Transcript View - Oncology Hematology Associates

Pancreatic Cancer
Sheri Ziegler
2017
2007 Estimated US Cancer Cases*
33, 730 cases/yr
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
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2007.
All Other Sites
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
ONS=Other nervous system.
Source: American Cancer Society, 2007.
24%
23%
All other sites
Histology
 Adenocarcinoma
 Neuroendocrine tumors
 Rare – Lymphoma, etc
Pancreatic Cancer: An Imminent Threat
 Incidence: 11.7 per 100,000
 Rising incidence
 6.7% increase 19952005
 Lifetime risk: 1.41%
 1 in 71 Americans will be
diagnosed w/ PC
Matrisian, Cancer Res, 2014
SEER, 2009
Pancreatic Cancer:
Challenges
 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 time of
diagnosis
 Pancreatic cancer is not very chemosensative
 Many patients suffer from rapidly declining performance
scores
Predisposing Factors
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


Age (average age 70-80s)
Smoking
Chronic pancreatitis
Obesity
Diabetes mellitus
Familial syndromes





Hereditary Breast and Ovarian cancer
Peutz-Jeghers
Familial atypical mole/ melanoma
Lynch syndrome
Hereditary pancreatitis
Presentation





Abdominal pain
Jaundice (often painless)
Weight loss
New onset diabetes mellitus
Pancreatic enzyme insufficiency
(diarrhea, floating/fatty stools)
The Pancreas
Case
 76 yr female presented with painless
jaundice
 Developed anorexia, 14 lb weight loss/2
mths
 U/S- intra and extra hepatic biliary ductal
dilitation
 CT- 2.4cm pancreatic head mass, 18mm
CBD, dilated pancreatic duct
Diagnosis
 FNA of the primary mass or distant




metastases
ERCP with stent and brushings/biopsy
FNA of the primary with EUS
(endoscopic ultrasound)
EUS is also useful for staging, invasion
into surrounding vessels (SMA, SMV)
Determination of resectability
ERCP
ERCP - Diagnostic
Double duct sign
CBD Stricture
Common
Bile Duct
GB
PD stricture
Pancreatic Duct
EUS – Endoscopic ultrasound
TNM Staging
Primary Tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ (also PanIN 3)
T1
Tumor limited to pancreas, <=2cm
T2
Tumor limited to pancreas, >2cm
T3
Tumor extends beyond pancreas w/o
involvement of celiac axis or SMA
T4
Tumor invades celiac axis or SMA
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
Stage IB
T1 N0 M0
T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage III T4 Any N M0
Stage IV
Any T Any N M1
Staging: Patients Often Staged
Clinically, Not by TNM Classification
 Resectable

Absence of extrapancreatic disease, no evidence of direct tumor
extension to the SMA or celiac axis, patent PV
 (Borderline resectable)

Absence of extrapancreatic disease, SMA encasement < 180o SMV/portal
impingement, short segment SMV occlusion, celiac encasement < 180o,
abutment/encasement of hepatic artery
 Locally advanced/unresectable
 Absence of extrapancreatic disease, SMA encasement > 180o,
unreconstructable SMV/portal vein occlusion; any celiac abutment or
celiac encasement > 180o, aortic invasion or encasement, lymph node
metastases beyond field of resection
 Metastatic

Liver being the most common site for distant disease
Pancreatic Cancer by Stage
Stage Classification
% at Diagnosis 5-Yr Survival, %
Localized
8
22
Locally
advanced/
unresectable
27
9
Metastatic
65
2
Five-year Relative Survival (%) during Three Time Periods By
Cancer Site
Site
All sites
Breast (female)
Colon
Leukemia
Lung and bronchus
Melanoma
Non-Hodgkin lymphoma
Ovary
Pancreas
Rectum
Urinary bladder
Surveillance, Epidemiology, and End Results Program, 2006.
1975-1977
50
75
51
35
13
82
48
37
2
49
73
1984-1986
53
79
59
42
13
86
53
40
3
57
78
1996-2002
66
89
65
49
16
92
63
45
5
66
82
Why is pancreatic cancer so hard
to treat?
Factors to Overcome
 No adequate screening test
 High incidence of metastatic disease at
presentation
 Fulminant clinical course
 Lack of adequate systemic therapies
Resectable Disease
PV
SMA
SMV
Resectable
Borderline Resectable
Locally Advanced
Surgery
(tumors of head or neck)
 Pancreaticoduodenectomy (Whipple)
 Operative mortality <2-3% in major surgical centers
Surgery
(tumors of body or tail)
 Often present late with larger tumors and frequent metastases
 Distal pancreatectomy +/- splenectomy
Poor survival even after surgery
 Even without clinical
evidence of metastasis,
5y survival after
resection is poor
 Mostly due to
metastatic disease
Agarwal et al., Pancreas 2008
Adjuvant Therapy
Adjuvant therapy
 Rationale:
High risk of local and systemic recurrence
 5-yr survival after resection:
25% node-neg vs. 10% node-pos
 Current standard:
No universally accepted standard approach
Adjuvant therapy
 5 major randomized trials
 Over 1200 patients studied
 Significant methodological differences
 Chemoradiotherapy in N. America
(GITSG, RTOG)
 Chemotherapy alone in Europe
(EORTC,ESPAC-1, CONKO)
Gemcitabine-based adjuvant therapy
 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)
Neoadjuvant Therapy
Rationale for Neoadjuvant therapy
 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
 No randomized studies comparing to
adjuvant
 Small, Phase II, mostly single instituiton
 5-fu and Gemcitabine chemoradiation have
been studied
Locally Advanced, Unresectable
Disease
Locally Advanced (Stage III)
SMV
SMA
Locally advanced, unresectable
 27% 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
Chemoradiation > RT alone
 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
Krzyzanowska, JCO 2003
Treatment of Metastatic
Disease
Metastatic Pancreatic Cancer: The Basis of Gemcitabine
as the Mainstay of Treatment
 Gemcitabine as first-line
treatment for patients with
advanced pancreatic cancer
Median survival (vs bolus
5-FU): 5.65 vs 4.41 mos.
(P = .0025)
 1-year survival: 18% vs 2%
 Clinical benefit: 23.8% vs
4.8%
 Response rate: 5.4% vs 0%
Patients Surviving (%)

