An open-label phase I pilot study of continuous intrapleural infusion of escalated doses of methotrexate in malignant pleural mesothelioma.
OBJECTIVE
The aim of this study was to evaluate the toxicity from escalated methotrexate (MTX) doses infused intrapleural over 5 days and to determine pleural and systemic drug levels with this chemotherapeutic approach.


METHODS
Five patients with malignant pleural mesothelioma were treated with 3 cycles of intrapleural MTX infused through a pigtail catheter inserted in the pleural space. MTX 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 5 days with simultaneous intravenous calcium folinate. The total cycle dose for the first, second, and third cycles were: 300, 501, and 750.5 mg/m, respectively.


RESULTS
The mean serum MTX level was 1.72 µmole/L, whereas that of the pleural fluid was 503.224 µmole/L. The mean serum/pleural ratio was 0.00396, whereas 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.


CONCLUSIONS
This study demonstrates no grade II toxicity from 750.5 mg/m of MTX infused intrapleural over 5 days. This approach allows attaining MTX pleural levels that are 95 to 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.
Departments of *Clinical Oncology §Interventional Radiology, Faculty of Medicine ‡Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University †Ministry of Higher Education, Cairo, Egypt.
Mahmoud Mahmoud Abbass
MM
Ellithy
Noha Salah El Din M
NS
El Baghdady
Lamia Mohamed
LM
El Wakeel
Karim Ahmed
KA
Abdeltawab
Osama Ahmed
OA
Badary
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D010865:Pilot Projects; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate