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Pancreatic Cancer

Pancreatic Cancer. Yoo-Joung Ko. 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. Epidemiology Risk Factors Pathology

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Pancreatic Cancer

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  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 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-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 Men289,550 Women270,100 Lung & bronchus 31% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney 3% All other sites 24% 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 ONS=Other nervous system. Source: American Cancer Society, 2007.

  7. JP Hoffman ASCO 2006

  8. Poor Survival

  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. 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 (>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 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

  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% HR=0.71 (0.55, 0.92), p=0.009 NEJM 2004; 350:1200-10

  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

  27. 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

  28. RTOG 9704 Trial WF Regine et al JAMA 299:1019-1029, 2008

  29. CONKO-1

  30. 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

  31. 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 297:267-277, 2007

  32. 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 297:267-277, 2007

  33. 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

  34. ESPAC-3(v1) Trial Design Patients with ductal adenocarcinoma undergoing ‘curative’ resection Target N=990 RANDOMISE 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 OBSERVATION Target N=330 330 per group to detect 10% difference in 2y survival rate ( = 5%, 1-b = 80%) Trial opened July 2000

  35. 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

  36. 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)

  37. 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)

  38. Reported Toxicity Number of patients with at least one NCI CTC v2. grade 3/4 event 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 * Exploratory analysis: sig level p<0.005 using Bonferroni adjustment

  39. 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

  40. Treatment Approach

  41. 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

  42. 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

  43. Phase III study of Gemcitabine vs 5-FU • Multi-centre, single-blind, randomized study • Clinical benefit primary endpoint Burris et al JCO 1997

  44. Gemcitabine vs 5-FU survival

  45. Gemcitabine + Bevacizumab in Pancreatic cancer

  46. 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.

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