Search

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; pinteraction=0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (

Context: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. Objective: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. Evidence acquisition: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. Evidence synthesis: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. Conclusions: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a “second wave” of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. Patient summary: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

Background: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. Objective: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. Design, setting, and participants: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11 862 patients. Patients received one of the six permutations of low-dose RT (64 to

Supplementary materials document.

Data used in study analyses

Purpose:Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy.Experimental Design: Three cohorts of patients (n = 134) were recruited. The early cohort (n = 32) was followed sequentially up to 12 months post-radiotherapy to assess early radiation enteropathy. Linear mixed models were used to assess microbiota dynamics. The late cohort (n = 87) was assessed cross-sectionally to assess late radiation enteropathy. The colonoscopy cohort compared the intestinal mucosa microenvironment in patients with radiation enteropathy (cases, n = 9) with healthy controls (controls, n = 6). Fecal samples were obtained from all cohorts. In the colonoscopy cohort, intestinal mucosa samples were taken. Metataxonomics (16S rRNA gene) and imputed metataxonomics (Piphillin) were used to characterize the microbiome. Clinician- and patient-reported outcomes were used for clinical characterization.Results:In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (P = 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy (P = 0.05). A consistent association between low bacterial diversity and late radiation enteropathy was also observed, albeit nonsignificantly. Higher counts of Clostridium IV, Roseburia, and Phascolarctobacterium significantly associated with radiation enteropathy. Homeostatic intestinal mucosa cytokines related to microbiota regulation and intestinal wall maintenance were significantly reduced in radiation enteropathy [IL7 (P = 0.05), IL12/IL23p40 (P = 0.03), IL15 (P = 0.05), and IL16 (P = 0.009)]. IL15 inversely correlated with counts of Roseburia and Propionibacterium.Conclusions:The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects.See related commentary by Lam et al., p. 6280

PURPOSE Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Purpose Radiation therapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer. Yet, the broader influence of radiation therapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma, and stools sampled from patients undergoing PLNRT for high-risk prostate cancer. Methods and Materials Samples were taken from 32 patients at 6 timepoints: baseline, 2 to 3 and 4 to 5 weeks of PLNRT; and 3, 6, and 12 months after PLNRT. We characterized the global metabolome of urine and plasma using 1H nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography-mass spectrometry, and of stools with nuclear magnetic resonance. Linear mixed-effects modeling was used to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest. Results Metabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to 1 year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT fecal butyrate levels directly associated with increasing gastrointestinal side effects, as did a sharper fall in those levels during and up to 1 year postradiation therapy, mirroring our previous results with metataxonomics. Conclusions We showed for the first time that an overall metabolic effect is observed in patients undergoing PLNRT up to 1 year posttreatment. These metabolic changes may effect on long-term morbidity after treatment, which warrants further investigation.

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.Lay abstract The male sex hormone testosterone promotes the growth of prostate cancer cells. Some drug treatments for prostate cancer, such as gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists, work to reduce the production of testosterone. However, GnRH receptor agonists like leuprolide acetate can increase testosterone levels at first, before reducing it, and this temporary increase can cause side effects, such as bone pain. Drugs of this type have also been linked to a higher risk of heart attacks, strokes, and death. Relugolix works a different way; it is a GnRH receptor antagonist that reduces testosterone without an initial increase. A clinical study showed that relugolix reduced testosterone levels more quickly than leuprolide acetate, a commonly used injectable drug for the treatment of prostate cancer. After stopping treatment, levels of testosterone in the blood returned to normal faster in men who received relugolix than in men who received leuprolide acetate. Men who received relugolix had a lower incidence of heart attacks, strokes, and death compared with men who received leuprolide acetate. The US FDA approved relugolix as the first oral, once-daily GnRH receptor antagonist for the treatment of advanced prostate cancer, offering men a new treatment option.

Background STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. Methods Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). Results Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. Conclusions There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial.The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test.The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/β = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/β = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/β = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but α/β ratio estimates remained stable.Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/β ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/β ratio assumptions of 3 to 5 Gy.

