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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA087971-11A1
Application #
8741242
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (M1))
Project Start
2000-07-01
Project End
2015-06-30
Budget Start
2014-09-10
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$281,463
Indirect Cost
$85,810
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Simone 2nd, Charles B; Cengel, Keith A (2014) Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol 41:820-30
Han, Sung Wan; Mesquita, Rickson C; Busch, Theresa M et al. (2014) A Method for Choosing the Smoothing Parameter in a Semi-parametric Model for Detecting Change-points in Blood Flow. J Appl Stat 41:26-45
Liang, Xing; Wang, Ken Kang-Hsin; Zhu, Timothy C (2013) Feasibility of interstitial diffuse optical tomography using cylindrical diffusing fibers for prostate PDT. Phys Med Biol 58:3461-80
Maas, Amanda L; Carter, Shirron L; Wileyto, E Paul et al. (2012) Tumor vascular microenvironment determines responsiveness to photodynamic therapy. Cancer Res 72:2079-88
Friedberg, Joseph S; Culligan, Melissa J; Mick, Rosemarie et al. (2012) Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg 93:1658-65; discussion 1665-7
Grossman, Craig E; Pickup, Stephen; Durham, Amy et al. (2011) Photodynamic therapy of disseminated non-small cell lung carcinoma in a murine model. Lasers Surg Med 43:663-75
Sandell, Julia L; Zhu, Timothy C (2011) A review of in-vivo optical properties of human tissues and its impact on PDT. J Biophotonics 4:773-87
Busch, Theresa M; Wang, Hsing-Wen; Wileyto, E Paul et al. (2010) Increasing damage to tumor blood vessels during motexafin lutetium-PDT through use of low fluence rate. Radiat Res 174:331-40
Wang, Ken Kang-Hsin; Finlay, Jarod C; Busch, Theresa M et al. (2010) Explicit dosimetry for photodynamic therapy: macroscopic singlet oxygen modeling. J Biophotonics 3:304-18
Busch, Theresa M (2010) Hypoxia and perfusion labeling during photodynamic therapy. Methods Mol Biol 635:107-20

Showing the most recent 10 out of 37 publications