Level III-IV Inferior Vena Caval Thrombectomy Without Cardiopulmonary Bypass: Long-Term Experience with Intrapericardial Control

Author's Accepted Manuscript Level III-IV Inferior Vena Caval Thrombectomy Without Cardiopulmonary Bypass: Long-term Experience with Intrapericardial Control Mukul B. Patil, Jeremy Montez, Jeffrey Loh-Doyle, Jie Cai, Eila C. Skinner, Anne Schuckman, Duraiyah Thangathurai, Donald G. Skinner, Siamak Daneshmand

PII: DOI: Reference:

S0022-5347(14)03311-4 10.1016/j.juro.2014.03.112 JURO 11376

To appear in: The Journal of Urology Accepted Date: 20 March 2014 Please cite this article as: Patil MB, Montez J, Loh-Doyle J, Cai J, Skinner EC, Schuckman A, Thangathurai D, Skinner DG, Daneshmand S, Level III-IV Inferior Vena Caval Thrombectomy Without Cardiopulmonary Bypass: Long-term Experience with Intrapericardial Control, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.03.112. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

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Level III-IV Inferior Vena Caval Thrombectomy Without Cardiopulmonary Bypass: Long-term Experience with Intrapericardial Control

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Mukul B. Patil, Jeremy Montez, Jeffrey Loh-Doyle, Jie Cai, Eila C. Skinner, Anne Schuckman, Duraiyah Thangathurai, Donald G. Skinner & Siamak Daneshmand

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Running Title: Intrapericardial Control for IVC Tumor Thrombus without Bypass

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Center for Comprehensive Urologic Oncology, USC Institute of Urology Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Correspondence: Siamak Daneshmand, MD

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Total words: Abstract: 246 (250 max), Text: 2500 (2500 max) References: 30 Tables: 5 Figures: 2

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Associate Professor of Urology (Clinical Scholar) Director of Urology Oncology University of Southern California Institute of Urology USC/Norris Comprehensive Cancer Center 1441 Eastlake Avenue, Suite 7416 Los Angeles California 90089 Phone number: (+1) 323-865-3700 Fax number: (+1) 323-865-0120 Email address: [email protected]

Keywords (1-5) Kidney; Inferior Vena Cava; Renal Cell Carcinoma; Tumor Thrombus; intrapericardial.

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Abstract Purpose: Inferior vena cava tumor thrombectomy requires experienced surgical teams due to complex hemodynamic considerations, often utilizing vascular bypass techniques that introduce additional

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risk. Control of the IVC within the pericardium obviates the need for cardiopulmonary bypass (CPB). We reviewed our experience with intrapericardial control during IVC tumor thrombectomy to evaluate perioperative outcomes and determine factors associated with overall survival.

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Materials and Methods:

We completed a retrospective review of 87 patients who underwent nephrectomy with IVC tumor

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thrombectomy using intrapericardial IVC control from 1978-2012. This technique was performed in all cases of intrahepatic (n=43) and supradiaphragmatic (n=35) thrombi, and select cases of intraatrial (n=9) thrombi. Patient demographics, operative variables, and post-operative outcomes were examined. Multivariate regression analysis was used to determine associations between clinical variables and overall survival.

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Results:

Perioperative mortality (30-day) was 9.2% and incidence of high-grade complications was 19.5%. Median survival was 3.1 years and 2.5 years for pT3bN0 and pT3cN0 patients, respectively. Extended regional lymphadenectomy, performed in all cases revealed nodal metastasis in 36% of

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patients. On multivariate analysis, ECOG >2 and pT3c stage were associated with worse survival. Histologic grade, perinephric fat invasion and presence of lymph node involvement were not

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associated with worse survival.

Conclusions:

Intrapericardial control of the IVC allows a single surgical team to safely perform tumor thrombectomy for intrahepatic and supradiaphragmatic thrombi, eliminating risk and morbidity related to CPB. Though supradiaphragmatic extent and ECOG >2 are associated with worse survival, complete resection with lymphadenectomy can allow long-term survival in patients with locally advanced disease.

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Introduction Despite the downstaging of diagnosed renal masses since the advent of multidetector computed tomography (CT), locally advanced renal masses are still common. Invasion of the

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venous system occurs in approximately 4-10% of cases, and of those, into the inferior vena cava (IVC) in 22-70%.1 Recent population-based inquiry has demonstrated median survival of 5 months without surgical intervention.2 With imminent fatal progression of these tumors, an aggressive surgical approach has been advocated given an associated overall 5-year survival rate of 39-60%.3, 4

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As early as 1956, the potential for long-term survival beyond 10 years has been reported.5 With the evolution of targeted therapy and its use in the peri-operative setting, an increasing number of

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patients are potential candidates for surgical excision.

