomes was examined by proportional hazards model for TTP, OS (updated as of 1-Dec-2008), and PFS.Results: Approximately 60% of pts in both treatment groups had A-F intervals of >2 years. Median TTP, OS, and PFS (months) by A-F interval groups are listed in the Table. A-F interval 1-2 years A-F interval >2 years D, n=151PLD+D, n=155HR (CI)*; P**D, n=221PLD+D, n=221HR (CI)*; P**TTP5.77.80.67 (0.52, 0.87); .0027.710.60.63 (0.50, 0.79); <.001OS15.817.90.90 (0.69, 1.16); .40424.722.91.10 (0.86, 1.40); .448PFS5.57.70.67 (0.52, 0.87); .0027.710.00.65 (0.51, 0.81); <.001ORR25%34%P=.086†27%36%P=.042† A-F interval 1-2 years, N=306 A-F interval >2 years, N=442 HR (CI)***; P**TTP6.6 8.9 0.74 (0.63, 0.88); .001OS17.2 23.4 0.63 (0.52, 0.75); <.001PFS6.5 8.7 0.74 (0.62, 0.87); <.001ORR30% 31% P=.826†*Proportional hazard model for PLD+D vs D; **Log-rank test; ***Proportional hazard model for >2 years vs ≤2 years A-F; †Cochran-Mantel-Haenszel test.Overall, HFS and stomatitis occurred more often in pts treated with PLD+D. The overall incidence of CHF was 1%.Conclusions: An A-F interval of >2 years reduced the risk for TTP, OS, and PFS, regardless of treatment. However, similar to results of the overall study, treatment with the combination PLD+D resulted in statistically significant improvement of TTP and PFS, but not OS, compared with D among pts with ABC, regardless of A-F interval. The addition of PLD to a D-based regimen is an active option for pts with ABC previously treated with adjuvant anthracycline regimens. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2095.