Abstract
Objectives:
To determine if the presence of adverse pathologic features in patients eligible for active surveillance are prognostic of poor oncologic outcomes, independent of pretreatment risk.
Patients & Methods:
A retrospective analysis was performed on patients who underwent radical prostatectomy at two institutions (CCF, MSKCC) between 1987–2008 and who had subsequent follow-up. Rates of biochemical recurrence, metastasis and death from prostate cancer were compared among patients with adverse pathologic features (Gleason ≥7, ≥pT3, or lymph node invasion) based on D’Amico clinical risk (low vs. intermediate/high). We also compared survival outcomes between patients with and without pathologic upgrading/upstaging among D’Amico low-risk patients. Univariate and multivariable Cox regression models were used to assess the association between clinical risk, pathologic reclassification and oncologic outcomes.
Results:
We identified 16,341 patients who underwent radical prostatectomy, of whom 6,371 were clinically low-risk. Adverse outcomes in men with adverse pathologic features were significantly lower in those with low clinical risk, with an approximate 50% and 70% reduction in the risk of metastasis and death, respectively. Only pathologic upgrading/upstaging to Gleason ≥8, seminal vesicle invasion, and lymph node invasion from clinical low-risk disease were associated with adverse outcomes. However, these types of reclassification were rare.
Conclusion:
Clinical low-risk patients with pathological upgrading/upstaging have substantially lower rates of important oncologic outcomes compared to those with higher pre-treatment risk and not substantially different than low-risk patients without pathological upgrading/upstaging. These results call into question the use of this endpoint to counsel patients about the merits and risks of surveillance.
Keywords: clinical risk, pathologic upgrading, pathologic upstaging, prostate cancer, radical prostatectomy, survival outcomes
Introduction
Clinical risk assessment of prostate cancer (PCa) is imperfect. While adjunctive tools such as genomic classifiers, molecular biomarkers and multiparametric prostate magnetic resonance imaging (mpMRI) have shown promise for improving risk categorization when combined with standard trans-rectal ultrasound (TRUS) biopsy 1,2, a significant number of patients who undergo radical prostatectomy (RP) will harbor worse disease features (pathologic Gleason upgrading or pathologic upstaging) than clinically predicted 3. With current guidelines advocating active surveillance (AS) as the standard for patients with National Comprehensive Cancer Network (NCCN) very-low and low-risk PCa 4, the risk of pathologic upgrading/upstaging after deferred radical therapy is of increasing concern 5. However, the clinical and prognostic significance of pathologic upgrading/upstaging from clinical very-low and low-risk disease remains controversial 6,7. In addition, novel molecular biomarkers and genomic classifiers have demonstrated accuracy in predicting adverse pathology and biochemical recurrence (BCR) after RP and help to risk-stratify patients who are candidates for AS 8–11. Previous work has shown that low-risk patients have improved rates of BCR among those with adverse pathology at RP 12. However, whether adverse pathology or BCR negatively impacts harder endpoints, such as metastases and survival in clinical low-risk patients remains unclear.
We therefore investigated the role that pre-operative clinical risk plays in estimating the risk of oncologic outcomes including BCR, distant metastases and cancer-specific survival (CSS) in the context of adverse pathologic features, including upstaging and upgrading.
Patients & Methods
After obtaining institutional review board approval, we identified 11,925 patients who underwent primary radical prostatectomy at Memorial Sloan Kettering Cancer Center (MSKCC) between 1987 and 2015. We also identified 4,868 patients who underwent primary radical prostatectomy at Cleveland Clinic Foundation (CCF) between 1987 and 2008. Patients were excluded if they were unable to be assigned a D’Amico risk classification due to missing data (N=462), leaving 16,341 patients in the final cohort.
We aimed to assess the association between pre-operative risk and the risk of BCR and distant metastases among men found to have adverse pathology. D’Amico risk classifications were used to identify clinically low, intermediate and high-risk PCa. We addressed the problem in both directions, that is, we asked both “For men with high-risk surgical pathology, is preoperative risk associated with outcome?” and “For men with low preoperative risk, is high-risk surgical pathology associated with outcome?”
