Surgical and Oncologic Outcomes of Laparoscopic Versus Open Radical Nephrectomy with Venous Thrombectomy: A Propensity-Matched Retrospective Cohort Study

Background: To compare the surgical and oncologic outcomes between laparoscopic and open radical nephrectomy with venous thrombectomy (LRN-VT, ORN-VT) in patients with renal tumor and venous thrombus. Materials and Methods: We conducted a propensity-matched retrospective cohort study of 302 patients with renal tumor and venous thrombus from January 2014 to January 2021. We compared surgical outcomes and we used the Kalan-Meier method to assess the overall survival (OS), tumor-specific survival (TSS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). The Pearson chi-square test and Fisher exact test, Wilcoxon rank sum test, Cox proportional hazards regression model and log-rank test were used. Results: After 1:1 matching, 94 patients were identified in each group and baseline characteristics were comparable. The LRN-VT group had less operative time (median 292min vs 326min, P < 0.001), less blood loss (median 500 ml vs 1000 ml, P < 0.001), fewer packed red blood cells transfusion (median 800 ml vs 1200 ml, P < 0.001) and less fresh frozen plasma transfusion (median 400 ml vs 600 ml, P < 0.001). The ORN-VT group had higher complication rate (39.4% vs 21.3%, P = 0.007), higher Clavien grade (P = 0.005) and longer postoperative hospital stay (median 10d vs 8d, P < 0.001). The median time to local recurrence were 36mon after a median follow-up of 31mon in the LRN-VT group and 8mon (IQR 6-15 mon) after a median follow-up of 32mon in the ORN-VT group (P = 0.007). The hazard ratio of LRFS for the LRN-VT group was 0.18 (95% CI 0.05–0.62, P = 0.007). Conclusions: LRN-VT can result in favorable surgical outcomes and a better LRFS compared with ORN-VT. CORRESPONDING AUTHORS: Cheng Liu and LuLin Ma Department of Urology, Peking University Third Hospital, Beijing, People’s Republic of China, 49 North Garden Rd, Haidian District, Beijing 100191, China chengliu@bjmu.edu.cn; malulinpku@163.com


INTRODUCTION
Renal tumors, especially the renal cell carcinoma (RCC), can enlarge from the kidney and involve the venous system. Venous thrombus occurs up to 10% in patients with RCC [1]. Radical nephrectomy and venous thrombectomy (RN-VT) can offer reasonable long-term survival in such patients and the 5-yr disease-specific survival rate can be 53% to 64% [2,3]. Open surgery remains the preferred treatment option [4]. Nevertheless, several reports have introduced the application and confirmed the feasibility of pure laparoscopy or handassisted laparoscopy in RN-VT [5][6][7][8][9][10]. Until now, less literature reported the comparative analysis between laparoscopic radical nephrectomy with venous thrombectomy (LRN-VT) and open radical nephrectomy with venous thrombectomy (ORN-VT) in patients with renal tumor and venous thrombus.
In this study, we performed a propensity-matched retrospective cohort study to compare the surgical and oncologic outcomes following LRN-VT and ORN-VT in patients with renal tumor and venous thrombus. We hypothesized that LRN-VT could achieve comparable outcomes compared with ORN-VT.

DATA SOURCE AND STUDY COHORT
We followed the STROBE statement and this study is fully compliant with the STROCSS criteria [11]. Our registration unique identifying number is researchregistry7016.
Following institutional review board approval, we retrospectively reviewed our database (Peking University Third Hospital Thrombus Database, PUTH-TD) containing medical records of all patients with renal vein thrombus or inferior vena cava (IVC) thrombus from January 2014 to January 2021 (n = 350). The database has been constructed prospectively since January 2014. Two fulltime clinical data managers had all access to the data through electric case report forms (eCRF) and were responsible for data entry, verification and quality control. The demographic, perioperative, postoperative and follow-up data were accurately recorded. The inclusive criteria were as follows: (1) pathologically confirmed tumor of renal origin; (2) detailed information on surgical procedures; (3) no comorbidity of hemorrhagic disease; (4) minimum follow-up of 6 mon. The patients who were treated by robot-assisted LRN-VT (RALRN-VT) or who didn't receive surgical treatment were excluded.

