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Objectives: To quantify the ability of two new comorbidity indices to adjust for confounding, by benchmarking a target trial emulation against the randomized controlled trial (RCT) result., Study Design and Setting: Observational study including 18,316 men from Prostate Cancer data Base Sweden 5.0, diagnosed with prostate cancer between 2008 and 2019 and treated with primary radical prostatectomy (RP, n = 14,379) or radiotherapy (RT, n = 3,937). The effect on adjusted risk of death from any cause after adjustment for comorbidity by use of two new comorbidity indices, the multidimensional diagnosis-based comorbidity index and the drug comorbidity index, were compared to adjustment for the Charlson comorbidity index (CCI)., Results: Risk of death was higher after RT than RP (hazard ratio [HR] = 1.94; 95% confidence interval [CI]: 1.70-2.21). The difference decreased when adjusting for age, cancer characteristics, and CCI (HR = 1.32, 95% CI: 1.06-1.66). Adjustment for the two new comorbidity indices further attenuated the difference (HR 1.14, 95% CI 0.91-1.44). Emulation of a hypothetical pragmatic trial where also older men with any type of baseline comorbidity were included, largely confirmed these results (HR 1.10; 95% CI 0.95-1.26)., Conclusion: Adjustment for comorbidity using two new indices provided comparable risk of death from any cause in line with results of a RCT. Similar results were seen in a broader study population, more representative of clinical practice., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences., Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy., Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023., Exposure: Nonmetastatic PCa., Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling., Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa., Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Objective: To examine associations between objective signs of progression (triggers) and transition from active surveillance (AS) to radical treatment for prostate cancer (PC)., Patients and Methods: This case-control study included men with low- or favourable intermediate-risk PC in the region of Halland, with data from The National Prostate Cancer Register (NPCR), Sweden, starting AS between 2008 and 2020. Cases were men who transitioned to radical treatment. For each case, 10 controls who remained in AS were selected without further matching. Triggers for transition to treatment were histopathological progression, magnetic resonance imaging (MRI) progression and increases in prostate-specific antigen (PSA) levels. We compared the probabilities for triggers between cases and controls, in 2008-2014 and 2015-2020, using logistic regression., Results: Amongst 846 men, we identified 98 cases in 2008-2014 and 172 cases in 2015-2020. Histopathological progression was associated with transition, most strongly in the later period (2008-2014: odds ratios [OR] 6.88, 95% confidence interval [CI] 3.69-12.80; and 2015-2020: OR 75.29, 95% CI 39.60-143.17). MRI progression was associated with transition in 2015-2020 (OR 6.38, 95% CI 2.70-15.06), whereas an increase in PSA was weakly associated with transition in the early period. The absence of triggers was associated with no transition (2008-2014: OR 0.24, 95% CI 0.15-0.40, and 2015-2020: OR 0.09, 95% CI 0.06-0.14). The probability of no trigger was 27% in cases 2015-2020., Conclusion: The increase in association between histopathological trigger and transition to treatment indicates increased quality of AS. Still, amongst men treated from 2015 to 2020, 27% transitioned without any trigger.

Assessment of comorbidity is crucial for confounding adjustment and prediction of mortality in register-based studies, but the commonly used Charlson comorbidity index is not sufficiently predictive. We aimed to develop a multidimensional diagnosis-based comorbidity index (MDCI) that captures comorbidity better than the Charlson Comorbidity index. The index was developed based on 286,688 men free of prostate cancer randomly selected from the Swedish general population, and validated in 54,539 men without and 68,357 men with prostate cancer. All ICD-10 codes from inpatient and outpatient discharges during 10 years prior to the index date were used to define variables indicating frequency of code occurrence, recency, and total duration of related hospital admissions. Penalized Cox regression was used