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Pancreatic CancerYoo-Joung Ko
Recent Media Exposure
October 23, 1960 – July 25, 2008Died 2 years after undergoing a Whipple procedure in 2006
Patrick Swayze
Diagnosed with stage IV pancreatic cancer Jan 2008Died Sept 14, 2009
Overview
Epidemiology
Risk Factors
Pathology
Presentation
Surgical treatment
Adjuvant therapy
Treatment of metastatic disease
2007 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.
Men766,860
Women678,060
26% Breast
15% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Non-Hodgkin lymphoma
4% Melanoma of skin
4% Thyroid
3% Ovary
3% Kidney
3% Leukemia
21% All Other Sites
Prostate 29%
Lung & bronchus 15%
Colon & rectum 10%
Urinary bladder 7%
Non-Hodgkin4% lymphoma
Melanoma of skin 4%
Kidney 4%
Leukemia 3%
Oral cavity 3%
Pancreas 2%
All Other Sites 19%
10th most common cancer
2007 Estimated US Cancer Deaths*
ONS=Other nervous system.Source: American Cancer Society, 2007.
Men289,550
Women270,100
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Brain/ONS
2% Liver & intrahepaticbile duct
23% All other sites
Lung & bronchus 31%
Prostate 9%
Colon & rectum 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4%bile duct
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin 3% lymphoma
Kidney 3%
All other sites 24%
4th leading cause of cancer death
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
Painless obstructive jaundice (pancreatic head tumors -2/3)
Abdominal pain
Anorexia, weight loss
Trousseau’s sign
Depression
diabetes
Sites of Metastasis
Liver
Peritoneum
Lung
Adrenal
Bone
Rarely CNS
Pancreatic Epithelial Malignancies
Malignant Ductal adenocarcinoma (majority) Mucinous cystadenocarcinoma Acinar cell carcinoma Small cell carcinoma
Uncertain malignant potential Mucinous cystadenoma Solid and cystic papillary neoplams
Ductal Adenocarcinoma
•Nuclear atypia•Significant fibrosis
Treatment Approach
Patient Workup
Birphasic CT
ERCP + stent + /- biopsy
PET scan for possible resection
Surgical Resectability
No evidence of extra-pancreatic disease Liver Retroperitoneum Peritoneal disease
No evidence of SMA, hepatic or celiac encasement (>180 degrees)
Fewer than 20% are surgical candidates
Whipple Procedure
Goal is R0 resection R2 or R1 resection have
outcomes similar to unresectable nonmetastatic disease
Operative mortality is associated with high volume centres
Effect of Hospital Volume
How good is surgery?
Does a whipple increase survival by minutes?
Post Surgical Therapy
No standard of care for adjuvant therapy
European standard Chemotherapy alone
US standard chemoradiotherapy
GITSG- Cancer 1987
First randomized study
N=43!!!
Observation versus RT (splite course, 40 Gy + FU bolus then adjuvant 5FU)
2 year survival 46% versus 18%
European Standard: ESPAC-1
Survival rates 2-year 5-yearNo CRT: 41.4% 19.6%CRT: 28.5% 10.0%HR=1.28 (0.99, 1.66), p=0.053
ESPAC-1ESPAC-1
NEJMNEJM 2004 2004; ; 350:1200-10 350:1200-10
ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed
Survival rates 2-year 5-yearNo CT: 30.0% 8.4%CT: 39.7% 21.1%HR=0.71 (0.55, 0.92), p=0.009
ESPAC-1ESPAC-1
NEJM 2004; NEJM 2004; 350:1200-10 350:1200-10
ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed
ESPAC 1 Trial
Lack QA for RT plans
RT field size and techniques not specified
Split course RT used, low dose (20 Gy/10 f x 2)
US approach: Study Design
Note that absence of no XRT arm
Gem 5FUMed survival 20.5 m 16.9 m3 yr survival 31% 22%
WF Regine et al JAMA 299:1019-1029, 2008
RTOG 9704 Trial
RTOG 9704 Trial
WF Regine et al JAMA 299:1019-1029, 2008
CONKO-1
CONKO 1 Trial
surgery vs postop gem alone
Total of 368 pts with R0/R1 resection
Gem 1000 mg/m2 weekly 3 of 4 wks
Primary endpoint was DFS, not OS
