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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 6  |  Page : 277-283

The incremental benefit of upfront surgery in renal cell carcinoma with venous tumor thrombus of the inferior venae cavae


1 Department of Urology, Singapore General Hospital, Singapore
2 Centre for Quantitative Medicine, Duke-NUS, Singapore

Date of Web Publication22-Nov-2018

Correspondence Address:
Lui Shiong Lee
Department of Urology, Level 5, The Academia 20 College Road, Singapore 169856
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_31_18

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  Abstract 

Background: Surgical extirpation for renal cell carcinoma (RCC) with inferior venae cavae (IVC) thrombi is the standard of care. The incremental impact of upfront surgery has not been well described. Objective: We aim to quantify the overall survival (OS) benefit of upfront surgery in RCC with IVC thrombi when compared to a conservative approach and also analyze perioperative outcomes. Materials and Methods: Patients with RCC with IVC thrombus between January 1, 2001, and December 31, 2014, in a single institution were identified, and data reviewed for demographics, performance status, and tumor thrombus levels. Pathological and operative outcomes were analyzed in the surgical cohort (Sx). Survival outcomes were computed with Kaplan–Meier analysis. Prognostic factors were determined using univariate and multivariate analyses. Statistical significance was defined as P < 0.1. Results: There were 51 patients identified, comprising 31 and 20 in the Sx and nonsurgical (NSx) cohorts. For the Sx cohort, 5-year OS and recurrence-free survival were 48% and 45%, respectively, with a median OS of 51.7 months. Nodal involvement was an independent predictor for OS (P < 0.1) on multivariate analysis. In the NSx cohort, 75% (15/20) had distant metastasis at diagnosis, with a 5-year OS of 13.4 months. Patients with better baseline ECOG statuses had better survival outcomes (P < 0.1). The mean OS of patients (n = 5) with M0 disease was 18.8 months. The advantage conferred by surgery was a 38.2-month longer median OS (P < 0.0001). In the Sx cohort, 87% had no or minor perioperative complications. Conclusion: Nephrectomy and IVC thrombectomy have an OS survival advantage of 38.2 months with acceptable perioperative morbidity. Therefore, it is preferred over an initial nonsurgical approach where possible.

Keywords: Nephrectomy, renal cell carcinoma, thrombectomy


How to cite this article:
Huned D, Carsen JA, Huang HH, Lee LS. The incremental benefit of upfront surgery in renal cell carcinoma with venous tumor thrombus of the inferior venae cavae. Urol Sci 2018;29:277-83

How to cite this URL:
Huned D, Carsen JA, Huang HH, Lee LS. The incremental benefit of upfront surgery in renal cell carcinoma with venous tumor thrombus of the inferior venae cavae. Urol Sci [serial online] 2018 [cited 2018 Dec 13];29:277-83. Available from: http://www.e-urol-sci.com/text.asp?2018/29/6/277/238432


  Introduction Top


Since the first description of radical nephrectomy with inferior venae cavae (IVC) thrombectomy in 1913 by Berg,[1] technical advancements have been made in this complex surgical condition. However, the procedure remains challenging and remains the primary treatment modality for renal cell carcinoma (RCC) with a concomitant venous tumor thrombus. However, there are no studies in the literature comparing outcomes in these patients between contemporary cohorts managed with initial surgery versus a nonsurgical approach. In addition, patient and disease heterogeneity can make comparisons difficult.

This study aims to ascertain the operative and oncological outcomes following upfront surgery for primary RCC and IVC tumor thrombus and determine the incremental benefit of upfront surgery in comparison to a contemporary cohort managed with an initial nonsurgical approach.


  Materials and Methods Top


With SingHealth Institutional Research Board consent (SingHealth 2009/763/D), all patients who underwent radical nephrectomy and tumor thrombectomy between January 1, 2001, and December 31, 2014, for primary RCC with tumor extension into the IVC, in a single institution, were identified from a prospectively maintained cancer registry. These patients were staged preoperatively with axial imaging to establish clinical staging. In an effort to assess the benefit of upfront surgery, patients with a similar stage of disease but who were managed medically were also identified.

