Tissue photosensitizer dosimetry using spectrally-resolved fluorescence for pre-clinical and clinical verteporfin-PDT of pancreatic cancer

Abstract

Photodynamic therapy (PDT) mediated with verteporfin is currently being investigated to treat pancreatic cancer in patients who are not surgical candidates. Clinically, interstitial light delivery is administered through a fiber, via percutaneous needle implantation guided by ultrasound and/or verified by CT. Tumor response to PDT is based on photosensitizer (PS) dose, light dose, light dose rate and the timing of light application following PS injection. However, studies have shown that even when matching administered PDT treatment parameters such as drug dose and light level, there can be significant inter-patient variation in tissue damage post-PDT, and this has been primarily attributed to imprecise PS concentration at the target tissue site. In order to achieve optimal tumor response from PDT without causing major damage to surrounding tissue, it would be advantageous to measure the PS concentration in the target tissue just prior to light application. From these measurements, the clinician can adapt the light application dose to the measured target tissue PS concentration (i.e. insufficient target tissue PS concentrations compensated by higher light doses and vice versa.) in order to provide an optimal light dose for each patient. In animal studies, a spectrometer-based in-vivo fluorescence dosimetry system has been used to assess accumulated PS levels (verteporfin) in situ. Measurements are taken from skin, leg muscle, buccal mucosa and tumor tissue locations one hour after injection of the photosensitizer. Real-time spectral fitting, subtraction of background autofluorescence and ratiometric analysis is performed on the raw data to extract out only the photosensitizer fluorescence and therefore concentration. Using a pre-measured calibration data set of varying concentrations for verteporfin in tissue phantoms composed of intralipid and whole blood, it was possible detect concentrations of the photosensitizer below 0.5nM. In the clinical studies being performed at UCL Hospital in which verteporfin-PDT treatment is being given to patients with pancreatic cancer, the dosimetry system is being used to assess PS concentration the pancreatic tumor tissue prior to interstitial light dose treatment. The goal of the work here is to determine whether the dosimetry system can accurately and efficiently be used clinically by evaluating the measured local tissue PS concentration to treatment outcome (area of necrosis established). The results of this study will partially determine the need for fluorescence dosimetry to individualize PDT treatment for patients based on local tissue PS concentration.