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Pancreatic Cancer
Review
Gina Vaccaro, MD
May 20, 2009
Outline
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Anatomy
Histologic types
Epidemiology
Precursor lesions
Presentation
Treatment
Anatomy of the pancreas
DePinho, Nature Reviews, 2002
Anatomy of the pancreas
DePinho, Nature Reviews, 2002
Histology
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Ductal adenocarcinoma, PDAC (>85%)
Acinar cell carcinoma
Pancreatic Neuroendocrine Tumor
Cystic neoplasms
Other- Lymphoma (NHL)
DePinho, Nature Reviews, 2002
DePinho, Nature Reviews, 2002
Ductal Adenocarcinoma by the Numbers
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33,730 cases/yr in US
30,000 deaths/yr
7th- 8th decade of life- peak incidence
72 years- median age at diagnosis
4th- most common cause of Ca-related
death in US
15-20%- 5 yr survival if resectable
3%- 5 yr survival, all stages
2007 Estimated US Cancer Cases*
Men
766,860
Women
678,060
Prostate
29%
26%
Breast
Lung & bronchus
15%
15%
Lung & bronchus
Colon & rectum
10%
11%Colon & rectum
Urinary bladder
7%
6%
Uterine corpus
Non-Hodgkin
lymphoma
4%
4%
Non-Hodgkin
lymphoma
Melanoma of skin
4%
4%
Melanoma of skin
Kidney
4%
4%
Thyroid
Leukemia
3%
3%
Ovary
Oral cavity
3%
3%
Kidney
Pancreas
2%
3%
Leukemia
19%
21%
All Other Sites
All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2007.
2007 Estimated US Cancer Deaths*
Lung & bronchus
31%
Men
289,550
Women
270,100
26%
Lung & bronchus
15%
Breast
Colon & rectum
Prostate
9%
Colon & rectum
9%
10%
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
3%
Esophagus
4%
Non-Hodgkin
lymphoma
Urinary bladder
3%
3%
Uterine corpus
Non-Hodgkin
lymphoma
3%
2%
Brain/ONS
2%
Kidney
3%
Liver & intrahepatic
bile duct
All other sites
24%
ONS=Other nervous system.
Source: American Cancer Society, 2007.
23%
All other sites
Predisposing Factors
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Age
Smoking
Chronic pancreatitis
Obesity
Diabetes mellitus
None?
Familial Syndromes
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Hereditary Breast and Ovarian cancer
(BRCA2)
Peutz-Jeghers (LKB1)
Familial atypical multiple mole
melanoma (p16INK4a)
Lynch syndrome (MSH2, MLH1, etc.)
Hereditary pancreatitis (PRSSI)
Familial Syndromes
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Account for < 20% of the familial aggregation
of PC
National Familial Pancreas Tumor Registry
(Hopkins)- 1200 families
Familial PC- at least two 1st degree relatives
Risk is 18X baseline
Second degree relatives in familial PC
kindreds have increased risk (3.7% vs. 0.6%)
Precursor Lesions
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PanIN (Pancreatic intraepithelial neoplasia)
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MCN (Mucinous cystic neoplasm)
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IPMN (Intraductal papillary mucinous
neoplasm)
Genetic Progression Model
DePinho, Nature Reviews, 2002
Regeneration 
Tumorigenesis
DePinho, Nature Reviews, 2002
KRAS mutation is necessary, but not sufficient
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Activating mutations are the 1st known
genetic alterations
Occur sporadically in normal pancreatic
tissue
Detected in ~30% of early neoplasms
Nearly 100% of advanced PDAC
Mice with pancreas-specific
KRASG12Ddevelop PanIN, can progress to
PDAC in the appropriate tumor suppressor
background.
A Target Rich Environment
DePinho, Gen Dev, 2006
Presentation
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Abdominal pain (Bad sign)
Jaundice (Head lesions)
Weight loss
New onset diabetes mellitus
Pancreatic enzyme insufficiency
(diarrhea, floating/fatty stools)
Diagnosis
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FNA of the primary mass or distant
metastases
FNA of the primary is obtainable with
EUS (endoscopic ultrasound)
EUS is also useful for staging, invasion
into surrounding vessels (SMA, SMV)
Determination of resectability
Case 1
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66 yo female presented with upper
abdominal pain
Non-smoker, father has pancreatic cancer
Started on PPI by PCP
Pain continued, developed anorexia, 8 lb
weight loss
U/S- intra and extra hepatic biliary ductal
dilitation
CT- 1.4cm pancreatic head mass, 18mm
CBD, dilated pancreatic duct
Case 1
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EUS- 2 x 1.8cm pancreatic head
mass, 18 mm CBD, no nodes
FNA- adenocarcinoma
Staged T3N0
No involvement of critical vascular
structures.
