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

A theoretical model of contraceptive decision‐making and behaviour in diabetes: A qualitative application of the Health Belief Model

AimPeople with diabetes have contraceptive needs that have been inadequately addressed. The aim of this qualitative study was to develop a theoretical model that reflects contraceptive decision‐making and behaviour in the setting of diabetes mellitus.MethodsWe conducted semi‐structured, qualitative interviews of 17 women with type 1 or type 2 diabetes from Michigan, USA. Participants were recruited from a diabetes registry and local clinics. We adapted domains from the Health Belief Model (HBM) and applied reproductive justice principles to inform the qualitative data collection and analysis. Using an iterative coding template, we advanced from descriptive to theoretical codes, compared codes across characteristics of interest (e.g. diabetes type), and synthesized the theoretical codes and their relationships in an explanatory model.ResultsThe final model included the following constructs and themes: perceived barriers and benefits to contraceptive use (effects on blood sugar, risk of diabetes‐related complications, improved quality of life); perceived seriousness of pregnancy (harm to self, harm to foetus or baby); perceived susceptibility to pregnancy risks (diabetes is a ‘high risk’ state); external cues to action (one‐size‐fits‐all/anxiety‐provoking counselling vs. personalized/trust‐based counselling); internal cues to action (self‐perceived ‘sickness’); self‐efficacy (reproductive self‐efficacy, contraceptive self‐efficacy); and modifying factors (perceptions of biased counselling based upon one’s age, race or severity of disease).ConclusionsThis novel adaptation of the HBM highlights the need for condition‐specific and person‐centred contraceptive counselling for those with diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167788/1/dme14434.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167788/2/dme14434_am.pd

Confidence in Women’s Health: A Cross Border Survey of Adult Nephrologists

A range of women’s health issues are intimately related to chronic kidney disease, yet nephrologists’ confidence in counseling or managing these issues has not been evaluated. The women’s health working group of Cure Glomerulonephropathy (CureGN), an international prospective cohort study of glomerular disease, sought to assess adult nephrologists’ training in, exposure to, and confidence in managing women’s health. A 25-item electronic questionnaire was disseminated in the United States (US) and Canada via CureGN and Canadian Society of Nephrology email networks and the American Society of Nephrology Kidney News. Response frequencies were summarized using descriptive statistics. Responses were compared across provider age, gender, country of practice, and years in practice using Pearson’s chi-squared test or Fisher’s exact test. Among 154 respondents, 53% were women, 58% practiced in the US, 77% practiced in an academic setting, and the median age was 41–45 years. Over 65% of respondents lacked confidence in women’s health issues, including menstrual disorders, preconception counseling, pregnancy management, and menopause. Most provided contraception or preconception counseling to less than one woman per month, on average. Only 12% had access to interdisciplinary pregnancy clinics. Finally, 89% felt that interdisciplinary guidelines and/or continuing education seminars would improve knowledge. Participants lacked confidence in both counseling and managing women’s health. Innovative approaches are warranted to improve the care of women with kidney disease and might include the expansion of interdisciplinary clinics, the development of case-based teaching materials, and interdisciplinary treatment guidelines focused on this patient group

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes

Glomerular diseases (GDs) represent the third leading cause of end stage kidney disease (ESKD) in the U.S.. Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research In DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 ml/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of glomerular diseases and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population