External validation of the Briganti nomogram to estimate the probability of specimen-confined disease in patients with high-risk prostate cancer

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1 External validation of the Briganti nomogram to estimate the probability of specimen-confined disease in patients with high-risk prostate cancer Mathieu Roumiguié, Jean-Baptiste Beauval, Thomas Filleron*, Thibaut Benoit, Pascal Rischmann, Alexandre de la Taille, Laurent Salomon, Michel Soulié, Bernard Malavaud and Guillaume Ploussard Department of Urology, CHU Rangueil, Toulouse, *Department of Biostatistics, Insitut Claudius Régaud, Toulouse and Department of Urology, CHU Mondor, Créteil, France Objective To establish an external validation of the updated nomogram from Briganti et al., which provides estimates of the probability of specimen-confined disease using the variables age, prostate-specific antigen (PSA), clinical stage and biopsy Gleason score in preoperatively defined high-risk prostate cancer (PCa). Patients and Methods The study included 523 patients with high-risk PCa, as defined by d Amico classification, undergoing radical prostatectomy (RP) and bilateral lymph node dissection in one of two academic centres between 1990 and Specimen-confined disease was defined as pt2 pt3a node-negative PCa with negative surgical margins. The receiver operator characteristic (ROC) curve was obtained to quantify the overall accuracy (area under the curve [AUC]) of the model in predicting specimen-confined disease. A calibration curve was then constructed to illustrate the relationship between the risk estimates obtained by the model (x-axis) and the observed proportion of specimen-confined disease (y-axis). The Kaplan Meier method was used to assess biochemical recurrence (BCR)-free survival. Results Patients median age and PSA level were 64 years and 21 ng/ml, respectively. The definition of high-risk PCa was based on PSA level only in 38.3%, a biopsy Gleason score >7 in 34.5%, a clinical stage >T2b in 6.9%, or a combination of these two or three factors in 20.3% of patients. Positive surgical margins were observed in 43.6%, with a rate of 14.8% in pt2 cancers and lymph node metastasis in 12.1% of patients. pt stage was pt0 in 0.9%, pt2 in 28.9%, pt3a in 37.5% and pt3b 4 in 32.7% of patients. Overall, 44.4% of patients (N = 232) had specimen-confined disease. PSA and ct stage were independently predictive of specimen-confined disease. The median (range) 2-, 5-, and 8-year BCR-free survival rates were significantly higher in specimen-confined disease as compared with non-specimen-confined disease: ( ) vs ( )%, ( ) vs ( )% and ( ) vs ( )%, respectively (P < 0.001). The ROC curve analysis showed relevant accuracy of the model (AUC , 95% CI ) although the calibration plot suggested that, for risks ranging from 0.3 to 0.5, the odds of extracapsular extension were underestimated. Conclusions This external validation of the Briganti nomogram shows relevant accuracy, although the relative imprecision for intermediate risk may limit its clinical relevance. Our follow-up findings confirm the large proportion of specimen-confined PCa with good oncological outcomes in this heterogeneous subgroup of patients with high-risk PCa. Keywords prostate cancer, radical prostatectomy, high-risk, specimen confined disease, nomogram Introduction In Europe, prostate cancer (PCa) is the most common solid malignancy, with an incidence rate of 214 cases per 1000 men, and the second most common cause of death attributable to cancer [1]. Despite the widespread use of PSA screening, some patients are diagnosed with locally advanced and/or high-risk PCa. According to the D Amico classification, patients with PSA >20 ng/ml and/or a preoperative Gleason score of 8 10 and/or clinical stage T2careconsideredtobeathighriskof disease progression, despite radical treatment with curative intent [2]. doi: /bju Published by John Wiley & Sons Ltd. BJU Int 2014; 114: E113 E119 wileyonlinelibrary.com

2 Roumiguié et al. For patients with high-risk PCa, external beam radiation therapy associated with hormone therapy and radical prostatectomy (RP) are currently two recommended treatment options [3]. Nevertheless, treatment decision-making favours radiotherapy rather than surgery, even in the urologist community [4]. Long-term follow-up series of patients with high-risk PCa undergoing RP, with or without adjuvant therapies, however, have shown good oncological outcomes, highlighting the potential underuse of surgery in such settings [5]. Retrospective population-based studies recently suggested that oncological outcomes in terms of disease-specific mortality were similar in patients with high-risk PCa treated with