St. John Providence Health System 2013 GI Cancer Symposium Advanced Surgical Techniques For Pancreatic Cancer Dr. Janak Parikh, MD, MSHS November 2, 2013 St. John Providence Health System

Overview Background Basic Whipple Operation History Resection criteria 2013 GI Surgery Symposium Overview Background Basic Whipple Operation History Resection criteria Technique (Pylorus-Preservation vs. Classic) Advanced Whipple Operation Vascular resection/reconstruction Laparoscopic Whipple Robotic Whipple Distal Pancreatectomy Technique (w/ or w/o splenectomy, Appleby) Minimally invasive (Laparoscopic, Robotic)

Incidence and Mortality 2013 GI Surgery Symposium Incidence and Mortality 45,000 new cases in US in 2013 3% of malignancies in the United States Fourth leading cause of cancer death in the United States

Most patients are treated with palliative therapies 2013 GI Surgery Symposium Pancreatic Cancer High incidence of regionally advanced and metastatic disease Only 10-15% pts have resectable disease Head 60% Body/Tail 40%   20% resectable <5% resectable   20% 5-yr survival <15% 5-yr survival   <3% alive at 5 years Most patients are treated with palliative therapies

Historical Context (1985-2008) 2013 GI Surgery Symposium Historical Context (1985-2008) By way of introduction, while pancreatic cancer accounts for only 2% of all new cancers diagnosed in the United States, it remains the fourth leading cause of cancer-related death in both men and women. Because it is usually diagnosed at an advanced stage, survival rates remain poor compared to that in other types of cancer. The overall incidence and mortality rates in pancreatic cancer have changed little over the past three decades although evidence suggests that both the incidence and death rate have increased slightly since 2003. In 2007, an estimated 37,130 individuals will be diagnosed with pancreatic cancer and an estimated 33,370 deaths will occur as a result of this disease. It is estimated that approximately $1.5 billion is spent in the United States each year on the treatment of pancreatic cancer. Here’s data form the National Cancer Institutes SEER Program showing essentially parallel incidence and morality rates for pancreas cancer over a twenty-three year period of time. Incidence and Mortality Rates 1985-2008 NCI’s SEER Program http://www.seer.cancer.gov/ 5

Fewer Than 1/3 Of Resectable Patients Receive Surgery 2013 GI Surgery Symposium Fewer Than 1/3 Of Resectable Patients Receive Surgery

Pancreatoduodenectomy—Whipple Operation 2013 GI Surgery Symposium Pancreatoduodenectomy—Whipple Operation History and Evolution

History of Pancreatoduodenectomy 2013 GI Surgery Symposium History of Pancreatoduodenectomy George Hirschel (1914) OttorinoTenani (1922) Friedrich Trendelenburg (1882) Allan O. Whipple (1935) Walter Kausch (1909) Allesandro Codivilla (1898)

2013 GI Surgery Symposium “Whipple Operation” Allen Oldfather Whipple

1960’s – 1970’s High perioperative morbidity Hospital mortality – 25% 2013 GI Surgery Symposium 1960’s – 1970’s High perioperative morbidity Hospital mortality – 25% Long term survival for pancreatic cancer – 5% Calls to abandon PD for pancreatic cancer Crile, Surgery Gyn Obstet 1970;130:1049-53

Improving the Whipple Operation 2013 GI Surgery Symposium Improving the Whipple Operation The real key to the paper from Hopkins is that Dr Cameron followed up on this initial report by assembling a talented group of GI surgeons and began to assimilate an experience that was unrivaled and audacious. 145, 201, 650, the numbers Began rolling out and with them lower and lower morbidity and mortality rates, and higher survival rates. This Japanese also got caught up in this numeric proliferation. The end result of this technological frenzy was set of standards proposed for surgeons doing pancreatic resections which harkens back to the pleas made by Howard and Crile. 11

Pancreatic Surgery Is Safe At High-Volume Hospitals 2013 GI Surgery Symposium Pancreatic Surgery Is Safe At High-Volume Hospitals This seminal paper reviewed over 2.5 million medicare patients undergoing cv and cancer operations between 1994 and 1999. Notably, pancreatic resection (with esophagectomy) were the two cancer operations in which dramatic differences in mortality were seen between low and high-volume hospitals NEJM 2002;346(15):1128-37

