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Pancreatic Cancer

Pancreatic Cancer. Malcolm J. Moore MD Princess Margaret Hospital. Pancreatic Cancer. US incidence: 32,180 new cases estimated for 2005 1 2% of all new cancer cases Screening, early detection not on the horizon Most patients are diagnosed with advanced disease.

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Pancreatic Cancer

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  1. Pancreatic Cancer Malcolm J. Moore MD Princess Margaret Hospital

  2. Pancreatic Cancer • US incidence: 32,180 new cases estimated for 20051 • 2% of all new cancer cases • Screening, early detection not on the horizon • Most patients are diagnosed with advanced disease 1 CA Cancer J Clin 2005;55:10-30

  3. Pancreatic Cancer – Outcome is Poor • US mortality: 31,800 deaths estimated for 20051 • 4th and 5th leading cause of cancer-related death in males and females, respectively • 5% to 6% of all cancer deaths • 5 year survival less than 5%2. Median survival 3-4 • metastatic disease 3-6 months • locally advanced disease 9 months • Resected disease 14 months 1 CA Cancer J Clin 2005;55:10-30 2 SEER Cancer Statistics Review. http://seer.cancer.gov 3 Am J Surg 1993;165:68 4 JCO 2005; 23:4538

  4. Pancreatic Cancer • Epidemiology • Increases with age • No major geographical differences • Genetics • P16, DPC, p53, k-ras • Familial • Poorly understood

  5. Pancreatic Tumors • Most are ductal adenocarcinomas. • Most common site is head of pancreas • Dense fibrous reaction. • Precursor lesions – PanIN • Other subtypes • Adenosquamous • Acinar cell, medullary, undifferentiated

  6. Pancreatic Cancer – Ductal Adenocarcinoma most common

  7. Pancreatic Tumors • Serous cystadenoma/adenocarcinoma. • Mucinous neoplasms • Endocrine tumors • Range of differentiation-not all malignant • Functioning vs non • Well circumscribed • Vascular Tumors of the pancreas, Armed Forces Institute of Pathology, Washington 1997. p.145.

  8. Well differentiated endocrine tumor - + chromogranin

  9. Pathology • Most are ductal adenocarcinoma • But not all, so … • Biopsy essential • Although usually can predict non-adenocarcinoma by imaging or clinical course.

  10. Making the diagnosisCommon symptoms • Pain • Gastric obstruction • Biliary obstruction • Diabetes • Hypercoaguability • Malabsorption

  11. CA 19-9 • Tumor associated antigen • Elevated in most cases of pancreatic cancer. • Also elevated in other GI cancers, pancreatitis. • Slightly better specificity and sensitivity than CEA. • Unknown value in clinical studies. Am J Gastroenterol 1999;94:1941-6.

  12. Pain Pancreatic Cancer • Pain often due to local invasion of tumor. • Improved by XRT +/- chemo in 35-65% of cases • Improved by palliative chemo • Celiac axis blocks

  13. Pancreatic CancerGastric/duodenal obstruction • Occurs in cancers of pancreatic head. • Consider in patients with refractory nausea/vomiting • Remedies are • Gastrojejunostomy- open or laparoscopic • Duodenal stenting • ? Role of prophylactic gastrojejunostomy

  14. Pancreatic CancerBiliary obstruction • Cancers of pancreatic head. • Often presenting problem. • ? Surgical vs Endoscopic stenting. • Both effective. • Surgery a better long term solution. • Stent occlusion/replacement • Percutaneous drainage not recommended

  15. Pancreatic CancerDiabetes • ? A risk factor for disease. • Can be a presenting problem. • More than just loss of pancreatic function. • Treat symptomatically. • Not a contraindication to steroids

  16. Hypercoaguability • Well recognized association -Trousseau’s syndrome. • Can be both central and peripheral. • Generally resistant to oral agents. • Long term therapy required. • Association with early deaths • ? Role of prophylactic anti-coagulation

  17. Malabsorption • Pancreatic insufficiency • One reason for weight loss • Use of narcotics may mask usual symptoms • Trial of pancreatic enzymes

  18. Surgery • Only 15-20% are resectable. • Whipples resection (pancreaticoduodenectomy) for tumors of the head • 3 anastamoses • Should be done in high volume centres

