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Pancreatic Cancer

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Pancreatic Cancer Yoo-Joung Ko What lessons have we learned? Locally advanced and metastatic disease should be separated VEGF inhibition not encouraging EGFR ... – PowerPoint PPT presentation

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Title: Pancreatic Cancer


1
Pancreatic Cancer
  • Yoo-Joung Ko

2
Recent Media Exposure
October 23, 1960 July 25, 2008 Died 2 years
after undergoing a Whipple procedure in 2006
3
Patrick Swayze
Diagnosed with stage IV pancreatic cancer Jan
2008 Died Sept 14, 2009
4
Overview
  • Epidemiology
  • Risk Factors
  • Pathology
  • Presentation
  • Surgical treatment
  • Adjuvant therapy
  • Treatment of metastatic disease

5
2007 Estimated US Cancer Cases
Men 766,860
Women 678,060
10th most common cancer
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-Hodgkin 4
lymphoma Melanoma of
skin 4 Kidney 4 Leukemia 3 Oral
cavity 3 Pancreas 2 All Other Sites 19
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2007.
6
2007 Estimated US Cancer Deaths
4th leading cause of cancer death
Men 289,550
Women 270,100
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
intrahepatic bile 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
ONSOther nervous system. Source American Cancer
Society, 2007.
7
JP Hoffman ASCO 2006
8
Poor Survival
AJCC Stage Median Survival
Resectable (I-II) 14-25months
Locally Advanced (II) 8-15 months
Metastatic (IV) 3-7 months
9
Risk Factors
  • Smoking
  • Age, gender
  • Obesity
  • Diet high fat, low fibre
  • Chronic pancreatitis
  • Family history BRCA2
  • ?-napthylamine

10
Clinical Presentation
  • Painless obstructive jaundice (pancreatic head
    tumors -2/3)
  • Abdominal pain
  • Anorexia, weight loss
  • Trousseaus sign
  • Depression
  • diabetes

11
Sites of Metastasis
  • Liver
  • Peritoneum
  • Lung
  • Adrenal
  • Bone
  • Rarely CNS

12
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

13
Ductal Adenocarcinoma
  • Nuclear atypia
  • Significant fibrosis

14
Treatment Approach
15
Patient Workup
  • Birphasic CT
  • ERCP stent /- biopsy
  • PET scan for possible resection

16
Surgical Resectability
  • No evidence of extra-pancreatic disease
  • Liver
  • Retroperitoneum
  • Peritoneal disease
  • No evidence of SMA, hepatic or celiac encasement
    (gt180 degrees)
  • Fewer than 20 are surgical candidates

17
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

18
Effect of Hospital Volume
19
How good is surgery?
  • Does a whipple increase survival by minutes?

20
Post Surgical Therapy
  • No standard of care for adjuvant therapy
  • European standard
  • Chemotherapy alone
  • US standard
  • chemoradiotherapy

21
GITSG- Cancer 1987
  • First randomized study
  • N43!!!
  • Observation versus RT (splite course, 40 Gy FU
    bolus then adjuvant 5FU)
  • 2 year survival 46 versus 18

22
European Standard ESPAC-1
23
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 HR1.28 (0.99,
1.66), p0.053
NEJM 2004 3501200-10
24
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 HR0.71 (0.55,
0.92), p0.009
NEJM 2004 3501200-10
25
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)

26
US approach Study Design
Note that absence of no XRT arm
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RTOG 9704 Trial
Gem 5FU Med survival 20.5 m
16.9 m 3 yr survival 31 22
WF Regine et al JAMA 2991019-1029, 2008
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RTOG 9704 Trial
WF Regine et al JAMA 2991019-1029, 2008
33
CONKO-1
34
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 lt2.5 x normal

35
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
Oettle et al JAMA 297267-277, 2007
36
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
H Oettle et al JAMA 297267-277, 2007
37
ESPAC Adjuvant Trials 5FU/FA vs Observation
Overall survival
Survival rates 2-year 5-year Obs
37 14 5FU/FA
49 24
Cumulative survival
HR 0.68 (0.50, 0.92) p 0.001
N 458
Br J Cancer 2009 100 246-50
38
ESPAC-3(v1) Trial Design
Patients with ductal adenocarcinoma undergoing
curative resection Target N990
RANDOMISE
5FU/ FA 5-FU 425mg/m2 FA 20mg/m2 for 5 days
every 28 days for 6 cycles Target N330
GEMCITABINE 1000mg/m2 once a week for 3 of 4
weeks for 6 cycles Target N330
OBSERVATION Target N330
330 per group to detect 10 difference in 2y
survival rate (? 5, 1-b 80)
Trial opened July 2000
39
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 lt 2
  • Life-expectancy of more than 3 months
  • Fully informed written consent

40
Survival by Treatment
Median S(t) 23.0 months (95CI21.1,
25.0) Median S(t) 23.6 months (95CI21.4, 26.4)
c2LR0.74, p0.39, HRGEM VS 5FU/FA0.94 (95CI
0.81, 1.08)
41
PFS by Treatment
Median PFS(t) 14.1months (95CI12.5,
15.3) Median PFS(t) 14.3months (95CI13.5, 15.7)
c2LR0.59, p0.44, HRGEM VS 5FU/FA0.95 (95CI
0.83, 1.09)
42
Reported Toxicity
Number of patients with at least one NCI CTC v2.
grade 3/4 event
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)
p0.013 p0.94 p0.0034 p0.37 p0.34 plt0.001 p
1.0 p0.16 plt0.001 p0.027
Exploratory analysis sig level plt0.005 using
Bonferroni adjustment
43
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

44
Treatment Approach
45
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

46
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

47
Phase III study of Gemcitabine vs 5-FU
  • Multi-centre, single-blind, randomized study
  • Clinical benefit primary endpoint

Burris et al JCO 1997
48
Gemcitabine vs 5-FU survival
49
Gemcitabine Bevacizumab in Pancreatic cancer
50
Gemcitabine Bevacizumab
  • Phase II trial (n52)
  • 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.
51
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
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What happened?
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EGFR Agents in Pancreatic Cancer The Greatest
Thing Since ?
  • EGFR antagonists in NSCLC?

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NCIC PA.3
Gemcitabine plus erlotinib 1st combination
therapy to demonstrate a survival advantage over
gemcitabine alone
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Gemcitabine Cetuximab
  • Phase II trial (n41)
  • 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.
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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?
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