For the first set of analyses, we examined the role of pre-operative risk among four cohorts of men who were identified based on the presence of four adverse pathologic features: men with extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI) and pathologic Gleason grade ≥ 7. In each cohort, we calculated Kaplan Meier (KM) estimates and used log rank tests to test for differences in BCR-free survival, metastasis-free survival and CSS between men with adverse pathologic features who had clinical low-risk disease and men who did not have clinical low-risk disease. To assess whether the association between pre-operative risk and oncologic outcomes for men with adverse pathology persist when controlling for other pathologic features, we created a multivariable Cox proportional hazards model that was adjusted for pre-operative PSA, pathologic Gleason grade (≤ 6, 7 or ≥ 8), and the presence of ECE, SVI and LNI (N0, N1, or Nx), and applied this model separately to each cohort. To investigate whether clinical risk affected the risk of BCR, distant metastasis, or CSS differently between the two cohorts, the analyses were repeated separately in each cohort, and heterogeneity Chi squared tests using Cochran’s Q were performed. Since data was available for Cleveland Clinic patients to 2008, and for MSKCC patients to 2015, we repeated the analyses excluding MSKCC patients from 2009 to 2015 as sensitivity analyses.
For the second set of analyses, we included D’Amico low-risk, androgen deprivation naïve patients who underwent RP at CCF between 1987 and 2008 and who had subsequent follow-up. Upgrading and upstaging were categorized in several ways: Gleason 3+4 upgrading; Gleason 4+3 upgrading; Gleason ≥8 upgrading; pT3a upstaging; SVI or LNI upstaging; and Gleason ≥8 or SVI or LNI. Analyses were performed using Stata 13.1 (StataCorp, College Station, TX) and SPSS version 22 (IBM, Chicago, IL).
Results
Patient and disease characteristics stratified by site and by D’Amico risk are reported in Table 1a and 1b, respectively. In the combined cohort, 6,371 (39%) men had D’Amico clinically low-risk PCa, while 9,970 (61%) had D’Amico intermediate or high-risk PCa. Among the 16,341 men in this cohort, 2,827 (men had biochemical recurrence, 679 men developed distant metastases, and 295 men died of PCa. Median follow-up for survivors was 4.3 years (interquartile range 1.8, 8.0). There were 5,596 and 2,124 men followed for 5 and 10 years without BCR, respectively. Meanwhile, 7,028 and 2,900 men were followed for 5 and 10 years without distant metastasis, respectively. A total of 2,121 men were followed for 10 years without BCR, distant metastasis, or death from PCa.
Table 1a.
Patient and disease characteristics for the combined cohort analysis (N=16341).
| CCF (N=4756) |
MSKCC (N=11585) |
|
|---|---|---|
| Median age at surgery (IQR) | 61 (56, 65) | 61 (56, 66) |
| Median pre-operative PSA (N=16153) (IQR) | 5.9 (4.5, 8.7) | 5.4 (3.9, 8.0) |
| Biopsy Gleason score (N=15941) | ||
| ≤ 6 | 3000 (63%) | 4988 (45%) |
| 7 | 1379 (29%) | 4950 (44%) |
| 8–10 | 368 (7.8%) | 1256 (11%) |
| Clinical T stage (N=16092) | ||
| T0 | 0 (0%) | 11 (0.1%) |
| T1 | 3192 (68%) | 6769 (59%) |
| T2 | 1458 (31%) | 4109 (36%) |
| T3 | 47 (1.0%) | 502 (4.4%) |
| T4 | 0 (0%) | 4 (<0.1%) |
| Clinical D’Amico risk classification | ||
| Low | 2441 (51%) | 3930 (34%) |
| Intermediate | 1691 (36%) | 5354 (46%) |
| High | 624 (13%) | 2301 (20%) |
| Pathologic Gleason Score (N=15159) | ||
| ≤ 6 | 1392 (33%) | 2931 (27%) |
| 7 | 2545 (60%) | 6943 (64%) |
| 8–10 | 295 (7.0%) | 1053 (10%) |
| ECE (N=16282) | 1578 (33%) | 3979 (34%) |
| Seminal vesicle invasion (N=16287) | 406 (8.6%) | 1000 (8.7%) |
| Lymph node invasion (N=16329) | ||
| Positive | 123 (2.6%) | 847 (7.3%) |
| Negative | 2470 (52%) | 9736 (84%) |
| No LND performed | 2163 (45%) | 990 (8.6%) |
| Positive surgical margins (N=16298) | 1372 (29%) | 2164 (19%) |
| Year of surgery | ||
| 1987–1990 | 201 (4.2%) | 125 (1.1%) |
| 1991–1995 | 532 (11%) | 744 (6.4%) |
| 1996–2000 | 1037 (22%) | 1439 (12%) |
| 2001–2005 | 2001 (42%) | 2831 (24%) |
| 2006–2010 | 985 (21%) | 3621 (31%) |
| 2011–2015 | 0 (0%) | 2825 (24%) |
Table 1b.
