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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. - PowerPoint PPT Presentation

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  • Pancreatic CancerMalcolm J. Moore MDPrincess Margaret Hospital

  • Pancreatic CancerUS incidence: 32,180 new cases estimated for 20051 2% of all new cancer casesScreening, early detection not on the horizonMost patients are diagnosed with advanced disease1 CA Cancer J Clin 2005;55:10-30

  • Pancreatic Cancer Outcome is PoorUS mortality: 31,800 deaths estimated for 200514th and 5th leading cause of cancer-related death in males and females, respectively5% to 6% of all cancer deaths5 year survival less than 5%2.Median survival 3-4metastatic disease 3-6 monthslocally advanced disease 9 months Resected disease 14 months1 CA Cancer J Clin 2005;55:10-302 SEER Cancer Statistics Review. http://seer.cancer.gov3 Am J Surg 1993;165:684 JCO 2005; 23:4538

  • Pancreatic CancerEpidemiologyIncreases with ageNo major geographical differencesGeneticsP16, DPC, p53, k-rasFamilialPoorly understood

  • Pancreatic TumorsMost are ductal adenocarcinomas.Most common site is head of pancreasDense fibrous reaction.Precursor lesions PanINOther subtypesAdenosquamousAcinar cell, medullary, undifferentiated

  • Pancreatic Cancer Ductal Adenocarcinoma most common

  • Pancreatic TumorsSerous cystadenoma/adenocarcinoma.Mucinous neoplasmsEndocrine tumorsRange of differentiation-not all malignantFunctioning vs nonWell circumscribedVascular

    Tumors of the pancreas, Armed Forces Institute of Pathology, Washington 1997. p.145.

  • Well differentiated endocrine tumor - + chromogranin

  • PathologyMost are ductal adenocarcinomaBut not all, so Biopsy essentialAlthough usually can predict non-adenocarcinoma by imaging or clinical course.

  • Making the diagnosisCommon symptomsPainGastric obstruction Biliary obstruction Diabetes Hypercoaguability Malabsorption

  • CA 19-9Tumor associated antigenElevated 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.

  • 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

  • Pancreatic Cancer Gastric/duodenal obstructionOccurs in cancers of pancreatic head.Consider in patients with refractory nausea/vomitingRemedies areGastrojejunostomy- open or laparoscopicDuodenal stenting? Role of prophylactic gastrojejunostomy

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

  • 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

  • HypercoaguabilityWell recognized association -Trousseaus 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

  • MalabsorptionPancreatic insufficiencyOne reason for weight lossUse of narcotics may mask usual symptomsTrial of pancreatic enzymes

  • SurgeryOnly 15-20% are resectable.Whipples resection (pancreaticoduodenectomy) for tumors of the head3 anastamosesShould be done in high volume centres

  • Is there a role for adjuvant therapy?

  • Original Adjuvant TrialGITSG [N=43]1

    Median survival 20 versus 11 months5 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 25-FU + XRT with systemic 5-FU X 1 yrvsNo additional treatment

  • ESPAC-1 Trial DesignNeoptolemos NEJM 2004 350(12):1200-102x2 Factorial Design (Target 280)Observation CT

    CRT CRT CTChemotherapy 5-FU/LV [Mayo] X 6Chemoradiation 4000/20 [split] + bolus 5-FU.

    Adenocarcinoma pancreatic cancer undergoing curative resectionRandomise(stratified by centre, tumour type, resection margins)

  • Survival by Adjuvant ChemoradiotherapyMedian survivalNo chemoRT 17.9 moChemoRT 15.9 moHR 1.28 [0.99-1.66], p=0.05N Engl J Med 2004 Mar 18;350(12):1200-10

  • Survival by Adjuvant ChemotherapyMedian survivalNo Chemo 15.5 moChemo 20.1 moHR 0.71 [0.55-0.92], p=0.009N Engl J Med 2004 Mar 18;350(12):1200-10

  • CONKO-001Neuhaus ASCO 2005 Resected pancreatic cancer368 patients

    Stratification: R; T; NFollow up every 8 weeksGemcitabinefor 6 monthsObservationfor 6 monthsJ Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  • Tumor CharacteristicsJ Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

    Characteristic

    Chemotherapy(N=179)

