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Competing Interests: Disclosure CO: advisory role: secondment as clinical advisor to Astex Pharmaceuticals; speaker’s honoraria and/or advisory board participation: AstraZeneca, Ipsen, Roche, Sandoz; research funding: PharmaMar (non-financial), all outside the submitted work. RGB has declared no conflicts of interest.

Purpose/objective: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT., Material/methods: A cohort of 302 men who received PORT at 2 academic institutions was pooled. PORT was predominately delivered as salvage (62% of cases); 20% received HT+PORT. Specimens were centrally reviewed for IDC/CA presence. In 104 cases, GC scores were determined. Endpoints were biochemical relapse-free (bRFR) and metastasis-free (mFR) rates., Results: After a median follow-up of 6.49-years, 135 (45%) and 40 (13%) men experienced biochemical relapse and metastasis, respectively. IDC/CA were identified in 160 (53%) of cases. Men harboring IDC/CA experienced inferior bRFR (HR 2.6, 95%CI 1.8-3.2, P<0.001) and mFR (HR 3.1, 95%CI 1.5-6.4, P = 0.0014). Patients with GC scores, 22 (21%) were stratified low-, 30 (29%) intermediate-, and 52 (50%) high-risk. GC low-risk was associated with superior bRFR (HR 0.25, 95%CI 0.1-0.5, P<0.001) and mFR (HR 0.15, 95%CI 0.03-0.8, P = 0.025). On multivariable analyses, IDC/CA and GC independently predicted for bRFR, corresponding to improved discrimination (C-index = 0.737 (95%CI 0.662-0.813))., Conclusions: IDC/CA subpathologies and GC predict for biochemical relapse and metastasis beyond conventional clinicopathologic indexes in the PORT setting. Patients harboring IDC/CA are at higher risk of relapse after maximal local therapies, thus warranting consideration for treatment intensification strategies. Conversely, for men with absence of IDC/CA and low GC scores, de-intensification strategies could be explored., Competing Interests: Conflict of interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer., Competing Interests: Declarations of interests SGW reports grant support from Bristol-Myers Squibb; consultancy fees and travel support from Astellas Pharma, Janssen, Bayer, Amgen, and Noxopharm paid to institution; and chaired the prostate cancer subcommittee of the Australia and New Zealand Urogenital and Prostate clinical trials group, during which time he received scientific grant support from Bayer and Astellas Pharma. SS reports advisory board fees paid to institution and grant support from AstraZeneca, Merck Sharp & Dohme, Amgen, Endocyte, Bristol-Myers Squibb, and Genentech. EC reports speaker honorarium and advisory board fees from Beckman Coulter Singapore, Janssen, Astellas Pharma, Bayer, Ipsen, AstraZeneca, Ferring, Amgen, and grant support from Janssen and Astellas Pharma. HB reports research support from AbbVie, Janssen, Millennium, Eli Lilly, and Astellas Pharma; and has served as advisor or consultant for Janssen, Astellas Pharma, Sanofi Genzyme, Merck Sharp & Dohme, Pfizer, Amgen, and Blue Earth. CMM reports speaker fees from Astellas Pharma, Janssen, and Steba Biotech; and grant support from SpectraCure. RGB reports no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle-invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin-eligible patients who opt for bladder preservation warrants further evaluation., Patients and Methods: Patients with MIBC treated with NAC followed by CRT at the Princess Margaret and Durham Regional cancer centers from 2008 to 2017 were retrospectively reviewed. Gemcitabine-cisplatin NAC was given for 2 to 4 cycles, followed by reassessment for CRT. External-beam radiotherapy (60-66 Gy) over 6 weeks was given with concurrent weekly cisplatin at 40 mg/m 2 . Kaplan-Meier method was used for survival analyses., Results: We identified 57 consecutive patients. Median age was 72 (range 45-87), and all had an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Stage II disease (65%), stage III disease (25%), and regional nodal metastases (11%) were included. Most completed planned NAC (95%). All patients completed external-beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median (range) follow-up was 19.3 (4.8-96.1) months. Median overall survival (OS) was not reached. Two-year OS and disease-specific survival rates were 74% (95% confidence interval, 57.7-84.9) and 88% (95% confidence interval, 78.5-98.1), respectively. Two-year bladder-intact disease-free survival was 64%. Salvage cystectomy was performed in 14%. Distant relapse occurred in 11%, and 9% died of metastatic disease. OS was associated with baseline hydronephrosis and with bladder-intact disease-free survival