(UroToday.com) At the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU) practical applications of novel imaging and genomic approaches in the management of clinically localized prostate cancer session, Dr. Peter Carroll discussed active surveillance for prostate cancer as it stands in 2021. Dr. Carroll notes that active surveillance is a preferred form of treatment for many men, but should be seen, as well, as a response to the over-detection and over-treatment of prostate cancer brought about by widespread and repeated PSA screening. The uptake of active surveillance by the urology community helped pave the way for an upgraded assessment by The U.S. Preventive Services Task Force (USPSTF) on the early detection of prostate cancer.
At UCSF, Dr. Carroll has developed a robust active surveillance cohort, including 2,148 enrolled patients through 2020. Among these patients, the median year of diagnosis was 2010 (IQR 2006-2013), mean age of diagnosis was 62 years (SD 7.6), median PSA at diagnosis was 5.6 ng/mL (IQR 4.2-7.5), median duration of follow-up was 76 months (IQR 46-116), and 87% were Gleason Group 1 (13% Gleason Group >=2). The upgrade-free survival was 40% at 7 years for men with Gleason Group 1 disease and 54% for men with Gleason Group >=2. The treatment-free survival was 60% at 7 years for men with Gleason Group 1 disease and 50% for men with Gleason Group >=2. Dr. Carroll then discussed the outcome after delayed radical prostatectomy, noting that in their UCSF series the median time to radical prostatectomy was 27 months (IQR 15.5-46.5). Men with grade group 2 with two or more high-grade cores at diagnosis was associated with an increased risk of recurrence compared to grade group 1 disease (HR 3.29, 95% CI 1.49-7.26).1 Among 1,450 men meeting inclusion criteria, over a median follow-up of 77 months (IQR 49-114), the 7-year metastasis-free survival rate was 99%.2 Additionally, the 7-year prostate cancer specific survival was greater than 99%. Metastases developed in 15 men at a median of 62 months (IQR 29-104), of which 69% were confined to lymph nodes. Men with Gleason Group 2 disease had a lower metastasis-free survival rate compared to those with Gleason Group 1 disease. On multivariable analysis Gleason Group 2, PSA velocity and PI-RADS 4-5 lesions on mpMRI were associated with a higher risk of metastases.
The impact of new technology, according to Dr. Carroll, is seen in the new genomic tests that are available. The 2019 NCCN guidelines suggest that those with low risk disease (T1-T2a, grade group 1, and PSA <10 ng/mL) should consider a genomic test if their life expectancy is >10 years, whereas those with intermediate risk disease (T2b-T2c, or grade group 2-3, or PSA 10-20 ng/mL) should consider a genomic test if the disease is favorable/intermediate-risk and if their life expectancy is >10 years. Clinically available genomic tests include Decipher, GPS, and Prolaris – all of these assays have prognostic value, but not are predictive biomarkers.
The Oncotype DX GPS assay is a quantitative 17-gene RT-PCR assay on manually microdissected tumor tissue from needle biopsy. Genes and biological pathways are predictive of multiple endpoints, with an emphasis on clinical recurrence. This assay is optimized for very small tissue input with six 5 micron sections of a single needle biopsy block from as little as 1 mm of tumor length. Dr. Carroll’s group showed that GPS score was associated with upgrading on active surveillance in that a 5-unit increase in GPS score was associated with Gleason ≥3+4 disease (HR 1.27, 95% CI 1.18-1.38).3 Furthermore, a 5-unit increase in GPS score was associated with adverse pathology (HR 1.16, 95% CI 1.06-1.26) and PSA relapse (HR 1.10, 95% CI 1.00-1.21) among those undergoing delayed radical prostatectomy.4
Dr. Carroll notes that there are some concern with genomic classifiers, including:
- The issue with tumor heterogeneity
- Do all patients benefit? It is unlikely that very low risk patients benefit from a genomic assay, but which low and favorable intermediate risk patients do?
- Are they cost-effective?
- What are the long-term outcomes?
Other biomarkers highlighted by Dr. Carroll include PSA density, which in their UCSF cohort showed that a PSA density of 0.10-0.15 was associated with biopsy progression (vs <0.1: HR 2.06, 95% CI 1.30-3.29), as was a PSA density of >0.15 (vs. <0.1: HR 2.83, 95% CI 1.73-4.62).5 Additionally, multiparametric MRI PI-RADS scoring has been associated with upgrading on active surveillance in the UCSF cohort. Men with a PI-RADS 4 lesions (vs PI-RADS 1-2) have a 2.62x higher risk of upgrading (HR 2.62, 95% CI 1.45-4.76), as do men with PI-RADS 5 lesions (vs PI-RADS 1-2: HR 4.38, 95% CI 2.36-8.16). Dr. Carroll notes that with regards to serial mpMRIs, changes are common, but really only PI-RADS 4-5 lesions and any increase in PI-RADS score predicts disease progression.