SURGICAL PROCEDURES
The techniques of LRN-VT and ORN-VT at our institution have been described previously [8,[12][13][14]. For LRN-VT, both transperitoneal approach and retroperitoneal approach were used in our center depending on the thrombus level, tumor side, surgery history and invading the IVC wall or not. For level 0 thrombus, we didn't block the IVC and we cut off the renal vein from the segment without tumor thrombus. For level I thrombus, the IVC was partially clamped using a Satinsky clamp. We incised the IVC and removed the thrombus and then irrigated the IVC with heparinized saline before suturing. For level II thrombus, we clamped the IVC below the thrombus, the contralateral renal vein and the IVC above the thrombus sequentially after we cut off the renal artery on the tumor side. The contralateral renal artery was blocked for the left tumor, while the left renal artery was not blocked for the right tumor. Segmental resection of the IVC would be considered if the thrombus invaded the IVC wall extensively. If minor involvement of the IVC wall occurred, we performed resection of the invaded vessel wall rather than segmental resection. For level III or IV thrombus, the first porta hepatis should be blocked and the Foley catheter-assisted six-step thrombectomy technique [12] was used in our center. If the right atrium was involved, ORN-VT is usually needed. We usually incised the thoracoabdominal midline and the "milking" technique is performed to squeeze the intra-atrial thrombus back into the IVC.

FOLLOW-UP
We provided the same follow-up plan to all patients and follow-up data were regularly collected (symptoms and signs, laboratory tests, imaging examination of the chest,

Highlights:
• This single-center retrospective cohort study compared the surgical and oncologic outcomes between laparoscopic and open radical nephrectomy with venous thrombectomy. • LRN-VT is a reliable and effective procedure in the treatment of renal tumor with venous thrombus and LRN-VT has advantages in operative time, blood loss, complications and postoperative hospital stay compared with ORN-VT. • LRN-VT is not inferior to ORN-VT with regard to OS, TSS and MFS.
• LRN-VT can result in a better LRFS than ORN-VT.
abdomen and pelvis). The laboratory tests included routine blood test and blood biochemical test. The imaging examination included computed tomography (CT), magnetic resonance imaging (MRI) and X ray. Patients were followed up every 3 mon after surgery in the first year, then 6 mon to the third year, then annually thereafter. We determined the death reason according to the death certificate issued by the local medical institution if a patient died during the interval of followup visit or we determined that by the treating physicians.

OUTCOMES AND DEFINITIONS
Primary outcomes contained surgical outcomes and oncologic outcomes. The surgical outcomes were represented by perioperative and postoperative outcomes (operative time, blood loss and complication rate, et al) between the two groups and the oncologic outcomes were represented by the overall survival (OS), tumorspecific survival (TSS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). Complications were evaluated within 30 days after surgery. OS meant the length of time from surgery to death from any cause. TSS was defined as the time from surgery to death due to tumor. LRFS was defined as the time from surgery to local recurrence (tumor recurrence in or abutting the previous surgical bed) based on CT or MRI. MFS was defined as the time from surgery to the development of metastatic disease (new lesions in other organs, brain, lung, liver, bone, et al) based on CT or MRI. MFS was only assessed in patients with M0 diseases.
The presence of local symptoms was defined as a palpable mass, pain, gross hematuria. Patients with edema, fever, swelling, fatigue and weight loss, et al were thought to have systemic symptoms. The American Society of Anesthesiologists Physical Status classification system (ASA level) [15] was introduced to estimate the operative risk of patients. Thrombus level was classified using the Mayo Clinic classification of tumor thrombus level [1]. Postoperative complications were graded according to the Clavien-Dindo grading system [16].
The histological diagnosis of renal tumors was based on the World Health Organization (WHO) classification (2004 and 2016 version) [17,18]. The Fuhrman system was applied to RCC nuclear grading [19]. A sarcomatoid differentiation was defined as RCC accompanied by histological appearance of spindle-cell sarcoma. The 2017 version of the tumor-node-metastasis (TNM) classification was used for clinical staging based on postoperative pathological specimen.

