Long-term Survival in Patients Undergoing Radical Nephrectomy and Inferior Vena Cava Thrombectomy: Single-Center Experience

EUROPEAN UROLOGY 57 (2010) 667 672 available at www.sciencedirect.com journal homepage: www.europeanurology.com Kidney Cancer Long-term Survival in Patients Undergoing Radical Nephrectomy and Inferior Vena Cava Thrombectomy: Single-Center Experience Gaetano Ciancio, Murugesan Manoharan, Devendar Katkoori, Rosely De Los Santos, Mark S. Soloway * Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA Article info Article history: Accepted June 9, 2009 Published online ahead of print on June 21, 2009 Keywords: Inferior vena cava Thrombectomy Radical nephrectomy Survival Long term Abstract Background: Renal cell carcinoma (RCC) with a tumor thrombus extension into the inferior vena cava (IVC) demands aggressive surgical management. Objective: To evaluate the long-term survival in patients undergoing radical nephrectomy and IVC thrombectomy. Design, setting, and participants: We performed a retrospective analysis of 87 patients undergoing surgery between 1997 and 2008. The patients were grouped according to the extent of tumor thrombus, with level I involving the IVC at the level of the renal vein, level II being infrahepatic IVC, level III being intrahepatic IVC, and level IV being suprahepatic IVC or right atrium. Relevant clinical and pathologic data were analyzed. Measurements: Disease-free survival (DFS) and disease-specific survival (DSS) were studied. Results and limitations: The median follow-up was 22 mo, and 19, 14, 40, and 14 patients had level I, II, III, and IV IVC thrombus, respectively. Among patients with M0 disease, 22 developed metastases. The 5-yr DFS was 64% for all levels and 74%, 69.5%, 59.5%, and 58% for levels I, II, III, and IV, respectively. Of the level I group, 16% of patients died of disease compared to 57% of the level IV group. The 5-yr DSS for all levels was 46% and 71%, 48%, 40%, and 35% for levels I, II, III, and IV, respectively. Patients with level IV thrombus had a significantly lower 5-yr DSS compared to level I ( p = 0.03). However, when analyzed in two groups supradiaphragmatic and infradiaphragmatic there was no significant difference in DSS (P = 0.14). On univariate analysis, metastasis at presentation, non clear-cell histology, lymph node metastases, and higher nuclear grade were statistically significant prognostic factors influencing DSS. Only higher nuclear grade ( p = 0.03), metastasis at presentation ( p < 0.01), and non clear-cell histology ( p = 0.03) were independent prognostic factors on multivariate analysis. Conclusions: Radical nephrectomy and IVC thrombectomy offer reasonable longterm survival. The level of tumor thrombus is not an independent prognostic factor. Distant metastasis at presentation, higher nuclear grade, and non clear-clear cell histology are significant prognostic factors influencing DSS. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, USA. Tel. +1 305 243 6596; Fax: +1 305 243 4653. E-mail address: msoloway@med.miami.edu (M.S. Soloway). 0302-2838/$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2009.06.009

668 EUROPEAN UROLOGY 57 (2010) 667 672 1. Introduction Renal cell carcinoma (RCC) accounts for 3.5% of all adult malignant neoplasms [1,2]. It is the most lethal of all the urologic cancers, with a 40% mortality rate, and accounts for 2.3% of cancer-related deaths. RCC has a tendency to invade the renal venous system and form a tumor thrombus that can extend into the inferior vena cava (IVC). Nearly 4 10% of RCC cases have a tumor thrombus involving the IVC, and in 1% of cases, the tumor thrombus extends into the right atrium [3]. Since the first description of nephrectomy with IVC thrombectomy in 1913 by Berg [4], aggressive surgical management has significantly improved the outcome for patients with RCC and associated IVC thrombus. Studies document 45 69% 5-yr survival rates for patients with venous tumor thrombi in the absence of metastases [5]. Identifying the level of tumor thrombus is an important step in disease management, given that the level of tumor thrombus dictates the surgical approach [6]. Whether the level of thrombus independent of pathologic stage has an impact on survival is still a controversial topic. It is known, however, that higher-level tumor thrombi tend to be associated with a higher grade and a more advanced T stage. We analyzed patients undergoing surgery for RCC and tumor thrombus extension into the IVC to evaluate longterm survival. 