Supplementary Table S1. Best overall response (RECIST version 1.1)

PURPOSE Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (–3.5 to –0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION Surveillance is a safe management approach—advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

OBJECTIVES:To assess the long-term treatment efficacy of low-dose-rate (LDR) brachytherapy for the treatment of localized prostate cancer. PATIENTS AND METHODS:Cause-of-death annotation in our prospective database was supplemented with death certificate information obtained via an internal audit of patients treated from 1999 to 2017 with LDR prostate brachytherapy as monotherapy or as combination with androgen deprivation therapy and/or external beam radiotherapy. Overall and disease-specific survival were the primary outcomes, estimated with Kaplan-Meier and competing risks multi-state models. Clinical variables influencing mortality were assessed with Cox proportional hazards regression in a sub-analysis of men to assess the predictive value of prostate-specific antigen (PSA) level at 48 months post implant. RESULTS:The audit process began in October 2017 and culminated in June 2020 with a curated series of 2936 patients. All-cause and prostate cancer-specific death prevalence were 11% and 2.9%, respectively. The median (range) follow-up time was 10 (3-21) years and the median (range) time to death from any cause was 9 (3-21) years. At 15 years post implant the overall and prostate cancer-specific survival probability were 81% and 95%, respectively. The 15-year cumulative incidence rates of death not due and due to prostate cancer were 14% and 5%, respectively. A greater risk of death due to prostate cancer was conferred by increasing age at therapy (hazard ratio [HR] 1.1, P < 0.001), advanced clinical stages relative to T1a-T2a (HR 1.9, P = 0.048 for T2b; HR 2.7, P = 0.023 for T2c-T3b) and a 48-month PSA level >1.0 ng/mL (HR 6.8, P < 0.001). CONCLUSION:This study constitutes the largest retrospective analyses of long-term mortality outcomes from prospectively collected prostate brachytherapy data and confirms the excellent treatment efficacy of LDR prostate brachytherapy for localized prostate cancer. T2 clinical stage subdivisions and 48-month PSA level >1.0 ng/mL appear to be strong indicators of prostate cancer-related survival.

OBJECTIVES:To report clinical and functional outcomes for patients who have undergone salvage robot-assisted seminal vesicle excision (RA-SVE) for the focal treatment of isolated seminal vesical (SV) recurrence after treatment for prostate cancer by low-dose-rate brachytherapy.PATIENTS AND METHODS:Patients with rising prostate-specific antigen (PSA) after low-dose-rate prostate brachytherapy (LDR-PB) underwent multi-parametric magnetic resonance imaging (mp-MRI) of the prostate and 11 C-Choline or 68 Ga-prostate-specific membrane antigen (68 Ga-PSMA) positron emission tomography/computed tomography (PET/CT) scan, followed by targeted transperineal biopsy of the prostate and SVs. Isolated SV recurrence were identified in 17 (0.38%) LDR-PB patients. These 17 patients were offered RA-SVE.RESULTS:The median total operative time was 90 min and blood loss 50 mL with no postoperative transfusions required. The median hospital stay was 1 day. No intra- or postoperative complications were documented. Continence status was unaffected, no patient required urinary pads. Postoperative pathology confirmed SV invasion in all specimens. Surgical margins were positive in seven (41%) patients. All patients had at least one positive imaging study, although three (18%) mp-MRI and five (29%) PET/CT assessments were negative. One (6%) pre-SVE biopsy was also negative but with positive imaging. Salvage SVE failure, defined as three consecutive PSA rises or the need for further treatment, occurred in six patients of whom three had a positive margin. Overall failure-free survival rates were 86%, 67%, and 53% at 1, 2, and 3 years after SVE, respectively.CONCLUSIONS:Salvage RA-SVE appears to be a safe focal treatment, with very low morbidity, for patients with localised SV recurrence after LDR-PB. It permits deferral of androgen deprivation therapy in selected patients. Bilateral SVE is mandatory. This surgical option should be considered in patients with isolated prostate cancer recurrence to the SV.

