Intracranial radiosurgery in the Netherlands. A planning comparison of available systems with regard to physical aspects and workload.

Different planning and treatment systems for intracranial stereotactic radiosurgery available in the Netherlands are compared. The systems for intracranial radiosurgery include: Gamma Knife, Cyberknife, Novalis, and Tomotherapy. Electronic data of 5 patients was transferred to all participating centres and treatment plans were generated according to 2 different prescription protocols. For this study, plans were also generated for a conventional linac. Even systems with a high resolution (Gammaknife and Novalis) have conformity indices in violation with RTOG guidelines (CI > 2.5) when target volumes of <0.5 cc are treated. For medium sized targets (0.5-1 cc) all systems performed reasonably well, but for the different systems a large range of conformity indices was seen (1.1 to 3.7). The differences are partly system dependent but depend also on specific planning choices made. For larger target volumes (> 1 cc), all systems perform well. The workload of the different techniques was comparable although the treatment times were usually longer for Gamma Knife radiosurgery. We conclude that small targets should be treated by dedicated systems, larger volumes (> 0.5-1 cc) can also be treated using conventional treatment systems equipped with a MLC.

Performance of isotropic light dosimetry probes based on scattering bulbs in turbid media.

In a previous paper the calibration of an isotropic light detector in clear media was described and validated. However, in most applications the detector is used to measure light distribution in turbid (scattering) media, that is, in tissues or tissue equivalent optical phantoms. Despite its small diameter (typically 0.8 mm), inserting the detector in a turbid medium may perturb the light distribution and change the fluence rate at the point of measurement. In the present paper we estimate the error in the fluence rate measured by a detector in turbid media after calibration in a clear medium (air), using an optical phantom and detector bulbs of different optical properties. The experimental results are compared with calculations using the diffusion approximation to the transport equation in a spherical geometry. From measurements in optical phantoms and the results of the calculations it appears that introduction of the detector into a water-based turbid medium with refractive index, absorption- and scattering coefficients different from those of the detector bulb may require corrections to the detector response of up to 10-15%, in order to obtain the true fluence rate in that medium. The diffusion model is used to explore the detector response in a number of tissues of interest in photodynamic therapy, using tissue optical properties from the literature. Based on these model calculations it is estimated that in real tissues the fluence rate measured by the detector is up to 3% below the true value.

Relationship between tensile stress and plaque growth after balloon angioplasty treated with and without intracoronary beta-brachytherapy.

AIMS: We investigated the influence of tensile stress on plaque growth after balloon angioplasty with and without beta-radiation therapy. METHODS AND RESULTS: Thirty-one consecutive patients successfully treated with balloon angioplasty were analysed qualitatively and quantitatively by means of an ECG-gated three-dimensional intravascular ultrasound post-procedure and at follow-up. Eighteen patients were irradiated with catheter-based beta-radiation ((90)Sr/(90)Y source) and 13 were not (control). Studied segments were divided into 2 mm subsegments. Thus 184 irradiated and 111 non-irradiated subsegments were included. Tensile stress was calculated according to Laplace's law. The radiation dose was calculated by means of dose-volume histograms. Plaque growth was positively correlated to tensile stress in both the radiation and control groups (r=0.374, P=0.0001 and r=0.305, P=0.001). Low-dose subsegments (<6 Gy) had a significant correlation (r=0.410, P=0.0001) whereas no correlation was observed in the effective-dose subsegments (> or = 6 Gy). Multivariate analysis identified tensile stress as the only independent predictor of plaque increase in non-irradiated subsegments, whereas actual dose and plaque morphology were stronger predictors in irradiated subsegments. CONCLUSION: The results of this study suggest that plaque growth is related to tensile stress after balloon angioplasty. Intracoronary brachytherapy may alter the biophysical process on plaque growth when the prescribed dose is effectively delivered.

Three-dimensional intravascular ultrasound assessment of noninjured edges of beta-irradiated coronary segments.

BACKGROUND: The "edge effect," late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary beta-irradiation. METHODS AND RESULTS: Fifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm(3)) in the noninjured edges of the irradiated vessels at follow-up (P:=0. 001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization. CONCLUSIONS: The edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.

Residual plaque burden, delivered dose, and tissue composition predict 6-month outcome after balloon angioplasty and beta-radiation therapy.

BACKGROUND: Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS: Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS: Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

Endovascular brachytherapy in coronary arteries: the Rotterdam experience.

