Data from the national CaPSURE registry indicated that the percentage of prostate cancers with low-risk characteristics increased from approximately 27% in 1990 to 1994, to 45% in 2004 to 2006.2
A recent analysis based on Surveillance, Epidemiology, and End Results data demonstrated a similar trend.14
During this period, prostate cancer mortality rates at the US population level have fallen by roughly 40%,1
but this gain has come at the cost of overtreatment of many tumors.4
Therefore, with careful risk stratification, a growing subset of men diagnosed with prostate cancer are recognized to be candidates for at least a trial of AS.5,7,15
To date, a number of studies using AS have reported favorable short- to intermediate-term outcomes among men with low-risk disease, including cohorts from the University of Toronto,8
Johns Hopkins University,16
Memorial Sloan-Kettering Cancer Center,17
the Royal Marsden Hospital,18
Results from these series have established the viability of AS protocols for selected men, though specific inclusion criteria vary across the institutions. At 3- to 5-year follow-up, men in these studies have generally done well, with 20% to 35% moving to active treatment on the basis of disease progression and/or patient preference. Nonetheless, relatively few men with eligible low-risk disease elect AS, a trend which holds even among older men.2,19–21
The University of Toronto cohort was recently updated with a report on 450 men, including 14% with PSA higher than 10 ng/mL, 17% with Gleason sum 7, and 3% with both risk factors. Just under 9% had clinical stage ≥ T2b. Nineteen percent were intermediate-risk based on PSA higher than 15 ng/mL, Gleason 7, and/or clinical stage T3. Clinical stage, PSA, and Gleason score, as well as PSADT all predicted intervention among those starting with AS. However, the outcomes were not explicitly stratified between low- and intermediate-risk groups.8
At UCSF, the ideal criteria for AS are relatively strict, including PSA lower than 10 ng/mL, no Gleason pattern higher than 3, clinical stage T1-2a, and ≤ 33% of biopsy cores positive. Moreover, at least a sextant biopsy is required, and men with less than a 10-core biopsy at diagnosis are recommended to undergo an immediate extended-template biopsy at UCSF.7
Less stringent criteria tend to be associated with higher rates of upgrading and/or upstaging among those later undergoing surgery.22
However, many men come to our institution interested in AS who do not meet the strict criteria. Such men are advised that their risk of progression may be higher, and indeed, younger men with higher-risk disease (generally high-volume Gleason 3+4 tumors) are explicitly recommended to undergo treatment. If they are strongly motivated, however, and are willing to accept these risks they are offered a trial of AS. Many participate in the Prostate Active Surveillance Study sponsored by the Canary Foundation and the National Cancer Institute's Early Detection Research Network,6
under which clinical data and biospecimens are collected prospectively for future identification of better markers of progression.23
In this study, we defined as intermediate-risk men with CAPRA 3 to 5 prostate cancer—a validated definition of intermediate risk—as well as men with low CAPRA scores, but with Gleason 3+4 disease.7
Early outcomes were favorable for men with both low- and intermediate-risk disease whether measured by upgrading on rebiopsy, PSADT, or incidence of active treatment. Men at intermediate risk had higher rates of adverse pathologic findings after RP. Additional follow-up is needed to determine whether biochemical outcomes are comparable to those among low-risk men.
While high-risk prostate cancer is frequently lethal even among older men, intermediate-risk disease may be marked by a more indolent course, depending in part on how risk is defined. Competing sources of mortality far outweigh prostate cancer in determining outcomes for men with prostate cancer with Gleason score ≤ 7 managed conservatively.4
Data from the Prostate Cancer Prevention Trial demonstrated that 2.3% of the enrolled population of men with PSA levels lower than 4.0 ng/mL harbored prostate cancer with Gleason score ≥ 7.24
The population risk of prostate cancer mortality is 2.8%25
; thus many men clearly harbor Gleason 7 histologic tumors which never progress.