Many authors have advocated the use of vascular bypass techniques, including venovenous bypass and cardiopulmonary bypass (CPB) with and without hypothermic circulatory arrest.1, 6, 7 Others recommend the reservation of bypass techniques exclusively for Level IV thrombi as CPB itself carries additional intraoperative risk and significant potential for post-operative neurologic and hematologic complications.8, 9 Hypothermic circulatory arrest in tumor thrombectomy series

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has also been associated with perioperative mortality ranging 3-16%.3 Level III/IV thrombi have been found to be associated with increased rates of complications, ranging between 17.5-47%, and perioperative mortality as high as 40%.1, 6, 10

The thoracoabdominal incision has been used for the resection of advanced renal cell

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carcinoma for over six decades.11 The technique of intrapericardial control, which predates the introduction of highly-sensitive abdominopelvic imaging and improvements in bypass techniques,

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assists in the prevention of intraoperative pulmonary embolism, minimizes hepatic ischemia time, avoids systemic heparinization, and obviates the need for median sternotomy. By avoiding CPB, a single surgical team can safely perform a majority of vena cava tumor thrombectomy cases. We reviewed our experience with this surgical approach, which has undergone minimal alteration during the study period, to determine perioperative outcomes and examine overall survival in patients with advanced IVC tumor thrombi.

Materials and Methods

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With approval from the Institutional Review Board, patients who underwent open radical nephrectomy and tumor thrombectomy between 1978 and December 2012 were identified from an existing nephrectomy database. Of 210 patients with IVC tumor thrombus, 87 patients with Level III and IV thrombi who underwent intrapericardial control were identified and included for

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analysis. All clinical information - including initial consultation, inpatient notes, operative records, order sheets, pathology reports, hospital discharge summaries, outpatient encounters, readmission records and personal communication - was retrospectively reviewed. Karnofsky and ECOG status was determined from pre-operative records. Operative time was determined from surgical incision

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to completion of surgical closure. All complications within 30 days of surgery were considered related to surgery and graded by two independent reviewers according to the 2004 Clavien-Dindo

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grading system. Grading discrepancies prompted reexamination of the medical record until consensus was reached. All complications were further classified by organ system. Prior to the introduction of CT and MRI, patients underwent venography and arteriography to determine cranial extent of tumor thrombus. With introduction of computed tomography in the early 1980’s patients underwent pre-operative imaging at the discretion of the operating surgeon. Since 2003, all patients

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have undergone intraoperative transesophageal echocardiography regardless of tumor level.

Surgical Approach

A right-sided thoracoabdominal incision was used for all cases, regardless of tumor laterality to allow complete vascular exposure; extension from the midline to the left

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costochondral junction was performed in selected left-sided cases. The intrapericardial IVC was isolated with a curved pedicle clamp and controlled with a Rummel tourniquet (Figure 1).

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Hepatic vascular isolation was performed via Pringle maneuver, occluding the porta hepatis. Concomitantly, vascular control of the superior and inferior mesenteric arteries was performed in order to limit portal vein inflow. After complete vascular control, a longitudinal cavotomy was performed from the renal vein ostium toward the inferior (short) hepatic veins. Digital manipulation, balloon catheter withdrawal or tissue elevators were used to remove the tumor thrombus in its entirety. Since 2008 cavoscopy using a 16F flexible cystoscope has been performed to permit direct visualization of the entire vena cava. Cavectomy was performed if intra-operative examination revealed caval invasion. In order to prevent bland thromboembolism, IVC interruption (via

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DeWeese clip placement or segmental resection) or filter placement was performed if evidence of bland thrombus was found pre- or intraoperatively.12 Though all cases were performed in a bypass-ready operating room with cardiothoracic surgical teams available, a combined surgical approach was required only for

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cases of intra-atrial thrombi. A purse-string suture was placed on the atrial appendage; through an atriotomy, the tumor thrombus was pushed inferiorly with subsequent control of the intrapericardial IVC. After control was obtained, atriotomy closure and thrombus extraction were performed

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simultaneously. Perioperative anticoagulation was not standardized throughout the study period.

