Active surveillance in low- and intermediate-risk prostate cancer

Based on the GLOBOCAN statistics 2023, prostate cancer is the first and most commonly diagnosed cancer and the second cause of cancer death in men, with estimated 288 300 new cancer cases and 34 700 deaths.1 Interestingly, the incidence rate of prostate cancer decreased around 40% from 2007 to 2014. This reflects the recommendation of the United States Preventive Services Task Force (USPSTF) to avoid prostate-specific antigen (PSA) testing screening for ≥75 years old men in 2008 and for all men in 2012.1 In the 1990s, PSA testing for screening purpose was widely adopted. In a few years, considering how common prostate cancer is, many issues related to overdiagnosis and overtreatment of early detected localized prostate cancer raised in scientific community.2 Several studies showed that patients with early moderately and highly differentiated prostate cancer who did not undergo local treatment have a low death rate. Considering that curative treatment options such as surgery or radiotherapy are at risk of significant side effects, definition of deferred treatment approach for those patients started to become a medical need. Two different conservative approaches with different goals and inclusion criteria are considered with the aim to reduce overtreatment: active surveillance (AS) and watchful waiting (WW), as shown in Table 1. In this opinion, we will focus on AS.3,4Table 1: Active surveillance and watchful waiting (adapted from European Association of Urology guidelines 20234)AS is an observational strategy that differs from WW, in terms of aims and methods of execution. The goal is to actively monitor the evolution of prostate cancer disease and to intervene with curative treatments in case of progression. The purpose of AS remains curative. The criteria of choice are based on patient's estimated life expectancy, comorbidities, and disease characteristics. For a more accurate evaluation of the health status and comorbidities, a geriatric assessment is recommended.3,4 This strategy cannot be applied to all patients. In low-risk prostate cancer patients, it is quite well defined; for intermediate-risk patients, selection is more debated. Unfortunately, all protocols available for AS are not considering biological features of prostate cancer; and in the future, genetic features and molecular biology should be integrated into decision-making discussions.5 ACTIVE SURVEILLANCE IN LOW-RISK PROSTATE CANCER PATIENTS Patients with very low-risk prostate cancer are defined as patients with tumors carrying all the following characteristics: clinical T1c stage; grade group 1 (GG1); PSA level 10 years estimated life expectancy and no comorbidities impacting on life expectancy, AS, as an alternative to immediate treatment such as radical prostatectomy or radiotherapy, due to different studies showing benefits in terms of mortality, cancer-specific mortality and tolerability, is recommended by the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines.3,4 There is only one randomized clinical trial (Prostate Testing for Cancer and Treatment PROTECT) comparing AS to curative treatments available in this population. Recommendations are mainly based on formal systemic review of different AS protocols. Those protocols can have different eligibility criteria, heterogeneity of variables defining "low-risk prostate cancer" and different follow-up strategies.6 In patients eligible for AS, a confirmatory testing like a rebiopsy or multiparametric magnetic resonance imaging (mpMRI) to evaluate PSA density, if not performed at the beginning, is strongly suggested within the first 6 months to 12 months. A confirmation is needed to avoid underestimation of tumor grade or volume of initial biopsy. If an mpMRI has been performed before diagnostic biopsy, a confirmatory testing is not mandatory.3,4 A recent pathology consensus suggested excluding AS for low-risk prostate cancer patients with predominant ductal carcinoma, cribriform histology, sarcomatoid or small cell carcinoma, extraprostatic extension, lymphovascular infiltration, or perineural invasion in needle biopsy.7 ACTIVE SURVEILLANCE IN INTERMEDIATE-RISK PROSTATE CANCER PATIENTS AS could be considered as an option in selected intermediate-risk prostate cancer patients and a life expectancy >10 years. Good candidates are patients included in a favorable subgroup defined as follow: one of the intermediate-risk factors (without high or very high group features; clinical T2b–T2c or PSA level 10–20 ng ml−1) but GG1 or GG2, <50% positive biopsy cores, and low PSA density. Patients with GG3 disease should be excluded from AS protocols.3,4 ACTIVE SURVEILLANCE FOLLOW-UP AND RECLASSIFICATION CRITERIA In intermediate-risk prostate cancer patients, AS follow-up should be applied. NCCN and EAU guidelines recommend digital rectal examination (DRE) every 12 months, PSA testing every 6 months, and repeat prostate biopsy and mpMRI every 12 months.3,4 If during follow-up, life expectancy of patients became <10 years, or new comorbidities impacting general health status are diagnosed, switch to WW approach should be considered.3,4 The major criteria influencing a change in management from AS to curative treatment are worsening of tumor grade on repeat biopsy, increase in tumor volume, a rise in PSA density, and patient's anxiety. Data showed that during AS follow-up, around 10% of patients developed with anxiety.8 Management should not be modified only based on rising PSA level. In patients with PSA doubling time shorter than 3 years, a new mpMRI should be performed; and in case of modification, a rebiopsy is highly recommended.8 CONCLUSIONS AS is a well-recognized treatment option in very low, low, and selected intermediate-risk prostate cancer patients. About 50%–68% of eligible patients may delay active treatment, and possible treatment-related side effects, without impact on cure rate.9,10 Adherence to protocols is critical to follow the aim of this strategy. More efforts should be done to include genetic features and molecular biology as risk factors. AUTHOR CONTRIBUTIONS LC wrote the first draft of the manuscript. LC, GR, and FC commented and revised the manuscript. All authors read and approved the final manuscript. COMPETING INTERESTS All authors declare no competing interests.