2. Materials and methods We retrospectively analyzed all of the patients who underwent radical nephrectomy (RN) and IVC thrombectomy at our institution from 1997 to 2008. After obtaining Institutional Review Board approval, all relevant study variables were entered into a database and analyzed. We divided the patients into four groups: (1) level I, tumor thrombus involving the IVC at the level of the renal vein; (2) level II, infrahepatic IVC; (3) level III, intrahepatic IVC; and (4) level IV, suprahepatic IVC or right atrium involvement [6,7]. We did not differentiate IVC involvement in terms of tumor infiltration versus tumor thrombus alone, as this information was not uniformly reported. The 1997 World Health Organization (WHO) classification was used to classify the histologic subtype as clear cell or non clear cell. The Fuhrman grading system was used for reporting nuclear grade. The revised 2002 American Joint Committee on Cancer TNM system was used for pathologic staging. The outcome variables studied were disease-free survival (DFS), diseasespecific survival (DSS), and overall survival (OS). The surgical technique has been described in detail in a previous publication [6,8]; however, the extent of surgical dissection is dictated by the extent and level of the tumor thrombus. We use livertransplantation techniques and mobilize the liver off of the IVC to separate the IVC from the posterior abdominal wall. This maneuver provides excellent exposure, and the vascular control is also good. We adopt a totally intra-abdominal approach without cardiopulmonary bypass (CPB) or a veno-venous bypass. In our series, we used CPB in only three patients [6]. The patients were followed postsurgery at 1 mo, and then every 3 mo with history, physical examination, metabolic panel, and liver function tests. A chest x-ray was obtained every 6 mo, and an abdominal computed tomography scan was obtained every year. Statistical analysis was performed using the SPSS v.16 (SPSS, Chicago, IL, USA). A two-sided p value 0.05 was considered statistically significant. For univariate analysis, the Kaplan-Meier method for survival analysis and the log-rank test were used. The Cox proportional hazards regression model was used for multivariate analysis of the prognostic factors. 3. Results In total, 87 patients were included in the study. Nine patients had M1 disease; among those nine patients, six had nonpulmonary metastases. All patients with M1 disease underwent surgery in view of pain and hematuria. The Eastern Cooperative Oncology Group performance status was available for five patients: It was 0 for two patients and 1 for three patients. Table 1 summarizes patient variables for the entire cohort and for various level groups. CPB was used in three patients. In other patients, for whom access to the atrium was required, the procedure was performed by opening the diaphragm transabdominally. A veno-venous bypass was not used in any patient. The perioperative mortality rate was 3.5%, with three perioperative deaths. Although no intraoperative deaths were noted, two of the deaths occurred on the first postoperative day in the level III group, one as a result of cardiac arrhythmia and the other the result of pulmonary failure in a patient with chronic obstructive pulmonary disease. The third death occurred as a result of hepatic failure in a patient with level IV thrombus and Budd-Chiari syndrome. No pulmonary embolisms were noted in any of these patients, and none of these patients had a CPB. The median follow-up was 22 mo (range: 3 99). Of the 78 patients who were free of distant metastases at the time of surgery, 22 patients (28%) developed metastases. The sites where metastases occurred were lung (n = 13), brain (n = 2), bone (n = 2), and liver (n = 1), and, in four patients, metastases occurred at multiple sites. There was one local recurrence in a patient operated with a level IV thrombus: This patient also developed metastases at multiple sites. One-fourth of patients in the level II group developed distant metastases compared to nearly one-third of patients in the level III and level IV groups. Table 2 summarizes the data on metastases in each group and the 5-yr DFS calculated for these 78 patients. The difference in DFS between the groups was not statistically significant ( p = 0.7). In the entire cohort, 32 disease-specific deaths were observed. The median time to death was 17 mo (range: 3 42). Of patients with level I thrombus, 16% died, in contrast to 57% patients with level IV thrombus (Table 2). The 5-yr OS and DSS are summarized in Table 2. Patients with level IV thrombus had a significantly lower 5-yr DSS compared to patients with level I thrombus ( p = 0.03). There was no significant difference in DSS among levels II, III, and IV (Fig. 1). Further analysis compared levels I III as one group (below the diaphragm) and level IV (above the diaphragm) as another group, similar to the TNM classification; there was no statistically significant difference in DSS between the groups ( p = 0.14; Fig. 2). Patients with metastases at presentation experienced high mortality. One patient died perioperatively, one patient died as a result of a pelvic fracture 3 mo after surgery, and seven patients died of disease. The median time to death in these patients was 8 mo (range: 0 27; mean: 10.5 mo).