Statistical Analysis

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All statistical analysis in this study was performed with SAS® Version 9.3 (SAS Institute Inc., Cary, NC, USA). Pearson’s chi-square or Fisher’s exact test were used to examine the association between categorical demographic and clinical variables. Overall survival is the primary outcome analyzed in this study. Time to overall survival was calculated from the date of surgery to the date of death (all causes), or to the date of last follow-up if patient was still alive at the last follow-up. Kaplan-Meier plots were used to estimate the probabilities of

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overall survival for every year after surgery. The logrank tests were used to compare the differences of survival in subgroups. Multivariate Cox regression analysis was used to evaluate the independent prognostic factors for overall survival. All p-values reported are 2-

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sided and p<0.05 is considered statistically significant.

Results

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Patients

In 87 patients who underwent surgery, cases included 43 intrahepatic (Mayo Level III) thrombi and 44 thrombi above the diaphragm (Mayo Level IV), including 35 supradiaphragmatic cases, and 9 intra-atrial cases. Mean age was 61.8 years (25-81 years) and 66.6% of patients were men (n=58). Body mass index ranged between 17-42 (mean 28.4). Tumors were left sided in 21 cases (24.1%). Karnofsky performance status was ≥60 in 51.7% of patients. Of 55 patients with determinable ECOG status, performance level was 0 in 25% (n=14), 1 in 43.6% (n=24), 2 in 20.0% (n=11), 3 in 7.3% (n=4), and 4 in 3.6% (n=2). Patient demographic information and tumor thrombus data are included in Table 1.

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Operative and Perioperative Details Overall median OR duration was 325 minutes (180-831), and mean number of intraoperative transfusions of packed red blood cells was 16.2 (0-79). The mean number of post-operative

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transfusions was 0.3 (0-5). The mean Pringle maneuver time was 13.8 minutes (3-27min). Average length of ventilator dependence was 1.9 days (0-29); 42 patients (48.3%) were extubated at the termination of surgery. All patients underwent intensive care monitoring, for an average duration of 5.8 days (1-35). Average length of hospitalization was 12.9 days (4-85). Operative and

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perioperative details are summarized in Table 2. Additional caval procedures included cavectomy in 9, caval interruption in 29, IVC filter placement in 7, and cavoscopy in 16 patients, respectively. No

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complications occurred during performance of adjunctive procedures. In three patients, cavoscopy revealed residual tumor, thus providing indication for cavectomy.

Pathology

Pathology revealed clear cell RCC in 70 patients (80.5%), non-clear cell pathology in 12 patients (13.8%), and was unknown in 5 patients. Non-clear cell pathology included papillary RCC (n=8),

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urothelial carcinoma (n=1), adrenocortical carcinoma (n=1), nephroblastoma (n=1), and carcinoid tumor (n=1). Sarcomatoid features were found in 11 patients. Invasion into sinus or perinephric fat was found in 49 patients and nodal metastases in 31 patients. Venous wall invasion was found in 41 patients, including invasion into the renal vein (n=23) and IVC (n=18). A summary of

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Complications

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pathologic findings is included in Table 3.

Forty patients (46%) patients experienced no complications (Table 4). Based on the Clavien-Dindo surgical complication classification system, low-grade complications (Grade 1-2) occurred in 23 patients (26.4%). Grade III and IV complications occurred in 17 patients (19.5%). Intraoperative mortality in 3 patients was due to massive pulmonary embolism (n=2, Cases #5, 22) and uncontrollable hemorrhage (n=1, Case #21). No intra-operative mortality has occurred since 1990. Five patients died in the post-operative period resulting in a total 30-day perioperative mortality rate of 9.2%.

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Survival and Multivariate Analysis For patients surviving the perioperative interval, median overall survival for pT3bN0, pT3cN0, pN+ and pM+ was 2.8 years, 1.5 years, 1.3 years and 1.1 years, respectively. Two-year survival for pT3bN0, pT3cN0, pN+ and pM+ was 59.6%, 55.2%, 34% and 27.3% respectively. Ten-year

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survival for pT3bN0, pN+ and pM+ was 21.2%, 6.8%, and 4.8% (Table 5). Worse performance status was associated with decreased overall survival when analyzed both as a dichotomous (ECOG 0-1 vs. >1, p=0.02) and ordinal variable (ECOG 0-1 vs. 2 vs 3-4, p<0.0001). Kaplan-Meier survival curves are included in Figure 2. Other factors, including Karnofsky status <60, histologic grade, fat

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invasion and presence of pathologic lymph node metastasis, were not associated with overall survival. Multivariate analysis revealed that pT3c (p=0.011) and distant metastasis (p=0.032)

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showed statistically significant association with worse overall survival.

