Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10

PURPOSE Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial assessing dose intensification. PATIENTS AND METHODS Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25. RESULTS Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02). CONCLUSION Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms.

Hybrid Monte Carlo dose algorithm for low energy X-rays intraoperative radiation therapy

Low energy X-rays Intra-Operative Radiation Therapy (XIORT) treatment delivered during surgery (ex: INTRABEAM, Carl Zeiss, and Axxent, Xoft) can benefit from accurate and fast dose prediction in a patient 3D volume.

Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation

Germ-line mutation induction at mouse minisatellite loci by acute irradiation with x-rays was studied at premeiotic and postmeiotic stages of spermatogenesis. An elevated paternal mutation rate was found after irradiation of premeiotic spermatogonia and stem cells, whereas the frequency of minisatellite mutation after postmeiotic irradiation of spermatids was similar to that in control litters. In contrast, paternal irradiation did not affect the maternal mutation rate. A linear dose–response curve for paternal mutation induced at premeiotic stages was found, with a doubling dose of 0.33 Gy, a value close to those obtained in mice after acute spermatogonia irradiation using other systems for mutation detection. High frequencies of spontaneous and induced mutations at minisatellite loci allow mutation induction to be evaluated at low doses of exposure in very small population samples, which currently makes minisatellite DNA the most powerful tool for monitoring radiation-induced germ-line mutation.

The measurements of neutron and gamma dose rates in mixed radiation fields, using a liquid scintillation counter

Measurements of neutron and gamma dose rates in mixed radiation fields, and gamma dose rates from calibrated gamma sources, were performed using a liquid scintillation counter NE213 with a pulse shape discrimination technique based on the charge comparison method. A computer program was used to analyse the experimental data. The radiation field was obtained from a 241Am-9Be source. There was general agreement between measured and calculated neutron and gamma dose rates in the mixed radiation field, but some disagreement in the measurements of gamma dose rates for gamma sources, due to the dark current of the photomultiplier and the effect of the perturbation of the radiation field by the detector. An optical fibre bundle was used to couple an NE213 scintillator to a photomultiplier, in an attempt to minimise these effects. This produced an improvement in the results for gamma sources. However, the optically coupled detector system could not be used for neutron and gamma dose rate measurements in mixed radiation fields. The pulse shape discrimination system became ineffective as a consequence of the slower time response of the detector system.

Utilisation de la tomodensitométrie à deux énergies pour le calcul de dose en curiethérapie à bas débit

Dans la pratique actuelle de la curiethérapie à bas débit, l'évaluation de la dose dans la prostate est régie par le protocole défini dans le groupe de travail 43 (TG-43) de l'American Association of Physicists in Medicine. Ce groupe de travail suppose un patient homogène à base d'eau de même densité et néglige les changements dans l'atténuation des photons par les sources de curiethérapie. En considérant ces simplifications, les calculs de dose se font facilement à l'aide d'une équation, indiquée dans le protocole. Bien que ce groupe de travail ait contribué à l'uniformisation des traitements en curiethérapie entre les hôpitaux, il ne décrit pas adéquatement la distribution réelle de la dose dans le patient. La publication actuelle du TG-186 donne des recommandations pour étudier des distributions de dose plus réalistes. Le but de ce mémoire est d'appliquer ces recommandations à partir du TG-186 pour obtenir une description plus réaliste de la dose dans la prostate. Pour ce faire, deux ensembles d'images du patient sont acquis simultanément avec un tomodensitomètre à double énergie (DECT). Les artéfacts métalliques présents dans ces images, causés par les sources d’iode, sont corrigés à l'aide d’un algorithme de réduction d'artefacts métalliques pour DECT qui a été développé dans ce travail. Ensuite, une étude Monte Carlo peut être effectuée correctement lorsque l'image est segmentée selon les différents tissus humains. Cette segmentation est effectuée en évaluant le numéro atomique effectif et la densité électronique de chaque voxel, par étalonnage stoechiométrique propre au DECT, et en y associant le tissu ayant des paramètres physiques similaires. Les résultats montrent des différences dans la distribution de la dose lorsqu'on compare la dose du protocole TG-43 avec celle retrouvée avec les recommandations du TG-186.

Utilisation de la tomodensitométrie à deux énergies pour le calcul de dose en curiethérapie à bas débit

Dans la pratique actuelle de la curiethérapie à bas débit, l'évaluation de la dose dans la prostate est régie par le protocole défini dans le groupe de travail 43 (TG-43) de l'American Association of Physicists in Medicine. Ce groupe de travail suppose un patient homogène à base d'eau de même densité et néglige les changements dans l'atténuation des photons par les sources de curiethérapie. En considérant ces simplifications, les calculs de dose se font facilement à l'aide d'une équation, indiquée dans le protocole. Bien que ce groupe de travail ait contribué à l'uniformisation des traitements en curiethérapie entre les hôpitaux, il ne décrit pas adéquatement la distribution réelle de la dose dans le patient. La publication actuelle du TG-186 donne des recommandations pour étudier des distributions de dose plus réalistes. Le but de ce mémoire est d'appliquer ces recommandations à partir du TG-186 pour obtenir une description plus réaliste de la dose dans la prostate. Pour ce faire, deux ensembles d'images du patient sont acquis simultanément avec un tomodensitomètre à double énergie (DECT). Les artéfacts métalliques présents dans ces images, causés par les sources d’iode, sont corrigés à l'aide d’un algorithme de réduction d'artefacts métalliques pour DECT qui a été développé dans ce travail. Ensuite, une étude Monte Carlo peut être effectuée correctement lorsque l'image est segmentée selon les différents tissus humains. Cette segmentation est effectuée en évaluant le numéro atomique effectif et la densité électronique de chaque voxel, par étalonnage stoechiométrique propre au DECT, et en y associant le tissu ayant des paramètres physiques similaires. Les résultats montrent des différences dans la distribution de la dose lorsqu'on compare la dose du protocole TG-43 avec celle retrouvée avec les recommandations du TG-186.

