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Xeloda versus 5-FU/LV in adjuvant colon cancer: what’s your conclusion?

Xeloda versus 5-FU/LV in adjuvant colon cancer: what’s your conclusion?. David Kerr University of Oxford Oxford, UK. Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer ?. Against: Axel Grothey For: Jim Cassidy. Against. Axel Grothey

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Xeloda versus 5-FU/LV in adjuvant colon cancer: what’s your conclusion?

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  1. Xeloda versus 5-FU/LV in adjuvant colon cancer: what’s your conclusion? David Kerr University of OxfordOxford, UK

  2. Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer? Against: Axel Grothey For: Jim Cassidy

  3. Against Axel Grothey Mayo ClinicRochester, Minnesota, USA

  4. Large body of evidence for 5-FU in adjuvant treatment of colon cancer • 5-FU/LV (Mayo Clinic regimen) versus observation • Mayo Clinic regimen versus Roswell Park regimen • Bolus 5-FU/LV versus continuous infusion 5-FU/LV (LV5FU2) • IFL vs Roswell Park (CALGB89803) • FOLFIRI versus infused 5-FU/LV (PETACC-3, ACCORD-2) • FLOX versus bolus 5-FU/LV (NSABP C-07) • FOLFOX versus LV5FU2 (MOSAIC)

  5. Bolus 5-FU/LV evolved as standardof care for stage III colon cancer 1O’Connell MJ et al. J Clin Oncol 1997;15:246–50 2IMPACT investigators. Lancet 1995;345:939–443Wolmark N et al. J Clin Oncol 1993;11:1879–87 MOF = lomustine (MeCCNU), vincristine, 5-FU

  6. Continuous infusion versus bolus 5-FU/LV: similar efficacy, improved safety *Not significant André T et al. J Clin Oncol 2003;21:2896–903

  7. Landmark trials: recent evidence for 5-FU-based combinations 1de Gramont A et al. Proc ASCO 2005 (Abst 3501) 2Wolmark N et al. Proc ASCO 2005 (Abst LBA3500) 3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500) 4Van Cutsem E et al. Proc ASCO 2005 (Abst LBA8)

  8. Patient management with 5-FU/LV • Regular visits to hospital/clinic with i.v. regimens ensures • greater opportunity for face-to-face interaction with clinicians and nurses • reduced risk of over and under compliance

  9. Critical points on Xeloda • Xeloda monotherapy has always been compared with the Mayo Clinic regimen in the adjuvant and palliative settings • the most toxic way to give 5-FU/LV • More appropriate comparators • in the USA: Roswell Park regimen • in Europe: LV5FU2 • Question of appropriate dosing of Xeloda

  10. 5-FU/LV: the evidence • Large body of clinical trial data for 5-FU/LV and 5-FU-based combination regimens • In the 1990s, bolus 5-FU/LV became the standard of care in the adjuvant setting • Infusional 5-FU/LV has similar efficacy and an improved safety profile compared with bolus 5-FU/LV • Xeloda has not been tested against infusional 5-FU/LV • 5-FU-based combinations with oxaliplatin have evolved as standard of care

  11. For Jim Cassidy Beatson Oncology CentreGlasgow, UK

  12. Evidence for Xeloda comes from two phase III trials: X-ACT and XELOXA (n=3848) • 1° endpoint: DFS Xeloda (n=1004) Stage III, resection £8 weeks X-ACT 24 weeks Bolus 5-FU/LV (n=983) • 1° endpoint: DFS XELOX(n=937) 24 weeks Stage III colon cancer XELOXA Bolus 5-FU/LV (Mayo Clinic or Roswell Park) (n=924)24 or 32 weeks

  13. Continuous infusion 5-FU/LV or Xeloda? • Mayo Clinic regimen was the standard of care • Superiority of infused vs bolus 5-FU/LV not shown1 • Xeloda has a significantly improved safety profilevs bolus 5-FU/LV (p<0.001)2 • In a meta-analysis in MCRC, Xeloda offers at least equivalent efficacy with superior safety vs continuous infusion 5-FU3 1André T et al. J Clin Oncol 2003;21:2896–903 2Cassidy J et al. Ann Oncol 2002;13:566–75 3Cole S et al. Proc ASCO 2005 (Abst 3591)

