MRI-guided active surveillance strategy Patient risk stratification: Diagnostic, prognostic and monitoring
before making definite clinical recommendations. Assessment of mutation status may aid in decisions when balancing AS over immediate active curative treatment. Although, the prevalence of such mutations is very low in low risk PCa AS cohorts, and genetic testing and counselling of all men on surveillance seem very circumstantial and costly. Thus, until larger scale studies with long-term follow-up become available, AS may still be considered a feasible option for well-informed men with low risk PCa if they are carefully monitored at specialised clinics, preferably using MRI-guided surveillance and biopsies with shorter surveillance intervals. Conclusion The advantages of an MRI-guided AS strategy is its high sensitivity and negative predictive value for aggressive cancer, which in turn, confirms a patients eligibility for AS. It also provides detailed images of the prostate to detect any changes in tumour conspicuity such as shape, size, and location, during the monitoring phase. At present, abandoning protocol-based confirmatory biopsies in all men with stable MRI-findings cannot be recommended in routine practice, but emerging data suggest that if the MRI is performed accordingly with high image quality in expert-centres, surveillance-biopsies may be avoided if PSA-kinetics and/or PSA-density and clinical impression (DRE) is concordant. Several tools for standardised MRI reporting at diagnosis (PI-RADS), MRI quality control assurance (PI-QUAL) and MRI criteria for radiological progression during AS (PRECISE) are now available, which further encourages the use of MRI as an additional biomarker both at diagnoses to confirm eligibility for AS, and during follow-up in an MRI-guided AS management strategy. However, MRI findings should always be used in conjunction with familiar/genetic risk and clinical parameters for individualised patient-tailored AS-risk management. References 1. Drost F-JH, Osses DF, Nieboer D, et al: Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst. Rev. 2019. DOI: 10.1002/14651858.cd012663.pub2. 2. Sathianathen NJ, Omer A, Harriss E, et al: Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis. Eur. Urol. 2020; 78: 402-414 3. Schoots IG, Petrides N, Giganti F, et al: Magnetic resonance imaging in active surveillance of prostate cancer: A systematic review. Eur. Urol. 2015; 67: 627–636. 4. Bokhorst LP, Valdagni R, Rannikko A, et al: A Decade of Active Surveillance in the PRIAS Study: An Update and Evaluation of the Criteria Used to Recommend a Switch to Active Treatment. Eur. Urol. 2016; 70: 954–960. 5. Klotz L, Pond G, Loblaw A, et al: Randomized Study of Systematic Biopsy Versus Magnetic Resonance Imaging and Targeted and Systematic Biopsy in Men on Active Surveillance (ASIST): 2-year Postbiopsy Follow-up. Eur. Urol. 2020; 77. 6. Moore CM, Giganti F, Albertsen P, et al: Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer: The PRECISE Recommendations—A Report of a European School of Oncology Task Force. Eur. Urol. 2017; 71: 648–655. 7. Giganti F, Stabile A, Stavrinides V, et al: Natural history of prostate cancer on active surveillance: stratification by MRI using the PRECISE recommendations in a UK cohort. Eur. Radiol. 2021; 31. 8. Rajwa P, Pradere B, Quhal F, et al: Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer Progression During Active Surveillance: A Systematic Review and Meta-analysis. Eur. Urol. 2021; 80. 9. Perera M, Jibara G, Tin AL, et al: Outcomes of Grade Group 2 and 3 Prostate Cancer on Initial Versus Confirmatory Biopsy: Implications for Active Surveillance. Eur. Urol. Focus 2022. DOI: 10.1016/j.euf.2022.12.008. 10. Remmers S, Helleman J, Nieboer D, et al: Active Surveillance for Men Younger than 60 Years or with Intermediate-risk Localized Prostate Cancer. Descriptive Analyses of Clinical Practice in the Movember GAP3 Initiative. Eur. Urol. Open Sci. 2022; 41: 126–133. 11. Carter HB, Helfand B, Mamawala M, et al: Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur. Urol. 2019; 75: 743–749. Monday, 13 March 13:35 - 13:45 Thematic Session: How to assess men with familial prostate cancer Yellow Area, eURO Auditorium 2
