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*
10th most common cancer
Men 766,860
Women 678,060
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%
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
Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.4 million new cases of cancer will be diagnosed in Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women.
*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
Lung & bronchus 31%
Prostate 9%
Colon & rectum 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4% bile duct
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin % lymphoma
Kidney 3%
All other sites %
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 cancer is, by far, the most common fatal cancer in men (31%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death.
ONS=Other 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
Β-napthylamine

10. Clinical Presentation
Painless obstructive jaundice (pancreatic head tumors -2/3)
Abdominal pain
Anorexia, weight loss
Trousseau’s 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. Adjuvant chemotherapy
Treatment Approach
Resectable disease
Stages I-II
(20%)
Surgery
Adjuvant chemotherapy
Adjuvant radiation

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 (>180 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 N=43!!!
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 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:

24. 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:

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

29. RTOG 9704 Trial Gem 5FU Med survival 20.5 m 16.9 m
3 yr survival % %
WF Regine et al JAMA 299: , 2008

32. RTOG 9704 Trial
WF Regine et al JAMA 299: , 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 <2.5 x normal

35. CONKO-001 Trial Med DFS 13.4 m Gem 6.9 m Obs OS 3/5 yr 34/22.5% Gem
Oettle et al JAMA 297: , 2007

36. CONKO-001 Trial: R1 vs R0 Med surv 13.1 m Gem 7.3 m Obs
H Oettle et al JAMA 297: , 2007

37. ESPAC Adjuvant Trials: 5FU/FA vs Observation
Overall survival
Survival rates year 5-year
Obs: % %
5FU/FA: % %
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 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

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 < 2
Life-expectancy of more than 3 months
Fully informed written consent

40. 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)

41. 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)

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)
(% of 537 pts)
WBC 32
(6%) 53
(10%)
Neutrophils
121
(22%)
119
Platelets 8
(1.5%)
Nausea 19
(3.5%) 13
(2.5%)
Vomiting 17
(3%) 11
(2%)
Stomatitis 54 1
(0%)
Alopecia
Tiredness 45
(8%)
Diarrhoea 72
(13%) 12
Other 67
(12%) 43
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=0.027
* Exploratory analysis: sig level p<0.005 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. Locally Advanced stage III
Treatment Approach
Inoperable disease
Locally Advanced stage III
(30-40^)
Chemoradiation
Chemotherapy
Metatatic Stage IV
(40-50%)
Supportive Care

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 (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: , 2005.

51. Anticipated accrual : 602 patients
Next Step: Phase III
CALGB – 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

56. What happened?

58. EGFR Agents in Pancreatic Cancer The Greatest Thing Since …?
EGFR antagonists in NSCLC?

60. NCIC PA.3
Gemcitabine plus erlotinib: 1st combination therapy to demonstrate a survival advantage over gemcitabine alone

62. 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: , 2004.

71. 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?