BACKGROUND: Pemetrexed‐cisplatin chemotherapy is the standard of care in the first‐line treatment of unresectable malignant pleural mesothelioma (MPM). Second‐line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first‐line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine‐vinorelbine combination in pemetrexed‐pretreated patients with MPM.METHODS: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum‐derivative were enrolled. Gemcitabine 1000 mg/m² and vinorelbine 25 mg/m² were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity.RESULTS: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1–26.5%), and 10 patients (33.3%; 95% CI, 17.3–52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5–62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6–12.1 months), and the median survival was 10.9 months (range, 0.8–25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild.CONCLUSIONS: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed‐pretreated patients with MPM. The role of second‐line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors. Cancer 2008. © 2008 American Cancer Society.

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.

BACKGROUND: Thymic malignancies are rare tumors. The insulin‐like growth factor‐1 (IGF‐1)/IGF‐1 receptor (IGF‐1R) system is involved in the development of the thymus. IGF‐1R expression in thymic epithelial malignancies is unknown.METHODS: The authors investigated the expression of IGF‐1R and phosphorylated AKT serine 473 (p‐AKT) by using immunohistochemistry and examined the clinicopathologic correlations in a retrospective, single‐institution surgical series of 132 patients with thymic epithelial malignancies.RESULTS: Earlier disease stage, less aggressive histologic types, and complete resection were significant positive prognostic factors for disease‐related survival and progression‐free survival, and being a woman was a better prognostic factor for disease‐related survival. IGF‐1R and p‐AKT protein levels were expressed in 20% and 36% of thymic tumors, respectively. Both markers were expressed more commonly in recurrent disease than in primary tumors, in more aggressive subtypes, and in more advanced disease stages. There was a trend toward better survival and progression‐free survival in patients who were negative for IGF‐1R or p‐AKT expression in the whole series. When only the 91 primary tumors, IGF1R expression was associated with worse progression‐free survival (P < .001).CONCLUSIONS: The current retrospective analysis demonstrated that disease stage, tumor histology, sex, and resection type were major prognostic factors in the survival of patients with thymic malignancies. The expression levels of IGF‐1R and p‐AKT in thymic tumors suggested that IGF‐1R is a potential target for treatment. Cancer 2010. Published 2010 by the American Cancer Society.