Finite Element Guided Dosimetry for Interstitial Photodynamic Therapy

• Main Author: Oakley, Emily R
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2020
• Subjects: Biomedical engineering; Biophysics; Oncology
• ISBN: 9798582508250

Interstitial Photodynamic Therapy (I-PDT) is a promising treatment for locally advanced cancers that either failed to respond or recurred following standard of care therapies (surgery, radiation therapy, and chemotherapy). Treatment planning and dosimetry are the most important issues for patient safety and response during and following I-PDT. The response to I-PDT is a function of the intratumoral oxygen levels, photosensitizer accumulation and retention, light irradiance (mW/cm2 ), and light fluence (J/cm2 ). While several investigators have suggested that a threshold light fluence is the necessary dosimetry parameter for achieving local tumor control following I-PDT, the impact of the light irradiance on tumor response has not been investigated. The objective of this engineering-focused thesis was to develop a treatment planning technique and dosimetry model for I-PDT of locally advanced cancers based on finite element modeling of the light irradiance (mW/cm2 ) and fluence (J/cm2 ). In previous studies, we have developed and tested an image-based finite element method (FEM) for simulating light propagation using a finite element software (COMSOL Multiphysics) to solve the diffusion approximation to the equation for radiative transfer. In this thesis, I hypothesized that our FEM for simulating the light propagation in tumor and adjacent critical structures will predict antitumor response to I-PDT of locally advanced tumors by defining the biophysical parameters, namely the FEM intratumoral light irradiance and fluence distribution, that contribute to treatment response. In pre-clinical studies, our image-based FEM was used to guide the light delivery during IPDT with porfimer sodium (Photofrin®) in the treatment of locally advanced squamous cell carcinomas in mice and rabbits. C3H mice with locally advanced SCCVII tumors (400-600 mm3 ) and New Zealand White (NZW) rabbits with large VX2 tumors (3,000 – 15,000 mm3 ) were treated with either light only or with Photofrin®-mediated I-PDT (drug-light interval of 24 hours). In the mice, our FEM was used to define an effective light regimen for Photofrin®- mediated I-PDT that could be successfully translated into the treatment of the larger VX2 tumors. It was hypothesized that a minimum irradiance and fluence were required for effective Photofrin® activation. Based on the response studies, a FEM minimum intratumoral light irradiance and fluence ≥8.4 mW/cm2 and ≥45 J/cm2 , respectively, were required to achieve high cure rates (70-90%) in the treatment of the locally advanced mouse tumors. In addition, there was a high probability (81.3-92.7%) of predicting cures in the mice based on the FEM minimum light irradiance and fluence, initial tumor treatment volume and Photofrin® dose. In the rabbits, a higher FEM minimum light irradiance of ≥15.3 mW/cm2 was associated local tumor control and cures from Photofrin®-mediated I-PDT. Although less effective than I-PDT, the light alone was able to produce some cures (40-60%) in the mouse tumors. No tumor growth delay was observed in the rabbits treated with light only. Based on the success of the animal studies, our image-based FEM and effective light regimen (≥8.4 mW/cm2 and ≥45 J/cm2 ) was applied in the treatment planning for Photofrin®-mediated IPDT of human patients with locally advanced head and neck cancer (LAHNC) and locally advanced lung cancer (LALC). In total, two patients with LAHNC (up to 85,000 mm3 ) and two patients with LALC (up to 12,700 mm3 ) were treated with Photofrin®-mediated I-PDT according to the individualized image-based FEM treatment planning. In all four patients, I-PDT was safely administered without any adverse events. In one of the LAHNC patients, the tumor was almost completely ablated and gone using our effective light regimen (≥8.4 mW/cm2 and ≥45 J/cm2 ). The response of the LALC to I-PDT are still being monitored.Overall, the results from the pre-clinical and clinical studies confirmed that the FEM intratumoral light irradiance and fluence can be applied to plan and predict the response to Photofrin®-mediated I-PDT in the safe and effective treatment of locally advanced cancers. One main conclusion from this study is that the intratumoral irradiance is a key predictive biophysical parameter influencing the response of locally advanced cancers to I-PDT. Therefore, I-PDT dosimetry needs to incorporate the light irradiance when assessing treatment safety and efficacy. As this thesis focused on the engineering aspect of the intratumoral light irradiance as a dosimetry parameter for I-PDT response, future work aims at evaluating how the irradiance affects the biological response mechanisms during I-PDT such as vascular shut down and blood oxygenation. Additionally, in the in vivo mouse studies, light alone did cause some cures indicating that at our effective light regimen for Photofrin®-mediated I-PDT, light induced tissue heating to ablative temperatures can occur and may contribute to treatment response. In future studies, we plan on evaluating the impact of the thermal dose during I-PDT on the physical and biological anti-tumor response. Lastly, future works will also attempt to incorporate the measurement of tissue optical properties during treatment and apply our FEM to guide the safe and effective delivery of a prescribed light irradiance and fluence during other interstitial light therapies.