Dr. Lars Boesen Dept. Of Urology, Herlev and Gentofte Hospital (DK)
lars.ploug.boesen@ regionh.dk
Active surveillance (AS) for early-stage prostate cancer (PCa) should be offered to men with low- or favourable intermediate-risk cancer, who are expected to have slow-growing and non-aggressive disease. AS traditionally involves close monitoring through regular PSA measurements, digital rectal examinations (DRE) and protocol-based biopsies. Active curative treatment can be initiated if the cancer shows signs of progression. Disease progression is defined clinically by rising PSA and/ or DRE-upstaging, or pathologically by the Gleason score/grade group (GG) upgrading or tumour- volume upscaling at biopsy. However, PSA, DRE and systematic biopsies contribute to poor risk assessment with high misclassification rates at diagnosis. This results in high ‘AS-failures’ over time, due to clinical progression, histological reclassification, or patient intolerance to stringent AS protocols that often include multiple repeat biopsy sessions. AS is designed to retain oncological safety while avoiding side effects of active treatment, but there is a risk of missing significant tumours at diagnosis and/or during surveillance. The optimal AS selection criteria and monitoring strategies are currently not agreed on across different institutions and centres. More precise tools are needed to help identify which patients have an indolent disease and can safely be monitored with AS, and which patients may require more aggressive treatment. There is a need for improved patient risk stratification using diagnostic, prognostic/predictive, and monitoring biomarkers. Growing scientific evidence supports the use of MRI as a biomarker in AS to meet this demand (Fig. 1). Prostate MRI as a biomarker in AS The use of prostate MRI in PCa management has shown several advantages over standard systematic biopsies for significant PCa detection, localisation, and staging [1]. Because MRI provides detailed images of the prostate gland, allowing for the precise location and size of suspicious lesions to be identified with high sensitivity, it can be used as a diagnostic biomarker for guiding MRI-targeted biopsies for improving detection of significant disease. Conversely, several studies have shown that MRI has a high negative predictive value >90% for ruling out significant GG ≥2 PCa, avoiding the need for invasive biopsies [2]. In men considered eligible for AS, MRI improved detection of GG ≥2 PCa at initial assessment and identified men with more aggressive disease potentially qualifying for active treatment [3]. The MRI-improved detection of higher-grade cancers at inclusion match well with the up to 30% protocol- based discontinuation of AS due to upgrading within the first years of AS enrolment. This is probably caused by undergrading and misclassification at inclusion [4]. Equally, a normal MRI can rule out significant disease with a high negative predictive value confirming AS eligibility. The use of an MRI-first diagnostic pathway in biopsy-naïve men with suspicion of PCa has been shown to reduce detection of men with GG 1 PCa by up to 50%, slightly increase detection of men with higher-grade cancer (GG ≥2) potentially needing active treatment, and improve tumour-grade determination compared with radical prostatectomy specimen. This could potentially reduce the overall number of men needing AS because fewer men are diagnosed with GG1 PCa initially, while less men with unfavourable disease would be enrolled in AS. Furthermore, a normal MRI could confirm AS eligibility in men with ‘grey-zone’ PCa risk-features such as multiple positive biopsy cores, PSA between 10-20 ng/mL and/or low volume GG2 disease. Several MRI features such as the visibility of the lesions, high PI-RADS scores, and low ADC-values on diffusion-weighted imaging have all been associated with adverse pathology and unfavourable outcomes. Men on AS with visible
Figure 1: Prostate MRI as a biomarker in active surveillance.