  19. Is there a role for adjuvant therapy?

  20. Original Adjuvant Trial GITSG [N=43]1 • Median survival 20 versus 11 months • 5 year survival 18 vs 8% But… - 43 patients in 8 years. • A larger EORTC trial (n=114 pancreatic cancer) failed to confirm the benefit of adjuvant CRT 2 5-FU + XRT with systemic 5-FU X 1 yr vs No additional treatment

  21. 2x2 Factorial Design (Target 280) Observation CT CRT CRT CT Chemotherapy – 5-FU/LV [Mayo] X 6 Chemoradiation – 4000/20 [split] + bolus 5-FU. ESPAC-1 Trial DesignNeoptolemos NEJM 2004 350(12):1200-10 Adenocarcinoma pancreatic cancer undergoing ‘curative’ resection Randomise (stratified by centre, tumour type, resection margins)

  22. Survival by Adjuvant Chemoradiotherapy Median survival No chemoRT 17.9 mo ChemoRT 15.9 mo HR 1.28 [0.99-1.66], p=0.05 N Engl J Med 2004 Mar 18;350(12):1200-10

  23. Survival by Adjuvant Chemotherapy Median survival No Chemo 15.5 mo Chemo 20.1 mo HR 0.71 [0.55-0.92], p=0.009 N Engl J Med 2004 Mar 18;350(12):1200-10

  24. CONKO-001Neuhaus ASCO 2005 Resected pancreatic cancer 368 patients Stratification: R; T; N Observation for 6 months Gemcitabine for 6 months Follow up every 8 weeks J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  25. Tumor Characteristics J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  26. CONKO-001 Kaplan Meier Disease Free Survival ObsMedian DFS 7.46 mo Gem Median DFS 14.21 mo Log rank p < 0.001 J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  27. CONKO-001 Kaplan Meier Overall Survival Gemcitabine53 % patients censored (+) Observation45 % patients censored (+) J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  28. ESPAC –3/ NCIC PA.2 Pancreatic Adenocarcinoma cancer undergoing ‘curative’ resection Randomise (stratified by centre, tumour type, resection margins) 5FU/FA N=500 Gemcitabine N=500 5-FU/FA:FA 20 mg/m2 iv, 5-FU 425 mg/m2 iv X5 every 28 days, x6 cycles GEMCITABINE:1000 mg/m2 iv once weekly x3 wks, 1 wk rest, x6 cycles

  29. Adjuvant Therapy of Pancreatic Cancer • Adjuvant 5FU improves survival compared to observation • Preliminary results show improved PFS (and now survival) with adjuvant gemcitabine vs. observation • The optimal chemotherapy regimen (5FU/gemcitabine) not known • Role of XRT still controversial.

  30. Locally Advanced Pancreatic Cancer

  31. Pancreatic Cancer: Unresectable Moertel1Radiation Alone 6.3 monthsRadiation and 5-FU 10.4 monthsGITSG (randomized) 260 Gy Alone 5.3 months40 Gy + 5-FU 8.4 months60 Gy + 5-FU 11.4 months 1 Lancet 2:865-867, 1969 2 Cancer 48:1705-1710, 1981

  32. Gemcitabine + Radiation PMH Phase I/II study GEMCITABINE 1000 mg/m 2 IV x7 Followed by GEMCITABINE 40 mg/m 2 IV 2X/week with XRT 3500-5250cGy over 4-6 weeks • Patients with locally advanced (31), resected (32) disease-March 1999 to July 2001. • 35 patients received initial gemcitabine. • 8 [23%] of these did not get XRT Unpublished Data

  33. Gemcitabine + Radiation PMH Phase I/II study • 32 adjuvant patients • Median time to progression 14.3 months • Median survival 17.9 months • 5 year survival 19% • 31 locally advanced • 1 complete response, 2 partial responses • 10 stable disease • Median survival 15.1 months • 2 year survival 19% Unpublished Data

  34. Locally Advanced Pancreatic Cancer • Chemoradiation in locally advanced pancreatic cancer improves: • survival1-2 • and pain in 35-65% of patients 3-6 • Outcomes are still poor and better radiation sensitizers are needed • Most use up front chemo for 2 months and then chemo XRT

  35. Tumor in the body and tail of pancreas with liver metastasis

  36. GemcitabineRegistration Study in Pancreatic Cancer † Composite of measurements of pain (analgesic consumption and pain intensity), KPS and weight Burris HA, Moore MJ, Andersen J,et al. J Clin Oncol. 1997;15:2403-2413

  37. Gemcitabine vs MMPI: NCIC.PA1 GEM = 6.67m (5.75-8.02) BAY = 3.74m (2.79-4.57) HR = 0.565 (0.44-0.73) P= 0.0001 GEM BAY • Survival of untreated metastatic disease is short. • Salvage of patients with crossover is not possible. • Gemcitabine needs to be included in all treatments.

