Late-Stage Prostate Cancer and Prostate Cancer Mortality : A Population-Based Study

Postponed access: the file will be accessible after 2020-05-29AIMS OF THE THESIS The aim of this thesis was to provide a better understanding of the final stages of PCa, metastatic castration resistant PCa and PCa death. We further aimed to address the consequences of possible undertreatment of elderly PCa patients. PATIENTS AND METHODS Paper I: The study was a retrospective analysis of a consecutive sample of patients with mCRPC seen at the urological unit of a local hospital from 2000 to 2005, their mCRPC diagnosis based on rising prostate-specific antigen (PSA) during androgen depletion treatment (ADT). Several easily accessible parameters were identified and their prognostic value was tested. Paper II: The study included all 764 patients from Vestfold County who had PCa and who died in 2009-2014. The true cause of death of all patients was evaluated based on patient medical records. Paper III: Retrospective analysis of 117 patient records (PCa death, Vestfold County, M0 at diagnosis, no radical treatment). Decision rationales at diagnosis with regard to treatment were identified. Local and systemic complications during the further course of the disease were registered. National data from the Cancer Registry of Norway (CRN, N=1874, ≥75 years at diagnosis, localized high-risk/ locally advanced PCa, WHO 0, diagnosed 2009-2017) were obtained and PCa specific survival was analyzed in patients who had received local treatment versus patients with no local treatment. RESULTS Paper I: Median overall survival for the entire cohort of mCRPC patients was 12.3 months (range 0.2-108 months), while 3-year survival was 16.9% (95% confidence interval 0.11-0.24). Two patients were alive at the end of follow-up. PSA doubling time following the onset of mCRPC, hemoglobin and alkaline phosphatase levels at the onset of mCRPC and PSA nadir during ADT prior to the onset of mCRPC were strong predictors of overall survival. Paper II: Over-reporting of PCa deaths in patients whose death certificate indicated that they died of PCa was 33% while under-reporting in the two groups who according to their death certificates died of other causes was 19% and 5%, respectively. The correlation between registered and observed causes of death was 0.81 (95% confidence interval 0.78-0.83). Misattribution of prostate cancer deaths increased significantly with patient age and decreasing Gleason score. Paper III: For the cohort of Vestfold patients age was the reason for choosing conservative treatment in 37% of patients (N=43), despite good health and functional status. Ninety percent of patients developed local complications attributable to PCa growth. National CRN data suggested a significant survival benefit for patients aged 75-79 years who had received local treatment. 5-year cause-specific survival of 98.9 percent (CI 96.7-99.7) compared to 90.8 percent in patients who had received no local treatment (CI 86.9-93.6). CONCLUSIONS Late stage PCa (mCRPC) is a heterogeneous condition with diverse survival. Its natural course can be defined by easily accessible parameters. PCa death reported on death certificates is unreliable particularly among the elderly and it is unsuitable as a stand-alone, population-based outcome measure in Norway. There are indications of undertreatment at diagnosis both in patients who later develop late-stage PCa and in patients who die of PCa and decisions with regard to radical treatment for patients with NMPCa are unduly influenced by patient age. The majority of elderly patients with high risk or locally advanced NMPCa who are not treated with local therapy suffer considerable local complication

DNA ploidy and PTEN as biomarkers for predicting aggressive disease in prostate cancer patients under active surveillance

Background: Current risk stratification tools for prostate cancer patients under active surveillance (AS) may inadequately identify those needing treatment. We investigated DNA ploidy and PTEN as potential biomarkers to predict aggressive disease in AS patients. Methods: We assessed DNA ploidy by image cytometry and PTEN protein expression by immunohistochemistry in 3197 tumour-containing tissue blocks from 558 patients followed in AS at a Norwegian local hospital. The primary endpoint was treatment, with treatment failure (biochemical recurrence or initiation of salvage therapy) as the secondary endpoint. Results: The combined DNA ploidy and PTEN (DPP) status at diagnosis was associated with treatment-free survival in univariable- and multivariable analysis, with a HR for DPP-aberrant vs. DPP-normal tumours of 2.12 (p < 0.0001) and 1.94 (p < 0.0001), respectively. Integration of DNA ploidy and PTEN status with the Cancer of the Prostate Risk Assessment (CAPRA) score improved risk stratification (c-index difference = 0.025; p = 0.0033). Among the treated patients, those with DPP-aberrant tumours exhibited a significantly higher likelihood of treatment failure (HR 2.01; p = 0.027). Conclusions: DNA ploidy and PTEN could serve as additional biomarkers to identify AS patients at increased risk of developing aggressive disease, enabling earlier intervention for nearly 50% of the patients that will eventually receive treatment with current protocol

Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy : study protocol

Introduction Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting. This study aims to test statins' efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT. Methods and analysis In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial. Ethics and dissemination This study is approved by the Regional ethics committees of the Pirkanrnaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.Peer reviewe

Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol

Introduction Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins’ efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT.Methods and analysis In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial.Ethics and dissemination This study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.</p

Late-Stage Prostate Cancer and Prostate Cancer Mortality : A Population-Based Study

