Improving benefit-harm ratio of prostate cancer screening and active surveillance:By developing individual risk-based approaches using long-term data

The findings presented in this thesis contribute to the ongoing goal of reducing the morbidity and mortality associated with prostate cancer and underscore the value of long-term data in this challenge. Drawing on decades of follow-up from large-scale population-based trials and international surveillance cohorts, this work provides additional evidence that supports a transition from one-size-fits-all approaches to individualized, risk-based strategies. For screening, long-term outcomes from trials such as ERSPC demonstrate that PSA-based screening can substantially reduce prostate cancer-specific mortality and metastatic disease, but only when implemented in a structured, repeated, and age-appropriate manner. Furthermore, the fact that currently screening is performed in an opportunistic, unorganized manner, associated with a lack of benefit but increased overdiagnosis and overtreatment, calls for the implementation of organized, stepwise screening pathways that integrate multivariable risk calculators, biomarkers, MRI, and age to better identify men most likely to benefit. Such strategies can minimize unnecessary testing, reduce overdiagnosis, and optimize resource allocation wich are critical considerations for implementing cost-effective, population-based screening programs. For active surveillance, long-term data from cohorts such as PRIAS confirm its safety as a standard management option for men with low-risk prostate cancer, with exceptionally low rates of metastasis and prostate cancer-specific mortality. However, overtreatment still occurs, often due to unnecessary transitions to definitive therapy driven by anxiety, rigid protocols, or grade shift caused by evolving diagnostic techniques. This thesis supports two key strategies to reduce overtreatment: expanding eligibility criteria to include select men with MRI-detected favorable-risk Grade Group 2 cancers, and implementing dynamic, personalized follow-up schedules based on risk prediction models. These strategies not only reduce the burden of surveillance but also improve adherence and patient quality of life. Ultimately, by identifying individuals more likely to benefit or be at risk of harm from specific interventions, prostate cancer screening and active surveillance can reduce harm while maintaining the benefits of these interventions.