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PURPOSE: Approximately 1 in 10 patients without prior prostate biopsy undergoing surgery for lower urinary tract symptoms harbors incidental prostate cancer; however, practice guidelines do not provide recommendations for its management. We aimed at describing the oncologic outcomes of patients with Grade Group (GG) 1 and GG2 prostate cancer diagnosed at transurethral resection of the prostate (TURP). MATERIALS AND METHODS: This was a nationwide, population-based, observational study of patients undergoing TURP in Denmark from 2006 to 2022 using the Danish Prostate Registry. We estimated the cumulative incidence of further biopsies and MRI, curative treatment, endocrine treatment, and cause-specific mortality with competing risk analyses. RESULTS: Among 24,494 patients who underwent TURP, there were 1016 men with GG1 and 381 with GG2 prostate cancer. The 5-year cumulative incidence of further MRIs or biopsies was 36% (95% CI 33%-39%) for GG1 and 30% (95% CI 25%-34%) for GG2 disease. Fifteen-year prostate cancer mortality was 8.4% (95% CI 5.3%-11%) for GG1 and 14% (7.5%-21%) for GG2. A total of 270 men with GG1 disease underwent a biopsy after the TURP, and 162 (60%) had no cancer; in this group, prostate cancer mortality after 15 years was 0.6% (95% CI 0%-1.8%). Men with post-TURP biopsy ≥ GG2 had a prostate cancer mortality of 30% (95% CI 9%-50%) 15 years post TURP. The major limitation was the heterogeneous follow-up, which could lead to an overestimation of prostate cancer mortality compared to a more standardized follow-up. CONCLUSIONS: We observed high prostate cancer mortality after TURP with GG1 or GG2, likely due to unsampled high-grade cancer in the peripheral zone. Patients with incidental prostate cancer should be further investigated to rule out high-grade cancer. For patients with GG1 on TURP, once a subsequent biopsy does not show cancer, follow-up should be lessened similar to that of patients with an initial nonmalignant biopsy.
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INTRODUCTION: High-intensity focused ultrasound (HIFU) is regarded as a promising alternative treatment option for localized prostate cancer (PCa) as it has been proposed to offer similar oncologic control to the standard of care, but with significantly reduced treatment-related side effects. This systematic literature review assesses the available evidence of whole-gland HIFU as primary treatment for localized PCa. METHODS: MEDLINE (PubMed) was searched for studies investigating oncological and functional outcomes following whole-gland HIFU as primary treatment for localized PCa. Our primary outcomes for the review were biochemical disease-free survival rates (BDFS), overall and PCa-specific survival rates as well as negative biopsy rates. Our secondary outcomes were functional results and complications of the treatment. RESULTS: A total of 375 articles were identified, of which 35 were included in the present review. All 35 articles were prospective or retrospective case series. Mean/median duration of follow-up across studies was 10.9 to 94 months, and 6618 patients were included in the review. The BDFS rate varied greatly across studies from 21.7% to 89.2% during follow-up. The 10-year PCa-specific survival rate following HIFU was 90%, 99%, and 100% in 3 studies. Negative biopsy rates post-HIFU ranged from 20% to 92.7% across studies. Common side effects to HIFU included urinary incontinence (grade 1: 0%-22.7%), erectile dysfunction (11.6%-77.1%), urinary tract infections (1.5%-47.9%), and bladder outlet obstruction mainly as urethral strictures (7%-41.2%). CONCLUSION: Great variation in oncological and functional outcomes was seen across studies. More prospective trials are needed before whole-gland HIFU can be considered as a treatment option for localized PCa.
Subject(s)
Prostatic Neoplasms , Humans , Male , Disease-Free Survival , High-Intensity Focused Ultrasound Ablation/methods , High-Intensity Focused Ultrasound Ablation/adverse effects , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Treatment Outcome , Ultrasound, High-Intensity Focused, Transrectal/adverse effects , Ultrasound, High-Intensity Focused, Transrectal/methodsABSTRACT
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.