PURPOSE: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far. METHODS AND MATERIALS: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n = 31), for compassionate use (n = 25), in the Beta-Cath System trial (n = 27) and in the Beta Radiation in Europe (BRIE, n = 14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 microCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 microCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively. RESULTS: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges. CONCLUSIONS: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.

Preserved endothelium-dependent vasodilation in coronary segments previously treated with balloon angioplasty and intracoronary irradiation.

BACKGROUND: Abnormal endothelium-dependent coronary vasomotion has been reported after balloon angioplasty (BA), as well as after intracoronary radiation. However, the long-term effect on coronary vasomotion is not known. The aim of this study was to evaluate the long-term vasomotion of coronary segments treated with BA and brachytherapy. METHODS AND RESULTS: Patients with single de novo lesions treated either with BA followed by intracoronary beta-irradiation (according to the Beta Energy Restenosis Trial-1.5) or with BA alone were eligible. Of these groups, those patients in stable condition who returned for 6-month angiographic follow-up formed the study population (n=19, irradiated group and n=11, control group). Endothelium-dependent coronary vasomotion was assessed by selective infusion of serial doses of acetylcholine (ACh) proximally to the treated area. Mean luminal diameter was calculated by quantitative coronary angiography both in the treated area and in distal segments. Endothelial dysfunction was defined as a vasoconstriction after the maximal dose of ACh (10(-6) mol/L). Seventeen irradiated segments (89.5%) demonstrated normal endothelial function. In contrast, 10 distal nonirradiated segments (53%) and 5 control segments (45%) demonstrated endothelium-dependent vasoconstriction (-19+/-17% and -9.0+/-5%, respectively). Mean percentage of change in mean luminal diameter after ACh was significantly higher in irradiated segments (P=0.01). CONCLUSIONS: Endothelium-dependent vasomotion of coronary segments treated with BA followed by beta-radiation is restored in the majority of stable patients at 6-month follow-up. This functional response appeared to be better than those documented both in the distal segments and in segments treated with BA alone.

Short- and long-term normal tissue damage with photodynamic therapy in pig trachea: a fluence-response pilot study comparing Photofrin and mTHPC.

The damage to normal pig bronchial mucosa caused by photodynamic therapy (PDT) using mTHPC and Photofrin as photosensitizers was evaluated. An endobronchial applicator was used to deliver the light with a linear diffuser and to measure the light fluence in situ. The applied fluences were varied, based on existing clinical protocols. A fluence finding experiment with short-term (1-2 days) response as an end point showed considerable damage to the mucosa with the use of Photofrin (fluences 50-275 J cm(-2), drug dose 2 mg kg(-1)) with oedema and blood vessel damage as most important features. In the short-term mTHPC experiment the damage found was slight (fluences 12.5-50 J cm(-2), drug dose 0.15 mg kg(-1)). For both sensitizers, atrophy and acute inflammation of the epithelium and the submucosal glands was observed. The damage was confined to the mucosa and submucosa leaving the cartilage intact. A long-term response experiment showed that fluences of 50 J cm(-2) for mTHPC and 65 J cm(-2) for Photofrin-treated animals caused damage that recovered within 14 days, with sporadic slight fibrosis and occasional inflammation of the submucosal glands. Limited data on the pharmacokinetics of mTHPC show that drug levels in the trachea are similar at 6 and 20 days post injection, indicating a broad time window for treatment. The importance of in situ light dosimetry was stressed by the inter-animal variations in fluence rate for comparable illumination conditions.

Comparison of brachytherapy strategies based on dose-volume histograms derived from quantitative intravascular ultrasound.

PURPOSE: We present in this paper the comparison, by simulation, of different treatment strategies based either on beta- or gamma-sources, both with and without a centering device. Ionizing radiation to prevent restenosis is an emerging modality in interventional cardiology. Numerous clinical studies are presently being performed or planned, but there is variability in dose prescription, and both gamma- and beta-emitters are used, leading to a wide range of possible dose distributions over the arterial vessel wall. This paper discusses the potential merits of dose-volume histograms (DVH) based on three-dimensional (3-D) reconstruction of electrocardiogram (ECG)-gated intravascular ultrasound (IVUS) to compare brachytherapy treatment strategies. MATERIALS AND METHODS: DVH describe the cumulative distribution of dose over three specific volumes: (1) at the level of the luminal surface, a volume was defined with a thickness of 0.1 mm from the automatically detected contour of the highly echogenic blood-vessel interface; (2) at the level of the IVUS echogenic media-adventitia interface (external elastic lamina [EEL]), an adventitial volume was computed considering a 0.5-mm thickness from EEL; and (3) the volume encompassed between the luminal surface and the EEL (plaque + media). The IVUS data used were recorded in 23 of 31 patients during the Beta Energy Restenosis Trial (BERT) conducted in our institution. RESULTS: On average, the minimal dose in 90% of the adventitial volume was 37 +/- 16% of the prescribed dose; the minimal dose in 90% of the plaque + media volume was 58 +/- 24% and of the luminal surface volume was 67 +/- 31%. The minimal dose in the 10% most exposed luminal surface volume was 296 +/- 42%. Simulations of the use of a gamma-emitter and/or a radioactive source train centered in the lumen are reported, with a comparison of the homogeneity of the dose distribution. CONCLUSIONS: It is possible to derive DVH from IVUS, to evaluate the dose delivered to different parts of the coronary wall. This process should improve our understanding of the mechanisms of action of brachytherapy.