EUROPEAN UROLOGY 57 (2010) 667 672 669 Table 1 Summary of study variables Study variable All levels Level I Level II Level III Level IV p value * Patients, no. (%) 87 19 (22) 14 (16) 40 (46) 14 (16) Age, yr 61 12 64.5 10 63 10 60 13.5 57 11.5 0.3 y Gender Male 47 (54) 6 (31.5) 8 (57) 27 (67.5) 6 (43) 0.06 Female 40 (46) 13 (68.5) 6 (43) 13 (32.5) 8 (57) Side Right 60 (69) 6 (31.5) 11 (78.5) 34 (85) 9 (64) 0.001 Left 27 (31) 13 (68.5) 3 (21.5) 6 (15) 5 (36) Tumor size (cm SD) 10.25 4.4 8.9 1.95 8.75 3.5 12 5 8.36 4 0.003 y T stage 3b 69 (80) 17 (90) 13 (93) 39 (97.5) 0 3c 11 (12) 0 0 0 11 (78.5) 4 7 (8) 2 (10) 1 (7) 1 (2.5) 3 (21.5) N+ patients, no. (%) 18 (20.5) 2 (10.5) 2 (14) 11 (27.5) 3 (21.5) 0.45 M+ patients, no. (%) 9 (10.5) 0 2 (14) 4 (10) 3 (21.5) 0.25 Histologic type Clear cell 62 (71) 15 (79) 9 (64) 28 (70) 10 (71.5) 0.8 Non clear cell 25 (29) 4 (21) 5 (36) 12 (30) 4 (28.5) Nuclear grade II 14 (16) 3 (16) 3 (21.5) 7 (17.5) 1 (7) 0.1 III 40 (46) 7 (37) 8 (57) 16 (40) 9 (65) IV 24 (28) 5 (26) 0 17 (42.5) 2 (14) Missing 9 (10) 4 (21) 3 (21.5) 0 2 (14) SD = standard deviation; ANOVA = analysis of variance. * All p values are two sided. y ANOVA; others are Pearson x 2 test. Table 2 Survival analysis: 5-year disease-free, disease-specific, and overall survival All levels Level I Level II Level III Level IV Metastases *, no. (%) 22:78 3 (16) 3 (25) 12 (33) 4 (36) 5-yr DFS (SE) * 64 (6.5) 74 (14) 69 (15) 59 (10) 58 (17) Death, no. (%) 32 3 (16) 5 (36) 18 (45) 8 (57) 5-yr OS (SE) 39 (6) 63 (13) 41 (17) 35 (10) 30 (15) 5-yr DSS (SE) 46 (7) 71 (14) 48 (16) 40 (10) 35 (14) 5-yr DSS (SE) 49 (8) Below the diaphragm 35 (14) Above the diaphragm DFS = disease-free survival; SE = standard error; OS = overall survival; DSS = disease-specific survival. * Calculated for patients with M0 status at the time of surgery. On univariate analysis, metastasis at presentation ( p = 0.01), non clear-cell histology ( p = 0.02), lymph node metastases ( p = 0.02), and higher nuclear grade ( p = 0.02) were statistically significant prognostic factors influencing DSS. Independent prognostic factors on multivariate analysis were higher nuclear grade ( p = 0.03), metastasis at presentation ( p < 0.01), and non clear-cell histology ( p = 0.03) (Table 3). Level of thrombus itself was not an independent prognostic factor. 4. Discussion Aggressive surgical treatment is indicated in all patients with RCC and IVC thrombus, as nephrectomy alone is associated with a dismal prognosis [9]. RN with IVC thrombectomy is one of the most challenging surgeries; however, a multitude of developments have made this procedure reasonably safe. Advances in surgical technique, intraoperative monitoring, and judicious use of CPB all contribute to a safer perioperative outcome. This procedure is associated with a perioperative mortality of 3 16% [9 12]. Long-term survival, however, is still low. A 5-yr survival rate from 32% to 64% [7,12,13] has been reported. In our analysis, the 5-yr DSS was 46% for the entire cohort and 54.5% for pn0 M0 disease. Blute et al reported a 59% survival rate for pn0 M0 disease and 5.8% for N1/N2 M1 disease [10]. In the current TNM staging, a tumor thrombus below the diaphragm is staged as T3b; above the diaphragm, it is staged ast3c. This determination is based on the assumption that a higher level of tumor thrombus is associated with a worse prognosis. Although some studies reported lower survival in patients with a more cephalad tumor thrombus, other studies did not report such differences. A large retrospective analysis from 13 European institutions reported a median survival of 52 mo for renal vein thrombus, 26 mo for subdiaphragmatic IVC thrombus, and 18 mo for supradiaphragmatic IVC thrombus. They concluded that IVC invasion at any level significantly and

