Very High-Risk Localized Prostate Cancer
Very High-Risk Localized Prostate Cancer
We first validated known risk factors for metastasis and cancer-specific mortality including number of NCCN high-risk features, biopsy Gleason sum and volume of high-grade cancer (as assessed by proportion of positive cores on biopsy with Gleason pattern 4 or 5), all of which were significant predictors of metastasis and death in this cohort. In contrast, PSA, PSA velocity and clinical stage were not prognostic for either outcome (data not shown). Alternate permutations of adverse risk factors (number of high-risk features, volume of high-grade cancer on biopsy and pattern of high-grade cancer) comprised 28 alternate VHR criteria. Within these VHR test definitions, hazard ratios for metastasis ranged from 1.82–3.98 and those for cancer-specific mortality ranged from 1.86–4.82 (Table 1). VHR test definitions with hazard ratios in the highest quartile for both MFS and CSS were subject to multivariable analysis
Among the five VHR test definitions analyzed by multivariable modeling, 'primary pattern 5' had the highest adjusted hazard ratios but it included only 6.9% of the high-risk cohort; therefore, it was not considered any further. Of the four remaining VHR test definitions, adjusted hazard ratios for metastasis and cancer-specific mortatlity were similar (Table 2), indicating nearly equivalent abilities to discriminate outcomes within the high-risk cohort. Subsequently, the ultimate VHR definition was selected according to inclusion of the highest proportion of the high-risk cohort (15.1%) to maximize clinical utility. This definition included men presenting with: primary Gleason pattern 5, or ≥5 cores with Gleason sum 8–10 or multiple NCCN high-risk features.
When compared with the remainder of the high-risk cohort, VHR men presented more commonly with clinical T3 disease (14.9% vs 5.8%, P<0.001) and perineural invasion on biopsy (36.8% vs 24.4%, P=0.005) but had equivalent positive surgical margin rates (26.3% vs 28.5%, P=0.609) (Table 3). Median follow-up was 5.0 years in both the high-risk and VHR cohorts. VHR criteria discriminated men with significantly divergent BFS, MFS, CSS and OS Kaplan–Meier curves (log-rank P<0.001 for all measures) (Figure 1). At 10 years, BFS for VHR was 0.21 (95% CI: 0.09, 0.36) compared with 0.41 (95% CI: 0.36, 0.46) for the remainder of the high-risk cohort (Table 4). Ten-year MFS for VHR men was 0.37 (95% CI: 0.20, 0.54) compared with 0.78 (95% CI: 0.72, 0.83) for the remainder of the high-risk cohort (Table 4). Similarly, 10-year CSS for VHR men was 0.62 (95% CI: 0.45, 0.76) compared with 0.90 (95% CI: 0.85, 0.93) for high-risk men (Table 4). The independent contributions of each component of the VHR criteria were assessed in multivariable models (Supplementary Table S1). All three components were significantly associated with risk of metastasis. In a sub-analysis of men diagnosed with extended biopsy sampling in the modern Gleason grading era (n=275), VHR criteria remained the strongest predictors of metastasis in univariate and multivariable analyses (Supplementary Table S2).
(Enlarge Image)
Figure 1.
Kaplan–Meier freedom from biochemical recurrence (BFS), metastasis (MFS), cancer death (CSS) and all-cause mortality (OS) stratified by very-high-risk classification. JHU, Johns Hopkins University; RP, radical prostatectomy.
Rates of additional treatment post-RP (adjuvant or salvage radiation, androgen deprivation and/or chemotherapy) were compared between the VHR and high risk groups. Post-operative, pre-metastatic treatments occurred in 51.8% of VHR men but only 35.2% of the remainder of the high-risk cohort (P=0.001) (Table 3).
Further, we evaluated our high-risk cohort in regards to their CAPRA score. Like our dichotomous classifier, CAPRA has the advantage over typical nomograms of being fairly easy to apply in the clinical setting with minimal calculation.
Within the entire NCCN high-risk cohort, the mean CAPRA score was 5.3 (median 5.0, range 2–9). No metastases or PCa-specific deaths were seen among men with CAPRA <3 or ≥9, both of which contained small numbers of patients (Supplementary Table S3). In unadjusted (Supplementary Table S4) and adjusted (Table 5) models, the final VHR criteria, compared with all CAPRA cut-points, was the only significant predictor of both MFS and CSS, though multiple CAPRA cut-points were significantly associated with MFS. The CAPRA cut-point that best discriminated MFS and CSS was 6. In MFS and CSS survival curves stratified by CAPRA ≥6 and the VHR criteria, MFS stratified similarly between the two different criteria, but the log-rank P-value for CSS by CAPRA ≥6 was not significant (P=0.140). Among 28 men with intermediate-risk CAPRA (3–5) who subsequently developed metastases, 4/28 (14.3%) met VHR criteria.
