GENITOURINARY CANCER Prognostic Factors in De Novo Metastatic original reports Renal Cell Carcinoma: A Report From the Latin American Renal Cancer Group Diego Abreu, MD1; Gustavo Carvalhal, MD2; Guillermo Gueglio, MD3; Ignacio Tobia, MD3; Patricio Garcia, MD3; Alvaro Zuñiga, MD4; Luis Meza, MD5; Rubén Bengió, MD6; Carlos Scorticati, MD7; Ricardo Castillejos, MD8; Francisco Rodriguez, MD8; Ana Marı́a Autran, MD9; Carmen Gonzales, MD9; Jose Gadu, MD10; Alejandro Nolazco, MD11; Carlos Ameri, MD12; Hamilton Zampolli, MD13; Raúl Langenhin, MD14; Diego Muguruza, MD14; Marcos Tobı́as Machado, MD15; Pablo Mingote, MD16; Juan Yandian, MD17; Jorge Clavijo, MD17; Lucas Nogueira, MD18; Omar Clark, MD19; Fernando Secin, MD20; Agustı́n Rovegno, MD20; Ana Vilas, MD21; Enrique Barrios, MD22; Ricardo Decia, MD1; Gustavo Guimarães, MD23; Sidney Glina, MD24; Sumanta K. Pal, MD25; Oscar Rodriguez, MD26; Joan Palou, MD26; Philippe Spiess, MD27; Primo N. Lara Jr, MD28; W. Marston Linehan, MD29; Antonio Luigi Pastore, MD30; and Stenio C. Zequi, MD23 abstract PURPOSE To assess the effect of clinical and pathological variables on cancer-specific and overall survival (OS) in de novo metastatic patients from a collaborative of primarily Latin American countries. PATIENTS AND METHODS Of 4,060 patients with renal cell carcinoma diagnosed between 1990 and 2015, a total of 530 (14.5%) had metastasis at clinical presentation. Relationships between clinical and pathological pa- rameters and treatment-related outcomes were analyzed by Cox regression and the log-rank method. RESULTS Of 530 patients, 184 (90.6%) had died of renal cell carcinoma. The median OS of the entire cohort was 24 months. American Society of Anesthesiology classification 3-4 (hazard ratio [HR]: 1.64), perirenal fat in- vasion (HR: 2.02), and ≥ 2 metastatic organ sites (HR: 2.19) were independent prognostic factors for 5-year OS in multivariable analyses. We created a risk group stratification with these variables: no adverse risk factors (favorable group), median OS not reached; one adverse factor (intermediate group), median OS 33 months (HR: 2.04); and two or three adverse factors (poor risk group), median OS 14 months (HR: 3.58). CONCLUSION Our study defines novel prognostic factors that are relevant to a Latin American cohort. With external validation, these easily discerned clinical variables can be used to offer prognostic information across low- and middle-income countries. JCO Global Oncol 7:671-685. © 2021 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION American Renal Cancer Group has undertaken a Renal cell carcinoma (RCC) represents a tumor type collaborative study involving centers of excellence for with highly variable outcomes and accounts for 2%- patients with RCC within Latin America and Spain. The 3% of all cancers. It is estimated that 338,000 new aim of this study was to identify prognostic factors for RCC cases occur each year worldwide, and its highest cancer-specific survival (CSS) and overall survival (OS) incidence has been observed in North America and in patients presenting with de novo mRCC and to Eastern and Northern Europe. Mortality rates because derive clinical prognostic variables for use in coun- of RCC have stabilized in most developed countries but seling patients. Author affiliations are increasing in Latin America.1-3 Mortality rates are PATIENTS AND METHODS and support still high because 20%-30% of patients with RCC have information (if Patient Population applicable) appear at metastatic disease at presentation, with a further 20%- the end of this 30% progressing to metastatic disease after initial Of the 4,060 patients with RCC who were treated at 28 article. treatment.1,2 In the latter group, more than 90% of institutions from eight Latin American countries Accepted on March metachronous metastases present within 5 years.4 (Uruguay, Brazil, Argentina, Mexico, Chile, Peru, 22, 2021 and Most data concerning the epidemiology of meta- Bolivia, and Spain), 530 patients presented with published at static RCC (mRCC) are derived from studies performed metastasis and were included in the study. All the ascopubs.org/journal/ go on May 11, 2021: in Europe and North America.1-4 There is lack of data enrolled subjects provided written informed consent, DOI https://doi.org/10. on the clinical and pathologic characteristics of mRCC and Protocols were approved by the local Ethical 1200/GO.20.00621 within Latin America. Given this void, the Latin Committees. 