with residual disease on cystoscopy., Conclusion: NAC followed by CRT can result in encouraging outcomes and tolerability in cisplatin-eligible patients., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Enhanced autophagy has been observed in hypoxic regions of solid tumors. Here we address the hypothesis that autophagy is required for survival of hypoxic cells. We evaluated sensitivity to hypoxia of three human tumor cell lines (MCF7, PC3, and LNCaP) and their autophagy-deficient variants with shRNA knockdown of the genes ATG7 and BECLIN1. Hypoxia-induced cell death was more rapid for autophagy-deficient cells and was increased in the presence of the proton pump inhibitor pantoprazole that inhibits autophagy. Autophagy-deficient cells had a lower rate of oxygen consumption than wild-type cells. In xenografts derived from the three cell lines, autophagy (as determined by increased LC3 and reduced p62/SQSTM1) colocalized with hypoxic regions (identified by EF5). Xenografts derived from autophagy-deficient cells grew more slowly than wild-type tumors. Both LC3 expression and hypoxia were decreased in xenografts generated from single-knockdown cells and absent in double-knockdown tumors. Our results are consistent with the hypothesis that autophagy facilitates the survival of hypoxic cells, although reduced oxygen consumption of autophagy-deficient cells may contribute to lack of hypoxia in tumors derived from them. Because hypoxia is associated with resistance to anticancer therapy, inhibition of autophagy has potential to enhance the effectiveness of cancer treatment., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to characterize treatment-related toxicities, health-related quality of life (HRQOL), and biochemical outcomes in patients treated with postoperative image guided intensity modulated radiation therapy (IMRT) for prostate cancer using a consensus guideline for defining the clinical target volume., Methods and Materials: Between August 2007 and October 2008, patients considered for radiation therapy (RT) after prostatectomy were enrolled. The clinical target volume (prostate bed) was delineated according to published consensus guidelines, and patients were prescribed a dose of 66 Gy in 33 fractions. Radiation treatment planning prioritized rectal dose constraints over target volume coverage. Treatment was delivered by use of IMRT and daily cone beam computed tomographic guidance. Toxicity (graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events) and HRQOL assessments according to the Expanded Prostate Cancer Index Composite (EPIC) questionnaire were collected prospectively at baseline, at week 5 (during RT), at 3 months, and at yearly follow-up visits. Cumulative toxicity and biochemical relapse-free rates were calculated by the Kaplan-Meier method. Paired Student t tests with multiple testing correction were used to assess changes in HRQOL., Results: A total of 68 men were evaluated, with median follow-up of 5.9 years. Fifty-three patients (77.9%) and 15 patients (22.1%) were treated with salvage and adjuvant RT, respectively. Primary planning objectives were met in most cases (97.1%), but planning target volume coverage was compromised in 40% of cases because of large planning target volumes (mean 347.6 cm(3)). There were no grade 3 or 4 acute toxicities. Cumulative 5-year incidence of late gastrointestinal and genitourinary grade 2 toxicities was 12.3% (95% confidence interval [CI], 11.1%-13.5%) and 10.6% (95% CI, 9.5%-11.6%), respectively. No grade 3 or 4 late toxicities were observed. Transient declines in EPIC gastrointestinal domain summary score (mean 87.66 at 3 months vs 92.76 at baseline; P = .006) and genitourinary irritative subscale (week 5 mean score 83.37 vs 89.45 at baseline; P = .007) were observed. Complete recovery occurred between 3 and 12 months after therapy, remaining stable compared with baseline at 5-year follow-up. Sexual HRQOL remained stable at 5 years, with an improving trend in bother subscale. Biochemical relapse-free rate at 5 years was 72.7% (95% CI, 61.9%-83.5%)., Conclusions: Guideline-based postprostatectomy image guided IMRT with rigid rectal dose constraints resulted in favorable toxicity profiles; long-term stability in gastrointestinal, genitourinary, and sexual HRQOL; and expected biochemical control rates. Concerns regarding toxicity and HRQOL should not preclude recommendation for RT after prostatectomy., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Prostate cancer (CaP) is the most commonly diagnosed malignancy in men in the Western world. In North America, more than 275,000 men are diagnosed annually, whereby