to predict 10-year all-cause mortality. The MDCI predicted risk of death better than the Charlson comorbidity index, with a c-index of 0.756 (95% confidence interval [CI] = 0.751, 0.762) vs 0.688 (95% CI = 0.683, 0.693) in the validation cohort of men without prostate cancer. Men in the lowest vs highest MDCI quartile had distinctively different survival in the validation cohort of men with prostate cancer, with an overall hazard ratio [HR] of 5.08 (95% CI = 4.90, 5.26). This was also consistent within strata of age and Charlson comorbidity index, e.g. HR = 5.90 (95% CI = 4.65, 7.50) in men younger than 60 years with CCI 0. These results indicate that comorbidity assessment in register-based studies can be improved by use of all ICD-10 codes and taking related frequency, recency, and duration of hospital admissions into account., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Westerberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Randomised controlled trials have demonstrated prolonged survival with new upfront treatments in addition to standard androgen deprivation therapy (ADT) in men with de novo metastatic castration-sensitive prostate cancer. We describe patient characteristics, time trends and regional differences in uptake of these new treatment strategies in clinical practice., Material and Methods: This descriptive study consisted of men registered in the National Prostate Cancer Register of Sweden from 1 January 2018 to 31 March 2022 with de novo metastatic castration-sensitive prostate cancer defined by the presence of metastases on imaging at the time of diagnosis. Life expectancy was calculated based on age, Charlson Comorbidity Index and a Drug Comorbidity Index., Results: Within 6 months from diagnosis, 57% (1,677/2,959) of men with de novo metastatic castration-sensitive prostate cancer and more than 3 years of life expectancy had received docetaxel, abiraterone, enzalutamide, apalutamide and/or radiotherapy. Over time, there was a 2-fold increase in uptake of any added treatment, mainly driven by a 6-fold increase in use of abiraterone, enzalutamide or apalutamide, with little change in use of other treatments., Conclusions: Slightly more than half of men diagnosed with de novo metastatic castration-sensitive prostate cancer and a life expectancy of at least 3 years received additions to standard ADT as recommended by national guidelines in 2019-2022 in Sweden. There was a 2-fold increase in use of these treatments during the study period; however, efforts to further increase adherence to guidelines are warranted.

Importance: Recently, life-prolonging treatments for patients with advanced prostate cancer have been introduced in clinical practice., Objective: To investigate if the introduction of doublet therapy is associated with changes in survival on a population-basis., Design, Setting, and Participants: This nationwide population-based cohort study used data from the Prostate Cancer data Base Sweden from 2008 to 2020. Men registered with de novo metastatic castration-sensitive prostate cancer (mCSPC) were included., Exposure: The proportion of men with mCSPC who received doublet therapy, ie, androgen deprivation therapy plus androgen receptor pathway inhibitor drugs or chemotherapy was assessed., Main Outcomes and Measures: Standardized overall survival, taking age, comorbidity, and cancer characteristics into consideration, was estimated by use of a parametric survival model., Results: A total of 11 382 men were included in this study (median [IQR] age, 74.0 [68-81] years). There was a shift toward less advanced prostate cancer during the study period with a decrease in median (IQR) prostate-specific antigen at diagnosis in men with mCSPC from 145 (39-571) ng/mL to 107 (27-426) ng/mL. Upfront treatment with doublet therapy in these men simultaneously increased from 1% (7 of 991) in 2016 to 44% (402 of 922) in 2020. The adjusted 5-year overall survival increased from 26% (95% CI, 25%-28%) from 2008 to 2012 to 35% (95% CI, 31%-40%) from 2017 to 2020. During the first 5 years after diagnosis, there was an increase in mean survival of 6 months, from 2.7 (95% CI, 2.6-2.8) years from 2008 to 2012 to 3.2 (95% CI, 3.1-3.1) years from 2017 to 2020., Conclusions and Relevance: In parallel with improvements in treatment of advanced prostate cancer, a clinically meaningful increase in mean survival was observed in men with de novo mCSPC in Sweden between 2008 and 2020 in this study.