671 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al CONTEXT Key Objective Are prognostic factors in de novo metastatic renal cell cancer different in Latin American population than those reported in other international cohorts? Knowledge Generated A study from a multicentric, multinational cohort identified the American Society of Anesthesiology classification 3-4, perirenal fat invasion, and ≥ 2 metastatic organ sites as independent prognostic factors of 5-year overall survival in a setting where cytoreductive nephrectomy was the norm. Relevance We believe that these findings are useful to provide a simple tool for management decisions in a heterogeneous world region, where resources for systemic treatments are limited. The clinical variables obtained for analysis were age, sex, 162 months) and 13 months excluding those patients alive body mass index (BMI), Eastern Cooperative Oncology with , 6 months of follow-up. Of the 530 patients, 203 died Group performance status (ECOG-PS), American Society of (38.3%), of which 184 (90.6%) died of RCC. Of 451 pa- Anesthesiology (ASA) risk classification, the presence of tients with data on the number of metastases, 111 (24.6%) symptoms at diagnosis, and serum hemoglobin levels. and 340 (75.4%) had single and multiple metastases, Clinical staging was coded according to the 2010 American respectively. The organs most frequently affected with Joint Committee on Cancer (TNM) staging. Pathologic metastasis were lungs (45.5%), bone (21.5%), lymph variables included histologic subtype according to the 2004 nodes (10.6%), liver (8.7%), adrenals (4%), and brain WHO, tumor size, nodal status, Fuhrman, necrosis, peri- (2.2%). Among patients with multiple metastases, a single renal fat invasion, vein invasion, and sarcomatoid features. organ was affected in 173 cases (51%), two organs in 128 Staging included computed tomography or magnetic res- cases (37.8%), three organs in 36 cases (10.6%), and four onance imaging of the abdomen and pelvis, and a chest organs in two cases (0.6%). In 511 of the 530 patients x-ray. Bone scans were performed selectively. (96.4%), nephrectomies were performed, 483 of which Statistical Analysis were radical (94.5%) and 28 partial (5.5%). Further treatment for metastases was performed in 177 patients Survival time was calculated as the difference between the (34.1%), of whom 124 (70%) received systemic treat- date of diagnosis and the date of last follow-up or death. ments: 95 (76.6%) received tyrosine kinase inhibitors and Chi-square and Fisher’s exact tests were used to comparing 29 (23.4%) were treated with immunotherapy (either qualitative variables. The Kaplan-Meier product limit interferon-alpha or interleukin-2). Sixteen patients received method was used to estimate OS and CSS, and differences radiotherapy to metastatic sites (9%), 5 patients (2.8%) in the curves were assessed using log-rank tests. Univariate underwent metastasectomies, whereas 31 patients and multivariate Cox proportional hazards regression (17.5%) received other treatments (Table 1). models were used to evaluate the relationship of clinical and pathologic variables with OS and CSS. Only signifi- cantly associated variables with survival in univariate Univariate and Multivariate Analysis analysis (P , .1) were included for multivariate modeling. Factors positively associated with multiple metastases were The proportional hazards assumption was evaluated using positive lymph nodes (pN1) (P = .010), Fuhrman ≥ 3 Schoenfeld residuals. We created a risk group stratification (P = .008), perirenal fat invasion (P = .019), necrosis according to the variables that were significantly associated (P , .0001), nonclear cell histology (P = .042), and serum with OS in the multivariable analysis. Hb , 11 g/dL (P = .007). Metastases in ≥ 2 organ sites The model of risk group stratification was compared with were associated with ECOG-PS ≥ 1 (P = .004), pN1 the multivariable model using the Bayesian information (P = .001), renal vein invasion (P = .042), and nonclear cell criterion. The Statistical Package for Social Sciences soft- subtype (P = .003). Interestingly, BMI ≥ 25 kg/m2 was ware (v. 19) and Stata v16 were used. associated with the presence of a single-organ site and single metastasis (P = .018) (Tables 2 and 3). RESULTS The median OS for the whole cohort was 24 months (95% Patient Characteristics and Outcomes CI, 18.1 to 29.8), and the 2-year OS was 48% (Fig 1). The median age of the 530 patients was 61 years (23-94 Excluding patients with , 6 months of follow-up, the years): 359 (68%) patients were male and 169 (32%) were median follow-up was 13 months and median OS was female. The median follow-up was 6 months (0- 22 months, with a 2-year OS of 46%. 672 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma TABLE 1. Patients’ Clinical and Pathologic Characteristics TABLE 1. Patients’ Clinical and Pathologic Characteristics (Continued) Patients Patients Total No. Patients Total No. Patients Variable Evaluated (N = 530) No. % Variable Evaluated (N = 530) No. % Age, years 491 Metastases 451 Median 61 Single 111 24.6 Range 23-94 Multiple 340 75.4 Sex 528 Metastases 339 Male 359 68 1 organ 173 51 Female 169 32 ≥ 2 organs 166 49 ECOG PS 373 Metastatic site 321 0 76 20.4 Lungs 146 45.5 ≥1 297 79.6 Bone 69 21.5 ASA 342 Liver 28 8.7 1-2 232 67.8 Brain 7 2.2 3-4 110 32.2 Adrenal gland 13 4 Symptoms at presentation 489 Lymph node 34 10.6 No 114 23.3 Others 24 7.5 Yes 375 76.7 Survival status 455 Histologic subtype 347 Alive 252 55.4 Clear cell 285 82.1 Dead 203 44.6 Papillary 9 2.6 Dead by cancer 184 90.6 Chromophobe 4 1.2 Abbreviations: ASA, American Society of Anesthesiology; ECOG PS, Unclassified 15 4.3 Eastern Cooperative Oncology Group performance status; IFN, Sarcomatoid differentiation 34 9.8 interferon; IL, interleukin; VEGF, vascular endothelial