BJUI CompassVolume 2, Issue 1 p. 9-10 EDITORIALOpen Access Low-Dose-Rate Prostate Brachytherapy (LDR-PB) adopts postsurgical PSA value for definition of cure Jennifer Uribe, Jennifer Uribe The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorSantiago Uribe-Lewis, Corresponding Author Santiago Uribe-Lewis santiago.uribe@nhs.net orcid.org/0000-0002-2801-360X The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UK Correspondence Santiago Uribe-Lewis, The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, GU2 7XX, UK. Email: santiago.uribe@nhs.netSearch for more papers by this authorSara Khaksar, Sara Khaksar The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorCarla Perna, Carla Perna The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorChristos Mikropoulos, Christos Mikropoulos The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorSophie Otter, Sophie Otter The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorRobert Laing, Robert Laing The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorStephen Langley, Stephen Langley The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this author Jennifer Uribe, Jennifer Uribe The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorSantiago Uribe-Lewis, Corresponding Author Santiago Uribe-Lewis santiago.uribe@nhs.net orcid.org/0000-0002-2801-360X The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UK Correspondence Santiago Uribe-Lewis, The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, GU2 7XX, UK. Email: santiago.uribe@nhs.netSearch for more papers by this authorSara Khaksar, Sara Khaksar The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorCarla Perna, Carla Perna The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorChristos Mikropoulos, Christos Mikropoulos The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorSophie Otter, Sophie Otter The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorRobert Laing, Robert Laing The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this authorStephen Langley, Stephen Langley The Stokes Centre for Urology, Royal Surrey Hospital NHS Foundation Trust, Guildford, UKSearch for more papers by this author First published: 19 October 2020 https://doi.org/10.1002/bco2.49Citations: 4AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Long-term remission, and likely cure, of clinically localized prostate cancer is considered when there is no evidence of prostate-specific antigen (PSA) or radiographic progression 10 years after initial localized therapy.1 The PSA level thresholds to define the posttreatment (biochemical) progression differ based on the mechanism of action of a surgical or radiotherapeutic approach, making cross-modality comparisons cumbersome. A PSA threshold of ≥0.2 ng/mL is commonly used to report biochemical relapse after radical prostatectomy (RP). In contrast, radiation oncologists most often use the Phoenix definition, a threshold 10-fold greater, of 2 ng/mL above the posttreatment nadir when reporting the outcome of external beam radiotherapy (EBRT) or brachytherapy. Permanent implants with low-dose-rate brachytherapy seeds (LDR-PB) have shown over the last 20 years to be a very effective ablative treatment for early prostate cancer resulting in low and stable PSA values. The recent large collaborative study by Crook et al identified a PSA threshold value after LDR-PB associated with cure, defined as long-term (10-15 year) freedom from prostate cancer.2 Prospective data were collected from 7 institutions identifying 14 220 patients with localized prostate cancer who were treated with LDR-PB, either alone (n = 8552) or in combination with EBRT (n = 1175), androgen deprivation (n = 3165), or both (n = 1328). Of the 14 220 cases 8746 patients were selected based on absence of clinical failure 4 years (±6 months) after treatment and availability of a 4-year PSA value. The median (range) follow-up time was 8 (3.5-21.3) years. For patients with 4-year PSA ≤ 0.2 ng/mL, the threshold for RP, the freedom-from-recurrence (FFR) rates were 98.7% at 10 years and 96.1% at 15 years. These results were validated using three independent prospective prostate brachytherapy data sets. One was the brachytherapy arm of the ASCENDE-RT phase III randomized trial. The trial compared biochemical progression-free survival (bPFS) in unfavorable intermediate (31%) and high-risk patients (69%) who underwent dose escalated EBRT plus ADT, with or without an LDR-PB boost, with more than 10 years follow-up. The published results of the trial showed that men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.3 Interestingly the authors re-analyzed