Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

BACKGROUND: Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. STUDY DESIGN: The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. ENDPOINTS: The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. PATIENTS AND METHODS: A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. TRIAL REGISTRATION: Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

Standardized prostate cancer incidence and mortality rates following initial non-malignant biopsy result.

OBJECTIVES: To compare the incidence of subsequent prostate cancer diagnosis and death following an initial non-malignant systematic transrectal ultrasonography (TRUS) biopsy with that in an age- and calendar-year matched population over a 20-year period. SUBJECTS AND METHODS: This population-based analysis compared a cohort of all men with initial non-malignant TRUS biopsy in Denmark between 1995 and 2016 (N = 37 231) with the Danish population matched by age and calendar year, obtained from the NORDCAN 9.1 database. Age- and calendar year-corrected standardized prostate cancer incidence (SIR) and prostate cancer-specific mortality ratios (SMRs) were calculated and heterogeneity among age groups was assessed with the Cochran's Q test. RESULTS: The median time to censoring was 11 years, and 4434 men were followed for more than 15 years. The corrected SIR was 5.2 (95% confidence interval [CI] 5.1-5.4) and the corrected SMR was 0.74 (95% CI 0.67-0.81). Estimates differed among age groups (P < 0.001 for both), with a higher SIR and SMR among younger men. CONCLUSION: Men with non-malignant TRUS biopsy have a much higher incidence of prostate cancer but a risk of prostate cancer death below the population average. This underlines that the oncological risk of cancers missed in the initial TRUS biopsy is low. Accordingly, attempts to increase the sensitivity of initial biopsy are unjustified. Moreover, current follow-up after non-malignant biopsy is likely to be overaggressive, particularly in men over the age of 60 years.

Exercise training to increase tumour natural killer-cell infiltration in men with localised prostate cancer: a randomised controlled trial.

OBJECTIVES: To explore the effects of preoperative high-intensity interval training (HIIT) compared to usual care on tumour natural killer (NK)-cell infiltration in men with localised prostate cancer (PCa), as NK-cell infiltration has been proposed as one of the key mechanisms whereby exercise can modulate human tumours. PATIENTS AND METHODS: A total of 30 patients with localised PCa undergoing radical prostatectomy (RP) were randomised (2:1) to either preoperative aerobic HIIT four-times weekly (EX; n = 20) or usual care (CON; n = 10) from time of inclusion until scheduled surgery. Tumour NK-cell infiltration was assessed by immunohistochemistry (CD56+ ) in diagnostic core needle biopsies and corresponding prostatic tissue from the RP. Changes in cardiorespiratory fitness, body composition, blood biochemistry, and health-related quality of life were also evaluated. RESULTS: The change in tumour NK-cell infiltration did not differ between the EX and CON groups (between-group difference: -0.09 cells/mm2 , 95% confidence interval [CI] -1.85 to 1.66; P = 0.913) in the intention-to-treat analysis. The total number of exercise sessions varied considerably from four to 30 sessions. The per-protocol analysis showed a significant increase in tumour NK-cell infiltration of 1.60 cells/mm2 (95% CI 0.59 to 2.62; P = 0.004) in the EX group. Further, the total number of training sessions was positively correlated with the change in NK-cell infiltration (r = 0.526, P = 0.021), peak oxygen uptake (r = 0.514, P = 0.035) and peak power output (r = 0.506, P = 0.038). CONCLUSION: Preoperative HIIT did not result in between-group differences in tumour NK-cell infiltration. Per-protocol and exploratory analyses demonstrate an enhanced NK-cell infiltration in PCa. Future studies are needed to test the capability of exercise to increase tumour immune cell infiltration.

Impact of previous depression on the risk of suicide among prostate cancer patients.

