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).

Time trends in systemic treatment for patients with metastatic prostate cancer: a national cohort study.

BACKGROUND: Several new systemic treatments for primary metastatic prostate cancer patients (mPCa) were introduced in the last decade for both hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC). However, little is known about the introduction of these treatments in clinical practice. In this national cohort study, we described users and non-users of systemic treatment beyond androgen deprivation therapy (ADT). We also explored whether there was a shift in treatment patterns after the introduction of Docetaxel for mHSPC patients. MATERIALS AND METHODS: All patients registered in the Cancer Registry of Norway with mPCa diagnosed in 2010-18 were included. Data on systemic therapy (Docetaxel, Abiraterone, Enzalutamide, Cabazitaxel, and Radium-223) were provided from the Norwegian Prescription Database, the Norwegian Patient Registry, and the Norwegian Control and Payment of Health Reimbursement Database. Descriptive results about patient and disease characteristics were presented using frequencies and proportions, means and standard deviations, or medians and interquartile ranges. RESULTS: Of the 2770 patients included in this study, 48% received systemic treatment beyond ADT. The proportion of patients receiving systemic treatment increased during the study period. Systemic treatment users were younger, in better general condition, and had more aggressive tumors than non-users. A treatment shift was observed after 2015, with 48% of patients receiving systemic treatment (mainly Docetaxel) in the mHSPC phase compared to 4% of those diagnosed 2010-14. No significant treatment differences were observed across health regions. CONCLUSIONS: An increasing proportion of patients received systemic treatment during the period 2010-18. However, less than 50% of patients in our study received systemic treatment. In accordance with updated guidelines, Docetaxel was introduced after 2015 with an increasing proportion of patients receiving systemic treatment as mHSPC. Further studies should address the disease course and treatment given to patients who do not receive systemic treatment.

Survival trends for patients with primary metastatic prostate cancer before and after the introduction of new antitumor drugs.

BACKGROUND: During the past two decades, new antitumor drugs (Abiraterone, Enzalutamide, Radium-223, Cabazitaxel, and Docetaxel) have been introduced for treatment of prostate cancer with distant metastases (mPCa). Each drug have demonstrated a survival gain in studies, but little is known about the impact in a general population of mPCa patients. In this study we assessed survival before and after introduction of the new drugs for Norwegian mPCa patients. METHODS: Survival was assessed in 5542 patients with primary mPCa. The patients were diagnosed between 2004 and 2018, identified in the Norwegian Cancer Registry. We also analyzed a subgroup of 2738 patients possibly eligible for treatment with new drugs (age <80 years, WHO performance status ≤2 and not dead within 3 months from diagnosis). We estimated overall (OS) and cause-specific survival (CSS) across three diagnostic time periods reflecting to the drugs' introduction in Norway: Before (2004-2009), "in between" (2010-2014) and after the introduction (2015-2018). We used Kaplan-Meier survival analysis and multivariable Cox regression. RESULTS: Median OS increased from 2.3 years in 2004-2009 to 3.3 years in 2015-2018. 3-year OS improved from 41% in 2004-2009 to 51% in 2015-2018. An earlier diagnostic period, a more advanced T stage, higher ISUP grade group, lower WHO status and higher PSA levels were associated with a lower CSS. Similar results was found for the subgroup. CONCLUSIONS: Median OS of mPCa has increased by one year since 2004 for mPCa patients in Norway. Survival improvement persisted after adjustment for recognized prognostic factors and may be related to the introduction of new drugs in Norway.

Late Adverse Health Outcomes and Quality of Life after curative radiotherapy + long-term ADT in Prostate Cancer Survivors: Comparison with men from the general population.