ASCENDE-RT data using a surgical PSA threshold of ≤0.2 ng/mL.4 In the trial, all subjects had undetectable PSA values at the completion of radiation therapy/ADT, thus providing a unique opportunity to evaluate bPFS after definitive radiation therapy using the surgical threshold to define biochemical relapse. Compared to the nadir + 2 ng/mL definition, the >0.2 ng/mL PSA threshold doubled the number of relapse events from 69 to 139. However, this increase was confined to the DE-EBRT arm of the trial. The 7-year Kaplan-Meier bPFS after DE-EBRT declined from 76% using nadir + 2 ng/mL to 38% using the >0.2 ng/mL threshold (P < .001). Among the LDR-PB subset, there was no significant difference, the 7-year Kaplan-Meier bPFS was 85% (>0.2 ng/mL) vs 88% (nadir + 2 ng/mL) (P = .319). The authors concluded that combined modality therapy using a brachytherapy boost provided bPFS outcomes for men with unfavorable risk disease that are at least as good as any published results for RP. In view of the work reported by Crook et al,2 we analyzed the 10- and 15-year FFR rates from our own prostate brachytherapy database that currently holds baseline, treatment, and prospective follow-up details of over 4500 patients. Clinical relapse in our series was defined as local, nodal, or distant recurrence, or biochemical failure triggering salvage treatment. After selection for patients without relapse within 3.5 years from implantation and an available PSA measurement 48 months (±6 months) post-implant we identified 1923 cases. The median (range) follow-up time was 10 years (4-21) and age at treatment 65 years (44-83). There were 681 (35%) low-risk patients, 997 (52%) intermediate, and 245 (13%) high-risk. Treatment types were LDR-PB monotherapy in 1279 (67%) patients, ADT + LDR-PB in 385 (20%), and ADT + EBRT + LDR-PB boost in 259 (13%). Kaplan-Meier analyses showed overall 10- and 15-year FFR rates of 98% and 95% in patients with a 48-month PSA ≤ 0.2 ng/mL (Figure 1); multivariable Cox proportional hazards regression,5 adjusted for age at treatment, risk classification, and treatment modalities (including the use of ADT), indicated survival rates were not dependent on these predictor variables in patients with a 48-month PSA ≤ 0.2 ng/mL. FIGURE 1Open in figure viewerPowerPoint Kaplan-Meier relapse-free survival analysis of patients who received LDR-PB (alone or as combination with ADT and/or EBRT) stratified by their PSA value (ng/mL) 48 months post-implant Previously we reported that 92% of relapse-free high-risk patients with an available PSA 10 years after implantation had a PSA level ≤ 0.2 ng/mL.6 Therefore, from our own long-term experience and that of others, adoption of a PSA value of ≤ 0.2 ng/mL at 48 months posttreatment as a biochemical definition of cure for patients treated with LDR-PB is reasonable and evidence based. Importantly, a 48-month PSA value > 0.2 ng/mL does not necessarily translate into a longer term clinical relapse but does mean such patients would need continued surveillance and reassuringly many of which may ultimately be deemed rid of their disease. CONFLICT OF INTEREST JU and SUL report personal fees from BXTAccelyon Limited and Theragenics Corporation, outside the submitted work. SL and RL report personal fees, nonfinancial support, and other from BXTAccelyon Limited, outside the submitted work. SK, CP, CM, and SO have nothing to disclose. All authors have read and approved the final article. REFERENCES 1Available from: https://www.auanet.org/Documents/education/clinical-guidance/Clinically-Localized-Prostate-Cancer.pdf 2Crook JM, Tang C, Thames H, Blanchard P, Sanders J, Ciezki J, et al. A biochemical definition of cure after brachytherapy for prostate cancer. Radiother Oncol. 2020; 27(149): 64– 9. 3Morris WJ, Tyldesley S, Rodda S, Halperin R, Pai H, McKenzie M, et al. Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017; 1(98): 275– 85. 4Morris WJ, Pickles T, Keyes M. Using a surgical prostate-specific antigen threshold of >0.2 ng/mL to define biochemical failure for intermediate- and high-risk prostate cancer patients treated with definitive radiation therapy in the ASCENDE-RT randomized control trial. Brachytherapy. 2018; 17: 837– 44. 5Therneau T. A package for survival analysis in R. 2020. Available from https://CRAN.R-project.org/package=survival 6Laing R, Uribe J, Uribe-Lewis S, Money-Kyrle J, Perna C, Chintzoglou S, et al. Low-dose-rate brachytherapy for the treatment of localised prostate cancer in men with a high risk of disease relapse. BJU Int. 2018; 122: 610– 7. Citing Literature Volume2, Issue1January 2021Pages 9-10 FiguresReferencesRelatedInformation