Objectives: To study how handling missing data on M stage in a clinical cancer register affects estimates of incidence of metastatic prostate cancer., Study Design and Setting: Estimates of age-standardized incidence of metastatic prostate cancer were obtained by the use of data in a population-based clinical cancer register in Sweden and using four methods for imputation of missing M stage. Adjusted survival was used to compare men with known and imputed M stage., Results: The proportion of men with missing M stage was high (66%) and varied according to the risk group and over calendar time. The estimated incidence of metastatic disease varied depending on imputation method, with all methods indicating a decreasing incidence over time. A combination of deterministic imputation (DI) and multiple imputation (MI) produced adjusted survival curves for men with imputed M stage that best resembled the survival for men with known M stage., Conclusions: Plausible estimates of incidence of metastatic prostate cancer in clinical cancer registers can be obtained by the use of a combination of DI of missing M stage and MI., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Androgen deprivation therapy (ADT) has been hypothesized to protect against COVID-19, but previous observational studies of men with prostate cancer on ADT have been inconsistent regarding mortality risk from coronavirus disease 2019 (COVID-19). Using data from the Prostate Cancer data Base Sweden (PCBaSe), we identified a cohort of 114 547 men with prevalent prostate cancer on the start of follow-up in February 2020, and followed them until 16 December 2020 to evaluate the association between ADT and time to test positive for COVID-19. Among men testing positive for COVID-19, we used regression analyses to estimate the association between ADT and risk of COVID-19-related hospital admission/death from any cause within 30 days of the positive test. In total, 1695 men with prostate cancer tested positive for COVID-19. In crude analyses, exposure to ADT was associated with a 3-fold increased risk of both testing positive for COVID-19 infection and subsequent hospital admission/death. Adjustment for age, comorbidity and prostate cancer risk category substantially attenuated the associations: HR 1.3 (95% CI: 1.1-1.5) for testing positive for COVID-19, and OR 1.4 (95% CI: 1.0-1.9) for risk of subsequent hospital admission/death. In conclusion, although these results suggest increased risks of a positive COVID-19 test, and COVID-19-related hospital admission/death in men on ADT, these findings are likely explained by confounding by old age, cancer-associated morbidity and other comorbidities being more prevalent in men on ADT, rather than a direct effect of the therapy., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Androgens facilitate entrance of the severe acute respiratory syndrome coronavirus 2 into respiratory epithelial cells, and male sex is associated with a higher risk of death from corona virus disease (COVID-19). Androgen deprivation therapy (ADT) could possibly improve COVID-19 outcomes., Methods: In a case-control study nested in the Prostate Cancer data Base Sweden (PCBaSe) RAPID 2019, we evaluated the association between ADT and COVID-19 as registered cause of death in men with prostate cancer. Each case was matched to 50 controls by region. We used conditional logistic regression to adjust for confounders and also evaluated potential impact of residual confounding., Results: We identified 474 men who died from COVID-19 in March-December 2020. In crude analyses, ADT exposure was associated with an increased risk of COVID-19 death (odds ratio [OR] 5.05, 95% CI: 4.18-6.10); however, the OR was substantially attenuated after adjustment for age, comorbidity, prostate cancer characteristics at diagnosis, recent healthcare use, and indicators of advanced cancer (adjusted OR 1.25, 95% CI: 0.95-1.65). If adjustment has accounted for at least 85% of confounding, then the true effect could be no more than a 5% reduction of the odds for COVID-19 death., Conclusions: The increased mortality from COVID-19 in men with prostate cancer treated with ADT was mainly related to high age, comorbidity, and more advanced prostate cancer. There was no evidence to support the hypothesis that ADT is associated with improved COVID-19 outcomes.

Introduction: For clinical decision-making, an estimate of remaining lifetime is needed to assess benefit against harm of a treatment during the remaining lifespan. Here, we describe how to predict life expectancy based on age, Charlson Comorbidity Index (CCI) and a Drug Comorbidity Index (DCI), whilst also considering potential future changes in CCI and DCI using population-based data on Swedish men., Methods: Simulations based on annual updates of vital status, CCI and DCI were used to estimate life expectancy at population level. The probabilities of these transitions were determined from generalised linear models using prostate cancer-free comparison men in PCBaSe Sweden. A simulation was performed for each combination of age, CCI, and DCI. Survival curves were created and compared to observed survival. Life expectancy was then calculated as the area under the simulated survival curve., Results: There was good agreement between observed and simulated survival curves for most ages and comorbidities, except for younger men. With increasing age and comorbidity, there was a decrease in life expectancy. Cross-validation based on six regions in Sweden also showed that simulated and observed survival was similar., Conclusion: Our proposed method provides an alternative statistical approach to estimate life expectancy at population level based on age and comorbidity assessed by routinely collected information on diagnoses and filled prescriptions available in nationwide health care registers., (© 2022. The Author(s).)