DATA QUALITY AND BIAS CONTROL
We designed a precise eCRF containing all the necessary medical information and standardized the definition, naming method and data type of each variable. We set up mandatory fields to reduce data missing and two trained data managers performed data entry to reduce logic errors. The data managers were blinded to the study design. A third party checked the database regularly to keep the authenticity and accuracy.
We set strict criteria for inclusion and exclusion to reduce the selection bias. We performed a propensitymatched comparative analysis to minimize the influence of confounding bias and to identify a cohort of patients with comparable baseline characteristics. The propensity score was estimated by a multivariable logistic regression model and the 1:1 matching without replacement was performed with a caliper width equal to 0.02. Patients were matched regarding age, body mass index (BMI), ASA level, comorbidity, tumor diameter, thrombus level and metastasis at diagnosis. Matching was performed by a researcher who didn't know the outcomes.
An independent researcher who was blinded to the matched-cohort analyzed the outcomes to control the information bias. Except for the routine review after surgery, the data managers conducted telephone interviews every 3-6 mon and collected the follow-up information to reduce the withdraw bias.

STATISTICAL ANALYSIS
Baseline characteristics were shown for categorical variables and continuous variables. We reported the medians and interquartile ranges for non-normally distributed continuous variables and the means and standard deviations for normally distributed continuous variables. Categorical variables were reported as frequencies and proportions. The chained multiple imputation was used to resolve the missing data. We compared differences between non-normally distributed continuous data and ordered categorical data with the Wilcoxon sum rank test and compared differences between unordered categorical data with the Chi-square test and Fisher exact test. In the matched cohort, the paired t-test, the Wilcoxon signed rank or the McNemar test was applied to compare differences. We used the Kaplan-Meier method to perform survival analysis and assessed the differences between the propensity-matched groups with log-rank test. Cox proportional hazards regression model was used to estimate the relative oncologic outcomes after adjusting the variables that satisfied the proportional hazards assumptions (thrombus level, lymph node metastasis and distant metastasis, perinephric fat invasion, adjuvant therapy, et al). A hazard ratio (HR) less than 1.0 favored LRN-VT. All statistical tests were performed by SPSS version 25.0 (IBM, Armonk, NY, USA) and the R statistics package version 3.6.1 (R Project for Statistical Computing, www.r-project.org). All tests were two-sided, and the significance level was set at p < 0.05.

PATIENT CHARACTERISTICS
Of consecutive 350 patients identified, 32 patients were excluded for pathologically confirmed tumors that were not renal origin, 6 patients were excluded for RALRN-VT, 6 patients were excluded because of conservative treatment and 4 patients were excluded for shorter than 6 mon of follow-up. 302 patients were matched, including 148 patients treated with LRN-VT and 154 patients treated with ORN-VT. Before propensity matching, significant differences existed in several baseline variables ( Table 1). After matching, 94 patients were matched in each group and no significant differences were found in baseline characteristics.

