pancreatic cancer –recent progress - … cancer –recent progress richard d. schulick, md, mba,...

Pancreatic Cancer – Recent Progress

Richard D. Schulick, MD, MBA, FACSProfessor and Chair of Surgery

Mountain States Cancer ConferenceNovember 5, 2016

Colorectal Cancer Metastases to Liver

Disclosures

Co-inventor of patent to use genetically modified Listeria monocytogenes to generate inflammatory response to cancer

Licensed to Aduro BiotechManaged by Johns Hopkins University

Board of Noile ImmuneNot compensated

Consultant to grandrounds.comProvide remote second opinions for surgical

oncology cases

Colorectal Cancer Metastases to LiverPancreatic Cancer Incidence and Death

in USA 2016

USAIncidence: 53,000Deaths: 42,000


Distal Pancreatectomy for Body and Tail Cancer

Colorectal Cancer Metastases to LiverPancreaticoduodenectomy for Head and

Uncinate Cancer


Historical Perspective

1898William S. Halsted1st Chair of Surgery at Johns Hopkins1st successful resection of ampullary cancer

in jaundiced patientTransduodenal local resectionReanastamosed pancreatic and bile ducts to

duodenumPatient redeveloped jaundice 3 months later

requiring reoperation and cholecystoduodenostomy

Patient died 6 months later of recurrence

Halsted, Boston Med Surg J, 1898



1909Walter KauschProfessor of Surgery of Viktoria Hospital in

BerlinFirst successful 2-stage en bloc resection

of head of pancreas and duodenumPatient presented with obstructive jaundice

from ampullary cancer1st stage – cholecystojejunostomy and

side-to-side enteroenterostomy2nd stage – resection of head of pancreas,

pylorus, and 1st and 2nd portions of duodenum

Reconstructed with gastroenterostomy, closure of common bile duct, and anastomosis of pancreatic remnant to 3rd portion of duodenum

Patient died 9 months later of cholangitiswithout visible tumor at autopsy

Kausch, Zentralbl Chir, 1909



1935

Allen O. Whipple

Professor and Director of Surgery Presbyterian Hospital, New York (1921 – 1946)

Clinical Director Memorial Hospital, New York (1946 – 1951)

Reported 3 patients with ampullary cancer managed by 2-stage pancreaticoduodenectomy

3 patients survived 30 hours, 8 months, and 25 months

Whipple, Ann Surg, 1935



Two-stage procedure reported in 1935 One-stage procedure reported in 1942

Whipple, Ann Surg, 1935 Whipple, Rev Surg, 1963



Pancreaticoduodenectomy during the 1940’s – 1970’sMany centers reported:Operative mortalities 20 – 40 %Postoperative morbidities 40 – 60 %

Pancreaticoduodenectomy during the 1980’s – presentMany centers reporting operative mortalities 1 – 2 %

Postoperative morbidities remain high 30 – 50%

John Cameron MD Murray Brennan MD

Colorectal Cancer Metastases to LiverPancreaticoduodenectomies Performed at

Johns Hopkins per Year

0

50

100

150

200

250

300

1980 1985 1990 1995 2000 2005 2010

Whipples


0.1

.2.3

.4.5

.6.7

.8.9

1.0

Proportion Surviving

0 12 24 36 48 60months

1970s 1980s1990s 2000s

Survival - Pancreaticoduodenectomy for DuctalAdenocarcinoma per Decade

n=23

n=65

n=573n=514

Winter, JoGS, 2006

Colorectal Cancer Metastases to LiverImportance of Hospital Volume in Management

of Pancreas Cancer

Health Services Cost Review Commission (HSCRC) Data in the State of Maryland from 1995-2004

Hospital Discharges for State of Maryland after Pancreaticoduodenectomy

Data collected:Number of PD’s performedPresurgical morbid condition of patientsPostoperative mortalityPostoperative morbidity


Mortality (n=2939)

