Real-time PDT Dose Dosimetry for Pleural Photodynamic Therapy

Abstract

PDT dose is the product of the photosensitizer concentration and the light fluence in the target tissue. For improved dosimetry during plural photodynamic therapy (PDT), an eight-channel PDT dose dosimeter was developed to measure both the light fluence and the photosensitizer concentration simultaneously from eight different sites in the pleural cavity during PDT. An isotropic detector with bifurcated fibers was used for each channel to ensure detected light was split equally to the photodiode and spectrometer. The light fluence rate distribution is monitored using an IR navigation system. The navigation system allows 2D light fluence mapping throughout the whole pleural cavity rather than just the selected points. The fluorescence signal is normalized by the light fluence measured at treatment wavelength. We have shown that the absolute photosensitizer concentration can be obtained by applying optical properties correction and linear spectral fitting to the measured fluorescence data. The detection limit and the optical property correction factor of each channel were determined and validated using tissue-simulating phantoms with known varying concentration of Photofrin. Tissue optical properties are determined using an absorption spectroscopy probe immediately before PDT at the same sites. The combination of 8-channel PDT dosimeter system and IR navigation system, which can calculate light fluence rate in the pleural cavity in real-time, providing a mean to determine the distribution of PDT dose on the entire pleural cavity to investigate the heterogeneity of PDT dose on the pleural cavity.

1. INTRODUCTION

Type II PDT is a multi-faceted, dynamic process that involves the interactions of light, photosensitizer, and ground state oxygen (³O₂), to create reactive singlet oxygen (¹O₂) [1]. PDT dose has been used as a dosimetric quantity in preclinical settings for some time. However, few direct clinical measurements of PDT dose are available for clinical trials even though preclinical results have strongly indicated that PDT dose is a better dosimetrical quantity than light fluence alone [2–5]. PDT treatment outcome depends on both the light dose and the photosensitizer concentration, and PDT dose is a quantitiy that incoroporates both as a product. Heterogeneities in both light and photosensitizer concenration add to challenges in dosimetry [6]. Existing real-time dosimetry has focused on light fluence in vivo, but with concurrent measurement of the photosensitizer in treated tissue, PDT dose can be evaluated in real time. This study summarizes the current state of art of multi-channel PDT dose measurements in a mesothelioma pleural PDT clinical trial.

2. MATERIALS AND METHODS

2.1. Clinical Trial

In a phase II/III randomized clinical trial, patients with pleural mesothelioma received lung-sparing surgery in conjunction with PDT on one arm, while patients on other randomized arm received only the surgery. For those patients receiving PDT, Photofrin (Pinnacle Biologics, Chicago, IL, USA) was administered at a dose of 5 mg per kg of body weight 24 hours before surgery. PDT treatment was performed with 632 nm light to a total fluence of 60 J/cm². Light was delivered via a bare optical fiber embedded in a modified endotracheal tube filled with 0.1% Intralipid. The pleural cavity was also filled with Intralipid to aid with light scattering.

2.2. PDT Dose Dosimeter Instrumentation

Isotropic detectors (Medlight, Switzerland) were used to collect light fluence data during treatment. Eight locations within the plerual cavity were chosen to represent the entire area, and isotropic detectors were sutured onto the pleural cavity surface. Light fluence rate and cumulative fluence were monitored during PDT to determine the delivered dose.

The PDT dose instrument evolved from the initial two to four and now all eight isotropic detectors were used in the clinical protocol. Bifurcated optical fibers (Ocean Optics, Inc., Dunedin, FL, USA) were coupled to the isotropic detectors. One arm of the bifurcation was connected to the dosimetry system to do the light dosimetry measurements. The other arm of the bifurcation was connected to a 633 nm RazorEdge long-pass filter (Semrock, Inc., Rochester, NY, USA) to block the treatment light and then the CCD spectrometer (Exemplar, B&W Tek, Inc., Newark, DE, USA). Figure 1(a) shows the picture of the final instrument and Fig. 1(b) shows a schematic of the 4 channel PDT instrument set-up.

