Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results

Abstract

Lessons learned: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged.

Background: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial.

Methods: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days.

Results: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively.

Conclusion: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.

Trial registration: ClinicalTrials.gov NCT01909830.

© AlphaMedPress; the data published online to support this summary is the property of the authors.

Figures

Figure 1.

Effect of different schedules of combination of pemetrexed (PEM) with carboplatin (CARBO) (A), gemcitabine (GEM) (B), or mitomycin C (MITOC) (C) on three colon cancer cells lines. Cell viability was determined by SRB assay, and the results were expressed as the mean of an octuplicate from three independent experiments. Bars represent standard deviation (*p < .05). Statistical significance was determined using the GraphPad Prism Software Holm‐Sidak method. Treatment dose: #1 (PEM 1 mM ‐ CARBO 0.8 mM), #2 (PEM 10 mM ‐ CARBO 8 mM), #3 (PEM 100 mM ‐ CARBO 80 mM), #4 (PEM 1 mM ‐ GEM 0.4 mM), #5 (PEM 10 mM ‐ GEM 4 mM), #6 (PEM 100 mM ‐ GEM 40 mM), #7 (PEM 1 mM ‐ MITOC 0.03 mM), #8 (PEM 10 mM ‐ MITOC 0.3 mM), and #9 (PEM 100 mM ‐ MITOC 3 mM). Abbreviations: CARBO, carboplatin; GEM, gemcitabine, MITOC, mitomycin C; SRB, sulforhodamine B; WO, wash‐out.