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

Permo-Triassic stratigraphy of the pelagonian zone in central Evia island (Greece)

A new subdivision of the pre-Jurassic Pelagonian Units in central Evia island is proposed these units are represented by syn- and post rift sequences, separated by a volcano-sedimentary episode. The syn-rift sequences comprise Permian siliciclastic sediments in Verrucano tectofacies, (Ano Mavropoulon Formation) and a small carbonate platform (Zigos Limestones) developed from the Permian to the Middle Anisian. The Ano Mavropoulon Fro, is subdivided into three members: the lower member (Permian s.l.) lying on the basement and characterised by medium-coarse elastic terrigenous sedimentation the middle member (Late Permian) Koprises limestones, made up of shallow-water limestones; the upper member (Latest Permian-Early Triassic) comprising elastic terrigenous and minor reworked carbonate sediments. A regional unconformity (earliest Triassic) separates the Zigos Lm. from the top of the Ano Mavropoulon Fm. The peritidal carbonates belonging to the Zigos Lm, have been subdivided into three lithofacies ranging in age from Spathian to Pelsonian (late Early Triassic to Middle Anisian). The volcanic episode is well constrained in all the Pelagonian domain. In central Evia, it has been dated from Middle Anisian to Early Carnian. The sub-alkaline to alkaline basalts comprised in the volcano-sedimentary sequence (Volcano-sedimentary Complex) have a within-plate affinity. The volcanism occurs between the syn-rift and post-rift stages, and it is probably not linked to the passive margin evolution proper. The post-rift sequences are represented by the onset of the Pelagonian platform aggradation (''Pantokrator'' Carnian to Middle-Late? Jurassic) The northern passive margin sequence of Pelagonia (palaeogeographic sense) is interpreted as related to the Maliak ocean opening during the Early Mesozoic

U-Pb and Ar-Ar geochronological data from the Pelagonian basement in Evia (Greece): geodynamic implications for the evolution of Paleotethys

High precision U-Pb zircon and Ar-40/Ar-39 mica geochronological data on metagranodiorites, metagranites and mica schists from north and central Evia island (Greece) are presented in this study. U-Pb zircon ages range from 308 to 1912 Ma, and indicate a prolonged magmatic activity in Late Carboniferous. Proterozoic ages represent inherited cores within younger crystals. Muscovite Ar-40/Ar-39 plateau ages of 288 to 297 Ma are interpreted as cooling ages of the magmatic bodies and metamorphic host rocks in upper greenschist to epidote-amphibolite metamorphic conditions. The multistage magmatism had a duration between 308 and 319 hla but some older intrusions, as well as metamorphic events, cannot be excluded. Geochemical analyses and zircon typology indicate calc-alkaline affinities for the granites of central Evia and alkaline to calc-alkaline characteristics for the metagranodiorites from the northern part of the island. The new data point towards the SE continuation, in Evia and the Cyclades, of a Variscan continental crust already recognised in northern Greece (Pelagonian basement). The Late Carboniferous magmatism is viewed as a result of northward subduction of the Paleotethys under the Eurasian margin

P‐T‐t evolution of the Cycladic blueschist unit in Western Anatolia / Turkey: Geodynamic implications for the Aegean region

International audienceEclogite and blueschist facies rocks occurring as a tectonic unit between the underlying Menderes Massif and the overlying Afyon Zone / Lycian Nappes and the Bornova Flysch Zone in western Anatolia represent the eastward continuation of the Cycladic Blueschist Unit in Turkey. This high-P unit is attributed to the closure of the Pindos Ocean and consists of (i) a Triassic to Upper Cretaceous coherent series derived from passive continental margin sediments and (ii) the tectonically overlying Upper Cretaceous Selçuk mélange with eclogite blocks embedded in a pelitic epidote-blueschist matrix. The coherent series has experienced epidote-blueschist facies metamorphism (490 ± 25°C / 11.5 ± 1.5 kbar; 38 km depth). 40 Ar/ 39 Ar white mica and 206 Pb/ 238 U monazite dating of quartz metaconglomerate from coherent series yielded middle Eocene ages of 44 ± 0.3 and 40.1 ± 3.1 Ma for epidote-blueschist facies metamorphism, respectively. The epidote-blueschist facies metamorphism of the matrix of the Selçuk mélange culminates at 520 ± 15°C / 13 ± 1.5 kbar, 43 km depth, and is dated 57.5 ± 0.3-54.5 ± 0.1 Ma (40 Ar/ 39 Ar phengite). Eclogite facies metamorphism of the blocks (570 ± 30°C / 18 ± 2 kbar, 60 km depth) is early Eocene and dated at 56.2 ± 1.5 Ma by 206 Pb/ 238 U zircon. Eclogites experienced a nearly isothermal retrogression (490 ± 40°C / ~ 6-7 kbar) during their incorporation into the Selçuk mélange. The retrograde overprints of the coherent series (410 ± 15°C / 7 ± 1.5 kbar from Dilek Peninsula and 485 ± 33°C / ~ 6-7 kbar from Selçuk-Tire area) and the Selçuk mélange (510 ± 15°C / 6 ± 1 kbar) are dated at 35.8 ± 0.5-34.3 ± 0.1 Ma by 40 Ar/ 39 Ar white mica and 31.6 ± 6.6 Ma by 206 Pb/ 238 U allanite dating methods, respectively. Regional geological constrains reveal that the contact between the Menderes Massif and the Cycladic Blueschist Unit originally formed a lithosphere-scale transform fault zone. 40 Ar/ 39 Ar white mica age from the contact indicates that the Cycladic Blueschist Unit and the Menderes Massif were tectonically juxtaposed under greenschist facies conditions during late Eocene, 35.1 ± 0.3 Ma