growth factor. Nephrectomy 511 Univariate analysis showed associations between 5-year OS Radical 483 94.5 and CSS and the presence of ECOG-PS ≥ 1 (P = .005 and Partial 28 5.5 P = .007), ASA classification 3-4 (P , .0001 for both), pT3- Treatment of metastasis 177 4 (P = .019 and P = .009), pN1 (P = .001 and P , .0001), Surgery 5 2.8 Fuhrman ≥ 3 (P = .010 and P = .008), necrosis (P = .024 Radiotherapy 16 9.0 and P = .016), perirenal fat invasion (P , .0001 for both), Other 31 17.5 Hb , 11 g/dL (P = .001 and P = .002), multiple metastases (P = .002 and P = .001), and ≥ 2 involved organs (P = .002 Immunotherapy 177 and P = .005). IFN 17 9.6 The median OS and CSS were both 43 months in the IL-2 8 4.5 presence of a single metastasis and 16 months and IFN + IL-2 1 0.6 20 months, respectively, for multiple metastases. Two-year Second-line anti-VEGF after 177 OS and CSS were 67% and 70% for single metastasis, and Immunotherapy 3 1.7 44% and 45% for multiple metastases, respectively Anti-VEGF 2 1.1 (hazard ratio [HR] for OS: 1.94, 95% CI, 1.28 to 2.95, Systemic therapy 177 P = .002 and HR for CSS: 2.07, 95% CI, 1.33 to 3.23, P = .001) (Fig 2). Sunitinib 63 35.6 Pazopanib 12 6.8 The median OS and CSS were 30 months and 33 months, Sorafenib 6 3.4 respectively, for patients with metastasis in a single organ and were both 14 months for patients with ≥ 2 involved Bevacizumab 5 2.8 organs. Two-year OS and CSS were 55% and 56% for Temsirolimus 2 1.1 patients with metastasis in a single organ and 36% and Anti-VEGF + others 5 2.8 38% for patients with metastases in multiple organs, re- (Continued in next column) spectively (HR for OS: 1.67, 95% CI, 1.21 to 2.32, P = .002 JCO Global Oncology 673 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al TABLE 2. Association of Demographic and Clinical-Pathological Variables With Single Versus Multiple Metastases in Renal Cell Carcinoma Metastasis Variables All Cases (N = 530) Single (n = 111) Multiple (n = 340) P Age, years .295 Median (range) 61 (23-94) 63 (40-90) 61 (23-94) Age, years .544 ≤ 65 267 (63.4) 64 (61) 203 (64.2) . 65 154 (36.6) 41 (39) 113 (35.8) Sex .080 Male 300 (66.8) 81 (73.6) 219 (64.6) Female 149 (33.2) 29 (26.4) 120 (35.4) BMI, kg/m2 .018 , 25 125 (44.3) 29 (33.7) 96 (49) ≥ 25 157 (55.7) 57 (66.3) 100 (51) ECOG PS .076 0 40 (13) 11 (20.4) 29 (11.4) ≥1 268 (87) 43 (79.6) 225 (88.6) ASA .330 1-2 203 (68.6) 66 (72.5) 137 (66.8) 3-4 93 (31.4) 25 (27.5) 68 (33.2) Symptoms .552 No 80 (19.2) 17 (17.2) 63 (19.9) Yes 336 (80.8) 82 (82.8) 254 (80.1) Size, pT .196 ≤ 7 cm 109 (39.6) 41 (45.1) 68 (37) . 7 cm 166 (60.4) 50 (54.9) 116 (63) Stage, pN .010 pN0 136 (68.7) 54 (80.6) 82 (62.6) pN1 62 (31.3) 13 (19.4) 49 (37.4) Fuhrman .008 1-2 81 (37) 26 (53.1) 55 (32.4) 3-4 138 (63) 23 (46.9) 115 (67.6) Perirenal fat invasion .019 No 179 (59.9) 63 (70) 116 (55.5) Yes 120 (40.1) 27 (30) 93 (44.5) Renal vein invasion .857 No 210 (71.2) 64 (71.9) 146 (70.9) Yes 85 (28.8) 25 (28.1) 60 (29.1) Necrosis , .0001 No 170 (56.7) 66 (74.2) 104 (49.3) Yes 130 (43.3) 23 (25.8) 107 (50.7) Histologic subtype .372 Clear cell 247 (92.5) 86 (95.6) 161 (91) Papillary 7 (2.6) 1 (1.1) 6 (3.4) Unclassified 13 (4.9) 3 (3.3) 10 (5.6) (Continued on following page) 674 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma TABLE 2. Association of Demographic and Clinical-Pathological Variables With Single Versus Multiple Metastases in Renal Cell Carcinoma (Continued) Metastasis Variables All Cases (N = 530) Single (n = 111) Multiple (n = 340) P Histological subtype .042 Clear cell 247 (84.3) 86 (90.5) 161 (81.3) No-clear cell 46 (15.7) 9 (9.5) 37 (18.7) Sarcomatoid features .270 No 179 (82.5) 43 (87.8) 136 (81) Yes 38 (17.5) 6 (12.2) 32 (19) Hemoglobin, g/dL .007 , 11 107 (33.3) 20 (22) 87 (37.8) ≥ 11 214 (66.7) 71 (78) 143 (62.2) Abbreviations: ASA, American Society of Anesthesiology; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status. and HR for CSS: 1.62, 95% CI, 1.15 to 2.27, P = .005) 10 months for those who did not; the median CSS was 41 (Fig 3). and 12 months, respectively. Two-year OS was 60% and The comparison of patients with bone metastasis (BM) 38% (HR: 2.17, 95% CI, 1.46 to 3.23, P , .0001) for those versus lung metastasis (LM) revealed that the median OS who received vsersus those who did not receive systemic and CSS for patients with BM were both not reached, therapy, whereas 2-year CSS was 60% and 40%, re- whereas for LM both were 21 months. The 2-year OS and spectively (HR: 2.18, 95% CI, 1.45 to 3.28, P , .0001) CSS were both 70% for patients with BM, and 45% and (Fig 9). The median OS was 24 months for patients who 47%, respectively, for patients with LM (HR for OS: 2.10, received only local treatment of the metastatic sites (ra- 95% CI, 1.14 to 3.88, P = .017 and HR for CSS: 2.03, 95% diotherapy and/or surgery). CI, 1.10 to 3.76, P = .024) (Fig 4). The comparison of In multivariate analysis, ASA 3-4 was an independent patients with BM (nonvertebral) versus BM (vertebral) prognostic factor of 5-year OS (HR: 1.64, 95% CI, 1.08 to revealed that the median OS and CSS were both not 2.49, P = .020). Other independent prognostic factors of 5- reached for patients with nonvertebral BM and were both year OS and CSS were perirenal fat invasion (HR: 2.02, 14 months for patients with vertebral BM. The 2-year OS 95% CI, 1.32 to 3.09, P = .001 and HR: 2.21, 95% CI, 1.40 and CSS were 75% and 45%, respectively, for both groups to 3.47, P = .001) and the presence of . 