An Open Label Phase I Pilot study of Continuous Intrapleural Infusion of Escalated Doses of Methotrexate in Malignant Pleural Mesothelioma

ABSTRACT

Objectives:

The aim of this study was to evaluate the toxicity from escalated methotrexate doses infused intrapleural over five days and  determine pleural and systemic drug levels with this cemotheraputic approach . 

Patients and Methods:

Five patients with malignant pleural mesothelioma were treated with three cycles of intra pleural methotrexate infused through a pig tail catheter inserted in the pleural space. Methotrexate levels were estimated in the pleural fluid and serum once daily throughout the treatment cycles. Fourteen days between cycles were calculated from the last day of the previous one.The total dose for each cycle was infused over five days with simultaneous intravenous calcium folinate. The total cycle dose for the first, second and third cycles were; 300mg/m², 501 mg/m² and 750.5 mg/m² respectively.

Results:

The mean serum methotrexate level was 1.72 µmole/l while that of the pleural fluid was 503.224 µmole/l. The mean serum/pleural ratio was 0.00396, while the pleural/serum ratio was 396.21.

No remarkable toxicity was observed in the 5 patients except for; patient 1 who developed fluid leakage around the puncture site. Patient 2 developed grade I hepatotoxicity and both patients developed grade I pleuritic chest pain and dry irritative cough.

Conclusion:

This study demonstrates no grade II toxicity from 750.5mg/m² of methotrexate infused intra pleural over five days. This approach allows attaining methotrexate pleural levels that are 95- 3000 times higher than systemic serum levels, with minimal toxicity.

The results mandate performing this trial on a wider scale as a preliminary step for a formal phase II study. 

Key words: Intra pleural; Methotrexate; Pleural; Mesothelioma.