Pemetrexed in gastric cancer: clinical experience and future perspectives

The development of more effective and convenient chemotherapy regimens for the treatment of gastric cancer that incorporate novel agents remains an exciting area of research. A phase II study was conducted to assess the response rate and toxicity profile of pemetrexed, a novel multitargeted antifolate, in previously untreated patients with measurable, advanced, or metastatic adenocarcinoma of the stomach or gastroesophageal junction. In this study, pemetrexed-induced toxicity at the starting dose of 500 mg/m(2) intravenously once every 21 days was considerable with each of the first six patients who experienced at least one episode of grade 3/4 toxicity. Two patients discontinued from study, and two patients died. All deaths were caused by drug-related toxicity. No responses were seen in this briefly treated group. These observations led to an amended study protocol designed to improve tolerability of pemetrexed with folic acid supplementation. Supplementation with folic acid 5 mg was given orally once daily for 2 days before pemetrexed on the day of treatment, and for 2 days following treatment. Tumor evaluation was performed after every two cycles of therapy. The trial was recently closed to accrual and preliminary clinical results are reported here. Thirty-two patients were enrolled and 30 patients were evaluable for efficacy. A total of 129 courses of pemetrexed were administered, and the median number of courses received per patient was four (range, one to eight courses). Two complete and five partial responses were observed, with four patients experiencing stable disease. In an intent-to-treat analysis, the overall response rate was 22%, and 23% for the evaluable patients. Median duration of response was 4.4 months (range, 3 to 11 months) and median time to treatment failure was 2.6 months (range, 0.5 to 12 months). Of the 32 patients treated, eight experienced grade 4 neutropenia and one had grade 4 thrombocytopenia. The most common nonhematologic toxicities were diarrhea, fatigue, mucositis, nausea and vomiting, skin rash, and reversible abnormalities in liver function. There was no case of nonhematologic grade 4 toxicity. Although the clinical experience with pemetrexed in advanced gastric cancer remains limited, the promising activity observed in this study indicates that combination studies are warranted. In addition, high-dose intermittent oral folic acid given in this study allowed administration of pemetrexed at the dose and schedule explored with a highly satisfactory safety profile and with no apparent compromise in efficacy. This article discusses how pemetrexed may be investigated in future clinical trials in gastric cancer.