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Objectives

To investigate the impact of age and life expectancy on treatment decisions and its consequences for outcomes among men with intermediate and high-risk prostate cancer (PCa).

Materials and methods

We studied men in Prostate Cancer data Base Sweden (PCBaSe) diagnosed between 2008 and 2022 with intermediate-risk or high-risk localized or locally advanced PCa and life expectancy between 2.5 and 15 years in the absence of PCa. Estimates of life expectancy were based on age and two comorbidity indices.

Results

A total of 32 196 men were included in the analyses. Of these, 17 419 (54%) had a life expectancy between 10 and 15 years, of whom 11 147 (64%) received primary radical treatment. Age had a stronger influence than life expectancy on the selection of treatment. Around 10% of deaths within 10 years of diagnosis could potentially have been avoided if men with >10 years life expectancy, regardless of age, had received radical treatment, based on assumptions of high treatment efficacy (30% reduction in all-cause mortality) and high uptake of treatment (90%).

Conclusion

A substantial proportion of healthy older men with intermediate and high-risk PCa did not undergo radical treatment. According to our model and assumptions, 10% of deaths within 10 years of diagnosis in these men could potentially have been avoided if they had received radical treatment.

Active surveillance (AS) for prostate cancer was introduced to address overtreatment resulting from prostate-specific antigen (PSA) testing. Despite advancements such as Magnetic Resonance Imaging (MRI) and targeted biopsies, PSA remains crucial in prostate cancer diagnostics, leading to ongoing challenges of overdiagnosis and overtreatment. This thesis aimed to investigate different aspects of AS and follow-up of early prostate cancer and provide new insights to reduce overtreatment and enhance surveillance and follow-up. In Paper I, the rationale and methodology of a randomized controlled trial, the Prostate Cancer Active Surveillance Trigger trial/Scandinavian Prostate Cancer Group study no. 17 (PCASTt/SPCG17), were outlined. This trial's objective is to evaluate the safety of an AS protocol based on MRI and standardized triggers for repeat biopsies and transition to radical treatment. Patient recruitment is anticipated to conclude in 2024. Paper II investigated the risks of biochemical recurrence, metastatic disease, and prostate cancer-related death in patients following radical prostatectomy. The analysis was conditioned on time after radical prostatectomy without biochemical recurrence. For patients with favourable histopathology in prostatectomy specimens and no biochemical recurrence five years post-prostatectomy, the probability of developing metastatic disease or dying from prostate cancer within 20 years after surgery was very low. This suggests shorter follow-up for selected patients. Paper III compared outcomes of AS for men from different healthcare regions in Sweden with varying traditions of AS. Regions with lower uptake in AS demonstrated a higher probability of transitioning from AS to radical treatment, but no difference in AS failure. The results suggest overtreatment in regions with low uptake in AS. Paper IV explored the associations between potential triggers for transitioning from AS to radical treatment and the transition to treatment. We analysed how this association changed with the introduction of prostate MRI. We found an increasingly strong association between triggers, particularly histopathological progression, and transition. However, most treated men had not experienced histopathological progression. The introduction of MRI did not contribute much to the change. In conclusion, this thesis outlines an ongoing study on defined triggers for transitioning from AS to radical treatment, suggests shorter follow-up after radical prostatectomy for selected patients, reveals overtreatment in regions with low uptake in AS, and shows an increasing use of histopathological progression as a trigger for transition to radical treatment.

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, start-ing 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 pros-tate-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 trig-gers 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.

Background: Regional differences in active surveillance (AS) uptake for prostate cancer (PC) illustrate an inequality in treatment strategies.

Objective: To examine the association between regional differences in AS uptake and transition to radical treatment, start of androgen deprivation therapy (ADT), watchful waiting, or death.

Design, setting, and participants: A Swedish population-based cohort study was con-ducted including men in the National Prostate Cancer Register in Sweden with low -risk or favorable intermediate-risk PC, starting AS from January 1, 2007 and continuing till December 31, 2019.

Intervention: Regional tradition of low, intermediate, or high proportions of immediate radical treatment. Outcomes measurements and statistical analysis:Probabilities of transition from AS to radical treatment, start of ADT, watchful waiting, or death from other causes were assessed.