2 metastatic (HR: 3.61, 95% CI, 1.00 to 12.98, P = .035 for both) (Fig 5). organ sites (HR: 2.19, 95% CI, 1.43 to 3.34, P , .0001 The comparison of patients with ≤ 5 versus . 5 LM showed and HR: 2.01, 95% CI, 1.27 to 3.19, P = .003) (Table 4). that the median OS and CSS were 30 and 11 months, We created a risk group stratification according to the respectively. The 2-year OS and CSS were 62% and 27% variables which were significantly associated with OS in the (HR: 3.21, 95% CI, 1.47 to 7.00, P = .003) for both groups, multivariable analysis: perirenal fat invasion, ≤ 2 metastatic respectively (Fig 6). The median OS according to the organ sites, and presence of ASA classification 3-4 at the number of LM was stratified into three groups: 2-5 me- time of surgery. tastases, 33 months; 6-10 metastases, 14 months; and . 10 metastases, 7 months. Two-year OS was 67%, When there were no adverse risk factors (favorable group), 47%, and 0% (Fig 7). Both median 5-year OS and median the median OS was not reached. When one adverse factor 5-year CSS according to the number of involved organs was present, the median OS was 33 months (intermediate were as follows: one organ, 33 months; two organs, group; HR: 2.04; 95% CI, 1.14 to 3.65; P = .016). When 15 months; and three or four organs, 7 months. The two or three adverse factors were present (poor risk group), median OS of patients with . 10 LM versus ≥ 2 metastatic the median OS was 14 months (HR: 3.58; 95% CI, 2.02 to organ sites was 7 and 14 months, and 2-year OS was 0% 6.34, P , .0001) (Fig 10). and 37%, respectively (HR: 1.96, 95% CI, 0.99 to 3.88, The model using risk stratification was more parsimonious P = .043) (Fig 8). than the multivariable model with a similar value of the The median OS was 33 months for patients who received Bayesian information criterion (1,005.9 v 1,009.2, systemic therapy (immunotherapy or targeted therapy) and respectively). JCO Global Oncology 675 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al TABLE 3. Association of Demographic and Clinical-Pathologic Variables With Metastasis in 1 Organ Versus ≥ 2 Organs in Renal Cell Carcinoma Metastasis Variable All Cases (N = 530) 1 Organ (n = 321) ‡ 2 Organs (n = 166) P Age, years .179 Median (range) 61 (23-94) 62 (23-91) 60 (23-94) Age, years .555 ≤ 65 287 (63.8) 184 (62.8) 103 (65.6) . 65 163 (36.2) 109 (37.2) 54 (34.4) Sex .507 Male 327 (67.4) 219 (68.4) 108 (65.5) Female 158 (32.6) 101 (31.6) 57 (34.5) 2 BMI, kg/m .002 , 25 135 (46.2) 75 (39.5) 60 (58.8) ≥ 25 157 (53.8) 115 (60.5) 42 (41.2) ECOG PS .004 0 58 (17.2) 48 (21.3) 10 (8.9) ≥1 279 (82.8) 177 (78.7) 102 (91.1) ASA .898 1-2 213 (68.5) 145 (68.7) 68 (68) 3-4 98 (31.5) 66 (31.3) 32 (32) Symptoms .569 No 96 (21.4) 65 (22.2) 31 (19.9) Yes 353 (78.6) 228 (77.8) 125 (80.1) Size, pT .947 ≤ 7 cm 119 (39.3) 83 (39.2) 36 (39.6) . 7 cm 184 (60.7) 129 (60.8) 55 (60.4) Stage, pN .001 pN0 155 (69.5) 120 (75.9) 35 (53.8) pN1 68 (30.5) 38 (24.1) 30 (46.2) Fuhrman .764 1-2 89 (35.7) 65 (36.3) 24 (34.3) 3-4 160 (64.3) 114 (63.7) 46 (65.7) Perirenal fat invasion .139 No 202 (61.2) 148 (63.8) 54 (55.1) Yes 128 (38.8) 84 (36.2) 44 (44.9) Renal vein invasion .042 No 233 (71.7) 171 (75) 62 (63.9) Yes 92 (28.3) 57 (25) 35 (36.1) Necrosis .575 No 194 (59) 135 (60) 59 (56.7) Yes 135 (41) 90 (40) 45 (43.3) Histologic subtype .096 Clear cell 274 (92.6) 202 (93.5) 72 (90) Papillary 8 (2.7) 7 (3.2) 1 (1.3) Unclassified 14 (4.7) 7 (3.2) 7 (8.8) (Continued on following page) 676 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma TABLE 3. Association of Demographic and Clinical-Pathologic Variables With Metastasis in 1 Organ Versus ≥ 2 Organs in Renal Cell Carcinoma (Continued) Metastasis Variable All Cases (N = 530) 1 Organ (n = 321) ‡ 2 Organs (n = 166) P Histologic subtype .003 Clear cell 274 (84.8) 202 (88.6) 72 (75.8) No-clear cell 49 (15.2) 26 (11.4) 23 (24.2) Sarcomatoid features .099 No 202 (82.1) 149 (84.7) 53 (75.7) Yes 44 (17.9) 27 (15.3) 17 (24.3) Hemoglobin, g/dL .174 , 11 111 (32.3) 68 (29.8) 43 (37.1) ≥ 11 233 (67.7) 160 (78) 73 (62.9) Abbreviations: ASA, American Society of Anesthesiology; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status. DISCUSSION (21% v 39.4%). When nodal metastases are present, Data concerning the natural history and treatment-related 5-year OS ranges from 11% to 35%.12,13 outcomes among mRCC in Latin America are lacking. In Interestingly, a BMI of ≥ 25 kg/m2 was associated with our cohort, the prevalence of mRCC (de novo) was 14.5%, single metastases and with single-organ involvement in our which is less than the prevalence rate of 20%-30% re- cohort, so being overweight was a protective factor. In our ported in the literature.3-7 However, this may be an un- results, the OS rates were 41 months for ≥ 25 kg/m2 BMI derestimation since our cohort consisted of mostly of versus 25 months for , 25 kg/m2 BMI. The International patients who had received nephrectomy—it is possible that Metastatic Renal Cell Carcinoma Database Consortium many patients with mRCC may be treated by a medical informed that being overweight was associated with a better oncologist exclusively. Our study identified ASA classifi- response to treatment.14 Our results indicate that BMI is a cation 3-4, perirenal fat invasion, and ≥ 2 metastatic organ variable that should be more extensively studied. sites as independent predictors of 5-year OS. Of critical importance, these are simple variables that are easily discerned in a urology practice in low- and middle-income countries when a cytoreductive nephrectomy is performed. 