Active Surveillance: From Benchmark to Bedside

Educational Objectives

The goal of this program is to improve the management of early prostate cancer. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the most important predictors of metastatic disease in patients with early prostate cancer.
2. Choose patients with prostate cancer for whom treatment with active surveillance is appropriate.

Summary

Metastasis in patients with low-risk prostate cancer: most common reason missed concurrent high-grade cancer

Tumor biology: tumor biology and molecular genetics of Gleason pattern 3 disease profoundly different from higher-grade disease; 90% of cells in pattern 3 tumors resemble normal tissue; reported cases of metastasis in pathologically confirmed Gleason pattern 3 tumors few; rate of missed Gleason pattern 4 within pattern 3 tumors 25% to 30%; of misattribution significantly reduced in era of magnetic resonance imaging (MRI); of biologic progression of grade low; of adverse molecular features in Gleason 3+3 tumors ≈10%; progression of biologic grade — incidence 1% to 2% per year; clinically important in patients followed for 10 to 15 yr

Molecular genetics: burden of mutations increases with grade of tumor; study from Johns Hopkins found PTEN loss (key molecular event conferring invasive potential) almost nonexistent in Gleason 3+3 tumors; Gleason pattern 3 cells within higher-grade tumors more likely to harbor deletion; PTEN loss may signal progression of pattern 3 cells to pattern 4 or extracellular microvesicle transfer (recently described phenomenon in which cells share genetic material); higher-grade cancer cells shed microvesicles (can be taken up and influence biologic behavior of lower-grade cells); multiple genetic events must occur to cause dedifferentiation; studies in animal models found that PTEN loss or MYC activation alone not associated with metastases or death from prostate cancer, but outcomes uniformly lethal when both present

Stratification of risk in prostate cancer: all guidelines differentiate very low risk (eg, Epstein criteria) from low risk (more extensive Gleason 6 tumor); volume of cancer found on systematic biopsy associated with likelihood of high-grade cancer; nomography from Johns Hopkins incorporates MRI findings, laterality, and extent of disease; prostate-specific antigen (PSA) density included in all nomography; laterality marker for volume of disease; considered together, nomography strong tool for predicting risk for high-grade cancer

Prospective studies: >15,000 patients followed prospectively in active surveillance programs; range of criteria for eligibility and outcomes vary; program at University of Toronto included patients with intermediate-risk cancer (22% of patients); found development of metastases in 30 of ≈1000 patients; 1.5% died of prostate cancer; rate of intervention ≈30%; rate of intervention in Johns Hopkins program (criteria for entry stricter) only slightly lower; in University of Toronto program, actuarial 15-yr rate of mortality from prostate cancer ≈5%; in Johns Hopkins program, 0.5%; difference linked to selection of patients; University of Toronto program included all patients with Gleason 6 tumors (eg, those with PSA >10 ng/mL); patients underwent treatment only for progression of grade; Johns Hopkins group treated patients with increased volume of Gleason 6 tumors; subsequent analysis from University of Toronto found that presence of Gleason pattern 4 at baseline predicts development of metastatic disease; intermediate risk confers 4-fold increase in cause-specific survival; PSA >10 ng/mL does not affect survival rate; in recursive partitioning analysis, rate of 15-yr metastasis-free survival in highest-risk group of patients with Gleason 3+3 tumors ≈90%; rate in lowest-risk group of patients with Gleason 3+4 tumors ≈30%

Active surveillance program in Sweden: total of 474 patients included 104 patients with intermediate risk; 5 of 6 deaths caused by prostate cancer found in intermediate-risk group (hazard ratio ≈5 for Gleason 3+4 tumors)

Study from Cleveland Clinic: 117 men with intermediate-risk prostate cancer treated by active surveillance followed for 10 yr; found incidence of metastasis, failure of active surveillance, and rate of curative intervention similar to patients at low risk; shorter follow-up may explain better results (many deaths occur at >10 yr)

Optimizing active surveillance programs: criteria at University of Toronto too inclusive (≈50% of all new patients with prostate cancer enrolled in active surveillance); at Johns Hopkins, too stringent (≈20% enrolled in active surveillance); active surveillance appropriate in vast majority of patients with Gleason 6 tumors and in selected patients with Gleason 7 tumors; Johns Hopkins relaxed criteria (active surveillance no longer limited to patients fulfilling Epstein criteria)