Long-Term Survival Better At High-Volume Hospitals 2013 GI Surgery Symposium Long-Term Survival Better At High-Volume Hospitals P=0.001 High Volume Hospital Low Volume Hospital A number of studies have demonstrated that surgical resection at high-volume centers is associated with improved short term survival. Whether long-term survival after resection for cancer are superior at high-volume centers is unknown. Fong, Ann Surg 2005; 242:540-7

High-Volume Surgeons Have Better Outcomes 2013 GI Surgery Symposium High-Volume Surgeons Have Better Outcomes

Pancreatoduodenectomy—Whipple Operation 2013 GI Surgery Symposium Pancreatoduodenectomy—Whipple Operation Evolution of Operative Techniques

Is Diagnostic Laparoscopy Necessary? 2013 GI Surgery Symposium Is Diagnostic Laparoscopy Necessary? Used less often with the evolution of imaging quality. Considered when: Marked weight loss Very high CA19-9 Pain Frail patient

Steps of the Whipple Abdominal exploration to r/o occult metastases. 2013 GI Surgery Symposium Steps of the Whipple Abdominal exploration to r/o occult metastases. Mobilization of duodenum and head of pancreas. Check for aberrant anatomy. Isolation of bile duct, GDA, pylorus. Tunnel under neck of pancreas.

2013 GI Surgery Symposium The Resection

2013 GI Surgery Symposium The Reconstruction

Pylorus Preserving vs. Classic Whipple? 2013 GI Surgery Symposium Pylorus Preserving vs. Classic Whipple?

Theoretical Advantages 2013 GI Surgery Symposium Theoretical Advantages Pylous –preservation More physiologic Less dumping Classic Better tumor clearance

Reality You can do it however you want. No difference in DGE 2013 GI Surgery Symposium Reality You can do it however you want. No difference in DGE No difference in wt loss/wt gain Everything evens out at around 6-8 weeks

Methods of Reconstruction 2013 GI Surgery Symposium Methods of Reconstruction Pancreatojejunostomy Most common reconstruction More physiologic Pancreatogatrostomy Lower leak rate Access to PD Techniques Duct-to-mucosa Invagination Externalization

Externalizing the Pancreatic-Enteric Anastomosis 2013 GI Surgery Symposium Externalizing the Pancreatic-Enteric Anastomosis Used by some for high-risk patients: Soft gland Small duct Frail patient

Palliation of Pain with Alcohol Splanchnicectomy 2013 GI Surgery Symposium Palliation of Pain with Alcohol Splanchnicectomy Lillemoe, et al. Ann Surg 217:447-457, 1993

2013 GI Surgery Symposium Vascular Resection Venous resection is acceptable to achieve an R0 resection. Arterial resections not recommended. Associated with increased blood loss, increased transfusions, increased OR time, and increased morbidity. No difference in mortality

2013 GI Surgery Symposium Vascular Resection Most require partial vein resection with primary repair. Reconstruction options include: Oversew or patch end-to-end vs. interposition graft (internal jugular vein, left renal vein, PTFE) Postop anticoagulation varies by surgeon: none, ASA/plavix, coumadin

Methods of Reconstruction 2013 GI Surgery Symposium Methods of Reconstruction Tseng, JF, et. al. Pancreaticoduodenectomy With Vascular Resection: Margin Status and Survival Duration, J GASTROINTEST SURG 2004;8:935–950 Harrison, LE, et. al. Isolated Portal Vein Involvement in Pancreatic Adenocarcinoma A Contraindication for Resection? ANNALS OF SURGERY 1996 Vol. 224, No. 3, 342-349

Methods of Reconstruction 2013 GI Surgery Symposium Methods of Reconstruction

Venous Resection in Pancreas Cancer 2013 GI Surgery Symposium Venous Resection in Pancreas Cancer Author N Op Mort. Vessel Invasion 1 yr. survival Median Survival Ishikawa 35 6% 86% n.r. 9 Takahashi* 79 17% 61% 38% 14 Roder 31 0% 77% 20% 8 Tseng 141 2% 72% 23 Harrison 58 5% 59% 13 Yekebas 136 4% 73% 58% 15 I.U. 73 3% 65% 71% These are some of the representative series reported in the literature utilizing portal vein resection for pancreatic adenocarcinoma. There patient numbers are low, but reasonable, and except for the series by Takahashi which included both venous and arterial reconstructions in their data, the mortality rate is no different than patients who do not undergo portal vein reconstruction. Of note, is the high incidence of transmural venous invasion in both the Japanese and European experience. Harrison’s report from Memorial Sloan Kettering and our own Series did not assess the histologic venous invasion. The one year survivals are respectable, and the median survivals, except for the experience Of Ishikawa and Roder are similar to the standard Whipple. Portal venous resection and reconstruction can be done with acceptable morbidity and mortality. These patients must be carefully selected to maximize the opportunity to achieve a margin negative resection. Although this type of operation has not been shown to improve survival, it has similar survival to patients who undergo the standard operation