1.0 Most metastases were multiple at the time of presentation, with the lungs being the most commonly affected organs, 0.8 followed by bone, lymph nodes, and liver, as in the literature.8,9 In roughly half of the cases, metastases in- OS (probability %) volved a single site (51%). Bianchi et al8 reviewed 11,157 48% 0.6 patients with mRCC from the Nationwide Inpatient Sample cohort and found that 61% were affected with metastasis in 33% a single organ. 0.4 In our series, the increased percentage of patients with multiple metastases (75.4%) and with ≥ 2 metastatic sites (49%) could be responsible for the high mortality (44.6%) 0.2 over a relatively short follow-up. Our 2-year OS, however, was similar to that reported by others.10,11 In our series, lymph node involvement (pN1) was associ- 0 12 24 36 48 60 ated with multiple metastases and with more than one metastatic site. In the literature, nodal dissemination is Time (months) No. at risk: highly associated with the presence of distant metastases. All 469 160 87 51 25 17 Moreover, the 5-year survival in patients with distant me- patients tastases and positive lymph nodes is worse than that in patients with distant metastases and negative lymph nodes FIG 1. OS for the entire patient cohort. OS, overall survival. JCO Global Oncology 677 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al 1.0 1.0 Single Single Multiple Multiple 67% 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 23% 0.4 0.4 44% 0.2 0.2 P = .002 (HR: 1.94, 95% CI, 1.28 to 2.95) P = .001 (HR: 2.07, 95% CI, 1.33 to 3.23) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: Single 102 41 29 16 6 6 Single 101 41 29 16 6 6 Multiple 314 96 47 28 16 9 Multiple 309 94 46 28 16 9 FIG 2. OS and CSS in relation to the presence of a single metastasis versus multiple metastases. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. There are many predictive models of progression-free cohort, patients with multiple metastases had almost twice survival and OS in mRCC.10,15-19 Although some stress the risk of death compared with patients with single me- the prognostic value of the metastatic sites, others report tastases. As to the number of metastatic sites involved, it that the number of metastases is more relevant.15-20 In our has been reported that having more than one metastatic 1.0 1.0 1 organ 1 organ ≥ 2 organs ≥ 2 organs 0.8 0.8 55% CSS (probability %) OS (probability %) 0.6 0.6 0.4 0.4 0.2 36% 0.2 P = .002 (HR: 1.67, 95% CI, 1.21 to 2.32) P = .005 (HR: 1.62, 95% CI, 1.15 to 2.27) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: 1 organ 280 104 62 36 19 14 1 organ 278 104 62 36 19 14 ≥ 2 organs 157 41 17 10 4 2 ≥ 2 organs 153 39 16 10 4 2 FIG 3. OS and CSS in relation to the metastasis in a single-organ versus metastatic involvement of two or more organs. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. 678 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma 1.0 1.0 Bone metastases Bone metastases Lung metastases Lung metastases 70% 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 0.4 0.4 45% 0.2 0.2 P = .017 (HR: 2.10, 95% CI, 1.14 to 3.88) P = .024 (HR: 2.03, 95% CI, 1.10 to 3.76) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: Bone metastases 58 23 16 9 6 4 Bone metastases 58 23 16 9 6 4 Lung metastases 133 46 21 10 6 5 Lung metastases 132 46 21 10 6 5 FIG 4. OS and CSS in relation to the presence of bone versus lung metastasis. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. site increases the risk of death by 20%-50%.15,18,19 Han 27 months, and the risk of death was two times greater for et al20 showed that patients with disease in multiple organ multiple metastatic sites. Our results are similar with twice sites fare worse than patients with disease limited to either the risk of death for the group of patients with ≥ 2 metastatic lung or bone with a median survival of 11, 27, and sites. 1.0 Nonvertebral 1.0 Nonvertebral 75% Vertebral Vertebral 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 0.4 0.4 45% 0.2 0.2 P = .035 (HR: 3.61, 95% CI, 1.00 to 12.98) P = .035 (HR: 3.61, 95% CI, 1.00 to 12.98) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: Nonvertebral 23 13 8 5 3 2 Nonvertebral 23 13 8 5 3 2 Vertebral 14 5 4 1 1 0 Vertebral 14 5 4 1 1 0 FIG 5. OS and CSS in relation to the presence of nonvertebral versus vertebral bone metastasis. