Pancreatic Cancer

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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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<ul><li><p>Pancreatic CancerMalcolm J. Moore MDPrincess Margaret Hospital</p></li><li><p>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</p></li><li><p>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</p></li><li><p>Pancreatic CancerEpidemiologyIncreases with ageNo major geographical differencesGeneticsP16, DPC, p53, k-rasFamilialPoorly understood</p></li><li><p>Pancreatic TumorsMost are ductal adenocarcinomas.Most common site is head of pancreasDense fibrous reaction.Precursor lesions PanINOther subtypesAdenosquamousAcinar cell, medullary, undifferentiated</p></li><li><p>Pancreatic Cancer Ductal Adenocarcinoma most common</p></li><li><p>Pancreatic TumorsSerous cystadenoma/adenocarcinoma.Mucinous neoplasmsEndocrine tumorsRange of differentiation-not all malignantFunctioning vs nonWell circumscribedVascular</p><p>Tumors of the pancreas, Armed Forces Institute of Pathology, Washington 1997. p.145.</p></li><li><p>Well differentiated endocrine tumor - + chromogranin</p></li><li><p>PathologyMost are ductal adenocarcinomaBut not all, so Biopsy essentialAlthough usually can predict non-adenocarcinoma by imaging or clinical course.</p></li><li><p>Making the diagnosisCommon symptomsPainGastric obstruction Biliary obstruction Diabetes Hypercoaguability Malabsorption </p></li><li><p>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.</p></li><li><p>Pain Pancreatic Cancer</p><p>Pain often due to local invasion of tumor.Improved by XRT +/- chemo in 35-65% of cases Improved by palliative chemo Celiac axis blocks </p></li><li><p>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</p></li><li><p>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</p></li><li><p>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</p></li><li><p>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</p></li><li><p>MalabsorptionPancreatic insufficiencyOne reason for weight lossUse of narcotics may mask usual symptomsTrial of pancreatic enzymes</p></li><li><p>SurgeryOnly 15-20% are resectable.Whipples resection (pancreaticoduodenectomy) for tumors of the head3 anastamosesShould be done in high volume centres</p></li><li><p>Is there a role for adjuvant therapy?</p></li><li><p>Original Adjuvant TrialGITSG [N=43]1</p><p>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</p></li><li><p>ESPAC-1 Trial DesignNeoptolemos NEJM 2004 350(12):1200-102x2 Factorial Design (Target 280)Observation CT</p><p> CRT CRT CTChemotherapy 5-FU/LV [Mayo] X 6Chemoradiation 4000/20 [split] + bolus 5-FU.</p><p>Adenocarcinoma pancreatic cancer undergoing curative resectionRandomise(stratified by centre, tumour type, resection margins) </p></li><li><p>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</p></li><li><p>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</p></li><li><p>CONKO-001Neuhaus ASCO 2005 Resected pancreatic cancer368 patients</p><p>Stratification: R; T; NFollow up every 8 weeksGemcitabinefor 6 monthsObservationfor 6 monthsJ Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092</p></li><li><p>Tumor CharacteristicsJ Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092</p><p>Characteristic</p><p>Chemotherapy(N=179)</p><p>Observation(N=177)</p><p>T</p></li><li><p>CONKO-001 Kaplan Meier Disease Free SurvivalObs Median DFS 7.46 mo Gem Median DFS 14.21 moLog rank p &lt; 0.001J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092</p></li><li><p>CONKO-001 Kaplan Meier Overall SurvivalGemcitabine 53 % patients censored (+)Observation 45 % patients censored (+)J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092</p></li><li><p>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</p><p>GEMCITABINE: 1000 mg/m2 iv once weekly x3 wks, 1 wk rest, x6 cycles</p></li><li><p>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.