Overall Survival Benefit for Sequential Doxorubicin-Docetaxel Compared to Concomitant Doxorubicin and Docetaxel in Node-Positive Breast Cancer. 8-Yr. Results of the Breast International Group (BIG) 2-98 Phase III Adjuvant Trial.
Authors: Di Leo A. , Francis P. , Crown J. , de Azambuja E. , Quinaux E. , Gutierrez J. , Nordenskjold B. , Andersson M. , Margeli Vila M. , Piccart-Gebhart M. , Jakesz R. , Viale G. , Olsen S. 
Published: December 2010

Background: In 2006 the 5-yr results of the BIG 2-98 trial suggested better disease-free survival (DFS) in the sequential docetaxel arm compared with both the combination doxorubicin-docetaxel arm (HR 0.83) and the sequential doxorubicin-based control arm (HR 0.79) in patients with node-positive (N+) breast cancer (Francis et al, JNCI 2008,100:121-133).Methods: Treatment (in mg/m2) was given intravenously every 3 weeks unless otherwise stated.Arm 1: doxorubicin (A) 75 × 4 → CMF × 3 (oral cyclophosphamide (C) 100 days 1-14, methotrexate 40 and 5FU 600 days 1 and 8, q 28 days); Arm 2: AC 60/600 × 4 → CMF × 3; Arm 3: A 75 × 3 → docetaxel (T) 100 × 3 → CMF × 3; Arm 4: AT 50/75 × 4 → CMF × 3. Randomization was in the ratio (1:1:2:2). Endocrine and radiotherapy were administered subsequently as per local guidelines. No indications for adjuvant trastuzumab were available when the trial was recruiting. Hereunder we report the updated results at a median follow-up of 8 years.Results: 2,887 patients were enrolled between June '98 and June '01 by 173 centers in 21 countries and 9 BIG groups. In May '09 median follow-up was 93.4 months and total number of events was 916. For the primary comparison (A → T + AT vs. A+AC) DFS was similar (HR 0.91; 95% CI 0.80-1.05). However, DFS appeared significantly better when docetaxel was given sequentially (A → T) compared with control (A) (HR 0.81; 95% CI 0.67-0.99) and compared with combination (AT) (HR 0.84; 95% CI 0.72-0.99). Overall survival (OS) was not significantly better overall (HR 0.91; 95 % CI 0.77-1.08), but appeared significantly better when docetaxel was given sequentially (A → T) compared with combination (AT) (HR 0.79; 95% CI 0.65-0.98) (Table 1). Analyses based on central pathology review defining 4 breast cancer sub-types (highly or incompletely endocrine-responsive, triple negative, HER2 +) and also taking into account patient age and ovarian function are being performed and will be presented at the meeting.Discussion: These data suggest that docetaxel given sequentially after doxorubicin may provide a survival benefit in N+ breast cancer and lend some support to the Norton-Simon hypothesis, which predicted that drug resistance might be overcome by sequential delivering of cytotoxic agents at the maximally tolerated dose. Results by molecular sub-type might provide information on patient cohorts deriving the largest benefit from T.[Table 1. Hazard Ratio (HR) and 95 % CI for DFS and OS]ComparisonHRs for DFS [95% C.I.] p-valueHRs for OS [95% C.I.] p-valueA-T+AT vs A+AC (primary)0.91 [0.80 - 1.05] 0.1870.91 [0.77 - 1.08] 0.28A-T vs A (secondary)0.81 [0.67 - 0.99] 0.0360.86 [0.67 - 1.11] 0.24AT vs AC (secondary)1.02 [0.84 - 1.23] 0.850.96 [0.76 - 1.21] 0.71A-T vs AT (secondary)0.84 [0.72 - 0.99] 0.0350.79 [0.65 - 0.98] 0.028 

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 601.