100
Gemcitabine
5-FU
80
60
40
20
0
0
Burris HA, et al. J Clin Oncol. 1997;15:2403-2413.
2
4
6 8 10 12 14 16 18 20
Survival Time (Mos)
International Phase III
Trial
Pancreatic cancer
(locally advanced
or metastatic)
Gemcitabine 1000 mg/m2
weekly x 3 of 4
Gemcitabine 1000 mg/m2
+
Nab-Paclitaxel 125 mg/m2
weekly x 3 of 4
Phase III trial:Gemcitabine
and Abraxane
Gemcitabine
Gemcitabine and
Abraxane
Overall Survival
6.7 mths
8.5 mths
1 Year Survival
22 %
33 %
N= 861 Pts
Phase III Trial of Gemcitabine vs FOLFIRINOX
Gemcitabine 1000 mg/m2
weekly x 7 of 8,
then weekly x 3 of 4
(n = 171)
Metastatic Pancreatic Cancer
Conroy T, et al. N Eng J Med. 2011;364:1817-1825.
FOLFIRINOX
Oxaliplatin 85 mg/m2
LV 400 mg/m2
Irinotecan 180 mg/m2
5-FU bolus 400 mg/m2, then
2400 mg/m2 infusional over 46
hrs (n = 171)
FOLFIRINOX vs Gemcitabine: Overall Survival
Overall Survival
Patients Alive (%)
100
HR: 0.57 (95% CI: 0.45-0.73;
P < .001
75
FOLFIRINOX
50
Gemcitabine
25
0
0 3 6 9 1215182124273033363942
Pts at Risk, n
Gemcitabine
FOLFIRINOX
171 134 89 48 28 14 7
171 146 116 81 62 34 20
Months
6
13
3
9
3
5
Conroy T, et al. N Eng J Med. 2011;364:1817-1825
2
3
2
2
2
2
2
2
1
2
Outcome
FOLFIRINOX
GEMCITABINE
Response Rate
31.6%
9.4%
Medium
Survival
11.1
6.8
1 Year Survival
48.4%
20.6%
Is FOLFIRINOX Tolerable? Safety and Toxicity
Event, n/N (%)
FOLFIRINOX
(n = 171)
Gemcitabine
(n = 171)
P Value
75/164 (45.7)
35/167 (21.0)
< .001
 Febrile neutropenia
9/166 (5.4)
2/169 (1.2)
.03
 Thrombocytopenia
15/165 (9.1)
6/168 (3.6)
.04
 Anemia
13/166 (7.8)
10/168 (6.0)
NS
 Fatigue
39/165 (23.6)
30/169 (17.8)
NS
 Vomiting
24/166 (14.5)
14/169 (8.3)
NS
 Diarrhea
21/165 (12.7)
3/169 (1.8)
< .001
 Sensory neuropathy
15/166 (9.0)
0/169
< .001
 Elevated ALT
12/165 (7.3)
35/168 (20.8)
< .001
 Thromboembolism
11/166 (6.6)
7/169 (4.1)
NS
Hematologic
 Neutropenia
Nonhematologic
Conroy T, et al. N Eng J Med. 2011;364:1817-1825.
Targeted Therapy
Erlotinib - Targeted Agent Approved for Pancreatic
Cancer
Gemcitabine + Erlotinib
 Expression of EGFR is common, poor prognosis
 Phase III study
 569 patients randomized to:




Moore, JCO 2007
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)
FDA approved in 2005 in combination with
gemcitabine
Moore, JCO 2007
Metastatic Pancreatic Cancer
 Pancreatic cancer remains a clinical challenge
 Current therapies offer only modest benefits
 FOLFIRINOX
 Gemcitabine and Abraxane
 Gemcitabine
 Numerous studies incorporating new, targeted
agents have offered little/no benefit over
Gemcitabine alone.
Conclusions
 Localized disease -> Surgery
 Most adjuvant therapy -> ChemoXRT
 Combination chemotherapy and multimodality therapy
for earlier stages of disease (locally advanced,
resectable) need to be clarified
 Locally advanced (non-resectable)-> Chemotherapy vs
Radiation vs ChemoXRt
 Chemotherapy options: evolving and improving in
advanced pancreatic cancer (eg, FOLFIRINOX)
 “Targeted” therapeutic agents have been disappointing
Conclusions
 Pancreatic cancer is a horrible disease
 Median survival less than one year for most
 Majority found with metastatic disease
 Surgery is the only treatment that may lead to
durable cure at this point in time
Pancreatic Neuroendocrine tumors
Case
 62 yo male presented with L flank
 Presented to urgent care, palpated an
abdominal mass
 CT done- 11 x 8 cm mass in the body of
the pancreas, no mets, obliteraion of
portal, splenic, SMV
 Patient has no symptoms, no weight
loss, no pain
Case
Histology
 Nonfunctional
 Functional
 Insulinomas -> Hypoglycemia
 Gastrinomas -> Peptic Ulcer Disease
 Glucagonomas -> Diabetes
 EUS/FNA- low grade neuroendocrine
neoplasm
 Resect if possible
 Prognosis is good, even in metastatic
disease -> median survival >5yrs
 Options:
Observation
Somatostin analog
Chemotherapy
Biologic therapy