ADJUVANT TREATMENT IN RESECTABLE PANCREAS CANCER

1. ADJUVANT TREATMENT IN RESECTABLE PANCREAS CANCER Dr Sernaz UZUNOĞLU Trakya University of MedicalFaculty, MedicalOncologyDepartment 1

2. Pancreatic CancerScope of the Problem • Projected 55,440 new cases of pancreatic cancer in United States in 2018, with 44,330 deaths • Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type • By 2030, pancreatic cancer is expected to rise to the second leading cause of cancer-related mortality in the United States (after lung cancer) • The vast majority of patients (> 80%) are inoperable at time of diagnosis 1. American Cancer Society. Cancer facts & figures 2018. 2. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30. 3. Rahib L, et al. Cancer Res. 2014;74:2913-2921.

3. Screening for Pancreatic Cancer: Identifying High-Risk Individuals

5. WHAT IS THE DEFINITION OF THE RESECTABILITY OF PANCREAS CANCER? • WHICH CASES ARE CONSIDERED ‘’BORDERLINE RESECTABLE’’?

8. Definition accordingtothethreedistinctdimensions

9. Adjuvant Therapy • About 10-20% of patients have resectable disease at the time of pancreatic cancer diagnosis. • The 5-year survival rate following resection is 25-30% for node-negative disease and 10% for node-positive cancers. • The high risk of local and systemic disease recurrence, as well as overall poor prognosis, laid down the rationale for adjuvant therapy after resection of pancreatic adenocarcinoma.

12. survival

16. ESPAC 1 (2001) • Randomized trial with 2 X 2 factorial design • Patients randomized to • Chemoradiation • Chemoradiation followed by Chemotherapy • Chemotherapy alone • Observation • Radiation was split course RT (total dose 40Gy; 2 week course) • Chemotherapy was 5FU + Leucovorin

19. Significant protocol violations in all arms; cross-over allowed

20. Chemoradiotherapyarm ; 2 and 5 yearsurvivalrates (%29 and %10 ) • No chemoradiotherapyarm 2 and 5 yearsurvivalrates (%41 and %20) Therewas a trend towardworsesurvivalforthegroupreceivingchemoradiotherapy

21. RTOG 9704 (ASCO 2006) • 538 patients enrolled; 451 eligible & analyzable • T1-T4 N0-1 M0 • 381 pancreatic head lesions • Patients randomized to 5FU CT pre and post chemoRT vs. GEM CT pre and post chemoRT

22. RTOG 9704Treatment Paradigm JAMA 2008;299

24. RTOG 9704 Results • No statistically significant difference in OS between the two arms when all patients analyzed • However, therewas a trend towardbettermedianandfive-yearsurvivalwithgemcitabinebasedadjuvanttherapy. • MS 20.5 vs. 17.1 months • 5 y OS 22% vs. 18% • Althoughtneitherdifferencewasstatisticallysignificant.

29. 5 year OS (21 versus 10 percent) 10 year OS (12.2 versus 7.7 percent)

30. Theyrandomized 1088 patientstosixmonths of postoperativeadjuvanttreatmentwitheither GEM or FUFA

31. At a medianfollowup of 34 months, mediansurvivalwassimilar. Thepatientsassignedto FU\LV had more grade3-4 treatmentrelatedtoxicity

32. MulticentertrialESPAC-3 (JAMA 2010;304:1073) • Someinformation on timingandduration of adjuvantchemotherapyfrom an analysis of thistrial; • OS favoredpatientswhocompletedthefullsixmonths of therapyoverthosewhodid not(28 monthsvs 15 months) • Time to start of chemotherapy (within 8 weeks of surgeryversuslater) was an importantsurvivalfactoronlyforthesubgroup of patientswhodidnotcompleteallsixmonths of therapy. Neoptolemos JP, et al. JAMA. 2010;304:1073-1081.