  14. 3-year DFS Xeloda (n=1004) 64.2% 5-FU/LV (n=983) 60.6% Absolute difference at 3 years: 3.6% Trend to superior DFS with Xeloda (ITT) Estimated probability 1.0 0.8 0.6 0.4 HR=0.87 (95% CI: 0.75–1.00) Compared to HR upper limit 1.20, p<0.0001 Test for superiorityp=0.0528 0 1 2 3 4 5 6 Years Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

  15. Fewer and later onset of key grade 3/4 adverse events with Xeloda versus 5-FU/LV Estimated probability of agrade 3/4 adverse event 5-FU/LV Xeloda 1.0 0.8 0.6 0.4 0.2 0.0 p<0.001 0 1 2 3 4 5 6 7 8 Months • Grade 3/4 diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

  16. Oral Xeloda offers freedom withouta loss of effective management • Proven compliance in clinical trials • Patients lead a more normal lifestyle with home-based treatment • Patients prefer oral chemotherapy • Patient education is a priority • time allocated before treatment begins • patients advised on side-effect management up-front • telephone follow-up • Less time in hospital = more face-to-face time with family

  17. = Visit to hospital/clinic for i.v. administration = Administration of oral tablet at home; point at which dose modification can occur Flexibility with Xeloda: 28 opportunities for modifying dose per cycle Dose modification = interrupt, delay or reduce 5-FU/LV 425/20mg/m2(i.v. bolus) Day 1 8 15 21 28 Repeat cycle at day 28 Xeloda1250mg/m2 twice daily(oral) Days 1–14 Rest am Repeat cycle at day 21 pm

  18. Xeloda (n=995) 5-FU/LV (n=974) Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV Mean visitsper patient 30 20 10 0 AE treatment Drug administration Total McKendrick JJ et al. J Clin Oncol Proc ASCO 2004;23:265 (Abst 3578; poster update)

  19. Replacing infused 5-FU/LV withXeloda: less time per patient Total ‘chair’ time 150 155–305 30* *Upfront patient education

  20. Xeloda is a uniquely ‘dominant’ treatmentin cancer chemotherapy: UK perspective Net costs per patient versus 5-FU/LV (£) 4000 2000 0 –2000 –4000 Total Drugs Administration Hospital Medications Consultations (€2 721) use Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl. 3):iii73 (Abst 274PD)

  21. Xeloda versus Mayo Clinic regimen in adjuvant treatment Benefits • At least equivalent efficacy • Trend to improved DFS + OS • Improved RFS •  toxicity • Convenience • Cost savings Risks •  hand-foot syndrome

  22. Xeloda is an ideal combination partner in the adjuvant setting 1Schmoll H-J et al. Proc ASCO 2005 (Abst 3523) 2André T et al. N Engl J Med 2004;350:2343–51 3Smith R et al. Proc Am Soc Clin Oncol 2003;22 (Abst 1181; poster update)

  23. Xeloda: the evidence • At least as effective as 5-FU/LV for stage III colon cancer • strong trend to superior DFS, superior RFS and trend to superior OS • Fewer grade 3/4 toxicities than 5-FU/LV • Dosing flexibility improves side effect management • Convenience of oral administration allows patients to lead a more normal lifestyle • Cost effective • Effective, safe and convenient combination partner, simplifying combination treatment • The fluoropyrimidine of choice in the adjuvant treatmentof colon cancer

  24. Debate summary David Kerr University of OxfordOxford, UK

  25. The need for improved adjuvant treatment for colon cancer • Adjuvant 5-FU/LV has benefits, but • considerable discrepancy between consensus recommendations and use1 • 40–50% of elderly patients (>69 years) with stage III disease do not receive adjuvant chemotherapy2 • Need for more effective and convenient regimens 1Grothey A et al. Med Klin 2002;97:270–7 2Hensley-Alford S et al. Proc Am Soc Clin Oncol 2003;23:748 (Abst 3008)

  26. Adjuvant Xeloda: a favorable benefit/risk ratio • Single-agent Xeloda is at least as effective as, and better tolerated than, 5-FU/LV • proven role in stage III • should also be considered for stage II patients • efficacy and safety benefits maintained in older patients • cost savings with improved outcomes and lifestyle • Xeloda can replace 5-FU/LV as it offers the best balance of efficacy, safety and convenience for patients

  27. Authorities have approved Xeloda as adjuvant treatment for colon cancer • EMEA approved Xeloda (31 March 2005) . . . Xeloda is indicated for the adjuvant treatmentof patients following surgery for stage III (Dukes’ stage C) colon cancer FDA approved 15 June 2005

  28. Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer?

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