Figure 1:

(a) A picture of the PDT dose dosimeter and (b) Schematic of the PDT dose dosimeter system set up.

2.3. Spectroscopy

Fluorescence spectra were collected with eight single channel CCD spectrometer. To investigate the fluorescence excited by the treatment light (632 nm), a long-pass filter was used to only allow signal after 633 nm. The raw spectrum was fitted to the basis spectrom of Photofrin and the laser spectrum using single value decomposition (SVD) fitting and comparing spectra to those from phantoms with known concentrations of photofrin (Fig. 2).

Figure 2:

(a) Fluorescence intensity for various Photofrin concentrations (b) Calibration curve between the SVD amplitude and Photofrin concentration. (taken from Ref. [7])

2.4. Optical Property Correction

Fluorescence signal registered by the spectrometer is affected by the optical properties of the surrounding tissues. To determine the correction factor for Photofrin concentration as measured by fluorescence, absorption and scattering coefficients (μ_a and μ_s’ respectively) were measured for several Intralipid, ink, and Photofrin phantoms [8, 9]. An empirical optical property correction factor of the following form was determined [7]:

$$CF=C_1\left({\mu }_a^{b_1}{\mu }_s^{\prime b_2}+C_2\right)$$ (1)

where μ_a and μ_s’ are the absorption and the reduced scattering coefficient of the tissue optical properties at the emission wavelength (630 nm). Experiment in tissue-simulating phantoms with different intralipid concentrations (μ_s’ ~ 5 – 24 cm⁻¹) and varying amounts of ink (μ_a ~ 0.1 – 0.9 cm⁻¹) and known Photofrin concentrations (0.0625 - mg/kg) to determine the fitting parameter (CF_p, Table 1) as well as the calibration curve between fluorescence intensity (SVD). Monte Carlo calculations were performed to determine the fitting parameters (CF_MC, Table 1). Details of these experiments and MC simulations can be found elsewhere [7]. Figure 3 shows (a) SVD variation for different tissue phantoms (μ_a 0.1 – 0.9 cm⁻¹ and μ_s’ 5 – 24 cm⁻¹) with 3 mg/kg of Photofrin and (b) the resulting correction factors fitted to Eq. 1.

Table 1:

MC simulation (CF_MC) and experimentally determined (CF_p) fitting parameters for Eq. 1 [7]

Parameters	C 1	b 1	b 2	C 2
CF MC	22.43	0.943	−0.973	0.011
CF P	25.49 ± 0.65	0.902 ± 0.1	−1.094 ± 0.12	0.016 ± 0.05

Figure 3:

(a) Photofrin SVD amplitude for a fixed Photofrin concentration (3 mg/kg) in tissue simulating phantom of various μ_a (0.1 – 0.9 cm⁻¹) and μ_s’ (5 – 24 cm⁻¹). (b) The corresponding correction factor SVD_corr = SVD*CF for the same range of μ_a and μ_s’. (Taken from Ref. [7])

2.5. IR navigation system

A commercial IR navigation system (Polaris, NDI, Waterloo, Canada) was used for tracking the light delivery during pleural PDT [10–13]. The camera consists of a pair of cameras that measure the light reflection from a modulated laser source (with a wavelength of 850 nm). The stereo-cameras typically track 9 passive reflective markers with known geometry in real-time at a rate of 20–60 Hz). The light dose to each point on the cavity is a sum of the primary (direct) component and the scattered component of the light [10]. The primary component of the light fluence rate (ϕ) can be calculated by

$$\varphi =\frac{S}{4\pi r^2}$$ (2)

where S is the source power and r is the distance from the point light source to the point of interest on the pleural cavity surface.