33. JASPAC 01 trial(lancet 2016) 385 japanesepatients

34. S-1 wasfoundto be noninferiortogemcitabine, andpatientstreatedwith S-1 actually had a lowermortality rate.

35. Fewtrialshavedirectlycomparedchemotherapywithandwithoutchemoradiotherapy as an adjuvantstrategy

37. 2 • 90 patients, 70% nodepositive, 97% R0 resection • 2 cycles of weeklygemcitabinefollowedby RT withconcurrentgemcitabine 300mg\m2 onceweekly(5-6 weeks) • Fourcycles of gemcitabine (n:41) • Therates of distantprogressionweresimilar • Chemoradiotheraywas not deleterious, median PFS 12 versus 11 months,median OS 24 months in botharms

41. COMBİNATİON CHEMOTHERAPY REGIMENS AS AN ADJUVANT THERAPY ??

43. Phase III ESPAC-4: Adjuvant Gemcitabine ± Capecitabine in Resected Pancreatic Cancer 100 Median OS: 25.5 mos (95% CI: 22.7- 27.9) Median OS: 28.0 mos (95% CI: 23.5-31.5) 80 60 OS (%) HR: 0.82 (95% CI: 0.68-0.98) 40 Gemcitabine Gemcitabine + capecitabine 20 Mos 0 0 10 20 30 40 50 60 70 80 Patients at Risk, n Gemcitabine Gemcitabine +capecitabine 61 83 27 50 9 19 3 10 0 1 366 364 302 328 207 219 109 139 Neoptolemos JP, et al. Lancet. 2017;389:1011-1024.

45. PRODIGE 24/CCTG PA.6: mFOLFIRINOX vs Gemcitabine in Resected Pancreatic Cancer • Randomized, multicenter phase III trial (data cutoff: April 13, 2018) • Median follow-up: 33.6 mos (95% CI: 30.3-36.0) Stratified by center, resection margin (R0 vs R1), post-op CA 19-9 level (≤ 90 U/mL vs 91-179), pN0 vs pN1 mFOLFIRINOX* Q2W x 12 cycles (n = 247†) Patients 18-79 yrs of age with histologically confirmed R0 or R1 resected pancreatic ductal adenocarcinoma; CA19-9 level < 180 U/mL ≤ 12 wks post surgery; ECOG PS 0/1; no prior chemotherapy or RT (N = 493) CT scans every 3 mos Gemcitabine 1000 mg/m2 Days 1, 8, 15 of 28-day cycle x 6 cycles (n = 246‡) *On Day 1 of each cycle, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and irinotecan 180 mg/m2 (reduced to 150 mg/m2 due to 20% grade 3/4 diarrhea rate in first 30 patients); continuous fluorouracil IV 2.4 g/m2 over 46 hrs. †n = 238 treated. ‡n = 243 treated. • Primary endpoint: DFS, defined as no tumor, metastasis, second cancer, or death • Secondary endpoints: toxicity, OS, cancer-specific survival, metastasis-free surviva Conroy T, et al. ASCO 2018. Abstract LBA4001.

46. IN A PRELIMINARY REPORT Adjuvant treatment with modified FOLFIRINOX resulted in the longest overall survival yet reported for patients with resected pancreatic cancer, according to the results of the phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial, presented at the 2018 ASCO Annual Meeting¹. At a medianfollowup of 30.5 months, With adjuvant modified FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin), median overall survival was 54.4 months, compared with 35.0 months with gemcitabine. 1. Conroy T, Hammel P, Hebbar M, et al: Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenterinternationalrandomizedphase III trial of adjuvantmFOLFIRINOXversusgemcitabine in patientswithresectedpancreaticductaladenocarcinomas. 2018 ASCO Annual Meeting. Abstract LBA4001. PresentedJune 4, 2018.

47. WHİCH COMBINATION IS THE MOST EFFECTIVE? • Therearenotrialsdirectlycomparingadjuvant FOLFIRINOX withgemcitabinepluscapecitabine • Based on theseresults, offprotocol, forpatientswith an excellent PS whoareabletotolerate it, we can suggestmodified FOLFORINOX ratherthangemcitabinealoneforadjuvanttherapy, we can alsopreferthisregimenovergemcitabinepluscapecitabine.

48. NEOADJUVANT THERAPY • Thelow rate of margin-negativeresection • A patientdeemedresectable on CT scanningstill has a 40 % chancethatitscancerwill be unresectable at surgery • Thepoorlong-termoutcomesfollowingpancreaticoduodenectomywithadjuvanttherapy • Thefactthatprolongedrecoverypreventsthedelivery of postopadjuvantchemotherapy in approximatelyone-fourth of patients; Haveledtotheinvestigation of neoadjuvanttherapy in patientswithpotentiallyresectable PC

49. NEOADJUVANT TRIALS

50. NEOADJUVANT THERAPY? • The role of neoadjuvanttherapy in patientswithpotentiallyresectablepancreaticcancer is evolving • Immediatesurgeryorneoadjuvanttherapy?