SURGICAL OUTCOMES
Surgical outcomes were showed in Table 2 The complication rate of ORN-VT was higher than that of LRN-VT (39.4% vs 21.3%, P = 0.007) and the Clavien grade was higher in the ORN-VT group than that in the LRN-VT group (P = 0.005). The median postoperative hospital stay of LRN-VT group was shorter than that of ORN-VT group (8d vs 10d, P < 0.001).  Table 3 summarized the data on follow-up in each group.  (Figure 1A, B and C). Patients who underwent LRN-VT had a lower risk of local recurrence compared to patients who underwent ORN-VT (Adjusted HR 0.18, 95% CI 0.05-0.62, P = 0.007) (Figure 1D). Table 4 showed the pathological results of the renal tumors between the two groups. We couldn't observe a statistically significant difference in either T stage (P = 0.16), lymph node metastasis (0.09), perinephric fat invasion (0.39), histological type (P = 0.37), adrenal

DISCUSSION
LRN-VT has been proved to be an effective surgical approach [6, 10, 20-22] despite insufficient high-level medical-evidence support its overwhelming superiority over ORN-VT. Our propensity-matched cohort study favored that LRN-VT had advantages in operative time, blood loss, postoperative hospital stay as well as complications. However, the survival analysis showed that LRN-VT could not result in a better oncologic outcome when comparing OS, TSS and MFS. Our finding indicated that patients in the LRN-VT group had a better LRFS than those in the ORN-VT group. The first laparoscopic procedure for renal vein thrombus was reported in 1996 [23] and after that,

LRN-VT(N = 94) ORN-VT(N = 94) P VALUE
Surgical approach (n/%) -      [6] reported the transfusion rate was 80% (4/5) and the Clavien I-II grade complication rate was 80% (4/5). Secondly, 21 patients (22.3%) had pathologically confirmed thrombus involving the venous wall and 9 patients (9.6%) received segmental resection of IVC in our LRN-VT cohort. Lastly, 41 patients (43.6%) underwent adrenalectomy. All the factors made our LRN-VT more extensive and more traumatic and led to a relatively higher transfusion rate and a higher complication rate. Randomized trials focusing on the comparative outcomes of LRN-VT and ORN-VT have not been reported. Some observational studies analyzed the outcomes of the two procedures. Xu et al. [24] compared the surgical outcomes of laparoscopic versus open procedure directly and found that LRN-VT had shorter operative time, less blood loss, shorter hospital stay and less transfusion than ORN-VT. Our surgical outcomes were consistent with  their findings. However, some differences still existed.