Patient and disease characteristics for both MSKCC and CCF patients (N=16,341) stratified by clinical D’Amico risk.
| Low Risk (N=6371) | Intermediate or High Risk (N=9970) | |
|---|---|---|
| Median at age surgery (IQR) | 59 (55, 64) | 62 (57, 66) |
| Median pre-operative PSA (IQR) (N=16153) | 5.0 (3.8, 6.4) | 6.2 (4.4, 10.5) |
| Biopsy Gleason score (N=15941) | ||
| ≤6 | 6371 (100%) | 1617 (17%) |
| 7 | 0 (0%) | 6329 (66%) |
| 8–10 | 0 (0%) | 1624 (17%) |
| Clinical T stage (N=16092) | ||
| T0 | 0 (0%) | 11 (0.1%) |
| T1 | 5098 (80%) | 4863 (50%) |
| T2 | 1273 (20%) | 4294 (44%) |
| T3 | 0 (0%) | 549 (5.6%) |
| T4 | 0 (0%) | 4 (<0.1%) |
| Clinical D’Amico risk classification | ||
| Low | 6371 (100%) | 0 (0%) |
| Intermediate | 0 (0%) | 7045 (71%) |
| High | 0 (0%) | 2925 (29%) |
| Pathologic Gleason Score (N=15159) | ||
| ≤6 | 3176 (52%) | 1147 (13%) |
| 7 | 2895 (47%) | 6593 (73%) |
| 8–10 | 60 (1.0%) | 1288 (14%) |
| ECE (N=16287) | 1016 (16%) | 4541 (46%) |
| Seminal vesicle invasion (N=16282) | 70 (1.1%) | 1336 (13%) |
| Lymph node invasion (N=16329) | ||
| Positive | 23 (0.4%) | 947 (10%) |
| Negative | 3712 (58%) | 8494 (85%) |
| No LND performed | 2632 (41%) | 521 (5.2%) |
| Positive surgical margins (N=16298) | 1027 (16%) | 2509 (25%) |
| Year of surgery | ||
| 1987–1990 | 68 (1.1%) | 258 (2.6%) |
| 1991–1995 | 389 (6.1%) | 887 (8.9%) |
| 1996–2000 | 1146 (18%) | 1330 (13%) |
| 2001–2005 | 2515 (39%) | 2317 (23%) |
| 2006–2010 | 1717 (27%) | 2889 (29%) |
| 2011–2015 | 536 (8.4%) | 2289 (23%) |
Oncologic outcomes were assessed in four cohorts of men. The ECE cohort included 5,557 men, of whom 1,016 (18%) had low-risk disease. The SVI cohort included 1,406 men, with 70 of those men having low-risk disease (5%). The LNI cohort included 970 men, with 23 men having low-risk disease (2.4%). 2163 (45%) of the CCF patients did not undergo lymphadenectomy and was mainly due to the low nomogram-predicted risk of LNI based on clinical features and non-suspicious nodes at the time of RP. The largest cohort included 10,836 men with pathologic Gleason scores ≥ 7, of whom 2,955 had low-risk disease (27%) preoperatively.
The results of our first set of analyses are shown in table 2a, 2b, 2c. Amongst men with adverse features on surgical pathology, preoperative low-risk status was associated with an approximate 50% and 70% reduction in the risk of PCa death and metastasis respectively. The results for LNI differ slightly, but these analyses are based on very small numbers of patients and are associated with very wide confidence intervals. KM rates of BCR-free survival, metastasis-free survival and CSS of patients with pathologic ECE, SVI, Gleason ≥7 and LNI and stratified by clinical risk are shown in supplementary figures 1, 2 and 3, respectively.
Table 2a.
Univariable and multivariable analysis of the association between preoperative risk and biochemical recurrence in patients with adverse pathology. For example, the hazard ratio (HR) of 0.26 for extracapsular extension means that, amongst men with extracapsular extension, the hazard of recurrence was about two-thirds lower in men who had preoperative low-risk features in comparison to men with preoperative intermediate or high-risk disease.
| Adverse Feature (Low-risk vs. Intermediate/High Risk) |
Univariable | Multivariable | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Extracapsular extension | 0.26 (0.22, 0.31) | <0.0001 | 0.49 (0.40, 0.59) | <0.0001 |
| Seminal vesicle invasion | 0.44 (0.30, 0.64) | <0.0001 | 0.65 (0.44, 0.96) | 0.029 |
| Pathologic Gleason 7+ | 0.25 (0.22, 0.29) | <0.0001 | 0.46 (0.39, 0.53) | <0.0001 |
| Lymph node invasion | 0.46 (0.25, 0.87) | 0.016 | 0.47 (0.23, 0.95) | 0.036 |
Table 2b.
