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Due to the frequent use of intrapleural interleukin-2 (IL-2) to treat pleural effusions from malignant mesothelioma (MMe), we measured nitric oxide (NO) end product nitrite (NO 2 − ) in pleural effusions of 12 MMe patients with chronic or chronic-relapsing pleurisy. Through high performance liquid chromatography analysis, NO 2 − was found in the initial pleural fluid sample of all patients (156.25 pmolml −1 ), and increased significantly following IL-2 intrapleural instillation, both at 24 (589.91 pmolml −1 , P ⩽0.0005) and 48 h (756 pmolml −1 , P ⩽0.0005). Even though it is difficult to argue if the large amounts of NO end product NO 2 − we observed is produced by IL-2-stimulated and recruited immune cells, by MMe cells themselves, or by both, it is possible that NO could contribute to the complex antitumor activity of IL-2.

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months,and most patients die within two years of diagnosis. There is an urgent need to identify new therapies for treating MPM patients.

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1–9 and 9–12 months; mesothelioma-related pleural effusion severely impairs the patients’ quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40–84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9 000 000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3 000 000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5–39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.