TARA SEERY, MD

• Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type
• The vast majority of patients are inoperable at the time of diagnosis
• Pancreatic cancer is inherently resistant to most currently available therapies
• Many patients suffer from rapidly declining performance status
• Compared with other cancer types, research funding for pancreatic cancer is disproportionately low given its mortality rate (fourth for cancer-related deaths in the US population)

Ryan DP et al. N Engl J Med 2014;371:1039-1049
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 Very high rate of activating mutations in KRAS (>90%)
 Propensity for both local invasion and distant metastasis
 Extensive stromal reaction
 Hypovascular and hypoxic microenvironment
 Reprogramming of cellular metabolism
 Evasion of tumor immunity

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Incidence of 10 per 100,000
•80% ductal adenocarcinoma
•10% other exocrine tissue–
Acinar cell, cyst adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)
•10% neuroendocrine
KKrejs GJ. Dig Dis. 2010; 28:355-358

Lab studies
– Tumor markers i.e.CA19-9
– Glucose intolerance
•Imaging modalities
– CT scan
– EUS
– ERCP
– MRI/MRCP
– PET scanning
– Staging laparoscopy

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Resectable -- Locally advanced -- Metastatic
TNM Staging
 Stage 1
T1 (≤ 2cm) N0 M0
T2 (≥ 2cm) N0 M0
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Stage 2
T3 (beyond the pancreas but with out involvement of celiac axis or SMA) N0 M0
T1/2 N1 (regional LN) M0
Stage 3
T4 (involves celiac axis or SMA) Nx M0
Stage 4
M1

T3 (Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery) vs T4 (Tumor involves the celiac axis or superior mesenteric artery (unresectable primary tumor))

Ryan DP et al. N Engl J Med 2014;371:1039-1049

 For all stages combined, the 1-year relative survival rate is 25%, and the 5 year survival is less than 5%
 For Local Disease – 5 year survival is approx 20%
 For Locally Advanced and for Metastatic Disease the median survival is 10 and 6 months with treatment
 Untreated metastatic has a median survival of 3-5 months

 Radical pancreatic resection:
 Whipple procedure (pancreaticoduodenal resection)
 Total pancreatectomy when necessary for adequate margins
 Distal pancreatectomy for tumors of the body and tail of the pancreas
 Radical pancreatic resection with:
 Postoperative chemotherapy (gemcitabine or 5FU)
 Postoperative chemotherapy and radiation therapy

Ryan DP et al. N Engl J Med 2014;371:1039-1049

 Gemcitabine and capecitabine (ESPAC-4)
 Gemcitabine and erlotinib (CONKO-005)
 Gemcitabine with or without 5FU chemoradiation
(RTOG 0848)
 Gemcitabine vs Gemcitabine/Abraxane
 Preoperative chemotherapy (ACOSOG) --
FOLFIRINOX
 Preoperative chemotherapy and radiation therapy

 Technically unresectable because of local vessel impingement or invasion by tumor
 Benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological
 Stage III and stage IV pancreatic cancer are both incurable, the natural history of stage III (locally advanced) disease may be different than it is for stage
IV disease
 30% of patients presenting with stage III disease died without evidence of distant metastases

 Palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement
 Chemotherapy with gemcitabine, gemcitabine and erlotinib or abraxane, or FOLFIRINOX
 Chemoradiation (for obstructions) followed by chemotherapy
 Chemotherapy followed by chemoradiation for patients without metastatic disease --- now LAP07 trial worse with XRT

Ryan DP et al. N Engl J Med 2014;371:1039-1049

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600,000 to 1,000,000 cases diagnosed worldwide every year
5 th most common cancer worldwide
2 nd leading cause of cancer-related death worldwide
Incidence and yearly deaths essentially the same
Men > Women
50% of cases & deaths thought to occur in China alone
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Increasing incidence in “Western” countries
Hepatitis C viral infection
Obesity Epidemic
Rates per 100,000

Liver Cancer Incidence: Males
Rate Per 100,000
International Agency for Research on Cancer. GLOBOCAN 2002. Available at: http://www-dep.iarc.fr. Accessed May 5, 2008 .

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More than 80% of HCC is associated with chronic liver disease
HBV infection is most common in Asia & Africa
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380,000,000 cases HBV worldwide
More than 8% of the population in these regions have chronic HBV infection
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100x increase in risk of developing HCC vs. non-carrier
Up to 40% who develop HCC are non-cirrhotic
Responsible for 60% of HCC in developing countries, and 23% of
HCC in developed countries
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HCV infection/cirrhosis in Western countries & Japan
170,000,000 cases worldwide
Responsible for 33% of HCC in developing countries, and 20% of HCC in developed countries
Alcoholic cirrhosis
Non-Alcoholic Steatohepatitis (NASH)

 Doubling time for HCC tumors is 2 to 3 months
 Normal life expectancy for HCC (Child-Pugh
A) is 8 to 12 months from diagnosis
 Mean survival for symptomatic patients with
HCC is 2 to 3 months
 5-year survival (all patients – U.S.) is 26%

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Surgical Resection
•
•
• Hemihepatectomy
Segmentectomy
Non Anatomic wedge resection
Orthotopic Liver
Transplantation
• For selected cases of hepatoma, hepatoblastoma, neuoroendocrine tumors
Radiofrequency ablation
Microwave ablation
Chemoembolization
Radioembolization
Systemic chemotherapy
Irreversible electroporation

European Association for the Study of the Liver; J. Hepatol. 56, 908–943 (2012).

