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Prognostic Risk Stratification and Clinical Outcomes in Patients Undergoing Surgical Treatment for Renal Cell Carcinoma with Vascular Tumor Thrombus
Adult Urology Prognostic Risk Stratification and Clinical Outcomes in Patients Undergoing Surgical Treatment for Renal Cell Carcinoma with Vascular Tumor Thrombus Erica H. Lambert, Phillip M. Pierorazio, Ahmad Shabsigh, Carl A. Olsson, Mitchell C. Benson, and James M. McKiernan OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Approximately 4% to 10% of patients with renal cell carcinoma (RCC) present with vascular tumor thrombus. Often, these patients also present with metastatic disease. This study examined the clinical outcome and morbidity of patients with RCC and vascular tumor thrombus treated with aggressive surgical therapy. From 1989 to 2006, 118 patients were identified with Stage pT3b or pT3c RCC who had undergone radical nephrectomy and thrombectomy. Disease-specific survival (DSS) and overall survival were measured by Kaplan-Meier statistics with the log-rank test to assess differences in survival stratified by the clinical and pathologic variables. Cox regression techniques were used to identify significant predictors of DSS. The median follow-up was 18 months (range 1 month to 13.55 years). Tumor thrombus was at the level of the renal vein in 67 patients (56.8%), the infradiaphragmatic inferior vena cava in 39 (33%), and the supradiaphragmatic inferior vena cava in 12 patients (10%). Of the 118 patients, 42 (35.6%) presented with metastasis. The median tumor size was 8.2 cm. The 5-year overall survival rate was 40.7%. The 5-year DSS rate was 60.3% in those without metastasis and 10% in those with metastasis (P ⬍0.001). The level of tumor thrombus did not significantly affect survival (P ⫽ 0.85). When the patients without metastasis were analyzed separately, nodal positivity (P ⫽ 0.03) and a tumor diameter greater than 7 cm (P ⫽ 0.05) were significant predictors of DSS. Our results support the role of radical nephrectomy and thrombectomy in patients with RCC and vascular tumor thrombus. The absence of significant morbidity makes aggressive radical surgery feasible in the patients with tumor thrombus and metastatic disease. The current TNM staging system may need to be revised, given the evidence that the level of tumor thrombus invasion does not affect the survival outcomes. UROLOGY 69: 1054 –1058, 2007. © 2007 Elsevier Inc.
R
enal cell carcinoma (RCC) invasion into the renal vein and/or the inferior vena cava is present in approximately 4% to 10% of patients with RCC.1,2 The primary modality of treatment for these patients is radical nephrectomy and thrombectomy.3 Multiple studies have evaluated whether the level of thrombus affects survival, but many have not shown a survival benefit.2–7 Up to one third of these patients will have metastatic disease at presentation.8 Historically, the
Phil Pierorazio is a Doris Duke Charitable Foundation Clinical Research Fellow. From the Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York Reprint requests: Erica H. Lambert, M.D., Department of Urology, Columbia University Medical Center, Atchley Pavilion, 11th Floor, 161 Fort Washington Avenue, New York, NY 10032. E-mail: [email protected] Submitted: September 27, 2006; accepted (with revisions): February 26, 2007
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© 2007 Elsevier Inc. All Rights Reserved
morbidity of thrombectomy and the lack of effective adjuvant treatment in the setting of metastatic disease were thought to be contraindications to aggressive surgical management.9 Recent data have suggested that patients with metastatic disease have a survival advantage when treated with cytoreductive nephrectomy followed by immunotherapy.10 The present study reports the experience of aggressive surgical treatment of patients with RCC and venous thrombus, with a particular focus on the predictors of clinical outcomes and perioperative morbidity.
MATERIAL AND METHODS The institutional review board-approved Columbia University Urologic Oncology Database was reviewed. We identified 1016 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.02.052
patients who had undergone nephrectomy from 1988 to September 2006. Of those patients, 118 were identified with renal vein or inferior vena cava (IVC) thrombi (pathologic Stage T3b and T3c disease). A retrospective review was performed to evaluate patient demographics, clinical stage, surgical approach, perioperative complications, pathologic features, and clinical outcomes. Preoperative staging relied on chest x-ray, chest, abdominal, and pelvic computed tomography, and selective use of magnetic resonance imaging, echocardiography, ultrasonography, and bone scanning. Tumor extension into the venous system was classified as involving the renal vein only, the IVC below the diaphragm, and the IVC above the diaphragm. Vena cavotomy, vena cavectomy, and vena caval reconstruction were performed at the discretion of the operating surgeon. For cases that involved the supradiaphragmatic IVC, cardiopulmonary bypass and/or hypothermic circulatory arrest were used with the consultation of the cardiothoracic surgical team. In several patients, resection of a metastatic focus (involving the lung, bone, or abdominal soft tissue) occurred at the same operative setting. Patients were followed up with physical examination, laboratory work (complete blood count, basic metabolic panel, and liver function tests), and imaging (chest x-ray and computed tomography of the abdomen and pelvis) at 6-month intervals. Patients with simultaneous or metachronous metastases were offered immunotherapy for the duration of the data collection period. The outcomes were defined as disease-specific survival (DSS), disease-free survival, and overall survival (OS). Differences in survival were analyzed for patients stratified by thrombus level, TNM stage, laterality, sex, tumor size, and tumor grade. Kaplan-Meier techniques with the log-rank test were used to measure differences in survival among groups. Univariate regression techniques (Cox proportional hazard model) were used to assess the impact of age, tumor size, laterality, tumor stage, thrombus level, metastasis, and histologic type on DSS. An additional Cox regression model was then fit with significant predictors from the univariate analysis in a multivariate assessment of outcome. Using the above method, a separate analysis was performed in patients without metastatic disease. Statistical significance was set at P ⫽ 0.05. Analyses were performed using STATA SE, version 9.0 (StataCorp, College Station, Tex).
