The emerging role of antifolates in the treatment of malignant pleural mesothelioma

Clinicians have long regarded malignant pleural mesothelioma as a chemoresistant neoplasm and as a result no standard chemotherapy regimen has emerged. Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged: the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma. Indeed, responses were seen in cisplatin-refractory patients. Based on the promising results from these combination trials, two large phase III studies have begun. The first study was a multicenter, multinational trial sponsored by Eli Lilly and Company, which randomized more than 430 patients with malignant pleural mesothelioma to cisplatin with or without pemetrexed. That trial completed enrollment in February 2001 and is the largest trial ever conducted in mesothelioma. The second trial is being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and compares cisplatin with or without raltitrexed with planned accrual of 240 patients. In both trials, survival is the main endpoint. These trials will help to define the role of these new antifolates in malignant pleural mesothelioma.