145 Background: Studies are conflicting regarding the association between statin use and biochemical recurrence after surgery or radiotherapy for localized prostate cancer. A handful of studies have observed favorable associations between statins and prostate cancer-specific (PCSM) and overall mortality (OS), however, this has not been studied in an advanced disease cohort nor has the combination of statins and androgen deprivation therapy (ADT) been specifically studied. Methods: Patients with PSA >3 ng/mL after >1 year following primary or salvage radiotherapy (RT) were enrolled in a randomized trial of intermittent (IAD) vs. continuous (CAD) ADT (NCT00003653). Statin use at baseline and during the study was captured and modeled as a time-dependent covariate. The primary end-point was OS. Models were adjusted for age, time from RT to ADT and PSA at baseline. As results were nearly identical between the IAD and CAD arms they are reported as aggregates unless otherwise indicated. Results: Of 1,364 patients enrolled, 585 (43%) reported statin use during the study. Statin users were younger (72.7 vs. 73.8, p=0.001) and less likely to have PSA >15 (20 vs. 25%, p=0.04). Median follow-up was 6.9 years and 524 deaths occurred. Statin use was associated with a reduced risk of overall death (HR: 0.64; 95% C.I. 0.53 – 0.78, p

Purpose Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). Methods and Materials Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. Results Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. Conclusions Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.

External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist.To evaluate the safety and efficacy of relugolix to achieve and maintain castration.A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015.Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control).The primary endpoint was the rate of effective castration (testosterone1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned.Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation.Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action.Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.

391 Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R2=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.

304 Background: Five-year results from the CHHiP trial indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Reporting of long-term efficacy and side effects is essential in a patient population that remain at risk of recurrence years after treatment. Here we report specific co-morbidity data collected at 10 years and an update of efficacy. Methods: Between October 2002 and June 2011, 3216 men with node negative T1b-T3a localised prostate cancer with risk of seminal vesical involvement ≤30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Patients received 3-6 months of androgen deprivation prior to radiotherapy. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to control. Data on specific radiotherapy related co-morbidities were collected at 10-year follow-up and are presented as frequency and percentages. Analysis was by intention-to-treat; HRs quoted are unadjusted. Results: With a median follow up of 12.1 years, 10-year BCF-free rates (95% CI) were 74Gy: 76.0% (73.1%, 78.6%); 60Gy: 79.8% (77.1%, 82.3%) and 57Gy: 73.4% (70.5%, 76.1%). For 60Gy/20f, non-inferiority was confirmed: HR60=0.84 (90% CI 0.72, 0.97) with borderline significance for superiority (HR=0.84 (95% CI 0.70, 1.00). As in the primary analysis, for 57Gy/19f, non-inferiority could not be declared: HR57=1.13 (90% CI 0.98, 1.30). 10-year overall survival (95% CI) was 78.5% (75.9%, 81.0%), 82.9% (80.4%, 85.0%) and 79.9% (77.3%, 82.2%) in the 74Gy, 60Gy and 57Gy groups. Bone fractures were reported in 2% (15/700), 2% (19/771) and 3% (22/719) of patients in the 74Gy, 60Gy and 57Gy groups respectively at 10 years. The most common intervention reported was a sigmoidoscopy with 12% (79/681), 8% (60/739) and 9% (65/702) in the 74Gy, 60Gy and 57Gy groups respectively. Of those patients who underwent a sigmoidoscopy it was due to symptoms for 81% (63/78) 81% (48/59) and 85% (55/65) of patients in the 74Gy, 60Gy and 57Gy group respectively. Frequencies of all other pre-specified co-morbidities or related interventions (ureteric obstruction, bowel strictures, trans-urethral resection of prostate, urethrotomy, urethral dilatation or long term catheterisation or treatment of proctopathy with steroid, sucralfate, formalin, laser coagulation or rectal diversion) were

Background Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naive prostate cancer (mHNPC) following the LATITUDE trial findings. However, a "risk"-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE "low-risk" M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP). Objective Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial. Design, setting, and participants A post hoc subgroup analysis of the 2017 STAMPEDE "abiraterone comparison". Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria. Outcome measurements and statistical analysis The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis. Results and limitations A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44–0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17–0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints. Conclusions Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for "risk" or "volume". Patient summary Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.