0

20

40

60

80

100

120

1 to 10 11 to 29 >30

Hospital volume/year

Percent mortality

AliveDead

Importance of Hospital Volume in Management of Pancreas Cancer

p < 0.001

(38 Hosp) (2 Hosp) (1 Hosp)


0

20000

40000

60000

80000

100000

1 to 10 11 to 29 >30

Hospital volume/year

Total charges/case $44,533 $79,622 $33,158

Importance of Hospital Volume in Management of Pancreas Cancer

Hospital Charges per Case (n = 2939)

p < 0.001

(38 Hosp) (2 Hosp) (1 Hosp)

Colorectal Cancer Metastases to LiverWhat Needs to be Accomplished in the Next

Decade?

Impact on SurvivalBetter understanding of molecular events and impaired pathways leading to disease

PreventionEarlier detectionMore effective systemic therapiesMultidisciplinary care of patients

Impact on Quality of Life and Morbidity of SurgeryProper use of laparoscopic pancreatectomy


Better Understanding of Molecular Events and Impaired Pathways Leading to Disease

Colorectal Cancer Metastases to LiverModel of Progression from Normal Cell to

Metastatic Pancreatic Cancer

Iacobuzio-Donahue, Clin Ca Res, 2012

Colorectal Cancer Metastases to LiverCore Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

(n=24)24 patients20,661 genes analyzed by sequencing1327 had at least one mutation148 had two or more mutationsHigh number of alterations per cancer/patient

Jones, Science, 2008Bert Vogelstein MD

Colorectal Cancer Metastases to LiverCore Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

(n=24)

Majority of pancreatic cancers have genetic alterations in 12 partially overlapping processes

Pathway components that are altered in any individual tumor vary widely

Unlike other neoplasms, driven by a single targetable oncogene, pancreatic cancer result from alterations of a large number of pathways and processes

Best hope for therapeutics will be in discovery of agents that target physiologic effects of altered pathways and processes rather than individual genes Jones, Science, 2008

BRCA mutational signature burdencorrelates with response to platinumand PARP inhibitors


Prevention of Pancreatic Cancer


Risk Factor Odds Ratio 95% CIFormer Smoker 1.29 1.07 - 1.54Current Smoker 3.40 2.28 - 5.07Diabetes 2.54 1.87 - 3.46Long-standing Diabetes 3.09 2.02 – 4.72Diabetes and Current Smoker 4.79 3.00 – 7.65Long-standing Diabetes and Current Smoker 6.03 3.41 – 10.85


Earlier Detection:Patients with Premalignant CystsPatients in High Risk Families


Earlier Detection

Colorectal Cancer Metastases to LiverPrevalence of Unsuspected Pancreatic Cysts (CT)

Laffan, AJR, 2008

Colorectal Cancer Metastases to LiverCystic Lesions of the Pancreas

Intraductal

Papillary

Mucinous

Neoplasm

Mucinous

Cystic

Neoplasm

Serous

Cystadenom

a

Solid and

Pseudo-

Papillary

Neoplasm

Lymphoepitheli

al Cyst

Cystic Neuro-

Endocrine

Tumor

Cunningham, Schulick, WJGISurg, 2010


IPMN - Introduction

Develops from pancreatic ductal epithelium:• Mucin production• Cystic dilatation of pancreatic duct• Intraductal papillary growth

World Health Organization in 2000 classified these tumors as IPMNIPMN further classified histologically:

• Adenoma (benign)• Borderline (moderate dysplasia)• Carcinoma in situ (high grade dysplasia)• Malignant (carcinoma)

Sohn, Ann Surg, 2004


IPMN - Introduction

IPMN can further be classified by location

Main duct Branch duct


IPMN – Diagnostic Workup

Traditionally•ERCP with classic triad:

