Project 1-lntraperitoneal PDTPI: Douglas FrakerPeritoneal carcinomatosis is a clinical problem which causes considerable morbidity and is uniformly fatal.Complete surgical resection is not possible, conventional radiation therapy is unable to safely treat all areasat risk, and systemic therapy with available agents is limited by drug delivery and efficacy. Intraperitonealspread represents cancer progression on a complex surface and all areas of the abdominal cavity are at risk.During the first grant funding cycle we have demonstrated that surgical tumor debulking to minimal diseaseand intra-operative photodynamic therapy can be performed to treat all surfaces at risk. There were clinicalresponses seen in this heavily pre-treated population but the majority of patients recurred within theperitoneal cavity. This initial Phase II trial using photofrin was limited primarily by low photosensitizerretention in tumor compared to normal tissues. Other potential problems include the difficulty in deliveringuniform light dose to a complex surface, and tumor hypoxia which may decrease PDT cytotoxicity.In the current proposal, Project I will address these problems by utilizing a second generation photosensitizerin combination with targeting agents to alter the signal transduction cascade in tumors. We propose toevaluate the second generation photosensitizer, benzoporphyrin derivative (BPD) in combination with theEGFR inhibitor, C225 based upon preliminary data suggesting this will increase the therapeutic index of IPPDT. Initial preclinical studies will be conducted in rabbits including peritoneal PDT at increasing doses ofphotosensitizer with and without bowel anastomoses. A Phase l/ll clinical trial will be performed on patientswith peritoneal carcinomatosis from ovarian or gastro-intestinal cancers who have no other treatmentoptions. The initial phase of the trial will identify and optimal dose of BPD and light energy. A second phaseof the protocol will add C225 to assess response rates. In all parts of the trial malignant and normal tissuewill be analyzed for sensitizer concentration, molecular markers related to PDT response, and intraoperativelyfor optical properties.
Showing the most recent 10 out of 127 publications
