|Ahead of print
Survival analysis and predictors of long-term outcomes following radical nephrectomy with inferior vena cava (IVC) thrombectomy in renal cell carcinoma
Harshit Garg, Brusabhanu Nayak, Ashish Kumar, Prabhjot Singh, Rishi Nayyar, Aashir Kaul, Amlesh Seth
Department of Urology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||03-Jan-2020|
|Date of Decision||08-Jul-2020|
|Date of Acceptance||19-Oct-2020|
|Date of Web Publication||24-Jun-2022|
Department of Urology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Background: Renal cell carcinoma (RCC) presents with inferior vena cava (IVC) thrombus in 10%–30% cases and surgical management forms the mainstay of the treatment. The objective of this study is to assess the outcomes of the patients undergoing radical nephrectomy with IVC thrombectomy.
Methods: A retrospective analysis of patients undergoing open radical nephrectomy with IVC thrombectomy between 2006 till 2018 was done.
Results: A total of 56 patients were included. The mean (±standard deviation) age was 57.1 (±12.2) years. The number of patients with levels I, II, III, and IV thrombus were 4, 29,10, and 13, respectively. The mean blood loss was 1851.8 mL, and the mean operative time was 303.3 minutes. Overall, the complication rate was 51.7%, while the perioperative mortality rate was 8.9%. The mean duration of hospital stay was 10.6 ± 6.4 days. The majority of the patients had clear cell carcinoma (87.5%). There was a significant association between grade and stage of thrombus (P = 0.011). Using Kaplan–Meier survival analysis, the median overall survival (OS) was 75 (95% confidence interval [CI] = 43.5–106.5) months, and the median recurrence-free survival (RFS) was 48 (95% CI = 33.1–62.3) months. Age (P = 0.03), presence of systemic symptoms (P = 0.01), radiological size (P = 0.04), histopathological grade (P = 0.01), level of thrombus (P = 0.04), and invasion of thrombus into IVC wall (P = 0.01) were found to be significant predictors of OS.
Conclusion: The management of RCC with IVC thrombus poses a major surgical challenge. Experience of a center along with high-volume and multidisciplinary facility particularly cardiothoracic facility provides better perioperative outcome. Though surgically challenging, it offers good overall-survival and recurrence-free survival.
Keywords: Inferior vena cava thrombus, radical nephrectomy, renal cell carcinoma, survival analysis
Key Message A multi-disciplinary approach is indispensable for surgical management of renal cell carcinoma with inferior vena cava thrombus. Age, radiological size, grade and level of thrombus appear to be significant predictors of overall survival after surgery.
|How to cite this URL:|
Garg H, Nayak B, Kumar A, Singh P, Nayyar R, Kaul A, Seth A. Survival analysis and predictors of long-term outcomes following radical nephrectomy with inferior vena cava (IVC) thrombectomy in renal cell carcinoma. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 5]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=348195
| » Introduction|| |
Renal cell carcinoma (RCC) accounts for about 2%–3% of all malignancies in adults. The potential of tumor thrombus formation and migration to the venous system including the renal vein and inferior vena cava (IVC) forms the unique feature of this malignancy. Conventionally, 4%–10% of patients have thrombus in the venous system at presentation. Though the recent stage migration with increased incidental detection of small localized renal masses might have decreased the prevalence of advanced RCC, the detection of advanced RCC with venous thrombus is not uncommon. The median survival of untreated RCC with IVC thrombus is approximately five months. Hence, aggressive surgical resection of the renal mass with IVC thrombectomy forms the mainstay of treatment. The 5-year cancer-specific survival after complete surgical resection ranges between 40% and 60%. However, the 30-day mortality ranges between 1.5% and 10% while the postoperative complication rate ranges between 20%–45%.