Only included pts with Ca 19-9 <2.5 x normal
Oettle et al JAMA 297:267-277, 2007
CONKO-001 Trial
Med DFS 13.4 m Gem 6.9 m Obs
OS 3/5 yr 34/22.5% Gem 20.5/11.5% Obs
H Oettle et al JAMA 297:267-277, 2007
CONKO-001 Trial: R1 vs R0
Med surv 13.1 m Gem 7.3 m Obs
Med surv 15.8 m Gem 5.5 m Obs
Br J Cancer 2009; Br J Cancer 2009; 100 :246-50
ESPAC Adjuvant Trials: 5FU/FA vs ESPAC Adjuvant Trials: 5FU/FA vs ObservationObservation
Survival rates 2-year 5-yearObs: 37% 14%5FU/FA: 49% 24%
Overall survival
N = 458
Cu
mu
lati
ve s
urv
ival
%
HR= 0.68 (0.50, 0.92) p = 0.001
ESPAC-3(v1) Trial DesignPatients with ductal adenocarcinoma
undergoing ‘curative’ resectionTarget N=990
RANDOMISE
5FU/ FA5-FU 425mg/m2 &FA 20mg/m2 for 5
days every 28 days for 6 cycles
Target N=330
GEMCITABINE1000mg/m2 once a
week for 3 of 4 weeks for 6 cycles
Target N=330
OBSERVATIONTarget N=330
330 per group to detect 10% difference in 2y survival rate ( = 5%, 1-= 80%)
Trial opened July 2000
Eligibility Complete macroscopic resection for pancreatic
ductal adenocarcinoma (WHO Classification)
R0 or R1 resection
No: ascites, liver or peritoneal metastasis, or any other distant abdominal or extra-abdominal organ spread
No previous or concurrent malignancy diagnoses
WHO performance status < 2
Life-expectancy of more than 3 months
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)
2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)
PFS by TreatmentMedian PFS(t)= 14.1months (95%CI:12.5, 15.3)Median PFS(t)= 14.3months (95%CI:13.5, 15.7)
2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)
Reported Toxicity
5FU/FA GEM
CTC 3/4 (% of 551 pts) CTC 3/4 (% of 537 pts)WBC 32 (6%) 53 (10%)
Neutrophils 121 (22%) 119 (22%)
Platelets 0 8 (1.5%)
Nausea 19 (3.5%) 13 (2.5%)
Vomiting 17 (3%) 11 (2%)
Stomatitis 54 (10%) 1 (0%)
Alopecia 1 (0%) 1 (0%)
Tiredness 45 (8%) 32 (6%)
Diarrhoea 72 (13%) 12 (2%)
Other 67 (12%) 43 (8%)
Number of patients with at least one NCI CTC v2. grade 3/4 event
* Exploratory analysis: sig level p<0.005 using Bonferroni adjustment
p=0.013
p=0.94
p=0.0034*
p=0.37
p=0.34
p<0.001*
p=1.0
p=0.16
p<0.001*
p=0.027
Conclusions
No difference in survival between adjuvant gemcitabine and 5-FU/FA in patients with resected pancreatic cancer
The safety profile of gemcitabine was better than that of 5-FU/FA
Data reinforce the perfect design of the ESPAC-4 trial comparing gemcitabine with the combination of gemcitabine with capecitabine
Treatment Approach
Palliation of Pancreatic Cancer
Pain management eg nerve block
Obstructive jaundice Percutaneous drain versus internal stent Metal versus plastic
Thromboembolism up to 20%
Depression
Fatigue, anorexia, weight loss
Chemotherapy versus BSC
Meta-analysis 3458 patients in 29 trials 9 trials with 5-FU combination vs BSC Median survival 6.4 vs 3.9 months
Phase III study of Gemcitabine vs 5-FU
Multi-centre, single-blind, randomized study
Clinical benefit primary endpoint
Burris et al JCO 1997
Gemcitabine vs 5-FU survival
Gemcitabine + Bevacizumab in
Pancreatic cancer
Gemcitabine + Bevacizumab
Phase II trial (n=52)
Metastatic advanced pancreatic cancer
Response: PR – 21%, SD – 46%
Median PFS: 5.4 months
Median OS: 8.8 months
VEGF levels did not correlate with outcome
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?
EGFR Agents in Pancreatic Cancer
The Greatest Thing Since …?EGFR antagonists in NSCLC?
NCIC PA.3
Gemcitabine plus erlotinib: 1st combination therapy to demonstrate a survival advantage over gemcitabine alone
Gemcitabine + Cetuximab
Phase II trial (n=41)
EGFR-positive advanced pancreatic cancer
Response: PR – 12.2%, SD – 63.4%
Median TTP: 3.8 months
Median OS: 7.1 months, 1 yr OS = 31.7%
Acneiform rash common (~90%) 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?