PI-RADS 4-5 lesions are significantly more likely to progress to active treatment, and the absence of a focal lesion has a very good PCa specific survival of 15+ years. Thus, MRI appearance on multiparametric sequences could be used as a prognostic biomarker to better distinguish between aggressive and non-aggressive PCa, where especially MRI-visibility seems one of the strongest predictors for adverse outcomes. Furthermore, the Assist trial [5] showed that an MRI performed before confirmatory biopsy in AS resulted in 50% fewer AS failures and less grade progression compared with systematic biopsies over 2-years of follow-up. Serial MRI-monitoring Optimally, repeated MRIs during the monitoring of AS could non-invasively track changes in disease aggression providing information on stability or progression. An MRI guided AS strategy where only progression on MRI (such as growth of lesions or appearance of new lesions) trigger either direct reclassification or repeat biopsies appears attractive for both the physician and the patient (Fig. 2). For this purpose, specific recommendations for using MRI for serial monitoring of men in AS have been published as the PRECISE criteria [6]. Like the PI-RADS score, which is designed to objectively assess the likelihood of significant cancer from a score of 1-5 in a detection-setting, PRECISE grades change on MRI from a score of 1-5 on the likelihood of tumour aggression in men on AS. The clinical purpose is to identify men who progress in a timely manner, promoting repeat biopsy and/or treatment, and to avoid standardised protocol-based biopsies in men with regression or stable MRI findings. Findings from the PRECISE task force showed that only 5% of men on AS with stability in PRECISE score (1-3) experienced clinical progression over a median follow-up of ~75 months [7]. Thus, regression or stability on MRI may be used non-invasively to avoid protocol-based AS-biopsies, which could reduce the intensity and burden of surveillance for both the individual and the healthcare system. Although the PRECISE score seems to be reproduceable and robust across centres and interobservers, it has not yet been validated in larger cohorts. There is no consensus regarding the threshold for tumour growth or change in conspicuity to define radiological progression. Furthermore, the timing of serial MRIs during follow-up has not been specified. The pooled sensitivity and specificity for serial MRIs to detect progression have been reported to be ~60%
and ~75% in a recent meta-analysis [8]. Although there is heterogeneity between included studies, the negative and positive predictive values range from 81-88% and 37-50%, Thus MRI is better at ruling-out than ruling-in progression and still cannot be recommended as a stand-alone test for prompting therapy or replacing surveillance biopsies. However, despite differences in AS-protocols and MRI reporting across institutions, emerging data show that men with both stable MRIs and PSA- kinetics should avoid routine surveillance biopsies. Interestingly, it seems that men with GG 1 PCa upgraded during monitoring on confirmatory biopsy tend to have less aggressive disease outcomes compared with men initially diagnosed with the same (up)-graded cancer [9]. More studies are needed to confirm whether it is safe to apply a more conservative treatment-strategy for men upgraded during surveillance. AS for everybody with low-risk PCa? While AS should be offered for most men with low-risk PCa, opinions differ on whether it is safe to include young men (≤60 yrs.) and men with a familiar history of PCa and/or known germline mutations. Various studies reporting age-ranges show that many clinical practice AS programs apply a lower age threshold for AS-recommendations. However, emerging data from a world-wide GAP3-database show that young men on AS may have a lower or at least an equal risk of disease progression and potentially even a lower risk of upgrading at radical prostatectomy compared with older men (>60 years) [10]. These results indicate that young men should not automatically be excluded from initial AS. A familiar history of PCa does not seem to predispose to progression on AS, but germline mutations have been found to be associated with more aggressive disease and prognosis. It has been reported that BRCA-mutation carriers with low-risk PCa in AS are associated with more aggressive cancer and potentially a higher risk of grade- reclassification compared with non-carriers [11]. However, most current data often include only small numbers of mutation carriers, short follow-up or pathology solely based on systematic biopsy with its inherent limitations.
Larger studies using contemporary MRI-guided surveillance are needed to confirm these findings
Figure 2: Tumour-suspicious lesion on MRI (a) at diagnosis in 2019 (white arrow) where targeted biopsies showed GG1 PCa with 6 mm maximum cancer core length (MCCL). The patient went on AS and confirmatory MRI after one year (b) showed revealed tumour-growth (larger lesion) with a more homogenous appearance and lower ADC-value. Repeated targeted biopsy showed upgrading to GG 2 with MCCL 9 mm.
European Urology Today
8
February/March 2023
Powered by FlippingBook