Pemetrexed and Gemcitabine for Chemotherapy Refractory Colorectal Cancer—Results of a Phase II and Translational Research Study

Karen-Lise Garm Spindler, Niels Pallisgaard, Rikke Fredslund Andersen, John Ploen, Anders Jakobsen

Department of Biochemistry, Vejle Hospital, Vejle, Denmark.
Department of Oncology, Vejle Hospital, Vejle, Denmark.

DOI: 10.4236/jct.2013.46A2006                

Abstract

Introduction: We investigated the safety and efficacy of pemetrexed with gemcitabine in heavily pre-treated, chemotherapy refractory, KRAS mutated colorectal cancer (mCRC) and the prognostic value of quantitative levels of cell free DNA (cfDNA) in plasma. Methods: Inclusion criteria comprised; histopathologically verified, KRAS mutant, chemotherapy resistant mCRC, adequate organ function and performance status. Patients received pemetrexed (initially 500 mg/m² q3w) + gemcitabine (1250 mg/m² days 1 and 8) until progression or unacceptable toxicity. RECIST version 1.1, NCI-CTCAE version 4.0 and Kaplan-Meier statistics were used for endpoint evaluation. Cell free DNA was quantified from pre-treatment EDTA plasma-samples by an in-house qPCR. Results: Forty patients were included. The median number of cycles was 3 (range 0 - 12). Thirty-six percent obtained disease stabilisation, but no objective response was observed. Median PFS and OS were 2.8 (range 2.1 - 4.0) and 5.4 (range 4.3 - 7.0) months, respectively. Adverse events caused immediate discontinuation of treatment or delay of the next cycle and consequently discontinuation in 5 patients. Translational research revealed a shorter PFS and OS with increasing levels of cfDNA. The median PFS in patients with cfDNA levels above the 75 percentile was 2 months compared to 4 months in the remaining patients, HR 3.23 (1.05 - 9.89), p = 0.0008. The median OS was 3 and 6 months, respectively, HR 2.9 (95%CI 0.98 - 8.34). Cox regression analysis confirmed that cfDNA remained a significantly independent prognostic factor for both PFS and OS. Conclusion: Pemetrexed and gemcitabine did not prove sufficient benefit and unacceptable toxicity was observed. The potential value of cfDNA should be investigated further.

Keywords

Metastatic Colorectal Cancer; KRAS; cfDNA; Plasma; Pemetrexed; Gemcitabine

Conflicts of Interest

The authors declare no conflicts of interest.

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