Subject(s)
Androgen Antagonists , Anilides , Nitriles , Prostatectomy , Prostatic Neoplasms , Tosyl Compounds , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/radiotherapy , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/therapy , Prostatic Neoplasms/surgery , Androgen Antagonists/therapeutic use , Androgen Antagonists/administration & dosage , Aged , Tosyl Compounds/therapeutic use , Tosyl Compounds/administration & dosage , Middle Aged , Anilides/therapeutic use , Anilides/administration & dosage , Nitriles/therapeutic use , Nitriles/administration & dosage , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Gonadotropin-Releasing Hormone/agonists , Prostate-Specific Antigen/blood , Combined Modality Therapy , Drug Administration ScheduleABSTRACT
BACKGROUND AND OBJECTIVES: Changes in work-up and histopathological assessment have caused stage and grade migration in men with prostate cancer (PCa). The aim of this study was to assess temporal trends in risk of PCa death for men with favourable-risk PCa managed with primary radical prostatectomy or observation. METHODS AND MATERIAL: Men aged 75 or younger with Charlson Comorbidity index 0-1 diagnosed with favourable-risk PCa (T1-T2, prostate specific antigen [PSA] <20 ng/mL and Gleason score 6 or 7[3+4]) in the period 2000-2016 who were treated with primary radical prostatectomy or managed with observation in PCBaSe 4.0. Treatment groups were compared following propensity score matching, and risk of PCa death was estimated by use of Cox regression analyses. RESULTS: A total of 9,666 men were selected for each treatment strategy. The 7-year cumulative incidence of PCa death decreased in all risk and treatment groups. For example, the incidence in men diagnosed with low-risk PCa and managed with observation was 1.2% in 2000-2005, which decreased to 0.4% in 2011-2016. Corresponding incidences for men with intermediate-risk PCa managed with observation were 2.0% and 0.7%. The relative risk of PCa death was lower in men with low-risk PCa managed with radical prostatectomy compared to observation: in 2000-2005 hazard ratio (HR) 0.20 (95% confidence interval [CI] 0.10-0.38) and in 2011-2016 HR 0.35 (95% CI 0.05-2.26). Corresponding risks for men with intermediate-risk PCa were HR 0.28 (95% CI 0.16-0.47) and HR 0.21 (95% CI 0.04-1.18). The absolute risk reduction of radical prostatectomy compared to observation for men with low-risk PCa was 1% in 2000-2005 and 0.4% in 2011-2016, and for men with intermediate-risk PCa 1.1% in 2000-2005 and 0.7% in 2011-2016. CONCLUSION: Men diagnosed in 2011-2016 with low-risk and favourable intermediate-risk PCa have a similar relative benefit but smaller absolute benefit of curative treatment compared to men diagnosed in 2000-2005.
Subject(s)
Prostatectomy , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Prostatic Neoplasms/mortality , Aged , Middle Aged , Watchful Waiting , Risk Assessment , Time Factors , Incidence , Neoplasm GradingABSTRACT
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).
Subject(s)
Conservative Treatment , Prostatic Neoplasms , Quality of Life , Aged , Aged, 80 and over , Humans , Male , Clinical Trials, Phase III as Topic , Prostatectomy , Prostatic Neoplasms/therapy , Prostatic Neoplasms/pathology , Randomized Controlled Trials as Topic , Multicenter Studies as TopicABSTRACT
PURPOSE: To evaluate the efficacy of a single perioperative dose of dexamethasone in reducing postembolization syndrome following prostatic artery embolization. MATERIALS AND METHODS: We conducted a single-center double-blind randomized controlled trial from March 2021 to May 2022 (NCT04588857). Participants were randomized to receive either i.v. 24 mg dexamethasone or saline. The primary outcome measures were temperature, pain, and quality of life in the first 5 days following prostatic artery embolization. Sample size of 60 patients was needed for the assessment of primary outcomes. Participants were followed for 6 months and assessed for a variety of secondary outcome measures including inflammatory markers and lower urinary tract symptoms severity. RESULTS: Due to lack of clinical effect and mild symptoms in the control group, the trial was terminated early. 31 participants (16 dexamethasone vs. 15 control) were enrolled and analyzed. A difference in mean temperature was observed on day 1 (37.23 ± 0.64 °C control vs 36.74 ± 0.41 °C dexamethasone, p = 0.02, 95% CI 0.09-0.89). Difference in pain (score out of 10) was seen only on day 5 (1.48 ± 1.2 control vs. 2.9 ± 2.24 dexamethasone, p = 0.04, 95% CI - 2.78-- 0.04). A difference in C-reactive protein values was observed on day 2 (108 [54-161] mg/l control vs 10 [5-33] mg/l dexamethasone, p < 0.01). No significant differences in other outcomes were observed. No side effects were recorded. CONCLUSIONS: Twenty-four milligrams of dexamethasone bolus is safe but does not reduce postembolization syndrome following prostatic artery embolization.
