Pegylated liposomal doxorubicin (PLD)-carboplatin (C) (C-D) vs paclitaxel-carboplatin (C-P) in relapsing sensitive ovarian cancer (OC): A 500-patient interim safety analysis of the CALYPSO GCIG Intergroup phase III study
E. Åvall‐LundqvistPauline WimbergerLaurence GladieffVal GebskiJens HuoberAnne FloquetBernard M. FitzharrisAlain G. ZeimetM. HeywoodBarbara Schmalfeldt
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5565 Background: The preliminary results from the phase III study of carboplatin - PLD (C-D) vs Paclitaxel-Carboplatin (C-P) in patients (pts) with OC in late relapse is presented. While the primary endpoint of the study is PFS, the specific toxicity observed from these 2 regimens is critically important. Methods: From 4/05 to 10/07, 974 pts were recruited. Pts were randomized to either (C-P) ([C] AUC 5 iv d1 + [P] 175 mg/m2 iv d1, q3 wks) or (C-D) ([C] + PLD [D] 30 mg/m2 iv d1 q4 wks) for at least 6 cycles. Results: The data from the first 500 pts (C-D, n=251; C-P, n=249) were analyzed (Table). Median number of cycles received was 6 (1- 14) in two arms. Haematological toxicity contributed to more cycle delays in the CD (21%) than in the CP (14%) arm. Neutropenia & infection rates were similar in both arms. G-CSF was administered more frequently to pts in C-D arm (21%) than in C-P arm (15%). Grade (G) > 2 non-haematological toxicity was more frequent in the C-P arm. There were 104 (76 related) severe adverse events (SAE) in the C-P arm vs. 81 (44 related) in the C-D arm. Conclusions: This planned interim safety analysis on the first 500 patients confirmed different toxicity profiles in the two arms, with less drug-related SAE and less early therapy termination in the C-D arm. TOXICITY % Pts in C-D arm % Pts in C-P arm Anaemia G3–4 13 7 Thrombocytopenia G3–4 18 4 Alopecia G>2 9 85 Neuropathy G>2 3 29 Allergic reactions G>2 6 19 Arthralgia /myalgia G>2 4 20 Hand-foot syndrome G>2 13 2 Mucositis G>2 15 7 Early treatment termination (toxicity related) 6 14 No significant financial relationships to disclose.Keywords:
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A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.
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AbstractThe combination of carboplatin and paclitaxel is widely used to treat multiple solid tumors including ovarian, lung and breast cancer. Usually these drugs are given simultaneously with little regard to the importance of scheduling to obtain a maximal response. To investigate the importance of sequencing, the human breast Bcap37 and ovarian OV2008 cancer cell lines were exposed to carboplatin and paclitaxel in three different sequences: 1) pretreatment with paclitaxel followed by carboplatin; 2) pretreatment of carboplatin followed by paclitaxel and 3) simultaneous treatment with these two agents. The combination of carboplatin and paclitaxel resulted in antagonistic interactions when tumor cells were exposed to carboplatin prior to paclitaxel or exposed to the two drugs simultaneously, but there was little antagonistic interaction observed when paclitaxel was administered before carboplatin. Biochemical examination revealed that pretreatment or cotreatment of carboplatin inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation. Further analyses demonstrated that carboplatin could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel was administered before carboplatin. These results indicate that the interaction between paclitaxel and carboplatin is highly schedule dependent. The optimal schedule for this combination is sequential exposure of paclitaxel followed by carboplatin.
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