By: Dan Sperling, MD

Active Surveillance (AS) for men with low risk prostate cancer (PCa) is increasingly recommended by physicians, and favored by patients, as a strategy for deferring whole-gland treatments that come with side effect risks. There is a lack of universal agreement on AS candidate criteria, but the European Association of Urology’s guidelines (PSA< 10 ng/ml, biopsy GS ? 6, ? 2 cancer-positive biopsy cores with ? 50% of tumor in any core and clinical stage ? T2a) are widely used.

There are several issues associated with AS:

1. Was the diagnosis reliable, given that TRUS has an average 30% false negative rate, and even positive biopsies may have missed the most aggressive cells?
2. What clinical indicators are predictors of adverse pathology when an AS patient finally seeks prostatectomy?
3. How long can a patient safely practice AS without missing a treatment window?
4. Will the patient be fully compliant with the physician’s protocol for monitoring, which usually consists of regular PSA blood tests, digital rectal exams, and surveillance TRUS biopsy at specified intervals?
5. Which risk factors, or combination thereof, should trigger a repeat biopsy?

This article pulls together data from four studies that address the first two issues.

The first study is based on a cohort of 862 patients who were on AS.[i] The authors analyzed clinical records to determine how many were upgraded based on repeat surveillance biopsies, and to determine which factors could predict for upgrading and/or trigger definitive treatment. The authors identified 592 men who had more than two biopsies (the original diagnosis and at least one repeat biopsy). Almost 80% had been diagnosed with low risk PCa, while about 20% were intermediate risk and a very small number (0.3%) were high risk. During AS, 31.3% of the men were upgraded (higher Gleason grade) based on a surveillance biopsy; of those, 15% were Gleason 8 or higher at upgrading. The authors correlated an initial higher PSA, a higher percentage of positive biopsy cores, and diagnosis of clinical stage T2 with a greater likelihood of upgrading during AS. This study raises the question of whether the 31.3% (almost a third) of patients were originally harboring more aggressive disease missed by the first TRUS biopsy. The results also suggest that genomic testing, if done more routinely, would identify cellular biomarkers indicating that the cancer line is potentially deadly and the patient therefore not a candidate for AS.

The next study likewise supported a statistic of about a third of AS patients found to be upgraded, this time as a result of eventual radical prostatectomy (RP) and post-surgery analysis of the specimens.[ii] The authors based their data on 13,159 cases from the National Prostate Cancer Register of Sweden from 2007-11. All the men were diagnosed with Gleason 6, clinical stage T1c/T2 prostate cancer. 4500 of the patients had RP; of these, 2025 had records on the extent of their disease from the original biopsy cores. Among the 4500 men who had RP, approximately 50% had adverse pathology (upgraded to Gleason >7) based on the lab analysis of the specimens. The authors then applied six different active surveillance protocols to determine, retroactively, which of the patients would have been considered candidates for AS using those protocols. They found that 33-45% of potential AS patients were upgraded to Gleason >7 following RP. The researchers found that predictors of upgrading were older age, higher PSA, PSA density >0.15 ng/ml/cm³, abnormal DRE and an extent of cancer greater than 4mm on biopsy. They concluded, “More than a third of men meeting the most stringent active surveillance criteria had adverse pathology at radical prostatectomy in this population based cohort. Active surveillance programs should consider prostate specific antigen density and extent of cancer on biopsy for patient selection.”

Another very recent study examined the SEER database records of 10,273 patients first diagnosed with clinically low risk disease (Gleason 6, PSA <10ng/mL, stage T1c/T2a) in 2010-11 who underwent RP.[iii] The low risk factors indicate that these men could have been considered candidates for AS. The study authors intended to determine the incidence of upgrading among this population, and identify predictors of having hidden advanced disease in order to assist with AS decision-making. They found a sobering 44% of low risk patients were upgraded beyond Gleason 6 after RP, and correlated age, PSA and percent positive cores with risk of hidden advanced PCa. Specific factors were age >60 and >25% positive cores were significantly associated with upgrading. When PSA values <10 were in the high end of the range (7.5-9.9) and >25% biopsy cores were positive, the incidence of upgrading was 60%. Thus, they recommended, “Nearly half of clinically low-risk patients harbor Gleason ?7 or ?pT3 disease and should be risk-stratified by PSA and percent positive cores for consideration of further testing before deciding on active surveillance.”