Underwent “Whipple” resection
Case 1
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Pathology:
2.5 cm ductal adenocarcinoma
T4N1 (1/19 nodes)
Positive SMA and radial margin
Angiolymphatic and perineural invasion
Poor prognosis- 5 yr survival 10-20%
Recommendation- Adjuvant
chemotherapy, chemoradiation (6 months)
Case 2
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62 yo male presented with L flank
Presented to urgent care, MD palpated
an abdominal mass
CT done- 11 x 8 cm mass in the body
of the pancreas, no mets, obliteraion of
portal, splenic, SMV
Also noted to have L renal stone
Patient has no symptoms, no weight
loss, no pain
Case 2
Case 2
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EUS/FNA- low grade neuroendocrine
neoplasm
Disease is not resectable
Prognosis is good, median survival >5yrs
Options:
Observation
Somatostin analog
Chemotherapy
Biologic therapy
Extent of disease at presentation
Localized/Resectable (15-20 %)
Locally Advanced/Unresectable (40 %)
Metastatic (40 %)
MS 15-19 mo
MS 8-12 mo
MS 3-6 mo
Staging (AJCC 2002)
Primary
TX
T0
Tis
T1
T2
T3
Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ (also PanIN 3)
Tumor limited to pancreas, <=2cm
Tumor limited to pancreas, >2cm
Tumor extends beyond pancreas w/o
involvement of celiac axis or SMA
T4
Tumor invades celiac axis or SMA
(unresectable)
Regional Lymph Nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Regional lymph node metastases
Distant Metastasis (M)
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
Stage Grouping
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2 N0 M0
Stage IIA T3
Stage IIB T1
T2
T3
N0
N1
N1
N1
M0
M0
M0
M0
Stage III T4 Any N M0
Stage IV Any T Any N M1
Five-year Relative Survival (%)* during Three Time Periods
By Cancer Site
1975-1977
50
1984-1986
53
Breast (female)
75
79
89
Colon
51
59
65
Leukemia
35
42
49
Lung and bronchus
13
13
16
Melanoma
82
86
92
Non-Hodgkin lymphoma
48
53
63
Ovary
37
40
45 †
Pancreas
2
3
5
Prostate
69
76
100
Rectum
49
57
66
Urinary bladder
73
78
82
Site
All sites
1996-2002
66
*5-year relative survival rates based on follow up of patients through 2003.
†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2006.
Why is pancreatic cancer
so hard to treat?
Factors to Overcome
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No adequate screening test
High incidence of metastatic disease at
presentation
Fulminant clinical course
Lack of adequate systemic therapies
Chemotherapy resistant
Radiation resistant
Lack of understanding of the biology
Resectable Disease
Criteria for Unresectability
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Determined by multi-disciplinary evaluation
Extrapancreatic involvement
– (extensive peripancreatic nodal involvement and/or distant
mets)
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Encasement or occlusion of the SMV or SMV-portal
vein confluence
– (SMV reconstruction may be feasible)
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Direct involvement of SMA, IVC, aorta, celiac axis
Surgery
(tumors of head, neck or uncinate process)
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Pancreaticoduodenectomy (Whipple)
Operative mortality <2-3% in major surgical centers
Surgery
(tumors of body or tail)
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Often present late with larger tumors and frequent metastases
Distal pancreatectomy +/- splenectomy
Chemotherapy
5-fluorouracil
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Pyrimidine analog
In use for over 40 yrs
Thymidylate synthase
inhibitor
Pancreatic, colon,
breast, esophageal,
gastic cancer, etc.