Many men with low-volume Gleason 3+4 cancer, particularly those with comorbid conditions, may be appropriate candidates for AS; others are highly motivated to avoid treatment even in the face of higher-risk factors. Patients electing AS, particularly those with intermediate- rather than low-risk disease, are counseled that in many cases AS denotes delayed rather than avoided treatment. During this interval quality of life is presumed to be maintained—though this has not yet been proved prospectively—and patients may benefit from advances in medical care that occur in the interim, including both clinicians' improvement along their learning curves26
and development and dissemination of improved treatments. Conversely, some men experience increasing anxiety on AS even in the absence of objective evidence of progression,27
and the risks of serial prostate biopsy are increasingly recognized.28,29
The most important risk, however, is the likelihood of disease progression during a period of AS. Contemporary studies of AS have found significant rates of upgrading and upstaging among men undergoing RP who meet various sets of criteria for surveillance,22,30
with the rates varying predictably with the specific criteria examined. However, PSA screening identifies cancers during what is typically a years-long lead-time before clinical progression, and the as-yet unanswered question is whether cancer actually progresses during AS or is undersampled by the diagnostic biopsy.31
The latter is presumed to be the more common scenario, highlighting the importance of a high-quality, extended-template biopsy before initiating AS.32
In the Toronto cohort, five men died of prostate cancer, but only one of these had been on AS for more than 2 years, suggesting that in most such cases aggressive tumor biology drives the outcome regardless of timing of intervention.8
A recent analysis from the Swedish cohort of the European Randomized Study of Screening for Prostate Cancer found that men who underwent RP after a mean 2.6-year delay had statistically similar pathologic and biochemical outcomes as those undergoing immediate surgery. The analysis corrected for clinical risk variables but was not randomized and may be subject to acknowledged selection bias.33
Such data suggest—though they do not prove—that a window of opportunity for cure is not commonly missed during a period of AS.
We found that in the short-term, AS may be a viable option for carefully selected men with intermediate-risk prostate cancer, assuming they are counseled regarding their possibly increased risk of progression. Important caveats to this analysis include, most critically, the definitions of progression used. It is more likely for a man in the low-risk group to upgrade to Gleason 3+4 due to resampling than for an intermediate-risk Gleason 3+4 tumor to be further upgraded to 4+3 or higher. Moreover, PSA kinetic measures and the other end points assayed are not uniformly predictive of clinical progression, and the decision for treatment may reflect anxiety and other factors rather than true progression. These definitions reflect the best available for AS cohorts, but we fully acknowledge that they remain arbitrary, and more work must be done to determine which definitions are optimal.34
Gleason grading standards have changed over time; most commonly, cases originally graded in the early 1990s would be upgraded if read to contemporary standards.35
Very few of the cases in this series were diagnosed so long ago, so we do not anticipate that this potential artifact affects our findings. Our database does not include consistent information on the number of prior negative biopsies before prostate cancer diagnosis. It would be expected that men with multiple negative prior biopsies might be less likely to upgrade during early surveillance, but we cannot verify that presumption. Among the small cohort of AS + RP men with intermediate-risk disease, upstaging was relatively common, though early biochemical outcomes in this cohort are reassuring.
Longer-term follow-up of these men beyond the timeframe of this study is required. Equally important, future research must establish better markers of both presumed indolence at diagnosis and of disease progression.6
Ultimately, with improved imaging and/or tissue-based biomarkers, a subset of prostate tumors may be determined to be indolent with sufficient confidence that they will not be called cancer.3
Furthermore, focal rather than radical therapy may become an acceptable option for growing numbers of patients with low-risk cancer, and may alleviate both the morbidity of radical therapy and—at least to an extent—the uncertainty and anxiety associated with surveillance.36
We would hope and anticipate that with better risk assessment through emerging biomarkers and better integration of clinical data,37
together with appropriately selected treatment, the ongoing controversy regarding prostate cancer screening will eventually fade, and men with high-risk disease will not miss the opportunity for early diagnosis and treatment for fear of overtreatment of indolent disease.