Discussion

Intrapericardial control has been described previously as a surgical approach for nephrectomy with advanced IVC tumor thrombectomy.5 Through a thoracoabdominal incision, this technique allows early vascular control of the kidney and the entire vena cava, assists in the

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prevention of pulmonary embolism, minimizes hepatic ischemia time, and obviates the need cardiopulmonary bypass and requisite systemic heparinization. Analysis from this retrospective series illustrates the efficacy of this technique, while using a standardized reporting system with extended follow-up.

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The first use of the Clavien-Dindo grading system applied to vena cava tumor thrombectomy was in 2011, where Ali et al reported an overall high grade complication rate of 14%

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and a 30-day mortality rate of 4%.13 These results were found with a cohort where 48% (24/50) cases were Level I and Level II thrombi. In a series of seventy-eight patients treated off-bypass, only 10 patients had Level III or IV thrombi.4 The overall complication rate was 43% (including high-grade complications in 18%) and the perioperative mortality rate was 6%. Many reports in the literature rarely include surgical patients with ECOG ≥2.4, 13, 14 Our cohort reviews an experience with 87 patients harboring intrahepatic, supradiaphragmatic and intra-atrial tumor thrombi, and with impaired performance status (ECOG ≥2 in more than 25% of patients. Thus, observed rates of high-grade complications (19.5%) and perioperative mortality (9.2%) are favorable considering expectations. This is underscored by the

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association of cranial extent of thrombus with higher complication rates,6, 15 and lower case volumes8-10, 15-17 or brief follow-up18, 19 found in existing series of intrahepatic or supradiaphragmatic tumor thrombi. Finally, perioperative mortality rates for Level III or Level IV thrombi have been reported to be as high as 40%.10

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Recommendations to limit the use of CPB are abundant, given associations with bleeding, sepsis, multi-system organ failure, and neurologic deficit.20 These may prolong hospitalization and increase mortality or rehabilitation requirements.21 We observed no neurologic events causing lasting morbidity using intrapericardial control to avoid CPB. Another known risk of CPB is

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increased peri-operative bleeding attributable to systemic heparinization. Though our observed range of intra-operative transfusion requirement is admittedly broad, the median number of

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intraoperative transfusions is consistent with comparable cohorts.19, 20 The limited need for postoperative transfusion within 30 days (average 0.3) is indicative of surgical efficacy. Many existing and historical studies regarding renal cell carcinoma with IVC tumor thrombi have focused on cancer-specific survival as primary outcome, resulting in survival data that may contain reporting bias; only a few have looked at overall survival.15, 22 Though it may act as a surrogate for cancer-specific survival in the setting of advanced malignancy, overall survival is an

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outcome that eliminates subjectivity associated with interpreting cause of death and is verifiable given the availability of the Social Security death index master file. With this analysis, we are able to demonstrate meaningful median overall survival benefit for even advanced cases of clear cell RCC. Our findings include overall survival outcomes at 2 years that compare favorably with

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contemporary series.13, 16 Remarkably, long term follow-up revealed demonstrable overall survival at 10 years, including patients with nodal metastasis and distant metastatic disease. These findings

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confirm the rationale for an aggressive surgical approach for a majority of patients with inferior vena cava tumor thrombi.

Lower overall survival has been associated with higher thrombus level, presence of metastasis and lower BMI.14 On multivariate analysis, we found several important findings. First, this series is consistent with other reports where pT3c and metastatic disease were associated with statistically significant survival differences.14, 23 Secondly, ECOG performance status >2 was independently associated with significantly worse overall survival. Though the Charlson Comorbidity Index has shown no association with survival in IVC thrombus cases, performance status has not been widely analyzed in series of IVC tumor thrombus.3, 7, 16, 18, 24, 25 Prior reports

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have analyzed ECOG when comparing RCC with and without venous involvement,26 have shown impact only on univariate analysis17 or have not included patients with ECOG >2.14, 27, 28 Though meaningful survival was found for patients with ECOG 0,1, and 2, dismal outcomes for patients with ECOG 3 and 4 may indicate a contraindication to surgical intervention. However, as only 55

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patients had determinable ECOG in our cohort, this finding must be considered preliminary; prospective analysis is underway.

