A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

Abstract

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for 1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and 2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. 137 models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs docetaxel, carboplatin vs paclitaxel and carboplatin vs docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. 65 eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3% n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01 Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5% n=88 compared to 49.4% n=85 for paclitaxel combined with other agents (p<0.001 Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets.