Background
In 2015, there will be nearly 62000 newly diagnosed cases of RCC and 14000 deaths due to RCC [
1]. RCC has the propensity to extend into the renal vein, inferior vena cava (IVC) and up to the right atrium in up to 23 %, 10 %, and 1 % of cases, respectively [
2,
3]. Refinements in clinical imaging, with CT and MRI, have improved accurate evaluation of primary tumors and the level of venous tumor thrombus (VTT) [
2,
4]. Radical nephrectomy (RN) and IVC thrombectomy (IVCT) is challenging, particularly with a high VTT level [
3‐
5].
Throughout the course of our experience, we have continued to improve our technique employing several modifications. We believe the most important modification we have made has been constantly ensuring we have the same urologic oncologists, cardiac anesthesia team, cardiac surgeons, and a dedicated cardiac scrub team at all cases. This brings familiarity to these challenging cases, which helps better manage both intraoperative and postoperative complications. Additionally, we have deferred from preforming sternotomies for high level 3 cases to avoid the morbidity of a sternotomy. With effective liver mobilization and use of pericardial windows extirpation of high level 3 is facilitated both safely and effectively. This has equated to improved patient recovery in the postoperative setting.
Herein, we review the management of RCC with VTT in the last 15 years, aiming to outline prognostic factors, outcomes, and complication rates in the context of a dedicated multidisciplinary surgical team.
Methods
Patient selection
Clinical data from electronic medical records of patients treated by radical nephrectomy (RN) for RCC with renal vein or IVC thrombus at our institution from January 1998 to June 2012 were retrospectively analyzed and placed into a UT Southwestern Medical Center IRB approved database. Research was carried out in compliance with the Helsinki Declaration. We did not obtain informed consent from patients, as this was a retrospective study. Relevant clinical data, pathological features, surgical techniques, hospital stay, perioperative morbidity and mortality, follow up and survival data were collected.
Preoperative evaluation and surgical techniques
The tumors were routinely staged by using abdominal and chest CT scans and chest radiography. MRI was used for better evaluation of VTT level at the discretion of the treating physician. Bone scans were used selectively when clinically indicated. Tumor thrombus extension was classified into 4 levels: level I, extension into the renal vein; level II, extension into the infrahepatic IVC; level III, IVC extension to the level of hepatic veins but below the diaphragm; and level IV, IVC extension above the diaphragm [
6].
Preoperative renal artery angioembolization was performed at the discretion of the surgeon to facilitate arterial vascular control in patients with bulky tumor thrombus, hilar adenopathy, or hypervascularity. Surgeries were managed by a multidisciplinary team which included an experienced urologic oncology surgeon, cardiothoracic surgeon and cardiac anesthesiologist, and cardiac scrub team. Trans-esophageal echocardiography was used intraoperatively by the anesthesiologist to verify the cephalad extent of the thrombus, to monitor for tumor emboli, to confirm the complete removal of VTT, and to assess hemodynamic stability. Data regarding the duration of surgery, estimated blood loss and intraoperative complications were recorded.
Pathologic evaluation
Pathologic staging was assigned according to the 2010 TNM staging system [
7]. Grading of the tumors was evaluated according to Fuhrman classification [
8]. Additionally, pathological tumor size, adrenal involvement, regional lymph node (LN) involvement, tumor necrosis, histopathological cell type and the presence of sarcomatoid differentiation were recorded.
Outcome evaluation and statistical analysis
Perioperative morbidity and mortality within the first 30 and 90 days were recorded and graded according to the Clavien-Dindo grading system [
9]. Patients without metastases were routinely followed after surgery every 3 months in the first year, every 6 months in the second year and then annually. Follow up included history, physical examination, metabolic panel, liver function tests, chest x-ray and an abdominal CT scan. Bone scan, chest CT, positron emission tomography or MRI were performed when clinically indicated.
Survival time was calculated from the date of the operation to the date of last follow up or date of death. Disease recurrence was defined as local failure in the RN bed or regional LNs, or distant metastasis. Disease-free survival (DFS) was defined as the time between the date of surgery and the development of local recurrence or distant metastasis. Censored survival values represent patients who were alive without clinical evidence of disease at the last follow up. Cancer-specific survival (CSS) and overall survival (OS) were defined as the time between the date of surgery and death due to cancer (CSS) or due to any cause (OS). The following factors that could potentially affect outcomes were analyzed: age, gender, body mass index and performance status; T stage, VTT level, pathological tumor size, nodal involvement, metastasis at presentation, grade, sarcomatoid differentiation, histological subtype, fat invasion, adrenal involvement and tumor necrosis. Endpoints were CSS and OS. DFS was analyzed only in M0 patients. Finally, independent predictors of disease recurrence and cancer specific mortality were determined using multivariate Cox Regression analyses including only factors significant in univariate analyses. Statistically significant difference was set at p < .05. All statistical tests were performed with SPSS version 19.0.
Discussion
Aggressive surgical resection is indicated in RCC with VTT as nephrectomy alone is associated with dismal prognosis [
10]. Through an experienced team, consisting of a urologic oncology surgeon, cardiothoracic surgeon, cardiac anesthesiologist, and cardiac scrub team we were able to achieve satisfactory surgical and oncological outcomes and decrease the incidence of complications.
We noticed a significant reduction in the rate of overall and high grade complications (45 % and 8 %, respectively) in the last 6 years compared to the earlier surgeries included in the study (67 % and 13 % respectively) [p = .008 and .03, respectively]. We believe this reduction may be due to our multidisciplinary team approach, which provides uniform and consistent management of patients with VTT. The team approach further supports meticulous perioperative and postoperative planning and delivery of care, refinement of surgical technique, and improved anesthesia.
In terms of oncological outcomes, metastasis was found to be the strongest independent predictor of survival. Patients with M+ had a 3.8 times risk of cancer specific mortality compared to M0 patients (
p < .001). While M0 patients had 5-Y CSS of 68 % and median survival that was not reached yet, M+ patients had a 17 % 5-Y CSS and 11 months median survival. Our survival rates were superior to those reported in the literature for M0 patients [
3‐
5,
11‐
24] but they were similarly poor in M+ patients who were reported to have 4-30 % 5Y-CSS and 11–20 months median survival [
3‐
5,
11‐
18,
21]. In this study, 29 % of patients had metastasis at presentation. This incidence was even higher in other series [
14,
16]. Surgery might be indicated not only to improve oncological outcomes but also to relieve symptoms and provide better quality of life. However, performance status and associated comorbidities should be considered [
10].
Overall, LN+ showed a trend toward poor CSS (HR 1.9, CI and
p = .06) and achieved prognostic significance only in M+ patients (HR 2.3 and
p = .03). Perhaps, statistical significance, in the analysis involving all patients, would be reached if the sample size was larger and/or follow up was longer. The independent prognostic role of LN+ was reported in other RN and IVCT series [
12,
14,
21,
24]. Previous studies support the role of aggressive debulking of regional nodal disease at the time of cytoreductive RN for metastatic RCC [
2,
25,
26].
There has been wide variation in reporting different prognostic factors and the prognostic value of VTT level has been debated. Our prognostic factors were similar to those reported in the largest European study that included 1192 patients from 13 European centers [
12] and the US based analysis including 1875 patients with RCC and VTT from the SEER database [
27]. In both studies, metastasis was the most important independent predictor of worse survival.
Interestingly, analysis of data for all patients showed that metastasis was the only independent predictor of oncological outcomes. However, in M0 patients, features associated with aggressive tumor behavior (high level VTT, large tumor size, and sarcomatoid differentiation) had an independent prognostic role. The size of the tumor has been implicated in staging of RCC. Large tumor size was among the strongest predictors of worse survival in the international RCC-VTT consortium that included 1215 RN and IVCT from 11 American and European institutions [
21] as well as in a population based analysis including 1875 patients with RCC and VTT from the SEER database [
27]. Sarcomatoid differentiation was reported with an incidence of 9 % and was among the independent predictors of worse survival in RN and IVCT series [
3,
14,
20]. We found sarcomatoid differentiation in 13 % of tumors and it did not correlate with higher VTT levels, as 95 % of tumors with sarcomatoid differentiation had level I or II VTT.
We acknowledge several limitations in this review. First, is the retrospective design with its inherited bias. Second, while our multidisciplinary approach has lead to a decrease in the rate of complications, other factors may have also lead to improved outcomes. Improvement in surgical technique, enhanced understanding of the biology of the disease, and improved delivery of medical care throughout the course of the study may have also lead to improved patient outcomes. Lastly, the impact of venous wall invasion by thrombus could not be evaluated, as it was not reported by consistent pathologic criteria over the period under review.
Conclusions
RN and VTT is a challenging surgery and while, improvements in surgical techniques and perioperative care have decreased surgical morbidity and mortality, we strongly advocate for management of these patients with an experienced multidisciplinary team. Our approach has resulted in improved overall complications and most importantly, high grade complications. A strong working relationship between all team members helps develop meticulous perioperative and postoperative planning and delivery of care, refinement of surgical technique, and improved anesthesia.
Abbreviations
IVC, Inferior vena cava; IVCT, Radical nephrectomy (RN) and IVC thrombectomy; LN, Lymph node; RCC, Renal Cell Carcinoma; RN, Radical nephrectomy; VTT, Renal Cell Carcinoma (RCC) with venous tumor thrombus