Results and limitations: We included 13 679 men. The median age was 66 yr, median PSA 5.1 ng/ml, and median follow-up 5.7 yr. Men from regions with a high AS uptake had a lower probability of transition to radical treatment (36%) than men from regions with a low AS uptake (40%; absolute difference 4.1%; 95% confidence interval [CI] 1.0-7.2), but not a higher probability of AS failure defined as the start of ADT (absolute difference 0.4%; 95% CI -0.7 to 1.4). There were no statistically significant differences in the probability of transition to watchful waiting or death from other causes. Limitations include uncertainty in the estimation of remaining lifetime and transition to watchful waiting.

Conclusions:A regional tradition of a high AS uptake is associated with a lower probability of transition to radical treatment, but not with AS failure. A low AS uptake suggests overtreatment.

Objective: Although surveillance after radical prostatectomy routinely includes repeated prostate specific antigen (PSA)-testing for many years, biochemical recurrence often occurs without further clinical progression. We therefore hypothesised that follow-up can be shortened for many patients without increasing the risk of prostate cancer death. We investigated the long-term probabilities of PSA recurrence, metastases and prostate cancer death in patients without biochemical recurrence five and 10 years after radical prostatectomy.

Design: Prospective cohort study. Stratification by Gleason score (<= 3+4=7or >= 4+3=7), pathological tumour stage (pT2 or >= pT3) and negative or positive surgical margins.

Setting: Between 1989 and 1998, 14 urological centres in Scandinavia randomised patients to the Scandinavian Prostate Cancer Group study number 4 (SPCG-4) trial.ParticipationAll 306 patients from the SPCG-4 trial who underwent radical prostatectomy within 1year from inclusion were eligible. Four patients were excluded due to surgery-related death (n=1) or salvage radiotherapy or hormonal treatment within 6weeks from surgery (n=3).

Primary outcome measures: Cumulative incidences and absolute differences in metastatic disease and prostate cancer death.

Results: We analysed 302 patients with complete follow-up during a median of 24 years. Median preoperative PSA was 9.8ng/mL and median age was 65 years. For patients without biochemical recurrence 5 years after radical prostatectomy the 20-year probability of biochemical recurrence was 25% among men with Gleason score <= 3+4=7and 57% among men with Gleason score >= 4+3=7; the probabilities for metastases were 0.8% and 17%; and for prostate cancer death 0.8% and 12%, respectively. The long-term probabilities were higher for pT >= 3versus pT2 and for positive versus negative surgical margins. Limitations include small size of the cohort.

Conclusion: Many patients with favourable histopathology without biochemical recurrence 5years after radical prostatectomy could stop follow-up earlier than 10 years after radical prostatectomy.

Introduction Overtreatment of localised prostate cancer is substantial despite increased use of active surveillance. No randomised trials help define how to monitor patients or when to initiate treatment with curative intent. Methods and analysis A randomised, multicentre, intervention trial designed to evaluate the safety of an MRI-based active surveillance protocol, with standardised triggers for repeated biopsies and radical treatment. The aim is to reduce overtreatment of prostate cancer. 2000 men will be randomly allocated to either surveillance according to current practice or to standardised triggers at centres in Sweden, Norway, Finland and the UK. Men diagnosed in the past 12 months with prostate cancer, <= T2a, prostate-specific antigen (PSA) <15ng/mL, PSA density <less than or equal to>0.2ng/mL/cc, any International Society of Urological Pathology (ISUP) grade 1 are eligible. Men with ISUP grade 2 in <30% of cores on systematic biopsy and <10mm cancer in one core on systematic or targeted biopsy are also eligible. Men diagnosed on systematic biopsy should have an MRI and targeted biopsies against Prostate Imaging and Reporting Data System V.2 3-5 lesions before inclusion. Identical follow-up in the two study arms: biannual PSA testing, yearly clinical examination and MRI every second year. In the experimental arm, standardised triggers based on MRI and PSA density elicit repeated biopsies. MRI and histopathological progression trigger radical treatment. Primary outcome measure is progression-free survival. Secondary outcome measures are cumulative incidence of metastatic disease, treatments with curative intent, pT3-4 at radical prostatectomy, switch to watchful waiting, prostate cancer mortality and quality of life. Inclusion started in October 2016 and in October 2018; 275 patients have been enrolled. Ethics and dissemination Ethical approval was obtained in each participating country. Results for the primary and secondary outcome measures will be submitted for publication in peer-reviewed journals. Trial registration number NCT02914873.