Madam — This letter is a response to the recent overview on high dose rate (HDR) brachytherapy in high-risk localised disease in the prostate cancer special issue by Morton and Alrashidi [ [1] Morton G.C. Alrashidi S.M. High dose rate brachytherapy in high-risk localised disease — why do anything else?. Clin Oncol. 2020; 32: 163-169 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar ].

Background: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.

ObjectivesTo report clinical outcomes of the Hemi‐Ablative Prostate Brachytherapy (HAPpy) trial evaluating treatment‐related toxicity and effectiveness of hemi‐gland (HG) low‐dose‐rate (LDR) prostate brachytherapy as a focal approach to control unilateral localised prostate cancer.Patients and MethodsSingle institution phase IIS pilot study of patients treated with focal 4D Brachytherapy™ (BXTAccelyon, Burnham, Buckinghamshire, UK). The primary outcome was patient‐reported toxicity 24 months after implant. The secondary outcome was assessment of disease control. Outcomes in HG patients were compared to whole‐gland (WG) controls obtained from our prospective cohort registry by negative binomial and linear regression models.ResultsPre‐treatment demography was similar between the 30 HG patients and 362 WG controls. Post‐implant dosimetry was similar for the prostate gland target volumes and significantly reduced for the urethra and bowel in HG patients relative to WG controls, but this did not translate into a difference in post‐implant mean symptom scores between the two groups. Nevertheless, the change in score from baseline indicated that the impact on pre‐treatment symptom status was less after HG implants. Only HG patients showed a return to baseline urinary scores as early as 12 months. Sexual potency was conserved in 73% and 67% of HG and WG patients, respectively (P = 0.84). Post‐implant prostate‐specific antigen (PSA) kinetics revealed that baseline PSA was reduced at 24 months by 78% and 88% in HG and WG patients, respectively (P < 0.05). Treatment relapse occurred in one (3%) HG patient 55 months after implant and in nine (3%) WG patients at 32–67 months after implant.ConclusionThis pilot study suggests that treatment‐related toxicity and biochemical outcomes after HG implants are broadly similar to those observed with WG treatment despite the lower dose delivered by HG implants.

Aims: To assess long-term outcomes and resource use of 4D Brachytherapy, a one-stage real-time implant for the treatment of prostate cancer that uses stranded and loose iodine-125 seeds, and to compare with the conventional two-stage (2S) technique. Materials and methods: Prospectively collected data of men who underwent 2S and 4D low dose rate brachytherapy in a single institution were analysed. Survival estimates were analysed using the Kaplan-Meier method and Log-rank test. Treatment failure rates were further compared by Cox proportional hazards (Coxph) regression or by a surrogate prostate-specific antigen value cut-off of 0.4 ng/ml 48 months post-implant. Treatment toxicity outcomes were also evaluated. Comparative costs were based on published English National Health Service data. Results: We compared outcomes of 690 men treated with 2S and 1031 men with 4D brachytherapy. Median follow-up times were 10.4 and 5.2 years (P < 0.001) for 2S and 4D cases, respectively. Day 0 post-implant dosimetry was improved in 4D brachytherapy patients. Five years post-implant >= 98% of cases were alive and >= 95% were free from disease relapse irrespective of technique. Coxph regression showed the risk of relapse after 4D brachytherapy was similar to the 2S technique (hazard ratio 0.67, 95% confidence interval 0.44-1.03, P = 0.065). Forty-eight months post-implant there was a significantly greater proportion of 4D brachytherapy cases with a prostate-specific antigen below 0.4 ng/ml relative to the 2S technique. Urinary and bowel symptom scores showed reduced toxicity after 4D implants and potency conservation was similar to the 2S technique. The reduction in time and resource use decreased the cost of 4D brachytherapy by 40% compared with the 2S technique. Conclusion: Two-stage and 4D brachytherapy are both highly effective for the control of localised prostate cancer. However, relative to the 2S technique, the 4D technique was associated with improved dosimetry, reduced treatment-related toxicity and reduced cost. Further follow-up will assess disease control superiority of 4D brachytherapy beyond 5 years post-implant. (C) 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