Minimally Invasive Pancreatoduodenectomy 2013 GI Surgery Symposium Minimally Invasive Pancreatoduodenectomy

Benefits of Laparoscopic Surgery 2013 GI Surgery Symposium Benefits of Laparoscopic Surgery Less post-operative pain Less post operative ileus Preserved immune function Decreased stress response Shorter hospital stay Improved cosmesis Decreased complications ? Faster time to receipt of chemo?

Drawbacks Learning curve Increased operative time Laparoscopic U/S 2013 GI Surgery Symposium Drawbacks Learning curve Increased operative time Laparoscopic U/S ? Cost ? Risk ? Malignancy Extent of resection Adequate surgical margins Lymph node basin dissection Port site recurrence

Laparoscopic Whipple First performed in 1994 by Gagner and Pomp. 2013 GI Surgery Symposium Laparoscopic Whipple First performed in 1994 by Gagner and Pomp. Coversion rate 40% OR time 8.5h Authors concluded no advantage

Laparoscopic Whipple 7 centers report more than 30 lap Whipples. 2013 GI Surgery Symposium Laparoscopic Whipple 7 centers report more than 30 lap Whipples. Feasibility established Lower EBL, fewer wound complications, shorter LOS Increased OR time (541 min vs 401min) No difference pancreatic fistula rates, overall complications, DGE, or mortality.

2013 GI Surgery Symposium Laparoscopic Whipple

Outcomes for Laparoscopic Whipple 2013 GI Surgery Symposium Outcomes for Laparoscopic Whipple Conv Lap Op Time Comp LOS Panc Author Year N (%) Recon (%) (Min) (days) Can (%) Gagner 1997 10 40 60 510 30 22.3 Dulucq 2006 25 12 50 287 32 16.2 44 Palanivelu 2007 42 100 370 31 10.1 21 Pugliese 2008 19 461 37 18 58 Kendrick 2010 65 4 95 368 7 47 40 of 42 for Palanivelu for malignancy

Robotic Whipple Advantages vs. Laparoscopic Whipple: 2013 GI Surgery Symposium Robotic Whipple Advantages vs. Laparoscopic Whipple: Better visualization (3-D) More precise suturing Disadvantages Steep learning curve Longer operative time Need for 2 experienced surgeons

Robotic Whipple Largest experience from U of Pitt (n=132). 2013 GI Surgery Symposium Robotic Whipple Largest experience from U of Pitt (n=132). 30-day mortality 1.5% 90-day mortality 3.8% Minor complications: 41% Major complications: 21%

Robotic Whipple HJ leak: 2% DJ leak: 6% Bleeding: 3.7% 2013 GI Surgery Symposium Robotic Whipple HJ leak: 2% DJ leak: 6% Bleeding: 3.7% Pseudoaneurysm: 14.8% Grade B fistula: 3.7% Grade C fistula: 3.7%

Robotic Whipple Mean OR time 527 min (360min last 50) Conversion: 8% 2013 GI Surgery Symposium Robotic Whipple Mean OR time 527 min (360min last 50) Conversion: 8% Reoperation: 3% LOS: 10 days Readmission: 28%

Distal Pancreatectomy 2013 GI Surgery Symposium Distal Pancreatectomy

Body/Tail Cancers Tend to present later and with larger tumors. 2013 GI Surgery Symposium Body/Tail Cancers Tend to present later and with larger tumors. Most will be metastatic at time of presentation (10-15% surgical candidates). Diagnostic laparoscopy performed for most (esp. w/ large tumors, high CA 19-9, debilitated patients)

Is Splenectomy Necessary? 2013 GI Surgery Symposium Is Splenectomy Necessary? Splenectomy is required during resection for malignancy to obtain adequate lymph node harvest. For premalignant or benign lesions, spleen-preservation attempted when possible. Warshaw technique: splenic artery and vein ligation without removal of spleen

Laparoscopic Approach Is Standard of Care 2013 GI Surgery Symposium Laparoscopic Approach Is Standard of Care Associated with: Decreased complication rate Decreased blood loss Shorter LOS Higher splenic preservation rate

Laparoscopic Distal Pancreatectomy 2013 GI Surgery Symposium Laparoscopic Distal Pancreatectomy

