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TP is noninferior to PE in overall survival and superior in time to progression and overall response rates. Because of slightly worse toxicity profile TP is not a first-line standard treatment for patients with extensive disease small-cell lung cancer.

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Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B 12 to the treatment regimen.We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation. Experimental Design: Patients with malignant pleural mesothelioma or non^small cell lung cancer received pemetrexed doses from 500 to 900 mg/m 2 + 75 mg/m 2 cisplatin once every 21days. Folic acid and vitamin B 12 were administered per label recommendations. Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m 2 + 75 mg/m 2 cisplatin. Based on this study, the recommended dose would be 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m 2 single-agent pemetrexed versus 500 mg/m 2 and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.Pemetrexed is an antifolate cytotoxic agent that has been approved in many countries in combination with cisplatin for first-line treatment of malignant pleural mesothelioma (MPM; ref. 1) and as single-agent therapy for second-line treatment of non-small cell lung cancer (NSCLC; ref. 2). Pemetrexed in combination with cisplatin has also been shown to be effective and well tolerated for first-line treatment of NSCLC (3) and was recently approved in Europe and the United States for that indication.The currently established dose of 500 mg/m 2 pemetrexed in combination with 75 mg/m 2 cisplatin every 21 days was established based on a phase I study of pemetrexed in combination with cisplatin that was conducted without folic acid and vitamin B 12 supplementation (4). During the pivotal phase III study, in which 500 mg/m 2 pemetrexed in combination with 75 mg/m 2 cisplatin was administered to patients with MPM (1), results from a multivariate regression analysis became available that indicated that an elevated baseline homocysteine level (consistent with subclinical folate deficiency) was highly correlated with more severe pemetrexed toxicities (5). To reduce the more severe drug-induced toxic effects, the protocol was amended to include supplementation of patients with folic acid and vitamin B 1...