Univariable and multivariable analysis of the association between preoperative risk and distant metastasis in patients with adverse pathology.
| Adverse Feature (Low-risk vs. Intermediate/High Risk) |
Univariable | Multivariable | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Extracapsular extension | 0.14 (0.09, 0.22) | <0.0001 | 0.32 (0.19, 0.51) | <0.0001 |
| Seminal vesicle invasion | 0.24 (0.10, 0.57) | 0.001 | 0.30 (0.12, 0.73) | 0.008 |
| Pathologic Gleason 7+ | 0.12 (0.08, 0.18) | <0.0001 | 0.30 (0.20, 0.47) | <0.0001 |
| Lymph node invasion | 0.10 (0.01, 0.70) | 0.020 | 0.09 (0.01, 0.69) | 0.020 |
Table 2c.
Univariable and multivariable analysis of the association between preoperative risk and death from prostate cancer in patients with adverse pathology.
| Adverse Feature (Low-risk vs. Intermediate/High Risk) |
Univariable | Multivariable | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Extracapsular extension | 0.15 (0.07, 0.29) | <0.0001 | 0.40 (0.19, 0.84) | 0.015 |
| Seminal vesicle invasion | 0.37 (0.14, 0.99) | 0.047 | 0.47 (0.17, 1.28) | 0.14 |
| Pathologic Gleason 7+ | 0.19 (0.11, 0.33) | <0.0001 | 0.48 (0.26, 0.87) | 0.016 |
| Lymph node invasion | 0.20 (0.03, 1.42) | 0.11 | 0.19 (0.03, 1.35) | 0.10 |
Since patients from two cohorts were included, we also investigated whether there was heterogeneity between institutions in the effect of clinical low-risk disease on oncologic outcomes. We found significant heterogeneity between sites for the outcome of BCR-free survival when comparing patients among patients with ECE or LNI, and for the outcomes of BCR-free and metastasis-free survival among patients with pathologic Gleason grade ≥7. For cases where significant heterogeneity in effect size was found, having clinical low-risk was associated with a reduction in risk of BCR or distant metastasis at both institutions, with one exception. The multivariable model for BCR-free survival among CCF patients with LNI showed a non-significant increase in risk of BCR for low-risk patients (HR 1.64, 95% CI 0.58, 4.66, p=0.4). However, there were only 5 patients from the CCF cohort who were clinically low-risk and had LNI.
As a sensitivity analysis, we dropped 4,428 MSKCC patients treated between 2009 and 2015 to restrict the cohort to the same years for both sites. No appreciable changes in the results were seen when excluding these patients.
Our second set of analyses examined whether pathologic upstaging or upgrading influenced survival outcomes in men with low-risk disease. Baseline characteristics for this group are described in table 3. Of the 2297 CCF D’Amico low-risk patients identified, 1,305 (57%) experienced any pathologic upgrading or upstaging, while 992 (43%) did not experience any pathologic upgrading or upstaging (Table 4). When isolating pT3a upstaging only, regardless of pathologic Gleason score, 402 (18%) patients experienced such reclassification, while 1858 (82%) did not. Kaplan-Meier estimates of 10 year CSS are presented in Table 4. Of all types of pathologic reclassification, only upgrading to Gleason ≥8 and upstaging to SVI or LNI were associated with worse CSS. However, reclassification on the basis of Gleason ≥8 or SVI or LNI was observed in only 62 (3%) patients. As there were only 8 deaths from PCa in the CCF cohort, a multivariable analysis was not performed.
Table 3.
Patient characteristics for the CCF cohort analysis (N=2297)
| Median age at surgery (IQR) | 60 (55, 64) |
| Median pre-operative PSA (IQR) | 5.2 (4.2, 6.5) |
| Biopsy Gleason score (%) | |
| ≤ 6 | 2297 (100%) |
| Clinical T stage | |
| T1a | 7 (0.3%) |
| T1b | 15 (0.7%) |
| T1c | 1,807 (78.7%) |
| T2a | 468 (20.3%) |
| D’Amico risk classification | |
| Low | 2297 (100%) |
| Year of surgery | |
| 1987–1990 | 63 (3%) |
| 1991–1995 | 218 (9%) |
| 1996–2000 | 489 (21%) |
| 2001–2005 | 1,090 (48%) |
| 2006–2008 | 437 (19%) |
Table 4.