BACKGROUND: Prior studies of suicide risk among prostate cancer patients are conflicting. We compared the risk of suicide in prostate cancer patients to cancer-free men including adjustment for clinical stage, socioeconomic position, somatic comorbidity, and previous depression. MATERIALS AND METHODS: A cohort of 37,527 men diagnosed with prostate cancer in Denmark during 1998-2011 was identified in the Danish Prostate Cancer Registry (DaPCaR) and compared with 357,384 cancer-free men matched by age at the time of diagnosis. The primary outcome was death from suicide. Data were analyzed using cumulative incidence functions and multivariable Cox regression models. RESULTS: Among prostate cancer patients, 3813 had a previous depression, defined as filed antidepressant prescription within three years before diagnosis. In the study period, 108 prostate cancer patients were registered with suicide as the cause of death, hereof 26 with previous depression. There was no difference in the cumulative incidence of suicide between prostate cancer patients and cancer-free men. There was no effect modification of previous depression on the risk of suicide (p = .12). The hazard ratio (HR) for suicide varied with time since diagnosis. A sensitivity analysis showed that the risk of suicide was highest within the first year of diagnosis where prostate cancer patients had a 1.70-fold increased hazard compared with cancer-free men (95% CI, 1.11-2.59). Men with prostate cancer and previous depression had a three-fold increased hazard for suicide compared with prostate cancer patients without a history of depression (HR 2.84, 95% CI, 1.82-4.45). CONCLUSION: The absolute risk of suicide is low following a prostate cancer diagnosis. Time since diagnosis and a history of depression was associated with the highest risk of suicide. Healthcare professionals should be aware of an increased risk of suicide among men with previous depression, especially in the immediate aftermath of the diagnosis.

Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14).

BACKGROUND: Historically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS). MATERIALS AND METHODS: Patients with hormone-naïve, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m2, q3w, 8-10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis. RESULTS: Between 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0-5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50-0.93; p = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49-0.94; p = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse. CONCLUSION: Docetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.

Risk of prostate cancer and death after benign transurethral resection of the prostate-A 20-year population-based analysis.

BACKGROUND: The oncological risks after benign histology on a transurethral resection of the prostate (TURP) remain largely unknown. Here, the risk of prostate cancer incidence and mortality following a benign histological assessment of TURP is investigated in a population-based setting. METHODS: Between 1995 and 2016, 64,059 men in Denmark underwent TURP without prior biopsy of the prostate; 42,558 of these men had benign histology. The risks of prostate cancer, prostate cancer with a Gleason score ≥ 3 + 4, and prostate cancer-specific death were assessed with competing risks. Specific risks for pre-TURP prostate-specific antigen (PSA) levels at 10 and 15 years were visualized by locally estimated scatterplot smoothing. RESULTS: The median age at TURP was 72 years (interquartile range [IQR], 65-78 years), and the median follow-up was 15 years (IQR, 10-19 years). The 10-year risks of any prostate cancer and prostate cancer with a Gleason score ≥ 3 + 4 and the 15-year risk of prostate cancer death showed clear visual relations with increasing PSA. The 15-year cumulative incidence of prostate cancer-specific death after benign TURP was 1.4% (95% confidence interval [CI], 1.3%-1.6%) for all men and 0.8% (95% CI, 0.6%-1.1%) for men with PSA levels <10 ng/ml. The primary limitation was exclusion due to missing PSA data. CONCLUSIONS: Men with low PSA levels and a benign TURP can be reassured about their cancer risk and do not need to be monitored differently than any other men. Patients with high PSA levels can be considered for further follow-up with prostate magnetic resonance imaging. These findings add to the literature suggesting that normal histology from the prostate entails a low risk of death from the disease. LAY SUMMARY: There is little knowledge about the oncological risks after the surgical treatment of benign prostatic hyperplasia. This study shows a very low risk of adverse oncological outcomes in men with prostate-specific antigen (PSA) levels below 10 ng/ml at the time of transurethral resection of the prostate. Patients with higher PSA levels may need more extensive follow-up.

Prescription rates for commonly used drugs before and after a prostate cancer diagnosis.

