Pemetrexed and Gemcitabine for Chemotherapy Refractory Colorectal Cancer—Results of a Phase II and Translational Research Study
- 1 Department of Oncology, Vejle Hospital, Vejle, Denmark
- 2 Department of Biochemistry, Vejle Hospital, Vejle, Denmark
- 3 Department of Biochemistry, Vejle Hospital, Vejle, Denmark
- 4 Department of Oncology, Vejle Hospital, Vejle, Denmark
- 5 Department of Oncology, Vejle Hospital, Vejle, Denmark
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/m 2 q3w) + g emcitabine (1250 mg/m 2 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 w as 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.
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