OBJECTIVES:To report clinical outcomes of 125 I low-dose-rate prostate brachytherapy (LDR-PB) as monotherapy or combined with androgen-deprivation therapy (ADT) and/or external beam radiotherapy (EBRT) in high-risk localised prostate cancer.PATIENTS AND METHODS:Analysis of clinical outcomes from a prospective cohort of patients treated with LDR-PB alone or combined treatment in a single institution. Men with a high risk of disease relapse were identified by the National Institute for Health and Care Excellence (NICE) criteria or by the National Comprehensive Cancer Network (NCCN) criteria. Relapse-free survival (RFS), overall survival (OS), prostate cancer-specific survival (PCSS), and metastases-free survival (MFS), were analysed together with patient-reported symptom scores and physician-reported adverse events.RESULTS:The NICE and NCCN criteria identified 267 and 202 high-risk patients, respectively. NICE-defined patients had significantly lower pre-treatment PSA levels, Gleason scores <7, and a greater proportion of patients who received LDR-PB monotherapy. At 9 years after implantation RFS was 89% and 87% in the NICE and NCCN groups, respectively (log-rank P = 0.637), and OS 93% and 94%, respectively (log-rank P = 0.481). All of the survival estimates were similar between LDR-PB monotherapy and combined therapies. Cox proportional hazards regression confirmed RFS was similar between the treatment types. Treatment-related toxicity was also similar between the treatment methods.CONCLUSION:LDR-PB is effective at controlling localised prostate cancer in patients with a high risk of disease relapse. As the present study was not randomised, it is not possible to define those patients who need the addition of ADT and/or EBRT. However, the NICE criteria appear suitable to define treatment options where patients could benefit from LDR-PB as monotherapy or combined treatment. This choice should be discussed with the patient taking into account comorbidities and presence of multiple high-risk factors.

162 Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( > 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients. Clinical trial information: ISRCTN78818544.

To report oncological and functional outcomes of men treated with low‐dose‐rate (LDR) prostate brachytherapy aged ≤60 years at time of treatment.

Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2.5% one-sided a for hazard ratio (HR) 0.75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0.94, 95% CI 0.79-1.11; p= 0.450), 81 months (41 to not reached) for SOC + Doc (0.78, 0.66-0.93; p= 0.006), and 76 months (39 to not reached) for SOC + ZA + Doc (0.82, 0.69-0.97; p= 0.022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

This analysis evaluates the impact of intrinsic and extrinsic factors on fluciclovine (18F) PET-CT scan detection rate (DR) in a biochemical relapse (BR) cohort.Diagnostic performance compared to histology and clinical follow-up is reported separately.METHODS: Data from 596 BR patients who underwent fluciclovine (18F) PET-CT scanning were subjected to subgroup analyses to evaluate the impact of: PSA at time of scanning, age, weight, race, prior treatment, Gleason and D'Amico risk scores on scan DR at a subject and region level.RESULTS: BED001 was conducted in accordance with ICH GCP and the Declaration of Helsinki.Overall, fluciclovine (18F) PET-CT scanning detected sites of recurrence in 68% (403/595) of patients.The influence of baseline PSA value (by quartile) on DR is summarized below.The DR, at Subject level, was 41.4% for patients in the 1st quartile compared to >75% for those in the 3rd and 4th quartiles.DR at region level was 14% (PSA <0.79 ng/mL) compared to >50% (PSA >2.03 ng/mL) in the Prostate region (P), and 31% compared to 45-59% in the Extra-Prostatic region (E-P).Subgroup analyses to report performance against the other factors above will also be presented.CONCLUSIONS: Results suggest that fluciclovine (18F) PET-CT is effective for visualising locations of prostate cancer relapse across a wide range of PSA values, including PSA <1ng/mL, with a Detection Rate proportional to PSA.