•Bulging ampulla of Vater•Mucin production•Dilated pancreatic duct

Presently•Multi-slice CT scan•EUS + FNA

Other tests•MRI/MRCP + secretin•Pancreatic ductoscopy

Tanaka, Pancreatology, 2005Tanaka, J Gastroent, 2005

Kawamoto, Radiographics, 2005

Colorectal Cancer Metastases to LiverMain Duct IPMNs More Aggressive Than

Branch Duct IPMNs

Tanaka, Pancreatology, 2006

Main Duct IPMN Branch Duct IPMN


Colorectal Cancer Metastases to LiverFamilial Pancreatic CancerHereditary Pancreatic Cancer

Syndromes of Chronic Inflammation

Templeton, SurgClinN Am, 2013


More Effective Systemic Therapies:Adjuvant TherapyImmunotherapy


Adjuvant Therapy of Pancreatic Cancer

Adjuvant therapy for pancreas cancer has become standard of care (GITSG, EORTC, ESPAC-1,CONKO-001, ESPAC-3, RTOG 97-04)

• Single-agent gemcitabine• 5FU/Leucovorin (S-1)Unresolved questions• Does chemoradiotherapy impact overall survival?• Does addition of a second or third cytotoxic or biologic agent improves outcome when added to gemcitabine?


Li, O’Reilly, Surg Onc Clinc N Am, 2016


KD:~100nM

CD112R/CD112

APC/Tumor

T, NK cell

CD155 CD112

CD226 TIGIT CD112R+ -‐ -‐

More Effective Systemic Therapies

Colorectal Cancer Metastases to LiverTargeting the CD112R pathway promotes antitumor response in mouse tumor model

CD112R

CD4

CD8

dLNs TILs

0

20

40

60

80

CD112R+%

CD4+ CD8+

**

**0

20

40

60

80

CD112R+%

***

0

10

20

30

40

50

CD112R+%

***

0

20

40

60

80

100 **

0

20

40

60

80 **

0

20

40

60

80 *

0

20

40

60

80 *

TIM-3 LAG3PD1

CD112R

CD8+ T cell

CD4+ T cell

A. B.CD112R is upregulated on TILs, and is co-expressed with other immune checkpoints

control amCD112R

0

1 0 0

2 0 0

3 0 0

4 0 0

Number of Nudules *

CD112R blockade improves anticancer immunity in a lung metastasis mouse model

CD112R CD112

aCD112R

More Effective Systemic Therapies

Colorectal Cancer Metastases to LiverThe CD112R complex holds significant potential as a novel therapeutic target

• CD112 expression and CD112R binding confirmed in multiple cancer models• Multiple reagents identified with encouraging initial data (mAB, CAR-T, Fusion Protein)• Preparing additional in vivo data

Proof of Principle

• University owned IP filed around compositions and methods• Background IP available through partnership• World class know-how in cell surface signaling, immunology and cancer

Intellectual Property

40

• Big Pharma: Merck, GSK, ONO• Startup and investors: Argenx, NextCure, Topokine,

Industrial Enthusiasms

PDAC0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

Melanoma

A B

Positive: 9/9

Expression Units

Positive: 7/9 TIL

PBMC

CD3control

CD112R

C

The CD112R pathway is heavily expressed in human cancers

CD112 CD112 CD112R


Borderline Resectable Pancreatic Cancer


TH 64 yo Female – June 2012

Colorectal Cancer Metastases to LiverDefinition of Borderline Resectable

Pancreatic AdenocarcinomaBorderline Resectable

•No distant metastases•Venous (SMV + PV)

•Abutment (< 180°)•short segment encasement (> 180°)•short segment occlusion with suitable

access for reconstruction

•Arterial (hepatic and superior mesenteric)

•SMA: Abutment (< 180°) but not encasement (> 180°)•HA: Short segment abutment (<180°) or encasement (>180°)

Evans, Schulick, Ann Surg Onc, 2009


TH 64 yo Female – Oct 2012


TH 64 yo FemaleUnderwent pancreaticoduodenectomy with resection of portal, superior mesenteric, and splenic vein confluence.