Background: Few studies have described the impact of urinary, bowel and sexual Adverse Health Outcomes (AHOs) on Quality of Life (QoL) in Prostate Cancer Survivors living for more than 5 years after curative radiotherapy ("long-term PCaSs"), and compared the findings with those in men from general population. Here we assess self-reported AHOs in such PCaSs focusing on the association between problem experience and QoL. The findings are compared to corresponding symptoms in age-similar men from the general population without a PCa diagnosis (Norms). Methods: Nine years (mean) after curative radiotherapy 1231 PCaSs and 3156 Norms completed the EPIC-26 questionnaire and the EORTC QLQ-C30 instrument. Domain Summary Scores (DSSs) for the urinary, bowel and sexual domains, the percentages of moderate/big dysfunctions and the proportions of overall problems were determined. Inter-cohort differences were interpreted based on cut-off values for published Minimal Clinically Important Differences (MCIDs). Multivariable linear regression models analyzed the associations between QoL and domain-related overall problems. Results: Only the inter-cohort differences regarding bowel and sexual DSSs exceeded the respective MCIDs. Among PCaSs 54% had at least one moderate/big problem (Norms: 30%). In PCaSs and Norms, QoL increased with decreasing urinary and bowel problems, For sexuality this association was weaker in Norms and was almost lacking in PCaSs. Multivariable-adjusted QoL was similar in PCaSs and Norms, with general health being the strongest covariate. Conclusions: During follow-up of long-term PCaSs health professionals should be aware of the survivors' persisting moderate/big urinary, bowel or sexual problems associated with reduced QoL. In particular , alleviation of urinary and bowel problems can increase the men's QoL.

A prospective study of patient reported urinary incontinence among American, Norwegian and Spanish men 1 year after prostatectomy.

OBJECTIVE: To compare pre- and post-radical prostatectomy (RP) responses in the urinary incontinence domain of Expanded Prostate Cancer Index Composite-26 (EPIC-26) in cohorts from the USA, Norway and Spain. METHODS: A prospective study of pre- and 1-year post-treatment responses in American (n=537), Norwegian (n=520) and Spanish (n=111) patients, establishing the prevalence of urinary incontinence defined according to published dichotomization. Thereafter we focused on the response alternatives "occasional dribbling", pad use and problem experience. A multivariate logistic regression analysis (significance level ≤ 0.01) considered risk factors for "not retaining total control". RESULTS: Compared to the European men, the American patients were younger, healthier and more presented with lower risk tumors. Before RP no inter-country differences emerged the prevalence of urinary incontinence (6%). One-year post-treatment urinary incontinence was described by 30% of the American and 41% of the European patients, occasional dribbling being the most frequent type of urinary leakage. In the multivariate analysis the risk of "not retaining total control" increased almost 3-fold in European compared to American patients, with age and co-morbidity being additional independent risk factor. CONCLUSION: After RP patients from Spain and Norway reported more unfavorable outcomes by EPIC-26 than the American patients to most of the urinary incontinence items, the difference between the European and American patients remaining in the multivariate analysis. The most frequent post-RP response alternative "occasional dribbling" needs to be validated with pad weighing as "gold standard".

Psychometric testing of the Norwegian version of the Expanded Prostate Cancer Index Composite 26-item version (EPIC-26).

OBJECTIVES: In patients with prostate cancer, evaluation of quality of care requires the inclusion of patient-reported outcomes measures assessed by validated and reliable instruments. Basic psychometric tests of the Norwegian version of the Expanded Prostate Cancer Index Composite with 26 items (EPIC-26) were performed in this study. MATERIAL AND METHODS: Translation of the original questionnaire (University of California, Los Angeles Prostate Cancer Index Composite), field testing and retranslation were done according to published guidelines. The final EPIC-26 items were subsequently selected from the Norwegian version of the EPIC-50 with slight verbal adjustments to comply with the English version of the EPIC-26. Reliability and validity were tested among 471 patients who, between 2009 and 2010, had been included in a prospective Norwegian multicenter study assessing adverse effects after radical prostatectomy or prostatic radiotherapy, usually combined with (neo)adjuvant hormone treatment. All patients completed the EPIC-26 before treatment and 3 and 12 months afterwards. RESULTS: Internal consistency was documented by Cronbach's alpha coefficients ranging from 0.64 to 0.91 for the five domains/subdomains. Item-to-scale correlation coefficients ranged from 0.20 to 0.88, with the lowest value (0.20) for overall sexual problem. Criterion validity was proven by significant correlations between individual responses to the International Prostate Symptom Score and sum scores of the irritative/obstructive subdomain score of the EPIC-26. Satisfactory sensitivity and responsiveness reflected clinical utility for assessing between-group differences and treatment-related changes. CONCLUSIONS: Based on basic psychometric tests, the Norwegian version of the EPIC-26 showed acceptable reliability and validity for assessment of adverse effects after treatment of non-metastatic prostate cancer.

