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In this issue of Cancer, Harnden and colleagues have provided critical new information in their systematic review and meta-analysis of patients who are found to have limited cancer on prostatic biopsy.1 These patients currently are the subject of substantial conjecture, which has led to a series of different management approaches. Articles and editorials in the internal medicine and general medical literature long have decried the treatment of localized prostate cancer as being “unnecessary” and “unproven.” Until it was demonstrated that treatment of localized prostate cancer with surgery increased life expectancy relative to that obtained with initial expectant management, an argument was made that no patient should receive treatment. Similarly, until a benefit of treatment had been demonstrated for treatment of localized prostate cancer, prostate-specific antigen (PSA) testing had not been supported routinely by all practice guidelines or screening recommendations. Until a decrease in death rates from prostate cancer was observed in the United States, a hue and cry was raised regarding “over treatment” of this condition.

A common target for concern of “over treatment” were patients who had limited prostate cancer detected on initial biopsy. These patients were considered comparable to men with “autopsy-detected” cancer, although the frequency of prostate cancer detection by biopsy is far lower than that reported in any patient subgroup in an autopsy series. It is now clear that even extended prostatic biopsies do not commonly detect “insignificant” prostate cancer, which typically is defined as <0.2 cc of cancer in the entire prostate, with low-grade cancer (Gleason ≤ 3 + 3 = 6). An increasingly popular approach is the recommendation of watchful waiting or active surveillance for men with limited-volume prostate cancer on biopsy. This recommendation appears to be especially common at centers in which surgical schedules are replete. Unfortunately, there are limited data on whether this approach is safe for the patient.

An underlying concept for initial watchful waiting in a patient with a life expectancy >10 years is the proposition that cancer can be detected before it grows and spreads beyond the prostate gland, where local therapy is more likely to fail. Indeed, it is assumed that localized cancer is present in these patients with limited cancer on initial biopsy. Harnden et al., in this issue of Cancer, have performed a detailed meta-analysis after systematic literature review of patients with limited prostate cancer on biopsy.1 Their results are particularly noteworthy, because they apply to men who are considered for watchful waiting. The meta-analysis indicated that previously published studies documented a median 13.5% frequency of extraprostatic disease (with up to 45% rates in some studies) and positive margins in operated patients in a median of 11% of patients (range, 5%–19%). So, many men with presumed “limited cancer” already had extracapsular disease or were otherwise at risk for positive margins. “Watching” these patients could only increase the risk of prostate cancer spread with its consequent risks of death from prostate cancer.

Of particular note, the authors observed that the more extensive prostate biopsy patterns that have been used recently did not significantly alter the risk of having locally extensive disease or subsequent treatment failure. Although different studies have used a wide variety of different definitions for “limited prostate cancer” on biopsy, it is not at all clear that the differences in definition actually could help to refine the chance of finding pathologically early or localized cancer. Finally, despite limited follow-up for most patients after treatment, it is evident that biochemical recurrence (median risk, 8.5%), progression, and death occurred in these patients who had “limited prostate cancer on biopsy,” reflecting the advanced stage of disease at detection of some “limited” cancers.

The results are sobering, because they remind us that even apparently nonaggressive, early prostate cancers on biopsy may be more important clinically than one might initially assume. The implications for management of these men include caution in the application of “conservative” watchful waiting or active surveillance protocols. In addition, we should remain careful in our assertions of the “benign” nature of limited prostate cancer on biopsy, because these biopsies clearly do not tell us what is going on throughout the entire prostate gland or provide us with an estimate of the risk of extracapsular disease. Finally, many assumptions made in the interpretation of individual series or anecdotes of prostate cancer should be held in check until similar systematic reviews and meta-analyses of published data are available. It is evident from this publication that more extended biopsies have not necessarily changed the frequency of detection of important cancers, even when they appear to be of limited value in multiple biopsy samples. In addition, despite individual studies that suggest otherwise, the evolving definitions of “limited prostate cancer on biopsy” have not allowed us to accurately define a subgroup of prostate cancer patients who truly have clinically insignificant prostate cancer.

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