RESULTS A total of 118 patients were identified with RCC and tumor extension to the renal vein or IVC. All patients were treated with open radical nephrectomy. Detailed patient and clinicopathologic characteristics are presented in Table 1. Tumor thrombus extended to the renal vein in 67 patients (56.8%), the infradiaphragmatic IVC in 39 (33.1%), and the supradiaphragmatic IVC in 12 (10.2%), of which six extended to the right atrium. All patients with supradiaphragmatic involvement underwent cardiopulmonary bypass with hypothermic arrest. One patient with an infradiaphragmatic thrombus underwent cardiopulmonary bypass without hypothermic arrest. Of the 118 patients, 42 (35.6%) presented with metastatic disease (M1), and most of these patients preUROLOGY 69 (6), 2007
Table 1. Patient characteristics Characteristic Preoperative Median age (yr) Sex (n) Female Male Race (n) African-American Asian White Hispanic Chief complaint* (n) Incidental Abdominal pain Hematuria Palpable mass Constitutional symptoms Combination Other Laterality (n) Left Right Bilateral Site of metastases (n) Lung Bone Nodes Liver Multiple Operative and pathologic Median diameter (cm) Histologic type (n) Conventional Granular Papillary Chromophobe Collecting duct Sarcomatoid Tumor grade (n) 1–2 3 4 Thrombus level (n) Renal vein Subdiaphragmatic Supradiaphragmatic T stage (n) T3b T3c T4 N stage (n) N0 N1 N2 Nx M stage (n) M0 M1 Mx
Value 61.9 43 (36.4) 75 (63.6) 5 (4.4) 5 (4.4) 101 (87.8) 4 (3.5) 26 (23.2) 19 (17.0) 39 (34.8) 2 (1.8) 11 (8.8) 10 (8.9) 5 (4.7) 42 (35.6) 75 (63.6) 1 (0.9) 41 20 (48.8) 7 (17.1) 5 (12.2) 2 (4.9) 7 (17.1) 8.2 97 (82.2) 11 (9.3) 1 (0.9) 1 (0.9) 1 (0.9) 7 (5.9) 32 (29.1) 45 (40.9) 33 (30.0) 67 (56.8) 39 (33.1) 12 (10.2) 102 (87.2) 11 (9.4) 4 (3.4) 44 (37.3) 10 (8.5) 10 (8.5) 54 (45.8) 72 (61.0) 42 (35.6) 4 (3.4)
Data in parentheses are percentages. * Constitutional symptoms included weight loss and fatigue; other symptoms included bone pain or nonspecified symptoms.
sented with lung metastases (20 of 42; 48.7%). The mean and median tumor size was 9.3 cm and 8.2 cm, respectively. 1055
Table 2. Complications Complication Total* (%) Anuria Abdominal injury† Arrhythmia PE Bleeding DVT Mortality Myocardial infarction Pericarditis Pneumonia Pulmonary edema Sepsis Wound infection
n 22/118 (18.8) 2 2 4 3 5 2 1 2 1 4 1 1 2
PE ⫽ pulmonary embolus; DVT ⫽ deep venous thrombosis. * A total of 22 patients experienced 30 complications. † Including splenic laceration and bowel ischemia.
The perioperative complications are presented in Table 2. Of the 118 patients, 22 (18.8%) experienced perioperative complications. One patient died secondary to a tumor embolus. Perioperative complications included atrial fibrillation, pneumonia, pulmonary embolus/deep vein thrombosis, hemorrhage, wound infection, and myocardial infarction, which subsequently resolved. No statistically significant difference was found in the rate of complications among the levels of thrombi (P ⫽ 0.69) or the presence or absence of metastatic disease (P ⫽ 0.15). The analysis of DSS demonstrated a 41.7% 5-year rate and 37.9% 10-year rate for the entire cohort. The diseasefree survival rate was 26.6% at 5 years and 19.8% at 10 years, and the OS rate was 40.7% and 37.1% at 5 and 10 years, respectively (Fig. 1a). The median follow-up was 17.8 months (range 1 month to 13.55 years). The DSS rate was 60.3% for patients without metastasis and 10.0% for patients with M1 disease. On univariate analyses, the presence of metastatic disease (P ⬍0.001) and the tumor grade (P ⫽ 0.006) were predictive of outcome. When nodal disease was characterized as node-negative disease (N0 or Nx) versus node-positive disease (N1-N2), the nodal stage was predictive of outcome (P ⫽ 0.05). A total of 20 patients had node-positive disease, 10 patients each with and without metastasis. The OS time for patients with N⫹M0 was 1.76 years and was 1.17 years for patients with N⫹M⫹ (P ⫽ 0.98). On multivariate analysis, the presence of metastatic disease was the only predictor of outcome (P ⬍0.001). Neither the thrombus level, characterized as renal vein, infradiaphragmatic, or supradiaphragmatic (P ⫽ 0.85), nor pathologic T stage (P ⫽ 0.24) were significant predictors of outcome. In a cohort of patients without metastatic disease (n ⫽ 76), the DSS rate was 60.8% at 5 and 10 years, the disease-free survival rate was 44.7% at 5 years and 36.4% at 10 years, and the OS rate was 60.3% at 5 and 10 years(Fig. 1b). Kaplan-Meier and log-rank analysis demonstrated a significant difference in survival between patients with N0 or Nx disease and those with N1 or N2 1056
Figure 1. (A) DSS, disease-free survival, and OS for entire cohort. (B) DSS, disease-free survival, and OS for patients without metastatic disease (M0).