Robotic Distal 30-, 90-day mortality: 0% Minor complications: 59% 2013 GI Surgery Symposium Robotic Distal 30-, 90-day mortality: 0% Minor complications: 59% Major complications: 13% Grade B fistula: 12% Grade C fistula: 4.8%

Robotic Distal OR time: 256 min LOS: 6 days Readmission: 28% 2013 GI Surgery Symposium Robotic Distal OR time: 256 min LOS: 6 days Readmission: 28%

2013 GI Surgery Symposium Appleby Procedure Originally described for locally advanced gastric cancer. Involves en-bloc resection of celiac axis, body/tail of pancreas and spleen. All should undergo neoadjuvant therapy before attempting an Appleby procedure.

Appleby: Plane of Resection 2013 GI Surgery Symposium Appleby: Plane of Resection Bonnet, S. et. al. Indications and surgical technique of Appleby's operation for tumor invasion of the celiac trunk and its branches. Journal de Chirurgie. Volume 146, Issue 1, February 2009, Pages 6–14

2013 GI Surgery Symposium Surgical Outcomes in 2013

Pancreatic Surgery Is Safe 2013 GI Surgery Symposium Pancreatic Surgery Is Safe 1423 Pancreaticoduodenectomies for Pancreatic Cancer N Mortality Morbidity Overall 1175 2% 38% 1970’s 23 30% - 1980’s 65 5% 1990’s 514 31% 2000’s 573 1% 45% Winter JM, et al. J Gastrointest Surg 2006, 10:1199-1210

Long-Term Survival Remains Poor 2013 GI Surgery Symposium Long-Term Survival Remains Poor Author Year N Median survival 5 year survival 10 year survival Predictors Ahmad 2001 116 16 mo 19% - Adj tx Cleary 2004 123 14 mo 15% 4% Stage, grade Winter 2006 1175 18 mo 18% 11% Size, LN, margin, grade Han 15 mo 12% Stage, margin Ferrone 2008 618 5% Stage, Margin

2013 GI Surgery Symposium Paradigm Shift? Neoadjuvant therapy for all patients with pancreatic adenocarcinoma. Potential benefits: Avoid surgery in patients with widely micrometastatic disease Down-size tumor to avoid vein resection Examination of tumor biology

Paradigm Shift? Opposition: 2013 GI Surgery Symposium Paradigm Shift? Opposition: Resectable patients progress to unresectable Complications of chemo prevent/delay surgery, increase complications

Pre-Operative Therapy Selects Patients Better than Upfront Surgery 2013 GI Surgery Symposium Pre-Operative Therapy Selects Patients Better than Upfront Surgery Surgery was avoided in 25-35% of the patients; their median survival was 7-10 mo. Local failure occurred in 10-25% of patients undergoing resection; suggesting radiation may have a role in preoperative setting. Avoids surgery in patients with rapidly progressive disease (unfavorable tumor biology). Avoids surgery in patients unable to tolerate the stress of pre-operative therapy (those revealed to be unfit). Protocol Regimen Number of pts Resection Rate Overall Survival MDA 98-020* Gem/XRT 86 74% 34 mo 01-341^ Gem/Cis 90 66% 31 mo Thus, our group at the University of Texas, MD Anderson Cancer Center has been interested in evaluating the role of preoperative chemoradiation in those patients who appear to have potentially resectable disease. This strategy allows all patients to undergo preoperative therapy and provides for early treatment of microscopic metastatic disease. Morevover, it provides an interval of time to observe for the development of overt metastatic disease which may not have been apparent at the time of presentation. The morbidity of surgery is thereby avoided n those patients with rapidly progressive disease. Lastly, since pancreatic cancer often develops in elderly patients with medical comorbidities, it provides an opportunity to observe patient tolerance to preoperative therapy as a predictor of tolerance to surgery. *Evans DB, et al. JCO, 2008 ^Varadhachary GR, et al. JCO, 2008

Pancreatic Cancer in 2013 Surgery can be done safely 2013 GI Surgery Symposium Pancreatic Cancer in 2013 Surgery can be done safely Venous resection acceptable for R0 rxn. Minimally invasive distal pancreatectomy should be standard of care. Minimally invasive Whipple feasible, safe at selected centers. Need better systemic therapy to impact long-term survival.

St. John Providence Health System 2013 GI Cancer Symposium Advanced Surgical Techniques For Pancreatic Cancer Dr. Janak Parikh, MD, MSHS November 2, 2013 St. John Providence Health System