Background and purpose: Advances in magnetic resonance imaging (MRI) and prostate sampling enable early identification of men with low to intermediate risk prostate cancer who are candidates for focal therapies that minimise side effects. We report dosimetry data from a pilot study evaluating the effectiveness of hemi-gland low dose rate (HG-LDR) brachytherapy as a focal therapy approach to control unilateral localised disease.Material and methods: Twenty-two men underwent HG-LDR brachytherapy. Multi parametric MRI and transperineal template mapping biopsies were used to identify low volume unilateral disease. Whole gland therapy controls (n =120) were retrospectively obtained. All implants were performed with 4D Brachytherapy.Results: Intraoperative and postimplant dosimetry complied with established brachytherapy parameters. Mean (standard deviation) postoperative D90 for the target hemi-gland was 153.8 (11.3) Gy compared to 47.5 (12.7) Gy for the contralateral hemi-gland (P < 0.001). Mean postoperative V100% was 93.1 (3.9) and 24.6 (10.5) for the target and contralateral hemi-glands respectively (P < 0.001). Urethra D30 was 150.4 (19.8) Gy and 174.2 (15.0) Gy for hemi-gland and whole gland implants respectively (P < 0.001). Significantly reduced dose was also observed for rectum and neurovascular bundles.Conclusions: HG-LDR focal brachytherapy is feasible with significant reduction in dose to the contralateral hemi-gland and organs at risk. Crown Copyright (C) 2016 Published by Elsevier Ireland Ltd. All rights reserved.

Abstract Introduction: TACT2, a multicentre randomized phase III trial in patients with node +ve or high risk node-ve invasive EBC with E-CMF as control tested two hypotheses in a 2x2 factorial design, presented results showing: i) no evidence of benefit from accelerated 2-weekly epirubicin (aE) compared to standard 3-weekly epirubicin (E) (Cameron 2012); and ii) capecitabine (X) gives equivalent efficacy but preferential side-effect profile to CMF (Canney 2014). Here we present prognostic and potential predictive value of translational biomarkers. We address two main hypotheses: i) aE is less effective in patients with luminal A than patients with other subtypes (Coates 2012) and ii) BCL2 is an independent prognosis marker (Callagy 2006). We also explore the relationship between CK5/6, EGFR and BCL2 and residual risk following chemotherapy. Methods: Tumour samples were collected prospectively from 3803 patients (86.6% of the 4391 TACT2 patients and 94.5% of those consenting). Tissue microarrays were constructed as per published guidelines and central ER, PgR, HER2, Ki67, CK5/6, EGFR and BCL2 staining performed and quantified by imaged analysis for ER, PgR, HER2, Ki67 and BCL2. EGFR and CK5/6 were dichotomised by light microscopy evaluation of cores. 94.5-97.6% of cases were stained and successfully analysed for individual biomarkers by IHC. Patients were categorised into 4 BC subtypes by central ER/PgR/HER2/Ki67 (Luminal A, B, HER2+ve, Triple-ve (TN)) with TN further divided into basal-like (CK5/6 or EGFR +ve) and 5-marker-ve (both CK5/6 and EGFR -ve). Log-rank tests assessed prognostic effect of each marker individually and cancer subtypes on time to tumour recurrence (TTR). Cox-regression models tested independent prognostic value of BCL2 in the presence of tumour size, grade, nodal status, and biological subtype. Results: No evidence of a difference in the efficacy of aE compared with E between the 4 patient subtypes was observed (Luminal A: n=608, HR (for aE compared with E) 0.80 (95% CI 0.47-1.38); Luminal B: n=1804, HR=0.97 (95% CI 0.76-1.23); HER2+ve: n=219, HR=1.03 (95% CI 0.53-1.99); TN: n=638, HR=1.00 (95% CI 0.72-1.39); Test for heterogeneity p=0.84). When subdividing the TN group into basal-like and 5-marker-ve, HRs were 0.66 (95% CI 0.45-0.98) and HR 1.56 (95% CI 0.82-2.96) respectively, post-hoc analysis for heterogeneity between these 2 subtypes p=0.025. No differential effect between subtypes was observed for the comparison of CMF and X. 82/434 (18.9%) patients with low BCL2 expression (≤10%) had a TTR event compared with 444/3158 (14.1%) with high BCL2 (>10%), univariate HR 1.39, 95% CI 1.10-1.76, p=0.006. However this difference was no longer seen after adjustment for clinical factors and biological subtype (HR 1.17 95% CI 0.90-1.52, p=0.25). Conclusion: We found no statistical evidence that luminal A cancers are associated with reduced benefit from aE vs E. A hypothesis generating observation that benefit from aE vs E might be different between basal-like and 5-marker-ve cancers should be interpreted with caution due to the small numbers of cases and the retrospective nature of the analysis. In this study BCL2 did not provide independent prognostic information when corrected for conventional histopathological features. Citation Format: James Morden, Judith Bliss, Jane Bayani, Robert Laing, Rajiv Agrawal, Jeremy Thomas, Andrew Goodman, Vivienne Loo, Peter Clark, Peter Canney, Peter Barrett-Lee, John Bartlett, David Cameron. Intrinsic subtypes and BCL2 as predictive and prognostic biomarkers in the TACT2 trial (CRUK/05/019) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-04.