3. RESULTS AND DISCUSSION

A representative result of Photofrin concentration over the entire PDT treatment was shown in Fig. 4a for eight treatment sites (PM – posterior mediastinum, ACW – anterior chest wall, PCW – posterior chest wall, Apex, AS – anterior diaphragmatic Surface, PS- Posterior diaphragmatic Surface, Diaph. – Diaphragm, Peri - pericardium). Figure 4b shows the locations of these sites. The smoothed photofrin concentration did not change over time during PDT. The larger variations of individual PS measurements (symbols in Fig. 4a) were due to the large fluctuation of incident treatment light fluence rate (0 – 1200 mW/cm²) which resulted in errors in PS fluorescence excited by the treatment light. Gaps in Photofrin concentration represent when the laser was off for a break in treatment or spectra was not collected.

Figure 4:

(a) Measured Photofrin concentration (in unit of mg/kg) at 8 sites (PM, ACW, PCW, Apex, AS, Diaph., PERI, and PS) during pleural PDT (b) geometrical locations of the detectors during PDT.

Because the PS concentration did not vary over time, the PDT dose can be calculated as the product of PS concentration and the total light fluence (60 Jcm²) per site:

$$\text{PDT dose }\left(\mu \text{MJ}/{\text{cm}}^2\right)=\text{PS}(\mu \text{M})\cdot 60\left(\text{J}/{\text{cm}}^2\right)$$ (3)

where a factor of 1. 650 μM/mg/kg (=1000/605.7, where 605.7 g is the molecular weight of Photofrin) is used to convert the PS concentration from mg/kg to μM. The variation of PS concentrations among the 8 sites were about 2 times.

Figure 5 shows the variation of CF_p calculated using the measured tissue optical properties in each treatment sites at treatment wavelength for 19 patients (07, 08, 12, 14, 16, 17, 18, 20, 27, 29, 32, 35, 37, 38, 40, 47, 49, 50, 52). The mean CF value of the correction factor (dashed line) was 1.16. The maximum variation among patient was 5.5 times and the maximum variation within each patient were 2.6 times. Patient 32 had no optical properties measurements. Earlier patients (07, 08, 12,14,16) had only two PDT dose probes. Patients (17, 18,20,27,29,32,35,37,38,40,49,50) had 4 PDT dose probes. Patient 52 was the first patient that we have attempted all 8 PDT dose probes.

Figure 5:

Correction factor CF_p for 19 patients at different sites as shown in the legend.

Results of PDT dose (right axis) or the Photofrin concentrations (left axis) per site of all 19 patients are shown in figure 6. The mean Photofrin concentration (dashed line, left axis) for all 19 patients was 4.53 μM and mean PDT dose (dashed line, right axis) for 19 patients was 448.5 μMJ/cm². The maximum variation among patient was 9.2 times and the maximum variation within each patient were 3.4 times. The large variation of PDT dose may provide an opportunity to improve the pleural PDT treatment by using the 8 channel PDT dose dosimeter to give uniform PDT dose to all sites.

Figure 6:

Photofrin concentrations (mg/kg, left axis) and PDT dose (μMJ/cm², right axis) for 19 patients at different sites.

Preliminary results for real-time navigation with feedback for light delivery are shown in figure 7 on a pleural phantom. The left figure corresponding to passive tracking of the light wand movement using the 3 isotropic detectors only. The right figure corresponding to tracking of the entire PDT treatment using the IR navigation system to achieve uniform total light fluence of 10 J/cm². It is obvious that real-time navigation can provide more uniform light dose distribution on the pleural surface. The navigation system has been used in clinical pleural PDT to track the motion of the light source during PDT and to assess the uniformity of light fluence distribution on the entire pleural cavity[14,15].

Figure 7:

Real-time determination of total light fluence (J/cm²) distribution on pleural phantom surface with (right) and without (left) real-time feedback of the navigation system.

4. CONCLUSION

A real-time 8-channel PDT dose dosimeter was developed and used during Photofrin-mediated pleural PDT. Mean PDT dose among 19 patients was 448.5 μMJ/cm² and it varied 920% among different patients and 340 % within the same patient. The 8-channel dose dosimeter provides a mean to initiate PDT dose-mediated pleural PDT. Future development incorporating the real-time navigation system to guide the light delivery can ensure the uniform distribution of PDT dose.