Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

Abstract

Background: Currently delivered light dose (J/cm²) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm²) and associated heating on tumour response and cure.

Methods: Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin^® I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry.

Results: In the mouse model, cure rates of 70-90% were obtained with I-PDT using 8.4-245 mW/cm² and ≥45 J/cm² in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin^® resulted in significantly (p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5-398 mW/cm² and ≥45 J/cm² in 100% of the tumour.

Conclusion: In Photofrin^®-mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.

Fig. 1

Pseudo-colourised temperature maps (°C) within the tumour as measured by MR thermometry at the end of the laser irradiation for different light intensities. A light energy of 100 J/cm was delivered through a single 2-cm cylindrical-diffuser fiber. There was no difference in the temperature field in mice treated with or without Photofrin. Hence, the images are shown as function of light intensity only (a–e): 60, 100, 150, 200, and 400 mW/cm. Yellow arrows denote location of treatment fibers. A nuclear magnetic resonance tube filled with cottonseed oil was used as a phase normalisation reference (white arrows). Noteworthy, the non-concentric isotherms, around the cylindrical-diffuser fibers, suggest that the fibers itself was not heated. The increase in temperature was attributed to light absorption by blood, as detailed in the discussion

Fig. 2

The distributions of percentage of tumour volume >60 °C were summarised using boxplots across the mW/cm settings. a Single fiber with 2-cm cylindrical diffuser at 100 J/cm. b Two fibers with 2-cm cylindrical diffusers at 540 J/cm. The top, middle, and bottom lines of a box in the boxplots indicate the 25th percentile, median, and 75th percentile, respectively. The “whiskers” in the boxplots represent the range of the data. Open circles in the plot show the values that are beyond 1.5 box lengths from the end of the box

Fig. 3

a The percent tumour volume that will be illuminated at 14–75 mW/cm² vs. light intensity delivered through two 2-cm cylindrical diffusers at 6.31 ± 0.11 mm apart. b The representative geometry (used in a) constructed from magnetic resonance imaging of a tumour (556 mm³) with two fibers, and the mesh generated in the finite-element modeling. c The three-dimensional distribution of the light irradiance for an input light intensity of 60 mW/cm per fiber. The minimum and maximum irradiances were 5.0 and 147 mW/cm², respectively. d Pseudo-colourised temperature maps (°C) within the tumour as measured by MR thermometry at the end of the laser irradiation for different light intensities. A light energy of 540 J/cm was delivered through two 2-cm cylindrical-diffuser fibers at 6 ± 1 mm apart. Yellow arrows denote location of treatment fibers. A nuclear magnetic resonance tube filled with cottonseed oil was used as a phase normalisation reference (white arrows)

Fig. 4

The cure rate (C), tumour progression (P), and death (D) of mice with locally advanced SCCVII treated with interstitial light (630 ± 3 nm; 540 J/cm) delivered through two-optical fibers with a 2-cm cylindrical light diffuser end, placed 6 ± 1 mm apart. a Mice treated with light-only or I-PDT with 5 mg/kg Photofrin^®. b Kaplan–Meier plots comparing LITH with I-PDT at 100 mW/cm, 540 J/cm with 3.3, 5.0, and 6.6 mg/kg Photofrin^®. The I-PDT with 6.6 mg/kg result in a 90% cure that was significantly better (p = 0.025) than light-only

Fig. 5

a Image of the rabbit treated with I-PDT. Visible in the image are the transparent close-end sharp catheters where treatment or dosimetry fibers were inserted. The blue probes are the optical thermometers that were placed on the tumour surface at margins. b 3D representation of the treatment plan. The tumour is represented in blue. The intended treatment fibers are in green and the intended location of dosimetry fibers are in red. c 3D representation of the intratumoural irradiance throughout the tumour. d CT scan prior to treatment, and (e) a CT scan, 13 weeks post treatment, showing no evidence of cancer