Non-muscle invasive bladder cancer remains one of the costliest cancer to treat, and while a cystectomy will reduce a patient’s risk of developing metastatic disease it reduced the patient’s quality of life. While Photofrin mediate Photodynamic Therapy was approved already in 1993, poor control over the photon density and drug accumulation in of target tissue resulted in overdosing the bladder muscle layers, causing permanent volume shrinkage and incontinence.
For an ongoing Phase Ib clinical trial, evaluating the safety of TLD1433 ([Ru(II)(4,4'-dimethyl-2,2'-bipyridine(dmb))2(2-(2',2'':5'',2'''-terthiophene)-imidazo[4,5-f][1,10]phenanthroline)]2+) a Ru(II) coordination complex, significant deviations from the previous studies are implemented. The photosensitizer is instilled, to reduce the sensitization of the muscle layer, 525 nm light is used to limit the light penetration into the bladder and the photon density is measured in each patient at up to 12 positions.
Improved tumour selectivity is provided by this photosensitizer as it is block by the Urothelium from entering healthy tissue, whereas it enters tumour cells, supposing via the transferrin receptor, as demonstrated in in-vitro and in vivo studies. The Ru(II) coordination complex stains tissues where the urothelium is damaged very strongly in an orange-rust colour, visible under white light illumination.
Preclinical in vivo studies showed the destruction of tumours up to 1 mm in depth following 1 hr of drug instillation, followed by 3 washes and the delivery of 90 Jcm-2 of 525nm light in the wistar rat Ay-27 tumour model. Histology showed very limited muscle damage and in general intact urothelium layers, with a moderate infiltration of macrophages.
To achieve the prescribed target radiant exposure of 90 Jcm-2, independent of the bladder tissue diffuse reflectivity and shape, an optical dosimetry system was developed which can be deployed via a cystoscope. The optical dose monitoring device allows the treating physician to adjust the source position to achieve the target optical dose for the 12 sensor positions. The optical radiation was delivered via a 0.8 mm diameter spherical diffuser at up to 2.5 W power.
The attainable photon density and the anticipated PDT dose are simulated for each patient using a photon propagation engine and the patient’s anatomical information. During these simulations, a range of tissue optical properties is simulated and compared to the initial photon density measurements to advise the physician further about the ability to achieve a homogenous illumination in each patient.
The multiplication factor of the irradiance inside the bladder, calculated based on the spherical volume equivalent size of the bladder, the delivered power and measured irradiance, varied between patients (from 1.1 to 2.5) and also over the course of the treatment. The changes over the course of the treatment were predominantly due to light diffusing proteinaceous material floating in the bladder.
Expanding prior work by the Rotterdam group on light propagation in the bladder we determined that the tissue albedo varied from 0.87 to 0.92 for 525 nm in this patient population. The estimated average effective attenuation coefficient for this population was approximately 1 mm adequate for the treatment of non-muscle invasive bladder cancer after transurethral resection of the large tumours.
Monte Carlo modelling demonstrated that the fluence as function of depth into the tissue is determined by the exposure of bladder wall elements to the remaining bladder surface and can vary by factor of more than 2 even when assuming homogenous tissue optical properties across the bladder wall surface.
These studies and analysis demonstrate the need for accurate light dosimetry in hollow organs when variations in the tissue albedo and the shape of the organ can influence the photodynamic dose significantly.