7 Academic Department of Urology, Edouard Herriot Hospital, Hôpitaux de Paris, René Descartes University, Paris,

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1 BJUI BJU INTERNATIONAL The role of American Society of Anesthesiologists scores in predicting urothelial carcinoma of the upper urinary tract outcome after radical nephroureterectomy: results from a national multi-institutional collaborative study Alexis Arvin Berod 1, Pierre Colin 2, David R. Yates 3, Adil Ouzzane 4, Marie Audouin 5, Emilie Adam 7, Fr é d é ric Arroua 9, Charles Marchand 10, Pierre Bigot 11, Michel Souli é 12, Mathieu Roumigui é 12, Thomas Polguer 13, Sol è ne Gardic 14, Pascal Gr è s 15, Emmanuel Ravier 8, Yann Neuzillet 16, Francky Delage 17, Thomas Bodin 18, G é raldine Pignot 6 and Morgan Roupr ê t 3 on behalf of the French national database of UUT UC 1 Berod Academic Department of Urology, CHRU Grenoble, University of Grenoble, Grenoble, 2 Academic Department of Urology, CHU Lille, Lille Nord de France University, Lille, 3 Academic Department of Urology of la Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, University Paris VI, 4 Department of Urology, Institut Mutualiste Montsouris, 5 Department of Urology, Val de Gr â ce Military Hospital, 6 G é raldine Pignot Academic Department of Urology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, René Descartes University, Paris, 7 Academic Department of Urology, Edouard Herriot Hospital, Claude Bernard Lyon 1 University, 8 Academic Department of Urology, Lyon Sud Hospital, Claude Bernard Lyon 1 University, Lyon, 9 Academic Department of Urology, CHU Marseille, University of Marseille, Marseille, 10 Academic Department of Urology, CHRU Reims, University of Reims, Reims, 11 Academic Department of Urology, CHRU Angers, University of Angers, Angers, 12 Academic Department of Urology, CHRU Toulouse, University of Toulouse, Toulouse, 13 Academic Department of Urology, CHRU Clermont-Ferrand, University of Clermont-Ferrand, Clermont- Ferrand, 14 Academic Department of Urology, CHRU Limoges, University of Limoges, Limoges, 15 Academic Department of Urology, CHRU N î mes, University of Nimes, Nimes, 16 Department of Urology, Foch Hospital, University of Paris-Ile de France Ouest, Suresnes, 17 Academic Department of Urology, CHRU Brest, University of Brest, Brest, and 18 Academic Department of Urology, CHRU Poitiers, University of Poitiers, Poitiers, France Accepted for publication 8 February 2012 Study Type Prognosis (cohort) Level of Evidence 2b OBJECTIVE To evaluate the impact of American Society of Anesthesiologists (ASA) scores on the survival of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UUT-UC). What s known on the subject? and What does the study add? Upper urinary tract urothelial carcinoma (UUT-UC) is a rare disease, usually treated by nephroureterectomy, occurring in a population with a median age of 70 years and with frequent tobacco use and other comorbidities. We know that the American Society of Anesthesiologists (ASA) score has prognostic value in urological oncology but this has not been assessed in UUT-UC. Using a multi-institutional French database, we have shown that the 5-year cancerspecific survival differed significantly between ASA 1, ASA 2 and ASA 3 patients (83.8%, 76.9% and 70.6%, respectively; P = 0.01). ASA status had a significant impact on cancer-specific survival in univariate and multivariate analyses, with a threefold higher risk of mortality at 5 years for ASA 3 compared with ASA 1 patients ( P = 0.04). PATIENTS AND METHODS A retrospective multi-institutional cohort study of the French collaborative national database of UUT-UC treated by RNU in 20 centres from 1995 to The influence of age, gender and ASA score on survival was assessed using a univariable and multivariable Cox regression analysis with pathological features used as covariables BJU INTERNATIONAL 110, E1035 E1040 doi: /j x x E1035