disease (P ⫽ 0.03). On univariate survival analysis, the extent of nodal disease was predictive of outcome with a hazard ratio of 2.47 for N1 disease and 1.22 for N2 disease (P ⫽ 0.01). Neither the thrombus level (P ⫽ 0.25, Fig. 1b) nor the pathologic stage (P ⫽ 0.21) was a significant predictor of outcome. Additionally, no survival differences were found between patients with renal vein only thrombus and infradiaphragmatic thrombus (P ⫽ 0.62), indicating that DSS was not affected by traditional categories of tumor thrombus classification (Fig. 2a). However, the primary tumor size as stratified by greater or less than 7 cm was a significant predictor of outcome in a univariate model (P ⫽ 0.05, Fig. 2b). Tumor laterality (P ⫽ 0.80), age (P ⫽ 0.78), sex (P ⫽ 0.10), grade (P ⫽ 0.69), ipsilateral adrenal involvement (P ⫽ 0.18), and renal pelvis involvement (P ⫽ 0.64) were not significant predictors of outcome. On multivariate analysis, nodepositive disease was the only variable to significantly affect outcome (P ⫽ 0.03). Of the 28 patients (23.7%) who received additional therapy, 17 received interferon-alpha, 9 received interUROLOGY 69 (6), 2007
Figure 2. Patients without metastatic disease (M0). (A) DSS stratified by level of thrombus. (B) DSS stratified by tumor diameter.
leukin-2, and 3 underwent radiotherapy. Of those patients, 75.0% had metastatic disease. Finally, 59 patients (50.0%) did not have information available regarding additional therapy.
COMMENT Radical nephrectomy with thrombectomy remains the standard of care for patients with RCC and venous extension.1,3,11 RCC has a tendency to invade the renal vein and inferior vena cava in up to 10% of cases12 and into the right atrium in 0.5% to 1% of cases.9 Of these patients, approximately one third also have distant metastases at presentation.8 In the cohort presented, 35.6% of patients with vascular tumor thrombus had metastases diagnosed preoperatively. Historically, treatment of nonmetastatic RCC and concurrent vena caval thrombus with radical nephrectomy and thrombectomy resulted in a 5-year survival rate of 15%.2,9 The complexity of the surgical procedure and the morbidity of the complications, coupled with the conflicting results reported in published studies, created confusion and a disinclination in some to perform vena cavotomy, thrombecUROLOGY 69 (6), 2007
tomy, and vena caval reconstruction.11 Increased experience and surgical refinements, such as cardiopulmonary bypass and hypothermic circulatory arrest, have improved the outcomes, resulting in survival rates after radical nephrectomy and tumor thrombectomy of 40% to 68% at 5 years for patients without metastatic disease.3–5,12 In our series, the estimated 5-year DSS rate was 60% for patients with nonmetastatic disease after radical nephrectomy and thrombectomy. Despite initial reports that suggested worse survival for patients with higher levels of thrombus,13,14 larger series have shown that no increased incidence of lymph node positivity, metastatic disease, or decreased survival is associated with greater levels of tumor thrombus.4,11,12,15 In fact, survival for patients without metastases after radical nephrectomy and vena caval thrombectomy, regardless of the tumor thrombus level, including extension into the right atrium, appears no different than that for patients who have tumor thrombus confined to the renal vein.2,5–7 The data presented in this analysis support the hypothesis that the level of thrombus does not significantly alter survival for patients with vascular tumor thrombus. In contrast, the primary tumor size, tumor grade, and nodal involvement significantly affected survival for patients without associated metastasis. Despite the effect the level of thrombus has on operative planning (specifically the use of cardiopulmonary bypass), there is no increased morbidity or cancer-specific outcomes for patients undergoing renal vein or IVC thrombectomy. The TNM staging system may need to be revised to reflect the lack of survival differences between patients with Stage T3bN0M0 and T3cN0M0 disease shown in this series and others. The data from this study may further suggest that T3bN0M0 and T3cN0M0 would be better characterized according to the primary tumor size, greater or less than 7 cm, with associated tumor thrombus. The natural history of metastatic RCC with concurrent vena caval thrombus is rapidly progressive, with a 3.5-month median survival without treatment.5 Swierzewski et al.11 showed that 100 patients undergoing radical nephrectomy and tumor thrombectomy had an OS rate at 5 years of 54% to 64% without metastasis, but 19.6% with metastatic disease (P ⫽ 0.003). Distant metastasis has been a significant predictor of decreased survival compared with localized disease in patients undergoing radical nephrectomy and vena caval thrombectomy.8 Thus, many have avoided radical surgery for patients with metastatic disease, believing that the limited chance of long-term survival did not justify the morbidity of such an extensive operation.9,11,12 In our series, patients with metastatic disease did not experience any added morbidity or mortality (P ⫽ 0.69) from undergoing an extensive operation compared with the patients without metastatic disease. Likely, this was because of the advancements in surgical technique and perioperative care. A multimodality treatment regimen has resulted in the 1057