Guidance of intracoronary radiation therapy based on dose-volume histograms derived from quantitative intravascular ultrasound.

Application of ionizing radiation to prevent restenosis in atherosclerotic vessels treated by balloon angioplasty is a new treatment under investigation in interventional cardiology and radiology. There is variability in dose prescription, and both gamma- and beta-emitters are used, leading to a wide range of dose distribution over the arterial vessel wall. We present a new modality of dosimetry based on a method that three-dimensional (3-D) image reconstruction of electrocardiogram (ECG)-gated intravascular ultrasound (IVUS) images. Dose volume histograms (DVH) are used to describe the cumulative distribution of dose over two specific volumes: i) at the level of the luminal surface, defined with a thickness of 0.1 mm from the automatically detected contour of the highly echogenic blood-vessel interface, and ii) the adventitia volume is computed considering a 0.5-mm thickness from the echogenic media-adventitia interface. DVH provide a tool for reporting the actual delivered dose at the site believed to be the target: the adventitia, and to detect excessive radiation which could lead to vascular complications. Simulation of a gamma-emitter or of a radioactive source train in the center of the lumen are possible. The data obtained from the first ten patients included in the beta-irradiation trial (BERT 1.5) conducted in our institution are presented, supporting the use of DVH based on quantitative IVUS measurements for optimal dose prescription in vascular interventional radiation therapy.

Improvements in the design of linear diffusers for photodynamic therapy.

The angular radiance distribution of several linear diffusers used for photodynamic therapy (PDT) was measured. The forward scattering found previously was not observed for these designs. The improved isotropy leads to a better agreement between intended treatment site and actual maximum of the fluence rate profile when the linear diffuser is used in a hollow, cylindrical organ.

Applicator for light delivery and in situ light dosimetry during endobronchial photodynamic therapy: First measurements in humans.

This paper presents a design of an applicator for light delivery and light dosimetry during endobronchial photodynamic therapy (EB-PDT). The design incorporates a linear diffuser that is fixed in the centre of the lumen by a steel spring basket that does not block air flow. An isotropic light detector is included in this design, to measure the light fluence actually delivered to the bronchial mucosa surface. The applicator is designed for use with common bronchoscopy equipment, and can be used with bronchoscopes with a large biopsy channel ( approximately 3 mm). The first clinical measurements were performed and caused no additional discomfort to the (nonphotosensitized) patients. The data showed considerable inter-patient variability of the light fluence rate measured as a result of fixed output power of the diffuser. This fact and the expected strong dependence of the fluence rate on the lumen diameter stress the importance of in situ fluence rate measurement for a proper evaluation of the relationship between light fluence and the biological response of EB-PDT.

Calibration of isotropic light dosimetry probes based on scattering bulbs in clear media.

Miniature light detectors with isotropic response (isotropic light probes) permit quantitative measurement of light energy fluence rates in turbid media such as biological tissues. These isotropic probes are, for example, applied in photodynamic therapy to correlate light fluence in tissue with (tumour) tissue response, in vitro and in vivo. After description of its construction, two methods of calibration of an isotropic probe in air are discussed, in collimated and in diffuse light. The probe was first calibrated in air in collimated light, after which its response to diffuse light was checked in a flat and in a spherical geometry. Subsequently, the probe's response to collimated light in clear media, for example, water or glycerine which have refractive indices larger than that of air, has been established experimentally. The diffusion approximation to the transport equation in a simple spherical geometry has been used to calculate the probe's response as a function of the refractive index of clear media. The extent of agreement between theory and experiment indicates that the physical mechanisms are understood and indirectly validates the theoretical models.