Magnetic resonance imaging: case study — patient underwent prostate biopsy because PSA mildly elevated; 10% Gleason 6 cancer found in one core; MRI revealed Prostate Imaging Reporting and Data System (PI-RADS) 4 lesion; targeted biopsy of lesion indicated Gleason 4+3 cancer; pathology indicated lesion much larger than predicted by MRI; performance of MRI — negative predictive value (NPV) 80% to 100%; ­PROMIS study (Ahmed et al 2017) found NPV 76%; NPV linked to underlying risk; in patient with low clinical risk and normal findings of MRI, risk for significant cancer low; factors with higher risk (eg, high PSA, more extensive Gleason 6 tumor) associated with lower NPV; recent study found NPV varied from 67% in high-risk patients to ≈90% in low-risk patients

Biomarkers: majority marketed for patients treated with active surveillance; previously, follow-up of patients treated with active surveillance focused on serial biopsies and PSA kinetics; emphasis on imaging and molecular markers increasing; goal to reduce rate of intervention (rates of mortality already low)

Guidelines: active surveillance recommended in low-risk patients; appropriate in selected patients with intermediate risk; follow-up tests include measurement of PSA every 3 to 6 mo, digital rectal examination annually, and repeat systematic biopsy within 1 yr of initial diagnosis and then every 3 to 5 yr; guidelines consider MRI investigational (speaker believes MRI appropriate in patients treated with active surveillance); use of biomarkers considered investigational

Health intervention: urologist following otherwise healthy patient with prostate cancer may be only practitioner caring for patient; impact on overall mortality rate of treating prostate cancer small; however, impact as sole provider treating patient potentially significant; cessation of smoking most cost-effective intervention in medicine; patients with recent diagnosis of cancer more receptive to counseling on smoking cessation; other recommendations include regular exercise, control of weight, moderate intake of red meat, and increased consumption of fruits and vegetables; statins — robust epidemiologic data suggest taking statins lowers risk for high-grade prostate cancer; data linking statins to nonprogression of prostate cancer in men treated with active surveillance lacking; vitamin D — deficiency common in northern locations and elderly individuals; may play beneficial role in prostate cancer; metformin — adverse effects in healthy patients without diabetes mellitus lacking; may cause weight loss; preclinical and epidemiologic data suggest benefit regarding prostate cancer

Conclusions: treatment not appropriate in patients with small-volume Gleason 6 cancers, normal findings of MRI, and low PSA density; patients with significant elements of Gleason pattern 4 should be treated with radical therapy; “gray zone” — use of radical therapy in patients with extensive Gleason 6 cancer appropriate (especially younger men); active surveillance in young men with small-volume Gleason 6 disease appropriate; in patients with Gleason 7 tumors but small volume of pattern 4, data suggest that when ≤5% Gleason pattern 4 found on core biopsy, pathology on specimens from radical prostatectomy similar to that of Gleason 6 tumors; prevalence of PI-RADS 4 or 5 lesions in which targeted biopsy indicates low-grade cancer increasing; these lesions often behave similarly to Gleason 6 tumors without restricted diffusion; BRCA mutations — patients with Gleason 6 cancer and BRCA2 mutation should be considered at higher risk and treated aggressively

Readings

Ahmed HU et al: Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017 Feb 25;389(10071):815-22; Inoue LY et al: Modeling grade progression in an active surveillance study. Stat Med 2014 Mar 15;33(6):930-9; Klotz L et al: Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015 Jan 20;33(3):272-7; Prada I, Meldolesi J: Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets. Int J Mol Sci 2016 Aug;17(8):1296; Tosoian JJ et al: Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol 2015 Oct 20;33(30):3379-85; van der Poel H et al: Role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers. World J Urol 2015 Jul;33(7):907-16.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Klotz presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Klotz was recorded at the Southwest Prostate Cancer Symposium 2018, presented by Grand Rounds in Urology and held April 11-14, 2018, in Scottsdale, AZ. For information on upcoming meetings from Grand Rounds in Urology, please visit grandroundsinurology.com. The Audio Digest Foundation thanks the speakers and Grand Rounds in Urology for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

UR412202

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

More Details - Certification & Accreditation