Cell free DNA and hepatic arterial infusion of oxaliplatin plus systemic capecitabine for patients with colorectal cancer liver metastases

Abstract

Background: Hepatic Arterial Infusion (HAI) where the cytotoxic agents are administered intrahepatic is an experimental treatment option for patients with colorectal cancer liver metastases (CRCLM). We aimed to investigate the level of cell free DNA(cfDNA) in patients with CRCLM receiving HAI with oxaliplatin and systemic capecitabine. Methods: Patients were treated according to a single arm phase II study including patients with liver limited mCRC from November 2004 to May 2010, who were not eligible for any other standard local treatment. Therapy comprised intrahepatic infusion of oxaliplatin 100 mg/m2 every second week with concomitant oral capecitabine 3500 mg/m2 every second week for up to 12 cycles. A pre-treatment plasma sample was used for quantification of cfDNA by a modified fluorescent assay. Survival was analyzed by the Kaplan-Meier method and Cox multiple regression analysis. Results: Baseline plasma samples were available from62 patients. The majority of patients were males (61%), the median age 61.3 years (range 40.8-74.8) and distribution of colonic/rectal cancers 68%/32%. The median level of cfDNA was 0.92 ng/lL (95%CI 0.84-1.00) with no significant differences according to pre-treatment patients characteristics apart fromsignificantly higher cfDNA levels with poor PS (p<0.001). Plasma cfDNA was significantly lower (0.91 ng/lL, 95% CI 0.76-0.98) in patients who achieved an objective response compared to non-responders (1.79 ng/lL, 95% CI 0.99-2.57, p=0.02). Patients with a baseline value of cfDNA above the 75th quartile had amedian overall survival of 2.4 years (95%CI 0.7-2.8), compared to 3.9 years (95%CI 2.8-5.9) for patients below the 75th quartile (p=0.02). In multivariate analysis, only increasing baseline level of cfDNA, (HR 1.90, 95% CI 1.07-3.38, p=0.03), and mutated KRAS status, (HR 3.17, 95%CI 1.67-6.03, p<0.001), remained associated with short survival. Conclusions: Patients with a low baseline level of plasma cfDNA had a favorable outcome from treatment with HAI and capecitabine for CRCLM. Consequently, cfDNA could hold clinically relevant predictive and prognostic information, which needs validation in this setting.