Light distribution by linear diffusing sources for photodynamic therapy.

The distribution of the light emitted by linear light diffusers commonly employed in photodynamic therapy (PDT) has been investigated. A device is presented which measures the angular distribution of the exiting light at each point of the diffuser. With these data the fluence rate in air or in a cavity at some distance from the diffuser can be predicted. The results show that the light is scattered from the diffuser predominantly in the forward direction. Experiments and calculations show that the fluence rate in air and in a cavity of scattering tissue at some distance from the diffuser has a maximum near the tip of the diffuser, instead of near the middle. However, the fluence rate resulting from an interstitial diffuser in a purely scattering tissue phantom shows a maximum in the bisecting plane of the diffuser as would be predicted when the diffuser emitted light isotropically. The scattering nature of the tissue is expected to cancel the anisotropy of the diffuser.

Intraperitoneal photodynamic therapy of the rat CC531 adenocarcinoma.

The goal of this study was to investigate the efficacy of photodynamic therapy (PDT) of a single tumour growing intraperitoneally. For this purpose the CC531 colon carcinoma, implanted in an intraperitoneal fat pad of Wag/RijA rats, was treated with intraperitoneal photodynamic therapy (IPPDT) using Photofrin as the photosensitiser. Two illumination techniques have been compared. An invasive illumination technique using Perspex blocks to illuminate 30 cm2 of the lower abdomen gave a significant delay in tumour growth with 25 J cm-2 applied 1 day after Photofrin. A minimally invasive illumination technique using a balloon catheter to illuminate 14 cm2 resulted in an equivalent growth delay with 75 J cm-2. The route of administration of the photosensitiser did not influence regrowth times of the tumour. Mitomycin C (MMC), a bioreductive agent, was used to exploit the known PDT-induced hypoxia. The combination of IPPDT with MMC resulted in an increased tumoricidal effect. In conclusion, IPPDT led to a significant growth delay for a single tumour implanted intraperitoneally and repetition of the PDT treatment was possible using a minimally invasive illumination technique. Repeated treatments resulted in increased tumour response.

Influence of fractionation and fluence rate in photodynamic therapy with Photofrin or mTHPC.

Various schedules of fractionated photodynamic therapy (PDT), delivered at two different light fluence rates, were investigated in the RIF1 tumor model in an attempt to minimize the development of hypoxia during PDT and thereby improve tumor response relative to single treatments. The photosensitizers Photofrin and meta-tetrahydroxyphenylchlorin (mTHPC) were used in combination with either interstitial or superficial illumination. For both methods of illumination, equal volumetric light doses gave similar tumor responses, as measured by tumor regrowth times and number of cures. Fractionation of superficial illumination did not generally improve tumor response compared with a single illumination with the same total light dose. The only fractionated schedules which demonstrated a trend for increased cure were six fractions of superficial illumination given with short (1 h) dark periods between illuminations. Using both photosensitizers, an increase in tumor regrowth time occurred when tumors were illuminated interstitially with continuous light at a linear diffuser output of 50 mW compared with 100 mW per cm diffuser length. Discontinuous illumination with alternating light and dark periods of 30 s improved the tumor response further for mTHPC-mediated PDT at a fluence rate of 100 mW cm(-1). No improvement in response was seen by discontinuous interstitial illumination after Photofrin-mediated PDT. These results demonstrate that lower fluence rates and/or fractionating the light dose delivered can improve the response of the RIF1 tumor to PDT but that the choice of dark intervals between fractions is critical.

Use of sheet color filters for video-endoscopic observation during intraluminal photodynamic therapy.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is currently evaluated in clinical studies for the treatment of bronchial and oesophageal tumors. STUDY DESIGN/MATERIALS AND METHODS: Usually, a cylindrical diffuser is entered into the lumen via a flexible endoscope. Subsequently, the diffuser is positioned at the tumor location under direct- or video-endoscopic vision and manually kept in position by the clinician during the treatment. However, video endoscopes are saturated (overexposure) due to the intense light from the diffuser tip and scattered light from the tissue. This hinders continuous monitoring of the diffuser position. RESULTS: A simple color filter sheet, suitable for use with endoscopes with removable CCD-video head, appeared to be very effective in improving video endoscopic monitoring during treatment. CONCLUSION: The standard fiberoptic endoscopes with the accessory CCD video head are more suitable for PDT treatment monitoring than modern endoscopes with the integrated CCD camera.