LRN-VT (N = 94) ORN-VT (N = 94) P VALUE
First of all, their study only contained renal tumor with level I and II thrombus, while our study included patients with level 0-IV thrombus. Next, they used complete retroperitoneal approach while we performed both transperitoneal and retroperitoneal approaches. Finally, they reported no complication in the LRN-VT group and only 2 patients (6.3%) in the ORN-VT had perioperative complications. They didn't observe statistically significant difference in complication rate between the two groups.
Ebbing et al. [25] reported that ORN-VT led to a two-fold higher complication rate than LRN-VT in patients with renal vein thrombus. In our study, we found a significant lower complication rate and a lower Clavien grade in the LRN-VT group than that in the ORN-VT group. We thought that was largely due to the wider and clearer vision of the laparoscope. Thanks to the improvement of surgical vision and high-definition picture, the surgeons could perform precise operation and avoid unnecessary injuries effectively, especially for the vessels. It was also noteworthy that open conversion due to anatomical difficulty, intraoperative bleeding or tumor control consideration occurred in 24 patients. That could reduce the postoperative complications and even the perioperative mortality which could have occurred in the LRN-VT group. The two most common complications in the ORN-VT group were anemia and bowel obstruction, while we didn't find any complication particularly associated to LRN-VT. These findings supported that LRN-VT had greater advantages in surgical outcomes over ORN-VT. RALRN-VT has been clinically applied in several centers since its first report in 2011 [4,[26][27][28]. Kyle et al. [29] compared the perioperative and oncologic outcomes of level I-II thrombus between RALRN-VT and ORN-VT and found that RALRN-VT produced shorter hospital stay, less transfusion and a lower complication rate with no statistically significant difference in OS. Gu et al. [30] concluded that RALRN-VT can achieve more favorable perioperative outcomes and similar oncologic outcomes compared with ORN-VT. In our study, we excluded the patients treated with RALRN-VT to control the bias and we didn't compare RALRN-VT with either LRN-VT or ORN-VT. However, based on the results mentioned, we thought that the minimally invasive procedures, including RALRN-VT and LRN-VT, might be superior surgical options over open surgery. We encouraged attempts to apply the minimally invasive procedures to patients with renal tumor and venous thrombus. Besides, we advised highlevel randomized controlled trials comparing the surgical outcomes of the three procedures to be conducted to confirm the superiority.
The precise operation of LRN-VT can minimize the surgical trauma and maximize the resection of tumor. However, when it comes to the oncologic outcomes, we didn't observe that LRN-VT could result in a better OS, TSS or MFS than ORN-VT after a median follow-up of 31 mon and 32 mon respectively. Xu et al. [24] found that laparoscopic approach had a similar TSS in level I-II thrombus compared with open surgery after a median follow-up of 18.2 mon. Gu et al. [30] also observed that robotic cohort had a comparable OS and TSS with open cohort in a propensity-matched cohort study after a median follow-up of 27 mon and 48 mon respectively. Rose et al. [29] reported that there was no statistically significant difference in OS and recurrence-free survival between robotic procedure and open procedure. However, in our study we found that LRN-VT was associated with a lower risk of local recurrence and the median LRFS was much longer in the LRN-VT group than that in the ORN-VT group. The patient with local recurrence in the LRN-VT group (postoperative 36 mon) had postoperative adjuvant targeted therapy with Sunitinib and Axinitib and only 1 patient with local recurrence (postoperative 17 mon) in the ORN-VT group (median local recurrence time 8 mon) had postoperative adjuvant targeted therapy with Pazopanib. We understand this from two perspectives. On the one hand, postoperative adjuvant targeted agents may help prolong the time from surgery to local recurrence. On the other hand, patients without adjuvant therapy in the LRN-VT group (n = 56) had no local recurrence and patients without adjuvant therapy in the ORN-VT group (n = 49) had 4 cases of local recurrence. This could better reflect the weight of surgery in local recurrence control and LRN-VT had superiority in LRFS over ORN-VT. However, owing to the relatively small number of recurrence events in the two groups, our results should not be taken as suggesting that surgical option determines LRFS. More local recurrence events and longer follow-up are necessary to better compare the LRFS between the two groups.
Our study has strengths that enhance the clinical applicability of the findings. To the best of our knowledge, this study represents the largest propensity-matched comparative analysis of LRN-VT versus ORN-VT. This study provided support to the application of laparoscopic procedure in the treatment of renal tumor with venous thrombus. In addition, we reported for the first time that LRN-VT could result in a better LRFS in such patients. However, this study has some limitations. The first one is its retrospective and non-randomized nature. Despite we matched, unknown confounders might exist and affect the results and then limit the internal validity. A large prospective cohort study or a randomized controlled study is needed to better compare the outcomes between the two surgical approaches. Furthermore, a relatively shorter follow-up time limited the observation of oncologic outcome events, especially for the local recurrence event. This study would definitely benefit from a longer follow-up.

CONCLUSIONS
LRN-VT is a reliable and effective procedure in the treatment of renal tumor with venous thrombus, despite open procedure remains the preferred surgical option. LRN-VT has advantages in operative time, blood loss, complications and postoperative hospital stay compared with ORN-VT. As for the oncologic outcomes, LRN-VT is not inferior to ORN-VT with regard to OS, TSS and MFS. LRN-VT can result in a better LRFS than ORN-VT and longer follow-up is needed to further validate the finding.

ADDITIONAL FILE
The additional file for this article can be found as follows: • Rawdata. Rawdata of the study cohort. DOI: https:// doi.org/10.29337/ijsonco.127.s1

ETHICS AND CONSENT
This article does not contain any studies with human participants or animals performed by any of the authors; and it receives ethics approval from Peking University Third Hospital Ethics Committee.