2 BEROD ET AL. RESULTS Overall, 554 patients were included. The median follow-up was 26 months (10 48 months), and the median age was 69.5 years (61 76 years). In total, 114 (20.6%) patients were classified as ASA 1, 326 (58.8%) as ASA 2 and 114 (20.6%) as ASA 3. The 5-year recurrence-free survival ( P = 0.21) and metastasis-free survival ( P = 0.22) were not significantly different between ASA 1 (52.8% and 76%), ASA 2 (51.9% and 75.3%) and ASA 3 patients (44.1% and 68.2%, respectively). The 5-year cancer-specific survival differed significantly between ASA 1, ASA 2 and ASA 3 patients (83.8%, 76.9% and 70.6%, respectively; P = 0.01). ASA status had a significant impact on cancer-specific survival in univariate and multivariate analyses, with a threefold higher risk of mortality at 5 years for ASA 3 compared with ASA 1 patients ( P = 0.04). CONCLUSIONS ASA classification correlates significantly with cancer-specific survival after RNU for UUT-UC. It is a further pre-operative clinical variable that can be incorporated into future risk prediction tools for UUT-UC to improve their accuracy. KEYWORDS upper urinary tract urothelial carcinoma, radical nephroureterectomy, prognosis, ASA score INTRODUCTION Urinary upper tract urothelial carcinoma (UUT-UC) is a rare disease, but its incidence is rising and has recently been estimated to be up to two cases per personyears in the USA [ 1 ]. Outcome is variable, and many prognostic factors have been described including pathological and clinical parameters. Pathological factors, such as tumour stage, grade and lymph node involvement, remain the most accurate factors according to a recent literature review [2 ]. More recent data have suggested that lymphovascular invasion could be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) [3 ]. However, determining these pathologic factors requires extirpative surgery because they are currently not accurately defined by other means, even with endoscopic biopsies [4 ]. Recent guidelines [5 ] have confirmed that radical nephroureterectomy (RNU) with bladder cuff excision is the standard treatment, whereas conservative management, primarily endoscopic, is indicated in imperative or selected elective cases [5 ]. The clinical prognostic factors studied so far have failed to help physicians make treatment decisions, with contradictory results in the few studies available [6,7 ]. Comorbidities are highly prevalent in this population, with frequent exposure to tobacco and with a median age of diagnosis of approximately 70 years [8 ]. The American Society of Anesthesiologists (ASA) score was developed to predict perioperative outcome according to these comorbidities (see TABLE 1 American Society of Anesthesiologists (ASA) physical status classification ASA Score ASA 1 ASA 2 ASA 3 ASA 4 ASA 5 ASA 6 Table 1 ) and it has been shown to have a prognostic impact in oncological urology [9,10 ]. No study has assessed the prognostic significance of ASA scores in patients with UUT-UC. Our objective was to evaluate the impact of ASA scores on the survival of patients treated for UUT-UC with RNU from our multi-institutional collaborative database. MATERIAL AND METHODS Description Normal healthy patient Patient with mild systemic disease Patient with severe systemic disease Patient with severe systemic disease that is a constant threat to life Moribund patient who is not expected to survive without the operation Declared brain-dead patient whose organs are being removed for donor purposes A national database on UUT-UC was investigated to obtain the medical reports of patients managed in 20 French institutions from 1995 to After a preoperative evaluation (cystoscopy, urine cytology, intravenous urography or abdominopelvic CT scan and chest radiography or thoracic CT scan), all patients treated for UUT-UC with RNU with curative intent were included. The recorded included gender, age at diagnosis, ASA score (see Table 1 ), tumour characteristics (2009 UICC TNM classification, 1973 WHO grade classification, lymphovascular invasion, lymph node involvement and tumour location), management, follow-up and outcome events. Specimens were analysed by dedicated genitourinary pathologists according to standardized procedures. Patients with an incomplete data set (ASA score missing) or with metastatic disease at diagnosis were excluded from the current study. Any patients with a synchronous or previous history of urothelial bladder carcinoma were excluded. Open RNU was performed by a standard double-access procedure: a loin, subcostal or midline incision for the nephrectomy portion followed by an iliac incision for management of the distal ureter and extravesical excision of a bladder cuff. The kidney, ureter and a bladder cuff were excised en bloc. A regional lymphadenectomy was performed when nodal involvement was suspected from the preoperative evaluation or was discovered during the procedure. Approximately 20% of patients received adjuvant chemotherapy for high-risk pathological features, e.g T3 stage or N + ve. The database does not include accurate data on salvage chemotherapy. E BJU INTERNATIONAL