Background: Men have a higher risk of death from COVID-19 than women and androgens facilitate entrance of the SARS-CoV-2 virus into respiratory epithelial cells. Thus, androgen deprivation therapy may reduce infection rates and improve outcomes for COVID-19. In the spring of 2020, Sweden was highly affected by COVID-19. The aim was to estimate the impact of androgen deprivation therapy on mortality from COVID-19 in men with prevalent prostate cancer by comparing all-cause mortality in the spring of 2020 to that in previous years., Patients and Methods: Using the Prostate Cancer data Base Sweden all men with prostate cancer on March 1 each year in 2015-2020 were followed until June 30 the same year. Exposure to androgen deprivation therapy was ascertained from filled prescriptions for bicalutamide monotherapy, gonadotropin-releasing hormone agonists (GnRH), or bilateral orchidectomy., Results: A total of 9,822 men died in March-June in the years 2015-2020, of whom 5,034 men were on androgen deprivation therapy. There was an excess mortality in 2020 vs previous years in all men. The crude relative mortality rate ratio for 2020 vs 2015-2019 was 0.93 (95% confidence interval (CI) 0.83 to 1.04) in men on GnRH, and 0.90 (95% CI 0.78 to 1.05) in men on bicalutamide monotherapy. After multivariable adjustment these ratios were attenuated to 1.00 (95% CI 0.89 to 1.12) and 0.97 (95% CI 0.84 to 1.12), respectively. When restricting the analysis to the regions with the highest incidence of COVID-19 or to the time period between 2 April to 10 June when mortality in 2020 was increased >30% compared to previous years, the results were similar to the main analysis., Conclusions: In this large national population-based cohort of men with prevalent prostate cancer, there was no clear evidence in support for an effect of androgen deprivation therapy on COVID-19 mortality., Competing Interests: Johan Styrke is a co-PI of the Covidenza trial of Enzalutmide for Covid 19: ClinicalTrials.gov Identifier: NCT04475601. Johan Styrke report no financial interest in the present study or in the Covidenza trial. Stacy Loeb reports equity in Gilead. Region Uppsala has, on behalf of NPCR, made agreements on subscriptions for quarterly reports quarterly reports from Patient-overview Prostate Cancer with Astellas, Janssen, and Bayer, as well as research projects with Astellas, Bayer, and Janssen. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All remaining authors have declared no conflicts of interest.

Background: The ability to account for comorbidity when estimating survival in a population diagnosed with cancer could be improved by using a drug comorbidity index based on filled drug prescriptions., Methods: We created a drug comorbidity index from age-stratified univariable associations between filled drug prescriptions and time to death in 326,450 control males randomly selected from the general population to men with prostate cancer. We also evaluated the index in 272,214 control females randomly selected from the general population to women with breast cancer., Results: The new drug comorbidity index predicted survival better than the Charlson Comorbidity Index (CCI) and a previously published prescription index during 11 years of follow-up. The concordance (C)-index for the new index was 0.73 in male and 0.76 in the female population, as compared with a C-index of 0.67 in men and 0.69 in women for the CCI. In men of age 75-84 years with CCI = 0, the median survival time was 7.1 years (95% confidence interval [CI] = 7.0, 7.3) in the highest index quartile. Comparing the highest to the lowest drug comorbidity index quartile resulted in a hazard ratio (HR) of 2.2 among men (95% CI = 2.1, 2.3) and 2.4 among women (95% CI = 2.3, 2.6)., Conclusions: A new drug comorbidity index based on filled drug prescriptions improved prediction of survival beyond age and the CCI alone. The index will allow a more accurate baseline estimation of expected survival for comparing treatment outcomes and evaluating treatment guidelines in populations of people with cancer., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Understanding the association between patients' history of prescribed medications and mortality rate could optimize characterization of baseline risk when the Charlson Comorbidity Index is insufficient., Methods: Using a Swedish cohort of men selected randomly as controls to men with prostate cancer diagnosed 2007-2013, we estimated the association between medications prescribed during the previous year and mortality rates, using Cox regression stratified for age., Results: Among the 326,450 older men with median age of 69 years included in this study, 73% were categorized as free of comorbidity according to the Charlson Comorbidity Index; however, 84% had received at least one prescription during the year preceding the follow-up. This was associated with a 60% overall increase in mortality rate (hazard ratio [HR] = 1.60, 95% confidence interval [CI] 1.56 to 1.64). Some drugs that were unexpectedly associated with mortality included locally acting antacids (HR = 4.7, 95% CI 4.4 to 5.1), propulsives (HR = 4.7, 95% CI 4.4 to 5.0), vitamin A and D (HR = 4.6, 95% CI 4.3 to 4.9), and loop diuretics, for example furosemide (HR = 3.7; 95% CI 3.6 to 3.8). Thiazide diuretics, however, were only weakly associated with a mortality risk (HR = 1.5; 95% CI 1.4 to 1.5). Surprisingly, only weak associations with mortality were seen for major cardiovascular drug classes., Conclusions: A majority of older men had a history of prescribed medications and many drug classes were associated with mortality rate, including drug classes not directly indicated for a specific comorbidity represented in commonly used comorbidity measures. Prescription history can improve baseline risk assessment but some associations might be context-sensitive., Competing Interests: The authors have declared that no competing interests exist.