RP as compared with those undergoing radiotherapy combined with androgen deprivation therapy [6,7]. Evidence also suggests that patients with high-risk PCa are those who benefit the most from RP [7 9]. Such good cure rates after surgery depend, at least in part, on the final pathological assessment that leads physicians to either promote multiple-treatment strategies such as adjuvant radiotherapy or not. Large multicentre series have reported that a significant percentage ( 30%) of PCa preoperatively defined as high risk was organ-confined and favourable in RP specimens [10 12]. These findings have led to the internal development of a nomogram aiming at predicting organ-confined disease in high-risk localized PCa. Such a tool, based on available clinical variables, may be routinely used before treatment decision-making to promote either RP or radiotherapy combined with androgen deprivation therapy. Its predictive value was found to be relevant (area under the curve [AUC] 0.72) in a training cohort of 1366 patients [13]. In the present study, we aimed to validate this predictive tool externally in a French multicentre cohort of patients with high-risk PCa treated with RP. Patients and Methods We retrospectively examined the data of 815 patients who underwent RP and bilateral extended pelvic lymph node dissection for clinically high-risk PCa (d Amico risk classification: PSA >20 ng/ml, clinical stage T2c or biopsy Gleason sum 8 10) between 1990 and 2013 in two French academic centres. Of those, we excluded 292 men because of missing information on preoperative PSA, Gleason score, clinical stage and pathological T stage. For the final analysis, all 523 patients included had complete preoperative data including age, PSA, clinical stage and biopsy Gleason score. The clinical stage was assigned according to the 2002 TNM staging system, prostate biopsy cores were obtained under TRUS guidance using a >10-core biopsy protocol, and pretreatment PSA was measured before DRE. Dedicated genitourinary pathologists assessed biopsy and pathological grading according to the Gleason grading system before 2005 and the modified International Society of Urological Pathology Gleason score after Prostate specimen were analysed according to the Stanford protocol and the pt stage according to the 2002 American Joint Committee on Cancer staging system for PCa. All patients were preoperatively staged for metastases with contrast-enhanced abdominopelvic CT and bone scintigraphy. As previously reported by Briganti et al. [13], specimen-confined disease was defined as a pt2 T3a PCa with negative surgical margins and no lymph node invasion. The updated nomogram, which estimates of the likelihood of specimen-confined disease from age, PSA, clinical stage and biopsy Gleason score, was used for each patient [13]. Biochemical recurrence (BCR) was defined as a PSA value of 0.2 ng/ml after RP, confirmed by at least two consecutive measurements. Statistical Analysis Data were summarised using frequency and percentages for categorical variables and median and ranges for continuous variables. Comparisons between groups were performed using the chi-square of Fisher s exact test for qualitative variables and the Mann Whitney test for quantitative variables. The performance of the model was quantified with respect to discrimination and calibration. Discrimination was quantified with the area under the receiver operator characteristic (ROC) curve. Calibration (i.e. agreement between observed outcome frequencies and predicted probabilities) was studied, with graphic representations of the relationship between the observed outcome frequencies and the predicted probabilities (calibration curves) for groups of patients. BCR-free survival was calculated from the date of surgery to the date of diagnosis of BCR. BCR was calculated using the Kaplan Meier method and comparison between groups was performed using the log-rank test. A logistic regression model with specimen-confined as the response variable and PSA, Gleason score and clinical stage at diagnosis as the predictor variables. All reported P values are two-sided. For all statistical tests, differences were considered significant at the 5% level. Statistical analyses were performed using the STATA 12.0 software and the R package RMS. Results Descriptive patient characteristics are shown in Table 1. The definition of high-risk PCa was based on PSA only in 38.3% of patients, clinical stage only in 6.9% of patients, and on biopsy Gleason score only in 34.5% of patients. Two and three factors were combined in 17.8% and 2.5% of patients, respectively. E114