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. JCO Global Oncology 679 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al 1.0 1.0 ≤ 5 lung metastases ≤ 5 lung metastases > 5 lung metastases > 5 lung metastases 62% 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 27% 0.4 0.4 0.2 0.2 P = .003 (HR: 3.21, 95% CI, 1.47 to 7.00) P = .003 (HR: 3.21, 95% CI, 1.47 to 7.00) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: ≤ 5 lung 34 18 10 5 3 3 ≤ 5 lung 34 18 10 5 3 3 metastases metastases > 5 lung 34 7 3 1 1 0 > 5 lung 34 7 3 1 1 0 metastases metastases FIG 6. OS and CSS in relation to the presence of ≤ 5 versus . 5 lung metastases. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. In most series, patients with BM and liver metastases have risk of mortality because of RCC and that patients with liver a worse prognosis in comparison to LM.15,18,19 Leibovich metastases have a 69% higher risk of mortality because of et al17 reported that patients with BM have a 35% higher RCC compared with patients with metastatic disease in 1.0 1.0 2–5 lung metastases 2–5 lung metastases 67% 6-10 lung metastases 6-10 lung metastases 0.8 0.8 > 10 lung metastases > 10 lung metastases CSS (probability %) OS (probability %) 0.6 0.6 0.4 0.4 P ≤ .0001 P ≤ .0001 47% 0.2 0.2 0% 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: 2-5 lung 30 16 8 5 3 3 2-5 lung 30 16 8 5 3 3 metastases metastases 6-10 lung 12 6 3 1 1 0 6-10 lung 12 6 3 1 1 0 metastases metastases > 10 lung 22 1 0 0 0 0 > 10 lung 22 1 0 0 0 0 metastases metastases FIG 7. OS and CSS in relation to the number of lung metastases. CSS, cancer-specific survival; OS, overall survival. 680 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma 1.0 1.0 ≥ 2 metastatic organ sites ≥ 2 metastatic organ sites > 10 lung metastases > 10 lung metastases 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 37% 0.4 0.4 0.2 0.2 0% P = .053 P = .029 (HR: 1.96, 95% CI, 0.99 to 3.88) (HR: 2.15, 95% CI, 1.07 to 4.28) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: ≥ 2 metastatic 157 41 17 10 4 2 ≥ 2 metastatic 153 39 16 10 4 2 organ sites organ sites > 10 lung 22 1 0 0 0 0 > 10 lung 22 1 0 0 0 0 metastases metastases FIG 8. OS and CSS in relation to the presence of . 10 lung metastases versus metastatic involvement of two or more organs. CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. other organs. Other studies did not find a difference in cytokines, however, confirmed that the presence of BM survival rates of patients with BM versus LM.20,21 Series implies a worse prognosis.22,23 A peculiar finding of our including patients treated with targeted therapies and study is that patients with BM had a better survival than IT and anti-VEGF 1.0 1.0 No ST 60% 0.8 0.8 CSS (probability %) OS (probability %) 0.6 0.6 0.4 0.4 0.2 0.2 38% P < .0001 (HR: 2.17, 95% CI, 1.46 to 3.23) P < .0001 (HR: 2.18, 95% CI, 1.45 to 3.28) 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) No. at risk: No. at risk: IT and anti-VEGF 116 72 37 20 10 6 IT and anti-VEGF 114 70 36 20 10 6 No ST 159 29 16 11 6 4 No ST 157 29 16 11 6 4 FIG 9. OS and CSS in relation to the receipt of systemic therapy (IT and targeted therapy). CSS, cancer-specific survival; HR, hazard ratio; IT, immu- notherapy; OS, overall survival; ST, systemic treatment; VEGF, vascular endothelial growth factor. JCO Global Oncology 681 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al TABLE 4. Cox Regression Analysis for OS and CSS 5-Year OS 5-Year CSS Univariate HR Multivariate HR Univariate HR Multivariate HR Variable (95% CI) P (95% CI) P (95% CI) P (95% CI) P ASA (3-4 v 1-2) 1.88 (1.37 to 2.57) , .0001 1.64 (1.08 to 2.49) .02 1.81 (1.31 to 2.50) , .0001 1.40 (0.89 to 2.21) .138 Size pT (. 7 cm v ≤ 7 cm) 1.61 (1.08 to 2.41) .019 1.17 (0.74 to 1.86) .481 1.77 (1.15 to 2.73) .009 1.25 (0.76 to 2.07) .367 Perirenal fat invasion 1.87 (1.31 to 2.67) , .0001 2.02 (1.32 to 3.09) .001 2.06 (1.42 to 2.99) , .0001 2.21 (1.40 to 3.47) .001 M+ (≥ 2 org. v , 2 org.) 1.67 (1.21 to 1.32) .002 2.19 (1.43 to 3.34) , .0001 1.62 (1.15 to 2.27) .005 2.01 (1.27 to 3.19) .003 Abbreviations: ASA, American Society of Anesthesiology; CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival. those with LM, and we are yet to ascertain the reasons for Targeted systemic therapies have been associated with this. We did not have biopsy confirmation of the BM in most increased progression-free survival and OS in mRCC.24 In patients (60%), and only radiologic and clinical information our series, systemic therapy conferred a significant benefit, was used; nevertheless, within confirmed cases, the dif- both in OS and in CSS. A limited number of patients 177 ferences in favor of BM were maintained. Notwithstanding, (34%) received systemic treatments; however, as patients we found that the location of the BM was important; there were treated from 1990 to 2015, most received either in- terferon or anti–vascular endothelial growth factor drugs. In was a threefold increase in the risk of death for patients with respect to immunotherapy considerations, as our cohort in vertebral BM. In addition, we found that nonvertebral bone this publication encompassed patients treated up to 2015, metastases were associated with a better prognosis than the use of the newer immune checkpoint inhibitor (ICI) oligometastases in the lungs. drugs was not available. In future publications, the use of The lungs were the most common metastatic site in our the newer ICIs will be contemplated. series, and the higher the number of lesions, the worse the Nephrectomy before systemic therapy may improve prognosis, which was very poor when there were . 