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Combination regimens for adjuvant therapy of stage III colon cancer: the next level of therapy

Combination regimens for adjuvant therapy of stage III colon cancer: the next level of therapy. Professor Eric Van Cutsem University Hospital Gasthuisberg Leuven, Belgium. Benefits of adjuvant therapy of early colon cancer. Risk of relapse after surgery stage II: 20–30% stage III: 25–80%

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Combination regimens for adjuvant therapy of stage III colon cancer: the next level of therapy

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  1. Combination regimens for adjuvant therapy of stage III colon cancer: the next level of therapy Professor Eric Van CutsemUniversity Hospital GasthuisbergLeuven, Belgium

  2. Benefits of adjuvant therapyof early colon cancer • Risk of relapse after surgery • stage II: 20–30% • stage III: 25–80% • Adjuvant therapy reduces risk of relapseand burden of disease • Adjuvant therapy prolongs survival

  3. Colon cancer survival rateNew American Joint Committee on Cancer, 6th Edition *SEER database – O’Connell J et al. J Natl Cancer Inst 2004;96:1420–5 †US National Cancer Database – Greene F et al. Ann Surg 2002;236:416–21

  4. Increased use of adjuvant therapyin stage III colon cancer in the US Patients (%) Surgery alone 100 Surgery + adjuvant chemotherapy Surgery + adjuvant chemotherapy + modifiers 75 Surgery + adjuvant chemotherapy +radiation 50 25 0 1990 1992 1994 1996 1998 2000 2002 Jessup JM et al. JAMA 2005;294:2703–11 Van Cutsem E and Costa F. JAMA 2005;294:2758–60

  5. 5-FU: historical standardin the adjuvant setting Observation1 5-FU/high-dose LV (Mayo)2 6 months5-FU/LV (Mayo)1 5-FU/low-dose LV (Mayo)3 LV5FU24 3-year DFS (%) 1. IMPACT Investigators. Lancet 1995;345:939–44 2. Wolmark N et al. J Clin Oncol 1993;11:1879–87 3. QUASAR Group. Lancet 2000;355:1588–96 4. André T et al. J Clin Oncol 2003;21:2896–903 Stage II and III colon cancer patients

  6. Current needs in the adjuvanttreatment of stage III colon cancer • Adjuvant chemotherapy is recommended for stage III1, but there hasn’t been a universal adoption in clinical practice • Older patients (>80 years) and women are less likely to receive adjuvant treatment2 • Toxicity is a significant issue • Need for chemotherapy regimens that are • more active • better tolerated • more convenient 1. NIH Consensus Conference 19902. Jessup JM et al. JAMA 2005;294:2703–11

  7. X-ACT: Xeloda Adjuvant Chemotherapy Trial of Dukes’ C colon cancer RANDO MIS ATION Xeloda 1250mg/m2 bid d1–14 q3w n=1004 Chemonaïve Dukes’ CResection ≤8 weeks Bolus5-FU/LV 5-FU 425mg/m2 + LV 20mg/m2d1–5 q4w n=983 • Primary endpoint: non-inferiority in DFS Scheithauer W et al. Ann Oncol 2003;14:1735–43

  8. Absolute difference at 3 years: 3.6% Test for superiorityp=0.0528 X-ACT: at least equivalent DFS with Xeloda Estimated probability 3-year DFS (%) 64.2 60.6 1.0 0.8 0.6 0.4 Xeloda (n=1004) 5-FU/LV (n=983) HR=0.87 (95% CI: 0.75–1.00) Compared to HR upper limit 1.20, p<0.0001 0 1 2 3 4 5 6 Years Twelves C et al. N Engl J Med 2005;352:2696–704

  9. Factors considered: age, gender, lymph nodes, time from surgery to randomisation, baseline CEA, country Consistent ~20% reduction in risk with Xeloda OS update late 2007 X-ACT: improved efficacy withXeloda – Multivariate analysis Twelves C et al. N Engl J Med 2005;352:2696–704

  10. X-ACT: improved safety with Xeloda Patients (%) Grade 3/4 AEs Xeloda (n=993) 5-FU/LV (n=974) * * * * HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia *p<0.001 Scheithauer W et al. Ann Oncol 2003;14:1735–43

  11. X-ACT: fewer outpatient visitsand hospitalisations with Xeloda Mean number per 100 patients Xeloda (n=995) 5-FU/LV (n=974) 150 125 100 75 50 25 0 3000 2500 2000 1500 1000 500 0 Outpatient visits Hospitalisations Xeloda 5-FU/LV Admission Total days Cassidy J et al. Br J Cancer 2006;94:1122–9