The variables of interest studied included demographics, American Society of Anesthesiologists physical status grade, pathological variables of tumor node metastasis (TNM) stage, histological subtype, Fuhrman grade,[2] and tumor thrombus level as defined by the Mayo classification.[3]

The surgical outcomes analyzed included perioperative estimated blood loss (EBL), operative time, the utilization of intraoperative cardiopulmonary bypass (CPB), need for Pringle's maneuver, and length of hospital stay (LOS). The incidence of operative complications occurring within 40 days of surgery was classified according to the Clavien-Dindo grading system.[4] All patients were restaged using the 2010 American Joint Committee on Cancer TNM staging system for the purposes of this study. The overall survival (OS) and recurrence-free survival (RFS) were calculated using censored data and compared by the log-rank test. RFS was determined only for the patients undergoing curative surgery. Univariate and multivariate analyses were used to identify potential prognostic factors predicting RFS, OS, and complications. Statistical significance was defined as P < 0.1. This was determined with the consideration that in a pilot study with a small sample size, it is reasonable to accept a larger type I error (false positive) to reduce the probability of a type II error (false negative).


  Results Top


Patient characteristics

A total of 52 patients were identified comprising 32 and 20 in the surgical (Sx) and nonsurgical cohorts (NSx), respectively. One patient was excluded, as the thrombectomy was not performed after nephrectomy due to technical factors. As such, the outcomes of 31 surgical patients were available for analysis.

The Sx comprised mainly males (74%) with a median age of 55 years. The NSx also comprised mainly males (n = 15) with a median age of 64 years. The majority of patients had good performance status [Table 1]a.


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Based on the Mayo classification, the patients comprised Level I thrombus (n = 9), Level II (n = 9), Level III (n = 6), and Level IV (n = 7), respectively, in the Sx cohort. For the NSx cohort, 60% had a Level I to II thrombus. In the NSx, there were six and two patients with Levels III and IV thrombus levels, respectively.

In the Sx cohort, there were 16% (n = 5/31) with distant metastasis, located in the lungs (n = 4) and supraclavicular lymph node (n = 1) [Table 1]a.

In the NSx cohort, 25% (n = 5/20) were non-metastatic at diagnosis. The remaining 75% of the cohort were metastatic with nodal or soft-tissue disease at presentation.

There were no bilateral tumors in this study population. In the Sx cohort, the median pathological tumor size was 10 cm, the smallest was 4 cm, and the largest was 21 cm. The pathological node positivity rate was 19% (n = 6), while a majority (77%, n = 24) had tumors with high Fuhrman grades.[3],[4] The histological subtype comprised clear cell carcinoma (n = 21, 68%), papillary carcinoma (n = 7, 23%), and others. There were n = 7 patients with sarcomatoid features [Table 1]b.

Surgical outcomes

There were five patients in the Sx cohort patients who underwent cytoreductive surgery, while the remaining 26 patients underwent thrombectomy with curative intent. When stratified by the risk criteria described by Motzer et al.,[5] those who underwent cytoreductive surgery comprised good risk (n = 1) and intermediate risk (n = 4).

The majority (n = 29) underwent open surgery, whereas two patients had attempted laparoscopic surgery with subsequent open conversion. Of the seven patients with a Level IV thrombus, five were associated with an atrial extension. A total of six patients required CPB, comprising those with Level III thrombus (n = 1) and Level IV thrombus (n = 5). There were four patients who required pulmonary embolectomy for concomitant tumor emboli in the pulmonary trunk. There were five surgical patients with distant metastasis at diagnosis, and therefore, the surgery was cytoreductive in intent.

The median operative time for Level I, II, II, and IV tumor thrombi was 205, 195, 352.5, and 335 min, respectively, P = 0.01 [Table 1]c. In this cohort, the median EBL was 1100 ml (mean = 1866, 150–6500), and a higher thrombus level was also associated with a greater EBL (800, 900, 2100, and 2750 ml for Levels I, II, III, and IV, respectively, P = 0.26).

The median LOS for the Sx cohort was 7 days (mean = 10, 3–37). When stratified by thrombus level, the difference in the LOS was statistically significant (respective values were 5, 10, 7.5, and 14 days, P = 0.06).

The incidence of surgical complications [Table 1]d included those with no complications (55%, n = 17), Grade I-II complications (32%, n = 10), Grade III (6%, n = 2), Grade IV (0%, n = 0), and Grade V (6%, n = 2). The mortalities occurred at postoperative day 4 and 38, respectively.