10 lung survival25-27 or not.28 Since the publication of the CAR- metastases. When patients were grouped according to the MENA trial,28 the role of cytoreductive nephrectomy is number of lung metastases, the median OS and CSS were being challenged. In our series, the impact of cytoreductive similar to those seen with grouping by the number of af- nephrectomy in mRCC could not be ascertained since fected organs. almost all patients were treated with nephrectomies. In 1.0 0.8 Favorable OS (probability %) Three risk factors: 0.6 ASA 3-4 Intermediate Perirenal fat invasion Metastatic ≥ 2 organs 0.4 Poor Risk Groups No. Risk Factors Median OS (months) 0.2 Favorable 78 0 NR 0 v 1 risk factor (HR: 2.04, 95% CI, 1.14 to 3.65, P = .016) Intermediate 118 1 33 0 v 2-3 risk factors (HR: 3.58, 95% CI, 2.02 to 6.34, P < .0001) Poor 93 2-3 14 0 12 24 36 48 60 Time (months) No. patients at risk: Favorable 78 40 27 16 10 7 Intermediate 118 51 24 15 4 3 Poor 93 35 16 6 3 2 FIG 10. OS according to three risk groups. ASA, American Society of Anesthesiology; HR, hazard ratio; NR, no response; OS, overall survival. 682 © 2021 by American Society of Clinical Oncology Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Prognostic Factors in De Novo Metastatic Renal Cell Carcinoma multivariate analyses, ASA 3-4, perirenal fat invasion, Our study has several limitations inherent to its retro- and ≥ 2 metastatic organ sites were an independent spective nature. Additionally, the absence of central pa- prognostic factor of 5-year OS. The ASA29 and the number thology review limits our assessment of certain elements of involved organs were associated with worse survival in such as sarcomatoid histology and other nonclear cell the literature. The involvement of perirenal fat has been subtypes. Treatment discrepancies among different cen- shown to affect the results of a series of both radical and ters might have led to variations in clinical presentation, partial nephrectomies.30 Although current management of surgical technique, and patient adherence to follow up. As mRCC has evolved, we believe that our prognostic data are our analyses were performed before the publication of the valid, especially regarding cases in which a cytoreductive CARMENA and SURTIME trials, cytoreductive nephrec- nephrectomy is indicated. tomies were the rule, which is not the case anymore. Fi- To our knowledge, we reported for the first time the role of nally, modern ICI therapies were not available at the time of prognostic factors in a large international cohort of patients this study, which may limit the applicability of our findings. with de novo mRCC in Latin America. The Latin American In conclusion, in mRCC, perirenal fat invasion and ≥ 2 Renal Cancer Group is active in growing and enhancing its metastatic sites predicted shorter OS and CSS; ASA 3-4 was an database, and the affiliated centers keep sending in new independent predictor of poor OS. Patients with nonvertebral cases. Recently, data and biological materials from some of BM had a better prognosis compared with those with LM. our centers’ tissue banks were made available for collab- Systemic treatments were associated with better survival rates. orative projects with North American institutions, such as External validation of these data could lead to a simple and the National Cancer Institute. straightforward prognostic tool for patients with de novo mRCC. AFFILIATIONS DISCLAIMER 1 Servicio de Urologı́a, Hospital Pasteur, Montevideo, Uruguay Our research is observational, does not involve participation of humans in 2 Hospital São Lucas da PUCRS, Porto Alegre, Brazil any kind of experiment, and preserves patients identifications. 3 Hospital Italiano, Buenos Aires, Argentina 4 Universidad Católica, Santiago de Chile, Chile 5 PRIOR PRESENTATION Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru 6 Presented in part at the Annual Meeting of American Urological Clinica Profesor Bengio, Cordoba, Argentina Association, Boston, MA, May 12-16, 2017. 7 Hospital de Clı́nicas, Buenos Aires, Argentina 8 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCNSZ), Ciudad de México, Mexico AUTHOR CONTRIBUTIONS 9 Fundación Jiménez Dı́az, Madrid, Spain Conception and design: Diego Abreu, Gustavo Carvalhal, Ignacio Tobia, 10 Hospital Militar, Ciudad de México, Mexico Jose Gadu, Hamilton Zampolli, Jorge Clavijo, Lucas Nogueira, Ricardo 11 Hospital Británico, Buenos Aires, Argentina Decia, Philippe Spiess, W. Marston Linehan, Antonio Luigi Pastore, 12 Hospital Alemán, Buenos Aires, Argentina Stenio C. Zequi 13 Instituto Arnaldo Vieira de Carvalho, São Paulo, Brazil Administrative support: Luis Meza, Philippe Spiess, Stenio C. Zequi 14 Coperativa Médica de Paysandú (COMEPA), Paysandú, Uruguay Provision of study materials or patients: Gustavo Carvalhal, Guillermo 