Portal and superior mesenteric vein reconstructed primarily with ligation of splenic vein

Path T3N1M02.8 cm adenocarcinoma5/16 LN positiveCancer did not infiltrate vein wall, but densely

adherentMargin negative

Patient survived 30 months and then died of metastatic disease


17/18 went to resection and R0


Progression Free Survival Overall Survival

Overall Survival and R

R0

R1

Overall Survival and Cycles

>12

8-114-7

1-3

• Long operative times and prosthetic grafts are risk factors

• Preferentially use primary, patch, vein interposition repair


Multidisciplinary Care of Pancreatic Cancer Patients

Colorectal Cancer Metastases to LiverTraditional Model of Taking Care of

Pancreatic Cancer Patients

Diagnosis

Meet w

ith Surgeon

Meet w

ith Chem

otherapy Dr.

Meet w

ith Radiation D

r.

Weeks0

Meet w

ith Gastroenterologist

Start Treatm

ent

1 2 3 4 5

Are they talking to each other?Do they remember who the patient is?

Are they offering the best cutting edge therapies?

Colorectal Cancer Metastases to LiverBetter Model of Taking Care of Pancreatic

Cancer Patients

Diagnosis

Meet w

ith Surgeon

Meet w

ith Chem

otherapy Dr.

Meet with

Radiation Dr.

0

Start Treatm

ent

1 2 3Weeks

Colorectal Cancer Metastases to LiverUniversity of Colorado HospitalPancreatic and Biliary Multidisciplinary

Clinic


Decreasing Surgical Impact on Quality of Life?Laparoscopic Pancreatic Surgery


Minimally Invasive Surgery for the Pancreas

Cons Pros

Faster Recovery

Fewer Wound Complications

Decreased Blood Loss

Technical Difficulty

Oncologic Completeness

Specialized Equipment

Colorectal Cancer Metastases to LiverTotally Laparoscopic Whipple Video


DISTRIBUTION OF CASES

TOTAL LAPAROSCOPIC WHIPPLE ATTEMPTED(Oct 2012 – August 2016)

TOTAL LAPAROSCOPIC WHIPPLE COMPLETED

CONVERTED TO OPEN

70 66 (94.3%) 4 (5.7%)

Colorectal Cancer Metastases to LiverDEMOGRAPHIC

VARIABLE N(%)

AGE

(median, range) 66.1 (55 – 72)

GENDER

Male 31 (44.3%)

BMI

(median, range) 25.4 (22.2-‐‑28.5)

SMOKING STATUS

Never 32 (45.7%)

Former 28 (40.0%)

Current 10 (14.3%)

COMORBIDITIES

COPD 13 (18.6%)

HTN 42 (45.7%)

Diabetes 11 (15.7%)

MI 2 (2.9%)

CKD 6 (8.6%)

DVT/PE 5 (7.1%)

ASA CLASS

I 1 (1.4%)

II 29 (41.4%)

III 40 (58.2%)


PRIOR SURGERIES

VARIABLE N (%)

PRIOR SURGERIES

Appendectomy 10 (14.3%)

Cholecystectomy 12 (17.1%)

Ventral Hernia 3 (4.3%)

TAH and/or BSO 12 (17.1%)

Gastric Resection 1 (1.4%)

Small Bowel Resection 1 (1.4%)

Large Bowel Resection 1 (1.4%)

Colorectal Cancer Metastases to LiverOPERATIVE & PERIOPERATIVECHARACTERISTICS

VARIABLE N (%)

OPERATIVE TIME (min)

Median (range) 335.5 (298– 377)

Mean (sd) 345.2 (± 66.6)

EBL (ml)

Median (range) 300 (150 -‐‑ 450)

Mean (sd) 334.2 (± 264.2)

TUMOR SIZE (cm, max diameter)

Median (range) 2.1 (1.3 – 3.2)

Mean (sd) 2.3 (± 1.4)

SURGICAL MARGINS

Negative (R0) 63 (95.5%)