Finally, a small study (197 patients) was designed to evaluate the risk of under-grading AS candidates, analyze possible clinical factors/biomarkers predictive of unfavorable disease, and follow the clinical course of AS candidates who had RP.[iv] All of their patients would have met the EAU surveillance guidelines listed in the opening of this article. These clinical factors were correlated to the final pathology results after RP to determine which patients had been undergraded at the time of diagnosis, and the clinical courses of these patients were followed to identify subsequent biochemical recurrence (rising PSA after RP). The research team found that 41.1% of potential AS patients were undergraded in the original biopsy (40.1% to Gleason 7, 1% Gleason 8). Perhaps surprisingly, they did not find among their cases a consistent correlation of preoperative PSA levels, PSA density and the number of positive cores predictive of upgraded disease after surgery. They did find, however, that a combination of intermediate PSA levels with 2 positive biopsy cores was associated significantly with positive surgical margins. Perhaps most thought-provoking, 19.9% of the undergraded patients experienced biochemical recurrence post-RP. The authors wrote, “In summary, this study shows that a multitude of patients fulfilling the criteria for AS are under-diagnosed.”

Given the growing professional guidelines that low risk patients be offered AS as an alternative to RP in order to limit immediate overtreatment while not missing a window of opportunity for cure, the above journal articles offer compelling evidence that candidates for AS be more thoroughly qualified. Though the problem of patient compliance with AS protocols was not touched on here, a patient who delays or avoids surveillance TRUS biopsies may be putting himself at increased risk of missing disease progression even if reasonably well-qualified to being with. For men interested in AS, the Sperling Prostate Center offers the most advanced multiparametric MRI as well as MRI-guided targeted biopsy as a way to rule out significant PCa before choosing an observational strategy. Multiparametric MRI can also be effective in monitoring for disease progression, and if imaging combined with a suspicious PSA indicates the need, an image-guided targeted biopsy has high reliability and validity in diagnosing PCa which can then be submitted for further genomic analysis.

It bears mentioning that focal laser ablation (FLA) offers a middle ground approach that bridges the gap between no treatment and radical treatment. By destroying any focus of significant disease, quality of life is preserved with a forward-looking strategy of observation/surveillance. In other words, FLA is neither undertreatment nor overtreatment, but rather it is precision treatment with minimal-to-no risk of side effects.

The concern that men on AS may miss a curative treatment window, or may have bought only a few years of assured quality of life before putting lifestyle on the line with surgery or radiation, is an important one. While the above studies give pause, there is cause for optimism thanks to advanced MRI, targeted biopsy, and precise laser ablation.

[i] Jain S, Loblaw A, Vesprini D et al. Gleason Upgrading with Time in a Large Prostate Cancer Active Surveillance Cohort. J Urol. 2015 Feb 4. pii: S0022-5347(15)00213-X. doi: 10.1016/j.juro.2015.01.102. [Epub ahead of print]

[ii] Vellekoop A, Loeb S, Folkvaljon Y, Stattin P. Population based study of predictors of adverse pathology among candidates for active surveillance with Gleason 6 prostate cancer. J Urol. 2014 Feb;191(2):350-7. doi: 10.1016/j.juro.2013.09.034. Epub 2013 Sep 23.

[iii] Dinh KT, Mahal BA, Ziehr DR et al. Incidence and Predictors of Upgrading and Upstaging Among 10,000 Contemporary Patients with Low-risk Prostate Cancer. J Urol. 2015 Feb 10. pii: S0022-5347(15)00254-2. doi: 10.1016/j.juro.2015.02.015. [Epub ahead of print]

[iv] Heidegger I, Skradski V, Steiner E et al. High risk of under-grading and -staging in prostate cancer patients eligible for active surveillance. PLoS One. 2015 Feb 6; 10(2):e0115537. Doi: 10.1371/journal.pone.0115537