Prostate bed radiotherapy is a standard treatment after radical prostatectomy. Recent evidence suggests that, for patients with a PSA 0.34 ng/ml, the radiotherapy treatment volume should include not only the prostate bed but also the pelvic lymph nodes. We describe the patterns of failure after prostate bed radiotherapy, focussing on the proportion of patients with radiologically confirmed pelvic nodal failure only, in the absence of distant disease.Patients included were men receiving prostate bed radiotherapy at the Royal Marsden Hospital between 1997 and 2013. The key outcome of interest was the pattern of radiologic failure after prostate bed radiotherapy. Baseline characteristics of patients experiencing pelvic nodal failure without distant disease were compared versus all other relapse patterns. Comparisons were by Chi-square test, with multiple testing adjusted p 0.005 significant.140 of 322 patients developed biochemical failure after salvage RT. Radiologic failure occurred in 89 patients. 35 of the 89 patients (39%) with radiologic failure had pelvic nodal failure without distant disease, with no significant differences in baseline characteristics when compared to all other patients. The rate of pelvic nodal failure was the same for patients with PSA above or below 0.34 ng/ml (16/149, 95% CI = 6-17% vs 19/171, 95% CI = 7-17%).Pelvic lymph node disease, without more distant disease, is a common site of failure in men receiving radiotherapy to the prostate bed, including those with PSA 0.34 ng/ml. This observation informs the case for including the pelvic lymph nodes in the radiotherapy treatment volume.

Highlights • Dosimetric benefits to the penile bulb was seen in patients treated with IGRT and reduced CTV-PTV margins. • Patients who had a lower planned dose to the penile bulb reported less erectile dysfunction. • A threshold mean penile bulb dose for erectile dysfunction was determined to around 20 Gy., Background and purpose The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy. Materials and methods Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed. Results Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p

Objectives: Quantify target volume delineation uncertainty for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer. Define optimal imaging sequences for target delineation. Methods: Six experienced radiation oncologists delineated clinical target volumes (CTVs) on CT and 2D and 3D-MRI in three patients with rectal cancer, using consensus contouring guidelines. Tumour GTV (GTVp) was also contoured on MRI acquired week 0 and 3 of radiotherapy. A STAPLE contour was created and volume and interobserver variability metrics were analysed. Results: There were statistically significant differences in volume between observers for CT and 2D-MRI-defined CTVs (p < 0.05). There was no significant difference between observers on 3D-MRI. Significant differences in volume were seen between observers for both 2D and 3D-MRI-defined GTVp at weeks 0 and 3 (p < 0.05). Good interobserver agreement (IOA) was seen for CTVs delineated on all imaging modalities with best IOA on 3D-MRI; median Conformity index (CI) 0.74 for CT, 0.75 for 2D-MRI and 0.77 for 3D-MRI. IOA of MRI-defined GTVp week 0 was better compared to CT; CI 0.58 for CT, 0.62 for 2D-MRI and 0.7 for 3D-MRI. MRI-defined GTVp IOA week three was worse compared to week 0. Conclusion: Delineation on MRI results in smaller volumes and better IOA week 0 compared to CT. 3D-MRI provides the best IOA in CTV and GTVp. MRI-defined GTVp on images acquired week 3 showed worse IOA compared to week 0. This highlights the need for consensus guidelines in GTVp delineation on MRI during treatment course in the context of dose escalation MRI-guided rectal boost studies. Advances in knowledge: Optimal MRI sequences for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer have been defined.

