How Does Confirmatory Biopsy Affect Recommendations for Active Surveillance?

By Andrew J. Stephenson, MD

Our prostate cancer management team at Cleveland Clinic Glickman Urological & Kidney Institute, based on positive results from several large prospective studies, increasingly recommends active surveillance (AS) for men with clinically indolent prostate cancer. However, clear guidelines for optimal AS practices are still lacking.

Our current protocol consists of periodic clinic visits every six to 12 months with prostate-specific antigen (PSA) testing and digital rectal examinations, a confirmatory biopsy within 12 months of initial diagnosis and followup biopsies based on physician discretion and shared decision making. This helps rule out understaged patients who are not suitable candidates for AS.

Confirmatory biopsy

However, we fully recognize the need to continue refining our approach and personalizing the management of patients on AS, including confirmatory biopsy.

In various studies, 27 percent of men have disease upgraded after confirmatory biopsy at 12-15 months after diagnosis. Other studies demonstrate that 21 to 52 percent of men have a negative confirmatory biopsy, with no disease identified in any of the cores sampled. The latter wide-ranging figures could be the result of a combination of low-volume disease and sampling error.

While we know that negative confirmatory biopsy is associated with decreased risk of pathologic reclassification, we were curious about whether grade and volume – or volume alone – affected reclassification. And we wanted to know how this might affect AS recommendations. Few previous studies differentiated between the type of reclassification, volume or grade as did our study.

We mined our institution’s AS database for subjects and identified 224 patients who met our criteria. These included grade reclassification from group 1 (Gleason score 6) to grade groups >2 (Gleason score > 3 + 4) or from grade group 2 (Gleason score 3 + 4) to grade groups > 3 (Gleason score > 4 + 3). Subjects also needed to have volume reclassification increases in greater than 33 percent of positive sample cores, or an increase in the number of cores > 50 percent involvement per core.

Of the 224 subjects, 111 (49.6 percent) had a negative confirmatory biopsy. The remaining 113 (50.4 percent) had stable disease on confirmatory biopsy. Median follow-up for both groups was 55.8 months, and the groups shared characteristics including age, PSA at diagnosis and initial grade group. We also found that men with negative confirmatory biopsies had fewer positive cores at initial biopsy.

Our findings

We reported our findings in the journal Urology.

The absolute risk of grade reclassification among all men was 22 percent (n = 50), and the absolute risk of volume reclassification was 24 percent (n = 53). We reported a five-year grade reclassification free survival of 84 percent vs 70 percent and reclassification free survival of 87 percent versus 66 percent in patients with a negative confirmatory biopsy compared with those without, respectively.

What the findings suggest

Overall, our findings suggest that very low volume disease, reflected by a negative confirmatory biopsy, may be a strong prognostic indicator for lower grade and volume reclassification, independent of age, PSA density and stage. Very low volume of disease may follow a more indolent natural history.

PSA density

PSA density is a measure that adjusts PSA to take into account prostate size and improve specificity for the volume of malignant prostate disease. Our study adds to the growing body of evidence suggesting that PSA density may be a predictor for grade reclassification for men on AS. PSA density has potential prognostic importance in guiding clinical decisions for patients on AS.

Key takeaways

Our study, as well as others, suggest that detectable pathology on confirmatory biopsy is an important predictor of subsequent reclassification on AS. Absence of cancer on the confirmatory biopsy is associated with a 49 percent decrease in the risk of grade reclassification and a 68 percent decrease in the risk of volume reclassification for men on AS.

These results may be valuable in determining the overall risk of reclassification — and thus the need for more or less aggressive surveillance strategies.

Clinicians and patients are often concerned that we may have missed occult high-grade disease in our biopsies. Our study adds credence to the theory that a negative confirmatory biopsy is reassuring that AS is the right choice. Further study is needed to confirm our results and continue refining the practice of AS for prostate cancer.