Erectile Dysfunction and Sexual Problems Two to Three Years After Prostatectomy Among American, Norwegian, and Spanish Patients.

BACKGROUND: The incidence of erectile dysfunction (ED) and sexual problems after radical prostatectomy has differed greatly in reports from different centers and countries; however, few studies have taken baseline factors into account. We compared the incidence of ED and sexual problems 2 to 3 years after radical prostatectomy in American, Norwegian, and Spanish men for whom selected clinically relevant demographic and medical pretreatment variables were available. PATIENTS AND METHODS: From 2003 to 2009, 1077 men (United States, n = 494; Norway, n = 472; and Spain, n = 111) scheduled for prostatectomy responded to an Expanded Prostate Cancer Index Composite questionnaire before treatment and 2 to 3 years after prostatectomy. On multivariate analysis, the odds ratios for ED and sexual problems were calculated, adjusted for the pretreatment variables found significant (P < .01) on univariate analysis. RESULTS: For all patients and for those without ED preoperatively, no statistically significant association was detected between the country of prostatectomy and the likelihood of reporting post-prostatectomy ED or sexual problems despite the significant differences among the 3 countries in the unadjusted analyses. CONCLUSION: Adjusting for important pretreatment variables, no intercountry differences were detected. Thus, a thorough knowledge about the pretreatment medical and demographic factors is essential for valid comparisons of the incidence of postprostatectomy ED and sexual problems among different studies.

Localized prostate cancer in Norway, the United States, and Spain: between-country differences of variables before treatment among patients eligible for curative treatment.

BACKGROUND: In men with PCa, large variations of PROs after RP or high-dose RAD might be related to between-country differences of medical and sociodemographic variables, and differences in PROs before treatment in the sexual and urinary domains. PATIENTS AND METHODS: In 1908 patients with localized PCa from Norway, the United States, or Spain, the relation between medical (prostate-specific antigen, Gleason score, cT-category) and sociodemographic variables (age, education, marital status) before treatment was investigated. Using the Expanded Prostate Cancer Index Composite questionnaire, PROs before treatment within the sexual and urinary domains were also considered. RESULTS: Compared with the European patients, American patients were younger, fewer had comorbid conditions, and more had a high education level. Fifty-three percent of the US men eligible for RP had low-risk tumors compared with 42% and 31% among the Norwegian and the Spanish patients, respectively. Among the Spanish RAD patients, 54% had had low-risk tumors compared with 34% of the American and 21% of the Norwegian men planned for RAD, respectively. Compared with the European patients, significantly fewer US patients reported moderate or severe sexual dysfunction and related problems. In most subgroups, the number of patients with sexual or urinary dysfunction exceeded that of patients with bother related to the reported dysfunction. CONCLUSION: Statistically significant between-country differences were observed in medical and sociodemographic variables, and in PROs before treatment within the sexual and urinary domains. Large differences between reported dysfunction and related problems within the sexual and urinary domains indicate that dysfunction and bother should be reported separately in addition to calculation of summary scores. The documented differences, not at least regarding PROs, might in part explain the large variation of side effects after treatment evident in the medical literature.