Background: Moderate hypofractionation is the recommended standard of care for localised prostate cancer following the results of trials including Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP). Evaluation of long-term patient-reported outcomes (PROs) is important to confirm safety and enhance patient information.Objective: To determine whether 5-yr PROs from the CHHiP quality of life (QoL) substudy confirm 2-yr findings and assess patterns over follow-up.Design, setting, and participants: A phase III randomised controlled trial recruited from 2002 to 2011. The QoL substudy completed accrual in 2009; participants were followed up to 5 yr after radiotherapy. Analyses used data snapshot taken on August 26, 2016. A total of 71 radiotherapy centres were included in the study (UK, Republic of Ireland, Switzerland, and New Zealand); all 57 UK centres participated in the QoL substudy. CHHiP recruited 3216 men with localised prostate cancer (cT1b-T3aN0M0).Intervention: Conventional (74 Gy/37 fractions/7.4 wk) or hypofractionated radiotherapy (60 Gy/20 fractions/4 wk or 57 Gy/19 fractions/3.8 wk) was delivered with intensity-modulated techniques.Outcome measurements and statistical analysis: University of California Los Angeles Prostate Cancer Index, Short Form 36 and Functional Assessment of Cancer Therapy—Prostate, or Expanded Prostate Cancer Index Composite and Short Form 12 questionnaires were administered at baseline, before radiotherapy, at 10 wk, and at 6, 12, 18, 24, 36, 48, and 60 mo after radiotherapy. The QoL primary endpoint was overall bowel bother.Results and limitations: The QoL substudy recruited 2100 patients; 1141 5-yr forms were available from 1957 patients still alive (58%). There were no statistically significant differences in 5-yr prevalence of overall “moderate or big” bowel bother: 19/349 (5.4%), 29/381 (7.6%), and 21/393 (5.3%) for 74, 60, and 57 Gy, respectively; overall urinary or sexual bother at 5 yr was similar between schedules. Bowel and urinary symptoms remained stable from 2 to 5 yr for all schedules. Some evidence of worsening overall sexual bother from baseline to 5 yr was less likely in the hypofractionated schedules compared with 74 Gy (odds ratios for increase in bother score vs 74 Gy: 0.55 [0.30–0.99], p = 0.009 for 60 Gy, and 0.52 [0.29–0.94], p = 0.004 for 57 Gy). General QoL scores were similar between schedules at 5 yr.Conclusions: Longer follow-up confirms earlier findings, with similar patient-reported bowel, urinary, and sexual problems between schedules overall. The continued low incidence of moderate or high bother confirms that moderate hypofractionation should be the standard of care for intermediate-risk localised prostate cancer.Patient summary: We looked at patient-reported outcomes up to 5 yr after treatment in a trial of different radiotherapy schedules for prostate cancer. The findings confirmed that shorter radiotherapy schedules were as safe as standard radiotherapy in terms of bowel, urinary, and sexual problems.Take Home Message: Bowel, urinary, and sexual symptoms were similar between schedules up to 5 yr. The continued low incidence of moderate/high bother confirms that moderate hypofractionated radiotherapy should be considered the standard of care for men with intermediate-risk prostate cancer.

Aims The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. Materials and methods Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. Results In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. Conclusion Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

5006 Background: We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration. Methods: We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS. Results: IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS. Conclusions: Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several. [Table: see text]