Our Institution has performed >2500 LDR I125 brachytherapy implants since 1999. The first one thousand patients were treated with a two stage pre-planned stranded I125 brachytherapy technique as popularised by the Seattle group. In 2009 we developed a one stage realtime implant technique using stranded seeds around the periphery of the gland and loose seeds within the centre. The number and length of stranded seeds were calculated from a bespoke nomogram. The stranded seeds are delivered pre-loaded. The positions of the loose seeds are planned intra-operatively to achieve target dosimetry. This technique has been termed 4D Brachytherapy. We present the outcomes of 350 consecutive patients from both cohorts after our learning curve in the brachytherapy technique to compare the dosimetry and clinical outcomes. Data was retrieved from a prospectively collected database. The two stage cohort dated from February 2002 to September 2004 and the 4D group from June 2009 to October 2011. There was no significant difference between the two groups of patients in terms of PSA, clinical stage, Gleason score or prostate size by Kolmogorov-Smirnov analysis. 58 of 292 (19.8%) two stage patients received EBRT followed by brachytherapy boost compared with 57 of 285 (20%) in the 4D group. There was a significant improvement in the post implant dosimetry for 4D Brachytherapy. The D90 target is 90 - 120% of prescribed dose. 98% of 4D patients are treated within this constraint as compared with 76% of the two stage technique (p<0.05). The V150 target is less than 65% and this occurred in 99% of the 4D patients as opposed to 83% of the two stage (p<0.05). V100 (%) two stage mean 90.4 ± 6.9, 4D 92.2 ± 3.5 demonstrating greater consistency in the 4D group (p<0.05) Rectal dosimetry is expressed as V100 in cc. This was improved in the 4D cohort: two stage mean 1.6 ± 1, 4D mean 0.7 ± 0.6 (p<0.05). Urethral V150(%) was lower in the 4D group: mean 4.0 ± 6.7 compared with mean 9.8 ± 9.6 for the two stage cohort (p<0.05) The urinary toxicity was measured as change from baseline. At 6 weeks and 1 year the mean IPSS change for 4D and two stage are respectively 8.5, 11.4 (p<0.05) and 1.4, 3.4 (p<0.05), showing less deterioration in symptoms for the 4D group. 4D brachytherapy takes approximately 35 minutes to perform, similar to the time taken for the second stage of a pre-planned implant. We have demonstrated improved dosimetry across all parameters irrespective of prostate size and an improvement in urinary toxicity.Tabled 1Two Stage4DP ValueProstate D90 (%)103.4 +/- 13.1105.1 +/- 6.9<0.05Prostate V100 (%)90.4 +/- 6.992.2 +/- 3.5<0.05Rectal v100 (cc)1.6 +/- 1.00.7 +/- 0.6<0.05Urethral vl50 (%)9.8 +/- 9.64.0 +/- 6.7<0.05D90 Target%%<90%14.21.090 to 120%75.998.0>120%9.91.0 Open table in a new tab

Background: Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy inAdvancing orMetastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort.Objective: Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group.Design, setting, and participants: STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014.Outcome measurements and statistical analysis: Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models.Results and limitations: A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n = 574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population.Conclusions: Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse.Patient summary: Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.