Elucidating the links between UV radiation and vitamin D synthesis : using an in vitro model

Ultraviolet radiation (UV) is the carcinogen that causes the most common malignancy in humans – skin cancer. However, moderate UV exposure is essential for producing vitaminDin our skin. VitaminDincreases the absorption of calcium from the diet, and adequate calcium is necessary for the building and maintenance of bones. Thus, low levels of vitamin D can cause osteomalacia and rickets and contribute to osteoporosis. Emerging evidence also suggests vitamin D may protect against falls, internal cancers, psychiatric conditions, autoimmune diseases and cardiovascular diseases. Since the dominant source of vitamin D is sunlight exposure, there is a need to understand what is a “balanced” level of sun exposure to maintain an adequate level of vitamin D but minimise the risks of eye damage, skin damage and skin cancer resulting from excessive UV exposure. There are many steps in the pathway from incoming solar UV to the eventual vitamin D status of humans (measured as 25-hydroxyvitamin D in the blood), and our knowledge about many of these steps is currently incomplete. This project begins by investigating the levels of UV available for synthesising vitamin D, and how these levels vary across seasons, latitudes and times of the day. The thesis then covers experiments conducted with an in vitro model, which was developed to study several aspects of vitamin D synthesis. Results from the model suggest the relationship between UV dose and vitamin D is not linear. This is an important input into public health messages regarding ‘safe’ UV exposure: larger doses of UV, beyond a certain limit, may not continue to produce vitamin D; however, they will increase the risk of skin cancers and eye damage. The model also showed that, when given identical doses of UV, the amount of vitamin D produced was impacted by temperature. In humans, a temperature-dependent reaction must occur in the top layers of human skin, prior to vitamin D entering the bloodstream. The hypothesis will be raised that cooler temperatures (occurring in winter and at high latitudes) may reduce vitamin D production in humans. Finally, the model has also been used to study the wavelengths of UV thought to be responsible for producing vitamin D. It appears that vitamin D production is limited to a small range of UV wavelengths, which may be narrower than previously thought. Together, these results suggest that further research is needed into the ability of humans to synthesise vitamin D from sunlight. In particular, more information is needed about the dose-response relationship in humans and to investigate the proposed impact of temperature. Having an accurate action spectrum will also be essential for measuring the available levels of vitamin D-effective UV. As this research continues, it will contribute to the scientific evidence-base needed for devising a public health message that will balance the risks of excessive UV exposure with maintaining adequate vitamin D.

Seasonal Variation in Measured Solar Ultraviolet Radiation Exposure of Adults in Subtropical Australia

Generating accurate population-specific public health messages regarding sun protection requires knowledge about seasonal variation in sun exposure in different environments. To address this issue for a subtropical area of Australia, we used polysulphone badges to measure UVR for the township of Nambour (26° latitude) and personal UVR exposure among Nambour residents who were taking part in a skin cancer prevention trial. Badges were worn by participants for two winter and two summer days. The ambient UVR was approximately three times as high in summer as in winter. However, participants received more than twice the proportion of available UVR in winter as in summer (6.5%vs 2.7%, P < 0.05), resulting in an average ratio of summer to winter personal UVR exposure of 1.35. The average absolute difference in daily dose between summer and winter was only one-seventh of a minimal erythemal dose. Extrapolating from our data, we estimate that ca. 42% of the total exposure received in the 6 months of winter (June–August) and summer (December–February) is received during the three winter months. Our data show that in Queensland a substantial proportion of people’s annual UVR dose is obtained in winter, underscoring the need for dissemination of sun protection messages throughout the year in subtropical and tropical climates.

A hybrid radiation detector for simultaneous spatial and temporal dosimetry

In this feasibility study an organic plastic scintillator is calibrated against ionisation chamber measurements and then embedded in a polymer gel dosimeter to obtain a quasi-4D experimental measurement of a radiation field. This hybrid dosimeter was irradiated with a linear accelerator, with temporal measurements of the dose rate being acquired by the scintillator and spatial measurements acquired with the gel dosimeter. The detectors employed in this work are radiologically equivalent; and we show that neither detector perturbs the intensity of the radiation field of the other. By employing these detectors in concert, spatial and temporal variations in the radiation intensity can now be detected and gel dosimeters can be calibrated for absolute dose from a single irradiation.

Investigation of stereotactic radiotherapy dose using dosimetry film and Monte Carlo simulations

This study uses dosimetry film measurements and Monte Carlo simulations to investigate the accuracy of type-a (pencil-beam) dose calculations for predicting the radiation doses delivered during stereotactic radiotherapy treatments of the brain. It is shown that when evaluating doses in a water phantom, the type-a algorithm provides dose predictions which are accurate to within clinically relevant criteria, gamma(3%,3mm), but these predictions are nonetheless subtly different from the results of evaluating doses from the same fields using radiochromic film and Monte Carlo simulations. An analysis of a clinical meningioma treatment suggests that when predicting stereotactic radiotherapy doses to the brain, the inaccuracies of the type-a algorithm can be exacerbated by inadequate evaluation of the effects of nearby bone or air, resulting in dose differences of up to 10% for individual fields. The results of this study indicate the possible advantage of using Monte Carlo calculations, as well as measurements with high-spatial resolution media, to verify type-a predictions of dose delivered in cranial treatments.