5084 Background: Current management of HRLPC includes long-term ADT with primary RT. Despite definitive primary treatment, these pts have a high risk of metastasis and death. The phase 3 ATLAS study (NCT02531516) is investigating whether treatment intensification with the addition of APA to neoadjuvant and adjuvant treatment with gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) will improve metastasis-free survival (MFS) in high-risk pts. Here we describe (1) the distribution of baseline characteristics in this high-risk pt population and (2) the application of different RT regimens reflecting recent international guidelines and clinical practice changes for pts with HRLPC. Methods: Eligible HRLPC pts (Gleason score [GS] ≥ 8 or 7 and prostate-specific antigen [PSA] ≥ 20 ng/mL and stage ≥ cT2c), with ECOG PS 0/1 and Charlson Comorbidity Index (CCI) ≤ 3 are stratified by GS, pelvic nodal status, use of brachytherapy boost, and region; pts are randomized 1:1 to APA or PBO plus GnRHa for 30 (28-d) treatment cycles. Study treatment is applied neoadjuvant/concurrent to RT with APA 240 mg/d vs bicalutamide 50 mg/d for 4 cycles; another 26 cycles are completed adjuvantly after RT with APA 240 mg/d vs PBO. Primary end point is MFS (time from randomization to first distant metastasis on CT/MRI/bone scan by independent central review blinded to treatment or death from any cause). Imaging is conducted at baseline and q6m from biochemical failure until MFS. The protocol has been amended to include PET imaging (PSMA, fluciclovine, or choline). Results: Pts (N = 1503) were randomized at 266 sites in 24 countries in North America, Latin America, Europe, and Asia. The study is fully enrolled, but ongoing. Baseline characteristics for the total population: median age, 67 yrs; ECOG PS 0/1; 89%/11%; tumor classification at study entry: high-risk, 66%/very high–risk, 34%; median PSA, 6.3 ng/mL; cT2, 44%/cT3, 50%; cN1, 13%. In 90% of ATLAS pts, RT used was standard EBRT to prostate/pelvis over 6-8 weeks (cumulative 78-81 Gy); in 10%, recent hypofractionation schedules (per CHHiP or NRG/RTOG 0415) were applied (20x3 Gy/d or 28x2.5 Gy/d). 5.6% of pts had EBRT combined with brachytherapy (per ASCENDE-RT). Conclusions: Baseline characteristics of the ATLAS study population are reflective of pts with high- and very high–risk features and pelvic nodal involvement undergoing primary RT in clinical practice. The RT schedules applied reflect recent evidence and guideline changes for the use of hypofractionation in this pt population. ATLAS is an example of how RT can be included in phase 3 trials of HRLPC, in combination with next-generation androgen receptor inhibitors (eg, APA). Clinical trial information: NCT02531516.

Background Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. Objective To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. Design, setting, and participants We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. Intervention SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six three-weekly cycles. Outcome measurements and statistical analysis The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results and limitations The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. Conclusions Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. Patient summary Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body., Take Home Message Docetaxel is a cost-effective intervention in patients with metastatic and nonmetastatic prostate cancer starting hormone therapy. Clinicians and National Health Service funding bodies should consider whether the evidence is now sufficiently compelling to support initiating docetaxel in patients with nonmetastatic disease.

Importance Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site. Objective To evaluate the association of bone metastasis count and location with survival benefit from prostate RT. Design, setting, and participants This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial's metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups. Interventions Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT. Main outcomes and measures The primary outcomes were OS and FFS. Results A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002). Conclusions and relevance In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease. Trial registration ClinicalTrials.gov Identifier: NCT00268476; ISRCTN.com Identifier: ISRCTN78818544.

BACKGROUND Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ���40 ng/mL) or relapsing with high-risk features (���12 months of total ADT with an interval of ���12 months without treatment and PSA concentration ���4 ng/mL with a doubling time of