10-year Kaplan-Meier unadjusted estimates with 95% confidence intervals for cancer-specific survival among D’Amico low-risk CCF patients who underwent RP between 1987 and 2008 (N=2297) and stratified by type of pathologic reclassification.
| Type of Reclassification | N | 10-Year CSS | p value |
|---|---|---|---|
| Upgrade to Gleason 3+4 | 0.9 | ||
| Yes | 952 (49%) | 100% (95% CI N/A) | |
| No | 992 (51%) | 100% (95% CI N/A) | |
| Missing Gleason Breakdown | 127 | ||
| Upgrade to Gleason 4+3 | 0.9 | ||
| Yes | 74 (7%) | 100% (95% CI N/A) | |
| No | 992 (93%) | 100% (95% CI N/A) | |
| Missing Gleason Breakdown | 127 | ||
| Upgrade to Gleason ≥ 8 | <0.001 | ||
| Yes | 28 (3%) | 94% (95% CI 83–100) | |
| No | 992 (97%) | 100% (95% CI N/A) | |
| Upstage to pT3a | 0.7 | ||
| Yes | 402 (18%) | 99% (95% CI 97–100) | |
| No | 1858 (82%) | 99% (95% CI 99–100) | |
| Upstage to SVI or LNI | <0.001 | ||
| Yes | 37 (3%) | 96% (95% CI 89–100) | |
| No | 992 (97%) | 100% (95% CI N/A) | |
| SVI, LNI or Gleason ≥ 8 | 0.001 | ||
| Yes | 62 (6%) | 97% (95% CI 93–100) | |
| No | 992 (94%) | 100% (95% CI N/A) |
Discussion
AS in patients with low-risk PCa is underutilized 13, and may be attributed, in part, to the perceived risk of upgrading or upstaging at RP. Our analysis of patients from MSKCC and CCF who underwent RP between 1987 and 2015 suggests that in patients who are candidates for AS based on clinical features, pathologic upgrading or upstaging from clinical low-risk PCa has limited long-term effects on BCR, metastasis-free survival and CSS rates among patients with adverse pathologic features. Intuitively, we believe that when matched for adverse pathologic findings, clinically low-risk patients will have superior outcomes when compared to clinically intermediate or high-risk patients. We therefore sought to describe the magnitude of this difference in outcome. We found that clinically low-risk patients with adverse pathologic features exhibited significantly better outcomes than patients with clinically intermediate or high-risk features. In addition, our analysis of 2297 CCF patients with clinical low-risk PCa who underwent RP suggests that the deleterious effects of adverse pathologic reclassification on CSS are of questionable significance. While patients with arguably the most severe forms of adverse pathologic reclassification (Gleason score ≥8, SVI and/or LNI) did exhibit significantly worse CSS rates, these forms of reclassification from low-risk disease were rare. Our results suggest that the risk of upgrading/upstaging from low-risk disease should not deter clinicians from offering AS to clinical low-risk patients.
Our results beg the question: why do patients with adverse pathological features have differing outcomes based on clinical features? We believe that the overall clinical picture of low-risk patients should be considered, regardless of final pathology. Clinically low-risk patients present not only with Gleason scores ≤6, but also with low serum PSA levels (<10 ng/ml) and clinically undetectable or minimally detectable disease volume (T1c or T2a). While we did not perform tumor volumetric analysis on our cohorts, we suspect that we would observe smaller tumor volumes in clinically low-risk patients. We also believe that the biology of clinical low-risk PCa that exhibit adverse pathologic features is different than those that present clinically with adverse features, even if the final pathologic specimens are categorized similarly. There is strong evidence to suggest that there is considerable biologic heterogeneity among clinical risk groups and we believe that these prior findings help to explain our results 10.
