1. Endoscopy in the Management of Pancreatic Cancer
Richard Kozarek, MD Digestive Disease Institute
Virginia Mason Medical Center
Seattle, Washington

2. Pancreas Cancer: The Problem
53,670 cases estimated in US in 2017
Lifetime risk of developing 1.5%
3rd highest cancer death rate in the US population
Worst survival statistics of any major cancer
5-year national survival rate (2007−13) 8.2%
5% of patients worldwide undergo resective surgery

5. GI Role Institutionally/ Skill Set DependentDx Dx
CT Staging
EUS
Staging Rx Rx
Primary GI Practice
Tertiary Referral Center

6. What is Not an Issue in 2017?
80% of patients require palliation for pancreatic cancer
EUS is the test of choice for tissue diagnosis
EUS celiac plexus block has replaced percutaneous route in pancreatic cancer
SEMS are preferable to plastic prostheses for palliation of MOJ in pancreatic cancer
There is no advantage to biliary decompression in the jaundiced patient with imminent resection

7. Endoscopic Ultrasound (EUS)

8. EUS is Particularly Useful in Detecting Small Lesions <3cm
EUS sensitivity
MDCT sensitivity
MRI sensitivity
Agarwal et al (81 pts, retrospective)
100%
86%
N/A
DeWitt et al (80 pts, prospective)
98%
For lesions <3cm
Muller et al. 1994
93%
53%
67%

9. EUS-FNA Has Largely Replaced CT-Core Bx for Pancreatic Mass
Retrospective review, VMMC 1/09-9/08
Negative EUS-FNA does not exclude malignancy
NPV 55-65%
May require repeat EUS, different sampling technique or CT-core Bx
EUS-FNA
CT-core Bx
No. of patients
260 47
Diagnostic accuracy
86%
84%
Hewitt et al. GIE Hebert-Magee et al. Cytopathology 2013

10. EUS Staging – Room for Improvement
T staging
- Accuracy 63 – 94%
N staging
- Sensitivity <65%
- Specificity >70%
M staging
- Right lobe of the liver is not visualized completely
DeWitt et al. WJG 2014.

11. EUS-FNA is Safe 8246 patients with pancreatic lesions
Pancreatitis 0.004% (75% were mild)
Pain 0.38%
Bleeding 0.1%
Fever 0.08%
Infection 0.02%
Peritoneal seeding of tumor cells 2.2%
Less than CT-Bx (16.3%)
Pre-op EUS-FNA NOT associated with increased needle track seeding or increased mortality
Wang et al. GIE 2011.
Micames et al. GIE 2003.
Ikezawa et al. GIE 2013.
Beane et al. Surgery 2011.

12. EUS-CPN/CPB Celiac plexus is located anterolateral
to the aorta near the
origin of celiac artery.
Celiac aa
aorta
Celiac ganglion

13. EUS-CPN/CPB in Pancreatic Cancer
Effective pain relief c/w conventional analgesia
Reduced analgesia use
*15% of patients may see no reduction in their use of narcotics
Multiple randomized controlled and meta-analyses8-12 have demonstrated that EUS-CPN provided effective pain relief in patients with pancreatic cancer compared with conventional analgesia.
There is also evidence that CPN reduces analgesia use. Two meta-analyses showed that CPN (either EUS or percutaneous approach) was associated with a significant reduction in narcotic use11,13. Additionally, a randomized controlled trial involving 96 patients with advanced pancreatic cancer reported that morphine consumption tended toward lower consumption at 3 months in the EUS-CPN group compared with a conventional treatment group11.
Nonetheless, approximately 15% of patients may see no reduction in their use of narcotics, and in this group, a repeat EUS-CPN has not been shown to be effective. A study of 24 patients with pancreatic cancer undergoing repeat EUS-CPN showed that repeat CPN was not as effective as index procedure in pain control (67% after the initial CPN vs. 29% at 1 month follow-up)14.
Arcidiacono PG, Calori G, Carrara S, McNicol ED, Testoni PA. Celiac plexus block for pancreatic cancer pain in adults. Cochrane Database Syst Rev 2011 : CD
Wyse JM, Carone M, Paquin SC, Usatii M, Sahai AV. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J Clin Oncol 2011; 29:
Yan BM, Myers RP. Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol 2007; 102:
Arcidiacono et al. Cochrane Database Syst Rev 2011.
Wyse et al. J Clin Oncol 2011.
Yan et al. Am J Gastro 2007.
McGreevy K et al. Pain Pract 2013.