reevaluation of aggressive surgery in the presence of metastatic disease. Cytoreductive nephrectomy has demonstrated improved survival for patients with metastatic disease.15–17 In a trial of 31 patients with metastatic RCC and venal caval thrombus, Naitoh et al.15 reported a 5-year survival rate of 17% after radical nephrectomy, vena caval thrombectomy, and subsequent immunotherapy. Also, 80% of their patients received postoperative immunotherapy.15 Our results have shown that patients with metastatic disease and venous extension had a 5-year DSS rate of 10%. In contrast to the aforementioned study, 24% of the patients had received adjuvant therapy during our 17-year experience. In the earlier series, availability and options for systemic therapy were limited. In addition, no study has demonstrated a survival benefit for immunotherapy in this population compared with cytoreductive nephrectomy alone. Because more effective systemic therapy is becoming available,16 it is now possible to pursue more aggressive surgery for patients with vena caval thrombus and metastatic RCC. Recent studies have shown improved survival for patients with metastatic disease who receive immunotherapy with interferon alpha-2b or interleukin-2, with a 3-year survival rate reported as great as 38%.17,18 A modest benefit also appears to result from performing cytoreductive nephrectomy in patients with metastatic disease before initiating immunotherapy.10 Given the emergence of more effective systemic therapies and improvements in surgical techniques and perioperative care, radical surgery for metastatic and nonmetastatic RCC with vena caval involvement is justified.
CONCLUSIONS Our results support the role for radical nephrectomy and vascular tumor thrombectomy in patients with RCC and vascular tumor thrombus. The procedure can be performed safely and gives patients with RCC and venous tumor thrombus but without metastasis excellent longterm survival. Furthermore, the procedure can be performed safely in patients with metastatic disease with minimal perioperative morbidity and mortality. The current TNM staging system may need to be revised given the evidence that level of tumor thrombus extension does not independently affect survival. References 1. Marshall FF, Dietrick DD, Baumgartner WA, et al: Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol 139: 1166 –1172, 1988.
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2. Hatcher PA, Anderson EE, Paulson DF, et al: Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 145: 20 –23, 1991. 3. Kaplan S, Ekici S, Dogan R, et al: Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 183: 292–299, 2002. 4. Glazer AA, and Novick AC: Long-term follow up after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 155: 448 – 450, 1996. 5. Staehler G, and Brkovic D: The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 163: 1671– 1675, 2000. 6. Kuczyk MA, Bokemeyer C, Kohn G, et al: Prognostic relevance of intracaval neoplastic extension for patient with renal cell cancer. Br J Urol 80: 18 –24, 1997. 7. Kim HL, Zisman A, Ken-Ryu H, et al: Prognostic significance of venous thrombus in renal cell carcinoma: are renal vein and inferior vena cava involvement different? J Urol 171: 588 –591, 2004. 8. Skinner DG, Pfister RF, and Colvin R: Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. J Urol 107: 711–716, 1972. 9. Montie JE, El Ammar R, Pontes JE, et al: Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 173: 107–115, 1991. 10. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alpha-2b compared with interferon alpha-2b alone for metastatic renal cell cancer. N Engl J Med 345: 1655– 1659, 2001. 11. Swierzewski DJ, Swierzewski MJ, and Libertino JA: Radical nephrectomy in patients with renal cell carcinoma with venous, vena caval, and atrial extension. Am J Surg 168: 205–209, 1994. 12. Libertino JA, Zinman L, and Watkins E: Long-term results of resection of renal cell cancer with extension into inferior vena cava. J Urol 137: 21–24, 1987. 13. Blute ML, Leibovich BC, Lohse CM, et al: The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumor thrombus. BJU Int 94: 33– 41, 2004. 14. Moinzadeh A, and Libertino JA: Prognostic significance of tumor thrombus level in long-term survival of patients with renal cell carcinoma and venous tumor thrombus extension. J Urol 171: 598 – 601, 2004. 15. Naitoh J, Japlan A, Dorey F, et al: Metastatic renal cell carcinoma with concurrent inferior vena caval invasion: long-term survival after combination therapy with radical nephrectomy, vena caval thrombectomy and postoperative immunotherapy. J Urol 162: 46 –50, 1999. 16. Wolf JS, Aronson FR, Small EJ, et al: Nephrectomy for metastatic renal cell carcinoma: a component of systemic treatment regimens. J Surg Oncol 55: 7–13, 1994. 17. Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8⫹ selected tumor infiltrating lymphocytes from primary tumor. J Urol 158: 740 –745, 1997. 18. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high dose interleukin alone. N Engl J Med 316: 889 – 897, 1987.