PURPOSE: To investigate differences in prescription rates of commonly used drugs among prostate cancer patients and cancer-free comparisons and between patients diagnosed with localized and non-localized disease. METHODS: We conducted a register-based study including all men aged 50-85 years diagnosed with prostate cancer in Denmark from 1998 to 2015 and an age-matched cancer-free comparison cohort. We calculated the number of new and total prescriptions from three years before to three years after the date of diagnosis of the case for selected drug classes divided by the number of person-months and stratified by stage at diagnosis. RESULTS: We included 54,286 prostate cancer patients and 249,645 matched comparisons. 30,712 patients were diagnosed with localized disease and 12,884 with non-localized disease. The rates of new prescriptions increased considerably among patients within the year before the diagnosis. Hereafter the rates varied between drug classes. For most drug classes, total prescription rates for patients and comparisons increased similarly in the study period. Total prescription rates varied between men with localized and non-localized disease for all drug classes apart from statins. CONCLUSION: Our findings indicate that a large proportion of prostate cancer cases are likely diagnosed during medical work-up for other reasons than prostate cancer. Increased rates occur within the last year before diagnosis and future studies on the interaction between drug use and prostate cancer should at least include a one year pre-diagnostic lag-time. Post-diagnostic prescription rates demonstrated an increased use of drugs most likely associated with the consequences of the disease.

A Nationwide Analysis of Risk of Prostate Cancer Diagnosis and Mortality following an Initial Negative Transrectal Ultrasound Biopsy with Long-Term Followup.

PURPOSE: Magnetic resonance imaging (MRI) targeted prostate biopsy has been shown to find many high-grade prostate cancers in men with concurrent negative transrectal ultrasound (TRUS) systematic biopsy. The oncologic risk of such tumors can be explored by looking at long-term outcomes of men with negative TRUS biopsy followed without MRI. The aim was to analyze the mortality after initial and second negative TRUS biopsy. MATERIALS AND METHODS: All men who underwent initial TRUS biopsies between January 1, 1995 and December 31, 2016 in Denmark were included. A total of 37,214 men had a negative initial TRUS biopsy and 6,389 underwent a re-biopsy. Risk of cause-specific mortality was analyzed with competing risks. Diagnosis of Gleason score ≥7 prostate cancer following negative biopsies was analyzed with multivariable logistic regression including time to re-biopsy, prostate specific antigen (PSA), age and digital rectal examination. RESULTS: The 15-year prostate cancer-specific mortality was 1.9% (95% CI: 1.7-2.1). Prostate cancer-specific mortality was 1.3% (95% CI: 0.9-1.6) and 4.6% (95% CI: 3.4-5.8) for men with PSA <10 and >20 ng/ml, respectively. Of the TRUS re-biopsies 12% were Gleason score ≥7 and risk of Gleason score ≥7 increased with longer time to re-biopsy (p <0.001). Mortality after re-biopsy was similar to after initial biopsy. CONCLUSIONS: Men with negative TRUS biopsies have a very low prostate cancer-specific mortality, especially with PSA <10 ng/ml. This raises serious questions about the routine use of MRI targeting for initial prostate biopsy and suggests that MRI targeting should only be recommended for men with PSA >10 ng/ml after negative biopsy.

Open vs robot-assisted radical cystectomy (BORARC): a double-blinded, randomised feasibility study.

OBJECTIVE: To examine surgical outcomes and feasibility of blinding patients and care providers to the surgical technique of radical cystectomy (RC). PATIENTS AND METHODS: Single-centre, parallel-group, double-blinded, randomised feasibility study of open RC (ORC) vs robot-assisted RC with intracorporeal urinary diversion (iRARC) in an 'Enhanced Recovery After Surgery' setup. A total of 50 patients aged ≥18 years with bladder cancer planned for RC with an ileal conduit were included. Patients with previous major abdominal/pelvic surgery, pelvic radiation or anaesthesiological contraindications were excluded. Primary outcomes were proportion of unblinded patients and success of blinding using Bang's Blinding Index. Secondary outcomes included length of stay (LOS), complication rates, blood loss, pain, and opioid consumption. RESULTS: A total of 26% of the patients were unblinded before discharge. We demonstrated that patients and doctors remained blinded for the allocated treatment, but nurses did not. Blood loss was greater in the ORC group as was operative time in the iRARC group. We found no difference in complication rate, LOS, or use of analgesics. CONCLUSIONS: The present study demonstrates that blinding of surgical technique in RC is possible. The results of secondary outcomes are consistent with the findings of previous unblinded randomised controlled trials. Our study highlights that it is possible to perform a blinded phase III study to explore the optimal surgical technique in RC.

