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.
Determining the light propagation in heterogeneous media is a challenging task which can only be approximated by solving the Boltzmann transport equation via diffusion theory. However, diffusion theory becomes very inaccurate at interfaces, boundaries, sources, and sinks, which are present in heterogeneous media. Monte Carlo methods are able to converge to the correct solution by simulating a sufficiently high number of photons, at the cost of increased runtime. Therefore, it is important to optimize the Monte Carlo simulator, thereby allowing more photons to be simulated and a more accurate solution within a given runtime. FullMonte is a full-featured simulator that uses processor-optimized operations to achieve the highest performance of any 3D tetrahedral Monte Carlo light propagation software to date. This paper presents two medical use cases which benefit from FullMonte, highlights new features and explains the optimizations that lead to its high performance.
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