UROLOGY 69 (6), 2007
METHODS
RESULTS
CONCLUSIONS
Approximately 4% to 10% of patients with renal cell carcinoma (RCC) present with vascular tumor thrombus. Often, these patients also present with metastatic disease. This study examined the clinical outcome and morbidity of patients with RCC and vascular tumor thrombus treated with aggressive surgical therapy. From 1989 to 2006, 118 patients were identified with Stage pT3b or pT3c RCC who had undergone radical nephrectomy and thrombectomy. Disease-specific survival (DSS) and overall survival were measured by Kaplan-Meier statistics with the log-rank test to assess differences in survival stratified by the clinical and pathologic variables. Cox regression techniques were used to identify significant predictors of DSS. The median follow-up was 18 months (range 1 month to 13.55 years). Tumor thrombus was at the level of the renal vein in 67 patients (56.8%), the infradiaphragmatic inferior vena cava in 39 (33%), and the supradiaphragmatic inferior vena cava in 12 patients (10%). Of the 118 patients, 42 (35.6%) presented with metastasis. The median tumor size was 8.2 cm. The 5-year overall survival rate was 40.7%. The 5-year DSS rate was 60.3% in those without metastasis and 10% in those with metastasis (P ⬍0.001). The level of tumor thrombus did not significantly affect survival (P ⫽ 0.85). When the patients without metastasis were analyzed separately, nodal positivity (P ⫽ 0.03) and a tumor diameter greater than 7 cm (P ⫽ 0.05) were significant predictors of DSS. Our results support the role of radical nephrectomy and thrombectomy in patients with RCC and vascular tumor thrombus. The absence of significant morbidity makes aggressive radical surgery feasible in the patients with tumor thrombus and metastatic disease. The current TNM staging system may need to be revised, given the evidence that the level of tumor thrombus invasion does not affect the survival outcomes. UROLOGY 69: 1054 –1058, 2007. © 2007 Elsevier Inc.
R
enal cell carcinoma (RCC) invasion into the renal vein and/or the inferior vena cava is present in approximately 4% to 10% of patients with RCC.1,2 The primary modality of treatment for these patients is radical nephrectomy and thrombectomy.3 Multiple studies have evaluated whether the level of thrombus affects survival, but many have not shown a survival benefit.2–7 Up to one third of these patients will have metastatic disease at presentation.8 Historically, the
Phil Pierorazio is a Doris Duke Charitable Foundation Clinical Research Fellow. From the Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York Reprint requests: Erica H. Lambert, M.D., Department of Urology, Columbia University Medical Center, Atchley Pavilion, 11th Floor, 161 Fort Washington Avenue, New York, NY 10032. E-mail: [email protected] Submitted: September 27, 2006; accepted (with revisions): February 26, 2007
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© 2007 Elsevier Inc. All Rights Reserved
morbidity of thrombectomy and the lack of effective adjuvant treatment in the setting of metastatic disease were thought to be contraindications to aggressive surgical management.9 Recent data have suggested that patients with metastatic disease have a survival advantage when treated with cytoreductive nephrectomy followed by immunotherapy.10 The present study reports the experience of aggressive surgical treatment of patients with RCC and venous thrombus, with a particular focus on the predictors of clinical outcomes and perioperative morbidity.
MATERIAL AND METHODS The institutional review board-approved Columbia University Urologic Oncology Database was reviewed. We identified 1016 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.02.052
patients who had undergone nephrectomy from 1988 to September 2006. Of those patients, 118 were identified with renal vein or inferior vena cava (IVC) thrombi (pathologic Stage T3b and T3c disease). A retrospective review was performed to evaluate patient demographics, clinical stage, surgical approach, perioperative complications, pathologic features, and clinical outcomes. Preoperative staging relied on chest x-ray, chest, abdominal, and pelvic computed tomography, and selective use of magnetic resonance imaging, echocardiography, ultrasonography, and bone scanning. Tumor extension into the venous system was classified as involving the renal vein only, the IVC below the diaphragm, and the IVC above the diaphragm. Vena cavotomy, vena cavectomy, and vena caval reconstruction were performed at the discretion of the operating surgeon. For cases that involved the supradiaphragmatic IVC, cardiopulmonary bypass and/or hypothermic circulatory arrest were used with the consultation of the cardiothoracic surgical team. In several patients, resection of a metastatic focus (involving the lung, bone, or abdominal soft tissue) occurred at the same operative setting. Patients were followed up with physical examination, laboratory work (complete blood count, basic metabolic panel, and liver function tests), and imaging (chest x-ray and computed tomography of the abdomen and pelvis) at 6-month intervals. Patients with simultaneous or metachronous metastases were offered immunotherapy for the duration of the data collection period. The outcomes were defined as disease-specific survival (DSS), disease-free survival, and overall survival (OS). Differences in survival were analyzed for patients stratified by thrombus level, TNM stage, laterality, sex, tumor size, and tumor grade. Kaplan-Meier techniques with the log-rank test were used to measure differences in survival among groups. Univariate regression techniques (Cox proportional hazard model) were used to assess the impact of age, tumor size, laterality, tumor stage, thrombus level, metastasis, and histologic type on DSS. An additional Cox regression model was then fit with significant predictors from the univariate analysis in a multivariate assessment of outcome. Using the above method, a separate analysis was performed in patients without metastatic disease. Statistical significance was set at P ⫽ 0.05. Analyses were performed using STATA SE, version 9.0 (StataCorp, College Station, Tex).