3 Validation of nomogram for probability of specimen-confined PCa Table 1 Descriptive statistics of 523 patients with clinical high-risk prostate cancer treated with radical prostatectomy and pelvic lymph node dissection. Overall Non-specimen confined disease Specimen-confined disease P Patients, N (%) (55.6) 232 (44.4) Median (range) age, years 64.0 ( ) 64.0 ( ) 64.0 ( ) Median (range) PSA, ng/ml 21.0 ( ) 24.0 ( ) 12.0 ( ) <0.001 High-risk prostate cancer factors, N (%) One factor PSA>20 ng/ml or 200 (38.3) 123 (61.5) 77 (38.5) Clinical stage >T2b or 36 (6.9) 19 (52.8) 17 (47.2) Biopsy Gleason score> (34.5) 71 (39.4) 109 (60.6) Two factors 94 (18.0) 68 (72.3) 26 (27.7) Three factors 13 (2.5) 10 (76.9) 3 (23.1) Clinical stage, N (%) T1 271 (51.8) 149 (51.2) 122 (52.6) T2 194 (37.1) 101 (34.7) 93 (40.1) T3 58 (11.1) 41 (14.1) 17 (7.3) Biopsy Gleason sum, N (%) <0.001 <7 51 (9.8) 16 (5.5) 35 (15.4) (48.5) 133 (45.7) 118 (52.0) >7 216 (41.7) 142 (48.8) 74 (32.6) Missing Specimen Gleason sum, N (%) < (57.6) 149 (49.5) 152 (50.5) >7 216 (41.3) 142 (65.7) 74 (34.3) Missing 6 (1.1) 0 (0.0) 6 (100) Surgical margin, N (%) <0.001 R0 295 (56.4) 63 (21.6) 232 (100.0) R1 228 (43.6) 228 (78.4) 0 (0.0) Pathological stage, N (%) <0.001 pt0 5 (0.9) 0 (0.0) 5 (2.2) pt2 151 (28.9) 24 (8.2) 127 (54.7) pt3a 196 (37.5) 96 (49.0) 100 (51.0) pt3b 170 (32.5) 170 (100) 0 (0.0) pt4 1 (0.2) 1 (0.3) 0 (0.0) Number of nodes removed, N (range) 10 (1 39) 10 (1 39) 12 (1 32) Missing, N Lymph node invasion, N (%) No 459 (87.9) 228 (78.4) 231 (100) Yes 63 (12.1) 63 (21.6) 0 (0) Missing Adjuvant treatment PSA failure, N 209 (40.0) 159 (76.1) 50 (23.9) <0.001 Follow-up, months Mean Median Range Overall, specimen-confined disease was found in 44.4% (N = 232) of patients. The median (range) serum PSA levels were 12.0 (0.3 92) ng/ml and 24.0 ( ) ng/ml for patients with and without specimen-confined disease, respectively (P < 0.001). Proportions of clinical stage were significantly different between patients with and without specimen-confined disease (ct1: 52.6% (N = 122) vs 51.2% (N = 149); ct2: 40.1% (N = 93) vs 34.7% (N = 101); and ct3: 7.3% (N = 17) vs 14.1% (N = 41); P = 0.04). The proportion of biopsy Gleason sum >7 was greater in the group of patients with specimen-confined disease than in those with non-specimen-confined disease (32.6% (N = 74) vs 48.8% (N = 142); P < 0.001). In the study population overall, specimen pathological features were: pt0: 1%; pt2: 28.9%; pt3a: 37.5%; pt3b: 32.6%; and pt4: 0.2%. Positive surgical margins were reported in 43.6% of patients (N = 228) and lymph node metastasis in 12.1% (N = 63) of patients. The rates of positive margins in pt2 and pt3 cancers were 14.8 and 55.7%, respectively. The proportion of specimen Gleason sum > 7 was higher in the group without specimen-confined disease (65.7%, N = 142 vs 34.3%, N = 74; P < 0.001). The number of nodes removed was not different between the two groups of patients. Futhermore, the rate of PSA failure was 40% after a mean follow-up of 25.2 months. This progression rate was lower in the group with specimen-confined disease (23.9%, N = 50 vs 76.1%, N = 159; P < 0.001). The ROC curve analysis showed relevant accuracy of the model (AUC 0.65, 95% CI (Fig. 1)). On the calibration plot, the predicted probability of the model is E115

4 Roumiguié et al. Fig. 1 Receiver operator characteristic (ROC) and area under curve of the nomogram described by Briganti et al. [13] in 523 patients with high-risk prostate cancer who underwent radical prostatectomy. Sensitivity represented on the x-axis and the observed proportion of specimen-confined disease is accounted on the y-axis. The 45 line indicates perfect congruity between predicted probability and observed proportion of specimen-confined disease. An underestimation of the odds of non-specimen-confined disease was noted for risks between 30 and 50% (Fig. 2). No significant changes have been reported regarding the performance of the nomogram when comparing three study periods (AUC 0.66; P = 0.018), (AUC 0.62; P = 0.03) and (AUC 0.65 P < 0.001). Table 2 shows the multivariable logistic regression model testing the association between predictors and specimen-confined disease at RP. Both PSA and clinical stage were significantly associated with the presence of specimen-confined disease. Conversely, biopsy Gleason sum >7 was not found to be an independent predictor of specimen-confined disease (P = 0.058). In the overall cohort, the mean (range) 2-, 5-, and 8-year BCR-free survival rates were ( )%, ( )% and ( )%, respectively. Figure 3 shows Kaplan Meier curves for the BCR-free survival rates according to specimen-confined disease at RP. The rate of BCR-free survival in specimen-confined disease was significantly higher at 2, 5 and 8 years (log-rank test, P < 0.001). Discussion Area under ROC