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

Nutritional Influences on Bone Health, Stress Fracture Risk and Training Progression in Royal Marine Recruits.

Nutritional factors affecting bone health throughout the lifecycle has received considerable attention in the literature but little is known about the influence of nutrition on stress fracture (SF) risk. Royal Marine (RM) recruits undergo a 32-week arduous military training programme, where the prevalence of SF has been -5% over recent years. The Institute of Naval Medicine was tasked by Surgeon General to investigate risk factors associated with stress fracture during RM training at the Commando Training Centre Royal Marines. The present thesis focuses on the nutritional aspects of this work, with the primary aim to identify the influence of past and present dietary intake and nutritional status on SF risk and bone health in RM recruits.A bespoke dietary assessment tool was developed to investigate nutritional intake relative to SF risk and training success in a cohort of RM recruits (n=545). No aspects of diet during training were associated with SF risk. However, recruits with a higher energy intake during training were more likely to successfully complete training (P<0. 05). Poor aerobic fitness, low body mass (less than 65 kg) and small thigh girth were independent risk factors for SF (n=27; P<0. 05). In a larger cohort of RM recruits (n=1090), childhood (0-12 y), adolescent (12-18 y) and pre-RM training diets were assessed with a food frequency questionnaire. Vitamin D and micronutrient status were assessed in serum blood samples. Childhood milk intake and adolescent fruit and vegetable intakes were associated with bone quality (assessed by Broadband Ultrasound Attenuation) (P<0. 05). Low milk intake during childhood, and high intake of fizzy drinks during adolescence, were associated with increased SF risk (n=75; P<0. 05). Importantly, serum 25(OH)D (as a marker of vitamin D status) <60 nmol. L-1 was associated with increased SF risk (P<0. 05). Stress fractured recruits (n=65) and matched controls (n=65) underwent Dual Energy X-ray Absorptiometry and peripheral Quantitative Computed Tomography scanning. Stress fractured recruits had lower bone density of the lumbar spine and hip, and narrower tibiae than their matched controls. These novel data suggest an important role for lifestyle factors in the pathogenesis of SF in a military population, with concomitant bone density/structure differences at key fracture sites. Further research (including a possible vitamin D supplementation intervention) is warranted

Nutritional Influences on Bone Health, Stress Fracture Risk and Training Progression in Royal Marine Recruits.

Nutritional factors affecting bone health throughout the lifecycle has received considerable attention in the literature but little is known about the influence of nutrition on stress fracture (SF) risk. Royal Marine (RM) recruits undergo a 32-week arduous military training programme, where the prevalence of SF has been -5% over recent years. The Institute of Naval Medicine was tasked by Surgeon General to investigate risk factors associated with stress fracture during RM training at the Commando Training Centre Royal Marines. The present thesis focuses on the nutritional aspects of this work, with the primary aim to identify the influence of past and present dietary intake and nutritional status on SF risk and bone health in RM recruits.A bespoke dietary assessment tool was developed to investigate nutritional intake relative to SF risk and training success in a cohort of RM recruits (n=545). No aspects of diet during training were associated with SF risk. However, recruits with a higher energy intake during training were more likely to successfully complete training (P<0. 05). Poor aerobic fitness, low body mass (less than 65 kg) and small thigh girth were independent risk factors for SF (n=27; P<0. 05). In a larger cohort of RM recruits (n=1090), childhood (0-12 y), adolescent (12-18 y) and pre-RM training diets were assessed with a food frequency questionnaire. Vitamin D and micronutrient status were assessed in serum blood samples. Childhood milk intake and adolescent fruit and vegetable intakes were associated with bone quality (assessed by Broadband Ultrasound Attenuation) (P<0. 05). Low milk intake during childhood, and high intake of fizzy drinks during adolescence, were associated with increased SF risk (n=75; P<0. 05). Importantly, serum 25(OH)D (as a marker of vitamin D status) <60 nmol. L-1 was associated with increased SF risk (P<0. 05). Stress fractured recruits (n=65) and matched controls (n=65) underwent Dual Energy X-ray Absorptiometry and peripheral Quantitative Computed Tomography scanning. Stress fractured recruits had lower bone density of the lumbar spine and hip, and narrower tibiae than their matched controls. These novel data suggest an important role for lifestyle factors in the pathogenesis of SF in a military population, with concomitant bone density/structure differences at key fracture sites. Further research (including a possible vitamin D supplementation intervention) is warranted

Clinical Study Incidence and Time to Return to Training for Stress Fractures during Military Basic Training

Currently, little is known about the length of time required to rehabilitate patients from stress fractures and their return to preinjury level of physical activity. Previous studies have looked at the return to sport in athletes, in a general population, where rehabilitation is not as controlled as within a captive military population. In this study, a longitudinal prospective epidemiological database was assessed to determine the incidence of stress fractures and the time taken to rehabilitate recruits to preinjury stage of training. Findings demonstrated a background prevalence of 5% stress fractures in Royal Marine training; femoral and tibial stress fractures take 21.1 weeks to return to training with metatarsal stress fractures being the most common injury taking 12.2 weeks. Rehabilitation from stress fractures accounts for 814 weeks of recruit rehabilitation time per annum. Stress fracture incidence is still common in military training; despite this stress fracture recovery times remain constant and represent a significant interruption in training. It takes on average 5 weeks after exercise specific training has restarted to reenter training at a preinjury level, regardless of which bone has a stress fracture. Further research into their prevention, treatment, and rehabilitation is required to help reduce these burdens

Impact of the occupational environment of a submerged submarine on cardiometabolic health of Royal Navy submariners

Objective: To determine the effect of prolonged exposure to a submarine environment on biomarkers of cardiometabolic risk in Royal Navy (RN) submariners

Four biomechanical and anthropometric measures predict tibial stress fracture: A prospective study of 1065 Royal Marines

Copyright © 2016 BMJ Publishing GroupBackground: Tibial stress fractures cause a significant burden to Royal Marines recruits. No prospective running gait analyses have previously been performed in military settings. Aim: We aimed to identify biomechanical gait factors and anthropometric variables associated with increased risk of TSF. Methods: 1065 Royal Marines recruits were assessed in week-2 of training. Bilateral plantar pressure and 3D lower limb kinematics were obtained for barefoot running at 3.6 m.s-1, providing dynamic arch index, peak heel pressure and lower limb joint angles. Age, bimalleolar breadth, calf girth, passive hip internal/external range of motion and body mass index (BMI) were also recorded. Ten recruits who sustained a TSF during training were compared with 120 recruits who completed training injury-free using a binary logistic regression model to identify injury risk factors. Results: Four variables significantly (p<0.05) predicted increased risk of TSF (odds ratios and 95% CI): smaller bimalleolar width (0.73, 0.58-0.93), lower BMI (0.56, 0.33-0.95), greater peak heel pressure (1.25, 1.07-1.46) and lower range of tibial rotation (0.78, 0.63-0.96). Summary: Reduced impact attenuation and ability to withstand load were implicated in tibial stress fracture risk