3 ASA SCORE AND UUT-UC TABLE 2 Study population characteristics All ( n = 554) For postoperative assessment the patients were followed up at 3 months, 6 months, then every 6 months for 3 years after RNU, and annually thereafter. Follow-up examinations included a history, physical examination, blood laboratory tests, urinary cytology, cystoscopic evaluation of the urinary bladder and a thoracoabdomino-pelvic CT scan. Disease recurrence was defined as any documented failure in the operative field, bladder or the contralateral UUT. Metastatic progression was defined as any recurrence in the regional lymph nodes or distant metastases. Chart reviews corroborated the cause of death. The 5-year RFS, metastasis-free survival (MFS) and CSS data were assessed according to these definitions. ASA 1 ( n = 114) ASA 2 ( n = 326) ASA 3 ( n = 114)P ASA Score Age at diagnosis (years) 0.59 Median Range Gender, n (%) 0.22 Female 175 (31.6) 34 (29.8) 112 (34.4) 29 (25.4) Male 379 (68.4) 80 (70.2) 214 (65.6) 83 (72.8) Pathological stage pt, n (%) 0.19 pta/ptis 152 (27.4) 38 (33.3) 81 (24.8) 33 (28.9) pt1 132 (23.8) 24 (21.1) 84 (25.8) 24 (21.1) pt2 57 (10.3) 10 (8.8) 30 (9.2) 17 (14.9) pt3 186 (33.6) 35 (30.7) 119 (36.5) 32 (28.1) pt4 27 (4.9) 7 (6.1) 12 (3.7) 8 (7.0) Grade (OMS 1973), n (%) 0.21 G1 45 (8.1) 12 (10.5) 23 (7.1) 10 (8.8) G2 195 (35.2) 46 (40.4) 117 (35.9) 32 (28.1) G3 314 (56.7) 56 (49.1) 186 (57.1) 72 (63.2) Lymph node status, n (%) 0.35 pnx 322 (58.1) 63 (55.3) 200 (61.3) 59 (51.8) pn0 186 (33.6) 43 (25.4) 99 (30.4) 44 (38.6) pn1/2 46 (8.3) 8 (7.0) 27 (8.3) 11 (9.6) Lymphovascular invasion, n (%) 0.97 No 453 (81.8) 94 (82.5) 266 (81.6) 93 (81.6) Yes 101 (18.2) 20 (17.5) 60 (18.4) 21 (18.4) Tumour location, n (%) 0.30 Pyelo-caliceal 297 (53.6) 62 (54.4) 178 (54.6) 57 (50.0) Ureter 161 (29.1) 37 (32.5) 85 (26.1) 39 (34.2) Multifocal 96 (17.3) 15 (13.2) 63 (19.3) 18 (15.8) Follow-up (months) 0.77 Median Range ASA: American Society of Anesthesiologists; WHO: World Health Organization; is: in situ. The demographic and clinicopathological features in the three ASA groups were compared using chi-squared tests for categorical variables and Kruskal Wallis tests for continuous variables. Postoperative survival was estimated using the Kaplan Meier method and compared between groups with the log-rank test. The oncological outcome analyses focused on RFS, MFS and CSS. Patients were censored at the last follow-up or death. Univariate and multivariate Cox proportional hazards regression analyses were conducted to ascertain the independent role of ASA status in cancer-specific mortality (CSM) variations. A P-value < 0.05 was considered significant. All statistical analyses were performed using SPSS version 17.0 statistical software (IBM Corp., Somers, NY, USA). RESULTS Overall, 554 patients were included in the current study. The median patient age was 69.5 years (interquartile range (IQR) 61 76), and the male-to-female ratio was 2.2 : 1. The median follow-up was 26 months (IQR 10 48). Patient comorbidities were thoroughly assessed by anaesthesiologists preoperatively to evaluate the patients ASA physical status; 114 (20.6%), 326 (58.8%) and 114 (20.6%) patients were finally classified ASA 1, ASA 2 and ASA 3, respectively. No patient classified as ASA 4 was managed with RNU with a curative intent. Demographic and clinicopathological features of the whole study population and the three ASA groups are summarized in Table 2 ; no significant difference was found between the ASA groups. Overall, 208 (37.5%) patients experienced recurrence during follow-up: 38 (18.3% of the recurrent patients) patients classified as ASA 1, 122 (58.6%) as ASA 2 and 48 (23.1%) as ASA 3 had a 5-year RFS estimated at 52.8%, 51.9% and 44.1%, respectively. The statistical analysis did not show any significant difference between ASA groups ( P = 0.21). A total of 109 patients (19.7%) developed metastases, of which 20 (18.3%), 62 (56.9%), 27 (24.8%) occurred in patients classified as ASA 1, ASA 2 and ASA 3, respectively. The 5-year estimated MFS were not significantly different for any of the ASA score (76% for ASA 1, 75.3% for ASA 2 and 68.2% for ASA 3; P = 0.22). In terms of CSS, 88 of 554 patients (15.9%) died of UUT-UC during follow-up; nine (10.2%) ASA 1, 55 (62.5%) ASA 2 and 24 (27.3%) ASA 3 patients, respectively. The Kaplan Meier method estimated that 5-year CSS was 83.3%, 76.9% and 70.6% for each group, respectively ( P = 0.01; Fig. 1 ). The univariate analysis confirmed this statistical significance with hazard ratios of CSM of 2.2 (95% CI ) for ASA 2 patients and 3.1 (95% CI ) for ASA 3 patients compared with the ASA 1 group. This was confirmed after controlling for pathological stage, tumour grade, lymph node status and tumour location in the multivariate analysis shown in Table BJU INTERNATIONAL E1037