Background Randomised controlled trials (RCTs) are the gold standard for evidence-based practice. However, RCTs can have limitations. For example, translation of findings into practice can be limited by design features, such as inclusion criteria, not accurately reflecting clinical populations. In addition, it is expensive to recruit and follow-up participants in RCTs. Linkage with routinely collected data could offer a cost-effective way to enhance the conduct and generalisability of RCTs. The aim of this study is to investigate how primary care data can support RCTs. Methods Secondary analysis following linkage of two datasets: 1) multicentre CHHiP radiotherapy trial (ISRCTN97182923) and 2) primary care database from the Royal College of General Practitioners Research and Surveillance Centre. Comorbidities and medications recorded in CHHiP at baseline, and radiotherapy-related toxicity recorded in CHHiP over time were compared with primary care records. The association of comorbidities and medications with toxicity was analysed with mixed-effects logistic regression. Results Primary care records were extracted for 106 out of 2811 CHHiP participants recruited from sites in England (median age 70, range 44 to 82). Complementary information included longitudinal body mass index, blood pressure and cholesterol, as well as baseline smoking and alcohol usage but was limited by the considerable missing data. In the linked sample, 9 (8%) participants were recorded in CHHiP as having a history of diabetes and 38 (36%) hypertension, whereas primary care records indicated incidence prior to trial entry of 11 (10%) and 40 (38%) respectively. Concomitant medications were not collected in CHHiP but available in primary care records. This indicated that 44 (41.5%) men took aspirin, 65 (61.3%) statins, 14 (13.2%) metformin and 46 (43.4%) phosphodiesterase-5-inhibitors at some point before or after trial entry. Conclusions We provide a set of recommendations on linkage and supplementation of trials. Data recorded in primary care are a rich resource and linkage could provide near real-time information to supplement trials and an efficient and cost-effective mechanism for long-term follow-up. In addition, standardised primary care data extracts could form part of RCT recruitment and conduct. However, this is at present limited by the variable quality and fragmentation of primary care data.

Background Optimal management of isolated local recurrence of prostate cancer after primary radiotherapy remains to be defined. Up-front androgen deprivation therapy (ADT) is widely used but may adversely affect the quality of life and is essentially a palliative treatment. Local salvage carries a different side-effect profile and is potentially curative, but it has not been compared to ADT. Materials and methods We conducted a propensity-matched analysis of cohorts of men treated with either whole gland cryotherapy (CRYO) or primary ADT following the diagnosis of locally recurrent prostate cancer. Our specific objectives were to compare overall survival (OS) and prostate cancer-specific mortality (PCSM) between CRYO vs. ADT. Results After a one-to-one matching, 169 patients from each cohort were included in comparisons. Median follow-up time was 6.7 years (ADT) vs. 18 years (CRYO). The 10-year PCSM was 18.5% (ADT) vs. 16.2% (CRYO), which was not statistically different [hazard ratioo (HR): 0.69, 95% CI: 0.36-1.34, p=0.27]. The median OS was 12.3 years (CRYO) versus 10.2 years (ADT) (HR: 0.63, 95% CI: 0.42-0.95, p=0.03). Conclusions While PCSM was similar between the two strategies, CRYO was associated with a longer OS compared to primary ADT. Given the retrospective nature of the trial, these results should be considered hypothesis-generating, and phase III trials comparing these two options are required to further explore these findings.

Background and purpose This study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. Materials and methods Planned dose distributions for up to 657 patients of the Trans Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar computed tomography dataset. Voxel-based multiple comparison permutation dose difference testing, Cox regression modelling and LASSO feature selection were used to identify regions where dose-increase was associated with grade ≥2 rectal bleeding (RB) or tenesmus, according to the LENT/SOMA scale. This was externally validated by registering dose distributions from the RT01 (n = 388) and CHHiP (n = 241) trials onto the same exemplar and repeating the tests on each of these data sets, and on all three datasets combined. Results Voxel-based Cox regression and permutation dose difference testing revealed regions where increased dose was correlated with gastrointestinal toxicity. Grade ≥2 RB was associated with posteriorly extended lateral beams that manifested high doses (>55 Gy) in a small rectal volume adjacent to the clinical target volume. A correlation was found between grade ≥2 tenesmus and increased low-intermediate dose (∼25 Gy) at the posterior beam region, including the posterior rectum and perirectal fat space (PRFS). Conclusions The serial response of the rectum with respect to RB has been demonstrated in patients with posteriorly extended lateral beams. Similarly, the parallel response of the PRFS with respect to tenesmus has been demonstrated in patients treated with the posterior beam.