Prescription rates for drugs used in treatment of benign prostatic hyperplasia and erectile dysfunction before and after prostate cancer diagnosis.

BACKGROUND: Symptoms and treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) may lead to prostate cancer workup, and patterns of prescriptions before diagnosis may affect findings of pharmacoepidemiological studies. Usage of BPH and ED drugs after diagnosis may be related to prostate cancer treatment. We investigated differences in prescription rates of BPH and ED drugs among prostate cancer patients and cancer-free comparisons and between patients with localized and non-localized disease. MATERIAL AND METHODS: A nationwide register-based study, including all Danish men aged 50-85 years diagnosed with prostate cancer during 1998-2015 and an age-matched comparison cohort without cancer. We calculated rates of new and total prescriptions in 1-month intervals from 3 years before to 3 years after cancer diagnosis for drugs used to treat BPH and ED, overall and stratified by clinical stage. RESULTS: We identified 54,286 men with prostate cancer and a comparison cohort of 249,645 age-matched men. The new prescription rate for BPH drugs increased for men with prostate cancer in the year before diagnosis and peaked 1 month before diagnosis with an 18-fold higher rate. Men with prostate cancer had a higher total prescription rate of BPH drugs 3 years before diagnosis, notably among men with localized disease. Before diagnosis, the new prescription rates for ED drugs were similar among men with prostate cancer and comparisons. After diagnosis, men with prostate cancer had a 7-fold higher rate of new prescriptions for ED drugs. Among men with localized disease, the total prescription rate of ED drugs increased in the months following diagnosis. CONCLUSION: Differences in prescription rates suggest increased prostate cancer surveillance among men receiving BPH drugs, whereas the post-diagnostic increase in ED drugs among men with localized disease is compatible with the increased risk of ED following prostate cancer treatment.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Risk of depression after diagnostic prostate cancer workup - A nationwide, registry-based study.

OBJECTIVE: To compare the risk of depression after diagnostic workup for prostate cancer (PCa), regardless of the histopathologic outcome, with that of a cancer-free population. METHODS: A nationwide cohort of Danish men who had a prostatic biopsy sample in 1998-2011 was identified from the Danish Prostate Cancer Registry and compared to an age-matched cohort from the background population. Men with other cancers, major psychiatric disorder, or prior use of antidepressants were excluded. The risk of depression defined as hospital contact for depression or prescription for antidepressants was determined from cumulative incidence functions and multivariate Cox regression models. RESULTS: Of 54,766 men who underwent diagnostic workup for PCa, benign results were found for 21,418 and PCa was diagnosed in 33,347. During up to 18 years of follow-up, the adjusted hazard of depression was higher in men with PCa than in the background population, with the highest risk in the two years after diagnosis (hazard ratio (HR) 2.77, 95% CI 2.66-2.87). Comorbidity and lowest or highest income were significant risk factors for depression and the cumulative incidence was substantially higher in men with metastatic or high-risk disease. In men with benign histopathology the HR for depression was 1.22 (95% CI 1.14-1.31) in the first two years but no different from the background population after that. CONCLUSIONS: Diagnostic workup for PCa is associated with an increased risk of depression, mainly among men with a diagnosis of PCa. Clinicians should be aware of depressive symptoms in prostate cancer patients.

Temporal changes in cause-specific death in men with localised prostate cancer treated with radical prostatectomy: a population-based, nationwide study.

BACKGROUND AND OBJECTIVE: Changes in diagnostic work-up, histopathological assessment, and treatment of men with prostate cancer during the last 20 years have affected the prognosis. The objective was to investigate the risk of prostate cancer death in men with clinically localised prostate cancer treated with radical prostatectomy in Sweden in 2000-2010. METHODS: Population-based, nationwide, study on men with clinically localised prostate cancer treated with radical prostatectomy in the period 2000-2010. Cox regression analyses were used to assess differences in risk of prostate cancer death according to calendar period for diagnosis and stratified on risk category. RESULTS: The study included 19 330 men with a median follow-up of 12.4 years. Men diagnosed in 2007-2008 and 2009-2010 had a significantly lower risk of prostate cancer death compared to men diagnosed in 2000-2002. The reduced risk of prostate cancer death was restricted to men with intermediate-risk prostate cancer with no differences observed in men with low- or high-risk prostate cancer. CONCLUSION: During the study period, the risk of prostate cancer death decreased in the total population of men with localised prostate cancer treated with radical prostatectomy. The decrease was restricted to men with intermediate-risk prostate cancer.