  38. Negative Combination Chemotherapy Trials 2004-2006 • Gemcitabine vs gemcitabine FDR + oxaliplatin [N=313] • Louvet C et al. ASCO 2004;22:14S(Abs. 4008) • Gemcitabine vs gem FDR + gem FDR + oxaliplatin [N= 835] • Poplin et al. ASCO 2006;24:14S (Abs. 4003) • Gemcitabine vs gemcitabine + pemetrexed [N=565] • Richards DA et al. ASCO 2004;22:14S (Abs. 4007) • Gemcitabine vs gemcitabine + irinotecan [N=360] • Roche Lima, J Clin Oncol 2004 • Gemcitabine vs gemcitabine + exatecan [N=349] • O’Reilly EM et al. ASCO 2004;22:14S (Abs. 4006) • Gemcitabine vs gemcitabine + capecitabine [N=319] • Hermann et al. ASCO 2005;23:14S (Abs. 4508) • Gemcitabine vs gemcitabine + 5FU/LV [N= 473] • Reiss et al. ASCO 2005;23:14S (Abs. 4509)

  39. Gemcitabine and Fluoropyrimidines Phase III trials • Trial Treatment arms n Overall survival p • Median 1-year • Berlin et al Gemcitabine 162 5.4 months 18 % 0.09 • Gem/bolus 5-FU 160 6.7 months 19 % • Riess et al Gemcitabine 236 6.2 months ~18% 0.683 • (2005) Gem/FU/LV 230 5.85 months ~18% • Herrmann et al Gemcitabine 159 7.3 months 31% 0.314 • (2005) Gem/capecitabine1 160 8.4 months 31% • Cunningham Gemcitabine 266 6.0 months 19% 0.026 • (2005) Gem/capecitabine2 267 7.4 months 26% 1 Gemcitabine 1000mg/m2wkly ×2 q3 weeks Capecitabine 1300mg/m2/day X 14 q3 weeks 2 Gemcitabine 1000mg/m2weekly ×3 q4 weeks Capecitabine 1660mg/m2/day for 21days q4 weeks

  40. 5FU/LV +/- Oxaliplatin Second Line therapy • 168 patients randomized • Mostly good PS status • PFS also better by 4 wks • Effect most pronounced in non- responders to gem in first line • Kubica et al ASCO 2008

  41. Gemcitabine + Drug Vs Gemcitabine?Heinemann, et al. ASCO 2007

  42. Combination Chemotherapy in Pancreatic Cancer • One positive study in first line ? • Gemcitabine + Capecitabine. • One positive study in second line. • 5FU + oxaliplatin. • Many negative studies • Incremental benefit of combination chemotherapy. • Restricted to patients with (very) good PS • Is it worth doing any more studies?

  43. Some key molecular abnormalities in Pancreatic Cancer

  44. Pancreatic Cancer: Other Molecular Targets Growth Factor Ligand (EGF, VEGF) ECM Integrin Homodimer Y Y Y Y Y Y ras FAK Src raf EGF Receptor PI3K Pro-MMP MEK Akt ERK Nucleus Regulation of Gene Transcription

  45. The Epidermal Growth Factor Signaling Pathway

  46. 5.9 6.4 SWOG: Gemcitabine +/- CetuximabOverall Survival HR = 1.09 (95% CI: 0.93, 1.27) PFS

  47. NCIC. PA.3 Study Schema Patient Population • Adenocarcinoma of pancreas • No prior chemotherapy • Measurable or non-measurable disease • EGFR status not an eligibility criterion Stratification • Center • PS (0/1 vs 2) • Stage of disease(Loc Adv / Metastatic) Gemcitabine + Erlotinib 100/150 mg RANDOM I ZE Gemcitabine + Placebo

  48. HR = 0.81* 95% CI (0.67, 0.97) P = 0.025 Gemcitabine + Erlotinib Median = 6.4 months 1 Year Survival = 24% Gemcitabine + Placebo Median = 5.9 months 1 Year Survival = 17% Overall Survival for All Patients

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