TOTAL PANCREATECTOMY AND ISLET AUTOTRANSPLANTATION Disclosure AS - - PDF document

9/26/2018 1 TOTAL PANCREATECTOMY AND ISLET AUTOTRANSPLANTATION AS TREATMENT FOR CHRONIC PANCREATITIS

Andrew Posselt, MD, PhD

• Dept. of Surgery

University of California, San Francisco

Disclosure

The speaker has no conflicts of interest or financial ties to disclose.

Chronic Pancreatitis

A benign disease of the pancreas characterized by: * DEBILITATING PAIN * inability to eat & anorexia * malnutrition & weight loss * diabetes (endocrine insufficiency) * chronic relapsing symptoms

Pseudocyst Neural inflammation Ischemia PD obstruction with increased PD pressure Duodenal and common duct

• bstruction

Inflammation

Etiology - Adults

* ethanol use (>100 g/day) 60 - 70% * idiopathic 20 - 30% * other causes 10% pancreas divisum hereditary pancreatitis hyperlipidemia autoimmune pancreatitis genetic polymorphisms

cystic fibrosis transmembrane conductance regulator (CFTR) pancreatic secretory trypsin inhibitor (SPINK1)

* affects approx. 80,000 people per year * $ 65,000,000 annual cost * 87% adults (mean age 40-50y), 13% children * 25-fold increased risk of pancreatic cancer

9/26/2018 2

Etiology - Children

* Mean age: 14 y (35% 5-12 y, 65% 13-19 y) * 44% male, 56% female * 7-8 y Abdominal pain * 5-6 y Dx of CP * 1-2 y Narcotic use

Schwarzenberg et al., JPeds 2015

67% 33%

Time to Onset of Diabetes Mellitus

 50% at 10 years after symptom onset, 80% at 25 years  Many continue to be c‐peptide positive

Malka et al., Gastroenterol 2000

Diabetes Insulin requirement

Treatment Options

• Narcotic pain meds, enzyme replacement
• Endoscopic therapies
• sphincterotomy, stents, dilations
• Celiac plexus ablation
• chemical, surgical
• Surgical decompression (Puestow, Frey, Beger) or

partial resection (Whipple, distal)

• NOT effective in most pts
• Total Pancreatectomy
• Very effective in most pts, but results in

brittle diabetes

• Islet Autotransplant restores endocrine

function after TP (TP/IAT)

Indications for TP-IAT

 Painful chronic pancreatitis or disabling acute relapsing

pancreatitis refractory to medical/endoscopic therapy

 Narcotic dependence and/or significantly impaired quality of life  Imaging/EUS evidence of CP (MRI, MRCP, CT, ERCP) OR

relapsing acute pancreatitis (>3 episodes over 6 mos) OR hereditary pancreatitis w/ Sx

 Non-diabetic OR C-peptide positive diabetes  Patient and family accept (and can manage) risk of diabetes and

need for lifelong pancreatic enzyme replacement Contraindications:

• Active alcohol use (documented abstinence for >6mos)
• Illegal drug use
• Pancreatic cancer (maybe not IPMN)
• Advanced liver, lung, heart disease
• Relative – absent C-peptide

9/26/2018 3

Timing

 Earlier is better!  Prior to development of central sensitization and opioid-induced

hyperalgesia which can lead to pain recurrence

 Optimization of islet yield/function

 Prior to invasive surgical procedures (partial resection, ductal drainage)  Prior to glucose intolerance/diabetes  Early in course of disease to minimize fibrosis  Younger children (fewer post-op complications and higher islet yields)

MI 16 GA 4 TX 13

VT:0 NH:0 MA:3 RI :1 CT:0 NJ:8 DE:0

I D 2 AZ 61 UT MT W Y 1 NM 1 CO 5 AL 91 FL 11 SC: 33 TN: 9 KY: 3 I N 15 OH 132 NC: 4 SD 10 KS 6 NE 1 MN 409 W I 16 I A 5 I L 15 MO 8 AR 2 MS 1 O K 3 ND 4 OR 1 CA 50 NV 1 W A: 0 AK PA: 13 ME 2 VA: 8 NY 7 W V 1

M D N J VT N H M A D E

15+ 11-15 6-10 1-5 HI

LA 3 MI 17 GA 4 TX 15

VT:0 NH:0 MA:3 RI :1 CT:0 NJ:8 DE:0 MD:3

Number of Patients

DC: 0

TP/IAT Cases by State: 1977- 2013

Pediatric TP/IAT Cases by State: 1977- 2016

OH 14 MN 75 CA 14 PA 10

14-18 yrs 27: 5-12 yrs 48: 13-19 yrs 9-18 yrs 4-16 yrs

Multi-Disciplinary Team Is A MUST!

Gastroenterology Nursing Pain Management Endocrinology Islet Manufacture Social Work Surgery ICU Team

Patient

Psychiatry

9/26/2018 4 The Procedure

Patient’s OWN islets No risk of rejection No immunosuppression

Day 1 PCA IV Anti-emetics NG out/GT to gravity, NPO Insulin drip Ambulate to chair Consult Endocrine, Pain Svcs Day 2 PCA Start TF/enzymes IV Anti-emetics Insulin drip Ambulate x1 Order PT/OT Eval & Treat Day 3 PCA transition basal to long-acting TF/enzymes IV Anti-emetics Insulin drip Ambulate x3 Day 4-5 PCA transition to short acting elixir Oral pain meds TF at goal Bowel Regimen Start Lantus, D/C insulin drip Start Diabetic education Day 6 ADAT Start TF education/Discharge class Bowel Regimen Continue plan, eval for complications Day 7-8 Supplement education prn Continue plan, eval for complications Consider transfer to Home/Rehab when following are met: TF stable Adequate water intake to prevent IV depletion/dehydration Diabetes stable, not requiring daily titration of Diabetes therapy No surgical concerns Narcotic dose stable, < 3 extra IV doses/day

