Doxorubicin and Paclitaxel Versus Fluorouracil, Doxorubicin, and Cyclophosphamide for Metastatic Breast Cancer
Authors: Carl D. Atkins, J. Jassem
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.14.3441 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11454896 Doxorubicin and Paclitaxel Versus Fluorouracil, Doxorubicin, and Cyclophosphamide for Metastatic Breast Cancer Carl D. AtkinsxCarl D. AtkinsSearch for articles by this author J. JassemxJ. JassemSearch for articles by this author Show More South Shore Hematology-Oncology Associates, Rockville Centre, NYMedical University of Gdansk, Gdansk, Poland https://doi.org/10.1200/JCO.2001.19.14.3441 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15072001In Reply:We appreciate Dr Atkins’ interest in our article, but we disagree with his critique. Our study found that overall response rate, time to progression, and overall survival significantly favored the AT regimen compared with FAC chemotherapy.1 Atkins questions the validity of our last finding, based on the “unusual feature” of greater difference between groups for overall survival compared with time to progression. In our study, the differences between the AT and FAC arm were significant for both time to progression and overall survival; P = .034 and .013, respectively. Although the absolute difference in medians was greater for overall survival than for time to progression, in relative terms the gain was greater for time to progression (34%) than for overall survival (28%), and thus, the result should not be considered “unusual.” Similar results were obtained in a recent study of Bishop et al2 comparing paclitaxel versus cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) in women with previously untreated metastatic breast cancer. These investigators found no significant difference in progression-free survival between treatment arms (P = .25) but, in a multivariate analysis, found that patients who received paclitaxel had a significantly longer overall survival time compared with those who received CMFP (P = .025).Atkins suggests that inferior postrelapse survival in patients who received FAC was most likely attributed to inadequate second-line chemotherapy in this arm and supports this conclusion with the following statement: “. . . 74% of patients in the FAC arm required second-line chemotherapy, but only 60% of these received chemotherapy.” We do not agree with this assertion. First, the calculation of Atkins is imprecise. Of the 133 patients in the FAC arm, 99 patients received salvage therapy in the form of surgery, radiotherapy, chemotherapy, or hormonal therapy. Of these 99 patients, 64 (65%) received second-line chemotherapy. More importantly, not all patients who relapse after primary chemotherapy for advanced breast cancer are appropriate candidates for second-line chemotherapy. The proportion of patients administered second-line chemotherapy in our series was typical of that reported in similar studies, with the exception of clinical trials that mandated or encouraged such management (eg, cross-over studies).Atkins also suggests that shorter survival in the FAC arm was caused by a low proportion of patients given a taxane as a second-line treatment. In our series, a taxane was given to 32 of 64 patients who received second-line chemotherapy. At the time our study was conducted (November 1996 to April 1998), literature on the efficacy of taxane-based salvage chemotherapy in advanced breast cancer after anthracycline therapy had only recently emerged. Also, outside of clinical trials, the availability of taxanes in the region of our investigation (Central & Eastern Europe and Israel) was limited. Still, the proportion of patients given the second-line taxane treatment in our study was similar to other trials comparing a taxane to nontaxane regimen in advanced breast cancer. For example, in the trial conducted by Bishop et al2 comparing paclitaxel to CMFP, second-line chemotherapy was given to 68 of 99 patients in the CMFP arm; however, only six of these patients received a taxane. In a study reported by Chan et al3 comparing single-agent docetaxel to doxorubicin, only 26% of patients in the doxorubicin group received taxane-containing salvage therapy. Currently, taxane-based second-line chemotherapy is commonly used. This strategy is justified, given the high activity of the taxanes in advanced breast cancer and recent documentation of a survival benefit.4Finally, many studies comparing primary chemotherapy regimens in cancer have been criticized for clouding the survival differences between arms by the frequent use of second-line chemotherapy (often the comparator regimen). This was not the case in our study. Indeed, a supplemental survival analysis using secondary chemotherapy as a time-dependent covariate in a Cox proportional hazard model showed that the effect of secondary chemotherapy was not significantly different between the two treatment arms. Furthermore, this analysis showed that patients receiving second-line chemotherapy had a significantly higher hazard than those who did not. This possibly indicates that second-line chemotherapy was administered to patients who had a bad survival prognosis at the time this management was considered.Given our data, we stand by our conclusion of the superiority of AT over FAC regimen in terms of overall response rate, time to progression, and overall survival. The question of whether the survival differences in patients treated with the FAC regimen may be compensated by the use of second-line therapy remains to be established.1. Jassem J, Pieńkowski T, Płuzańska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:: 1707,2001-1715, Link, Google Scholar2. Bishop JF, Dewar J, Toner GC, et al: Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 17:: 2355,1999-2364, Link, Google Scholar3. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:: 2341,1999-2354, Link, Google Scholar4. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17:: 1413,1999-1424, Link, Google Scholar