The evolving landscape of adjuvant treatment of colon cancer
Colon cancer survival rate *SEER database  –  O’Connell et al. J Natl Cancer Inst 2004   † US National Cancer Database – G...
Nederlandse Richtlijn <ul><li>Bij patiënten met een hoog risico stadium II coloncarcinoom dient adjuvante chemotherapie te...
Establishing effective adjuvant therapy <ul><li>X-ACT   </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Additi...
Establishing effective adjuvant therapy <ul><li>X-ACT   </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Additi...
X-ACT: Xeloda Adjuvant Chemotherapy Trial of stage III colon cancer <ul><li>Primary endpoint: non-inferiority in DFS </li>...
X-ACT:  trend to superior DFS with Xeloda 0.4 Xeloda  (n=1   004)  5-FU/LV (n=983) Years 5-year DFS (%) 60.8 56.7 0.6 0.8 ...
X-ACT:  trend to superior OS with Xeloda Years 1 2 3 4 5 6 7 8 0 0.4 0.6 0.8 1.0 Estimated probability Absolute difference...
X-ACT: improved safety with Xeloda Neutropenia Nausea/ vomiting Stomatitis Diarrhoea Febrile neutropenia HFS Patients (%) ...
X-ACT:  Xeloda as the ideal fluoropyrimidine   backbone <ul><li>Effective  </li></ul><ul><ul><li>superior DFS and OS vs bo...
Establishing effective adjuvant therapy <ul><li>X-ACT   </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Additi...
MOSAIC – superior OS with adjuvant oxaliplatin in stage III patients 4 6 2 8 0 0.0 0.2 0.4 0.6 0.8 1.0 Estimated probabili...
Nederlandse Richtlijn <ul><li>FOLFOX is de standaard adjuvante chemotherapie bij het stadium III coloncarcinoom. Omdat het...
Establishing effective adjuvant therapy <ul><li>X-ACT   </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Additi...
XELOXA (NO16968): XELOX – a new option in the adjuvant setting Chemo/ radiotherapy-naive  stage III  colon cancer  n=1   8...
Safety Schmoll et al.  JCO 2007 0.1 11.4 Neurosensory 15.9 8.8 Neutropenia 4.2 0.4 Febrile neutropenia 0.6 5.4 HFS 3.3 6.2...
Cross-trial comparison with MOSAIC Schmoll et al.  JCO 2007 *MOSAIC trial: André et al. NEJM 2004 12.4 11.4 Neurosensory 4...
Superior RFS with XELOX (excludes all non-cancer-related mortality) ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 X...
Immature Data: Trend to improved OS with XELOX ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 XELOX  5-FU/LV  Δ  at ...
Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease Years 2 4 6 0.4 0.6 0.8 1.0 0 0.4 0.6 0.8 1.0 Years 1...
Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 1.0 0.6 0.8 1.   André et al.  JCO  2009 1 2 3 4 5 6 ...
Adjuvant XELOX: favourable toxicity compared with FOLFOX4 and FLOX Grade 3   /   4 AEs Patients (%) XELOX 1 (n=938)  FOLFO...
<ul><li>Efficacy </li></ul><ul><ul><li>XELOX significantly improves DFS and RFS compared with bolus 5-FU/LV </li></ul></ul...
