Bruinsma SM, Nieboer D, Roobol MJ et al: Risk-based selection for active surveillance: results of the Movember Foundation’s Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative. J Urol 2021; 206: 62.

Active surveillance (AS) has become the preferred alternative treatment option to active treatment for men diagnosed with low-risk prostate cancer (PCa). AS reduces the risk of overtreatment of patients and associated side effects and thereby potentially increases quality of life for the patients. AS involves followup and offering curative treatment for men who show signs of reclassification or disease progression. AS has been shown to be a safe treatment option in the intermediate timeframe (5–16 years) with low rates of progression to metastatic disease or death from PCa. The majority of men undergoing AS are able to delay or even avoid treatment for their PCa, benefitting from increased quality of life compared to men who chose immediate curative treatment.¹

Although AS has emerged as the primary management option for men with low-risk disease, there are 2 primary concerns involving AS. First, the PCa may be misclassified at diagnosis such that a patient with aggressive cancer is incorrectly assumed to have low grade cancer (often referred to as reclassification). Second, low-risk PCa may evolve to high grade cancer during AS (often referred to as true progression). The aim of AS is to detect disease progression before the window of cure is lost.

To reduce the number of men switching to active treatment due to disease reclassification, the identification of patients for whom AS is appropriate is critical. However, selection of PCa patients for AS has traditionally proven to be challenging. This is reflected in the diversity of existing guidelines on the selection of patients for management with AS.² Risk-based selection of patients may avoid the inclusion of men who should initially opt for active treatment to increase their chance of cure.

A better understanding of the predictors of disease reclassification for PCa patients is needed to improve the selection of ideal candidates for AS. This requires validation in large and mature cohorts of men undergoing AS. This study therefore aims to identify predictors of short- and long-term disease reclassification to support risk-based selection of patients suitable for AS.

We conducted an individual patient data meta-analysis using data from multiple established AS cohorts within the Movember Foundations’ Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium (gap3.movemberprojects.com).³ GAP3 covers the largest centralized PCa AS database to date. The project’s primary goal is to create a global consensus on the selection and monitoring of men with low-risk PCa. Ultimately, worldwide uniform guidelines will be developed. Between 2014 and 2016, a global database was created by combining patient data from 28 AS cohorts worldwide (from Australia, Europe, North America and Asia). The database currently comprises data of over 21,000 patients and contains information on demographic and clinical characteristics at the time of PCa diagnosis and clinical followup, including information on discontinuation of AS and potential following treatments.

We included patients who received a biopsy at 1 and 4 years after start of AS, and disease reclassification was defined as any increase in Gleason Grade Group at followup biopsy. In total 5,570 men were available with at least 1 biopsy at 1 year and at 4 years followup 1,515 men were included. These timepoints were chosen as the majority of the protocols of the included cohorts had a planned biopsy at 1 and 4 years.

Among the 5,570 men evaluated at 1 year after starting AS, median age was 65 years and median prostate specific antigen (PSA) at diagnosis was 5.3 ng/mL. In total 815 (15%) reclassifications were observed at year 1. Among the 1,515 men evaluated at 4 years after starting AS the median age was 64 years and median PSA at diagnosis was 5.2 ng/mL. Among the 1,515 men evaluated at 4 years, 205 (15%) men were reclassified. The pooled 1-year and 4-year reclassification rates were 13% and 14%, respectively, and a substantial amount of heterogeneity was observed between the different cohorts (range 0–31% and 0–40%, respectively).

On multivariable analysis we found that older age at start of AS (OR 1.6 per 10 years), a smaller prostate volume (OR 0.54 per doubling), a higher T-stage (OR 1.45 for 2 versus 1), a higher number of biopsy cores with PCa (OR 1.67 for 2 versus 1), and a higher PSA at diagnosis (OR 1.22 per doubling) were all associated with a higher risk of disease reclassification at 1 year (see table). For disease reclassification at 4 years we found that higher age (OR 1.45 per decade), higher number of biopsy cores with PCa (OR 1.95 for 2 versus 1) and higher PSA density (OR 1.87 per doubling) were associated with a higher risk of reclassification.

Several predictors of disease reclassification were identified; however, the discriminative ability of these risk factors were limited and we observed an AUC of 0.68 when predicting 1-year disease reclassification and an AUC of 0.61 for predicting 4-year disease reclassification.

The purpose of this study was to identify predictors available at the time of diagnosis for disease reclassification at 1 or 4 year(s) to support risk-based selection of patients suitable for AS. Although AS of men with localized prostate cancer has become an increasingly popular management option, there is still concern about the risk of misclassification at initial diagnosis or reclassification during AS. Current guidelines might be improved by considering prostate volume for selecting patients eligible for AS. However, the identified predictors show limited discriminative ability for disease reclassification or progression. New biomarkers and imaging parameters are needed to improve the selection of true low-risk patients and patients for whom immediate treatment is warranted. The Movember GAP3 initiative is an ideal platform to initiate further multicentric studies in this area.