4 BEROD ET AL. DISCUSSION Current contemporary management decisions in urological oncology are underpinned by guidelines from key international regulatory bodies, levels of evidence, grades of recommendation and the development of accurate risk prediction models. These latter tools are complex statistical modelling techniques that necessitate the interpretation and correlation of specific variables with defined endpoints to generate a patient-specific risk probability [11 ]. In general, these variables can be clinical, pathological, radiological or even molecular. They can be used in a pretreatment or post-treatment setting to predict the risk of a variety of outcomes including disease stage, disease recurrence and survival. Survival is a heterogeneous endpoint because it encompasses overall, cancer-specific, recurrence-free and metastasis-free survival. oncological outcomes; patient age [7 ], gender [6 ], tumour location and multifocality [12 ], tumour grade [13 ], tumour stage [14 ], lymphovascular invasion [3 ], tumour architecture [15 ] and FIG. 1. Cancer-specific Kaplan Meier survival curves for upper urinary tract urothelial carcinoma after radical nephroureterectomy overall (left) and stratified by American Society of Anesthesiologists (ASA) score (right). Kaplan Meier estimated five-year cancer-specific survival was 83.3%, 76.9% and 70.6% for the ASA 1, ASA 2 and ASA 3 group, respectively ( P = 0.01). Survival, % Survival, % associated carcinoma in situ [16 ]. In various collective forms, they have been incorporated into nomogram models to predict either CSS [17 ] or disease stage at time of NU [18 ] ASA 1 ASA 2 ASA 3 For UUT-UC, the after clinical and pathological variables have been studied to examine their relationship with Time, months Time, months TABLE 3 Univariate and multivariate analyses of the impact of American Society of Anesthesiologists scores and covariables on overall and cancer-specific mortality for upper urinary tract urothelial carcinoma treated with radical nephrectomy Overall mortality Cancer-specific mortality Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis Covariables HR (95% CI) P HR (95%CI) p HR (95% CI) P HR (95% CIl) P Age (continuous variable) 1.02 ( ) ( ) ( ) ( ) ASA score < ASA 2 vs ASA ( ) ( ) ( ) ( ) ASA 3 vs ASA ( ) < ( ) < ( ) ( ) Tumour location < Ureter vs pelvi-caliceal 1.19 ( ) ( ) ( ) ( ) Multifocal vs pelvi-caliceal 2.07 ( ) ( ) ( ) < ( ) Pathological stage pt < < pt1 vs pta/ptis 1.32 ( ) ( ) ( ) ( ) 0,067 pt2 vs pta/ptis 2.65 ( ) ( ) ( ) ( ) 0,029 pt3 vs pta/ptis 4.52 ( ) < ( ) ( ) < ( ) pt4 vs pta/ptis 8.87 ( ) < ( ) < ( ) < ( ) <0.001 Grade (WHO 1973) < G2 vs G ( ) ( ) ( ) ( ) G3 vs G ( ) ( ) ( ) ( ) Lymph node status < < pnx vs pn ( ) ( ) ( ) ( ) pn1/2 vs pn ( ) < ( ) ( ) < ( ) Lymphovascular invasion Yes vs no 2.06 ( ) ( ) ( ) ( ) HR, hazard ratio; 95% CI, 95% confidence interval; ASA: American Society of Anesthesiologists; WHO: World Health Organization; is: in situ. E BJU INTERNATIONAL

5 ASA SCORE AND UUT-UC The ASA classification has been clearly proven to be associated with perioperative and postoperative outcomes in surgery in general. Wolters et al. [19 ] assessed 6301 surgical patients for the association of ASA score with perioperative and postoperative risk factors. On univariate analysis, significant association ( P < 0.05) between ASA class and perioperative complications (blood loss, duration of intensive therapy unit stay, duration of postoperative ventilation) was found. The risk of postoperative complications was significantly higher for ASA 3 (odds ratio (OR) 2.2) and ASA IV (OR 4.2) patients. It is also reported that the ASA classification is superior to other notable scoring systems including the Charlson score [10 ] and the New York Heart Association classification of cardiac insufficiency [20 ] in predicting operative outcomes. In urological terms, the ASA score has been evaluated in prostate and renal cancer to predict both survival [9,10 ] and perioperative and postoperative outcomes [21 ]. The ASA score has also been correlated with outcomes from laparoscopic urological surgery [22 ]. de Cassio et al. [9 ] studied 145 patients after nephrectomy for RCC. The ASA score was found to impact CSS on both univariate and multivariate analyses. Five-year CSS was 95.7, 71.1 and 39.8% for ASA 1, ASA 2 and ASA 3, respectively ( P = 0.007). ASA score also influenced overall survival ( P < 0.001). ASA 3 patients had a significant