Significance: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient.
Aim: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall.
Approach: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer’s specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram.
Results: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties.
Conclusions: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer’s specific uptake ratio.
Recurrent Non-Muscle Invasive Bladder Cancer (NMIBC) is a diffuse disease, and patients have failed standard BCG therapy face prophylactic cystectomy. PDT fell out of favour due to its variable outcome, and high morbidity. To overcome PDT associate toxicity to the bladder’s muscle layer, the use of shorter wavelength and instillation of the photosensitizer were suggested. While either approach was shown to improve the outcome in animal models they have not previously combined in human studies. Additionally, the effects of highly variable tissue optical properties of the bladder and its shape have not been studied. Here, we present surface dose histograms derived from light propagation simulation in 6 human bladders using CT images for anatomical detail and the FullMonte software package. The ability of a single light sensor versus 3 or 12 light sensors to measure the average irradiance on the bladder surface was evaluated as a function of the bladder wall’s tissue optical properties. Results show that the irradiance in non-spherical bladders can vary over an order of magnitude, but the irradiance histograms are affected little by displacement of the emitter inside the bladder void. As the surface area monitored by a single sensor depends strongly on the bladder shape, the responsivity of a single sensor to the average bladder irradiance can vary equally. Twelve light sensors monitor the entire bladder surface almost complete and hence their average responsivity is constant to the average irradiance on the bladder largely independent of shape. The dependency of the sensor’s response on the tissue optical properties is also lower.
While Photofrin mediated PDT for bladder cancer was the first approved indication for this technique, it failed to attract the confidence of urologists as a treatment option, primarily due to the high incidence of incontinence linked to PDT damage to the bladder muscle. To mitigate this hazard a phase I clinical trial using instillation of the Ru(II) coordination complex TLD1433 and 530 nm activation light was initiated. To achieve the intended drug doses of 0.35 and 0.7 mg/cm2 and a radiant exposure of 90 J/cm2 the concentration of the instillation was adjusted to each patients' bladder volume and the irradiance was measured at up to 12 positions in the bladder.
Irradiance monitoring proved helpful in adjusting the irradiation time to the bladder wall albedo and also for increased light scattering and absorption due to turbidity built up in the bladder void. The initial multiplication factors of the bladders (n=6) ranged from 1.1 to 2.8. Monte Carlo simulations based on CT-scans from all 6 participants approximate the range of irradiances observed during these studies. Nevertheless, a fraction of the surface can see a multiple of the average irradiance whereas other regions (typically less than 5% of the surface area) see significantly less than the average irradiance. These variations are due to the actual bladder shape and are somewhat independent of the position of the spherical emitter. Fitting of the measured surface irradiance to the simulated dose surface histograms enables extraction of the bladder wall and bladder void’s optical properties.
Background and Objectives: Finite Element Methods (FEM) and Monte Carlo (MC, FullMonte) simulations are employed to compute light propagation during interstitial photodynamic therapy. FullMonte models the light source as a fixed number of photons emitted from the center of the catheter. In the FEM, the light source is modeled as a flux of photons emitted from the outside diameter of the catheter. The objective of this study was to compare the FEM and MC computed light fluence rate distributions.
Methods: A solid phantom with tissue optical properties was used to compare MC simulations conducted using FullMonte and FEM using COMSOL Multiphysics. A tetrahedral mesh of approximately 400,000 elements was created to mimic experiments in the phantom with one central 2 cm cylindrical diffuser fiber, and five IP85 detector fibers were inserted 5, 10, 15, 20, and 25 mm from the light source. FEM and FullMonte simulations were conducted for 50 and 100 mW/cm source power, and the resulting fluence rates were compared, at the detector locations.
Results: Initially, the computed fluence rates differed significantly between the MC and FEM simulations. However, the light gradient was comparable between both methods. Changing the FEM boundary conditions such that the light source was modeled as a flux of photons emitted from inside the catheter approximately 0.6 mm from the outside diameter resulted in a better agreement (16% difference).
Conclusions: The light source boundary condition is a major contributor to the difference between FEM and FullMonte computed light distributions.
Acknowledgements: This work was supported in part by National Cancer Institute of the National Institutes of Health under Award Number R01CA193610 to G. Shafirstein
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