PubMed2004
Both phase I studies demonstrated that high-dose cisplatin can be delivered safely with acceptable complication rates. The maximum tolerated doses of 225 mg/m2 and 250 mg/m2 cisplatin, respectively, are higher than any other published report of intrapleural cisplatin. The intrapleural cisplatin doses reported in other trials have been 80 mg/m2, 100 mg/m2, and 200 mg/m2. Despite the use of high-dose intraoperative chemotherapy, the group of 50 patients who underwent EPP experienced mortality and morbidity comparable to the contemporaneous group of 41 patients who did not participate in the protocol, except for increased rates of deep venous thrombosis and diaphragmatic patch failure. The 44 patients who underwent P/D experienced a slightly higher mortality rate and creatinine toxicity rate than the first phase I trial. Given the demographics of this patient cohort (higher age, lower FEV1, and inability to withstand pneumonectomy because of limited cardiopulmonary reserve), however, the mortality and morbidity rates seem acceptable. The pharmacologic data from both studies support our hypothesis that high regional doses of cisplatin can be delivered with less systemic absorption than can be achieved with intravenous administration (data not shown). With the maximum tolerated dose of intracavitary cisplatin and safety of intraoperative administration after surgical resection firmly established by these phase I trials, we are prepared to implement phase II and III studies of EPP and P/D with intraoperative cisplatin lavage. We aim to monitor tumor recurrence and patient survival prospectively and compare these results with historic controls. We also intend to document prospectively the morbidity and mortality of the treatment protocols. Finally, we plan to evaluate the pharmacokinetics of cisplatin by measuring tissue and perfusate levels of active and inactive cisplatin. By approaching the problem of local recurrence after resection of MPM in a careful and methodical manner, we hope to decrease or delay the rate of recurrence and potentially improve longterm survival in patients with this lethal disease.