Project 1: Radical pleurectomy (RP) with intraoperative, pleural photodynamic therapy (pPDT) and post-operative chemotherapy produces an unprecedented median overall survival (OS) of over 41 months in patients with locally advanced, epithelial malignant pleural mesothelioma (MPM). Unlike most surgical series, >50% of RP/pPDT patients survive more than 12 months after MPM relapse;however, a subset of patients who experience early local relapse (LR, <12 mo after RP/pPDT) exhibit a rapidly progressive and fatal clinical course. One major uncertainty in these data is the how much pPDT contributes to the remarkably good outcomes. This uncertainty provides the motivation for Aim 1 of this Project, which is to perform a randomized Phase II trial in patients with epithelial MPM that will test the hypothesis that pPDT improves overall survival when added to RP followed by chemotherapy. Another uncertainty involves understanding the potential mechanisms underlying the poor prognosis for patients with early LR. Thus, Aim 1 also serves as a point of integration between the projects and cores by providing opportunities for analysis of patient-specific factors that relate to RP/pPDT patient outcome, including factors critical to pPDT dose such as light delivery and photosensitizer uptake in spatially corresponding areas. Finally, the impact of inter- and intra-patient heterogeneity on the conduct of the trial, the analysis of the data and the outcome of the patients remains unclear. Project 1 will work with the Physics and Dosimetry Core A, the Animal and Pathology Core C and the Administrative Core D to minimize the intrinsic heterogeneity of clinical practice and sample acquisition through the application of documents and protocols to standardize procedures across the Program Project. Finally, in Aim 2, the impact of heterogeneity in pPDT dose and expression of tumor-intrinsic pPDT resistance factors on patient outcome will be evaluated.
This aim will test the hypothesis that time-to-local recurrence after pPDT is a function of the intra-patient heterogeneity in delivered pPDT dose (photosensitizer uptake * light fluence). We also test whether the combination of adverse tumor features (molecular/vascular phenotypes associated with PDT resistance) and large intra-patient heterogeneity in pPDT dose identifies a subset of patients at high risk for poor outcome.

Public Health Relevance

Project 1 Narrative This project will more clearly define the role of pPDT in managing MPM and may shift treatment paradigms for this disease. We will also provide data and samples that will later feed back into the development of novel clinical trials. Moreover, by establishing the clinical value of pPDT, this project will help to remove a critical barrier to the more widespread application of resection with pPDT as a treatment paradigm in cancers with high rates of local recurrence following surgery.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-B (M1))
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University of Pennsylvania
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Kim, Michele M; Darafsheh, Arash; Ahmad, Mahmoud et al. (2016) PDT Dose Dosimeter for Pleural Photodynamic Therapy. Proc SPIE Int Soc Opt Eng 9694:96940Y
Sterman, Daniel H; Alley, Evan; Stevenson, James P et al. (2016) Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy. Clin Cancer Res 22:3791-800
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Zhu, Timothy C; Lu, Amy; Ong, Yi-Hong (2016) An improved analytic function for predicting light fluence rate in circular fields on a semi-infinite geometry. Proc SPIE Int Soc Opt Eng 9706:97061D
Penjweini, Rozhin; Kim, Michele M; Liu, Baochang et al. (2016) Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling. J Biophotonics 9:1344-1354
Penjweini, Rozhin; Kim, Michele M; Finlay, Jarod C et al. (2016) Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy. Proc SPIE Int Soc Opt Eng 9694:
Gemmell, Nathan R; McCarthy, Aongus; Kim, Michele M et al. (2016) A compact fiber-optic probe-based singlet oxygen luminescence detection system. J Biophotonics :

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