We believe that our results confirm the utility of standard TRUS biopsy alone as a risk-assessment tool for low-risk patients who are candidates for AS. While prostate mpMRI, molecular-based biomarkers and genomic classifiers aim to identify patients who potentially harbor more adverse pathologic features than clinically detected using traditional techniques, we question the value of identifying those that potentially harbor ECE or Gleason 3+4 disease, as their BCR, metastasis and survival rates do not seem to be adversely affected when compared to those without such pathologic features. Furthermore, we observed that the absolute rate of the most severe forms of pathologic reclassification is very low. Whether adjunctive tools are both sufficiently accurate and cost effective for identifying the most severe adverse pathologic features in a clinically low-risk population remains to be seen.
Additionally, we observed that among low-risk patients with adverse pathologic features and who developed BCR, the risk of subsequent PCa-related metastases or death was approximately half the risk of BCR, suggesting that BCR does not necessarily lead to morbidity from metastases or death. These findings are consistent with previous reports 12.
Our study results reflect those of previous analyses. In a recent study, similar BCR rates were seen among AS candidates who were pathologically upgraded from Gleason 3+3 to 3+4 14. Meanwhile, Muralidhar et al. demonstrated that patients with occult T3 disease exhibit better CSS than patients with clinical T3 disease 15. However, we believe our study is the first to analyze BCR, metastasis-free and survival rates from the viewpoint of both adverse pathologic features, stratified by D’Amico clinical risk and from the viewpoint of pathologic upstaging from clinical D’Amico low-risk disease. Our analyses from both vantage points reached similar conclusions. In addition, we believe our analysis of 2297 CCF patients with clinical low-risk disease and who were pathologically upgraded and/or upstaged at RP is the first to study various definitions of pathologic reclassification with such granularity.
Our study carries several limitations. Firstly, the retrospective nature of our study lends itself to inherent biases. For example, our cohorts likely carry a selection bias, since many patients diagnosed with clinically very-low or low-risk disease at our respective institutions pursue AS rather than curative treatments such as surgery or radiation. However, AS for low-risk disease as the accepted standard is relatively novel and was not widely employed at our respective institutions until the latter part of the study period, thus limiting the selection bias in our study population. Furthermore, previous reports have found no difference in pathologic outcomes between low-risk, AS patients who underwent deferred RP versus clinically similar patients who underwent immediate RP16. Secondly, prostate mpMRI and other adjunctive classifying tools were not routinely performed on our patient population. However, in current contemporary practice, only 6.5% of biopsy-naïve men undergo prostate MRI prior to biopsy17. Our study is therefore germane to the current state of urologic practice. Moreover, although a recent randomized trial concluded that MRI with MRI-fusion biopsy identifies more significant (Gleason ≥3+4) PCa than standard TRUS biopsy in biopsy-naïve men18, only 3% of patients in the CCF cohort experienced significantly adverse pathologic upgrading/upstaging. This calls into question the need for such adjunctive tools in a clinically low-risk population. Thirdly, while both cohorts were similar in most respects, heterogeneity analysis revealed that certain clinical characteristics of the MSKCC and CCF cohorts had different and statistically significant effects on BCR, metastases-free and CSS. Finally, our study period was long (1988–2015) and the Gleason scoring system changed over the course of this period. Of note, many patients who were graded as Gleason 3+3 in the pre-2005 system would have been scored as Gleason 3+4 in the 2005 International Society of Urological Pathology (ISUP) update. The 2005 update has led to a “Will Rogers Effect”: because more aggressive Gleason 6 tumors were reclassified, the Gleason reclassification lowered the risk of both Gleason 6 and Gleason 7 patients. As a result, any bias introduced by including pre-2005 patients is in the opposite direction to our hypothesis, in that contemporary (post-2005) low-risk patients are at lower risk than historical (pre-2005) patients and it is thus even less likely that upstaging or upgrading would lead to poor clinical outcome.
Despite these limitations, we believe our study contributes significant understanding regarding the long-term outcomes of clinical low-risk PCa patients regardless of adverse reclassification at RP. We believe that patients who exhibit either upgrading or upstaging at RP should be counseled that their long-term risk of adverse outcome is not necessarily worse than patients without pathologic reclassification. In particular, predicted risk of upstaging or upgrading should not be used to recommend immediate treatment in low-risk PCa patients who are eligible for AS.
Conclusion
Clinical low-risk patients with adverse pathologic findings at radical prostatectomy have substantially lower rates of important oncologic outcomes compared to those with higher clinical risk and not substantially different than low-risk patients with without upgrading or upstaging. These results call into question the risk of adverse pathologic reclassification as an endpoint to counsel patients about the merits and risks of AS.
Supplementary Material
Footnotes
Conflicts of Interest: None for all authors.
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