Subject(s)
Dexamethasone , Embolization, Therapeutic , Prostate , Humans , Male , Double-Blind Method , Embolization, Therapeutic/methods , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Prostate/blood supply , Aged , Middle Aged , Syndrome , Treatment Outcome , Lower Urinary Tract Symptoms/etiology , Lower Urinary Tract Symptoms/therapy , Lower Urinary Tract Symptoms/drug therapy , Quality of Life , Prostatic Hyperplasia/therapy , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic useABSTRACT
BACKGROUND: Debate regarding a nomenclature change for grade group 1 (GG 1) prostate cancer to noncancer has been revived, as this could be a powerful tool in reducing the overtreatment of indolent disease. OBJECTIVE: To describe outcomes for all men diagnosed with GG 1 prostate cancer in the Danish population, with a focus on men followed conservatively. DESIGN, SETTING, AND PARTICIPANTS: This was a population-based observational study using data from the Danish Prostate Registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the cumulative incidence of curative treatment, endocrine treatment, and cause-specific mortality. RESULTS AND LIMITATIONS: The cumulative incidence of endocrine therapy at 10 yr was 5.3% (95% confidence interval [CI] 4.3-6.3%) for men with initial active surveillance and 21% (95% CI 19-23%) for men with initial watchful waiting for localized GG 1. In the GG1 cohort, the prostate cancer-specific mortality rate at 15 yr was 14% (95 CI% 11-16%) for men on watchful waiting, 10% (95 CI% 6.7-14%) for men with prostate-specific antigen <10 ng/ml on watchful waiting, and 16% (95 CI% 13-19%) for men who did not receive curative-intent treatment or histological assessment. The study is limited by the historic nature of the observations over a period during which diagnostic procedures and treatments have evolved. CONCLUSIONS: GG 1 cancer can lead to disease-specific mortality in men with localized prostate cancer, and changing the nomenclature for all men may lead to undertreatment. PATIENT SUMMARY: Key opinion leaders have suggested that prostate cancers of Gleason grade group 1 (GG 1) should be renamed as noncancer to reduce overtreatment. The argument is that low-grade cancer does not metastasize. However, our nationwide population-based study showed that death from prostate cancer can occur in some men diagnosed with GG 1 disease. These men should be considered in discussions on changing the name for GG 1 prostate cancer.
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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.
Subject(s)
Prostate-Specific Antigen , Prostatic Neoplasms , Male , Humans , Docetaxel , Androgen Antagonists/therapeutic use , Neoplasm Recurrence, Local/pathology , Prostatic Neoplasms/pathology , Chronic Disease , Hormones/therapeutic use , Disease-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Treatment OutcomeABSTRACT
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.
Subject(s)
Prostatic Neoplasms , Male , Humans , Middle Aged , Incidence , Prostatic Neoplasms/pathology , Biopsy , Prostate/pathology , Prostate-Specific Antigen , Image-Guided BiopsyABSTRACT
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.
Subject(s)
Prostatic Neoplasms , Suicide , Male , Humans , Depression/epidemiology , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/diagnosis , Comorbidity , RegistriesABSTRACT
BACKGROUND: Radical cystectomy (RC) with urinary diversion is the recommended treatment for selected cases of non-metastatic high-risk non-muscle-invasive and muscle-invasive bladder cancer. It remains unknown whether robot-assisted laparoscopic cystectomy (RARC) offers any advantage in terms of safety compared to open cystectomy (ORC) in an Enhanced Recovery After Surgery (ERAS) setup. Blinded randomised controlled trials (RCTs) between RARC versus ORC have never been conducted in cystectomy patients. We will investigate the feasibility of conducting a double-blinded RCT comparing ORC with RARC with intra-corporal ileal conduit (iRARC) in an ERAS setup. METHODS: This is a single-centre, double-blinded, randomised (1:1) clinical feasibility study for patients with non-metastatic high-risk non-muscle-invasive or muscle-invasive bladder cancer scheduled for cystectomy. All participants are recruited from Rigshospitalet, Denmark. The planned sample size is 50 participants to investigate whether blinding of the surgical technique is feasible. Participants and postoperative caring physicians and nurses are blinded using a pre-study designed abdominal dressing and blinding of the patient's electronic health record. Study endpoints are assessed 90 days postoperatively. The primary aim is to study the frequency and pattern of unplanned unblinding after surgery and the number of participants who cannot guess the surgical technique at the day of discharge. Eleven secondary endpoints are assessed: length of stay, days alive and out of hospital, in-hospital complication rate, 30-day complication rate, 90-day complication rate, readmission rate, quality of life, blood loss, pain, rate of moderate/severe post-anaesthesia care unit (PACU) complications, and delirium. Participants are managed in an ERAS setup in both arms of the trial. DISCUSSION: We report on the design and objectives of a novel experimental feasibility study investigating whether blinding of the surgical technique in cystectomy patients is possible. This information is essential for the design of future blinded trials comparing ORC to RARC. There is a continued need to compare RARC and ORC in terms of both efficacy, safety, and oncological outcomes. Estimated end of study is March 2021. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03977831. Registered on the 6th of June 2019.