curve = Specificity Radical prostatectomy has gained acceptance as a treatment option for patients with high-risk disease and is currently recommended as a treatment option in guidelines. RP, either alone or combined with other treatments, has been shown to have good oncological outcomes in large multicentric series [10 12]. Post-surgery recurrence risk depends mainly on final pathological assessment in RP specimens; therefore, an accurate prediction of probability of disease recurrence is essential for proper patient selection and for treatment decision-making. Preoperatively, the identification of high-risk PCa can be based on three well-defined predictors of the disease extent and outcome after treatment as defined by d Amico et al. [2]. Several preoperative nomograms or scores have been developed and validated in internal and external studies, documenting a high level of consistency [14,15]. Nevertheless, the decision to perform surgery or radiotherapy is critical in cases of high-risk PCa, as many urologists consider radiotherapy combined with long-term androgen deprivation therapy in very high-risk PCa (seminal vesicle involvement). RP series have highlighted the great heterogeneity of preoperatively defined high-risk PCa with a significant rate of favourable organ-confined disease. The validation of a nomogram that would predict these favourable cases would be of great value. Patients with favourable organ-confined disease would be good candidates for RP and for radiotherapy with or without short-term androgen deprivation therapy. The type of surgery would also be different for these patients, including nerve-sparing procedure possibilities. Nevertheless, despite a good predictive accuracy among different risk groups, certain inconsistencies have been reported regarding high-risk cases [12,16 18]. Recently, Briganti et al. [13] assessed a new nomogram aimed at predicting favourable final pathology (pt2 pt3a, pn0 with no surgical margin). In the present study, we report its external validation. We found that accuracy was lower than the internal validation (area under the ROC curve 0.65 in the present study vs 0.72 in the study by Briganti et al. [13]). For intermediate risk, the calibration plot showed an underestimation of non-specimen-confined disease. Comparison of the cohorts in both the internal validation study and the present study showed that the median PSA level (21.3 vs 21.0 ng/ml), overall percentage of surgical margins (44.9 vs 43.6%) and median number of lymph nodes removed were similar. By contrast, in the Briganti et al. study, the percentage of clinical tumour stage T3 was larger (57 vs 11.1%), and proportion of biopsy Gleason score >7 was lower (25.4 vs 41.7%) than in the present study population. This difference in clinical stage could explain the better predictive accuracy observed by Briganti et al. Finally, the 8-year BCR-free survival rate was lower in the present study compared with that reported in the initial study by Briganti et al. (34.6 vs 59.4%); this can be explained by a significantly lower rate of adjuvant therapies in our population (5.5 vs 48.1%) and highlights the potential need for multiple-treatment strategies in this category of patients with high-risk PCa. Unfortunately, no data concerning the cancer-specific and the overall survival rates are available to draw any strong conclusions. E116

5 Validation of nomogram for probability of specimen-confined PCa Fig. 2 Nomogram calibration plot. The dotted plot indicates the location of the ideal nomogram, in which actual and predicted probabilities are identical. Expected performance on future data represented through the solid line. ROC, receiver operator characteristic. Actual Probability Dxy C (ROC) R2 D U Q Brier Intercept Slope Emax S:z S:p Ideal Logistic calibration Nonparametric Grouped observations Predicted Probability Table 2 Multivariable analysis predicting specimen-confined disease (pt2 3a R0 pn0) in 523 patients with clinically high-risk prostate cancer treated with radical prostatectomy and pelvic lymph node dissection. Odds ratio (95% CI) PSA 0.96 (0.95;0.97) <0.001 Clinical stage T1 1 T (0.18;0.74) T (0.09;0.38) <0.001 Biopsy Gleason sum < (0.70;1.57) > (0.27;1.02) Recently Mearini et al. [19] reported the first external validation of Briganti s nomogram in a cohort of 623 men with high-risk PCa. Preoperative PSA, biopsy Gleason score and stage differed significantly (all P < 0.001) between men with specimen-confined disease and those without. The nomogram s calibration estimated by the AUC curve was similar to that of our study (AUC 66.3, 95% CI %); however, it appeared that their cohort was less homogeneous than ours, with only 29% of specimen-confined