Personalizing the Use of Active Surveillance as an Initial Approach for Men With Newly Diagnosed

               Prostate Cancer

Journal of Clinical Oncology

Anthony V. D’Amico  10-20-2015

The clinical course of treated or untreate clinically localized adenocarcinoma of the prostate from diagnosis to metastatic progression and finally to death as a result of prostate cancer (PC) varies on the basis of prognostic factors at presentation. In addition, men of PC-bearing age often have competing risks for mortality, most notably heart disease, which can significantly shorten their life expectancies. Therefore, active surveillance (AS)—a management approach in which men are regularly monitored with serum prostate-specific antigen (PSA) testing, digital rectal examination, and repeat prostate biopsy—has become adopted as an initial option for men with low-risk PC for which progression to metastatic disease if left untreated is often protracted. Yet, it is also known that, as men age, the likelihood of being diagnosed with aggressive PC increases, and this increased risk has also been observed in African American (AA) men irrespective of age. The known biopsy sampling error associated with the standard 12-core transrectal ultrasound (TRUS) –guided prostate needle biopsy (PNB), for which undergrading that ranges from 41% to 48% in men with low-risk PC has been observed at the time of radical prostatectomy, complicates the issue of increased risk. Given this sampling error and, therefore, the possibility of missing occult high-grade PC at the time of TRUS-guided PNB with advancing age9 or in AA men, we are left with the dilemma of whether healthy men with a long life expectancy who are at high-risk for harboring occult high-grade PC—particularly healthy elderly or AA men—are ideal candidates for AS, should very-low-risk or low-risk PC be diagnosed on the initial TRUS-guided PNB. This dilemma is particularly poignant, because the assessments available (ie, PSA, digital rectal examination, and biopsy) for men who are observed with AS do not ensure that an occult high-grade and potentially life-threatening PC is identified when present.

In the article that accompanies this editorial, Tosoian et al report on a series of 1,298 men with a median age of 66 years (range, 41 to 92 years) who were diagnosed with very-low-risk (n = 926; 71%) or low-risk (n = 372; 29%) PC; 7.4% were AA, and all men were observed on an AS protocol for a median of 5 years. On the basis of projected cumulative incidence estimates of less than 1% for the occurrence of metastasis or death as a result of PC within 15 years from diagnosis, the authors suggest that men with favorable-risk PC should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider AS rather than curative intervention. There is no doubt that, for some men diagnosed today with very-low-risk or low-risk PC, this statement is valid; however, to whom specifically, on an individual basis, this statement should apply remains unanswered.

Toward that end, the authors confirm that increasing age at diagnosis is associated with an increased risk of eventually being diagnosed with Gleason score 7 or greater PC, such that, for every additional year of age at diagnosis, there was a 3% increase in the risk of subsequently being upgraded from Gleason score 6 to 7 or greater. However, this did not translate into an independent association with intervention, perhaps because of a higher likelihood of significant comorbidity in these aging men, for whom treatment of PC with a Gleason score 7 or greater may not be warranted because of limited life expectancy. Support for this conjecture was provided by the authors when they observed a 31% estimate of all-cause mortality by 15 years, of which only 0.1% was as a result of PC. In addition, as the authors noted in their discussion, their study lacks ethnic diversity: only 7.4% of the study cohort was AA. Therefore, the authors cannot comment on how the results of their study would look in AA men, who are more likely than white men, who were 88.4% of the study cohort, to have aggressive PC that could be missed on initial TRUS-guided PNB as a result of sampling error. Finally, although estimates of metastasis-free and PC-specific survival were reported at 10 and 15 years, the authors note that, because the median follow-up time was only 5 years and because PC has a long natural history, the 15-year rates for freedom from metastasis and PC death of greater than 99% overestimate the actual rates that would be observed when all men in the study have been observed for 15 years. Therefore, these findings should be viewed as preliminary, and studies with longer follow-up times will be informative.