The impact of positive surgical margins on salvage radiation or androgen deprivation therapy following radical prostatectomy - a nationwide study.

BACKGROUND: The extent to which positive surgical margins (PSM) affect the risk of subsequent salvage radiation therapy (sRT) or androgen depletion therapy (ADT) following radical prostatectomy (RP) is not well described. Initiation of additional therapies after RP depend on patient preference, individual factors, local guidelines, and life expectancy. The aim of this study was to analyze differences between margin status in risk of subsequent treatment for PCa following RP in a retrospective population-based cohort from Denmark. METHODS: Patients who underwent RP were identified in The Danish Prostate Cancer Registry (DaPCaR). Subsequent sRT and ADT were assessed in uni- and multivariate settings and validated with receiver operating characteristic (ROC). RESULTS: PSM was associated with an increased risk of sRT (HR = 1.85, p < .001) and receiving ADT (HR:1.39, p = .007). Margin status only had a minor impact on the predictive ability for sRT (area under the curve (AUC): p < .001) and no significant impact for subsequent ADT (AUC: p = 1). Significant inter-institutional difference in the association between PSM with sRT or ADT was observed. CONCLUSION: PSM is associated with the risk of sRT and initiation of ADT, however this association is weak. Our results underline that factors beyond tumor characteristics play a major role for initiation of sRT and ADT.

Vitamin D levels and the risk of prostate cancer and prostate cancer mortality.

BACKGROUND: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. METHODS: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25-50 (insufficient), 50-75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. RESULTS: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33-3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. CONCLUSION: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

Associations of low-dose aspirin or other NSAID use with prostate cancer risk in the Danish Diet, Cancer and Health Study.

PURPOSE: Epidemiologic studies suggest that use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. We examined these associations overall and according to clinical and lifestyle parameters. METHODS: We identified male participants in the Danish Diet, Cancer and Health Study (n = 26,339), holding information on anthropometric measures and lifestyle factors. From Danish nationwide registries and medical records, we retrieved complete prescription histories and prostate cancer occurrence and characteristics. Cox regression was used to estimate hazard ratios (HRs) for prostate cancer associated with low-dose aspirin or nonaspirin NSAID use, overall and by clinical characteristics, anthropometric measures, and lifestyle factors. RESULTS: We identified 1,927 prostate cancer cases during a median follow-up of 17.0 years. Low-dose aspirin use was not associated with overall prostate cancer risk, but a reduced HR for nonaggressive prostate cancer (high use [≥ 1,825 tablets]: 0.79; 95% confidence interval (CI) 0.60-1.04) and an increased HR for aggressive disease (high use: 1.27; 95% CI 1.00-1.61) was observed with low-dose aspirin use. Long-term, high-intensity use (≥ 10 years with ≥ 0.25 defined daily doses/day) of nonaspirin NSAIDs was associated with an increased HR for prostate cancer (1.35, 95% CI 0.99-1.84), confined to localized and nonaggressive disease. No consistent variation in HRs was seen in analyses stratified by height, body mass index, smoking, and alcohol use. CONCLUSION: Low-dose aspirin or other NSAID use was not associated with reduced prostate cancer risk, neither overall nor according to anthropometric measures, smoking, or alcohol use. The variation according to outcome characteristics warrants further investigation.

Elevated miR-615-3p Expression Predicts Adverse Clinical Outcome and Promotes Proliferation and Migration of Prostate Cancer Cells.

miR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P < 0.05, log-rank test). In addition, high miR-615-3p expression was a significant predictor of PC-specific survival in univariate (hazard ratio, 3.75; P < 0.001) and multivariate (hazard ratio, 2.66; P = 0.008) analysis after adjustment for the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) nomogram in a merged RP cohort (n = 734). Moreover, overexpression of miR-615-3p in PC cells (PC3M) significantly increased cell viability, proliferation, apoptosis, and migration. Together, our results suggest that miR-615-3p is a significant predictor of postoperative BCR and PC-specific survival and has oncogenic functions in PC cells.

