As compared to cystectomy for recalcitrant and progressing in situ bladder cancer, photodynamic therapy (PDT) can offer retention of organ function and successful disease ablation. However, bladder PDT has been used infrequently due to multiple cases of fibrosis, possibly due to light over-treatment and inhomogeneous light delivery. During bladder PDT, knowledge of diffuser placement and physical dimensions of the bladder are required for accurate dosimetry. Due to bladder tissue optical properties, the fluence rate (mW/cm2) and hence the prescribed dose (Joules/cm2) is higher than the calculated dose due to the ‘integrating sphere effect’. The added dose effect of multiple reflections inside the bladder can account for fluences up to nine times the simple calculation of input power divided by bladder wall area. We have used the ASAP® (Breault Research®, Tucson, AZ) optical modeling software as a rudimentary treatment planning system to calculate fluence presented to the bladder wall, consisting of both non-scattered and scattered illumination.

Prior to photosensitizer and treatment, the bladder is filled with saline and CT scanned in 1mm slices. The slices are then combined and reconstructed to form a 3-d volume image in digital format. This volume model is then used within ASAP® to calculate the treatment flux needed to achieve the desired prescribed light dosage. Bladder wall optical properties were chosen based upon the mean of previously published data. The source was also modeled in a similar fashion, and ‘moved’ within the virtual bladder to simulate non-isotropic and uneven non-scattered radiation. Significant (+- 100%) variances in fluence homogeneity and level were observed.

Dosimetry planning provided by software modeling may allow for improved therapeutic outcomes and diminished morbidity. The software is flexible and can be used immediately prior to and during treatment. Should further clinical data corroborate the modeling, PDT may become a viable treatment modality for bladder cancer.

ABSTRACTABSTRACT

Photodynamic therapy for bladder cancer – optimizing dosimetry as a means to improve outcome.

Bonnerup CA, Sibata CH, Allison, RR  East Carolina University, Department of Radiation Oncology, Greenville, North Carolina 27834

Tomographic images of a saline-filled bladder were obtained with 1mm slices for high resolution imaging. The slices were used to construct a 3-d model with computer-aided-drafting (CAD) software compatible with ASAP®. The model was then imported as a virtual tissue whose optical properties, wall thickness, and internal media can be defined by the user. A 2mm diameter isotropic spherical emitter model was used to simulate a standard treatment catheter, and placed within the model to characterize the effects of different geometries on bladder-wall fluence. Source power and location of the emitter within the volume were varied. Additionally, an intravesical scattering medium was modeled to simulate the often-used practice of using a diffusing medium within the bladder to homogenize the dose.

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METHODSMETHODS

RESULTSRESULTS

Figure 1 shows the completed bladder model; color is arbitrary. The total volume of the model is 238.7 cm3 with maximum length of 9.1cm and width of 6.5 cm. Internal surface area is 198 cm2. If treatment planning is based upon spherical shape from fluid volume, the radius would be calculated as 3.84 cm, with a surface area of 185 cm2.We compared the fluence on the long and short axis bladder wall based upon a spherical assumption, with 1000 mW emitter output. Data is shown in TABLE 1.

TABLE 1.As shown, treatment assumptions based upon incorrect geometrical shape and size can lead to ~2-fold dosage variations within the bladder.

Bladder Optical Properties:Bladder tissue is classified optically as a turbid media, meaning that photon migration in a representative volume is characterized by scattering and absorption, with penetration depth characterized by three predominant factors: the absorption coefficient (a), the scattering coefficient (s), and the anisotropy or cosine of the average angle of a scattered photon (g). The scattering and absorption coefficients are in units of inverse length, and the reciprocal of their sum is the average length a photon moves within tissue before a scattering or absorption event. The anisotropy can vary from -1 (perfect back-scatter) to +1 (perfect forward scatter). Most biological tissues are in the range of 0.7

to 0.9. Integrating Sphere Effect:An integrating sphere is used in the measurement and calibration of optical devices. It is a true sphere, with a highly reflective (>95%) internal coating which scatters light in an isotropic manner. Due to multiple internal reflections, the power incident on an area inside the sphere is higher than the input power. This increase in power is called the ‘sphere multiplier’, and is:

Where ρω is the internal reflectance and f is the ratio of the area of the detector to the total are of the sphere. Typical spheres have internal magnification factors of 9 to 10. For a turbid medium, an alternate formalism is the albedo, and is defined in terms of the optical coefficients as:

Optically, the human bladder resembles an integrating sphere due to a highly scattering urothelium, with s ~ 140 cm-1, a ~ 1.4 cm-1, and g = 0.9. (Star et.al, 1988). If these values are inserted in the above equation, the albedo approaches 99%, which can be compared with the highly reflective values in an integrating sphere with similar consequences for flux multiplication.

The data in TABLE 1 neglects the optical properties of tissue in general and the bladder in particular. We used the referenced values above to calculate the fluence on a spherical model of the same dimensions as before, both with and without an intravesical scattering medium (Intralipid, 0.2% in Saline). FIGURE 2 is an ASAP® representation of a spherical bladder filled with saline (optically clear), while FIGURE 3 shows the flux response with Intralipid scattering media. Absorption and scattering coefficients were applied to the model and the total flux on the bladder wall calculated. A 1000mW emitter was modeled as before. Results are shown in TABLE 2.

TABLE 2.

Spherical Assumption based upon 239 cm3 Volume

FLUENCE on BLADDER WALL (mW / cm2)

(1000mW output)

LONG AXIS (9.1 cm) 3.85

SHORT AXIS (6.5 cm) 7.53

FLUENCE on BLADDER WALL (mW / cm2)

(1000mW emitter output – optical properties ignored)

FLUENCE on BLADDER WALL (mW / cm2)

(1000mW emitter output – with typical bladder optical

properties)

Bladder Model - no scattering

media5.41 44.86

Bladder model with saline

5.32 43.55

Bladder with 0.2% Intralipid

1.34 7.65

CONCLUSIONCONCLUSION

The data demonstrate the need for rigorous dosimetry and modeling of the bladder prior to PDT. Large differences in planned and actual fluences and dosages are possible due to inherent physiological properties of tissue, and the bladders high scattering which can result in dose magnification. Excessive over treatment of the bladder can result in spasms, nocturia, dysuria, suprapubic pain, and fibrosis. In some instances cystectomy may have to be performed, negating the value of PDT. Further work is needed to refine the modeling accuracy, which can be enhanced by methods and tools to directly measure the bladder optical properties in vivo.

FIGURE 1.

FIGURE 2. FIGURE 3.

Star WM, , Marijnissen JPA and van Gemert MJC 1988 Light dosimetry in optical phantoms and in tissues: I.Multiple flux and transport theory Phys. Med. Biol. 33 437-54

Rem AI, et.al. 1996 Uniform irradiation of irregularly shaped cavities for photodynamic therapy Phys. Med. Biol. 42 583-93

REFERENCESREFERENCES