This study reports outcomes of a locally advanced nephrectomy series with completion of a systematic, extensive lymphadenectomy. Patients with node positive disease did not fare worse

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than patients without nodal involvement. Though studies examining the oncologic impact of lymphadenectomy in cT3-T4N0 RCC are limited,29 survival advantage has been demonstrated for

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patients undergoing lymphadenectomy in the setting of cN+ disease.30 Thus, while we cannot definitively attribute long-term survival to meticulous lymphadenectomy in the setting of caval thrombectomy, lymphadenectomy facilitates vascular exposure, control and safe surgical extirpation.

It is important to acknowledge that while this analysis reviews an intrapericardial caval isolation and mass excision technique that has undergone minimal alteration since its early

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description, methods used for perioperative management have changed considerably. This includes improved abdominopelvic imaging, transesophageal echocardiography and other anesthesia monitoring devices. Given the variability of adjuvant treatment during the study period, we were unable to report results related to progression. Though this report includes retrospective data,

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efforts with prospective data collection are underway to examine the temporal effect on the evolution of outcomes. Finally, this case series was performed at a tertiary-care, academic hospital

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with surgeons having undergone subspecialty training in urological oncologic surgery, and as such, these findings may have limited wide-spread applicability.

Conclusion

Intrapericardial control of the IVC allows a single surgical team to perform tumor thrombectomy for intrahepatic and supradiaphragmatic thrombi while demonstrating favorable complication and mortality rates compared to contemporary series. This approach allows complete vascular control of the inferior vena cava and avoids complications related to vascular bypass techniques. Though supradiaphragmatic extent and worse performance status were associated with

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worse survival, complete resection with lymphadenectomy may provide durable survival in patients with locally advanced disease. Long-term survival is possible even in cases of node-positive and distantly metastatic disease. ECOG 3 and above may represent contraindications to surgical

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intervention given dismal outcomes after resection.

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61.8 62 (25 – 81) 58 (66.7%) / 29 (33.3%) 28.4 28.1 (17.4-42.4) 64 (73.6%) 23 (26.4%) 33 (37.9%) 45 (51.7%) 9 (10.3%) 32 (36.8%) 14 (16.1%) 24 (27.6%) 11 (12.6%) 4 (4.6%) 2 (2.3%) 21 (24.1%) / 66 (75.9%)

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Table 1 – Patient Demographics and Thrombus Characteristics Mean Age Median (Range) Gender (% M / % F) Mean BMI Median (Range) ASA ≤3 >3 Karnofsky Unknown ≥60 <60 ECOG Unknown 0 1 2 3 4 Tumor Laterality (% L / % R)

43 (49.4%)

Mayo IV (extending above diaphragm)

44 (50.6%)

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Mayo III (Intrahepatic) At or above the level of hepatic veins but below diaphragm

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Supradiaphragmatic Intra-Atrial

35 9

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Table 2 – Operative and Perioperative Details

Intraop pRBC

Postop pRBC

Vent Dependence (d)

ICU LOS

Total LOS

371.7 348 (228-831)

333.8 300 (180-601)

294.2 292.5 (220-355)

351.3 325 (180-831)

12.2 12 (3-22)

15.8 15 (8-27)

15.4 14 (9-20)

14 13 (0-37) 0.4 0 (0-5) 1.5 1 (0-10) 4.6 5 (1-10)

20.4 17 (0-79) 0.2 0 (0-2) 3.2 1 (0-29) 8.4 5 (2-35)

13.8 12 (7-24) 0 0 (0) 1.2 1 (0-2) 5.7 5 (2-12)

11.4 10 (4-32)

14.5 11 (5-85)

0

Peri-op Mortality (within 30 days)

1

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Intra-op Mortality

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Overall (n=87)

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Pringle Time (min)

Intra-Atrial (n=9)

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Mean Median Range

Supra-diaphragmatic (n= 35)

13.8 13 (3-27)

16.2 14 (0-79) 0.3 0 (0-5) 1.9 1 (0-29) 5.8 5 (1-35)

14.2 13.5 (11-19)

12.8 11 (4-85)

1

2

3 (3.4)%

4

0

5 (5.7%)

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OR Time (min)

Intrahepatic (n= 43)

Table 3 – Pathologic Findings Pathologic Staging of Renal Cell Carcinoma pT3b pT3c pT4 N+ M+

37 34 10 31 29

Histologic Subtype Clear Cell Renal Cell Carcinoma Non-Clear Cell* Unknown

70 (80.5%) 12 (13.8%) 5 (5.7%)

Other Pathological Findings Sarcomatoid Features Fat Invasion (Hilar or Perinephric Fat) RV Wall Invasion IVC Wall Invasion

10 (11.5%) 48 (55.2%) 21 (24.1%) 18 (20.7%)

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(47.4%) (39.7%) (12.8%) (39.7%) (37.2%)

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* Papillary RCC (n=8), Adrenocortical (n=1), Urothelial (n=1),, Nephroblastoma (n=1), and Carcinoid (n=1).

