The role of gender in predicting for reduced drug clearance and increased toxicity in non-small cell lung cancer (NSCLC) patients receiving carboplatin and paclitaxel.

Abstract

7557 Background: There is wide variability in toxicity from chemotherapy attributed to multiple factors including pharmacogenomic (PG), ethnic and nutritional differences. Gender differences in tolerance of anticancer drugs have also been described. The aim of this ongoing study was to investigate predictors of toxicity in advanced NSCLC patients receiving palliative chemotherapy. Methods: Stage III-IV NSCLC patients, receiving paclitaxel (175 mg/m2) and carboplatin (AUC 6) 3 weekly were enrolled. Demographic, nutritional and inflammatory data were collected at baseline. Plasma samples were collected using a limited sampling strategy and drug concentrations measured using ICP-MS for carboplatin and LC-MS for paclitaxel. Empiric Bayesian estimates of clearance (CL) were obtained using population pharmacokinetic (PK) analyses and NONMEM software. Toxicities, monitored weekly in cycle 1, were graded according to CTCAEv3.0 and correlated with the PK data. Results: Forty-four male and 20 female patients were recruited. Median age was 63 years for both men and women. Women experienced more peripheral sensory neuropathy (73.7% vs. 33.3%, p = 0.003), stomatitis (26.3% vs. 7.1%, p = 0.04) and grade 2-3 vomiting (26.3% vs. 7.1%, p = 0.04) than men. There were no significant gender differences in haematological toxicities. PK analyses showed that women had lower paclitaxel CL (10.5 L/h vs. 13.0 L/h, p < 0.0001) and carboplatin CL (7.3 L/h vs. 9.3 L/h, p < 0.0001) than men. Median survival was longer for women (18.4 vs. 16.0 months), although this was not statistically significant. Asians had significant slower clearance of paclitaxel than Caucasians (11.1 L/h vs. 12.7 L/h, p = 0.044). Conclusions: Women with NSCLC had lower clearance of both carboplatin and paclitaxel than men, which was associated with an increased incidence of non-haematological toxicity. The causes for these differences should be explored with PG and metabonomic analyses.