INTRAPLEURAL ADMINISTRATION OF INTERLEUKIN-2 IN PLEURAL MESOTHELIOMA - A PHASE I-II STUDY

Twenty-three patients with pleural mesothelioma stage I-IIA were enter ed in a study of continuous daily intrapleural infusion of interleukin 2 (IL-2) for 14 days, repeated every 4 weeks. IL-2 was administered a ccording to a groupwise dose escalation schedule (group A, 3 x 10(4); group B, 3 x 10(5); group C, 3 x 10(6); group D, 6 x 10(6); group E, 1 8 x 10(6); and group F, 36 x 10(6) IU day(-1)). Each group consisted o f at least three patients. Intrapleural administration of IL(-2) was a ssociated with acceptable toxicity. All patients were treated on an ou tpatient basis except for the patients at dose levels E and F. Dose-li miting toxicity was observed at level F, 36 x 10(6) IU daily, and cons isted of catheter infection, fever and flu-like symptoms. Intrapleural IL-2 levels were high (>20 000 IU ml(-1)) at levels E and F, while se rum levels in most patients were not or barely detectable (<3-30 IU ml (-1)). Intrapleural IL-2 levels were up to 6000-fold higher than syste mic levels. Intrapleural tumour necrosis factor alpha (TNF-alpha) leve ls varied greatly and did not correlate with IL-2 dosage. Intrapleural mononuclear cells (MNCs) displayed IL-2-induced lymphokine-activated killer (LAK) activity in all patients. Two patients were not evaluable for response owing to catheter-related problems which precluded the d elivery of IL-2. Partial response (PR) occurred in 4 of 21 evaluable p atients (19%; 95% confidence interval 5-42%) with a median time to pro gression of 12 months (range 5-37). Stable disease (SD) occurred in se ven patients with a median time to progression of 5 months (range 2-7) . There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL -2 and response rate was observed. We conclude that IL-2 given intrapl eurally is accompanied with acceptable toxicity and has anti-tumour ac tivity against mesothelioma. In view of the refractory nature of the d isease IL-2 may be a treatment option for mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of do se-response relationship and the immunomodulatory effects seen at rela tively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day(-1) using the present treatment schedule.