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What is the reference cytotoxic regimen in advanced gastric cancer?

What is the reference cytotoxic regimen in advanced gastric cancer?. Florian Lordick Klinikum Braunschweig Germany. Chemotherapy in Advanced Gastric Cancer – What do we know ? (I). Chemotherapy prolongs survival Chemotherapy improves symptom control

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What is the reference cytotoxic regimen in advanced gastric cancer?

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  1. What is the reference cytotoxic regimen in advanced gastric cancer? Florian Lordick Klinikum BraunschweigGermany

  2. Chemotherapyin AdvancedGastricCancer– What do weknow? (I) • Chemotherapyprolongssurvival • Chemotherapyimprovessymptomcontrol • Combinationsaremoreactivethanmonotherapy Wagner et al. J ClinOncol2006; 24: 2903-9 • Elderly(>70 yearsage) benefitequally Trumper et al. Eur J Cancer 2006; 42: 827-34 Establishedstandard:Platinum-fluoropyrimidine-combination

  3. Chemotherapyin AdvancedGastricCancer– What do weknow? (I) • Oxaliplatincansubstituteforcisplatin • Oral fluoropyrimidinescansubstitutefor i.v. 5-FU • A 3rd drugmakesCTxmoreeffective but moretoxic Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442 Cunningham et al. N Engl J Med 2008; 358: 36-46 Kang et al. Ann Oncol 2009; 20: 666-673 Cunningham et al. N Engl J Med 2008; 358: 36-46 Ajani J et al. J ClinOncol2010; 28: 1547-1553 Van Cutsem et al. J ClinOncol2006; 24: 4991-7Wagner et al. J ClinOncol2006; 24: 2903-9

  4. Oxaliplatin

  5. Oxaliplatinin GastricCancer Real-2-Study (UK) E EpirubicinC CisplatinF Fluorouracil R A N D O M E EpirubicinC CisplatinX Xeloda (Capecitabine) N=964 E EpirubicinO OxaliplatinF Fluorouracil E EpirubicinO OxaliplatinX Xeloda (Capecitabine) Cunningham D et al. N Engl J Med 2008;358:36-46

  6. Oxaliplatinin GastricCancer Real-2-Study Cunningham D et al. N Engl J Med 2008;358:36-46

  7. Oxaliplatinin GastricCancer AIO-Study (Germany) R A N D O M PCisplatinLLeucovorinF 5-Fluorouracil N=220 OOxaliplatinL LeucovorinF 5-Fluorouracil Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

  8. AIO-study: FLO versus FLP Overall population PFS: p = 0.077 OS: p = 0.506 Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

  9. AIO-study: FLO versus FLP Elderly (patients> 65 years) PFS: p = 0.029 OS: p = n. s. Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

  10. Oxaliplatincansubstituteforcisplatin in gastriccancer!Potential advantages intheelderlyandfrailpopulation

  11. Oral fluoropyrimidines

  12. Capecitabine in GastricCancer Real-2-Study (UK) E EpirubicinC CisplatinF Fluorouracil R A N D O M E EpirubicinC CisplatinX Xeloda (Capecitabine) N=964 E EpirubicinO OxaliplatinF Fluorouracil E EpirubicinO OxaliplatinX Xeloda (Capecitabine) Cunningham D et al. N Engl J Med 2008;358:36-46

  13. Capecitabine in GastricCancer Real-2-Study Cunningham D et al. N Engl J Med 2008;358:36-46

  14. Capecitabine in GastricCancer ML17032-Study (Korea) R A N D O M F 5-FluorouracilPCisplatin Primary endpoint: overallsurvival(non-inferiority) N=316 X Xeloda (Capecitabine)PCisplatin Kang YK et al. Ann Oncol 2009; 20: 666-673

  15. ML17032-Study: XP versus FP Response rate 46% vs. 32%p=0.02 Progression-freesurvival 5.6 vs. 5.0 monp<0.001(non-inferior) Survival 10.5 vs. 9.3monp=0.008 (non-inferior) Kang YK et al. Ann Oncol 2009; 20: 666-673

  16. S-1/cisplatinversus 5-FU/cisplatin FLAGS-Study (multinational Western World) R A N D O M S-1 25mg/m22x/d d1-21 Cisplatin 75mg/m2 d1 q4w Primary endpoint: overallsurvival(superiority) N=1053 5-FU 1000mg/m2 d1-5 Cisplatin 100mg/m2 d1 q4w Ajani J et al. J ClinOncol2010; 28: 1547-1553

  17. S-1/cisplatinversus 5-FU/cisplatin In a Non-Asian patientpopulation S-1 was not superiorto 5-FU Ajani J et al. J ClinOncol2010; 28: 1547-1553