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Presentation chemotherapy

  1. 1. The evolving landscape of adjuvant treatment of colon cancer
  2. 2. Colon cancer survival rate *SEER database – O’Connell et al. J Natl Cancer Inst 2004 † US National Cancer Database – Greene et al. Ann Surg 2002 Eligible for adjuvant treatment Eligible for adjuvant treatment No adjuvant treatment? 27 † – 44* IIIc = Tx, N2 42 † – 64* IIIb = T3 or T4, N1 60 † – 83* IIIa = T1 or T2, N1 72* IIb = T4, N0 85* IIa = T3, N0 93* I = T1 or T2, N0 5-year survival (%) Stage (AJCC 6 th Edition)
  3. 3. Nederlandse Richtlijn <ul><li>Bij patiënten met een hoog risico stadium II coloncarcinoom dient adjuvante chemotherapie te worden overwogen. Voor de chemotherapie keuze gelden dezelfde overwegingen als voor het stadium III. </li></ul>Landelijke werkgroep Gastro Intestinale Tumoren, Versie: 2.0, Type: Landelijke richtlijn; 2009
  4. 4. Establishing effective adjuvant therapy <ul><li>X-ACT </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Addition of oxaliplatin prolongs survival in stage III Xeloda as the ideal fluoropyrimidine backbone XELOX is a new option for stage III   
  5. 5. Establishing effective adjuvant therapy <ul><li>X-ACT </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Addition of oxaliplatin prolongs survival in stage III Xeloda as the ideal fluoropyrimidine backbone XELOX is a new option for stage III   
  6. 6. X-ACT: Xeloda Adjuvant Chemotherapy Trial of stage III colon cancer <ul><li>Primary endpoint: non-inferiority in DFS </li></ul>Bolus 5-FU/LV 5-FU 425mg/m 2 + LV 20mg/m 2 d1–5 q4w Xeloda 1 250mg/m 2 bid d1–14 q3w Chemotherapy-naive stage III Resection ≤8 weeks n=1 987 R A N D O M I S A T I O N Twelves et al. ASCO GI 2008
  7. 7. X-ACT: trend to superior DFS with Xeloda 0.4 Xeloda (n=1 004) 5-FU/LV (n=983) Years 5-year DFS (%) 60.8 56.7 0.6 0.8 1.0 1 2 3 4 5 6 7 8 Absolute difference at 5 years: 4.1% 0 Estimated probability ITT population HR=0.88 (95% CI: 0.77–1.01) p=0.0682 Twelves et al. ASCO GI 2008
  8. 8. X-ACT: trend to superior OS with Xeloda Years 1 2 3 4 5 6 7 8 0 0.4 0.6 0.8 1.0 Estimated probability Absolute difference at 5 years: 3.1% HR=0.86 (95% CI: 0.74–1.01) p=0.0600 Xeloda (n=1 004) 5-FU/LV (n=983) 5-year OS (%) 71.4 68.4 ITT population Twelves et al. ASCO GI 2008
  9. 9. X-ACT: improved safety with Xeloda Neutropenia Nausea/ vomiting Stomatitis Diarrhoea Febrile neutropenia HFS Patients (%) Scheithauer et al. Ann Oncol 2003 * * * * *p<0.001 Xeloda (n=993) 5-FU/LV (n=974) Grade 3 / 4 AEs
  10. 10. X-ACT: Xeloda as the ideal fluoropyrimidine backbone <ul><li>Effective </li></ul><ul><ul><li>superior DFS and OS vs bolus 5-FU </li></ul></ul><ul><ul><li>equivalent to ci 5-FU in cross-trial comparison </li></ul></ul><ul><li>Superior safety vs bolus 5-FU </li></ul>
  11. 11. Establishing effective adjuvant therapy <ul><li>X-ACT </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Addition of oxaliplatin prolongs survival in stage III Xeloda as the ideal fluoropyrimidine backbone XELOX is a new option for stage III   
  12. 12. MOSAIC – superior OS with adjuvant oxaliplatin in stage III patients 4 6 2 8 0 0.0 0.2 0.4 0.6 0.8 1.0 Estimated probability FOLFOX4 (n=672) LV5FU2 (n=675) 6-year OS (%) 73.0 68.6 HR=0.80 (95% CI: 0.66–0.98) p=0.029 Absolute difference at 6 years: 4.4% André et al. J Clin Oncol 2009 Years