NUMBER OF NODES HARVESTED

Median (range) 18.5 (15.0-‐‑22.0)

Mean (sd) 18.8 (± 7.4)

EPIDURAL 4 (6.1%)

Colorectal Cancer Metastases to LiverOPERATIVE & PERIOPERATIVE

CHARACTERISTICS

VARIABLE N (%)

ICU LOS (days)

Median (range) 1 (1 – 1)

Mean (sd) 1.5 (±1.3)

ICU READMISSION 10 (15.2%)

HOSPITAL LOS (days)

Median (range) 10.5 (8-14)

Mean (sd) 13.5 (±11.1)

READMISSION (90 days) 16 (24.2%)

DEATH (30 days) 0

Colorectal Cancer Metastases to LiverCOMPLICATIONSVARIABLE N (%)

PANCREATIC FISTULA 35 (53.0%)

PANCREATIC FISTULA GRADE

Grade A 19 (28.8%)

Grade B 13 (21.7%)

Grade C 3 (5.0%)

DELAYED GASTRIC EMPTYING

Grade A 5 (7.6%)

Grade B 5 (7.6%)

Grade C 2 (3.0%)

BILE LEAK 4 (6.1%)

PSEUDOANEURYSM

GDA 2 (3.0%)

Pancreatic Artery 1 (1.5%)

CHYLE LEAK 3 (4.6%)

SURGICAL SITE INFECTION 5 (7.6%)

MARGINAL ULCER 6 (9.1%)

INTRABDOMINAL BLEEDING 13 (19.7%)

INCISIONAL HERNIA 2 (3.0%)

POSTOPERATIVE TRANSFUSION 11 (18.3%)


INTERVENTION

VARIABLE N (%)

INTERVENTION

Coil embolization 8 (12.1%)

PTC 8 (12.1%)

Percutaneous drain 17 (25.8%)

Gastrojejunal dilation 1 (1.5%)

Transfusion 11 (16.7%)

REOPERATION 5 (7.6%)


TUMOR RELATED OUTCOME

VARIABLE N (%)

FOLLOW UP (months)

Median (range) 6.0 (2.0 – 11.5)

Mean (sd) 8.1 (± 7.9)

RECURRENCE

Distant 7 (10.6%)

Loco-‐‑regional 4 (6.1%)


17%

8%

6%

14%

26%

2%

14%

5%3%

2%2%2%2%2%

Pancreatic ductal adenocarcinoma Neuroendocrine tumor

Duodenal adenocarcinoma Cholangiocarcinoma

Ampullary adenoma Ampullary neuroendocrine tumor

IPMN Solid pseudopapillary tumor

GIST Ampullary adenoma

Gastric cancer Sarcomatoid

Adenosqamous carcinoma Schwannoma

Total Laparoscopic PancreaticoduodenectomyPathology of Resected Lesions


200

300

400

500

600

Ope

rativ

e tim

e (m

inut

es)

0 20 40 60 80Patients in chronological order

Operative_Time (minutes) Fitted values

UCD ExperienceTotal Laparoscopic Pancreaticoduodenectomy


050

010

0015

00Es

timat

ed B

lood

Los

s (m

L)

0 20 40 60 80Patients in chronological order

EBL (ml) Fitted values

UCD ExperienceTotal Laparoscopic Pancreaticoduodenectomy


SummaryPancreatic cancer is a deadly diseasePancreatectomy can be performed with low mortality, but still with high complications rates

Best results are accomplished at high volume centersTo Impact on Survival• Better understanding of molecular events and impaired pathways leading to disease

• Prevention• Earlier detection• More effective systemic therapies• Multidisciplinary care of patientsTo impact on Quality of Life and Morbidity of Surgery• Proper use of laparoscopic pancreatectomy• (Decrease pancreatic fistula rate)

University of Colorado Medical Center

pancreatic cancer –recent progress - … cancer –recent progress richard d. schulick, md, mba,...

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