Download Pancreatic Cancer

Pancreatic Cancer
Yoo-Joung Ko
S
Recent Media Exposure
October 23, 1960 – July 25, 2008
Died 2 years after undergoing a
Whipple procedure in 2006
Patrick Swayze
Diagnosed with stage IV
pancreatic cancer Jan 2008
Died Sept 14, 2009
Overview
S Epidemiology
S Risk Factors
S Pathology
S Presentation
S Surgical treatment
S Adjuvant therapy
S Treatment of metastatic disease
2007 Estimated US Cancer Cases*
10th most common cancer
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*
4th leading cause of cancer death
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
JP Hoffman ASCO 2006
Poor Survival
AJCC Stage
Median Survival
Resectable (I-II)
14-25months
Locally Advanced (II)
8-15 months
Metastatic (IV)
3-7 months
Risk Factors
•Smoking
•Age, gender
•Obesity
•Diet – high fat, low fibre
•Chronic pancreatitis
•Family history – BRCA2
•Β-napthylamine
Clinical Presentation
S Painless obstructive jaundice (pancreatic head tumors -2/3)
S Abdominal pain
S Anorexia, weight loss
S Trousseau’s sign
S Depression
S diabetes
Sites of Metastasis
S Liver
S Peritoneum
S Lung
S Adrenal
S Bone
S Rarely CNS
Pancreatic Epithelial
Malignancies
S Malignant
S Ductal adenocarcinoma (majority)
S Mucinous cystadenocarcinoma
S Acinar cell carcinoma
S Small cell carcinoma
S Uncertain malignant potential
S Mucinous cystadenoma
S Solid and cystic papillary neoplams
Ductal Adenocarcinoma
•Nuclear atypia
•Significant fibrosis
Treatment Approach
Resectable disease
Stages I-II
(20%)
Surgery
Adjuvant chemotherapy
Adjuvant radiation
Patient Workup
S Birphasic CT
S ERCP + stent + /- biopsy
S PET scan for possible resection
Surgical Resectability
S No evidence of extra-pancreatic disease
S Liver
S Retroperitoneum
S Peritoneal disease
S No evidence of SMA, hepatic or celiac encasement (>180
degrees)
S Fewer than 20% are surgical candidates
Whipple Procedure
S Goal is R0 resection
S R2 or R1 resection have
outcomes similar to
unresectable nonmetastatic
disease
S Operative mortality is
associated with high volume
centres
Effect of Hospital Volume
How good is surgery?
S Does a
whipple
increase
survival by
minutes?
Post Surgical Therapy
S No standard of care for adjuvant therapy
S European standard
S Chemotherapy alone
S US standard
S chemoradiotherapy
GITSG- Cancer 1987
S First randomized
study
S N=43!!!
S Observation versus
RT (splite course, 40
Gy + FU bolus then
adjuvant 5FU)
S 2 year survival 46%
versus 18%
European Standard: ESPAC-1
ESPAC-1
ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed
Survival rates 2-year 5-year
No CRT:
41.4% 19.6%
CRT:
28.5% 10.0%
HR=1.28 (0.99, 1.66), p=0.053
NEJM 2004;
350:1200-10
ESPAC-1
ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed
Survival rates 2-year 5-year
No CT:
30.0% 8.4%
CT:
39.7% 21.1%
HR=0.71 (0.55, 0.92), p=0.009
NEJM 2004;
350:1200-10
ESPAC 1 Trial
S Lack QA for RT plans
S RT field size and techniques not specified
S Split course RT used, low dose (20 Gy/10 f x 2)
US approach: Study Design
Note that
absence of no
XRT arm
RTOG 9704 Trial
Gem
5FU
Med survival 20.5 m 16.9 m
3 yr survival 31%
22%
WF Regine et al JAMA 299:1019-1029, 2008
RTOG 9704 Trial
WF Regine et al JAMA 299:1019-1029, 2008
CONKO-1
CONKO 1 Trial
S surgery vs postop gem alone
S Total of 368 pts with R0/R1 resection
S Gem 1000 mg/m2 weekly 3 of 4 wks
S Primary endpoint was DFS, not OS
S Only included pts with Ca 19-9 <2.5 x normal
CONKO-001 Trial
Med DFS 13.4 m Gem
6.9 m Obs
Oettle et al JAMA 297:267-277, 2007
OS 3/5 yr 34/22.5% Gem
20.5/11.5% Obs
CONKO-001 Trial: R1 vs R0
Med surv 13.1 m Gem
7.3 m Obs
H Oettle et al JAMA 297:267-277, 2007
Med surv 15.8 m Gem
5.5 m Obs
ESPAC Adjuvant Trials: 5FU/FA vs
Observation
Cumulative survival %
Overall survival
Survival rates
Obs:
5FU/FA:
2-year
37%
49%
N = 458
Br J Cancer 2009; 100 :246-50
5-year
14%
24%
HR= 0.68 (0.50, 0.92)
p = 0.001
ESPAC-3(v1) Trial Design
Patients with ductal adenocarcinoma
undergoing ‘curative’ resection
Target N=990
