Download PANCREAS AND HEPATOBILIARY CANCERS

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)
Incidence = mortality
.
Ryan DP et al. N Engl J Med 2014;371:1039-1049
BIOLOGIC FEATURES
 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
Pancreatic cancer: epidemiology
•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
Diagnostic tools for pancreatic
cancer
Lab studies
– Tumor markers i.e.CA19-9
– Glucose intolerance
•Imaging modalities
– CT scan
– EUS
– ERCP
– MRI/MRCP
– PET scanning
– Staging laparoscopy
Major clinical stages
 Resectable -- Locally advanced -- Metastatic
 TNM Staging
 Stage 1
T1 (≤ 2cm) N0 M0
T2 (≥ 2cm) N0 M0
 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
Metastasis, M0 vs M1
T1 (<2cm) vs T2 (>2cm)
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))
N0 (No regional lymph node metastasis) vs N1
(Regional lymph node metastasis)
Ryan DP et al. N Engl J Med 2014;371:1039-1049
Overall survival
 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
Stage 1 and 2
 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
Whipple procedure
Ryan DP et al. N Engl J Med 2014;371:1039-1049
Treatment options under clinical evaluation
 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
Stage III
 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
Treatments
 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
Rates per 100,000

600,000 to 1,000,000 cases
diagnosed worldwide every year
•
•
•
•

•
5th most common cancer
worldwide
2nd 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
Increasing incidence in “Western”
countries
•
•
Hepatitis C viral infection
Obesity Epidemic
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.
More than 80% of HCC is associated with chronic liver disease
• HBV infection is most common in Asia & Africa
•
380,000,000 cases HBV worldwide
•
More than 8% of the population in these regions have chronic HBV
infection
•
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
• 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%
 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).
Ablation (RFA, cryoablation,
percutaneous ETOH, microwave)
 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
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
Potential Severe Adverse Events from
Chemoembolization
• Hepatic insufficiency or
infarction
• Abscess
• Hepatic failure
• Biliary necrosis
• Tumor rupture
• Non targeted embolisation of
gall bladder, stomach, small
bowel
HCC Management – Systemic Therapy
• 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)
Molecular Signalling Pathways in
HCC
Tumor Blood
Vessels
Growth
and
survival
factors
(eg, VEGF,
PDGF)
Sorafenib
Autocrine loop
EGF/HGF
Apoptosis
RAS
RAF
Mitochondria
MEK
ERK
HIF-2
EGF/HGF
PDGF
Nucleus
Wilhelm S, et al. Cancer Res. 2004;64:7099-7109.
VEGF
Proliferation
Survival
Tumor Cell
Phase III SHARP Trial
Study Design
 Multi-center, Phase III study
 Inclusion criteria
 Histology proven HCC
 Advanced, unresectable HCC
 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.
Sorafenib in Advanced HCC
(SHARP): Survival
Sorafenib median OS:
46.3 wks (10.7 mos)
(95% CI: 40.9-57.9)
Survival Probability
1.00
Placebo median OS:
34.4 wks (7.9 mos)
(95% CI: 29.4-39.4)
0.75
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 12
Mos Since Randomization
13
14
15
16
Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.
17
Sorafenib vs Placebo in Advanced HCC
(SHARP): Response
Result
Sorafenib
(n = 299)
Placebo
(n = 303)
 CR
0 (0)
0 (0)
 PR
7 (2.3)
2 (0.7)
SD, n (%)
211 (71)
204 (67)
PD, n (%)
54 (18)
73 (24)
PFS rate at Month 4, %
62
42
Median treatment duration, wks
21
17
Overall response,* n (%)
*RECIST criteria, independent review.
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.
Unmet Needs in Advanced HCC
 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.
Tivantinib – MET inhibitor
 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
Summary
 HCC is the 3rd 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