P1.06-15 Safety of Irradiation Combined with Intracavitary Cisplatin-Fibrin After Lung-Sparing Surgery in a Rat Model of Mesothelioma

Abstract

To investigate feasibility and toxicity of new localized therapeutic treatment combinations for malignant pleural mesothelioma (MPM), we performed lung-sparing surgery followed by cisplatin-fibrin application and hemithoracic irradiation in an orthotopic immunocompetent rat model of MPM. Male F344 rats (n=9) were implanted sub-pleurally (parietal pleura) with 1 million rat mesothelioma cells (IL45-luciferase). Formed tumor nodules confirmed by IVIS bioluminescence imaging (BLI) were resected on day 9 after implantation. Following resection, animals were treated with local-intracavitary cisplatin-fibrin or placebo (NaCl-fibrin). Three days later, CT guided local irradiation of the former tumor region, resembling IMRT in human patients, was performed. Irradiation was given in a single high dose application using the image-guided stereotactic small animal irradiation X-RAD SmART (small animal radiotherapy) and image guided biological irradiator PXi (precision X-Ray) with precise localization. Treatment schemes after tumor resection were as followed: i) Intracavitary cisplatin-fibrin application (n=2) ii) Irradiation with 10 Gy (n=2) iii) Irradiation with 20 Gy (n=1) iv) Intracavitary cisplatin-fibrin plus 10 Gy radiotherapy (n=2) v) Intracavitary cisplatin-fibrin plus 20 Gy radiotherapy (n=2) Wellbeing of the animals was monitored daily until the predefined termination criteria were reached. Particular attention was given to possible irradiation toxicity related pulmonary side effects and weight loss. We successfully treated 1-2 animals per group according to the methods above. The irradiation was performed after visualization of the tumor with BLI- and CT-imaging to ensure an individual treatment plan. None of the animals, whether with radiotherapy alone or in combination with cisplatin-fibrin application, showed any signs of pulmonary side effects. In addition, none had reduced pulmonary functions, measured by increased breathing or the appearance of blue or white colored ear/extremities/eyes assuming desaturation. Furthermore, neither significant body weight loss of ≥15%, deterioration of body conditioning score nor of the activity score were observed in the immediate post-interventional phase. In all animals, termination endpoint was reached because of tumor relapse. In this pilot study, we have shown that irradiation alone and in combination with local intracavitary cisplatin-fibrin application in rats is safe and feasible up to a dosage of 20 Gy. The efficacy of the various treatment schemes and a possible radio-sensitizing effect by intracavitary cisplatin is currently being evaluated in the same animal model.