14. EUS-CPN: Complications
Diarrhea
Hypotension
Abdominal pain
Rare but serious
- Paradoxical increase in pain
- Paralysis due to anterior spinal cord infection
- Necrotic gastric perforation
- Celiac artery thrombosis with infarction
Diarrhea, abdominal pain and hypotension (due to the disruption of the ANS)
Gunaratnam NT, Sarma AV, Norton ID, Wiersema MJ. A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain. Gastrointest Endosc 2001; 54:
Fujii L, Clain JE, Morris JM, Levy MJ. Anterior spinal cord infarction with permanent paralysis following endoscopic ultrasound celiac plexus neurolysis. Endoscopy 2012; 44 Suppl 2 UCTN: E265-E266.
Mittal MK, Rabinstein AA, Wijdicks EF. Pearls & oy-sters: Acute spinal cord infarction following endoscopic ultrasound-guided celiac plexus neurolysis. Neurology 2012; 78: e57-e59.
Loeve US, Mortensen MB. Lethal necrosis and perforation of the stomach and the aorta after multiple EUS-guided celiac plexus neurolysis procedures in a patient with chronic pancreatitis. Gastrointest Endosc 2013; 77:
García AZ, Elwassief A, Paquin SC, Sahai AV. Fatal complication after endoscopic ultrasound-guided celiac plexus neurolysis. Endoscopy 2012; 44 Suppl 2 UCTN: E267.
Jang HY, Cha SW, Lee BH, Jung HE, Choo JW, Cho YJ, JuHY, Cho YD. Hepatic and splenic infarction and bowel ischemia following endoscopic ultrasound-guided celiac plexus neurolysis. Clin Endosc 2013; 46:
A paradoxical increase in pain may occur in up to 9% of cases but generally resolves over several days18.
Rare but serious
Paralysis due to anterior spinal cord infection19,20
Necrotic gastric perforation21
Celiac artery thrombosis with infarction22,23
Gunaratnam et al. GIE 2001.
Fujii et al. Endoscopy 2012.
Mittal et al. Neurology 2012.
Loeve et al. GIE 2013.
Garcia et al. Endoscopy 2012.
Jang et al. Clin Endosc 2013.

15. Endoscopic Retrograde Cholangiopancreatography (ERCP)

16. Brush Cytology is Not Very Reliable

17. Main Role of ERCP in Pancreatic Cancer – Biliary Drainage
Plastic stent Metal stent
Source : 2010 JNCCN

18. Patency duration (mos)
Randomized Studies Comparing SEMS with Plastic Endoprostheses (PE) in Patients with Malignant Distal Strictures of the Biliary Tree
Patency duration (mos)
Dysfunction rate (%)

19. Preoperative Biliary Stenting
Van Der Gaag, et al (NEJM 2010;362:129): Prospective, randomized multi-center Dutch trial: PBD for 4-6 weeks vs early surgery
220 pts, 106 PBD endoscopically/96 early
↑ rate complix PBD, 76% vs 40%
PBD complix, 47% PBD vs 2%
Surgery-related complix, 47% PBD vs 38%
ō difference mortality, hospital stay
Conclusions:
Significant morbidity PBD
Comparable surgical outcomes with/without PBD
PBD not indicated routinely in resectable pts with obstructive jaundice with pancreatic neoplasms

20. Preoperative Biliary Stenting
Baron, Kozarek NEJM 2010;362:170
Initial success rates, ERCP <75%
Very high rates, pre-op cholangitis
Placement of SEMS preop, potential to improve outcomes
80% pts unresectable at diagnosis
Marginally resectable pts downstageable with SEMS
Placement of C-SEMS allows retrieval if Dx benign

21. What is Uncertain in 2017?
Are C-SEMS preferable to U-SEMS in the palliation of MOJ?
Does preoperative stenting in conjunction with neoadjuvant chemo improve resectability/affect survival in patients with borderline resectability?

