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

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

Nuisances olfactives liées aux effluents vinicoles. Origine et traitement des composés malodorants

La formation des composés malodorants dans les effluents d’industries vinicoles (caves, distilleries) se produit lors du traitement par évaporation naturelle en bassins (lagunes) mais aussi durant le stockage en amont des traitements d’épuration. Malgré les différences de composition entre les effluents de cave caractérisés par la prédominance de l’éthanol et ponctuellement de sucres et les vinasses de distilleries constituées de composés organiques simples (glycérol, acides organiques) et complexes, de matières en suspension et de minéraux (sulfate des vinasses de lies détartrées), les composés malodorants majoritairement formés dans les deux cas sont les acides gras volatils (AGV), notamment les acides butyriques, valérique et caproïde.Pour les effluents de cave, le traitement préventif des odeurs a été envisagé soit par inhibition des micro-organismes par biocides dans le cas du stockage en cuve, soit par orientation de l’activité anaérobie de la microflore de bassins d’évaporation par nitrate.Le biocide à base d’ammonium quaternaire présente un effet inhibiteur spécifique de la microflore acidogène et assure une très bonne conservation de l’effluent durant près de deux mois. Par contre, les produits à base de peroxyde d’hydrogène ont un effet limité à court terme et le produit chloré n’a pas d’effet.L’apport de nitrate favorise la dégradation et l’oxydation des composés organiques par la microflore selon un processus de respiration anaérobie (dénitrification) et empêche les processus microbiens anaérobies odorogènes (formation des AGV), en fonction du ratio NO3/DCO. L’étude en vraie grandeur du traitement préventif par nitrate (bassin d’évaporation 7000m2) durant deux années a confirmé l’absence totale de production d’AGV et la prévention d’odeurs (mesures olfactives).L’étude des traitements d’odeurs de bassins d’évaporation des vinasses a porté sur différents moyens d’action : traitement d’odeurs à la source, traitements préventifs et curatifs.La modification du procédé d’extraction de tartrate de calcium par substitution du sulfate par nitrate, expérimentée puis appliquée à grande échelle, supprime le risque majeur de production de sulfure et enrichit les vinasses en nitrate, favorable à la prévention de la formation d’AGV.Compte tenu de la forte charge organique des vinasses, le traitement préventif de la formation d’AGV par nitrate requiert des doses en nitrates élevées.La dégradation des AGV en présence de nitrate permet d’envisager le traitement curatif de bassins d’évaporation, mais les besoins en nitrate, relevant de la stoechiométrie de la respiration anaérobie, représentent des quantités importantes.Le traitement d’odeurs de bassins d’évaporation d’industries vinicoles par additifs biologiques commerciaux proposé par certaines sociétés s’avère inefficace et inadapté à la problématique des bassins d’évaporation.La meilleure connaissance des processus odorogènes, l’étude et l’évaluation de différents moyens de traitements : à la source, préventifs, curatifs, qui découlent de ce travail permettent de dégager des recommandations à destination des industries vinicoles confrontées aux nuisances olfactives de leurs effluent

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present