Gemcitabine
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Nucleoside analog
Difluorinated analog of
deoxycytidine
Pancreas, breast, lung
and ovarian
Adjuvant Therapy
Adjuvant therapy
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Rationale:
High risk of local and systemic recurrence
Overall poor prognosis
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5-yr survival after resection:
25-30% node-neg vs. 10% node-pos
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Current standard:
No universally accepted standard approach
Adjuvant therapy
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5 major randomized trials
GITSG, EORTC, ESPAC-1, RTOG 9704,
CONKO-1
Over 1200 patients studied
Significant methodological differences
Chemoradiotherapy in N. America
(GITSG, RTOG)
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Chemotherapy alone in Europe
(EORTC,ESPAC-1, CONKO)
5-fu based chemoradiation
Trial
GITSG
EORTC
ESPAC-1
RT dose
Chemo
40 Gy(split)
Bolus 5fu
None
None
1 yr %
2 yr %
20 (p=.01)
63
42
11
49
15
40 GY(split) CI 5-fu
17.1 (p=.099)
65
37
None
12.6
40
23
None
2x2 factorial design
MS (Mo)
ESPAC-1 (5-fu)
Chemoradiotherapy vs. none
MS
15.9 vs. 17.9 mos
2-yr survival
29 vs. 41 %
5-yr survival
10 vs. 20 %
Chemotherapy vs. none
Neoptolemos, NEJM 2004
MS
20.1 vs. 15.5 mos
2-yr survival
40 vs. 30 %
5-yr survival
21 vs. 8 %
Kaplan-Meier estimates of survival according to whether or not patients
Received chemoradiotherapy (Panel A) or chemotherapy (Panel B)
Neoptolemos, NEJM 2004
ESPAC-1 Limitations
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Trial design (2 x 2 factorial)
Possible selection bias
Suboptimal radiation dose
Only 70% received 40 Gy
Uses 5-fu based chemotherapy
Design delays initiation of adjuvant
chemotherapy in the combination arm
Gemcitabine-based adjuvant
therapy
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RTOG 9704 (ASCO 2006)
442 subjects
All received chemoradiation (50.4 Gy) + CI 5-fu
2 Arms: Additional 5-fu
Additional Gemcitabine
No overall difference in aggregate survival
Head lesions only  Gemcitabine arm superior
MS 20 vs. 17 mos
3-yr OS 32 vs. 21 % (p=0.047)
Gemcitabine-based adjuvant
therapy
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CONKO-001
368 subjects
Randomized to Obs vs. Gemcitabine x 6 cycles
10 % never received chemotherapy
62 % received all 6 cycles
Gr 3/4 toxicity 7.7 % in Gem arm vs. 2.5 % in Obs
Median DFS 13.4 vs. 6.9 mos (p<0.001)
No difference in overall survival (22 vs. 20 mos)
QOL similar in both groups
Disease-free and Overall Survival (Intent-to-Treat Analysis)
Oettle, JAMA 2007
Adjuvant therapy (Conclusions)
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Benefit of adjuvant chemotherapy is clear
Gemcitabine is better than 5-fu as adjuvant
chemotherapy
Role of chemoradiation therapy is uncertain
Clinical trial participation should be
encouraged
Molecularly-targeted therapies, vaccines are
under investigation
Future Directions
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Phase III: ESPAC-3
5-fu/LV vs. Gem vs. Obs
Phase II: Addition of targeted agents to
Gemcitabine
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Bevacizumab
Erlotinib
Erbitux
Capecitabine
Oxaliplatin
Neoadjuvant Therapy
Rationale for Neoadjuvant therapy
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Intact vasculature permits maintenance of
oxygenation in tissue necessary for
radiation-induced necrosis
Improved delivery of chemotherapy to tumor
May downstage tumor
20-30% of resected patients are unable to
receive adjuvant therapy
Saves patients with occult metastases from
morbidity of unnecessary surgery
Neoadjuvant therapy
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No randomized studies comparing to
adjuvant
Small, Phase II, mostly single instituiton
5-fu and Gemcitabine chemoradiation have
been studied
Neoadjuvant chemoradiation can be given
safely without excess surgical morbidity
ACOSOG Z5041
Gemcitabine-Erlotinib
Surgery
Gemcitabine-Erlotinib
Locally Advanced,
Unresectable Disease
Locally advanced, unresectable
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40% of newly diagnosed patients
Most with adherence to adjacent structures (celiac
or SM vessels)
Median survival 8-12 mos
Optimal treatment is controversial
Treatment options:
RT alone
Chemotherapy alone
Concurrent chemoradiation (+/- surgery)
Chemoradiation > RT alone
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GITSG (Morertel, Cancer 1981)
194 patients
Randomized to:
High dose RT
Moderate dose RT + 5-fu
High dose RT + 5-fu
1-yr survival:
11 % (60 Gy)
38 % (40 Gy + 5-fu)
36 % (60 Gy + 5-fu)
Chemoradiation > RT alone
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Medicare/SEER (Krzyzanowska, JCO 2003)
Large, retrospective cohort
1696 patients treated between 1991-96
Adjusted mean survival duration (weeks):
Chemoradiation
47
RT alone
29
Chemo alone
27
No therapy
15
Supports the use of chemoradiation over either
modality alone
RT + Gemcitabine
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NCCN states “Radiation is usually given in
combination with 5-fu chemotherapy.
