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

The clinical course of treated or untreated 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 PCbearing 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 lowrisk 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 age 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 patientand 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. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 30 OCTOBER 2