approximately 1 in 6 men will be diagnosed with CaP in their lifetime, and 1 in 34 men will die from castration-resistant metastatic disease. Unfortunately, current clinical prognostic factors explain only a proportion of the observed variation in clinical outcome from patient to patient. Furthermore, overtreatment of indolent and low-risk cancers leads to inappropriate morbidity following radiotherapy or surgery. As such, better predictors of individualized prognosis and treatment response are urgently needed to triage patients to customized and intensified CaP treatment. Recent developments in next-generation sequencing have made it possible to identify prognostic and predictive signatures based on genomic profiles. We discuss the genetic basis of CaP progression from localized to systemic disease (e.g., point mutations, copy-number alterations, and structural variants) in relation with unique features of CaP biology, including intraprostatic and interprostatic heterogeneity, multifocality and multiclonality, TMPRSS2:ERG, and other ETS-family gene fusions. Finally, we focus on the use of genomic markers as prognostic factors for local failure and for systemic disease, as novel risk-stratification tools, in triaging patients to existing treatment options, and ultimately the potential of genomics for the identification of molecular targets for therapy of CaP., (© 2013 Published by Elsevier Inc.)

Radiation and many chemotherapy agents work to kill cells by inducing free radicals that damage DNA and proteins. Antioxidants such as vitamin E, beta carotene, lycopene, and selenium have been associated with a reduction in cancer risk when ingested by prostate cancer patients. Selenium is a promising agent currently being evaluated as a prostate cancer prevention agent. Selenium is an essential trace element and is involved in antioxidant protection and the redox-regulation in humans. Several adverse effects of radiotherapy and chemotherapy in cancer patients have been linked to oxidative cell processes in the human body. Selenium supplementation may protect healthy tissues and reduce the side effects of treatment. Despite two decades of research into this question, no clear answer has appeared. Therefore, understanding the mechanism(s) by which dietary nutrients exert their effects in prostate carcinogenesis, may lead to the exploitation of new chemoprevention agents. A large body of epidemiological evidence, including observational, trials, and randomized controlled clinical trials, support the proposition that selenium may prevent prostate cancer in humans. These clinical studies are supported by in vitro and in vivo data using prostate cancer models. This systematic review provides the first evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. The pre-clinical and clinical evidence as to whether ingestion of supplemental selenium, in addition to radiotherapy/chemotherapy is beneficial, detrimental or neutral towards patient outcome is also discussed., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Purpose: To report the long-term results and examine factors associated with bladder preservation, risk of relapse, and survival in patients treated with radical radiotherapy for invasive bladder cancer., Materials and Methods: Between 1986 and 1997, 340 patients with T1-T4 bladder cancer were treated at Princess Margaret Hospital and received radiotherapy alone, radiotherapy and concurrent cisplatin chemotherapy, or neoadjuvant chemotherapy followed by radiotherapy. Patients having complete response were followed with regular cystoscopy. Cystectomy was undertaken in suitable patients with persistent or locally recurrent disease., Results: The median age of patients was 71 years, 13% had evidence of regional lymph node involvement, and 27% were medically unfit for radical cystectomy. A total of 247 patients received radiotherapy alone, 36 radiotherapy and concurrent cisplatin chemotherapy, and 57 neoadjuvant chemotherapy followed by radiotherapy. Complete response was obtained in 63.5% of patients overall, and median follow-up was 7.9 years. The 10-year overall survival, cause-specific survival, and local relapse-free rates were 19%, 35%, and 32%, respectively. In 131 patients with muscle-invasive disease confined to the bladder wall (T2N0M0), 10-year cause-specific survival (P = 0.02) and local relapse-free rates (P = 0.03) were 68% and 60% when carcinoma in situ was absent, and 47% and 28%, respectively, when present. In multivariable analysis, younger age, lower T category, and absence of carcinoma in situ were associated with a statistically significant improvement in survival and local control (P