disease. In addition, the present findings provide additional information to that reported by Mearini et al. as we associated the oncological outcomes after RP with the external validation of the nomogram. We also used two prospective databases from two high-volume centres. According to findings published by P Briganti et al., we highlighted that the nomogram led to an improved selection of patients with organ-confined disease as well as with better oncological outcomes after RP. Briganti et al. showed that the rate of specimen-confined disease significantly decreased with the increasing number of risk factors. Patients with one, two and three risk factors for high-risk PCa had specimen-confined disease in 45.2, 22.6 and9%ofcases,respectively(p < 0.001). Likewise the oncological results depended on the number of high-risk preoperative criteria. Indeed, from the patients with specimen-confined disease, the 10-year BCR-free survival was higher in those with one high-risk preoperative criterion compared with those with two or more (1 vs >1, 68.2 vs 56.8%, respectively; P = 0.03) [13]. Ploussard et al. [10] studied the oncological outcomes of RP for 813 patients at high risk of PCa progression according to the preoperative d Amico criteria. The risk of PSA failure after treatment was 1.5-fold and 2.8-fold higher in men with two and three criteria of high-risk disease preoperatively, respectively. The authors reported that clinical stage ct2 was the most predictive factor for extraprostatic extension, that biopsy Gleason score 8 10 was the most predictive for pathological Gleason score 8 10 and PSA >20 ng/ml was the most predictive for positive surgical margins and seminal vesicle invasion [10]. Similarly, Spahn et al. reported that men with only PSA >20 ng/ml as a single prognostic factor had the highest chance of having favourable histopathology (pt3a or E117

6 Roumiguié et al. Biochemical recurrence-free survival rate, % Fig. 3 Kaplan Meier estimates of biochemical recurrence-free survival according to pathological status (non-specimen-confined Non SC green and specimen-confined: SC red log-rank test: P < 0.001) Years Non-SC SC Non specimenconfined disease Biochemical recurrence- free rate % (95% confidence interval) 2 years [30.64; 44.44] 5 years [19.97; 34.36] 8 years [12.50; 27.70] Specimenconfined disease [73.67; 86.29] [52.37; 72.74] [41.49; 66.74] lower, Gleason score <7, R0, pn0) compared with those having all three risk factors (27.1 vs 0%; P < 0.001). The authors concluded that men with a PSA >20 ng/ml and a biopsy Gleason score <7 would benefit the most from surgery. Conversely, the risk of death from PCa appears to be very high in patients with high grade disease or with all three risk factors, despite radical surgery and a high rate of adjuvant and salvage treatment strategies [11]. The present findings confirmed the favourable oncological outcomes after RP. Such outcomes may be linked to the high rate of organ-confined disease in patients with high-risk PCa. According to several studies including ours, 20 30% of patients were pathologically downstaged to pt2 at the time of surgery [10,11] Several limitations of the present study should be noted. First, the study period was long, ranging from 1990 to 2013 and, with only 523 patients, subgroup analysis based on years of surgery was not statistically achievable. Changes over time in pathological assessment (Gleason score grading), patient selection and operating techniques, such as nerve-sparing procedures impacting the margin status, were sources of unavoidable bias. No centralised pathology was available between the two centres. Finally, because of missing key data required for the predictive tool, the final analysis only included 523 of the 814 patients identified. In conclusion, RP is playing an increasingly important role in the management of high-risk PCa. Our findings confirm that patients with preoperative high-risk PCa represent a heterogeneous group with high likelihood of specimen-confined disease and that RP offers good oncological outcomes. We externally validated the Briganti nomogram for the selection of patients with high-risk PCa with favourable pathology and thus, for whom RP offers the best chance of cure. Despite its relevant accuracy, based on the present multicentric cohort, this nomogram showed a lower accuracy for intermediate risk disease. Improvements are required to aid treatment decision-making, for example, by adding new variables such as multiparametric MRI and biomarkers. Conflicts of Interest Authors had no conflicts of interest. References 1 Jemal A, Siegel R, Ward E et al. Cancer statistics CA Cancer J Clin 2008; 58: E118

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