In an analysis of all patients who were randomly assigned and treated, the combination of pemetrexed and cisplatin was associated with a statistically significant improvement in survival compared with cisplatin alone; the median survival was 12.1 in the pemetrexed plus cisplatin arm versus 9.3 months in the cisplatin alone arm (P = .020). The hazard ratio for death of patients in the pemetrexed plus cisplatin arm versus those in the control arm was 0.77. Median time-to-progression was significantly longer in the pemetrexed plus cisplatin arm (5.7 months vs. 3.9 months, P = .001). This superiority in the combination arm was also demonstrated in the vitamin-supplemented subgroup. The median survival was 13.3 in the combination arm and 10.0 months in the cisplatin alone arm (P = .051). The principal adverse effects of the pemetrexed plus cisplatin regimen were myelosuppression, fatigue, nausea, vomiting, and dyspnea. Most grade 3 to 4 adverse effects were significantly reduced by vitamin supplementation without any decrease in efficacy.
A randomized, phase III trial of 250 patients was performed by the European Organisation for Research and Treatment of Cancer (EORTC-08983) to compare cisplatin alone with the combination of raltitrexed, a thymidine synthase inhibitor, and cisplatin in first-line treatment of patients with malignant pleural mesothelioma. Cisplatin (80 mg/m2 IV) was given on day 1, alone or combined with raltitrexed (3 mg/m2). No toxic deaths resulted, and the main grade 3 or 4 toxicities observed were neutropenia and emesis, which were reported twice as often in the combination arm. Among 213 patients with measurable disease, the response rate was 13.6% versus 23.6%, respectively (P = .056). No difference in quality of life was observed. The combination arm was associated with increased survival. Median overall survival was 8.8 months versus 11.4 months, and the 1-year survival rate was 40% versus 46% (P = .048).[Level of evidence: 1iiA]
Malignant Peritoneal Mesothelioma
A multi-institutional, registry study evaluated cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse, malignant, peritoneal mesothelioma. Among 401 patients, 187 (46%) had complete or near-complete cytoreduction, and 372 (92%) received HIPEC. Of the HIPEC patients, 311 (83%) received cisplatin and doxorubicin. The median follow-up period was 33 months (range, 1-235 months). Grade 3 to 4 complications were seen in 127 (31%) of the 401 patients, and 9 patients (2%) died perioperatively.