Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

Abstract

Background Currently delivered light dose (J/cm 2 ) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm 2 ) and associated heating on tumour response and cure. Methods Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin ® I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry. Results In the mouse model, cure rates of 70–90% were obtained with I-PDT using 8.4–245 mW/cm 2 and ≥45 J/cm 2 in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin ® resulted in significantly ( p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5–398 mW/cm 2 and ≥45 J/cm 2 in 100% of the tumour. Conclusion In Photofrin ® -mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.

Irradiance, Photofrin® Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models

“…In a recent preclinical light dose‐finding study for Photofrin ® ‐mediated I‐PDT, we demonstrated the importance of irradiance in obtaining tumor control and cures in the treatment of locally advanced cancers with Photofrin ® . In the study reported here, we further demonstrated the importance of irradiance during Photofrin ® ‐mediated I‐PDT by treating mice with FEM‐simulated subtherapeutic and therapeutic irradiances.…”

“…It is important to note that at 160 and 200 mW cm −1 , cures were obtained in both mice treated with Photofrin ® and mice treated with light only. We previously reported that at our effective light regimen for Photofrin ® ‐mediated I‐PDT with simultaneous light illumination, light‐induced tissue heating to temperatures ≥60°C (thermal ablation) occurred . In that study, this thermal ablation alone, although less effective than Photofrin ® ‐mediated I‐PDT, resulted in some cures (up to 40%) when treating locally advanced SCCVII.…”

“…A detailed description of the murine tumor model used in this study was previously described in Shafirstein et al 2018 . Briefly, female C3H mice were inoculated with SCCVII squamous cell carcinoma (10 6 cells), which is a common murine tumor model used for studying head and neck cancer .…”

“…Once the total dose of 1080 J (540 J cm À1 from the 2 cm cylindrical diffuser fiber) was administered, the laser light was turned off for no more than 5 min, and then, the tumor was illuminated with only the second RD20 fiber to administer an additional 1080 J (540 J cm À1 from the 2 cm cylindrical diffuser fiber). Tumor response was followed for up to 60 days, and a cure was defined as complete regression following the I-PDT and no evidence of tumor at least 60 days post-treatment, as previously reported (Shafirstein et al 2018). Animals were euthanized either at 60 days post-treatment or when the tumor volume reached ≥2000 mm 3 .…”

“…Several investigators have reported on the use of the intratumoral fluence (J cm À2 ) to plan and predict tumor control during I-PDT of prostate cancer (9)(10)(11)(12). Recently, we demonstrated through the use of our finite element method (FEM) for simulating light propagation that in addition to the fluence, the irradiance (mW cm À2 ) is a key parameter to achieving tumor control and cures from I-PDT with Photofrin â (3). In that study, we reported 70-90% cures from Photofrin â -mediated I-PDT in C3H mice with locally advanced squamous cell carcinoma VII (SCCVII) when the FEM-simulated irradiance and fluence were, respectively, ≥8.4 mW cm À2 and ≥45 J cm À2 .…”