</p></li><li><p> Locally Advanced Pancreatic Cancer</p></li><li><p>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</p></li><li><p>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</p></li><li><p>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%</p><p>Unpublished Data</p></li><li><p>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</p><p>Most use up front chemo for 2 months and then chemo XRT</p></li><li><p>Tumor in the body and tail of pancreas with liver metastasis</p></li><li><p>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</p><p>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</p></li><li><p>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.</p></li><li><p>Negative Combination Chemotherapy Trials 2004-2006Gemcitabine vs gemcitabine FDR + oxaliplatin [N=313]Louvet C et al. ASCO 2004;22:14S (Abs. 4008)</p><p>Gemcitabine vs gem FDR + gem FDR + oxaliplatin [N= 835]Poplin et al. ASCO 2006;24:14S (Abs. 4003)</p><p>Gemcitabine vs gemcitabine + pemetrexed [N=565]Richards DA et al. ASCO 2004;22:14S (Abs. 4007)</p><p>Gemcitabine vs gemcitabine + irinotecan [N=360]Roche Lima, J Clin Oncol 2004</p><p>Gemcitabine vs gemcitabine + exatecan [N=349]OReilly EM et al. ASCO 2004;22:14S (Abs. 4006) </p><p>Gemcitabine vs gemcitabine + capecitabine [N=319]Hermann et al. ASCO 2005;23:14S (Abs. 4508)</p><p>Gemcitabine vs gemcitabine + 5FU/LV [N= 473]Reiss et al. ASCO 2005;23:14S (Abs. 4509)</p></li><li><p>Gemcitabine and Fluoropyrimidines Phase III trials Trial Treatment armsn Overall survival pMedian1-year</p><p>Berlin et alGemcitabine1625.4 months18 %0.09 Gem/bolus 5-FU1606.7 months 19 %</p><p>Riess et alGemcitabine2366.2 months~18%0.683(2005)Gem/FU/LV2305.85 months ~18%</p><p>Herrmann et al Gemcitabine1597.3 months31%0.314(2005)Gem/capecitabine11608.4 months31%</p><p>Cunningham Gemcitabine2666.0 months19%0.026(2005)Gem/capecitabine22677.4 months26%</p><p>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 </p></li><li><p>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</p></li><li><p>Gemcitabine + Drug Vs Gemcitabine?Heinemann, et al. ASCO 2007 </p><p>HRSurvivalP-ValueNGem + platinum0.850.01623, 5 trialsGem + 5-FU0.900.03901, 6 trialsGood PS 90%+Poor PS 60- 80%0.761.08</p></li><li><p>Combination Chemotherapy in Pancreatic CancerOne positive study in first line ?Gemcitabine + Capecitabine.One positive study in second line.5FU + oxaliplatin. Many negative studiesIncremental benefit of combination chemotherapy.Restricted to patients with (very) good PSIs it worth doing any more studies?</p></li><li><p>Some key molecular abnormalities in Pancreatic Cancer</p><p>OncogeneRelevanceK-rasNoted in 75% to 90% of casesSignature defect of pancreatic cancerSonic HedgehogCrucial role in embryological signaling Evolving role in pancreas cancerAURKAEncodes Aurora-A kinaseOveramplification - chromosomal instabilitySuppressorRelevanceCDKN2A/p16Normal function induces cell cycle arrestEarly event enhances effect of K-rasSMAD4Encodes transcription factor; lost in 50% casesMay also potentiate K-ras phenotypep53Role in cell cycle arrest and apoptosis Loss contributes to chromosomal instability</p></li><li><p>YYYYYYrasFAKSrcrafERKMEK ECMIntegrin HomodimerPI3KAktNucleusRegulation of Gene TranscriptionPro-MMPGrowth Factor Ligand (EGF, VEGF)EGF ReceptorPancreatic Cancer: Other Molecular Targets</p></li><li><p>The Epidermal Growth Factor Signaling Pathway</p></li><li><p>SWOG: Gemcitabine +/- CetuximabOverall SurvivalHR = 1.09 (95% CI: 0.93, 1.27)PFS</p></li><li><p>Patient PopulationAdenocarcinoma of pancreasNo prior chemotherapyMeasurable or non-measurable diseaseEGFR status not an eligibility criterion</p><p>Stratification Center PS (0/1 vs 2) Stage of disease (Loc Adv / Metastatic)RANDOM I ZE</p><p>Gemcitabine +Erlotinib 100/150 mg</p><p>Gemcitabine +Placebo </p><p> NCIC. PA.3 Study Schema </p></li><li><p>Overall Survival for All Patients</p></li><li><p>Progression-Free Survival* Adjusted for PS, pain and disease extent at randomization</p></li><li><p>PA.3 Rash vs Survival</p><p>Grade 0N= 79Grade 1N= 108Grade &gt;2N= 103Median Survival5.295.7510.511 year Survival16%11%43%</p></li><li><p>NCIC PA.3: K-ras, EGFR &amp; SurvivalN= 569; 146 adequate specimens (26%)</p><p>Gem + ErlotinibGem + PlaceboHRPK-ras WT (21%)6.1 mths4.5 mths0.660.34K-ras Mut (79%)6.0 mths7.4 mths1.070.78</p><p>EGFR Pos (47%)5.2 mths5.2 mths0.900.32EGFR Neg (53%)8.4 mths6.7 mths0.600.08</p></li><li><p>PA3 : Impact of venous thromboembolism on survivalGemcitabine aloneGemcitabine + erlotinibIncidence 14% in both arms</p><p>Associated with poor outcome HR 2.1</p></li><li><p>VEGF and Angiogenesis</p></li><li><p>CALGB 80303Gemcitabine +/- BevacizumabKindler HL et al. J Clin OncolPhase II : 8.7 mos median survival; 5.8 mos PFS 67% tumor control rate (PR+SD)</p><p>GEM + BEVACIZUMAB(n=302)GEMALONE(n=300)HRpMedian survival (mos)5.86.11.030.78PFS (months)4.94.71.00.99Response (%) CR + PR1110 SD3631</p></li><li><p>Why were phase II and III data different?Kindler HL et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):420s (Abstract 4508)</p><p>Phase III Gem + BPhase III GemPhase II Gem + BMedian age646563PS 036%39%60% PS 1PS 253%11%52%9%38%2%Thrombosis-----------Permitted-----------Excluded</p></li><li><p>Primary endpoint: overall survival (6.9 - 9.0 months)Trial closed October 2006. Presented at ASCO 2008.Previously untreated metastatic pancreatic cancer (n=600)Gemcitabine + Erlotinib 100 mg + placeboGemcitabine + Erlotinib 100 mg + Bevacizumab 5mg/kg q 2 weeksPhase III trial of first-line Gemcitabine + Erlotinib +/- Bevacizumab in (AVITA)</p></li><li><p>ResultsTumor Control (CR + PR + SD): G + E = 54% G + B + E = 63%</p></li><li><p>Treating the individual patientOne size (gemcitabine) fits all?Probably not(with an admitted lack of level 1 evidence)Good performance status - KPS 90 +Consider combination chemotherapy I would use gemcitabine + cisplatin.K-ras wild typeGemcitabine + erlotinib.</p></li><li><p>Treating the individual patientLocally advanced disease should be approached differently than metastatic disease.Prophylactic anticoagulationNo phase III studies VTE is common - associated with bad outcomeI do it (low molecular wt heparin) routinely.</p></li><li><p>The way forward inClinical ResearchTest novel targets and combinations in the phase II setting.No phase III studies without a clear signal from phase II.Separate studies for locally advanced and metastatic disease.Translational research is critical!!Routine tissue collection in trialsWe need to understand a lot more about biology</p><p>*The incidence and mortality rates for pancreatic cancer are nearly identical, highlighting the poor prognosis for patients diagnosed with this disease.In 2005 it is estimated that there will be:32,180 new cases in the USA31,800 deaths from this disease.5-year survival has not improved substantially, despite the development of various new chemotherapeutic agents. These statistics reflect the early metastatic spread of pancreatic cancer and the inadequacy of current therapies.</p><p>*****Numbers changed slightly (Kalser Arch Surg 1985;120:899-903)</p><p>*****Chemotherapy for advanced pancreatic cancer is considered palliative.For locally advanced disease, 5-FU-based chemoradiation is standard treatment providing a survival advantage over radiation alone and palliative benefit.1 Gemcitabine has been the standard of care for advanced, metastatic pancreatic cancer since 1996. This is based on phase III data showing a benefit over 5-FU in alleviating pain, functional impairment, and weight loss, and giving significantly longer median survival.2 In the USA gemcitabine is approved for the treatment of patients with locally advanced (non-resectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas, either as a first-line treatment or following a 5-FU-containing regimen. In the EU gemcitabine is approved for the treatment of adults with locally advanced or metastatic, 5-FU-refractory adenocarcinoma of the pancreas. </p><p>1Li D, et al. Lancet. 2004;363:1049-10572Burris H, et al. J Clin Oncol. 1997;15:2403-2413*Phase III trials have investigated gemcitabine in combination with other chemotherapy agents: 5-FU + gemcitabine failed to improve survival compared with gemcitabine aloneIrinotecan and gemcitabine gave a better response rate than...</p></li></ul>