RESULTS A total of 118 patients were identified with RCC and tumor extension to the renal vein or IVC. All patients were treated with open radical nephrectomy. Detailed patient and clinicopathologic characteristics are presented in Table 1. Tumor thrombus extended to the renal vein in 67 patients (56.8%), the infradiaphragmatic IVC in 39 (33.1%), and the supradiaphragmatic IVC in 12 (10.2%), of which six extended to the right atrium. All patients with supradiaphragmatic involvement underwent cardiopulmonary bypass with hypothermic arrest. One patient with an infradiaphragmatic thrombus underwent cardiopulmonary bypass without hypothermic arrest. Of the 118 patients, 42 (35.6%) presented with metastatic disease (M1), and most of these patients preUROLOGY 69 (6), 2007
Table 1. Patient characteristics Characteristic Preoperative Median age (yr) Sex (n) Female Male Race (n) African-American Asian White Hispanic Chief complaint* (n) Incidental Abdominal pain Hematuria Palpable mass Constitutional symptoms Combination Other Laterality (n) Left Right Bilateral Site of metastases (n) Lung Bone Nodes Liver Multiple Operative and pathologic Median diameter (cm) Histologic type (n) Conventional Granular Papillary Chromophobe Collecting duct Sarcomatoid Tumor grade (n) 1–2 3 4 Thrombus level (n) Renal vein Subdiaphragmatic Supradiaphragmatic T stage (n) T3b T3c T4 N stage (n) N0 N1 N2 Nx M stage (n) M0 M1 Mx
Value 61.9 43 (36.4) 75 (63.6) 5 (4.4) 5 (4.4) 101 (87.8) 4 (3.5) 26 (23.2) 19 (17.0) 39 (34.8) 2 (1.8) 11 (8.8) 10 (8.9) 5 (4.7) 42 (35.6) 75 (63.6) 1 (0.9) 41 20 (48.8) 7 (17.1) 5 (12.2) 2 (4.9) 7 (17.1) 8.2 97 (82.2) 11 (9.3) 1 (0.9) 1 (0.9) 1 (0.9) 7 (5.9) 32 (29.1) 45 (40.9) 33 (30.0) 67 (56.8) 39 (33.1) 12 (10.2) 102 (87.2) 11 (9.4) 4 (3.4) 44 (37.3) 10 (8.5) 10 (8.5) 54 (45.8) 72 (61.0) 42 (35.6) 4 (3.4)
Data in parentheses are percentages. * Constitutional symptoms included weight loss and fatigue; other symptoms included bone pain or nonspecified symptoms.
sented with lung metastases (20 of 42; 48.7%). The mean and median tumor size was 9.3 cm and 8.2 cm, respectively. 1055
Table 2. Complications Complication Total* (%) Anuria Abdominal injury† Arrhythmia PE Bleeding DVT Mortality Myocardial infarction Pericarditis Pneumonia Pulmonary edema Sepsis Wound infection
n 22/118 (18.8) 2 2 4 3 5 2 1 2 1 4 1 1 2
PE ⫽ pulmonary embolus; DVT ⫽ deep venous thrombosis. * A total of 22 patients experienced 30 complications. † Including splenic laceration and bowel ischemia.
The perioperative complications are presented in Table 2. Of the 118 patients, 22 (18.8%) experienced perioperative complications. One patient died secondary to a tumor embolus. Perioperative complications included atrial fibrillation, pneumonia, pulmonary embolus/deep vein thrombosis, hemorrhage, wound infection, and myocardial infarction, which subsequently resolved. No statistically significant difference was found in the rate of complications among the levels of thrombi (P ⫽ 0.69) or the presence or absence of metastatic disease (P ⫽ 0.15). The analysis of DSS demonstrated a 41.7% 5-year rate and 37.9% 10-year rate for the entire cohort. The diseasefree survival rate was 26.6% at 5 years and 19.8% at 10 years, and the OS rate was 40.7% and 37.1% at 5 and 10 years, respectively (Fig. 1a). The median follow-up was 17.8 months (range 1 month to 13.55 years). The DSS rate was 60.3% for patients without metastasis and 10.0% for patients with M1 disease. On univariate analyses, the presence of metastatic disease (P ⬍0.001) and the tumor grade (P ⫽ 0.006) were predictive of outcome. When nodal disease was characterized as node-negative disease (N0 or Nx) versus node-positive disease (N1-N2), the nodal stage was predictive of outcome (P ⫽ 0.05). A total of 20 patients had node-positive disease, 10 patients each with and without metastasis. The OS time for patients with N⫹M0 was 1.76 years and was 1.17 years for patients with N⫹M⫹ (P ⫽ 0.98). On multivariate analysis, the presence of metastatic disease was the only predictor of outcome (P ⬍0.001). Neither the thrombus level, characterized as renal vein, infradiaphragmatic, or supradiaphragmatic (P ⫽ 0.85), nor pathologic T stage (P ⫽ 0.24) were significant predictors of outcome. In a cohort of patients without metastatic disease (n ⫽ 76), the DSS rate was 60.8% at 5 and 10 years, the disease-free survival rate was 44.7% at 5 years and 36.4% at 10 years, and the OS rate was 60.3% at 5 and 10 years(Fig. 1b). Kaplan-Meier and log-rank analysis demonstrated a significant difference in survival between patients with N0 or Nx disease and those with N1 or N2 1056
Figure 1. (A) DSS, disease-free survival, and OS for entire cohort. (B) DSS, disease-free survival, and OS for patients without metastatic disease (M0).