15 Escuela de Medicina, ABC, São Paulo, Brazil Gueglio, Ignacio Tobia, Carlos Scorticati, Carmen Gonzales, Alejandro 16 Policlinico Neuquén, Neuquén, Argentina Nolazco, Carlos Ameri, Raúl Langenhin, Diego Muguruza, Jorge Clavijo, 17 Hospital de Clı́nicas, Montevideo, Uruguay Omar Clark, Fernando Secin, Agustı́n Rovegno, Ana Vilas, Ricardo Decia, 18 Universidade de Minas Gerais, Belo Horizonte, Brazil Gustavo Guimarães, Sidney Glina, Oscar Rodriguez, Philippe Spiess 19 Hospital Militar, Montevideo, Uruguay Collection and assembly of data: Diego Abreu, Gustavo Carvalhal, 20 Centro de Educación Médica e Investigaciones Clı́nicas (CEMIC), Guillermo Gueglio, Ignacio Tobia, Patricio Garcia, Alvaro Zuñiga, Luis Buenos Aires, Argentina Meza, Rubén Bengió, Carlos Scorticati, Ricardo Castillejos, Francisco 21 Departamento de Patologı́a, Hospital Pasteur, Montevideo, Uruguay Rodriguez, Ana Marı́a Autran, Carmen Gonzales, Jose Gadu, Alejandro 22 Departamento de Métodos Cuantitativos, Facultad de Medicina, Nolazco, Carlos Ameri, Hamilton Zampolli, Diego Muguruza, Marcos Montevideo, Uruguay Tobı́as Machado, Pablo Mingote, Juan Yandian, Jorge Clavijo, Fernando 23 A.C. Camargo Cancer Center, São Paulo, Brazil Secin, Agustı́n Rovegno, Ana Vilas, Gustavo Guimarães, Sidney Glina, 24 Hospital Ipiranga, São Paulo, Brazil Oscar Rodriguez, Joan Palou, Stenio C. Zequi 25 City of Hope, Duarte, CA Data analysis and interpretation: Diego Abreu, Gustavo Carvalhal, Ignacio 26 Fundación Puigvert, Barcelona, Spain Tobia, Francisco Rodriguez, Raúl Langenhin, Omar Clark, Enrique 27 Lee Moffitt Cancer Center, Tampa, FL Barrios, Sumanta K. Pal, Primo N. Lara, W. Marston Linehan, Antonio 28 The University of California Davis Comprehensive Cancer Center, Luigi Pastore, Stenio C. Zequi Sacramento, CA Manuscript writing: All authors 29 Center for Cancer Research, National Cancer Institute, Bethesda, MD Final approval of manuscript: All authors 30 Department of Medico-Surgical Sciences and Biotechnologies, Accountable for all aspects of the work: All authors Sapienza University of Rome, Latina, Italy AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF CORRESPONDING AUTHOR INTEREST Diego Abreu, MD, Hospital Pasteur, Lombardia 6256, Montevideo CP The following represents disclosure information provided by the authors 11500, Uruguay; e-mail: die.abreu@gmail.com. of this manuscript. All relationships are considered compensated unless JCO Global Oncology 683 Downloaded from ascopubs.org by 84.88.183.253 on March 9, 2023 from 084.088.183.253 Copyright © 2023 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms. Abreu et al otherwise noted. Relationships are self-held unless noted. I = Immediate Sumanta K. Pal Family Member, Inst = My Institution. Relationships may not relate to the Consulting or Advisory Role: Pfizer, Novartis, Aveo, Myriad subject matter of this manuscript. For more information about ASCO’s Pharmaceuticals, Genentech, Exelixis, Bristol Myers Squibb, Astellas conflict of interest policy, please refer to www.asco.org/rwc or ascopubs. Pharma, Ipsen, Eisai org/go/authors/author-center. Open Payments is a public database containing information reported by Philippe Spiess companies about payments made to US-licensed physicians (Open Leadership: NCCN, Global Society of Rare Genitourinary Tumors Payments). Honoraria: UpToDate Other Relationship: NCCN Francisco Rodriguez Uncompensated Relationships: Moffitt Honoraria: Astellas Pharma, Bayer, Asofarma, Ferring, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD Oncology Primo N. Lara Consulting or Advisory Role: Astellas Pharma, Asofarma, GlaxoSmithKline, Consulting or Advisory Role: Janssen, Calithera Biosciences Janssen Oncology, MSD Oncology Research Funding: Janssen Biotech, Merck, Pharmacyclics, Incyte, Taiho Speakers’ Bureau: Astellas Pharma, Asofarma, Bayer, Janssen Oncology, Pharmaceutical MSD Oncology Stenio C. Zequi Travel, Accommodations, Expenses: Janssen Oncology, Asofarma Consulting or Advisory Role: Pfizer, Astellas Brazil Jose Gadu Speakers’ Bureau: Pfizer, Astellas Pharma, Bayer, Janssen, Astra Zeneca Speakers’ Bureau: Janssen, Bayer Brazil Hamilton Zampolli No other potential conflicts of interest were reported. Honoraria: Janssen Oncology Consulting or Advisory Role: Janssen Oncology ACKNOWLEDGMENT Lucas Nogueira The authors recognize the participation of the following LARCG members in providing data or input for the study: Alberto Jurado, Walter Henriques Consulting or Advisory Role: Bayer da Costa, Deusdedit Vieira Cortez da Silva Neto, Daniel Beltrame Ferreira, Speakers’ Bureau: Bayer, Astellas Pharma Miguel Sánchez, Pablo Martı́nez, Antonio Carlos Lima Pompeo, Nicolás Agustin Rovegno Ginestár, Matı́as Lopez, Boris Camacho, Roberto Puente, Sergio de Employment: Abbott Laboratories Miceu, Carlos Corradi, Marcelo Torrico, Martin Varela, Luis Montes de Honoraria: Baliarda SA Oca, Sebastian Savignano, Pablo Bouza, Rafael Alonso. Sidney Glina Honoraria: Pfizer REFERENCES 1. Znaor A, Lortet-Tieulent J, Laversanne M, et al: International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol 67:519-530, 2015 2. 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