Ex vivo light dosimetry and Monte Carlo simulations for endobronchial photodynamic therapy.

The light distribution during photodynamic therapy of the bronchial tree has been estimated by measuring the fluence rate in ex vivo experiments on dissected pig bronchi. The trachea was illuminated (630 nm) with a cylindrical diffuser and the fluence rate was measured with a fibre optic isotropic probe. The experiment with the diffuser on the central axis was also simulated with Monte Carlo techniques using the optical properties that were determined with a double-integrating-sphere set-up. The results from ex vivo experiments and the Monte Carlo simulations were found to agree within the error of measurement (15%), indicating that the Monte Carlo technique can be used to estimate the light distribution for varying geometries and optical properties. The results showed that the light fluence rate in the mucosa of the tracheal tract may increase by a factor of six compared to the fluence rate in air (in the absence of tissue). This is due to the scattering properties of the tissue and the multiple reflections within the cavity. Further ex vivo experiments showed that the positioning of the diffuser is critical for the fluence rate in the lesion to be treated. When the position of the diffuser was changed from the central axis to near the lesion, the fluence rate in the mucosa increased significantly by several orders of magnitude as compared to the initial (central) illumination. The inter- and intraspecimen variations in this increase were large (+/- 35%) because of variations in optical and geometrical properties and light source positioning, respectively. These variations might cause under- or overdosage resulting in either insufficient tumour necrosis or excessive normal tissue damage.

Intraperitoneal photodynamic therapy in the rat: comparison of toxicity profiles for photofrin and MTHPC.

Toxicity studies for intraperitoneal photodynamic therapy (IPPDT) were performed in Wag/RijA rats, using specially designed light delivery blocks for proper light distribution and light dosimetry. A recently developed photosensitizer mesotetrahydroxyphenylchlorin (mTHPC), excited at 652-nm wave-length, was compared with Photofrin (630 nm). Toxicity profiles for various sensitizer doses, light fluences and time intervals were investigated. A light fluence of 15 J.cm-2 delivered to the entire peritoneum 24 hr after 5 mg Photofrin per kg i.v. induced reversible impairment of intestinal, liver and kidney function. A dose of 0.2 mg mTHPC per kg i.v. followed by 6 J.cm-2 at 72 hr appeared to be equitoxic to the intestines; however, functional tests revealed little effect for this mTHPC-mediated IPPDT regime on liver or kidney. Histology demonstrated focal irreversible damage to the kidneys for both photosensitizers, not reflected in functional impairment. Light doses of 25 to 30 J.cm-2 at 24 hr after Photofrin or 8-12 J.cm-2, 72 hr after mTHPC caused lethal toxicity in the first 2 weeks due to intestinal damage. Higher light doses caused a shock syndrome and rhabdomyolysis resulting in death within 20 hr for both photosensitizers. In conclusion, maximum tolerable schedules for whole-abdomen IPPDT were defined for Photofrin and mTHPC. Both photosensitizers caused similar toxicity profiles depending on drug dose, light fluence and time interval.

Pilot study on light dosimetry for endobronchial photodynamic therapy.

Endobronchial photodynamic therapy (EB-PDT) using photofrin as the photosensitizer is currently being evaluated as a new treatment modality for inoperable endobronchial tumors. One of the current problems with EB-PDT is the lack of adequate light dosimetry, which hampers proper interpretation of treatment results. In this study exploratory light dosimetry experiments were performed in plastic bronchus models using either a microlens-tipped fiber (suitable for illumination of small superficial tumors) or a cylindrical diffuser fiber (suitable for intraluminal illumination or interstitial illumination of partially obstructing tumors). It is shown that the light fluence prescriptions of current clinical protocols yield a different fluence in tissue for each illumination modality. Depending on the actual placement of the cylindrical diffuser within the lumen, the light fluence at 5 mm depth in the homogeneous tissue model may vary by a factor of 3. The results were confirmed by in vivo experiments in the trachea of a pig. There is a possibility of enhanced tissue response by accidental hyperthermia induced during EB-PDT. The temperature rise was therefore estimated in vivo using a rat tumor model to mimic clinical EB-PDT. Temperature rises of at least 5 degrees C and 10 degrees C can be expected for intraluminal and intratumoral illumination, respectively, at 3.5 +/- 1 mm depth in tissue and 400 mW/cm diffuser output. Light fluence and its distribution in the bronchus strongly depend on the geometry and the optical properties of the tissue as well as on the technique of illumination. As a result of inadequate dosimetry, significant variations in treatment response between patients may be expected.