A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest-ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg·kg-1 ; 24 h drug-light interval) or 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) (4 mg·m-2 ;48 h) with wavelengths of 630 nm to 60J·cm-2 and 665 nm to 15-45J·cm-2 , respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III-IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8-2.0 CGE (range 50-75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two-year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1- and 2-year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced-stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect.

State of dose prescription and compliance to international standard (ICRU-83) in intensity modulated radiation therapy among academic institutions.

PURPOSE: The purpose of this study was to evaluate dose prescription and recording compliance to international standard (International Commission on Radiation Units & Measurements [ICRU]-83) in patients treated with intensity modulated radiation therapy (IMRT) among academic institutions. METHODS AND MATERIALS: Ten institutions participated in this study to collect IMRT data to evaluate compliance to ICRU-83. Under institutional review board clearance, data from 5094 patients-including treatment site, technique, planner, physician, prescribed dose, target volume, monitor units, planning system, and dose calculation algorithm-were collected anonymously. The dose-volume histogram of each patient, as well as dose points, doses delivered to 100% (D100), 98% (D98), 95% (D95), 50% (D50), and 2% (D2), of sites was collected and sent to a central location for analysis. Homogeneity index (HI) as a measure of the steepness of target and is a measure of the shape of the dose-volume histogram was calculated for every patient and analyzed. RESULTS: In general, ICRU recommendations for naming the target, reporting dose prescription, and achieving desired levels of dose to target were relatively poor. The nomenclature for the target in the dose prescription had large variations, having every permutation of name and number contrary to ICRU recommendations. There was statistically significant variability in D95, D50, and HI among institutions, tumor site, and technique with P values < .01. Nearly 95% of patients had D50 higher than 100% (103.5 ± 6.9) of prescribed dose and varied among institutions. On the other hand, D95 was close to 100% (97.1 ± 9.4) of prescribed dose. Liver and lung sites had a higher D50 compared with other sites. Pelvic sites had a lower variability indicated by HI (0.13 ± 1.21). Variability in D50 is 101.2 ± 8.5, 103.4 ± 6.8, 103.4 ± 8.2, and 109.5 ± 11.5 for IMRT, tomotherapy, volume modulated arc therapy, and stereotactic body radiation therapy with IMRT, respectively. CONCLUSIONS: Nearly 95% of patient treatments deviated from the ICRU-83 recommended D50 prescription dose delivery. This variability is significant (P < .01) in terms of treatment site, technique, and institution. To reduce dosimetric and associated radiation outcome variability, dose prescription in every clinical trial should be unified with international guidelines.

Deformable medical image registration of pleural cavity for photodynamic therapy by using finite-element based method.

When the pleural cavity is opened during the surgery portion of pleural photodynamic therapy (PDT) of malignant mesothelioma, the pleural volume will deform. This impacts the delivered dose when using highly conformal treatment techniques. To track the anatomical changes and contour the lung and chest cavity, an infrared camera-based navigation system (NDI) is used during PDT. In the same patient, a series of computed tomography (CT) scans of the lungs are also acquired before the surgery. The reconstructed three-dimensional contours from both NDI and CTs are imported into COMSOL Multiphysics software, where a finite element-based (FEM) deformable image registration is obtained. The CT contour is registered to the corresponding NDI contour by overlapping the center of masses and aligning their orientations. The NDI contour is considered as the reference contour, and the CT contour is used as the target one, which will be deformed. Deformed Geometry model is applied in COMSOL to obtain a deformed target contour. The distortion of the volume at X, Y and Z is mapped to illustrate the transformation of the target contour. The initial assessment shows that FEM-based image deformable registration can fuse images acquired by different modalities. It provides insights into the deformation of anatomical structures along X, Y and Z-axes. The deformed contour has good matches to the reference contour after the dynamic matching process. The resulting three-dimensional deformation map can be used to obtain the locations of other critical anatomic structures, e.g., heart, during surgery.

Targeted laryngeal photodynamic therapy with a balloon diffusing light source.

Photodynamic therapy (PDT) has been used for pre-malignant mucosal lesions. In an attempt to treat a patient with recurrent high-grade dysplasia of the glottic larynx, we were faced with technical challenges leading us to abandon the classic microlens fiber for a 2-cm long translucent diffusing balloon catheter to deliver photoactivating light to the targeted lesion. Real-time measurements confirmed stable photobleaching with augmentation of the prescribed light fluence secondary to light scatter in regions not in contact with the balloon diffuser. We report a potential new application of the balloon catheter that may be more suitable for anterior glottic lesions associated with minimal acute toxicity.

Interference with the Jaffé method for creatinine following 5-aminolevulinic acid administration.

BACKGROUND: The photosensitizer pro-drug 5-aminolevulinic acid (5-ALA) has been administered systemically for photodynamic therapy. Although several toxicities have been reported, nephrotoxicity has never been observed. MATERIALS AND METHODS: Patients with head and neck mucosal dysplasia have been treated on a phase 1 study of escalating light doses in combination with 60mg/kg of oral 5-ALA. Serum creatinine was measured with the modified Jaffe method or an enzymatic method in the first 24h after 5-ALA. Interference by 5-ALA, as well as by its photosensitizing product protoporphyrin IX, was assessed. RESULTS: Among 11 subjects enrolled to date, 9 of 11 had blood chemistries collected within the first 5h with 7 demonstrating significant grade 3 creatinine elevations (p=0.030). There was no additional evidence of compromised renal function or increased PDT-induced mucositis. Creatinine levels measured by the Jaffe assay increased linearly as a function of the ex vivo addition of ALA (p<0.0001). The exogenous addition of PpIX did not alter creatinine levels. ALA did not interfere with creatinine levels as measured by an enzymatic assay. A total of 4 of the 11 subjects had creatinine levels prospectively measured by both the Jaffe and the enzymatic assays. Only the Jaffe method demonstrated significant elevations as a function of time after ALA administration. CONCLUSIONS: The transient increase in creatinine after systematic ALA can be attributed, in part, if not entirely, to interference of ALA in the Jaffe reaction. Alternative assays should be employed in situations calling for monitoring of kidney function after systemic ALA.

The ratio of the spherical and flat Detectors at tissue surfaces during pleural photodynamic therapy.

An isotropic detector-based system was compared with a flat photodiode-based system in patients undergoing pleural photodynamic therapy. Isotropic and flat detectors were placed side by side in the chest cavity, for simultaneous in vivo dosimetry at surface locations for twelve patients. The treatment used 630nm laser to a total light irradiance of 30 J/cm2 (measured with the flat photodiodes) with photofrin® IV as the photosensitizer. Since the flat detectors were calibrated at 532nm, wavelength correction factors (WCF) were used to convert the calibration to 630nm (WCF between 0.542 and 0.703). The mean ratio between isotropic and flat detectors for all sites was linear to the accumulated fluence and was 3.4±0.6 or 2.1±0.4, with or without the wavelength correction for the flat detectors, respectively. The µeff of the tissues was estimated to vary between 0.5 to 4.3 cm-1 for four sites (Apex, Posterior Sulcus, Anterior Chest Wall, and Posterior Mediastinum) assuming µs' = 7 cm-1. Insufficient information was available to estimate µeff directly for three other sites (Anterior Sulcus, Posterior Chest Wall, and Pericardium) primarily due to limited sample size, although one may assume the optical penetration in all sites to vary in the same range (0.5 to 4.3 cm-1).