disease (P ⫽ 0.03). On univariate survival analysis, the extent of nodal disease was predictive of outcome with a hazard ratio of 2.47 for N1 disease and 1.22 for N2 disease (P ⫽ 0.01). Neither the thrombus level (P ⫽ 0.25, Fig. 1b) nor the pathologic stage (P ⫽ 0.21) was a significant predictor of outcome. Additionally, no survival differences were found between patients with renal vein only thrombus and infradiaphragmatic thrombus (P ⫽ 0.62), indicating that DSS was not affected by traditional categories of tumor thrombus classification (Fig. 2a). However, the primary tumor size as stratified by greater or less than 7 cm was a significant predictor of outcome in a univariate model (P ⫽ 0.05, Fig. 2b). Tumor laterality (P ⫽ 0.80), age (P ⫽ 0.78), sex (P ⫽ 0.10), grade (P ⫽ 0.69), ipsilateral adrenal involvement (P ⫽ 0.18), and renal pelvis involvement (P ⫽ 0.64) were not significant predictors of outcome. On multivariate analysis, nodepositive disease was the only variable to significantly affect outcome (P ⫽ 0.03). Of the 28 patients (23.7%) who received additional therapy, 17 received interferon-alpha, 9 received interUROLOGY 69 (6), 2007
Figure 2. Patients without metastatic disease (M0). (A) DSS stratified by level of thrombus. (B) DSS stratified by tumor diameter.
leukin-2, and 3 underwent radiotherapy. Of those patients, 75.0% had metastatic disease. Finally, 59 patients (50.0%) did not have information available regarding additional therapy.
COMMENT Radical nephrectomy with thrombectomy remains the standard of care for patients with RCC and venous extension.1,3,11 RCC has a tendency to invade the renal vein and inferior vena cava in up to 10% of cases12 and into the right atrium in 0.5% to 1% of cases.9 Of these patients, approximately one third also have distant metastases at presentation.8 In the cohort presented, 35.6% of patients with vascular tumor thrombus had metastases diagnosed preoperatively. Historically, treatment of nonmetastatic RCC and concurrent vena caval thrombus with radical nephrectomy and thrombectomy resulted in a 5-year survival rate of 15%.2,9 The complexity of the surgical procedure and the morbidity of the complications, coupled with the conflicting results reported in published studies, created confusion and a disinclination in some to perform vena cavotomy, thrombecUROLOGY 69 (6), 2007
tomy, and vena caval reconstruction.11 Increased experience and surgical refinements, such as cardiopulmonary bypass and hypothermic circulatory arrest, have improved the outcomes, resulting in survival rates after radical nephrectomy and tumor thrombectomy of 40% to 68% at 5 years for patients without metastatic disease.3–5,12 In our series, the estimated 5-year DSS rate was 60% for patients with nonmetastatic disease after radical nephrectomy and thrombectomy. Despite initial reports that suggested worse survival for patients with higher levels of thrombus,13,14 larger series have shown that no increased incidence of lymph node positivity, metastatic disease, or decreased survival is associated with greater levels of tumor thrombus.4,11,12,15 In fact, survival for patients without metastases after radical nephrectomy and vena caval thrombectomy, regardless of the tumor thrombus level, including extension into the right atrium, appears no different than that for patients who have tumor thrombus confined to the renal vein.2,5–7 The data presented in this analysis support the hypothesis that the level of thrombus does not significantly alter survival for patients with vascular tumor thrombus. In contrast, the primary tumor size, tumor grade, and nodal involvement significantly affected survival for patients without associated metastasis. Despite the effect the level of thrombus has on operative planning (specifically the use of cardiopulmonary bypass), there is no increased morbidity or cancer-specific outcomes for patients undergoing renal vein or IVC thrombectomy. The TNM staging system may need to be revised to reflect the lack of survival differences between patients with Stage T3bN0M0 and T3cN0M0 disease shown in this series and others. The data from this study may further suggest that T3bN0M0 and T3cN0M0 would be better characterized according to the primary tumor size, greater or less than 7 cm, with associated tumor thrombus. The natural history of metastatic RCC with concurrent vena caval thrombus is rapidly progressive, with a 3.5-month median survival without treatment.5 Swierzewski et al.11 showed that 100 patients undergoing radical nephrectomy and tumor thrombectomy had an OS rate at 5 years of 54% to 64% without metastasis, but 19.6% with metastatic disease (P ⫽ 0.003). Distant metastasis has been a significant predictor of decreased survival compared with localized disease in patients undergoing radical nephrectomy and vena caval thrombectomy.8 Thus, many have avoided radical surgery for patients with metastatic disease, believing that the limited chance of long-term survival did not justify the morbidity of such an extensive operation.9,11,12 In our series, patients with metastatic disease did not experience any added morbidity or mortality (P ⫽ 0.69) from undergoing an extensive operation compared with the patients without metastatic disease. Likely, this was because of the advancements in surgical technique and perioperative care. A multimodality treatment regimen has resulted in the 1057
