Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Density-Dependent Ecohydrological Effects of Piñon–Juniper Woody Canopy Cover on Soil Microclimate and Potential Soil Evaporation

Many rangeland processes are driven by microclimate and associated ecohydrological dynamics. Most rangelands occur in drylands where evapotranspiration normally dominates the water budget. In these water-limited environments plants can influence abiotic and biotic processes by modifying microclimate factors such as soil temperature and potential soil evaporation.Previous studies have assessed spatial variation in microclimate and associated ecohydrological attributes within an ecosystem (e.g., under vs. between woody canopies) or across ecosystems (e.g., with differing amounts of woody canopy cover), but generally lacking are assessments accounting systematically for both, particularly for evergreen woody plants. Building on recently quantified trends in near-ground solar radiation associated with a piñon-juniper gradient spanning 5% to 65% woody canopy cover, we evaluated trends in soil temperature and associated estimates of potential soil evaporation as a function of amount of woody canopy cover for sites overall and for associated canopy vs. intercanopy locations. Quantified soil temperature trends decreased linearly with increasing woody canopy cover for intercanopy as well as canopy patches, indicating the coalescing influence of individual canopies on their neighboring areas. Notably, intercanopy locations within high-density (65%) woody canopy cover could be as much as ~10 degreesC cooler than intercanopy locations within low-density (5%) cover. Corresponding potential soil evaporation rates in intercanopies within high-density woody canopy cover was less than half that for intercanopies within low density. Our results highlight ecohydrological consequences of density-dependent shading by evergreen woody plants on soil temperature and potential soil evaporation and enable managers to rapidly estimate and compare approximate site microclimates after assessing amounts of woody canopy cover. Such predictions of microclimate have general utility for improving management of rangelands because they are a fundamental driver of many key processes, whether related to understory forage and herbaceous species or to wildlife habitat quality for game or nongame species./Muchos procesos en los pastizales están definidos por microclimas y sus dinámicas eco-hidrológicas asociadas. Muchos pastizales se localizan en zonas áridas donde la evapotranspiración normalmente es el flujo dominante del balance hídrico. En estos ambientes donde el agua es escasa, las plantas pueden influenciar procesos ecológicos, bióticos y abióticos, mediante la modificación de factores micro-climáticos, como temperatura del suelo el potencial de evaporación desde la superficie. Estudios previos han definido que la variación en microclimas y los atributos asociados con la eco-hidrología dentro de los ecosistemas (por ejemplo debajo del dosel vs. en espacios entre el dosel aé de dos árboles) o a través de los ecosistemas (por ejemplo con diferentes cantidades de cobertura de dosel). Sin embargo, se carece generalmente de la determinación sistemática de ambos, particularmente para las plantas arbustivas siempre verdes. Basándose en tendencias cuantificadas recientemente para la radiación solar cerca de suelo en un gradiente de pino-junípero abarcando una cubierta de 5% a 65% de cobertura de dosel, se evaluaron las tendencias en la temperatura del suelo y se desarrollaron estimaciones asociadas con el potencial de evaporación de suelo en función de la cantidad de cubierta arbórea tanto para sitios en general (en función de la cobertura), como para aquellos asociados con la cubierta contra sitios ubicados entre los árboles (no directamente debajo de las copas). Las temperaturas del suelo cuantificadas tendieron a decrecer linealmente con el incremento en la cobertura arbórea en los espacios entre árboles, asícomo los espacios cubiertos por los árboles, indicando la relación entre la influencia de las copas individuals sobre sus áreas vecinas. Notablemente, los espacios entre árboles dentro de lugares con altas densidades (65%) de cubierta arbórea pueden ser hasta 10uC más fríos que los espacios entre árboles dentro de una densidad baja de cobertura aérea (5%). Con respecto al potencial de las tasas de evaporación en los espacios entre árboles en las áreas con niveles altos de cubierta de dosel, resultó siendo menos de la mitad de la que ocurriría en espacio sigualetne abiertos, pero localizados en zonas con baja cobertura de dosel arbóreo. Nuestros resultados resaltan los efectos eco-hidrológicos de la sombra producida por los árboles sobre la temperatura del suelo y el potencial de evaporación del suelo, y que dependen de la cantidad y densidad de árboles en el paisaje. Estos resultados permiten a los manejadores una rápida estimación y comparación del microclima en diversos sitios, después de determinar la cantidad de cubierta arbórea. Tales predicciones de microclimas tienen una utilidad general para mejorar el manejo de pastizales porque son fundamentales para muchos procesos esenciales, si se relacionan con pastos que se encuentran debajo de la cobertura arbórea, asícomo con las especies herbáceas o para la calidad del habitad de la vida silvestre de especies cinegéticas y no cinegéticas.The Rangeland Ecology & Management archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform August 202