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A phase I/II and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma

Cited 14 time in Web of Science Cited 18 time in Scopus
Authors
Chen, Jen-Shi; Chao, Yee; Bang, Yung-Jue; Roca, Enrique; Chung, Hyun C.; Palazzo, Felipe; Kim, Yeul H.; Myrand, Scott P.; Mullaney, Brian P.; Shen, Li J.; Linn, Carlos
Issue Date
2010-09
Citation
Anti-Cancer Drugs, Vol.21 No.8, pp.777-784
Keywords
advanced gastric carcinomacisplatinMTHFRpharmacogeneticsphase I/II clinical trialspemetrexedunresectable
Abstract
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 75mg/m(2). In phase I, the initial dose of pemetrexed was 600mg/m(2), escalated in 100mg/m(2) 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; 700mg/m(2) 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. Anti-Cancer Drugs 21: 777-784 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
ISSN
0959-4973
URI
https://hdl.handle.net/10371/172961
DOI
https://doi.org/10.1097/CAD.0b013e32833cfbca
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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