UCSF Inpatient Care Algorithm

TP-IAT at UMN



1.2% in-hospital mortality; 89% (adult) and 98% (child) 5-y survival



90% C-peptide pos., 33% partial function



30% insulin independent at 3 y (25% adults, 55% children)



Pain improved in 85% adults, 94% children (67% pain-free)



15.9% had complications requiring reoperation (bleeding, anastomotic leaks)

409 pts total 53 children (5-18y)

Sutherland et al., JACS 2012

Pain Relief

 In patients with CP whose pain persists after Endoscopic

Duct Drainage (EDD) procedures, TP-IAT can…

 Provide pain relief in the majority of patients  Give the chance to wean off narcotics  Preserve insulin secretion in most  Improve quality of life

 Effort is needed to identify in advance the few patients

whose life will not be made better by TP-IAT

9/26/2018 5 Durability of Pain Control

Genetic/Hereditary Nonhereditary

Pancreatitis pain Pain severity

QOL by SF-36 Assessment

QOL: Improved in 80%; Same in 15%; Worse in 5%  98% preferred diabetes to former pain  87% said pancreatitis was worse than diabetes  98% would have procedure again

School Attendance and Days of Impaired Activity

P<0.001 P<0.005  25-40% insulin independent in most large cohorts  Most insulin dependent patients have graft function

• Low insulin needs
• + C-peptide (nearly 90%)

 Benefit of islets, even if on insulin

• Stable glycemic control
• Avoid “brittle” (labile) diabetes
• Absent hypoglycemic episodes

Islet Function and Insulin Independence

Sutherland et al., Transplantation 2008 Ahmad et al., JACS 2005 Webb et al., Pancreas 2008 Sutherland et al., Transplantation 2008 Ahmad et al., JACS 2005 Webb et al., Pancreas 2008

9/26/2018 6 Durability of Islet Function

Insulin Requirements HbA1c

Wilson, et al., Ann Surg 2014

** VERY FEW pts developed diabetes-related complications

TP-IAT Particularly Effective in Children with CP

Narcotic Use Insulin Independence

Ped Ped Adult Adult

 Predictors:

• Islet number (mass/yield)
• 100% function, 70% independent with >5000 IE/kg
• 83% function, 30% independent with 2501-5000 IE/kg
• 59% function, 15% independent with <2500 IE/ kg
• Prior surgery
• Lower yield after surgical drainage/distal pancreatectomy
• Age
• Pediatric patients have high rates of insulin independence
• Other characteristics
• duration of disease, islet quality, insulin resistance

Who Becomes Insulin Independent?

Sutherland et al., Transplantation 2008 Ahmad et al., JACS 2005 Webb et al., Pancreas 2008

Insulin Independence and IEQ/Kg

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 6 months 12 months 24 months 36 months

<2500 2500‐5000 >5000 Allo

Sutherland et al., Transplantation 2008 Ahmad et al., JACS 2005 Webb et al., Pancreas 2008

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2000 4000 6000 8000 10000 12000 14000

0.0 5.0 10.0 15.0 20.0 IE/kg Age at Transplant (years)

Insulin Dependent Minimal Insulin Insulin Independent

High Likelihood of Insulin Independence in Young Children

 Children 5‐18 years of age:  44% ever achieve insulin independence  85% of children <10 years of age have

documented insulin independence

Islet Autotransplants Function Better Than Allotransplants

 Fewer islets needed needed (2500IE/kg vs. >7500IE/kg)  Most function >2yrs, approx 80% >3-4yrs; 70% >10yrs  No ‘late’ failures

Can’t be due to hepatic site

• Brain death
• Increased CIT
• Immunosuppression
• Alloimmunity
• Autoimmunity
• No precursors in

highly purified preps

• 32 adults since 2013 (8-10/y since 2016)
• 14 children (10 since 2015)
• 12 isolations for pts at UCLA
• Referrals from CA, NV, AL, AZ, CO, NY, TX, WA, Kaiser

UCSF Experience

• Mean hospital stay: 16d (10-60d)
• Readmissions: 2 within 30d, 3 within 6 mos
• Complications: bleeding (2), SBO (2), N/V (1)
• Mean IEQ/kg: 5700+2000 (a),7,400+176,000 (p)
• Insulin independence: 60% adults, 87% peds
• Pain control: 60% adults off meds, 40% weaning

100% peds off meds

Insurance Coverage is a Problem!

 All carriers cover TP, but only some cover AIT  AIT adds approx. $27,000-30,000 to overall cost.  OR time not significantly prolonged since isolation is

performed during biliary and intestinal reconstruction, and infusion takes approx. 20 mins.

 Overall LOS, hospitalization costs not significantly

increased

 QOL dramatically increased with AIT even if

independence is not achieved, but most pts cant raise adequate funds to cover procedure.

9/26/2018 8

Summary – TP/IAT

 TP/IAT is very effective in relieving pain while

minimizing risk of labile diabetes

 Diabetes outcomes are best with high yield,

surgically naïve pancreas, young children

 Long-term insulin independence and robust

insulin secretory capacity are feasible

 Overall benefit of the procedure is markedly

compromised w/o IAT

Thank You!

Islet Isolation:



Florinna Dekovic



Vinh Nguyen



Greg Szot Clinical Team:



Mustafa Arain



James Ostroff



Emily Perito



Sue Rhee



Steve Gitelman



Roger Long



Umesh Masharani



Michelle Klosterman



Giulia Worner



Mario DePinto



Aurora Bermudez



Kara Campbell



Takoui Kechedjian



The Transplant Surgeons