Results
We first validated known risk factors for metastasis and cancer-specific mortality including number of NCCN high-risk features, biopsy Gleason sum and volume of high-grade cancer (as assessed by proportion of positive cores on biopsy with Gleason pattern 4 or 5), all of which were significant predictors of metastasis and death in this cohort. In contrast, PSA, PSA velocity and clinical stage were not prognostic for either outcome (data not shown). Alternate permutations of adverse risk factors (number of high-risk features, volume of high-grade cancer on biopsy and pattern of high-grade cancer) comprised 28 alternate VHR criteria. Within these VHR test definitions, hazard ratios for metastasis ranged from 1.82–3.98 and those for cancer-specific mortality ranged from 1.86–4.82 (Table 1). VHR test definitions with hazard ratios in the highest quartile for both MFS and CSS were subject to multivariable analysis
Among the five VHR test definitions analyzed by multivariable modeling, 'primary pattern 5' had the highest adjusted hazard ratios but it included only 6.9% of the high-risk cohort; therefore, it was not considered any further. Of the four remaining VHR test definitions, adjusted hazard ratios for metastasis and cancer-specific mortatlity were similar (Table 2), indicating nearly equivalent abilities to discriminate outcomes within the high-risk cohort. Subsequently, the ultimate VHR definition was selected according to inclusion of the highest proportion of the high-risk cohort (15.1%) to maximize clinical utility. This definition included men presenting with: primary Gleason pattern 5, or ≥5 cores with Gleason sum 8–10 or multiple NCCN high-risk features.
When compared with the remainder of the high-risk cohort, VHR men presented more commonly with clinical T3 disease (14.9% vs 5.8%, P<0.001) and perineural invasion on biopsy (36.8% vs 24.4%, P=0.005) but had equivalent positive surgical margin rates (26.3% vs 28.5%, P=0.609) (Table 3). Median follow-up was 5.0 years in both the high-risk and VHR cohorts. VHR criteria discriminated men with significantly divergent BFS, MFS, CSS and OS Kaplan–Meier curves (log-rank P<0.001 for all measures) (Figure 1). At 10 years, BFS for VHR was 0.21 (95% CI: 0.09, 0.36) compared with 0.41 (95% CI: 0.36, 0.46) for the remainder of the high-risk cohort (Table 4). Ten-year MFS for VHR men was 0.37 (95% CI: 0.20, 0.54) compared with 0.78 (95% CI: 0.72, 0.83) for the remainder of the high-risk cohort (Table 4). Similarly, 10-year CSS for VHR men was 0.62 (95% CI: 0.45, 0.76) compared with 0.90 (95% CI: 0.85, 0.93) for high-risk men (Table 4). The independent contributions of each component of the VHR criteria were assessed in multivariable models (Supplementary Table S1). All three components were significantly associated with risk of metastasis. In a sub-analysis of men diagnosed with extended biopsy sampling in the modern Gleason grading era (n=275), VHR criteria remained the strongest predictors of metastasis in univariate and multivariable analyses (Supplementary Table S2).
(Enlarge Image)
Figure 1.
Kaplan–Meier freedom from biochemical recurrence (BFS), metastasis (MFS), cancer death (CSS) and all-cause mortality (OS) stratified by very-high-risk classification. JHU, Johns Hopkins University; RP, radical prostatectomy.
Rates of additional treatment post-RP (adjuvant or salvage radiation, androgen deprivation and/or chemotherapy) were compared between the VHR and high risk groups. Post-operative, pre-metastatic treatments occurred in 51.8% of VHR men but only 35.2% of the remainder of the high-risk cohort (P=0.001) (Table 3).
Further, we evaluated our high-risk cohort in regards to their CAPRA score. Like our dichotomous classifier, CAPRA has the advantage over typical nomograms of being fairly easy to apply in the clinical setting with minimal calculation.
Within the entire NCCN high-risk cohort, the mean CAPRA score was 5.3 (median 5.0, range 2–9). No metastases or PCa-specific deaths were seen among men with CAPRA <3 or ≥9, both of which contained small numbers of patients (Supplementary Table S3). In unadjusted (Supplementary Table S4) and adjusted (Table 5) models, the final VHR criteria, compared with all CAPRA cut-points, was the only significant predictor of both MFS and CSS, though multiple CAPRA cut-points were significantly associated with MFS. The CAPRA cut-point that best discriminated MFS and CSS was 6. In MFS and CSS survival curves stratified by CAPRA ≥6 and the VHR criteria, MFS stratified similarly between the two different criteria, but the log-rank P-value for CSS by CAPRA ≥6 was not significant (P=0.140). Among 28 men with intermediate-risk CAPRA (3–5) who subsequently developed metastases, 4/28 (14.3%) met VHR criteria.
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