Photodynamic therapy (PDT) is an effective treatment for surface malignancies. Widespread peritoneal cancers are tumors that spread in an intracavitary manner on all of the surfaces of the abdominal cavity. There is no effective treatment for patients with peritoneal malignancies and these patients suffer considerable morbidity and this condition is uniformly lethal. PDT is theoretically an ideal treatment strategy for these patients with peritoneal carcinomatosis or sarcomatosis. A recent Phase I trial with Photofrin (PF) demonstrated benefit for some patients with ovarian carcinomatosis, gastrointestinal carcinomatosis and sarcomatosis by performing surgical debulking and intraperitoneal photodynamic therapy (IP-PDT). The principle investigator and co-investigators have initiated a Phase II trial of IP-PDT based on the maximally tolerated dose of light and PF as defined in the Phase I trial. Some patients treated on this study have shown benefit, but the majority of patients develop recurrent disease. Optimization of the therapeutic effects of PDT may improve the survival and decrease morbidity for patients with peritoneal malignancies who have no other treatment options. We propose in Specific Aim 1 to complete the Phase II trial of PDT with PF defining the response rates with this sensitizer at maximally tolerated dose and light levels. The cytokine response will be assessed and hemodynamic parameters monitored in patients undergoing PDT as contributing factors to the pathophysiology of systemic inflammatory response syndrome (SIRS).
In Specific Aim 2, Lutetium Texaphyrin and mTHPC will be evaluated as candidate sensitizers for improving the results with IP-PDT. In preclinical studies these second generation sensitizers have improved tumor selectivity which may contribute to improved outcome. The efficacy and tumor selectivity of these sensitizers will be evaluated in a preclinical murine model of IP-PDT, and the toxicity will be evaluated in the canine model of IP-PDT.
In Specific Aim 3, a Phase I and II trial of the optimal agent will be conducted. A clinical trial will always be ongoing in the form of either the current Phase II trial or a proposed Phase I trial during the entire time period of the grant. These clinical trials will provide the cornerstone for interactive studies with other investigators in this program project grant.
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