The management of RCC and IVC thrombus varies in the surgical approach, need of special maneuvers like liver mobilization, Pringle's maneuver, milking of thrombus, and need for cardiopulmonary bypass and deep hypothermic arrest depending on the venous level of thrombus. A few studies have reported the long-term results of radical nephrectomy with IVC thrombectomy, particularly from the Indian subcontinent., This study aimed to study the perioperative and long-term outcomes of patients undergoing radical nephrectomy with IVC thrombectomy and predict the factors determining the outcome.
| » Methods|| |
A retrospective analysis of all patients undergoing radical nephrectomy with IVC thrombectomy over the past 12 years (from January 2006 till December 2018) at All India Institute of Medical Sciences (AIIMS), New Delhi was done. The study was carried in accordance with the Helsinki Declaration of 1975, as revised in 2000 and retrospective analysis of prospectively maintained database was done. The consent was obtained from all the patients included in the study. The study was approved by the Institute Ethics Committee (Certificate Number- IECPG-347/28.05.2021). Patients with thrombi involving only renal veins were excluded. All the patients underwent standard preoperative workup along with cross-sectional imaging, contrast-enhanced computed tomography if the renal function was normal, and magnetic resonance imaging (MRI) was done in selective cases. The pulmonary and/or cardiac evaluation was done in case of any suspicion of any pulmonary or cardiac issues. A computed tomography (CT) scan or MRI of the chest was done in cases with suspicion of pulmonary metastases. A Doppler ultrasonography was done in all patients in the evening before surgery to see the exact length of thrombus, the distance between the proximal extent of thrombus and the renal vein confluence, the inferior edge of the liver, or the confluence of the hepatic veins into the IVC or the cavo-atrial junction. The Doppler ultrasonography also tells about the presence or absence of distal thrombus. In cases of intra-cardiac extension, a cardiac echo was done to identify the proximal extent of thrombus into the right atrium/ventricle/pulmonary vessels. The details of preoperative workup, surgical incisions, and technique followed at our center have already been published by Seth et al. Briefly, tumor thrombectomy involved resection of renal vein ostium and tumor thrombus coupled with IVC closure. If there was evident tumor infiltration into the IVC wall or dense adherence of the tumor thrombus to the endothelium, partial or circumferential resection of the IVC was done and reconstruction of IVC either via primary closure or using a pericardial patch was done depending on the luminal narrowing.
Preoperative data such as age, gender, comorbidities, tumor size, stage, level of thrombus and perioperative outcomes such as operative time, blood loss, blood transfusions, need of cardio-pulmonary bypass, postoperative complications, length of hospital stay, final histology, and grade of RCC were recorded for all patients. The presence of systemic symptoms included weight loss, fever, loss of appetite, anemia, hypercalcemia. The RCC was classified according to the 7th American Joint Committee on Cancer, and the Mayo clinic classification was used for the stratification of various levels of IVC thrombus. Complications were recorded and graded as per the modified Clavien- Dindo classification. The perioperative blood transfusion was excluded from the complication owing to the nature of the procedure and the need for perioperative blood transfusion to most of the patients. This data has been reported separately. Among the complications, venous thromboembolism was radiographically confirmed. Ileus was defined as non-passage of flatus or stools with the inability to tolerate oral feeding and abdominal distension by postoperative day 5. The follow-up details and information about disease recurrence and death were retrieved.
Continuous variables were expressed as mean ± standard deviation (SD) or median (Interquartile range [IQR]) as appropriate. Categorical variables were compared using the Chi-square test and continuous variables were compared using Student's t-test, multiple analysis of variance (ANOVA), Mann-Whitney U test or Kruskal–Wallis test as appropriate. The correlation between two variables was assessed using Spearman's Rank Correlation or Pearson's coefficient as appropriate. Survival analysis was done using the Kaplan–Meier technique and included only patients who survived more than 30 days after surgery. Cox regression analysis was used to identify the predictors of survival. All statistical tests were two-sided. Statistical significance was taken as P < 0.05. Data were analyzed using IBM SPSS Statistics software (version 20.0, Chicago, Illinois).