Survival and oncological outcomes

A total of 51 and 26 patients were available for OS and RFS analysis, respectively. Excluding the two perioperative deaths, the Sx had a median follow-up of 26.6 months and median period from nephrectomy to mortality was 31 months. The median time interval from nephrectomy to disease relapse and mortality was 18.2 months. The median OS was 51.7 months (Sx) and 13.4 months, respectively (NSx) [Figure 1]a, and surgery was shown to provide a 38.2-month OS benefit when comparing across the entire cohort.
Figure 1: (a) Kaplan–Meier survival curve showing the overall survival of study cohort stratified by surgical status. (b) Kaplan–Meier survival curve showing recurrence-free survival of surgical cohort patients (gray margins indicate 95% confidence limits). (c) Kaplan–Meier survival curve showing overall survival of patients undergoing curative surgery (dotted line) versus cytoreductive surgery (solid line)

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Of the Sx patients undergoing curative surgery, the RFS was 50.5 months [Figure 1]b. Of those with systemic recurrence, 23% of the cohort received systemic therapy.

In those who underwent cytoreductive surgery, the median OS was 31 months [Figure 1]c. Systemic therapy was commenced at a median duration of 4.1 months after surgery. The patients were started on single-agent therapy as decided by the managing oncologist, which was sunitinib, pazopanib, or everolimus. Hence, when comparing the benefit of surgery in the metastatic setting, cytoreductive surgery conferred a potential OS benefit of 18 months. At the conclusion of the study, about 45% (14/31) of patients in the Sx cohort received systemic therapy.

In the NSx cohort, 45% (9/20) of individuals received systemic therapy at diagnosis, and all were commenced on sunitinib. The remaining 11 patients in this cohort were started on therapy at evidence of disease progression. They were treated with single therapeutic agents comprising sorafenib, pazopanib, or everolimus. The median OS of metastatic NSx patients was 10.9 months despite systemic therapy. All metastatic patients in the NSx cohort were intermediate risk by Motzer et al. criteria.[5]

We performed univariate and multivariate analysis to identify possible predictor factors affecting the incidence of surgical complications, RFS and OS. The following factors were analyzed surgical treatment (yes or no), tumor thrombus level by Mayo classification (I–IV), gender, race, age (as a continuous variable), ECOG performance status, need for either Pringles maneuver, lymphadenectomy, pulmonary embolectomy, atrial tumor removal or CPB, presence of nodal or distant metastasis, pathological Fuhrman grade (dichotomized to low [Grade 1–2] and high [3–4]), presence of adrenal extension or invasion of the collection duct, lymphovascular space, renal sinus fat, perinephric fat, presence of sarcomatoid features, tumor necrosis, and histological subtype (clear cell vs. nonclear cell histology).

Surgical treatment was found to be an independent and significant prognostic factor with a hazard ratio of 0.065 (0.017–0.246), P < 0.001. The need for atrial tumor removal predicted for a higher rate of complications on univariate analysis, P = 0.06 [Table 2]. Paradoxically, it was noted that the presence of nodal and distant metastases predicted for better OS (P = 0.085 and P = 0.02, respectively). Multivariate analysis was done based on purposeful selection, and the threshold for including univariable factors was P = 0.1. Accordingly, multivariate analyses was performed only for atrial tumor removal, which did not predict for a higher rate of complications on a multivariate logistic regression model (P = 0.52).
Table 2: Univariate logistic regression analysis of factors influencing overall survival, recurrence-free survival, and complications

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  Discussion Top


Although the literature is abound with publications focused on surgical outcomes following nephrectomy and venous thrombectomy,[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] they are largely limited to surgical technique and/or survival outcomes related to surgical intervention. However, the oncological value of upfront surgery has never been objectively quantified as there are limited publications comparing the survival outcomes in contemporary cohorts of such patients. To date, there are also no randomized controlled trials to ascertain the upfront benefit of surgical extirpation in patients with primary RCC with tumor thrombus in the IVC, presumably because recruitment of such patients would be clinically and ethically challenging. Hence, clinicians find it challenging to objectively quantify the absolute survival benefit of surgery, and this may limit clinical precision during patient counseling and clinical trial design.

This study demonstrates the presence of a significant survival benefit with successful surgical extirpation of the primary tumor burden in both curative and cytoreductive indications. In patients who did not undergo upfront surgery, a significantly shorter OS was observed, with the cause of mortality uniformly due to RCC. It can be argued that survival benefits of surgery in a predominantly nonmetastatic cohort may reflect patient selection based on performance status or systemic disease burden. Evidently, in the NSx cohort, there were higher proportions of patients with metastasis and at more than one metastatic site at diagnosis. However, most patients in the NSx cohort were of good performance status, and there were no mortalities from causes other than RCC. Furthermore, at least 45% of these patients received upfront anti-vascular endothelial growth factors (anti-VEGF) therapy rather than watchful waiting alone. In addition, cytoreductive surgery in the Sx cohort was associated with a potential OS benefit of 18 months, although we recognize the effect of selection bias in these patients.

