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.
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K. Spindler, N. Pallisgaard, R. Andersen, J. Ploen and A. Jakobsen, "Pemetrexed and Gemcitabine for Chemotherapy Refractory Colorectal Cancer—Results of a Phase II and Translational Research Study," Journal of Cancer Therapy, Vol. 4 No. 6, 2013, pp. 44-50. doi: 10.4236/jct.2013.46A2006.
 H. S. Hochster, “The Role of Pemetrexed in the Treatment of Gastrointestinal Malignancy,” Clinical Colorectal Cancer, Vol. 4, No. 3, 2004, pp. 190-195.
 C. Shih, V. J. Chen, L. S. Gossett, et al., “LY231514, a Pyrrolo[2,3-d]Pyrimidine-Based Antifolate That Inhibits Multiple Folate-Requiring Enzymes,” Cancer Research, Vol. 57, No. 6, 1997, pp. 1116-1123.
 C. Cripps, M. Burnell, J. Jolivet, et al., “Phase II Study of First-Line LY231514 (Multi-Targeted Antifolate) in Patients with Locally Advanced or Metastatic Colorectal Cancer: An NCIC Clinical Trials Group Study,” Annals of Oncology, Vol. 10, 1999, pp. 1175-1179.
 W. John, J. Picus, C. D. Blanke, et al., “Activity of Multitargeted Antifolate (Pemetrexed Disodium, LY231514) in Patients with Advanced Colorectal Carcinoma: Results from a Phase II Study,” Cancer, Vol. 88, No. 8, 2000, pp. 1807-1813. doi:10.1002/(SICI)1097-0142(20000415)88:8<1807::AID-CNCR8>3.0.CO;2-L
 C. Underhill, D. Goldstein, V. A. Gorbounova, et al., “A Randomized Phase II Trial of Pemetrexed plus Irinotecan (ALIRI) versus Leucovorin-Modulated 5-FU plus Irinotecan (FOLFIRI) in First-Line Treatment of Locally Advanced or Metastatic Colorectal Cancer,” Oncology, Vol. 73, No. 1-2, 2007, pp. 9-20. doi:10.1159/000120626
 S. R. Alberts, G. P. Kim, M. R. Mahoney, et al., “Pemetrexed and Oxaliplatin for Metastatic Colorectal Cancer: Results of a Phase I Mayo Cancer Center Research Consortium Trial, MC0248,” Clinical Colorectal Cancer, Vol. 6, No. 8, 2007, pp. 572-577.
 J. N. Atkins, S. A. Jacobs, H. S. Wieand, et al., “Pemetrexed/Oxaliplatin for First-Line Treatment of Patients with Advanced Colorectal Cancer: A Phase II Trial of the National Surgical Adjuvant Breast and Bowel Project Foundation Research Program,” Clinical Colorectal Cancer, Vol. 5, No. 3, 2005, pp. 181-187.
 R. Paulson, R. Paulson, J. Hainsworth, C. Geyer, et al., “A Phase II Trial of MTA (Multiple Targeted Antifolate, LY231514) in Patients with 5-FU and Irinotecan-Refractory Colorectal Cancer,” American Society of Clinical Oncology, Vol. 18, 1999, 297a.
 A. C. McDonald, P. A. Vasey, L. Adams, et al., “A Phase I and Pharmacokinetic Study of LY231514, the Multitargeted Antifolate,” Clinical Cancer Research, Vol. 4, No. 3, 1998, pp. 605-610.
 D. A. Rinaldi, H. A. Burris, F. A. Dorr, et al., “Initial Phase I Evaluation of the Novel Thymidylate Synthase Inhibitor, LY231514, Using the Modified Continual Reassessment Method for Dose Escalation,” Journal of Clinical Oncology, Vol. 13, No. 11, 1995, pp. 2842-2850.
 M. Merl, C. Hoimes, T. Pham, et al., “Is There a Palliative Benefit of Gemcitabine plus Fluoropyrimidines in Patients with Refractory Colorectal Cancer?” Expert Opinion on Investigational Drugs, Vol. 18, No. 9, 2009, pp. 257-1264. doi:10.1517/13543780903136724
 J. L. Tonkinson, J. F. Worzalla, C. H. Teng, et al., “Cell Cycle Modulation by a Multitargeted Antifolate, LY231514, Increases the Cytotoxicity and Antitumor Activity of Gemcitabine in HT29 Colon Carcinoma,” Cancer Research, Vol. 59, No. 15, 1999, pp. 3671-3676.
 A. Tesei, L. Ricotti, F. De Paola, et al., “In Vitro Schedule-Dependent Interactions between the Multitargeted Antifolate LY231514 and Gemcitabine in Human Colon Adenocarcinoma Cell Lines,” Clinical Cancer Research, Vol. 8, No. 1, 2002, pp. 233-239.
 T. M. De Pas, F. Toffalorio, C. Catania, et al., “Gemcitabine and Pemetrexed Combination: The Key Role of the Sequence of Drugs Administration,” Annals of Oncology, Vol. 20, No. 10, 2009, pp. 1747-1748.
 C. X. Ma, S. Nair, S. Thomas, et al., “Randomized Phase II Trial of Three Schedules of Pemetrexed and Gemcitabine as Front-Line Therapy for Advanced Non-SmallCell Lung Cancer,” Journal of Clinical Oncology, Vol. 23, No. 25, 2005, pp. 5929-5937.
 K. L. Spindler, N. Pallisgaard, I. Vogelius, et al., “Quantitative Cell Free DNA, KRAS and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan,” Clinical Cancer Research, Vol. 18, No. 4, 2012, pp. 1177-185.
 R. Ferrarotto, K. Machado, M. P. Mak, et al., “A Multicenter, Multinational Analysis of Mitomycin C in Refractory Metastatic Colorectal Cancer“, European Journal of Cancer, Vol. 48, No. 6, 2012, pp. 820-826.
 M. G. Fakih, A. Groman, J. McMahon, et al., “A Randomized Phase II Study of Two Doses of Vorinostat in Combination with 5-FU/LV in Patients with Refractory Colorectal Cancer,” Cancer Chemotherapy and Pharmacology, Vol. 69, No. 3, 2012, pp. 743-751.
 H. Yasui, T. Yoshino, N. Boku, et al., “Retrospective Analysis of S-1 Monotherapy in Patients with Metastatic Colorectal Cancer after Failure to Fluoropyrimidine and Irinotecan or to Fluoropyrimidine, Irinotecan and Oxaliplatin,” Japanese Journal of Clinical Oncology, Vol. 39, No. 5, 2009, pp. 315-320.