A phase I/II and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma.
This phase I/II study was conducted to determine the maximum recommended dose of pemetrexed when given in combination with a fixed dose of cisplatin, and the efficacy, toxicity and association of 5,10-methylenetetrahydrofolate reductase (MTHFR) variants with this pemetrexed--cisplatin combination, in patients with unresectable, advanced gastric carcinoma. Patients 18-70 years of age, with stage IV disease or post-surgery recurrence, no earlier palliative chemotherapy, 0 or 1 Eastern Cooperative Oncology Group performance status, were included. The cisplatin dose was 75 mg/m. In phase I, the initial dose of pemetrexed was 600 mg/m, escalated in 100 mg/m increments. In phase II, efficacy, including overall response rate, overall survival, as well as toxicity and MTHFR pharmacogenetics were investigated. Phase I enrolled 16 patients; 700 mg/m was defined as pemetrexed recommended dose. Thirteen serious adverse events were reported; the most common grade 3/4 toxicities were haematologic (10 of 13, 76.9%). Phase II enrolled 73 patients, 69 qualified for safety and 68 for efficacy analysis; 65 for pharmacogenomic analysis. Overall response rate was 23.5% (14.1%, 35.4%), disease control rate 55.9%, median overall survival 11.8 months (95% confidence interval, 7.2-18.5 months), progression-free survival 4.9 months (95% confidence interval, 2.8-7.1 months), and median response duration 5.4 months. Patients with MTHFR A1298C variants had median overall survival of 6.6 months, significantly shorter than patients with the wild type (median 18.5 months, P=0.001). The pemetrexed--cisplatin combination in patients with advanced gastric cancer generates modest efficacy and a manageable toxicity profile. The reduced overall survival in patients with MTHFR A1298C polymorphism variants deserves further investigation.
Chen
Jen-Shi
JS
Department of Hematology and Oncology, Chang-Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
Chao
Yee
Y
Bang
Yung-Jue
YJ
Roca
Enrique
E
Chung
Hyun C
HC
Palazzo
Felipe
F
Kim
Yeul H
YH
Myrand
Scott P
SP
Mullaney
Brian P
BP
Shen
Li J
LJ
Linn
Carlos
C
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005971:Glutamates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D000068437:Pemetrexed; D010597:Pharmacogenetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D005493:Folic Acid Antagonists; D005971:Glutamates; D026901:Membrane Transport Proteins; D000068437:Pemetrexed; D006147:Guanine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002945:Cisplatin