670 EUROPEAN UROLOGY 57 (2010) 667 672 Fig. 1 Kaplen-Meier plot showing disease-specific survival for different levels of inferior vena cava thrombus. Fig. 2 Kaplan-Meier plot for disease-specific survival in inferior vena cava thrombi in relation to diaphragm. independently decreased the rate of survival; however, the level of tumor thrombus did not significantly alter the OS [11]. In their review of 18 patients with level IV thrombus, Glazer and Novick did not find any significant difference in survival compared to other levels [13]. In a study of 153 patients, Moinzadeh and Libertino reported no significant difference in 5-yr cancer-specific survival (CSS) for all levels of IVC tumor thrombus [14]. In our study, patients with level IV IVC thrombus had a 36% 5-yr survival, which was significantly less than the DSS for patients with level I IVC thrombus. However, there was no statistically significant difference in survival among other levels; also, when grouped in reference to the level of the diaphragm, there was no significant difference in DSS. Kim et al reported similar results for level IV thrombus [15]. IVC thrombus is often associated with metastases at presentation. Most of the series reported in the literature have as many as 30% of patients with M1 disease. IVC thrombectomy is advocated even in the presence of metastases, as it may relieve the symptoms and potentially result in a better quality of life (QoL). A modest benefit has been reported in patients undergoing cytoreductive nephrectomy before giving immunotherapy [16]. A review by Kirkali and Van Poppel concluded that IVC thrombectomy can provide better QoL and may prolong survival even in a metastatic setting [17]. In a report from the Mayo Clinic, the 5-yr CSS was 15% for pn0 M1 disease and 6% for p N1/N2 M1 disease [10]. Staehler and Brkovic reported a median survival of 13 mo and a 26% 2-yr survival in patients with M1 disease [18]. In a series by Lambert et al, patients with metastatic disease did not experience any added morbidity or mortality compared to patients without metastatic disease [19]. In our analysis, 10% of patients had M1 disease, which is lower than in other series, and all of these patients died. The median time to death was 8 mo, with the longest survival at 27 mo. The prognostic significance of the level of tumor thrombus has been controversial. Some studies have reported that the level of tumor thrombus is an independent prognostic factor for survival [20,21]; others did not [13,15,19,22 24]. The presence of IVC invasion, not the level of tumor thrombus, was reported as an independent prognostic factor in some studies [25,26]. Wagner et al reported IVC invasion as an independent prognostic factor ( p = 0.008) [11]. In a review by Kirkali and Van Poppel, the recurrence rates were high, with RCC having vein invasion, and they suggested that this group may benefit from adjuvant therapy [17]. The presence of perinephric fat invasion in a patient