| » Results|| |
A total of 56 patients undergoing open radical nephrectomy with IVC thrombectomy were included. The mean (±SD) age was 57.1 ± 12.2 (range = 28-78) years. The majority of patients (45,80.3%) had a right renal tumor. Of the 56 patients, 29 (51.7%) patients had level II thrombus, while 13 (23.2%) patients had level IV thrombus. The systemic symptoms including weight loss, loss of appetite, fever, etc., were present in 32 (57.2%) patients. The patients with level IV thrombus had significantly more systemic symptoms as compared to level I or II thrombi (P = 0.001). The mean (±SD) maximum radiological diameter was 9.2 ± 2.3 cm with a similar size across all levels of venous thrombus. [Table 1] depicts the demographic profile of the patients included in the study.
|Table 1: Demographic details of the patients undergoing radical nephrectomy with inferior vena cava (IVC) thrombectomy|
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All the patients underwent open radical nephrectomy with IVC thrombectomy. The mean operative time significantly increased with the increasing level of thrombus ranging from approx 266 minutes in level I thrombus to 393 minutes in level IV thrombus. Fifteen patients underwent surgery under a cardio-pulmonary bypass. The mean blood loss was 1851.8 mL with the maximum blood loss (P = 0.038) and the need for blood transfusion (P = 0.01) for Level IV thrombus. [Table 2] depicts the perioperative characteristics of the patients included in the study. Overall, the complication rate was 51.7%. Among the complications, 16 patients had Clavien-Dindo Class I complications including postoperative atelectasis, paralytic ileus, and fever. Two patients developed a postoperative fever and intra-abdominal collection for which they underwent drain insertion under local anesthesia. All patients undergoing surgery with cardiopulmonary bypass assistance along with 6 patients of level II thrombus and 4 patients with level III thrombus received postoperative intensive unit (ICU) care. Five (8.9%) patients suffered mortality in the perioperative period. One patient with level II thrombus and one patient with Level III thrombus suffered pulmonary thrombo-embolism while 3 patients died in the postoperative intensive care unit. One of these patients had myocardial infarction, while two patients had aspiration pneumonitis and suffered mortality within 30 days of surgery. Other complications included postoperative paralytic ileus, acute kidney injury, and bilateral lower limb deep venous thrombosis. The mean duration of hospital stay was 10.6 ± 6.4 days. The hospital stay was significantly less for patients with Level I thrombus as compared to level IV thrombus (P = 0.029). [Table 2] depicts the perioperative characteristics and complications associated with surgery.
|Table 2: Perioperative characteristics of the patients undergoing radical nephrectomy with Inferior Vena cava (IVC) thrombectomy|
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The majority of the patients (49,87.5%) had clear cell carcinoma. Six patients had papillary RCC with one of them having thrombus reaching up to the right atrium. One of the patients had unclassified renal malignancy. The histopathological grading of RCC was done using the Fuhrman grading scheme. The most common Fuhramn grade was grade 2 (31,55.3%) on histopathology, and 9 (16.1%) patients had sarcomatous differentation (grade 4). Of these 9 patients, 5 patients had level IV thrombus, while 3 patients had level 2 thrombus. Fifteen patients (26.8%) had tumor thrombus wall invasion [Table 3]. Of these, 9 patients underwent primary closure while 6 patients had IVC repair using a pericardial patch. [Table 3] mentions the histopathological characteristics of patients with various levels of thrombus. There was a significant association between histopathological grade and level of thrombus (p=0.011).
|Table 3: Histopathological characteristics and outcomes of the patients undergoing radical nephrectomy with Inferior Vena cava (IVC) thrombectomy|
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Using Kaplan–Meier survival analysis, the oncological outcomes of the patients were studied. The median overall survival (OS) was 75 (95% confidence interval [CI] = 43.5–106.5) months, and the median recurrence-free survival (RFS) was 48 (95% CI = 33.1–62.3) months. The median follow-up period was 28 (14–55) months. [Figure 1] and [Figure 2] depict the Kaplan–Meier curves for OS and RFS stratified as per the level of thrombus.