Recent evidence suggests that concurrent
gemcitabine and radiation can yield similar
outcomes.”
Treatment of Metastatic
Disease
Efficacy endpoints
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Traditional tumor measurements to assess
RR are often inadequate in the primary
tumor site.
Characteristic desmoplastic reaction and
inflammatory response
Recent trials have included QOL endpoints
“Clinical benefit” and survival may be more
accurate determinants of efficacy.
Fluorouracil
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Extensively studied since 1950’s
LV-modulated 5-fu (infusional and bolus)
RR 0- 9%
MS 10-24 wks
Capecitabine (Cartwright, JCO 2002)
Phase II study, 42 patients
Chemotherapy-naive
24% achieved clinical benefit (pain intensity,
analgesic use, KPS)
7% PR
Well tolerated, 17% Gr 3 HFS
Gemcitabine
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Nucleoside analog structurally similar to cytarabine
Pivotal Trial (Burris, JCO 1997)
126 patients randomized:
Gem 1000mg/m2 IV qwk 7/8, then 3/4
5-fu 600mg/m2 IV qwk
Treatment was blinded to patients, not to investigators
Primary efficacy measure= Clinical benefit response
Composite of pain, KPS and weight
Clinical benefit required improvement >= 4 weeks
RR, TTP, OS
Gemcitabine
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No confirmed objective responses
Clinical benefit response 23.8% in Gem arm,
4.8% in 5-fu arm (P= .0022)
Median survival 5.65 vs. 4.41 mos (P= .0025)
Gemcitabine Combinations
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Gemcitabine has been combined with many other
active cytotoxic agents:
5-fu
Cisplatin
Docetaxel
Oxaliplatin
Irinotecan
Etc…
No survival benefit has been seen over
Gem alone
Nieto, The Oncologist, 2008
Molecularly targeted
therapy
(Hochster, Cancer 2006)
Nieto, The Oncologist, 2008
Targeting EGFR
Gemcitabine + Cetuximab
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SWOG S0205 (Philip, ASCO 2007)
Phase III study, 735 patients
Targeting VEGF
Gemcitabine + Bevacizumab
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Overexpression of VEGF/VEGFR are common
Phase II data promising for Gem/Bev combo
Phase III trial from CALGB 80303
(Kindler, ASCO 2007)
Gemcitabine + Erlotinib
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Expression of EGFR is common, poor prognosis
Phase III study from NCIC (Moore, JCO 2007)
569 patients randomized to:
Gemcitabine 1000mg/m2 weekly +/Erlotinib 100mg po daily
Few objective responses (8.6 vs. 7.9%)
Overall survival 6.2 vs. 5.9 mos favoring
combination
1-yr survival 23 vs. 17% (p=.023)
Adjusted HR for death in erlotinib 0.82 (p=.038)
FDA approved in 2005 in combination with
gemcitabine
(Moore, JCO 2007)
Gemcitabine + Erlotinib
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1st evidence of a survival benefit of EGFRTKI plus chemotherapy in any form of
cancer
1st Phase III trial to demonstrate significant
improvement in survival beyond that seen
with Gemcitabine alone in pancreatic cancer
Ongoing Trials
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Orathecin (rubitecan)- Oral Topo I inhibitor
GV1001- Telomerase peptide vaccine
AG-013736- Oral VEGFR/PDGFR-B inhibitor
Sorafenib- Oral Raf/VEGFR/PDGFR-B/CKIT
Aflibercept- VEGF Trap
AZD0530- Oral Abl/Src kinase inhibitor
PTK787/ZK 222584- VEGFR-TKI
Romidepsin (Depsipeptide)- HDAC inhibitor
MGCD0103 (MG-0103)- HDAC inhibitor
Conclusions
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Pancreatic cancer remains a clinical challenge
Current therapies offer only modest benefits
Numerous studies incorporating new,
targeted agents have offered little/no benefit
over Gemcitabine alone.
Rationally-designed combinations based on
tumor biology may be more effective.
Clinical trials