The authors provided helpful information about patient- and cancer-related parameters associated with upgrading to Gleason score 7 or greater at surveillance biopsy; parameters included increasing age, PSA density, and the number of positive cores. However, information about patient factors, including comorbidity, ethnicity, and family history, should also be considered in decisions about when to use AS and in which patients AS will not lead to missing occult high-grade PC that can progress to metastasis during their remaining life expectancy.

A randomized study of AS versus intervention, ProtecT (Prostate Testing for Cancer and Treatment), is expected to have initial results reported in 2016 and will be the first randomized study of men diagnosed by PSA screening to address the important issue of the role of AS versus intervention in men with favorable-risk and screen-detected PC. Although PROTECT is an important study, only age, PSA level, T category, and Gleason score were stratified before random assignment, which did not permit a prospective assessment of the impact of the important patient factors of comorbidity, ethnicity, and family history on time to metastasis and death as a result of PC for men who were randomly assigned to AS versus to intervention. Moreover, it should be recognized that less than 1% of men enrolled onto PROTECT were AA, the maximum age was 69 years, and not greater than 8% had a family history of PC. These factors, unfortunately, will not permit post–random-assignment hypothesis-generating analyses to evaluate outcomes after AS versus treatment in AA men or men older than age 70 years, all of whom are at high-risk for harboring occult high-grade PC that may be missed at biopsy.

Although AS may be the best initial approach for men in a low-risk subgroup (eg, 60 year-old white man with very-low-risk PC, a PSA of 4.3 ng/mL, Gleason score 3 + 3 in 5% of one core, and a 60-cm3 prostate gland with no family history of PC and with significant comorbidity), it may not be the best initial approach for men in high-risk subgroups (eg, 75-year-old AA man with no comorbidity, a 15-cm3 prostate gland, low-risk PC, a PSA of 7.8 ng/mL with two cores of Gleason score 3 + 3 involving 45% of each core, and a father who died as a result of PC at the age of 70 years), in whom more studies will be needed.

More recently, with the advent of multiparametric (mp) magnetic resonance imaging (MRI), it may be possible to identify occult high-grade PC in the peripheral zone and the anterior prostate by using diffusion-weighted imaging and the prostate imaging reporting and data system (ie, PIRADS). However, although mpMRI seems to be a step forward, the predictive ability (area under the receiving operator characteristic curve) of using targeted biopsies that are based on preoperative mpMRI findings to identify Gleason score 3 + 4 or greater PC compared with Gleason 3 + 3 and that are confirmed with whole-gland pathology after prostatectomy was recently reported to be 0.73 on the basis of 170 of 1,003 men in a study cohort who underwent radical prostatectomy. Therefore, there is room for additional refinement and improvement. Research is ongoing (ClinicalTrials.gov identifier NCT01858688) to examine the ability of mpMRI findings at study entry and to identify occult high-grade PC in men with Gleason score 3 + 3 before initiating AS and also before the annual targeted biopsy for men undergoing AS.

In closing, I offer the suggestion that our attention should shift away from establishing that long-term rates of metastasis and death as a result of PC are low for a population of men diagnosed with favorable-risk PC who are observed on an AS protocol or who are randomly assigned to AS versus intervention. Rather, we should focus on defining a validated risk assessment scheme that is based on a panel of cancer and patient factors capable of determining whether an individual man of a given age, health, and ethnicity, and with specific tumor characteristics, family history, and perhaps mpMRI imaging characteristics, is best served by being observed on a AS protocol. Specifically, until we identify a marker that can reliably assess when a patient should stop AS and receive treatment at a time when cure is still possible and needed to avoid the development of metastasis during his remaining life expectancy, a risk-group–based assessment scheme that incorporates both patient and cancer characteristics is needed to enable us to inform the individual man that his PC, if left untreated, is likely or unlikely to metastasize during his remaining life expectancy.

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