Characteristics of finasteride users in comparison with nonusers: A Nordic nationwide study based on individual-level data from Denmark, Finland, and Sweden.

PURPOSE: Published epidemiological studies on the association between finasteride use and the risk of male breast cancer have been inconclusive due to methodological limitations including a few male breast cancer cases included. Determinants of male breast cancer have been studied, but it remains unexplored whether these are also related to finasteride use and thereby constitute potential confounders. This study aimed to assess whether there are differences between finasteride users and nonusers with regard to numerous potential confounders. METHODS: In total, 246 508 finasteride users (≥35 years) were identified in the prescription registries of Denmark (1995-2014), Finland (1997-2013), and Sweden (2005-2014). An equal number of nonusers were sampled. The directed acyclic graph (DAG) methodology was used to identify potential confounders for the association between finasteride and male breast cancer. A logistic regression model compared finasteride users and nonusers with regard to potential confounders that were measurable in registries and population surveys. RESULTS: Finasteride users had higher odds of testicular abnormalities (odds ratio [OR] 1.40; 95% confidence interval [CI] 1.36-1.44), obesity (1.31; 1.23-1.39), exogenous testosterone (1.61; 1.48-1.74), radiation exposure (1.22; 1.18-1.27), and diabetes (1.07; 1.04-1.10) and lower odds of occupational exposure in perfume industry or in high temperature environments (0.93; 0.87-0.99), living alone (0.89; 0.88-0.91), living in urban/suburban areas (0.97; 0.95-0.99), and physical inactivity (0.70; 0.50-0.99) compared to nonusers. CONCLUSIONS: Systematic differences between finasteride users and nonusers were found emphasizing the importance of confounder adjustment of associations between finasteride and male breast cancer.

Use of Low-Dose Aspirin and Mortality After Prostate Cancer Diagnosis: A Nationwide Cohort Study.

Background: Recent studies suggest that aspirin use may improve survival in patients with prostate cancer. Objective: To assess the association between postdiagnosis use of low-dose aspirin and prostate cancer mortality. Design: Nationwide cohort study. Setting: Denmark. Patients: Men with incident prostate adenocarcinoma between 2000 and 2011. Measurements: Nationwide registry data on tumor characteristics, drug use, primary prostate cancer therapy, comorbidity, and socioeconomic parameters. Postdiagnosis use of low-dose aspirin (75 to 150 mg) was defined as 2 or more prescriptions filled within 1 year after prostate cancer diagnosis. Follow-up started 1 year after prostate cancer diagnosis. In secondary analyses, low-dose aspirin use was assessed within exposure periods of 5 or 7.5 years after prostate cancer diagnosis. Results: Of 29 136 patients (median age, 70 years), 7633 died of prostate cancer and 5575 died of other causes during a median follow-up of 4.9 years (interquartile range, 3.1 to 7.2 years), through 2015. Postdiagnosis low-dose aspirin use was associated with adjusted hazard ratios (HRs) of 0.95 (95% CI, 0.89 to 1.01) for prostate cancer-specific mortality and 1.12 (CI, 1.05 to 1.20) for other-cause mortality. The secondary analyses showed that prostate cancer mortality was slightly reduced with low-dose aspirin use after the 5-year (HR, 0.91 [CI, 0.83 to 1.01]) and 7.5-year (HR, 0.84 [CI, 0.72 to 0.97]) postdiagnosis exposure periods, notably among patients filling prescriptions for a large quantity of low-dose aspirin tablets during the 7.5-year period. Limitations: Data on over-the-counter aspirin use were unavailable. Some residual confounding was possible as a result of incomplete data on some prognostic factors. Conclusion: The study did not support an overall effect of postdiagnosis low-dose aspirin use on prostate cancer mortality. However, results for extended exposure periods suggest that low-dose aspirin use might be inversely associated with prostate cancer mortality after 5 years from cancer diagnosis. Primary Funding Source: Danish Cancer Society.