2. UroToday Home
  3. Conference Highlights
  4. AUA 2020
  5. AUA 2020 Prostate Cancer

AUA 2020

AUA 2020: Ramon Guiteras Lecture: Active Surveillance for Low and Intermediate Prostate Cancer - the Past or the Future?

(UroToday.com) The 2020 American Urological Association Virtual Annual Meeting’s Roman Guiteras Lecture was provided by Peter Carroll, MD, MPH, from the University of California, San Francisco (UCSF), discussing active surveillance for low and intermediate-risk prostate cancer. Dr. Carroll notes that active surveillance is a response to the over-detection and over-treatment of prostate cancer brought about by widespread and repeated PSA screening, particularly in the 1990s and early 2000s. Its uptake by the urology community helped pave the way for an upgraded assessment by the United States Preventative Services Taskforce (USPSTF) on the early detection of prostate cancer.

The goals of active surveillance are to:

  • Avoid or delay the costs, both functionally and monetarily, of treatment without compromising cancer cure
  • Compliant with screening and treatment guidelines. 
  • Based on the rationale that the initial assessment is reasonably accurate, and monitoring is accurate and identifies sub-clinical progression at a time that initial treatment options are still available and curative. 
At UCSF, Dr. Carroll has developed a robust active surveillance cohort, including 2,113 enrolled patients. Among these patients, the median year of diagnosis was 2010 (range 1990-2019), the mean age of diagnosis was 62.5 years (SD 7.68), median PSA at diagnosis was 5.5 ng/mL (IQR 4.2-7.5), the median duration of follow-up was 73 months (IQR 43-112), and 85% were low-risk disease (15% intermediate risk). The upgrade-free survival was 41% at 7 years, with 689 men upgrade at a median of 25 months (IQR 13-52). Interestingly, there was no difference in a progression based on those that were grade group 1 vs grade group 2 (p=0.22). The treatment-free survival was 59% at 7 years, with 682 men upgraded at a median of 27 months (IQR 15-50).  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 were associated with an increased risk of recurrence compared to grade group 1 disease (HR 3.29, 95% CI 1.49-7.26).1

The impact of new technology, according to Dr. Carroll, is seen in the new genomic tests that are available. The 2019 National Comprehensive Cancer Network (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 the 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 which 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).2 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.3

Dr. Carroll notes that there is 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).4 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 current controversies in active surveillance according to Dr. Carroll:

  • What risk categories are appropriate? Very low risk, low risk, those with low CAPRA scores, those with Gleason 3+4 disease?
  • Is it safe in African American men?
  • Are younger men appropriate candidates?
Data from Dr. Carroll’s group at UCSF suggest that active surveillance in young men is safe.5 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):

AUA2020_Cox_regression_analysis.png

On Cox regression analysis, younger age was independently associated with lower risk of biopsy-based Gleason score upgrade (HR per 1-year decrease: 0.969, 95% CI 0.956-0.983]), and persisted upon restriction to men meeting strict active surveillance inclusion criteria. Furthermore, there was no significant association between younger age and risk of definitive treatment or risk of biochemical recurrence after delayed radical prostatectomy.

Whether all men with Gleason 3+4 disease should undergo an immediate radical prostatectomy is unclear. Dr. Carroll notes that cancer risk is best assessed with multivariable instruments and not as a single variable. Furthermore, radical prostatectomy only has an (arguably marginal) benefit in those with palpable tumors, higher-risk disease, or those with a PSA > 10 ng/mL. 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.

Dr. Carroll highlighted the following cautionary remarks for men with Gleason 3+4 considering active surveillance:

  • High PSA density
  • PI-RADS 5 on mpMRI
  • Adverse genomics (ie. GPS score)
  • Cribriform (expansile) histology
  • Larger number of biopsy cores positive at diagnosis (volume)
Dr. Carroll provided the following diagram for assisting in navigating candidacy for active surveillance:

AUA2020_active_surveillance.png

To conclude his Ramon Guiteras 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
  • Its use remains highly variable, particularly in the United States
Presented by: Peter Carroll, MD, MPH, Department Head, University of California, San Francisco, San Francisco, CA, USA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, August, GA, USA, Twitter: @zklaassen_md, at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020

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 Urol 2019 Sep;202(3):506-510.
  2. 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 Urol 2019 Feb;201(2):300-307.
  3. 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 Urol 2019 Oct;202(4):702-709.
  4. 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 Urol 2015 Mar;193(3):807-811.
  5. Leapman MS, Cowan JE, Nguyen HG, et al. Active surveillance in Younger Men with Prostate Cancer. J Clin Oncol 2017 Jun 10;35(17):1898-1904.