RANDOMISE
OBSERVATION
Target N=330
5FU/ FA
5-FU 425mg/m2 &
FA 20mg/m2 for 5
days every 28 days
for 6 cycles
Target N=330
GEMCITABINE
1000mg/m2 once a
week for 3 of 4
weeks for 6 cycles
Target N=330
330 per group to detect 10% difference in 2y survival rate ( = 5%, 1-b = 80%)
Trial opened July 2000
Eligibility
S Complete macroscopic resection for pancreatic ductal
adenocarcinoma (WHO Classification)
S R0 or R1 resection
S No: ascites, liver or peritoneal metastasis, or any other
distant abdominal or extra-abdominal organ spread
S No previous or concurrent malignancy diagnoses
S WHO performance status < 2
S Life-expectancy of more than 3 months
S Fully informed written consent
Survival by Treatment
Median S(t)= 23.0 months (95%CI:21.1, 25.0)
Median S(t)= 23.6 months (95%CI:21.4, 26.4)
c2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)
PFS by Treatment
Median PFS(t)= 14.1months (95%CI:12.5, 15.3)
Median PFS(t)= 14.3months (95%CI:13.5, 15.7)
c2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)
Reported Toxicity
Number of patients with at least one NCI CTC v2. grade 3/4 event
WBC
Neutrophils
Platelets
Nausea
Vomiting
Stomatitis
5FU/FA
GEM
CTC 3/4 (% of 551 pts)
CTC 3/4 (% of 537 pts)
32 (6%)
53 (10%)
p=0.013
121 (22%)
0
p=0.94
p=0.0034*
119 (22%)
8 (1.5%)
19 (3.5%)
p=0.37
13 (2.5%)
17 (3%)
p=0.34
11 (2%)
54 (10%)
p<0.001*
1 (0%)
Alopecia
1 (0%)
p=1.0
1 (0%)
Tiredness
45 (8%)
p=0.16
32 (6%)
Diarrhoea
72 (13%)
p<0.001*
12 (2%)
Other
67 (12%)
p=0.027
43 (8%)
* Exploratory analysis: sig level p<0.005
using Bonferroni adjustment
Conclusions
S No difference in survival between adjuvant gemcitabine
and 5-FU/FA in patients with resected pancreatic cancer
S The safety profile of gemcitabine was better than that of
5-FU/FA
S Data reinforce the perfect design of the ESPAC-4 trial
comparing gemcitabine with the combination of
gemcitabine with capecitabine
Treatment Approach
Inoperable disease
Locally Advanced stage III
(30-40^)
Metatatic Stage IV
(40-50%)
Chemoradiation
Chemotherapy
Chemotherapy
Supportive Care
Palliation of Pancreatic Cancer
S Pain management eg nerve block
S Obstructive jaundice
S Percutaneous drain versus internal stent
S Metal versus plastic
S Thromboembolism up to 20%
S Depression
S Fatigue, anorexia, weight loss
Chemotherapy versus BSC
S Meta-analysis 3458 patients in 29 trials
S 9 trials with 5-FU combination vs BSC
S Median survival 6.4 vs 3.9 months
Phase III study of Gemcitabine
vs 5-FU
S Multi-centre, single-blind, randomized study
S Clinical benefit primary endpoint
Burris et al JCO 1997
Gemcitabine vs 5-FU survival
Gemcitabine + Bevacizumab
in Pancreatic cancer
S
Gemcitabine + Bevacizumab
S Phase II trial (n=52)
S Metastatic advanced pancreatic cancer
S Response: PR – 21%, SD – 46%
S Median PFS: 5.4 months
S Median OS: 8.8 months
S VEGF levels did not correlate with outcome
S GI perforation 8%, one pt : Gr 5 GI bleed
Kindler et al. JCO 23: 8033-40, 2005.
Next Step: Phase III
CALGB 80303 – Gemcitabine With Versus
Without Bevacizumab in Advanced
Pancreatic Cancer
Anticipated accrual : 602 patients
Press release June, 2006: Trial closed early at interim
analysis due to poor efficacy in experimental arm
What happened?
S
EGFR Agents in Pancreatic Cancer
The Greatest Thing Since …?
EGFR antagonists in NSCLC?
S
S
NCIC PA.3
Gemcitabine plus erlotinib: 1st combination therapy to demonstrate a
survival advantage over gemcitabine alone
Gemcitabine + Cetuximab
S Phase II trial (n=41)
S EGFR-positive advanced pancreatic cancer
S Response: PR – 12.2%, SD – 63.4%
S Median TTP: 3.8 months
S Median OS: 7.1 months, 1 yr OS = 31.7%
S Acneiform rash common (~90%)
S Severity of rash correlated with survival
Xiong et al. JCO 22: 2610-16, 2004.
What lessons have we learned?
•Locally advanced and metastatic disease should
be separated
•VEGF inhibition not encouraging
•EGFR inhibition not encouraging
•Role of combination biologic therapy?
•Other targets?
•Combination with capecitabine?