Highlights • Introduction of daily online prostate IGRT was feasible in a national randomised trial. • Dosimetric benefits seen in patients treated with IGRT and reduced CTV-PTV margins. • Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins., Background and purpose Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy. Materials and methods CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy. Results Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3–60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p

INTRODUCTION: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate.OBJECTIVE: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape.METHODS: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored.RESULTS: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92).CONCLUSIONS: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations.

Highlights • Data linkage allows combining patient records from different healthcare settings. • Linkage to GP data can support conduct of clinical trials and long-term follow-up. • The effect of co-morbidities and medications on cancer recovery is of interest. • Co-morbidities are potential risk factors for radiotherapy-related toxicity. • Statins or antihypertensives may potentially have protective effect., Background Patients receiving cancer treatment often have one or more co-morbid conditions that are treated pharmacologically. Co-morbidities are recorded in clinical trials usually only at baseline. However, co-morbidities evolve and new ones emerge during cancer treatment. The interaction between multi-morbidity and cancer recovery is significant but poorly understood. Purpose To investigate the effect of co-morbidities (e.g. cardiovascular and diabetes) and medications (e.g. statins, antihypertensives, metformin) on radiotherapy-related toxicity and long-term symptoms in order to identify potential risk factors. The possible protective effect of medications such as statins or antihypertensives in reducing radiotherapy-related toxicity will also be explored. Methods Two datasets will be linked. (1) CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) randomised control trial. CHHiP contains pelvic symptoms and radiation-related toxicity reported by patients and clinicians. (2) GP (General Practice) data from RCGP RSC (Royal College of General Practitioners Research and Surveillance Centre). The GP records of CHHiP patients will be extracted, including cardiovascular co-morbidities, diabetes and prescription medications. Statistical analysis of the combined dataset will be performed in order to investigate the effect. Conclusions Linking two sources of healthcare data is an exciting area of big healthcare data research. With limited data in clinical trials (not all clinical trials collect information on co-morbidities or medications) and limited lengths of follow-up, linking different sources of information is increasingly needed to investigate long-term outcomes. With increasing pressures to collect detailed information in clinical trials (e.g. co-morbidities, medications), linkage to routinely collected data offers the potential to support efficient conduct of clinical trials.

We agree with Mahal and colleagues that there is considerable imprecision in estimates of the duration of androgen suppression when used in conjunction with radiotherapy. This exists because of the variable duration of testosterone suppression after cessation of parenteral androgen suppression using luteinizing hormone–releasing hormone (LHRH) agonists. This is particularly marked with longer durations of treatment (≥6 mo), use of ≥3-mo depot preparations, and patient-related factors including age and pretreatment testosterone levels [...].

The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics.A case-control study design was used; 7 CRO and 5 PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1 to 5 years after-radiation therapy and did not have the symptom before radiation therapy. Controls did not experience the symptom at baseline or between 1 to 5 years after radiation therapy. The anorectum was recontoured from the anal verge to the rectosigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices, and bootstrapped receiver-operating-characteristic analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2-Gy equivalent schedules using α/β = 3 Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve with 95% confidence interval lower limits0.5 were considered statistically significant. Any constraint derived in95% to 99% of bootstraps was excluded.Statistically significant dose constraints were derived for CROs but not PROs. Intermediate to high doses were important for rectal bleeding, whereas intermediate doses were important for increased bowel frequency, fecal incontinence, and rectal pain. Spatial dose metrics did not improve prediction of CROs or PROs. A new panel of dose constraints for hypofractionated schedules to 60 Gy or 57 Gy are V20Gy85%, V30Gy57%, V40Gy38%, V50Gy22%, and V60Gy0.01%.Dose constraints differed among symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms after radiation therapy.

Evidence is accumulating for seven and less fractions in localised prostate cancer, including one large randomised trial. However, there is much more evidence yet to come and changing practice in advance of this may be premature. We review the reasons to persist with moderate hypofractionation for prostate cancer radiotherapy, until the results of further phase III studies are known.