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Table 4 - Complications

3 (3.4%)

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SC

Minor Complications – Clavien Grade 1-2 Cardiac (Atrial Fibrillation, supraventricular tachycardia) Gastrointestinal (Ileus) Renal (Acute tubular necrosis, treated medically) Thromboembolic/Hematologic (deep venous thrombosis, hemolytic reaction) Infectious (Urinary tract infection, pneumonia, thrombophlebitis, fevers) Nutritional (Parenteral Nutrition) Other (Endocrine, neurologic, wound separation)

40 (46.0%) 22 (25.3%) 17 (19.5%)

RI PT

Number of Patients without complications Number of Patients with highest grade complication 1-2 Number of Patients with highest grade complication 3-4 Number of Patients with Intraoperative Mortality Post-operative Mortality (Multisystem organ failure due to sepsis, Budd-Chiari, hemorrhagic stroke; progression of pulmonary metastasis; cardiac arrest)

AC C

EP

TE D

Major Complications - Clavien Grade 3-4 Pulmonary (Pleural and parapneumonic effusion, pneumothorax) Cardiac (Air embolism due to malfunctioning Cordis - successful resuscitation, pericardial effusion) Thromboembolic (Pulmonary Embolism requiring venous filter placement) Renal (Transient Hemodialysis – fluid overload, Cephalosporin-induced ATN) Gastrointestinal (Bowel injury requiring percutaneous drainage)

5 (5.7%)

15 1 3 3 9 3 3

12 2 1 2 1

ACCEPTED MANUSCRIPT

pN+ (n=31) 1.3y

pM+ (n=29) 1.1y

RI PT

pT3cN0M0 (n=21 ) 2.5y

2 yr OS

59.6%

55.2%

33.9%

27.3%

3-yr OS

51.4%

39.4%

25.4%

24.9%

5 yr OS

42.5%

31.7%

20.3%

17.8%

10 yr OS

21.2%

0%

6.8%

SC

Table 5 – Overall Survival pT3bN0M0 (n=29) Median Survival 3.1y

1 year OS

ECOG 0-1 75.4%

ECOG 2 50%

M AN U

TE D EP AC C

4.8%

ECOG 3-4 0%

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1 – Left: Surgical position for right-sided thoracoabdominal incision over the 7th or 8th rib, regardless of tumor laterality. Right: Cavoatrial junction exposed through thoracoabdominal incision; the intrapericardial IVC is outlined in blue.

ACCEPTED MANUSCRIPT

0

pT3c n=47

10

20

1.00 0.80 0.60 0.40 0.20 0.00

0.60

TE D

pN+ n=30

pN0 n=57

0

10

20

AC C

Years Since Surgery B. Node Positive (Blue) vs. Node Negative (Green)

ECOG 2,3,4 n=17

0.40 0.20 0.00

0

ECOG 01 n=37

10

20

Years Since Surgery

C. ECOG 0-1(Blue) vs. ECOG 2-4 (Green)

p<0.0001

1.00 0.75

EP

Est Probability of Survival

p=0.44

0.80

M AN U

Years Since Surgery A. Pathologic T3c (Green) vs. Pathologic T3b (Blue)

RI PT

pT3b n=39

p=0.02

1.00

SC

Est Probability of Survival

p=0.011

Estimated Probability of Survival

1.00 0.80 0.60 0.40 0.20 0.00

Est Probability of Survival

Figure 2 – Kaplan-Meier Overall Survival in patients with pathologic T3c vs. T3b tumors; (B) Kaplan-Meier OS in patients with pN+ vs. pN0 disease; (C) Kaplan-Meier OS in patients with ECOG 0-1 vs. ECOG >1; (D) Kaplan-Meier OS in patients with ECOG 0-1, ECOG 2, and ECOG 3-4.

ECOG 2 n=11

0.50 0.25

ECOG 3-4 n=6

ECOG 0-1 n=37

0.00 0 2 4 6 8 10 12 14 16 18

Years Since Surgery D. ECOG 0-1 (Blue) vs. 2 (Green) vs. 3-4 (Red)