Enhanced survival through repeated photodynamic therapy and almost complete tumor regression by prior radiation therapy in an orthotopic rat bladder cancer model

INTRODUCTION: The development of new organ-preserving treatment alternatives is still an important issue in bladder cancer (BCa) research. A combination of minimally-invasive photodynamic therapy (PDT) with ionizing radiation (IR) could be beneficial for bladder tumor regression. Here, we tested the hypothesis that PDT with the near-infrared photosensitizer tetrahydroporphyrin-tetratosylate (THPTS) could treat bladder tumors safely and effectively in an orthotopic rat model. MATERIALS AND METHODS: Response additivity analysis of cytotoxicity was investigated in cultured tumor cells (AY-27) and spheroids consisting of AY-27 and bladder fibroblasts of F344 Fischer rats. For in vivo evaluation, tumors were induced in female Fischer rats by intravesical instillation of AY-27 cells. Triple-time treatments were performed, with ten rats each in four treatment groups: untreated controls (UTC), PDT, IR, PDT with prior IR (IR + PDT). Animals were euthanized when reaching the termination criteria, and bladders were evaluated by macroscopy, histology and CD45 immunohistology. RESULTS: Synergism of combined treatment was demonstrated for all tested THPTS concentrations in AY-27/fibroblast spheroids but not in 2D cultured AY-27 cells. Tumor cell inoculation resulted in massive growth of solid bladder tumors (pT3a/b) in UTC. Triple-time treatment led to doubling of survival in the PDT group (mOS: 70 d) compared to UTC group (mOS: 36.5 d). IR monotherapy and IR + PDT resulted in complete survival without reaching the termination criteria. Histology revealed advantage of combination therapy vs. IR monotherapy by demonstrating treatment responses in all tumors of the IR + PDT group. CONCLUSION: This is the first in vivo study reporting doubling of survival time after PDT with a new near-infrared photosensitizer, and nearly complete tumor remission by neoadjuvant IR. This multimodal approach possibly allows minmally-invasive, organ-preserving BCa treatment.