 All tumors amendable
 Thermal ablation need a margin of normal tissue
 Accessible tumors by percutaneous, laparoscopic or open
 Caution with ablation near major vessels, major bile ducts, diaphragm, and intra-abdominal organs
 Curative in tumors ≤3 cm
 Tumors 3-5 cm may be treated to prolong survival using arterial directed therapies or with combination of an arterially directed therapy and ablation
 ≥5cm tumors use arterially directed therapies

 All tumors amenable provided that the arterial blood supply to the tumor may be isolated without excessive non-target treatment
 TAE (transarterial bland embolization), TACE
(chemoembolization) , TACE with drug eluting beads,
Y90
 Contraindicated if bili >3
 Y90 contraindicated if bili>2
 Contraindicated if main portal vein thrombosis and
CP class C

• Hepatic insufficiency or infarction
• Abscess
• Hepatic failure
• Biliary necrosis
• Tumor rupture
• Non targeted embolisation of gall bladder, stomach, small bowel

• Systemic Therapy
– Historically ineffective
• Hormonal agents – Tamoxifen
• Chemotherapeutic agents
– Doxorubicin – 16% response rate, no improved survival
– PIAF (cisplatin, Ifn-α, doxorubicin, 5-FU) – 26% partial response rate, no improved survival
• Octreotide
• Thalidomide
– Sorafenib and the SHARP Trial
• Multikinase inhibitor
– Blocks cell proliferation (Raf/MEK/ERK pathway)
– Blocks angiogenesis (VEGFR-2, VEGFR-3, PDGFR-β)

Tumor Blood
Vessels
Sorafenib
Growth and survival factors
(eg, VEGF,
PDGF)
EGF/HGF
Apoptosis
Autocrine loop
RAS
RAF
MEK
ERK
HIF-2
Nucleus
Mitochondria
EGF/HGF
PDGF
VEGF
Proliferation
Survival
Tumor Cell
Wilhelm S, et al. Cancer Res. 2004;64:7099-7109.

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Phase III SHARP Trial
Study Design
Multi-center, Phase III study
Inclusion criteria
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Histology proven HCC
Advanced, unresectable HCC
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At least one measurable untreated lesion
ECOG ≤ 2
 Child-Pugh class A
 No prior systemic treatment
Randomization
Double-blind placebo controlled trial (1:1)
Accrual: March 2005-April 2006
Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008; 359(4):378-90.

1.00
Sorafenib median OS:
46.3 wks (10.7 mos)
(95% CI: 40.9-57.9)
0.75
Placebo median OS:
34.4 wks (7.9 mos)
(95% CI: 29.4-39.4)
0.50
0.25
HR (S/P): 0.69 (95% CI: 0.55-0.87; P < .001
)
0
0 1 2 3 4 5 6 7 8 9 10 11
Mos Since Randomization
12 13 14 15 16 17
Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.

Result Sorafenib
(n = 299)
Placebo
(n = 303)
Overall response,* n (%)
 CR
 PR
SD, n (%)
PD, n (%)
PFS rate at Month 4, %
0 (0)
7 (2.3)
211 (71)
0 (0)
2 (0.7)
204 (67)
54 (18)
62
73 (24)
42
Median treatment duration, wks
*RECIST criteria, independent review.
21 17
Time to symptom progression (FSHI8-TSP scoring): no significant differences between treatment groups (P = .77)
Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.

 First-line therapies that improve clinical outcomes compared with treatment with sorafenib (the standard of care) [1,2] with regarding
 Efficacy [1]
 Safety and tolerability [1]
 Options also needed for patients who are ineligible
 Quality of life [3]
 Second-line therapies for patients who progress on or do not tolerate sorafenib [1]
Ongoing phase III trials are addressing unmet needs in first-line and second-line therapy for advanced HCC
1. Finn RS. Clin Cancer Res. 2010;16:390-397. 2. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
3. Fan SY, et al. Clin Gastroenterol Hepatol. 2010;8:559-564.

 A non-ATP-competitive inhibitor of c-Met, which has been implicated in cancer cell proliferation, migration, invasion, and metastasis
 The c-Met receptor tyrosine kinase is the only known highaffinity receptor for hepatocyte growth factor
 Binding of HGF to the c-Met extracellular ligand-binding domain results in receptor multimerization and phosphorylation of multiple tyrosine residues in the intracellular portion of c-Met

 HCC is the 3 rd most common cause of cancer death worldwide with increasing incidence in the U.S.
 HCC is a biologically heterogeneous tumor type due to longstanding hepatocyte regeneration and accumulated mutations from premalignant liver injury state
 Sorafenib remains the only proven agent with survival benefit with advanced HCC but novel agents are on the horizon