AIMS OF THE THESIS The aim of this thesis was to provide a better understanding of the final stages of PCa, metastatic castration resistant PCa and PCa death. We further aimed to address the consequences of possible undertreatment of elderly PCa patients. PATIENTS AND METHODS Paper I: The study was a retrospective analysis of a consecutive sample of patients with mCRPC seen at the urological unit of a local hospital from 2000 to 2005, their mCRPC diagnosis based on rising prostate-specific antigen (PSA) during androgen depletion treatment (ADT). Several easily accessible parameters were identified and their prognostic value was tested. Paper II: The study included all 764 patients from Vestfold County who had PCa and who died in 2009-2014. The true cause of death of all patients was evaluated based on patient medical records. Paper III: Retrospective analysis of 117 patient records (PCa death, Vestfold County, M0 at diagnosis, no radical treatment). Decision rationales at diagnosis with regard to treatment were identified. Local and systemic complications during the further course of the disease were registered. National data from the Cancer Registry of Norway (CRN, N=1874, ≥75 years at diagnosis, localized high-risk/ locally advanced PCa, WHO 0, diagnosed 2009-2017) were obtained and PCa specific survival was analyzed in patients who had received local treatment versus patients with no local treatment. RESULTS Paper I: Median overall survival for the entire cohort of mCRPC patients was 12.3 months (range 0.2-108 months), while 3-year survival was 16.9% (95% confidence interval 0.11-0.24). Two patients were alive at the end of follow-up. PSA doubling time following the onset of mCRPC, hemoglobin and alkaline phosphatase levels at the onset of mCRPC and PSA nadir during ADT prior to the onset of mCRPC were strong predictors of overall survival. Paper II: Over-reporting of PCa deaths in patients whose death certificate indicated that they died of PCa was 33% while under-reporting in the two groups who according to their death certificates died of other causes was 19% and 5%, respectively. The correlation between registered and observed causes of death was 0.81 (95% confidence interval 0.78-0.83). Misattribution of prostate cancer deaths increased significantly with patient age and decreasing Gleason score. Paper III: For the cohort of Vestfold patients age was the reason for choosing conservative treatment in 37% of patients (N=43), despite good health and functional status. Ninety percent of patients developed local complications attributable to PCa growth. National CRN data suggested a significant survival benefit for patients aged 75-79 years who had received local treatment. 5-year cause-specific survival of 98.9 percent (CI 96.7-99.7) compared to 90.8 percent in patients who had received no local treatment (CI 86.9-93.6). CONCLUSIONS Late stage PCa (mCRPC) is a heterogeneous condition with diverse survival. Its natural course can be defined by easily accessible parameters. PCa death reported on death certificates is unreliable particularly among the elderly and it is unsuitable as a stand-alone, population-based outcome measure in Norway. There are indications of undertreatment at diagnosis both in patients who later develop late-stage PCa and in patients who die of PCa and decisions with regard to radical treatment for patients with NMPCa are unduly influenced by patient age. The majority of elderly patients with high risk or locally advanced NMPCa who are not treated with local therapy suffer considerable local complication

Non-metastatic prostate cancer: rationale for conservative treatment and impact on disease-related morbidity and mortality in the elderly

Purpose: To determine the rationale for not offering local treatment to prostate cancer patients with non-metastatic disease at diagnosis who later died of prostate cancer and to document local and systemic complications caused by disease progression. Material and Methods: In this population-based, retrospective study we reviewed the medical records of all patients who died of prostate cancer in 2009–2014 in Vestfold County (Vestfold Mortality Study), who were non-metastatic at diagnosis and who had received no local treatment to the prostate (n = 117). Results: A review of patient records demonstrated that the chronological age of 75 years or older was the main rationale for not offering local treatment to the prostate (37%, n = 43). No consideration was given to the functional status and patient health. These elderly patients stood for almost one-fifth of the total PC mortality in Vestfold County. In addition to dying from PC, 86% of patients developed local complications attributable to PC progression. Observation of strict limits for local treatment with regard to tumor characteristics contributed further to the underuse of local treatment. Conclusions: Our study demonstrated systematic undertreatment of elderly patients with aggressive, non-metastatic PC with regard to local treatment based on chronological age alone. The patients in this study died of prostate cancer and the majority experienced significant morbidity caused by local tumor growth

High Norwegian prostate cancer mortality: evidence of over-reporting

<p><b>Objective:</b> This study aimed to determine the level of misattribution of prostate cancer deaths in Norway based on the county of Vestfold in the years 2009–2014.</p> <p><b>Materials and methods:</b> The study included 328 patients registered as dead from prostate cancer (PCD; part I of death certificate), 126 patients with prostate cancer as other significant condition at death (OCD; part II of death certificate) and 310 patients who died with a diagnosis of prostate cancer not registered on the death certificate (PC-DCneg) in Vestfold County in 2009–2014. The complete cohort with patients’ names and dates of birth was provided by the Norwegian Institute of Public Health and the Norwegian Cancer Registry. The true cause of death of all patients was evaluated based on patient journals.</p> <p><b>Results:</b> Over-reporting of prostate cancer deaths in the PCD group was 33% while under-reporting in the OCD and PC-DCneg groups was 19% and 5%, respectively. The correlation between registered and observed causes of death was 0.81 (95% confidence interval 0.78–0.83). Misattribution of prostate cancer deaths increased significantly with patient age and decreasing Gleason score.</p> <p><b>Conclusions:</b> Prostate cancer mortality statistics in Norway are relatively accurate for patients aged <75 years at death. However, overall accuracy of cause of death assignment is significantly reduced by misattribution among older patients (> 75 years), who represent the large majority of prostate cancer deaths. Over-reporting of prostate cancer deaths among elderly people may not be an exclusively Norwegian phenomenon and may affect prostate cancer mortality statistics in other countries.</p

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)