Timo Soeterik

30 CHAPTER 2 ABSTRACT Background: In daily practice, a wider range of patients with prostate cancer (PCa) are selected for active surveillance (AS) compared to those in AS trials, including higher- risk patients. However, less is known about the outcomes for off-protocol selected PCa patients who opt for AS. The aim of this study is to compare AS outcomes of higher-risk patients and very low-risk patients in a large cohort of patients diagnosed with PCa. Methods: Patients diagnosed with PCa between 2008 and 2015, with clinical stage ≥T1c and treated with AS at six large teaching hospitals were included for analysis. AS constituted of regular prostate-specific antigen (PSA) testing (every 3-6 mo), combined with a confirmatory biopsy 1 yr after diagnosis and every 3 yr thereafter. Using the inclusion criteria of the Prostate Cancer Research International Active Surveillance (PRIAS) study, outcomes of PRIAS-eligible patients (clinical stage T1c-T2, Gleason sum score ≤6, ≤2 positive biopsy cores, PSA ≤10 ng/mL and PSA density ˂ 0.2 ng/ml/ml) were compared with outcomes of PRIAS-ineligible patients. Rates of unfavourable outcomes following deferred surgery, biochemical recurrence, and metastasis were established using univariate and multivariate Cox regression analysis. Results: Of the 1000 patients included and treated with AS, almost half of the patients (49%) had higher-risk disease characteristics than the PRIAS inclusion criteria. PRIAS- ineligible patients discontinued AS, due to tumour progression, significantly earlier than PRIAS-eligible patients (HR 1.74, 95% confidence interval [CI] 1.44 - 2.11). PRIAS- ineligible patients also had a higher risk of positive surgical margins (odds ratio [OR] 2.15, 95% CI 1.11 - 4.17) and unfavourable pathological findings (OR 3.20, 95% CI 1.61 - 6.35) after deferred radical prostatectomy. PSA density ≥0.2 ng/ml/ml was the most important individual predictor and, in addition to a higher risk of tumour progression and unfavourable surgical outcomes, was associated with a significant higher risk of biochemical progression following deferred radical prostatectomy (OR 3.26, 95% CI 1.23 - 8.64). In the overall population, PSA density ≥0.2 ng/ml/ml was associated with a higher risk of metastasis (HR 2.71, 95% CI 1.23 – 5.96). Conclusions: In this cohort, approximately half of the patients did not meet the inclusion criteria of the PRIAS study. These patients had a twofold higher risk of opting out of AS due to tumour progression and a threefold higher risk of unfavourable outcomes following deferred prostatectomy. PSA density is an important individual predictor of unfavourable outcomes and should be taken into account when selecting patients for AS.