Vascular resection during pancreaticoduodenectomy. Ryan Turley, MD Research Fellow, Duke University

Vascular resection during pancreaticoduodenectomy. Ryan Turley, MD Research Fellow, Duke University

Vascular Resection during PD Outline Review of pancreatic adenocarcinoma Role of PD in treatment of pancreatic adenocarcinoma Theory for vascular resection for locally invasive disease Summary of current literature Types of reconstruction Duke experience Conclusions

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma Classic Presentation Jaundice, sometimes painless Dark urine Light colored stool Labs Bilirubin Ca 19-9 (Normal < 37) 37-100 less specific > 100 suggest malignancy

Pancreatic Adenocarcinoma Imaging Head mass with PV invasion Fine-cut CT scan High quality MRI scan Other EUS ERCP

Role of Pancreaticoduodenectomy (PD) PD is the only chance for cure. Mortality rates ranges from 0-8%. 5 year survival after resection ranges from 7-25%. 2 Survival after surgery is worse for patients with positive margins. 3 2. Bachellier, et al. Is pancreaticoduodenectomy with mesentericoportal venous resection safe and worthwhile. Am J Surgery 2001;182: 120-9. 3. Zervos EE et al. Surgical management of early-stage pancreatic cancer. Cancer Control. 2004; 11:23-31.

Pancreatic Adenocarcinoma SMV and Portal Venous Resection - Theory Grossly positive margins after resection associated with early recurrence. Close relationship between pancreatic head and superior mesenteric vein. Barriers to margin free resection include tumor involvement of SMV. Invasion of SMV can occur without retroperitoneal invasion. SMV not always accurately defined on pre-operative imaging.

Pancreatic Adenocarcinoma SMV/PV invasion Loss of the fat plane on CT Absence of normal pancreatic parenchyma between the low-density tumor and the vein wall

NCCN Practice Guidelines v.1.2009 Resectable No distant metastases Clear fat plane around celiac and superior mesenteric artery. Patent SMV/PV Borderline Resectable Severe unilateral or bilateral SMV/portal impingement Less than 180 degree tumor abutment of SMA Abutment or enasement of hepatic artery, if reconstructible. SMV occlusion, if of a short segment, and reconstructible. SMA or celiac encasement < 180 degrees. Unresectable Distant Metastases Greater than 180 degree SMA encasement, any celiac abutment. Unreconstructible SMV/Portal Vein Aortic invasion or encasement. Metastases to lymph nodes beyond the field of resection.

Flow Diagram- NCCN Guidelines Pancreatic Protocol CT scan Resectable Borderline Unresectable Resection Clinical Trial Neoadjuvant Therapy Resection Neoadjuvant Therapy Chemotherapy/ Radiation Restage Systemic Therapy Resection

History First PD with SMV reconstruction by Moore et al. at the University of Minnesota in 1951. Symbas et al. concluded autologous grafts vein grafts remained patent while synthetic prosthesis had high rates of occlusion in 1961. Asada et al. in Japan reported radical pancreatectomy with PVR in 1963. First attempts in the 1970s by Fortner produced poor results with high morbidity and mortality. Reemergence in the 1990s by the MD Anderson group.

Current literature Modern debate is charged in comparing vascular resection for isolated invasion of SMV, PV, or SMV-PV confluence. Reported Morbidity 25-55% PD with Vascular Resection has not yet been universally accepted due to failure to prove: (1) the procedure can be performed with acceptable morbidity and mortality even if margin free resections are increased. (2) PD with SM-PVR has survival similar characteristics as standard PD.

Reconstruction options V1 Tangential resection with saphenous vein patch V2 Segmental resection with splenic vein ligation and primary anastomosis V3 Segmental resection with splenic vein ligation and interposition graft. V4 Segmental resection without splenic vein ligation and primary anastomosis. V5 Segmental resection without splenic vein ligation and interposition graft.

Available SMV-PVR techniques Vein Patch Greater Saphenous Vein Continuous 6-0 prolene Choice for less extensive tumor involvement < 1/3 vessel circumference

Interposition Grafting More extensive tumor involvement (> 1/3 vessel circumference) Interrupted 6-0 prolene Splenic vein can be ligated or reimplanted in side of interposition graft.

Interposition Graft Graft types Splenic vein Left Renal Vein Internal Jugular Ovarian Vein Femoral Vein*

Primary Reconstruction A. Pancreatic head tumor and involvement of the portal vein. B. En-bloc PD with Segmental portal venous resection. C. Reconstruction of the portal vein.

