Urethra-Sparing Stereotactic Body Radiation Therapy for Prostate Cancer: Quality Assurance of a Randomized Phase 2 Trial.

PURPOSE: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. METHODS AND MATERIALS: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. RESULTS: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P < .001). Furthermore, the use of VMAT yielded better dosimetric results than IMRT for urethra planning-risk volume D98% (31.1 vs 30.8 Gy, P < .0001), PTV D2% (37.9 vs 38.7 Gy, P < .0001), homogeneity index (0.09 vs 0.10, P < .0001), Dice similarity coefficient (0.83 vs 0.80, P < .0001), and bladder wall V50% (24.5% vs 33.5%, P = .0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P <.0001). The inclusion of SV in the PTV negatively affected the rectal wall V90% (9.1% vs 10.4%, P = .0003) and V80% (13.2% vs 15.7%, P = .0003). CONCLUSIONS: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

Scattering of therapeutic radiation in the presence of craniofacial bone reconstruction materials.

PURPOSE: Radiation scattering from bone reconstruction materials can cause problems from prolonged healing to osteoradionecrosis. Glass fiber reinforced composite (FRC) has been introduced for bone reconstruction in craniofacial surgery but the effects during radiotherapy have not been previously studied. The purpose of this study was to compare the attenuation and back scatter caused by different reconstruction materials during radiotherapy, especially FRC with bioactive glass (BG) and titanium. METHODS: The effect of five different bone reconstruction materials on the surrounding tissue during radiotherapy was measured. The materials tested were titanium, glass FRC with and without BG, polyether ether ketone (PEEK) and bone. The samples were irradiated with 6 MV and 10 MV photon beams. Measurements of backscattering and dose changes behind the sample were made with radiochromic film and diamond detector dosimetry. RESULTS: An 18% dose enhancement was measured with a radiochromic film on the entrance side of irradiation for titanium with 6 MV energy while PEEK and FRC caused an enhancement of 10% and 4%, respectively. FRC-BG did not cause any measurable enhancement. The change in dose immediately behind the sample was also greatest with titanium (15% reduction) compared with the other materials (0-1% enhancement). The trend is similar with diamond detector measurements, titanium caused a dose enhancement of up to 4% with a 1 mm sample and a reduction of 8.5% with 6 MV energy whereas FRC, FRC-BG, PEEK or bone only caused a maximum dose reduction of 2.2%. CONCLUSIONS: Glass fiber reinforced composite causes less interaction with radiation than titanium during radiotherapy and could provide a better healing environment after bone reconstruction.

Urethra-sparing stereotactic body radiotherapy for prostate cancer: how much can the rectal wall dose be reduced with or without an endorectal balloon?

BACKGROUND: This is a dosimetric comparative study intended to establish appropriate low-to-intermediate dose-constraints for the rectal wall (Rwall) in the context of a randomized phase-II trial on urethra-sparing stereotactic body radiotherapy (SBRT) for prostate cancer. The effect of plan optimization on low-to-intermediate Rwall dose and the potential benefit of an endorectal balloon (ERB) are investigated. METHODS: Ten prostate cancer patients, simulated with and without an ERB, were planned to receive 36.25Gy (7.25Gyx5) to the planning treatment volume (PTV) and 32.5Gy to the urethral planning risk volume (uPRV). Reference plans with and without the ERB, optimized with respect to PTV and uPRV coverage objectives and the organs at risk dose constraints, were further optimized using a standardized stepwise approach to push down dose constraints to the Rwall in the low to intermediate range in five sequential steps to obtain paired plans with and without ERB (Vm1 to Vm5). Homogeneity index for the PTV and the uPRV, and the Dice similarity coefficient (DSC) for the PTV were analyzed. Dosimetric parameters for Rwall including the median dose and the dose received by 10 to 60% of the Rwall, bladder wall (Bwall) and femoral heads (FHeads) were compared. The monitor units (MU) per plan were recorded. RESULTS: Vm4 reduced by half D30%, D40%, D50%, and Dmed for Rwall and decreased by a third D60% while HIPTV, HIuPRV and DSC remained stable with and without ERB compared to Vmref. HIPTV worsened at Vm5 both with and without ERB. No statistical differences were observed between paired plans on Rwall, Bwall except a higher D2% for Fheads with and without an ERB. CONCLUSIONS: Further optimization to the Rwall in the context of urethra sparing prostate SBRT is feasible without compromising the dose homogeneity to the target. Independent of the use or not of an ERB, low-to-intermediate doses to the Rwall can be significantly reduced using a four-step sequential optimization approach.