increased risk of developing metastases (OR 10; P = 0.001). Froehner et al. [10 ] compared ASA score with Charlson score as predictors of survival after radical prostatectomy. Using a database of 444 patients with a mean follow-up 5.9 years, both classifications were able to predict comorbid (non-cancer) and overall survival. The ASA score was superior to the Charlson score in defining at-risk groups. Han et al. [21 ] retrospectively analysed 551 patients after nephrectomy for RCC. No difference in perioperative or postoperative complications was seen but ASA 3 patients had a higher risk of transfusion (42% vs 28%; P = 0.001). Matin et al. [22 ] evaluated 399 patients who had undergone laparoscopic urological surgery. Age > 65 years was not associated with complications on univariate and multivariate analysis. Patients > 65 years were hospitalized for longer (43 vs 24 h, P = 0.02). Patients with higher ASA scores were more likely to receive blood transfusions. On univariate analysis, no difference in rate of complications between ASA groups was seen but on multivariate analysis (ASA 1 vs ASA 3), the ASA 3 patients had a higher rate of complications ( P = 0.04). Herein, we have evaluated our large multi-institutional database on UUT-UC in respect of ASA influence on survival outcomes after RNU in 554 patients. Using univariate and multivariate regression analysis, we have shown that the 5-year CSS differed significantly between ASA 1, ASA 2 and ASA 3 patients (83.8%, 76.9% and 70.6%, respectively; P = 0.01). We found no influence on RFS ( P = 0.21) or MFS ( P = 0.22). ASA status had a significant impact on CSS in univariate and multivariate analyses, with a threefold higher risk of mortality at 5 years for ASA 3 compared with ASA 1 patients ( P = 0.04). The statistical difference in CSS ( P = 0.01) but not RFS ( P = 0.21) or MFS ( P = 0.22) is a point of interest. It implies that the ASA score does not directly impact biological cancer phenomena (e.g. recurrence or metastasis) but it is plausible that reduced CSS for the higher ASA score was a consequence of the patients not being eligible for salvage chemotherapy upon the development of recurrence or metastasis. However, although the statistic analysis did not show a difference there were definite trends for absolute difference when comparing ASA 1 with ASA 3. For 5-year RFS, a + 8.7% difference for ASA 1 (52.8% vs 44.1%) was seen. For 5-year MFS, +7.8% for ASA 1 (76% vs 68.2%) and for 5-year CSS, % for ASA 1 (83.3% vs 70.6%). We did not include the data on adjuvant or salvage chemotherapy because in a previous study of patients in our database we showed that giving adjuvant chemotherapy did not improve survival outcomes after RNU for UUT-UC [23 ]. We would like to address some limitations of our study. Our results were analysed in a retrospective fashion because the relative rarity of this disease makes a prospective study difficult to implement. Additionally, various physicians treated the patients over a long period of time and there was a lack of centralized pathological review. However, all centres in the study followed the recommendations of our national society of urology and the lack of a centralized pathological review is balanced by the relative standardization of practices that are imposed by our national urological and pathological society guidelines [24 26 ]. Also, the interobserver variability of ASA scoring between different anaesthesiologists in different institutions cannot be ruled out, as has already been shown [27 ]. To our knowledge, this is the first study to report the significant association of ASA score and survival outcome in UUT-UC patients after RNU. This identifies the ASA score as a predictive variable for UUT-UC and it should now be considered for inclusion in any future predictive modelling technique for UUT-UC outcomes after RNU. The ASA classification correlates significantly with CSS after RNU for UUT-UC. It is a further preoperative clinical variable that can be incorporated into future risk prediction tools for UUT-UC to improve their accuracy. CONFLICT OF INTEREST None declared. REFERENCES 1 Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, BJU Int 2011 ; 107 : Zigeuner R, Pummer K. Urothelial carcinoma of the upper urinary tract: surgical approach and prognostic factors. Eur Urol 2008 ; 53 : Novara G, Matsumoto K, Kassouf W et al. Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract: an international validation study. Eur Urol ; 57 : Smith AK, Stephenson AJ, Lane BR et al. 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