|Figure 1: Kaplan–Meier curve for overall survival for patients of renal cell carcinoma with various levels of inferior vena cava thrombus|
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|Figure 2: Kaplan–Meier curve for recurrence-free survival for patients of renal cell carcinoma with various levels of thrombus|
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Using Cox proportional regression analysis, predictors for the OS and RFS were determined. [Table 4] depicts the various predictive factors associated with OS and RFS in patients undergoing radical nephrectomy with IVC thrombectomy. Age (P = 0.03), presence of systemic symptoms (P = 0.01), radiological size (P = 0.04), histopathological grade (P = 0.01), level of thrombus (P = 0.04), and invasion of thrombus into the IVC wall (P = 0.01) were found to be significant predictors of OS, while the presence of systemic symptoms (P = 0.01), histopathological grade (P = 0.04) and invasion of thrombus into IVC wall (P = 0.02) significantly correlated with RFS.
|Table 4: Predictors of Overall Survival (OS) and Recurrence-Free Survival (RFS) for patients undergoing radical nephrectomy with Inferior Vena cava (IVC) thrombectomy using Cox regression for survival analysis|
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| » Discussion|| |
RCC forms the most lethal malignancies among genitourinary cancers and the presence of venous thrombus adds a challenge to the management. About 10% of patients with RCC present with vena cava thrombus. Complete surgical resection for RCC with IVC thrombus forms the mainstay of management. Despite increasing incidental detection of renal masses due to advancement in imaging, the incidence of advanced RCC with IVC thrombus has not decreased. Various studies have reported the outcome of radical nephrectomy with vena cava thrombus excision so that surgical resection has become the standard of care. However, literature regarding the predictors affecting the surgical outcome and the oncological results are still debatable. Our study shows the perioperative and oncological outcomes of radical nephrectomy with IVC thrombectomy at a tertiary care center. Owing to the nature of the surgery, a multi-disciplinary approach involving the vascular surgeons, gastrointestinal surgeons, and intensive care specialist is needed.
Most of the patients of venous thrombus had right RCC and present with one or more features of the classical triad of hematuria, pain, or lump. The presence of systemic symptoms at presentation appears to be an important prognostic marker. About 35% of patients presented with systemic symptoms in a study by Kulkarni et al. while Kaag et al. reported systemic symptoms in 26% of the patients. Our study had systemic features in 57.2% of patients. This could be explained because of the higher proportion of patients with level III and level IV thrombus compared to level I thrombus in our study.
The mean operative time in our study was 303 minutes and the mean blood loss was 1851 mL. The perioperative characteristics of this study were in line with the published literature.,,, The overall complication rate was 51.7% and 30-day mortality was 8.7%. Kaag et al., in a study of 78 patients of RCC with IVC thrombus, reported a 43% complication rate and 6% 30-day mortality. Kulkarni et al. reported a 38% complication rate and 2% perioperative mortality in 100 patients undergoing radical nephrectomy with IVC thrombectomy. Abel et al. studied 162 patients with suprahepatic IVC thrombus and reported a complication rate of 34% and 10% 90-day mortality. They reported presence of systemic symptoms and higher level of thrombus as significant predictors for complications. Haider et al. in a review reported 30-day mortality ranging between 1.5-10% with complication rate ranging from 18% in level I thrombus and 47% in level IV thrombus with 5 year disease-specific survival 40%–60%.
Freifeld et al. studied the outcomes of 2664 patients undergoing radical nephrectomy with vena cava thrombectomy in 573 institutions from the National Cancer Database and reported the role of impact of high-volume centers (defined as ≥3 cases/year) with 24% relative risk reduction for all-cause mortality compared to low volume centers. Over the past few years, the number of cases of radical nephrectomy with IVC thrombectomy had increased at our center, though, the center has always been a high volume center for such cases.