In this study, the administration of adjuvant therapy in the Sx could favorably influence OS outcomes, over and above the impact of surgery. However, the benefit of adjuvant therapy may be limited as it was not routine clinical practice before the release of ASSURE and S-TRAC study outcomes.[19],[20] In addition, ASSURE showed no benefit for routine adjuvant therapy, while S-TRAC demonstrated that adjuvant sunitinib provided a modest progression-free survival benefit without OS benefit. Hence, the impact of adjuvant therapy on OS would have been negligible. The administration of systemic therapy was also universal in both Sx and NSx cohorts at clinical detection of disease progression, and this would have influenced OS by a similar extent presumably.

Despite the development of therapeutic agents against anti-VEGF in metastatic disease, the utility of upfront systemic treatment in locally advanced RCC with venous tumor thrombi is not well established. Most available data are limited to Level IV evidence with variable outcomes after treatment with different agents.[17],[21] In clinical trials reporting outcomes following neoadjuvant therapy with anti-VEGF agents followed by surgery, patients with IVC thrombi form only a small proportion of eligible patient cohorts.[22],[23],[24],[25] Therefore, the statistical strength of prospective survival outcomes' analysis evaluating the role of neoadjuvant therapy and surgery is limited. Thus far, this sequence of therapy has not emerged as standard of care in this disease setting.

The largest surgical series, to date, is derived from the Surveillance, Epidemiology, and End Results database with patient data after 2004. In this cohort, 36% of individuals had nodal or distant metastasis at presentation. At a median follow-up of 12 months, the OS of nonmetastatic and metastatic patients was 90% and 60%, respectively. The median disease-specific survival (DSS) for those with metastatic disease was 16 months and not reached for those with organ-confined disease. Tumor grade, tumor stage, and the presence of metastasis were found to be prognostic for DSS.[22] However, there was limited information regarding tumor thrombus levels (4% were supradiaphragmatic) and individual performance status was not reported, thereby limiting the reader's ability to discern the absolute benefit of upfront surgery in a heterogeneous population. In comparison, patients in the same database with nontreated RCC with venous tumor thrombus[23] only had a median DSS of 5 months. These patients were largely metastatic at diagnosis (72%), and the overall prognosis was dismal with a median DSS of 5 months. Those without metastasis at diagnosis but were untreated had a median DSS of 9 months. Despite using a population-based cohort, the lack of information on individual performance status and systemic therapy administered makes it difficult to compare the outcomes with this current study and other similar studies. In addition, it is not known if the level of care received was similar to those of the Sx. Individuals who underwent surgery for tumor venous thrombus were more likely to be treated at a tertiary center, while those managed conservatively may not necessarily be so.

In this Sx, the removal of tumor thrombus extending into the atrium predicted for a higher risk of complications on univariate (P = 0.06) but not multivariate analysis. However, the use of CPB or tumor thrombi level was not significant predictors. This suggests that complex surgery for tumor venous thrombus is best performed by a dedicated team, who can reduce the potential for technically related complications. The importance is accentuated when dealing with patients with Level IV thrombi where the disease burden is highest, and the probability of altered patient cardiovascular physiology is greatest. As a comparison, the level of tumor thrombi was also not a significant predictor for complications in several other case series,[3],[16],[24],[25] likely reflecting the tertiary patterns of practice required to manage these patients safely.

The strengths of this study include the availability of prospectively curated data from an established database and an equivalent standard of care for all patients in the study cohort. The follow-up was complete, and hence, the cause of death and duration of survival was verifiable with source data (medical records).

The shortcomings of this study include its limited cohort size and the presence of a selection bias. There is also missing histopathological information from 55% of the NSx cohort, especially those from the earlier part of the study. However, it is assumed that most of such patients will harbor high-grade disease. In addition, the absence of histological grade does not statistically confound robust outcomes such as OS.


  Conclusion Top


This study demonstrates that upfront surgery, in carefully selected patients with IVC tumor thrombi, can provide safe and significant survival benefit as compared to a more conservative approach. There is also suggestion that this benefit is seen in cytoreductive indications, especially in patients with low metastatic burden.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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