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Transcript of 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
Colorectal Cancer Metastases to Liver
Distal Pancreatectomy for Body and Tail Cancer
Colorectal Cancer Metastases to LiverPancreaticoduodenectomy for Head and
Uncinate Cancer
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
Historical Perspective
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
Colorectal Cancer Metastases to Liver
Historical Perspective
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
Colorectal Cancer Metastases to Liver
Historical Perspective
Two-stage procedure reported in 1935 One-stage procedure reported in 1942
Whipple, Ann Surg, 1935 Whipple, Rev Surg, 1963
Colorectal Cancer Metastases to Liver
Historical Perspective
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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)
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
Prevention of Pancreatic Cancer
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
Earlier Detection:Patients with Premalignant CystsPatients in High Risk Families
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
IPMN - Introduction
IPMN can further be classified by location
Main duct Branch duct
Colorectal Cancer Metastases to Liver
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 Liver
Colorectal Cancer Metastases to LiverFamilial Pancreatic CancerHereditary Pancreatic Cancer
Syndromes of Chronic Inflammation
Templeton, SurgClinN Am, 2013
Colorectal Cancer Metastases to Liver
More Effective Systemic Therapies:Adjuvant TherapyImmunotherapy
Colorectal Cancer Metastases to Liver
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?
Colorectal Cancer Metastases to Liver
Li, O’Reilly, Surg Onc Clinc N Am, 2016
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
Borderline Resectable Pancreatic Cancer
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
TH 64 yo Female – Oct 2012
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
17/18 went to resection and R0
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
Decreasing Surgical Impact on Quality of Life?Laparoscopic Pancreatic Surgery
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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%)
Colorectal Cancer Metastases to Liver
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%)
Colorectal Cancer Metastases to Liver
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%)
Colorectal Cancer Metastases to Liver
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%)
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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
Colorectal Cancer Metastases to Liver
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