Previous Studies Author Location N (%) Mortality 30 days (%) Sindelar 1989 Trede 1990,97 Allema 1994 Fortner Harrison 1996 Roder 1996 Morbidity (%) NCI 20 20 55 12 Mannheim 60 (10.7) 6.7 12 Median Survival Amsterdam 20 (11.4) 15 55 8 15 MSK 58 (17.5) 5 12 (Re-X-Lap) 13 73 Munich 31 (10.4) 0 41.9 8 32 Neg Margins (%)

Previous Studies Author Location N (%) Mortality 30 days (%) Sindelar 1989 Trede 1990,97 Allema 1994 Fortner Harrison 1996 Roder 1996 Morbidity (%) NCI 20 20 55 12 Mannheim 60 (10.7) 6.7 12 Median Survival Amsterdam 20 (11.4) 15 55 8 15 MSK 58 (17.5) 5 12 (Re-X-Lap) 13 73 Munich 31 (10.4) 0 41.9 8 32 Neg Margins (%)

Previous Studies Author Location N (%) Mort. 30 days (%) Leach Furman 1996, 98 Tseng 2004 Imaizumi 1998 Nakao 1993, 95 Takahashi 1994, 97 Klempnauer 1996 MD Anderson MD Anderson 31 (41.7) 110 (38) Tokyo 172 (69) Nagoya (Japan) 104 (78) Keio 107 (55.7) Hannover 37 (19.6) Morbidity (%) Median Survival 0 30 22 87 1 18 23.43 78 5 23 8 14% 5-year Neg Margins (%) 49 3.8 23.1 19 26.5 13.5 35.1 (Re-X-Lap) 9.0

Previous Studies Author Location N (%) Mort. 30 days (%) Leach Furman 1996, 98 Tseng 2004 Imaizumi 1998 Nakao 1993, 95 Takahashi 1994, 97 Klempnauer 1996 MD Anderson MD Anderson 31 (41.7) 110 (38) Tokyo 172 (69) Nagoya (Japan) 104 (78) Keio 107 (55.7) Hannover 37 (19.6) Morbidity (%) Median Survival 0 30 22 87 1 18 23.43 78 5 23 8 14% 5-year Neg Margins (%) 49 3.8 23.1 19 26.5 13.5 35.1 (Re-X-Lap) 9.0

Previous Studies Author Location N (%) Mort. 30 days (%) Leach Furman 1996, 98 Tseng 2004 Imaizumi 1998 Nakao 1993, 95 Takahashi 1994, 97 Klempnauer 1996 MD Anderson MD Anderson 31 (41.7) 110 (38) Tokyo 172 (69) Nagoya (Japan) 104 (78) Keio 107 (55.7) Hannover 37 (19.6) Morbidity (%) Median Survival 0 30 22 87 1 18 23.43 78 5 23 8 14% 5-year Neg Margins (%) 49 3.8 23.1 19 26.5 13.5 35.1 (Re-X-Lap) 9.0

Duke Experience Hypothesis Superior mesenterico-portal venous tumor invasion is function of location and not a harbinger of metastatic disease or worse outcome after resection. Combined pancreaticoduodenectomy with vascular resection offers previously unresectable patients a chance for cure without significant additional morbidity or mortality.

Duke Experience 204 patients who underwent PD for pancreatic adenocarcinoma from 1997-2008. Patients who underwent PD with VR (N=42) were compared to patients who underwent standard PD (N=162). Vascular reconstructions were performed by a vascular surgeon using primary repair (N=7), vein patch (N=26), or interposition grafting (N=8) with saphenous or femoral vein conduit.

Inclusion Criteria All patients undergoing standard PD or PD with VR from 1997-2008 at Duke. Pathology confirming Pancreatic Ductal Adenocarcinoma.

Exclusion criteria Patients with significant missing clinicopathological data. All tumors not described in surgical pathology as pancreatic adenocarcinoma. Previous pancreas surgery.

Methods All available post-operative CT scans reviewed for patency by Duke radiology fellow KP. 2 test was used to compare categorical variables. Independent t tests were used to evaluate continuous variables. Survival and follow-up were calculated from the time of surgery to date of death or last follow-up. Overall survival was estimated using the method of Kaplan and Meier. The log-rank test was used to evaluate differences between survival curves. Multivariate analyses of the effects of potential prognostic factors on survival were done using a Cox proportional hazards regression.