  12. Xeloda: ‘dominant’ treatment in the UK Net costs per patient vs 5-FU/LV (€) 3000 1000 0 –1000 –3000 –5000 –7000 2219 14 –92 –390 –6558 Drugs Administration Hospitaluse Medications Consultations • Also cost-effective in Italy, USA, Portugal, France and the Czech Republic Cassidy J et al. Br J Cancer 2006;94:1122–9

  13. Xeloda: ‘dominant’ treatment in the UK Net costs per patient vs 5-FU/LV (€) • €5348 saved per patient 3000 1000 0 –1000 –3000 –5000 –7000 2219 14 –92 –390 –5348 –6558 Total savings Drugs Administration Hospitaluse Medications Consultations • Also cost-effective in Italy, USA, Portugal, France and the Czech Republic Cassidy J et al. Br J Cancer 2006;94:1122–9

  14. From single agents to combination regimens • Combination regimens are leading treatmentsin mCRC • 65–80% of patients • FOLFIRI and FOLFOX vs 5-FU/LV1–3 • improved efficacy • acceptable safety • OS is prolonged with increasing total number of agents administered over the course of treatment4 1. Saltz LB et al. N Engl J Med 2000;343:905–14 2. Douillard J-Y et al. Lancet 2000;355:1041–7 3. de Gramont A et al. J Clin Oncol 2000;18:2938–47 4. Grothey A et al. J Clin Oncol 2004;22:1209–14

  15. Combinations in adjuvantchemotherapy: recent evidence Survival update Molecular markers NR = not reported 1. de Gramont A et al. J Clin Oncol 2005;23(Suppl. 16S):246s (Abst 3501); 2. Wolmark N et al. J Clin Oncol 2005;23(Suppl. 16S):246s (Abst LBA3500); 3. Saltz L et al. J Clin Oncol 2004;22(Suppl 14S):245s (Abst 3500); 4. Van Cutsem E et al. J Clin Oncol 2005;23(Suppl. 16S):3s (Abst LBA8) 5. Ychou M et al. J Clin Oncol 2005;23(Suppl. 16S) (Abst 3502)

  16. MOSAIC: superior DFSwith FOLFOX4 in stage III 3-year DFS (%) Estimated probability FOLFOX4 (n=1123) 72.2 LV5FU2 (n=1123) 65.3 1.0 0.8 0.6 0.4 0.2 0.0 HR=0.76 (95% CI: 0.62–0.92)p=0.002 0 6 12 18 24 30 36 42 48 54 60 Months André T et al. N Engl J Med 2004;350:2343–51

  17. MOSAIC: consistent benefitwith FOLFOX4 vs LV5FU2 * * * * 1. de Gramont A et al. J Clin Oncol 2005;23(Suppl. 16S):246s (Abst 3501) 2. André T et al. N Engl J Med 2004;350:2343–51 *p<0.05

  18. NSABP C-07: superior DFSwith FLOX in stage III 3-year DFS (%) Estimated probability FLOX (n=1200) 76.5 5-FU/LV (n=1207) 71.6 1.0 0.9 0.8 0.7 0.6 0.5 HR=0.79 (95% CI: 0.67–0.93)p<0.004 0 1 2 3 4 Years Wolmark N et al. J Clin Oncol 2005;23(Suppl. 16S):246s (Abst LBA3500)

  19. XELOX: a new optionin the adjuvant setting RANDO MIS ATION XELOX Xeloda 1000mg/m2 bid d1–15 oxaliplatin 130mg/m2 d1 q3w n=944 Chemo/radiotherapy-naïve stage III colon cancer Bolus 5-FU/LVMayo Clinic or Roswell Park n=942 • Primary endpoint: DFS Schmoll H-J et al. J Clin Oncol 2007;25:102–9

  20. XELOXA: most common toxicities – XELOX vs 5-FU/LV Schmoll H-J et al. J Clin Oncol 2007;25:102–9

  21. Adjuvant XELOX: favourable toxicity compared with FOLFOX and FLOX Patients (%) Grade 3/4 AEs XELOX1 (n=938) FOLFOX42 (n=1108) FLOX3 (n=1200) † † † HFS Nausea Vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia Neurosensory 1. Schmoll H-J et al. J Clin Oncol 2007;25:102–92. André T et al. N Engl J Med 2004;350:2343–513. Wolmark N et al. J Clin Oncol 2005;23(Suppl. 16S):246s (Abst LBA3500) Cross-trial comparison †Not reported

  22. Phase III trials of chemotherapy± Avastin

  23. The next level of adjuvant therapyof stage III colon cancer • Xeloda is replacing 5-FU in the adjuvant setting • effective • at least equivalent DFS • safe • convenient and cost-effective • avoids complications of central venous catheters • reduced hospitalisation and costs • more freedom for the patients • XELOX has a favourable safety profile Xeloda is the ideal backbone for combination regimens

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