with tumor thrombus was identified as a prognostic factor in one study [27]. In our analysis, we found that although a level IV thrombus was a significant predictor of survival on univariate analysis, it was not an independent prognostic factor on multivariate analysis. Metastases at presentation, higher nuclear grade, and non clear-cell histology were found to be independent prognostic factors. These findings emphasize that the primary histologic factors are the more important predictors of prognosis. Table 3 Results of multivariate analysis Variable Univariate Multivariate HR CI p value M1 disease 0.01 3.1 1.25 8 0.002 Non clear-cell histology 0.02 2.4 1.2 6 0.029 LN+ 0.02 0.43 Nuclear grade IV 0.02 5.4 1.2 24 0.028 HR = hazard ratio; CI = confidence interval; LN+ = lymph node positive.

EUROPEAN UROLOGY 57 (2010) 667 672 671 Our study had several limitations: It is a retrospective study, the study population is small, and it is a singleinstitution experience. Our study did not attempt to differentiate tumor thrombus infiltration from thrombus alone, as this information was not always available. Our study has a relatively higher number of non clear-cell tumors compared to literature. The prognostic significance of perinephric fat invasion could not be assessed because of inconsistent pathologic data for this variable. Also, the number of patients with M1 disease is lower than other series. 5. Conclusions RN with IVC thrombectomy offers reasonable long-term survival. Although the survival decreased with higher levels of tumor thrombus, the level of tumor thrombus itself is not an independent prognostic factor influencing survival. Distant metastasis at presentation, higher nuclear grade, and non clear-clear cell histology are significant prognostic factors influencing DSS. Author contributions: Mark S. Soloway had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Ciancio, Soloway, Manoharan, Katkoori Acquisition of data: Katkoori, De Los Santos Analysis and interpretation of data: Katkoori, Manoharan, De Los Santos Drafting of the manuscript: Ciancio, Manoharan, Katkoori Critical revision of the manuscript for important intellectual content: Ciancio, Soloway, Manoharan, Katkoori. Statistical analysis: Katkoori, Manoharan, De Los Santos. Obtaining funding: None. Administrative, technical or material support: Ciancio, Soloway, Manoharan. Supervision: Ciancio, Soloway, Manoharan. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71 96. [2] Wotkowicz C, Wszolek MF, Libertino JA. Resection of renal tumors invading the vena cava. Urol Clin North Am 2008;35:657 71. [3] Marshall FF, Dietrick DD, Baumgartner WA, Reitz BA. Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol 1988;139:1166 72. [4] Berg AA. Malignant hypernephroma of the kidney, its clinical course and diagnosis, with a description of the author s method of radical operative cure. Surg Gynecol Obstet 1913;17:446 71. [5] Campbell SC, Novick AC, Bukowski RM. Renal tumors 8th ed. In: Walsh PC, Retik AB, Vaughan Jr ED, eds. Campbell s Urology, Vol. 4. Philadelphia, PA: Saunders; 2002. p. 2702. [6] Ciancio G, Livingstone AS, Soloway M. Surgical management of renal cell carcinoma with tumor thrombus in the renal and inferior vena cava: the University of Miami experience in using liver transplantation techniques. Eur Urol 2007;51:988 95, discussion 994 5. [7] Neves RJ, Zincke