Measurement and properties of the dose-area product ratio in external small-beam radiotherapy.

In small-beam radiation therapy (RT) the measurement of the beam quality parameter, i.e. the tissue-phantom ratio or TPR20,10, using a conventional point detector is a challenge. To obtain reliable results, one has to consider potential sources of error, including volume averaging and adjustment of the point detector into the narrow beam. To overcome these challenges, a different type of beam quality parameter in small beams was studied, namely the dose-area product ratio, or DAPR20,10. With this method, the measurement of a dose-area product (DAP) using a large-area plane-parallel chamber (LAC) eliminates the uncertainties in detector positioning and volume averaging that are present when using a point detector. In this study, the properties of the DAPR20,10 of a cone-collimated 6 MV photon beam were investigated using Monte Carlo (MC) calculations and the obtained values were compared to measurements obtained using two LAC detectors, PTW Type 34073 and PTW Type 34070. In addition, the possibility of determining the DAP using EBT3 film and a Razor diode detector was studied. The determination of the DAPR20,10 value was found to be feasible in external small-beam radiotherapy using cone-collimated beams with diameters from 4-40 mm, based on the results of the two LACs, the MC calculations and the Razor diode. The measurements indicated a constant DAPR20,10 value for fields 20-40 mm in diameter, with a maximum relative change of 0.6%, but an increase of 7.0% for fields from 20-4 mm in diameter for the PTW Type 34070 chamber. Simulations and measurements showed an increase of DAPR20,10 with increasing LAC size or dose integral area for the studied 4-40 mm cone-collimated 6 MV photon beams. This has the consequence that there should be a reference to the size of the used LAC active area or the DAP integration area with the reported DAPR20,10 value.

Perphenazine solid dispersions for orally fast-disintegrating tablets: physical stability and formulation.

AIM: The aim of this study was to prepare an orally fast-disintegrating tablet (FDT) by direct compression, containing a poorly soluble drug (perphenazine, PPZ) formulated as a stable solid dispersion. METHODS: The stability studies of the fast dissolving 5/1, 1/5, 1/20 (w/w), PPZ/polyvinylpyrrolidone K30 (PVP) or polyethylene glycol 8000 (PEG)) solid dispersions, and amorphous PPZ were conducted with differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy, small-angle X-ray scattering, and dissolution rate studies. RESULTS AND DISCUSSION: It was found that 1/5 PPZ/PEG was the most stable dispersion under elevated temperature and/or humidity. FDTs containing 60% of mannitol, 15% of calcium silicate, 15% of crospovidone, and 10% of 1/5 PPZ/PEG solid dispersion exhibited fast disintegration times (37 +/- 3), sufficient hardness (1.28 +/- 0.06 MPa), and fast onset of drug dissolution (34% of PPZ dissolved in 4 minutes), and these properties were found to be retained with storage. Thus, by optimizing the drug/excipient ratio of the solid dispersion and tablet composition, it was possible to produce FDTs that possessed fast disintegration and satisfactory drug dissolution in addition to adequate tensile strength, so that they can be handled and packed normally.

Optical gas sensing properties of thermally hydrocarbonized porous silicon Bragg reflectors.

In the present work, porous silicon (PS) based Bragg reflectors are fabricated, and the reactive PS surface is passivated by means of thermal carbonization (TC) by acetylene decomposition. The gas sensing properties of the reflectors are studied with different gas compositions and concentrations. Based on the results it can be concluded that thermally carbonized Bragg reflectors provide an easy and inexpensive means to produce chemically stable high quality PS reflectors with good gas sensing properties, which differ from those of unpassivated PS reflectors.

Intraorally fast-dissolving particles of a poorly soluble drug: preparation and in vitro characterization.

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.

Compatibility of chewing gum excipients with the amino acid L-cysteine and stability of the active substance in directly compressed chewing gum formulation.

Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.