Blute et al. reported outcomes of 191 patients undergoing radical nephrectomy with vena cava thrombectomy with 20 patients having level IV thrombus. They reported that the complication rate was not related to the level of thrombus and 5-year cancer-specific survival ranged between 31 and 39% for various levels of thrombus.
Various studies reported on the predictors of overall survival and disease-specific survival in patients undergoing radical nephrectomy with IVC thrombectomy. Blute et al. reported the tumor pathological stage, grade, tumor necrosis, presence of sarcomatoid component, and perinephric fat invasion as predictors of 5-year cancer-specific survival. Tang et al. studied 169 patients with a median follow-up of 45 months. They reported a median OS of 63 months. They found higher tumor thrombus level, nodal (N) stage, metastasis (M) stage, and adrenal gland invasion as predictors of overall survival. They did not study the presence of systemic symptoms or the pathological IVC wall infiltration. In another study involving 31 patients by Lien et al., the 5-year cancer-specific survival was reported as 30.8% and histopathological grade, capsular invasion, sarcomatoid differentiation, and positive surgical margins were found to be significant predictors of cancer-specific survival. In another study of 78 patients by Kaag et al., the median OS was 55.5 months and the presence of systemic symptoms, tumor stage, nodal stage, and pathological grade appeared to be significant predictors of overall survival.
The presence of systemic symptoms had been reported as a prognostic factor. Abel et al. noted the presence of systemic symptoms as a predictor of perioperative morbidity. Moreover, Kaag et al. reported the presence of systemic symptoms at the time of diagnosis as an independent predictor of overall survival. Similarly, in our study, the presence of systemic symptoms appeared to be independent predictors of overall survival.
The level of venous tumor thrombus extension has often been associated with worse survival but the results are conflicting. Tang et al. and Kulkarni et al. reported the level of thrombus as a significant predictor of oncological outcomes. On the contrary, Blute et al., Kaag et al., and Lien et al. did not find the level of thrombus as an independent predictor of overall or cancer-specific survival. The tumor thrombus level above or below diaphragm does form a part of TNM staging of RCC and hence, its role as a prognostic factor cannot be refuted completely. As per the results of the International RCC –Venous Thrombus Consortium, the tumor thrombus level is an independent survival predictive factor.
A few Indian studies have studied the outcome of radical nephrectomy with IVC thrombectomy. In an earlier study by Singh et al. involving 17 patients of RCC with IVC thrombus with two patients having cavo-atrial thrombus, 5-year overall survival was 29%. In another study by Kulkarni et al. involving 100 patients including six cases with cavo-atrial thrombus, 5-year overall survival was 63% and 5 year disease-specific survival was 55%. They also reported grade, histopathological type, and perinephric invasion as significant predictors of overall survival. In our study, the 5-year overall survival was 53% and 5-year disease-specific survival was 42%. The presence of systemic symptoms, the radiological size, age, histopathological grade, and level of thrombus appeared to be the independent predictors of survival.
This study has several strengths. It reports the perioperative and long-term outcomes of patients undergoing radical nephrectomy with IVC thrombectomy over the past 12 years. Only a few studies have addressed this issue, particularly from the Indian subcontinent. Only patients with IVC thrombus were included and the complications were graded using Clavien-Dindo classification. The number of patients included is comparable to various published literature.
The study has several limitations. Being a retrospective study, adds an inherent bias. Certain variables such as performance status, Charlson comorbidity index, and serum parameters were not available for all the patients. The histopathology was not studied by a single pathologist, however, reporting was done by experienced genito-urinary pathologists in all cases.
| » Conclusion|| |
The management of RCC with IVC thrombus poses a major surgical challenge. However, with expertise along with a multi-disciplinary approach particularly cardiothoracic facility provides better perioperative outcome. Though surgically challenging, it offers good oncological outcomes in terms of overall survival and recurrence-free survival.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interes
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]