24. Comparison of C-SEMS vs U-SEMS in the Management of MOJ
Lee et al. GIE 2013; 78:313
Outcome measures: time to recurrent biliary obstruction, survival, AE
749 patients, 171 C-SEMS, 578 U-SEMS
No significant difference in recurrent obstruction (35% vs. 38%), AE (28% vs. 28%), or survival (10.4 vs months)
↑ incidence of stent migration, pancreatitis C-SEMS

25. A RCT of a C-SEMS with Anti-Migration System Has Improved Patency vs U-SEMS
Kitano et al. Am J Gastroenterol 2013; 108:1713.
RCT 120 patients, 22 tertiary care centers, distal biliary obstruction from pancreatic cancer
Comparable survival time
Patient survival without stent dysfunction longer in the C-SEMS vs. U-SEMS (187 vs 132 days; p = 0.045)
Stent patency > C-SEMS (219 vs. 167 days; p = 0.047)
Comparable stent migration, pancreatitis, SAEs

26. Borderline Resectable Pancreatic Cancer Definition by AHPBA Consensus Criteria:
No distant metastases
May involve peripancreatic vessels as long as:
Not >180o SMA encasement
No celiac abutment
Any SMV/portal abutment/encasement as long as reconstructable
No aortic invasion or encasement
Adopted from Katz, JACS 2008
Callery, Ann Surg Onc 2009

27. VM Neoadjuvant Protocol
6 month course gemcitabine and docetaxol
16 cycles
Spaced 1−2 weeks apart
Toxicities include:
Nausea/vomiting
Pulmonary edema
Anemia/neutropenia

28. VM Neoadjuvant Protocol
VM Clinical Pathway
Biopsy +/- Stent
Laparoscopic Staging
VM Neoadjuvant Protocol
Restaged
Surveillance
Surgery
25-35%% are found to have peritoneal disease which would eliminate them from this study
Pts are restaged by CT scan and must show no evidence of progression or mets

29. Extended Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer
Bart Rose et al. Ann Surg Oncol 2014
64 patients VMMC with borderline pancreatic head cancer treated with 24 weeks of neoadjuvant chemotherapy.
39 (61%) underwent operative exploration
31 resected (48%)
27 (87%) RO resection
3 (10%) complete pathologic response
Median survival of all 64 patients 23.6 months (unresectable patients 15.4 months; 25 (81%) of resected patients still alive at median 22 months)
Conclusion: Extended neoadjuvant chemotherapy is well tolerated in borderline resectable pancreatic cancer and selects a subset of patients with favorable survival.

30. Tumor Response
Before
After
CA 19-9: 18,285
CA 19-9: 38

31. What is Uncertain in 2017?
What role does EUS play in the treatment of MOJ?
Is surgery really better than SEMS in palliating GOO?

32. EUS-Guided Biliary Drainage
ERCP successful in % of cases
When ERCP is unsuccessful
Percutaneous transhepatic biliary drainage (PTBD)
Surgical bypass
EUS-guided biliary drainage
ERCP for biliary access and drainage is successful in 90 to 95% of cases and is the preferred method of stenting the bile duct in obstructive jaundice from pancreatic cancer. In cases of unsuccessful ERCP due to difficult cannulation or altered anatomy, the alternatives have been precut papillotomy, percutaneous transhepatic biliary drainage (PTBD) and surgical bypass. Recently, EUS-guided biliary drainage has emerged as an alternative to these options. EUS-guided approach spares patients the discomfort of an external drain, and can be performed at the time of an unsuccessful ERCP, reducing the need for additional percutaneous interventions.

33. Park et al. Gastrointest Endosc 2013; 78:91
Prospective Evaluation of EUS-Guided Biliary Drainage after Failed ERCP
Park et al. Gastrointest Endosc 2013; 78:91
45 patients failed ERCP
41/45 (91% ITT) technical and functional success with intra/extrahepatic approach
Overall adverse event rate 11%

35. Endoscopic Palliation of Malignant Gastric Outlet Obstruction

37. Comparison Duodenal Stent Placement for Pancreatic vs Non-Pancreatic CA
Oh et al. Gastrointest Endosc 2015;82:460.
292 patients with malignant GOO – 196 patients pancreatic CA, 96 other causes.
↓ overall survival pancreatic CA 13.7 vs mo. (p=.004)
↓ clinical success rate 2 mos. (71% vs. 91%)
Comparable post-stent survival (2.7 vs. 2.4 mos.)
Post-SEMS chemoRx/absence of mets associated with ↑ survival (5.4 vs. 1.5 mo., p < .0001; 6.1 vs. 2.1 mos, p = .009).