  18. S-1/cisplatinversus 5-FU/cisplatin Toxicity in favorof S-1/cisplatin Ajani J et al. J ClinOncol2010; 28: 1547-1553

  19. Oral fluoropyrimidinescansubstitutefor i.v. 5-FU in gastriccancer!Lessseveretoxicityfor S-1/cisplatin

  20. Doubletsortriplets?Andwhichisthe relevant thirddrug?

  21. Cisplatinum HR = 0.83 (95% CI 0,76 – 0,91) in favorofcisplatinum Wagner et al. J ClinOncol2006; 24: 2903-9

  22. Anthracyclines HR = 0.77 (95% CI 0,62 – 0,95) in favorofanthracyclines Wagner et al. J ClinOncol2006; 24: 2903-9

  23. AnthracyclinesECF versus EOX Real-2-Study (UK) HR = 0.80 (95% CI, 0.66 to 0.97; P=0.02) Cunningham D et al. N Engl J Med 2008;358:36-46

  24. Docetaxel Tax-325-Study (multinational) Docetaxel 75mg/m2 d1 Cisplatin 75mg/m2 d1 5-FU 750mg/m2 d1-5 q3w R A N D O M Stage IVn=445 Primary endpoint: time toprogression (TTP) Cisplatin 100mg/m2 d1 5-FU 1000mg/m2 d1-5 q4w Van Cutsem et al. J Clin Oncol2006; 24: 4991-7

  25. Docetaxelas 3rd DrugTAX-325 Response rate 37% vs. 25% p=0.01 Time toprogression 5.6 vs. 3.7 months p<0.01 Survival 9.2 vs. 8.6 months p=0.02 Kaplan-Meier curve: time toprogression Van Cutsem et al. J Clin Oncol2006; 24: 4991-7

  26. DCF Toxicity Hematologictoxicityin DCF Neutropenia grade 3/482% Febrile neutropenia30% Van Cutsem et al. J Clin Oncol2006; 24: 4991-7

  27. Alternative docetaxel-basedregimen(AIO studies) GastroTax-1 regimenDocetaxel 40mg/m2 + cisplatin40mg/m22-weekly 5-FU 2000mg/m2 – folinicacid 200mg/m2weeklyResponse rate 46.6%Time toprogression (metastatic) 8.1 monthsSurvival (metastatic) 15.1 months Lorenzen et al. Ann Oncol2007; 18: 1673-9 FLOT regimenDocetaxel 50mg/m2 + modified FOLFOX 2-weeklyResponse rate 53% Time toprogression5.3 months Survival11.3 months Al-Batran et al. Ann Oncol 2008; 19:1882-87

  28. Alternative docetaxel-basedregimen(MSKCC) ModifiedDCF vs. classic DCF + G-CSF (rand. Ph. II) Median follow up 10.3 mo Modified DCF Classic DCF Fraction Surviving 12.6 mo 15.1 mo Months Shah et al. ASO 2010; abstract 4014

  29. The futureoftriplets in gastriccancer:Sequentialtreatment? AIO – YMO – Maintain Study (proposal) Induction 6 cyclesFLOT(3 months) Arm A (120 pat.) De-escalationS-1 CR, PR, SD R 2:1 Arm B (80 pat.) FLOT Progression

  30. Triplets aremoreeffectivethandoublets!But…Side effectsare an issue!Patients‘ preferences matter!Watch out foroverlappingsideeffectsandinteractions, whencombiningwithbiologics

  31. Arm A: EOX R Arm B: EOX-Panitumumab 3 + 1 = X…whentheunpredictablecomestrue REAL-3 study • EOX (Arm A): • Epirubicin 50mg/m2 IV D1 • Oxaliplatin 130mg/m2 IV D1 • Capecitabine 1250mg/m2/day PO in two divided doses D1-21 • mEOX-P (Arm B)1: • Epirubicin 50mg/m2 IV D1 • Oxaliplatin 100mg/m2 IV D1 • Capecitabine 1000mg/m2/day PO in two divided doses D1-21 • Panitumumab 9mg/kg IV D1 Wardell et al. ASO 2012; abstractLBA 4000

  32. 3 + 1 = X…whentheunpredictablecomestrue 100 80 60 Probability of Survival (%) 40 EOX HR 1.37 (95% CI: 1.07 – 1.76) 20 EOX-P 0 6 18 30 0 12 24 36 Months from Randomisation Number at risk EOC 275 49 3 EOC-P 278 38 2 Wardell et al. ASO 2012; abstractLBA 4000

  33. Reference regimensforadvancedgastriccancer in 2012 Triplets Indication: Severetumorsymptoms Patient preference (mostactivetx) Intactorganfunctions Regimens: EOX (epirubicine, oxaliplatin, cape.) mod. DCF (docetaxel, cisplatin, 5FU) FLOT (docetaxel + mod. FOLFOX)

  34. Reference regimensforadvancedgastriccancer in 2012 Doublets Indication: Patient preferenceforlesstoxicity Impairedorganfunctions Combinationwithbiologics Regimens: Capecitebine-cisplatin S-1-cisplatin FOLFOX-like / CapOx (elderly)

  35. Doubletor Triplet? 2 : 0 or 3 : 0 Let‘swinthematch!

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