There are several controversies in active surveillance, including utilization in younger men. Data from Dr. Carroll’s group at UCSF suggest that active surveillance in young men is safe.6 The 3- and 5-year biopsy-based Gleason score upgrade-free rates were 73% and 55%, respectively, for men ≤ 60 years old compared with 64% and 48%, respectively, for men older than 60 years (p < .01):
The impact of Gleason Grade is also an important controversy with regards to active surveillance eligibility. Dr. Carroll notes that cancer risk is best assessed with multivariable instruments and not as a single variable. Additionally, Gleason 3+4 disease alone may only add a little risk (1 point in CAPRA), and volume (rather than grade alone) is a predictor of adverse pathology. It is also important to note that the subtype of Gleason pattern 4 disease is important (ie. expansile, poorly formed, or fused). Those with cribriform histology and stromal reaction are associated with higher genomic scores and the risk of extracapsular extension/recurrence compared to glomerulation and no stromal reaction.
Special situations when assessing candidacy for active surveillance include patients with germline mutations (BRCA2 mutations) and African American men. Dr. Carroll states that we should be cautious offering active surveillance to men with BRCA2 mutation, whereas African American men make up a small percentage of men in active surveillance cohorts and race may be a poor surrogate of social construct or biology.
Dr. Carroll notes that we need to make active surveillance less burdensome for patients and decrease intensity in low risk patients. In data from their cohort,7 biopsy reclassification was associated with PSA density >=0.15 (HR 3.37, 95% CI 1.83-6.21), percentage biopsy cores positive (HR 1.27, 95% CI 1.05-1.54) and high genomic score (HR 2.81, 95% CI 1.21-6.52) at first surveillance biopsy and also at 1 to 3 years, after adjustment. PSA density >= 0.15 (HR 2.36, 95% CI 1.56-3.56) and PSA kinetics (HR 2.19, 95% CI 1.43-3.34) were also associated with reclassification at 3 to 5 years. Thus, this information should be used tailor active surveillance appropriately based on risk of reclassification.
Dr. Carroll provided the following diagram for assisting in navigating candidacy for active surveillance:
To conclude his lecture on active surveillance for prostate cancer, Dr. Carroll provided the following take-home messages:
- Active surveillance is the preferred form of treatment for men with very low, low-risk and selected patients with favorable intermediate-risk disease
- New technology (MRI and genomics) appears to make it safer
- Use of active surveillance remains highly variable, particularly in the United States
Presented by: Peter Carroll, MD, Urologic Cancer Surgeon Practicing at UCSF Health, San Francisco, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021
References:
1. Balakrishnan AS, Cowan JE, Cooperberg MR, et al. Evaluating the safety of active surveillance: Outcomes of deferred radical prostatectomy after an initial period of surveillance. J Urol2019 Sep;202(3):506-510.
2. Maggi M, Cowan JE, Fasulo V, et al. The long-term risks of metastases in men on active surveillance for early stage prostate cancer. J Urol. 2020 Dec;204(6):1222-1228.
3. Kornberg Z, Cowan JE, Westphalen AC, et al. Genomic Prostate Score, PI-RADS Version 2 and Progression in Men with Prostate Cancer on Active Surveillance. J Urol2019 Feb;201(2):300-307.
4. Kornberg Z, Cooperberg MR, Cowan JE, et al. A 17-Gene Genomic Prostate Score as a Predictor of Adverse Pathology in Men on Active Surveillance. J Urol2019 Oct;202(4):702-709.
5. Welty CJ, Cowan JE, Nguyen H, et al. Extended Followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer. J Urol2015 Mar;193(3):807-811.
6. Leapman MS, Cowan JE, Nguyen HG, et al. Active surveillance in Younger Men with Prostate Cancer. J Clin Oncol2017 Jun 10;35(17):1898-1904.
7. Lonergan PE, Washington 3rdSL, Cowan JE, et al. Risk factors for biopsy reclassification over time in men on active surveillance for early stage prostate cancer. J Urol 2020 Dec;204(6):1216-1221.