Dr. Loeb began by highlighting an increase in the percent of patients with intermediate-risk prostate cancer who are undergoing AS, increasing from 5.8% in 2010 to 9.6% in 2015 in the United States. Rates are even higher in other countries. The proportion of men with intermediate-risk disease undergoing AS in Sweden was as high as 19% in 2014.
Intermediate-risk prostate cancer is a heterogeneous disease, exemplified by the NCCN risk criteria (shown below). Patients can be classified as intermediate based on clinical T stage (cT2b or cT2c), Gleason score (Grade group 2 [Gleason 3+4] or 3 [Gleason 4+3]), or PSA (10-20). Based on these criteria, patients are stratified into favorable or unfavorable intermediate-risk groups.
Men are more likely to undergo AS if they are intermediate-risk because of PSA 10-20 with (14%) than if they have Gleason score 3+4 (4%). This is supported by data. A recent study found that there is no difference in upgrading or adverse pathology in men with Gleason 3+3 and PSA 10-15 compared to low-risk disease. Conversely, PSA > 15 or Gleason 3+4 had higher risk of adverse pathology and upgrading.1 Another recent study found that compared to men with Gleason 3+3 and PSA 10-20, men with Gleason 3+4 and PSA < 10 had significantly higher rates of pathologic upgrading, pathologic upstaging, and adverse pathology.2
Dr. Loeb moves on to discuss other factors that may factor into the decision for or against AS in men with intermediate-risk prostate cancer. One important consideration is the heterogeneity in Gleason 3+4 prostate cancer. Several studies have identified a relationship between the percentage of Gleason pattern 4 on biopsy with extra-prostatic extension on radical prostatectomy and biochemical recurrence. Another pathologic feature to consider is the presence of intraductal or cribriform histology. The European Association of Urology provides a strong recommendation that “patients with intraductal and cribriform histology on biopsy should be excluded from AS.”
An additional factor to consider in assessing candidacy for AS is the presence of pathogenic germline mutations. For men with low or intermediate-risk prostate cancer, the NCCN guidelines recommend germline genetic testing for those with intraductal/cribriform histology, Ashkenazi Jewish ancestry, or family history of high-risk germline mutation. Germline genetic testing should also be considered based on family history, as specified by the NCCN Prostate Cancer and Genetic/Familial High-Risk Assessment guidelines, should. Germline mutations in certain genes may impact the decision to pursue AS. For example, germline mutations in BRCA1, BRCA2, and ATM are associated with higher risk of reclassification during AS.
How to optimally monitor men on AS has not been established. The NCCN guidelines more clearly describe what not to do – PSA no more than every 6 months and digital rectal exam, MRI, and biopsy no more than every 12 months – than what exactly should be done. One study suggests that some patients undergo too much testing – while AS testing marginally increased quality-adjusted life years (QALYs) for men under age 50, it resulted in decreased QALYs for men over aged 65.3 Another study found that for men with low-risk prostate cancer, even one biopsy resulted in lost QALYs for men over aged 65; in contrast, AS is cost-effective even up to age 75 in men with intermediate-risk disease.4 These data support a risk-adapted approach to increase monitoring intensity for men with intermediate-risk disease. Further tailoring for individual patients can be performed in real-time using online risk calculators that provide a risk of Gleason upgrade at next biopsy.
Dr. Loeb moved on to discuss outcomes for men with intermediate-risk prostate cancer undergoing AS. One study found that more men with intermediate-risk disease (41%) discontinued AS at five years compared to those with low-risk disease (33%). However, it’s notable that more than half of men with intermediate-risk disease remain on AS five years later. A meta-analysis that included six AS studies found that compared to men with low-risk disease, those with intermediate-risk disease were just as likely to remain on AS at 10 years, but rates of metastasis-free survival and cancer-specific survival were significantly worse; albeit the absolute number of men who developed metastatic disease or who died of prostate cancer was low.5 One final consideration in a real-world setting is that approximately 10% of patients on AS will be lost to follow-up.
One benefit of AS is that it presents an opportunity for clinicians to promote lifestyle interventions. Men with intermediate-risk prostate cancer are still more likely to die from other causes, with cardiovascular disease presenting the biggest risk. Multiple studies demonstrate that lifestyle interventions, including dietary changes, exercise, and stress management, in men on AS for prostate cancer not only decrease cholesterol and improve cardiopulmonary fitness but also decrease PSA.6,7
Dr. Loeb concluded by highlighting two upcoming efforts that will inform our understanding of AS for men with intermediate-risk prostate cancer: 1) the Prostate Cancer Active Surveillance Project (PCASP), which will be the largest examination of utilization and quality of AS for intermediate-risk disease, and 2) results from the Movemeber Funding Priorities in Active Surveillance, which will be released in the coming months and provide a report on the best practices for clinical care.
Presented by: Stacy Loeb, MD, is a Professor of Urology and Population Health at NYU Langone Health and the Manhattan Veterans Affairs
Written by: Jacob Berchuck, MD, Genitourinary Medical Oncologist at the Dana-Farber Cancer Institute (Twitter: @jberchuck), during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday, Feb 17 – Saturday, Feb 19, 2022
References:
- Loeb S, Folkvaljon Y, Bratt O, Robinson D, Stattin P. Defining Intermediate Risk Prostate Cancer Suitable for Active Surveillance. J Urol. 2019 Feb;201(2):292-299.
- Lonergan PE, Jeong CW, Washington SL 3rd, Herlemann A, Gomez SL, Carroll PR, Cooperberg MR. Active surveillance in intermediate-risk prostate cancer with PSA 10-20 ng/mL: pathological outcome analysis of a population-level database. Prostate Cancer Prostatic Dis. 2021 Sep 10.
- Loeb S, Zhou Q, Siebert U, Rochau U, Jahn B, Mühlberger N, Carter HB, Lepor H, Braithwaite RS. Active Surveillance Versus Watchful Waiting for Localized Prostate Cancer: A Model to Inform Decisions. Eur Urol. 2017 Dec;72(6):899-907.
- de Carvalho TM, Heijnsdijk EAM, de Koning HJ. When should active surveillance for prostate cancer stop if no progression is detected? Prostate. 2017 Jun;77(9):962-969.
- Enikeev D, Morozov A, Taratkin M, Barret E, Kozlov V, Singla N, Rivas JG, Podoinitsin A, Margulis V, Glybochko P. Active Surveillance for Intermediate-Risk Prostate Cancer: Systematic Review and Meta-analysis of Current Protocols and Outcomes. Clin Genitourin Cancer. 2020 Dec;18(6):e739-e753.
- Ornish D, Weidner G, Fair WR, Marlin R, Pettengill EB, Raisin CJ, Dunn-Emke S, Crutchfield L, Jacobs FN, Barnard RJ, Aronson WJ, McCormac P, McKnight DJ, Fein JD, Dnistrian AM, Weinstein J, Ngo TH, Mendell NR, Carroll PR. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005 Sep;174(3):1065-9.
- Kang DW, Fairey AS, Boulé NG, Field CJ, Wharton SA, Courneya KS. Effects of Exercise on Cardiorespiratory Fitness and Biochemical Progression in Men With Localized Prostate Cancer Under Active Surveillance: The ERASE Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1487-1495.