    Observation(N=177)

    T

  • CONKO-001 Kaplan Meier Disease Free SurvivalObs Median DFS 7.46 mo Gem Median DFS 14.21 moLog rank p < 0.001J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  • CONKO-001 Kaplan Meier Overall SurvivalGemcitabine 53 % patients censored (+)Observation 45 % patients censored (+)J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

  • ESPAC 3/ NCIC PA.2Pancreatic Adenocarcinoma cancer undergoing curative resectionRandomise(stratified by centre, tumour type, resection margins) Gemcitabine N=5005FU/FAN=5005-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

  • Adjuvant Therapy of Pancreatic CancerAdjuvant 5FU improves survival compared to observationPreliminary results show improved PFS (and now survival) with adjuvant gemcitabine vs. observationThe optimal chemotherapy regimen (5FU/gemcitabine) not knownRole of XRT still controversial.

  • Locally Advanced Pancreatic Cancer

  • Pancreatic Cancer: Unresectable Moertel1 Radiation Alone 6.3 months Radiation and 5-FU10.4 months GITSG (randomized) 2 60 Gy Alone 5.3 months 40 Gy + 5-FU8.4 months 60 Gy + 5-FU11.4 months1 Lancet 2:865-867, 19692 Cancer 48:1705-1710, 1981

  • Gemcitabine + RadiationPMH Phase I/II studyPatients with locally advanced (31), resected (32) disease-March 1999 to July 2001.35 patients received initial gemcitabine.8 [23%] of these did not get XRTGEMCITABINE 1000 mg/m 2 IV x7 Followed byGEMCITABINE 40 mg/m 2 IV 2X/weekwithXRT 3500-5250cGy over 4-6 weeksUnpublished Data

  • Gemcitabine + RadiationPMH Phase I/II study32 adjuvant patients Median time to progression 14.3 monthsMedian survival 17.9 months5 year survival 19%31 locally advanced 1 complete response, 2 partial responses10 stable disease Median survival 15.1 months2 year survival 19%

    Unpublished Data

  • Locally Advanced Pancreatic CancerChemoradiation in locally advanced pancreatic cancer improves:survival 1-2and pain in 35-65% of patients 3-6Outcomes are still poor and better radiation sensitizers are needed

    Most use up front chemo for 2 months and then chemo XRT

  • Tumor in the body and tail of pancreas with liver metastasis

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

    GemcitabineN = 635-FU N = 63p-valueClinical benefit response24%5%0.002Survival Median survival, months5.74.40.002 1-year survival18%2%Partial response5.4%0Stable disease39%19%Time to progression, months2.30.90.0002

  • Gemcitabine vs MMPI: NCIC.PA1GEM = 6.67m (5.75-8.02)BAY = 3.74m (2.79-4.57)HR = 0.565 (0.44-0.73)P= 0.0001BAYGEMSurvival of untreated metastatic disease is short.Salvage of patients with crossover is not possible.Gemcitabine needs to be included in all treatments.

  • Negative Combination Chemotherapy Trials 2004-2006Gemcitabine 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]OReilly 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)

  • Gemcitabine and Fluoropyrimidines Phase III trials Trial Treatment armsn Overall survival pMedian1-year

    Berlin et alGemcitabine1625.4 months18 %0.09 Gem/bolus 5-FU1606.7 months 19 %

    Riess et alGemcitabine2366.2 months~18%0.683(2005)Gem/FU/LV2305.85 months ~18%

    Herrmann et al Gemcitabine1597.3 months31%0.314(2005)Gem/capecitabine11608.4 months31%

    Cunningham Gemcitabine2666.0 months19%0.026(2005)Gem/capecitabine22677.4 months26%

    1 Gemcitabine 1000mg/m2 wkly 2 q3 weeksCapecitabine 1300mg/m2/day X 14 q3 weeks 2 Gemcitabine 1000mg/m2 weekly 3 q4 weeksCapecitabine 1660mg/m2/day for 21days q4 weeks

  • 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

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

    HRSurvivalP-ValueNGem + platinum0.850.01623, 5 trialsGem + 5-FU0.900.03901, 6 trialsGood PS 90%+Poor PS 60- 80%0.761.08

  • Combination Chemotherapy in Pancreatic CancerOne po

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