Demographics PD + VR (n=42) Standard PD (n=162) P-value Gender, n (%) Male 22 (62) 81 (50) 0.97 ( ( 2 ) Female 16 (38) 81 (50) Med (mean) age (yr) 63.5 (62.4) 66 (64.5) 0.30 (T-test) Range 40-78 32-87 Race, n (%) Caucasian 33 (79) 126 (78) 0.93 ( ( 2 ) African-American American 8 (19) 32 (20) Other 1 (1) 4 (2) Med (mean) FU 10.7 (19.20) 13.1 (17.6) 0.67 (T-test) Range (0.1-123.7) 123.7) (0.8-73.6)

Clinicopathological PD + VR (n=42) Standard PD (n=162) P-value Neoadjuvant CRT, n (%) Yes 23 (55) 73 (45) 0.26 ( ( 2 ) No 19 (45) 89 (55) Path Tumor Size (cm) Median (Mean) 3 (3.4) 2.5 (2.6) 0.002 (T-test) Range (1.5-7) (0-7)*

Clinicopathological PD + VR (n=42) Standard PD (n=162) P-value Neoadjuvant CRT, n (%) Yes 23 (55) 73 (45) 0.26 ( ( 2 ) No 19 (45) 89 (55) Path Tumor Size (cm) Median (Mean) 3 (3.4) 2.5 (2.6) 0.002 (T-test) Range (1.5-7) (0-7)*

Comorbidities Coronary Artery Disease PD + VR (n=42) Standard PD (n=162) P-value 6 (14) 23 (14) 0.99 ( ( 2 ) Diabetes 10 (24) 41 (25) 0.84 ( ( 2 ) COPD 7 (4) 0 (0) 0.17 ( ( 2 ) Chronic Renal Insufficiency 5 (3) 1 (2) 0.81 ( ( 2 ) Hypertension 20 (48) 78 (48) 0.95 ( ( 2 ) Congestive Heart Failure 1 (2) 3 (2) 0.83 ( ( 2 )

Clinicopathological PD + VR (n=42) Standard PD (n=162) P-value Neg Margins, n (%) 31 (73) 117 (72) 0.84 ( ( 2 ) Positive LN, n (%) 21 (50) 61 (38) 0.14 ( ( 2 ) Histological Grade (n=181), n (%) 1 Well Diff 2 Mod Diff 3 Poor Diff 4 (10) 21 (52) 15 (38) 22 (16) 75 (53) 44 (31) 0.59 ( ( 2 )

Clinicopathological Length of Stay Median (mean) Estimated Blood Loss ml Median (mean) (n=162) PD + VR (n=42) Standard PD (n=162) P-value 13 (15) 12 (15) 0.99 (T-test) 875 (1040) 550 (700) 0.001 (T-test) Readmission in 30 days, n (%) 15 (36) 49 (30) 0.50 ( ( 2 ) Mortality, n (%) 2 (5) 6 (4) 0.73 ( ( 2 )

Clinicopathological Length of Stay Median (mean) Estimated Blood Loss ml Median (mean) (n=162) PD + VR (n=42) Standard PD (n=162) P-value 13 (15) 12 (15) 0.99 (T-test) 875 (1040) 550 (700) 0.001 (T-test) Readmission in 30 days, n (%) 15 (36) 49 (30) 0.50 ( ( 2 ) Mortality, n (%) 2 (5) 6 (4) 0.73 ( ( 2 )

Morbidity PD + VR (n=42) Standard PD (n=162) P-value (X 2 ) PJ Leak 4 (9) 30 (18) 0.16 Delay Gastric Emptying 8 (19) 22 (14) 0.37 Abscess 10 (24) 20 (12) 0.06 DVT 7 (17) 8 (5) 0.01 GI Bleed 4 (9) 7 (4) 0.19 Wound Disruption 16 (38) 63 (38) 0.93 Reoperation* 8 (19) 28 (17) 0.80 Fascial Dehiscence 0 (0) 2 (1) 0.46 ECF 3 (7) 4 (2) 0.15 *Any operation related to initial Whipple operation

Morbidity PD + VR (n=42) Standard PD (n=162) P-value (X 2 ) PJ Leak 4 (9) 30 (18) 0.16 Delay Gastric Emptying 8 (19) 22 (14) 0.37 Abcess 10 (24) 20 (12) 0.06 DVT 7 (17) 8 (5) 0.01 GI Bleed 4 (9) 7 (4) 0.19 Wound Disruption 16 (38) 63 (38) 0.93 Reoperation* 8 (19) 28 (17) 0.80 Fascial Dehiscence 0 (0) 2 (1) 0.46 ECF 3 (7) 4 (2) 0.15 *Any operation related to initial Whipple operation

Morbidity PD + VR (n=42) Standard PD (n=162) P-value (X 2 ) C. Diff Infection 3 (7) 15(10) 0.67 MI 1 (2) 4 (2) 0.97 Biliary Leak 1 (2) 4 (2) 0.96 Perc Drain 9 (22) 25 (15) 0.33 Pneumonia 3 (7) 10 (6) 0.82 Arrhythmia 6 (14) 13 (8) 0.21

