Randomized trial of intravenous versus bidirectional chemotherapy after cytoreductive surgery for malignant peritoneal mesothelioma

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease that progresses within the peritoneal cavity and only disseminates to systemic sites in the terminal months of the disease. For this malignancy, there are several regimens of chemotherapy that have been accepted as standard, principally intraperitoneal chemotherapy (IPC) and intravenous chemotherapy (IVC); however, there is no standardized method of treatment. Selected patients with MPM who are amenable to cytoreductive surgery (CRS) and are fit for surgery typically undergo resection with hyperthermic intraperitoneal chemotherapy (HIPEC). Though individual toxicity and efficacy studies of IPC plus IVC (bidirectional) and IVC chemotherapy for MPM have been conducted, a prospective randomized clinical trial has not been performed for this disease. MATERIALS AND METHODS: The study objective is to compare the efficacy and toxicity of normothermic bidirectional (IPC/IVC) chemotherapy versus IVC after CRS and HIPEC for epithelial MPM. The patient population are those individuals undergoing CRS for MPM. Exclusion criteria include previous therapy form mesothelioma. The study design is a randomized, nonblinded, phase II clinical trial comparing multicycle IVC with cisplatin (CDDP) and pemetrexed (PMTX) versus multicycle bidirectional chemotherapy with IVC CDDP and IPC PMTX after optimal CRS and HIPEC with CDDP and doxorubicin. The primary endpoint is 2-year disease-free survival. The secondary endpoint is 30-day post-treatment morbidity. The primary objective is to compare the 2-year rates of disease-free survival in the two treatment arms. The secondary objective is to compare the toxicity of each treatment. DISSEMINATION: The prospective randomized trial provides not only a standardized approach to treatment but also a path forward to optimize the survival of patients with MPM. In addition, any increase or decrease in the adverse events associated with PMTX administered as IPC will be demonstrated. Because MPM is a rare disease a multi-institutional implementation of the protocol is required.