Several findings merit further comment. First, it seems clear that clinical stage T2c should not be a sufficient finding to classify a patient to a high risk group. Patients stratified to high risk based solely on the basis of stage T2c (those labeled “intermediate/high” in ) in fact had a significantly lower risk of recurrence not only compared to those stratified to high risk using the more restrictive definition, but also compared to those stratified to intermediate risk. Clinical stage in CaPSURE is reported directly by clinicians; one possible explanation is that many patients with unilaterally palpable tumors may be incorrectly reported as stage T2c based on the finding of bilateral positive biopsies. It should also be noted that in both the original [10
] and revised [13
] Kattan preoperative nomograms—based on academic patient cohorts—T2b disease confers higher risk than T2c disease; in the CAPRA analyses, clinical stage conferred no independent information beyond PSA, Gleason score, and PPB until stage T3a [8
]. Moreover, under the standard definition, over 20% of the high risk group had CAPRA scores in the 0-2 range, indicating low risk disease, and had biochemical recurrence rates similar to D'Amico low risk patients with similar CAPRA scores [14
]. Using the more restrictive definition, these patients fell to just over 1% of the high risk group.
] and others [15
] have previously found that the downward stage- and risk-migration which was well-recognized in the 1990s has slowed considerably in the current decade, with an essentially constant proportion of patients found to have high risk disease since 2000 despite ongoing trends toward lower PSA thresholds for biopsy and higher numbers of cores taken on biopsy. Our prior analysis focusing on low risk patients did find downward risk migration within the low risk group as assessed by the CAPRA score [14
], with ongoing migration in the current decade. The present analysis, conversely, does not confirm downward migration within the high-risk group; indeed, since 2000 there are trends toward higher risk within the high risk group as assessed by the Kattan and CAPRA scores. One caveat is that pathologists' practices have changed over the past decade, such that a tumor read in contemporary years are more likely to receive a high grade than the same tumor read in the early 1990s [16
]. demonstrates that Gleason grade, rather than PSA or clinical stage, is more likely to explain assignment to the high risk group in the latter years of the analysis—so a portion of the rising risk within the high risk group may be an artifact of this change in pathology practice. On the other hand, the proportion of patients presenting with PSA >20 and/or >75% PPB has changed little in the current decade, indicative of a consistent pool of men at high true risk.
We found that the CAPRA score, as a multivariable instrument, was able to substratify the high risk group effectively in terms of biochemical recurrence following surgery. Other recent analyses have likewise demonstrated heterogeneity in outcomes among high risk patients [4
]. This increased heterogeneity compared to the low risk group is explainable by the fact that the D'Amico definition of high risk does not account for multiple adverse variables. Intuitively, a man with Gleason 4+4, PSA 4.2, clinical stage T1c is at much lower risk than a man with Gleason 4+5, PSA 28.8, clinical stage T2b; both of these men would be in the same high risk group in the 3-level classification, but would be appropriately substratified using a multivariable instrument such as the Kattan nomogram or CAPRA score.
It is evident from that whether or not they are routinely using a multivariable risk prediction instrument, urologists in the community already recognize the additive impact of multiple adverse risk factors. Within the high risk group, treatment patterns vary substantially with multivariable risk as measured by the CAPRA score: utilization of RP and brachytherapy falls markedly with increasing CAPRA score, while utilization of EBRT and primary androgen therapy rises. Evidence from multiple large randomized trials supports the addition of ADT to EBRT [17
]. Conversely, ADT does not improve outcomes following RP [19
] or brachytherapy [20
], and may adversely impact quality of life outcomes after the latter treatment [21
Use of primary androgen deprivation monotherapy in CaPSURE has increased consistently among high risk men. Moreover, utilization of neoadjuvant ADT in association with EBRT for high risk disease has been over 80% since 2000, but has changed little since that time, whereas utilization in combination with brachytherapy has continued to rise. While concern has been raised regarding possible overtreatment of low risk prostate cancer [14
], these figures raise concern regarding possible under
treatment of high risk disease. High volume centers have reported favorable outcomes after RP monotherapy even among patients with advanced disease [22
], and results may be improved further by addition of adjuvant EBRT for appropriately selected patients. Many patients at the higher end of the risk spectrum with clinically localized disease do not appear to be offered potentially curative local therapy, and rates of adjuvant EBRT are lower than would be expected after RP for high risk disease.
A few caveats to these analyses should be considered. Data are submitted only by patients and urologists; therefore, any treatments by other practitioners that are not reported by patients may not be captured. Quality assurance mechanisms, including medical record review of all hospital admissions, help to minimize this problem. The CaPSURE practice sites have not been chosen at random and thus do not constitute a statistically valid sample of the United States patient population. However, they represent a broad range of geographic locales and a mix of academic and community sites, which we believe to be the best available sample for the analysis of temporal trends in “real-world” practice. It is possible that the results would have been different with different grouping of the years of diagnosis, but given the consistently strong trends and low p-values realized, this seems unlikely. The CAPRA score has to date been validated only for RP patients, and results of our survival analysis should not yet be extrapolated to patients undergoing other treatments.
In summary, men stratified to the D'Amico high risk category represent a heterogeneous group whose outcomes may be better predicted by a multivariable instrument. Clinical stage T2c alone should not warrant high risk classification. There is little if any ongoing downward risk migration among high risk patients, suggesting that new strategies are needed to identify these patients more effectively and earlier in the disease course. Treatment strategies vary with multivariable risk within the high risk group, and treatment trends suggest that at least some men with high risk, localized disease treated with ADT monotherapy may be under-treated. Standardization of better definitions of risk are needed both for patient counseling in clinical practice and for clinical trial recruitment.