The Impact of Surgically Induced Inflammation on Outcomes Following Intraoperative Photodynamic Therapy in Patients with Thoracic Malignancies.

The goal of surgery in the multimodal treatment of pleural malignancies such as malignant pleural mesothelioma (MPM) or Non-small cell lung cancer with pleural spread (p-NSCLC) is to achieve a macroscopic compete resection (MCR). We have investigated the use of intraoperative photodynamic therapy to reduce the rate of local recurrence following MCR using a variety of photosensitizers, including porfimer sodium and HPPH. With lung sparing MCR and intraoperative PDT, patients with locally advanced, epithelial MPM experience median overall progression free and overall survival of 13 and 36 months, respectively. Similarly, patients with p-NSCLC experience median progression free and overall survival of 10 and 23 months, respectively. The results with MCR and PDT are highly encouraging. Nevertheless, a subset of patients treated with this approach experience aggressive local or systemic relapse of pleural disease within the first 12 months. In this study, we combine analysis of clinical data and pre-clinical models to examine the hypothesis that surgically mediated Inflammation affects outcomes following intraoperative PDT. In studies of clinical samples from patients with MPM undergoing surgery and intraoperative PDT, we found that increases in pro-inflammatory cytokines plasma levels from surgery prior to PDT experience earlier tumor recurrences than patients who did not experience a pro-inflammatory reaction to surgery. We have developed a preclinical model of surgically-mediated tumor injury (TI) that mimics these cytokine increases. Although PDT decreases tumor recurrences following partial debulking of tumors, we noted that TI reduces the efficacy of subsequently delivered PDT when compared to PDT of intact, size matched tumors. Mechanistically, this appears to involve surgically-mediated influx of myeloid derived suppressor cells into the tumor. Further analyses including RNAseq of clinical tumor samples and immunophenotyping of tumors and tumor draining lymph nodes in the TI model provide additional evidence to support the surgical inflammation hypothesis. Taken together, these results demonstrate that PDT can be safely and effectively adapted to treat the entire pleural surface and that PDT combined with multimodality, surgically based therapy demonstrates remarkably good patient outcomes. However, surgically induced inflammation impairs the full potential benefit of PDT. [ABSTRACT FROM AUTHOR]