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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.
Subject(s)
Prostatic Neoplasms , Quality of Life , Male , Humans , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Exercise , Prostate/pathology , Killer Cells, NaturalABSTRACT
Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary-testis axis function in patients receiving adjuvant ADT.
Subject(s)
Prostatic Neoplasms , Testis , Humans , Male , Androgen Antagonists , Androgens , Prostatic Neoplasms/drug therapy , Testosterone , Gonadotropins , Gonadotropin-Releasing HormoneABSTRACT
Postdiagnosis physical activity is associated with improved cancer outcomes, but biological mechanisms mediating anticancer effects remain unclear. Recent findings suggest that physiological adaptations to acute exercise comprise potential anticancer effects, but these remain poorly explored in clinical settings. The objective of this study was to explore the effects of a single exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer. Thirty patients with localized prostate cancer were randomized (2:1) to either one high-intensity interval training bout or no exercise on the day before radical prostatectomy. Immunohistochemical analyses were performed on prostatic tissue from surgery and assessed for tumor hypoxia, natural killer (NK) cell infiltration, and microvessel density (MVD). Acute systemic response in blood lymphocytes, epinephrine, norepinephrine, IL-6, tumor necrosis factor, cortisol, lactate, and glucose was also evaluated. We did not find between-group differences in tumor hypoxia (Mann-Whitney U test, U = 83.5, p = 0.604) or NK cell infiltration (U = 77.0, p = 0.328). Also, no significant correlation was found between MVD and tumor hypoxia or NK cell infiltration. One exercise bout is likely insufficient to modulate tumor hypoxia or NK cell infiltration. Future studies may elucidate if an accumulation of several exercise bouts can impact these outcomes (NCT03675529, www.clinicaltrials.gov).
Subject(s)
Hydrocortisone , Prostatic Neoplasms , Epinephrine , Exercise/physiology , Glucose , Humans , Interleukin-6 , Lactates , Male , Norepinephrine , Prostatic Neoplasms/therapy , Tumor Necrosis FactorsABSTRACT
Background: The immune system plays a vital role in cancer development and progression. Strategies mobilizing cytotoxic cells of the immune system to combat immunosuppression in cancer may help to improve the treatment response of patients. To this end, we aimed to characterize the anti-cancer effect of acute exercise, including the involvement of inflammatory signals. Patients and methods: Twenty patients with early-stage prostate cancer (PCa) scheduled to undergo prostatectomy performed one bout of acute exercise consisting of a watt-max test and four high-intensity intervals. Natural Killer (NK), NKT-like and T cell phenotype, NK cell cytotoxic activity (NKCA), and NKCA per-cell against cell lines of leukemia (K562) and prostate cancer origin (LNCaP and PC-3) were assessed. Inflammatory markers (TNF-α, IL-6, and CRP) were measured in plasma. Results: Exercise increased NK, NKT-like, and CD8 T cell concentration in the circulation. Furthermore, exercise shifted immune cells towards a mature and cytotoxic phenotype e.g., NK cells exhibited higher CD57 as well as lower NKG2A expression. NKT-like and CD8 cells exhibited elevated CD57, TIGIT and Granzyme-B expression. Exercise significantly improved NKCA against K562 (+16% [5%; 27%]; p = 0.002) and LNCaP (+24% [14%; 34%]; p < 0.001) but not PC-3. NKCA per NK cell decreased during exercise and increased 1-h post exercise compared to baseline in K562, LNCap, and PC-3 cell lines. Baseline IL-6 correlated with lymphocyte, monocyte and T cell concentration pre-exercise and inversely correlated with the fold-change of mobilized lymphocytes and CD8 T cells during exercise. Furthermore, baseline IL-6 and TNF-α inversely correlated with NKCA against PC-3 cells during exercise. Conclusions: Acute exercise mobilized cytotoxic immune cells and improved NKCA in patients with PCa whereas low-grade inflammation might impair the response. Whether the observed improvements impact long-term outcomes warrant further investigation. Clinical trial number: NCT03675529.
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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.
Subject(s)
Prostatic Hyperplasia , Prostatic Neoplasms , Transurethral Resection of Prostate , Aged , Humans , Male , Prostate/pathology , Prostate/surgery , Prostate-Specific Antigen , Prostatic Hyperplasia/pathology , Prostatic Hyperplasia/surgery , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Transurethral Resection of Prostate/adverse effects , Transurethral Resection of Prostate/methodsABSTRACT
Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design setting and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.