H. Surgical treatment of renal cancer with vena cava extension. Br J Urol 1987;59:390 5. [8] Ciancio G, Vaidya A, Savoie M, Soloway M. Management of renal cell carcinoma with level III thrombus in the inferior vena cava. J Urol 2002;168:1374 7. [9] Sosa RE, Muecke EC, Vaughan Jr ED, McCarron Jr JP. Renal cell carcinoma extending into the inferior vena cava: the prognostic significance of the level of vena caval involvement. J Urol 1984;132: 1097 100. [10] Blute ML, Leibovich BC, Lohse CM, Cheville JC, Zincke H. The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumour thrombus. BJU Int 2004;94:33 41. [11] Wagner B, Patard J-J, Méjean A, et al. Prognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma. Eur Urol 2009;55:452 60. [12] Skinner DG, Pritchett TR, Lieskovsky G, Boyd SD, Stiles QR. Vena caval involvement by renal cell carcinoma. Surgical resection provides meaningful long-term survival. Ann Surg 1989;210:387 92, discussion 392 4. [13] Glazer AA, Novick AC. Long-term followup after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 1996;155:448 50. [14] Moinzadeh A, Libertino JA. Prognostic significance of tumor thrombus level in patients with renal cell carcinoma and venous tumor thrombus extension. Is all T3b the same? J Urol 2004;171: 598 601. [15] Kim HL, Zisman A, Han KR, Figlin RA, Belldegrun AS. Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different? J Urol 2004;171:588 91. [16] Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171: 1071 6. [17] Kirkali Z, Van Poppel H. A critical analysis of surgery for kidney cancer with vena cava invasion. Eur Urol 2007;52:658 62. [18] Staehler G, Brkovic D. The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 2000;163: 1671 5. [19] Lambert EH, Pierorazio PM, Shabsigh A, Olsson CA, Benson MC, McKiernan JM. Prognostic risk stratification and clinical outcomes in patients undergoing surgical treatment for renal cell carcinoma with vascular tumor thrombus. Urology 2007;69:1054 8. [20] Haferkamp A, Bastian PJ, Jakobi H, et al. Renal cell carcinoma with tumor thrombus extension into the vena cava: prospective longterm followup. J Urol 2007;177:1703 8. [21] Quek ML, Stein JP, Skinner DG. Surgical approaches to venous tumor thrombus. Semin Urol Oncol 2001;19:88 97. [22] Tongaonkar HB, Dandekar NP, Dalal AV, Kulkarni JN, Kamat MR. Renal cell carcinoma extending to the renal vein and inferior vena cava: results of surgical treatment and prognostic factors. J Surg Oncol 1995;59:94 100. [23] Sweeney P, Wood CG, Pisters LL, et al. Surgical management of renal cell carcinoma associated with complex inferior vena caval thrombi. Urol Oncol 2003;21:327 33.

672 EUROPEAN UROLOGY 57 (2010) 667 672 [24] Tanaka M, Fujimoto K, Okajima E, Tanaka N, Yoshida K, Hirao Y. Prognostic factors of renal cell carcinoma with extension into inferior vena cava. Int J Urol 2008;15:394 8. [25] Hatcher PA, Anderson EE, Paulson DF, Carson CC, Robertson JE. Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 1991;145:20 3, discussion 23 4. [26] Ljungberg B, Stenling R, Osterdahl B, Farrelly E, Aberg T, Roos G. Vein invasion in renal cell carcinoma: impact on metastatic behavior and survival. J Urol 1995;154:1681 4. [27] Leibovich BC, Cheville JC, Lohse CM, et al. Cancer specific survival for patients with pt3 renal cell carcinoma can the 2002 primary tumor classification be improved? J Urol 2005;173:716 9.