Univariate Analysis of Survival Log Rank Test of Equality Variable P-value Vascular Resection 0.89 Sex (F vs M) 0.98 Tumor Size > 2 cm 0.03 Neoadjuvant CRT 0.006 Perineural Invasion (n=192) 0.001 Vascular Invasion (n=183) <0.001 Positive Margins 0.01 Positive LN 0.001 Grade (High vs Moderate/Low) (n=181) 0.09

0.00 0.25 0.50 0.75 1.00 Overall Survival 0 20 40 60 Months after Surgery Control (162)

0.00 0.25 0.50 0.75 1.00 Overall Survival Log-rank test for equality of survivor functions p=0.89 0 20 40 60 Months after Surgery Control (162) PVR (42)

Multivariate Analysis PVR (n=40) Standard PD (n=137) Hazard Ratio 95% CI P-value Vascular Resection 0.78 0.49-1.23 0.28 Tumor Size (cont) 1.20 1.04-1.39 1.39 0.01 Neoadjuvant CRT 0.68 0.46-1.01 0.053 Positive Margins 1.30 0.87-1.94 0.20 Negative LN (Cont) 0.98 0.94-1.02 0.37 Positive LN (Cont) 1.11 1.00-1.22 1.22 <0.01 Grade (Cont) 1.35 1.01-1.81 1.81 0.01

Multivariate Analysis (No Grade) PVR (n=42) Standard PD (n=156) Hazard Ratio 95% CI P-value Vascular Resection 0.85 0.55-1.31 0.47 Tumor Size (cont) 1.12 0.99-1.28 0.08 Neoadjuvant CRT 0.72 0.50-1.04 0.08 Positive Margins 1.25 0.86-1.82 0.24 Negative LN (Cont) 0.98 0.95-1.01 0.29 Positive LN (Cont) 1.16 1.06-1.27 1.27 <0.01

SMV-PV Reconstruction Outcomes Status N % Patent 27 75 SMV/PV Occlusion 3 8 Narrowing or Partial Vein Occlusion 6 17

SMV-PV Reconstruction Outcomes 0.00 0.25 0.50 0.75 1.00 Duke Kaplan-Meier Estimate 0 20 40 60 Months After Reconstruction *Only patients with Post-operative operative CT analyzed. Hepatic artery reconstruction excluded.

Arterial Reconstructions 6 patients underwent arterial reconstruction. 5 with post-operative imaging 4 Thrombosed 1 Indeterminant

Patent Reconstruction 78 year old woman. Surgery 2/27/08 Technique Femoral Interposition Graft Path T3N0, Margin Negative Patent 5/12/09 Disease Free 5/18/10 Survival 26.6 months Complications: ED Visit for leg Edema and later a DVT.

Partial Occlusion 73 year old man. Surgery 8/26/98 Technique Primary Venorraphy. Path T2N0, Margin Negative Non-occlusive thombus 9/16/02 on surveillance CT. Recurrence 6/12/02. Death 9/17/02 Survival 48.2 months Complications: None significant

Early Partial Occlusion, Late Failure 52 year old woman. Surgery 3/19/08 Technique IMV Patch Path T3N0, Margin Negative Partial Occlusion - 12/1/08 Surveillance CT scan Total Occlusion - 7/13/09 Recurrence Confirmed - 5/15/09 Death 1/31/10 Survival 21.8 months Complications Wound Infection, Failure to Thrive early in post-operative course.

Early Failure < 6 months 66 year old woman. Surgery 10/21/08 Technique Femoral Interposition Graft Path T3N0, Margin Negative SMV Occluded 11/15/08 with collateralization. CT scan for fever workup. Recurrence 3/10/09 Hospice Care Survival 15.3 months Complications: None significant

Morbidity Defined as major complications including 30 day mortality, reoperation, Pancreatic leak, GI bleed, Abscess, Fluid collection, Pneumonia, and MI as previously described by Tseng et al. J Gastrointest Surg. 2004 Dec;8(8):935-49

Mortality

Median Survival

Negative Margins

Conclusions Patients undergoing vascular resection had slightly larger tumors. Vascular resection was associated with greater blood loss and likelihood being diagnosed with a lower extremity DVT. Perioperative mortality, readmission rates, length of stay, and overall complication rates does significantly differ between standard PD and PD with VR. Duke outcomes are equivalent or superior to other institutions.

Acknowledgments Dr. White Dr. Barbas Dr. Tyler Dr. Ceppa Dr. Pappas Dr. McCann Dr. Clary