reevaluation of aggressive surgery in the presence of metastatic disease. Cytoreductive nephrectomy has demonstrated improved survival for patients with metastatic disease.15–17 In a trial of 31 patients with metastatic RCC and venal caval thrombus, Naitoh et al.15 reported a 5-year survival rate of 17% after radical nephrectomy, vena caval thrombectomy, and subsequent immunotherapy. Also, 80% of their patients received postoperative immunotherapy.15 Our results have shown that patients with metastatic disease and venous extension had a 5-year DSS rate of 10%. In contrast to the aforementioned study, 24% of the patients had received adjuvant therapy during our 17-year experience. In the earlier series, availability and options for systemic therapy were limited. In addition, no study has demonstrated a survival benefit for immunotherapy in this population compared with cytoreductive nephrectomy alone. Because more effective systemic therapy is becoming available,16 it is now possible to pursue more aggressive surgery for patients with vena caval thrombus and metastatic RCC. Recent studies have shown improved survival for patients with metastatic disease who receive immunotherapy with interferon alpha-2b or interleukin-2, with a 3-year survival rate reported as great as 38%.17,18 A modest benefit also appears to result from performing cytoreductive nephrectomy in patients with metastatic disease before initiating immunotherapy.10 Given the emergence of more effective systemic therapies and improvements in surgical techniques and perioperative care, radical surgery for metastatic and nonmetastatic RCC with vena caval involvement is justified.
CONCLUSIONS Our results support the role for radical nephrectomy and vascular tumor thrombectomy in patients with RCC and vascular tumor thrombus. The procedure can be performed safely and gives patients with RCC and venous tumor thrombus but without metastasis excellent longterm survival. Furthermore, the procedure can be performed safely in patients with metastatic disease with minimal perioperative morbidity and mortality. The current TNM staging system may need to be revised given the evidence that level of tumor thrombus extension does not independently affect survival. References 1. Marshall FF, Dietrick DD, Baumgartner WA, et al: Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol 139: 1166 –1172, 1988.
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2. Hatcher PA, Anderson EE, Paulson DF, et al: Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 145: 20 –23, 1991. 3. Kaplan S, Ekici S, Dogan R, et al: Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 183: 292–299, 2002. 4. Glazer AA, and Novick AC: Long-term follow up after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 155: 448 – 450, 1996. 5. Staehler G, and Brkovic D: The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 163: 1671– 1675, 2000. 6. Kuczyk MA, Bokemeyer C, Kohn G, et al: Prognostic relevance of intracaval neoplastic extension for patient with renal cell cancer. Br J Urol 80: 18 –24, 1997. 7. Kim HL, Zisman A, Ken-Ryu H, et al: Prognostic significance of venous thrombus in renal cell carcinoma: are renal vein and inferior vena cava involvement different? J Urol 171: 588 –591, 2004. 8. Skinner DG, Pfister RF, and Colvin R: Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. J Urol 107: 711–716, 1972. 9. Montie JE, El Ammar R, Pontes JE, et al: Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 173: 107–115, 1991. 10. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alpha-2b compared with interferon alpha-2b alone for metastatic renal cell cancer. N Engl J Med 345: 1655– 1659, 2001. 11. Swierzewski DJ, Swierzewski MJ, and Libertino JA: Radical nephrectomy in patients with renal cell carcinoma with venous, vena caval, and atrial extension. Am J Surg 168: 205–209, 1994. 12. Libertino JA, Zinman L, and Watkins E: Long-term results of resection of renal cell cancer with extension into inferior vena cava. J Urol 137: 21–24, 1987. 13. Blute ML, Leibovich BC, Lohse CM, et al: The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumor thrombus. BJU Int 94: 33– 41, 2004. 14. Moinzadeh A, and Libertino JA: Prognostic significance of tumor thrombus level in long-term survival of patients with renal cell carcinoma and venous tumor thrombus extension. J Urol 171: 598 – 601, 2004. 15. Naitoh J, Japlan A, Dorey F, et al: Metastatic renal cell carcinoma with concurrent inferior vena caval invasion: long-term survival after combination therapy with radical nephrectomy, vena caval thrombectomy and postoperative immunotherapy. J Urol 162: 46 –50, 1999. 16. Wolf JS, Aronson FR, Small EJ, et al: Nephrectomy for metastatic renal cell carcinoma: a component of systemic treatment regimens. J Surg Oncol 55: 7–13, 1994. 17. Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8⫹ selected tumor infiltrating lymphocytes from primary tumor. J Urol 158: 740 –745, 1997. 18. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high dose interleukin alone. N Engl J Med 316: 889 – 897, 1987.
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