38. GOO is a Poor Survival Indicator.
Post-stent survival <3
months in our series.
Clinical success 76% at
2 months.
Concurrent biliary
obstruction in ~2/3 of
patients with GOO due to pancreatic cancer.
Once GOO is diagnosed, mean life expectancy ranges from 7 to 20 weeks.2,11–14
2. Van Hooft JE, Dijkgraaf MG, Timmer R, et al. Independent predictors of survival in patients with incurable malignant gastric outlet obstruction: a multicenter
prospective observational study. Scand J Gastroenterol 2010;45(10):1217–22.
11. Cho YK, Kim SW, Hur WH, et al. Clinical outcomes of self-expandable metal stent and prognostic factors for stent patency in gastric outlet obstruction caused by
gastric cancer. Dig Dis Sci 2010;55(3):668–74.
12. Jeurnink SM, Steyerberg EW, Van Hooft JE, et al. Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction
(SUSTENTstudy): amulticenterrandomizedtrial. GastrointestEndosc2010;71(3):490–9.
13. Keranen I, Udd M, Lepisto A, et al. Outcome for self-expandable metal stents in malignant gastroduodenal obstruction: single-center experience with 104
patients. Surg Endosc [Epub ahead of print].
14. Kim HJ, Park JY, Bang S, et al. Self-expandable metal stents for recurrent malignant obstruction after gastric surgery. Hepatogastroenterology 2009;56(91/92):914–7.
GIE In Press.

39. Meta-Analysis Stenting vs GJ in Malignant GOO
Hosono et al., J Gastroenterol; 42:283
307 procedures/9 studies
Endoscopic Tx
Higher clinical success (p=0.007)
Shorter time to oral intake (p<0.001)
Less morbidity (p=0.02)
Lower incidence delayed gastric emptying (p=0.002)
Shorter hospitalization (p>0.001)
Comparable 30d mortality

40. What is the Future in Endoscopic Supportive Care?
Fiducials
PDT/chemo-laden stents
EUS facilitated GJ
EUS treatment for local control
TNFerade
RF ablation
Radioiodine seed placement

43. International MC Comparable Trial of EUS-GE Versus Surgical GJ for the Treatment of Malignant GOO
Khashab et al. Endosc Int Open 2017;5:E275
Retrospective 4 center trial 93 pts malignant GOO
—30 pts EUS-GE, 63 pts SGJ
Higher technical success SGJ (100% vs 87%)
Comparable clinical success (90% vs 87%)
Complix EUS (16 vs 25%)
Comparable LOHS
Comparable recurrent GOO
Comparable timing recurrent GOO

44. What is the Future in Endoscopic Supportive Care?
Recent FDA approval of Wallflex for Rx of MOJ in pancreatic cancer pts undergoing neoadjuvant Rx
Multicenter RCT trial C-Wallflex vs C-Wallflex for pts undergoing neoadjuvant Rx
Multicenter RCT pre-op biliary SEMS placement vs urgent surgery in MOJ

45. Conclusions
Endoscopic interventions provide non-invasive and effective palliation of jaundice, pain and GOO in patients with pancreatic cancer.
EUS has evolved as an important diagnostic and therapeutic tool for pancreatic cancer.
Malignant GOO remains a commonly encountered clinical entity. GOO is most
commonly diagnosed through an appropriate history, physical examination, imaging
studies, and evidence found during upper endoscopy. Treatment most commonly
includes open or laparoscopic surgical gastrojejunostomy, or enteral stent placement.Other treatment options include radiation, chemotherapy, nasoenteric tube placement,
and TPN.
Technical and clinical success rates for enteral stent placement are, in general,
extremely high. Complications include mild pain, fever, vomiting, perforation, fistula
formation, stent migration, stent obstruction, and hemorrhage and/or severe pain,
but major complications are relatively uncommon. Biliary stent placement should be
strongly considered concomitantly with enteral stent placement.
Enteral stent placement, in comparison with surgical options, is better suited for
patients with a shorter life expectancy and/or those patients who are poor surgical
candidates. Gastrojejunostomy is more beneficial in patients with resectable disease
and longer life expectancies. Enteral stent placement is a cost-effective procedure for
the palliation of GOO.

46. 9 4 3 2 5 7 1 6 8