  13. 13. Nederlandse Richtlijn <ul><li>FOLFOX is de standaard adjuvante chemotherapie bij het stadium III coloncarcinoom. Omdat het orale 5-FU analoge capecitabine minstens gelijkwaardig is in gemetastaseerde setting en het toxiciteitsprofiel, als monotherapie en in combinatieschema's, gunstiger is vergeleken met 5-FU, kan ook in adjuvante schema's 5-FU vervangen worden door capecitabine. </li></ul>Landelijke werkgroep Gastro Intestinale Tumoren, Versie: 2.0, Type: Landelijke richtlijn; 2009
  14. 14. Establishing effective adjuvant therapy <ul><li>X-ACT </li></ul><ul><li>MOSAIC </li></ul><ul><li>XELOXA </li></ul>Addition of oxaliplatin prolongs survival in stage III Xeloda as the ideal fluoropyrimidine backbone XELOX is a new option for stage III   
  15. 15. XELOXA (NO16968): XELOX – a new option in the adjuvant setting Chemo/ radiotherapy-naive stage III colon cancer n=1 886 Bolus 5-FU/LV Mayo Clinic or Roswell Park XELOX Xeloda 1 000mg/m 2 bid d1 – 15 oxaliplatin 130mg/m 2 d1 q3w <ul><li>Primary endpoint: superiority in DFS </li></ul>n=944 n=942 Schmoll et al. J Clin Oncol 2007 R A N D O M I S A T I O N
  16. 16. Safety Schmoll et al. JCO 2007 0.1 11.4 Neurosensory 15.9 8.8 Neutropenia 4.2 0.4 Febrile neutropenia 0.6 5.4 HFS 3.3 6.2 Vomiting 4.5 5.2 Nausea 8.9 0.6 Stomatitis 20.2 19.4 Diarrhoea 5-FU/LV n=926 XELOX n=938 Grade 3/4 AEs (%)
  17. 17. Cross-trial comparison with MOSAIC Schmoll et al. JCO 2007 *MOSAIC trial: André et al. NEJM 2004 12.4 11.4 Neurosensory 41.1 8.8 Neutropenia 1.8 0.4 Febrile neutropenia 2.0 5.4 HFS 5.8 6.2 Vomiting 5.1 5.2 Nausea 2.7 0.6 Stomatitis 10.8 19.4 Diarrhoea FOLFOX4 (MOSAIC)* n=1108 XELOX n=938 Grade 3/4 AEs (%)
  18. 18. Superior RFS with XELOX (excludes all non-cancer-related mortality) ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 XELOX 5-FU/LV 72.1% 69.7% 3-year RFS 67.5% 63.3% 4-year RFS 5-year RFS 60.9% 67.8% HR=0.78 (95% CI: 0.67–0.92) p=0.0024 Δ at 4 years: 6.4% Δ at 5 years: 6.9% Δ at 3 years: 4.6% Years
  19. 19. Immature Data: Trend to improved OS with XELOX ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 XELOX 5-FU/LV Δ at 5 years: 3.4% HR=0.87 (95% CI: 0.72–1.05) p=0.1486 Years 77.6% 5-year OS 74.2%
  20. 20. Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease Years 2 4 6 0.4 0.6 0.8 1.0 0 0.4 0.6 0.8 1.0 Years 1. André et al. JCO 2009 8 2 4 6 0 8 XELOX 5-FU/LV FOLFOX4 LV5FU2 XELOXA (57 mo) MOSAIC 1 (81.9 mo) ITT population
  21. 21. Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 1.0 0.6 0.8 1. André et al. JCO 2009 1 2 3 4 5 6 7 8 Years XELOX (n=944) FOLFOX4 (n=672) – 5-yr OS 6-yr OS 72.9% 77.6% NO16968 (XELOXA)* MOSAIC 1 ** – *Median observation time: 57.0 months ** Median follow-up: 81.9 months ITT population 0.4 0
  22. 22. Adjuvant XELOX: favourable toxicity compared with FOLFOX4 and FLOX Grade 3 / 4 AEs Patients (%) XELOX 1 (n=938) FOLFOX4 2 (n=1 108) FLOX 3 (n=1 200) Cross-trial comparison † Not reported Neutropenia Nausea Stomatitis Diarrhoea Febrile neutropenia HFS Vomiting Neurosensory † † 1. Schmoll et al. J Clin Oncol 2007 2. André et al. N Engl J Med 2004; 3. Kuebler et al. J Clin Oncol 2007 0 10 20 30 40 50
  23. 23. <ul><li>Efficacy </li></ul><ul><ul><li>XELOX significantly improves DFS and RFS compared with bolus 5-FU/LV </li></ul></ul><ul><ul><li>trend to improved OS with XELOX; follow-up ongoing </li></ul></ul><ul><li>Favourable safety profile </li></ul><ul><li>Ease of administration </li></ul><ul><ul><li>fewer study visits, no pumps or catheters </li></ul></ul><ul><li>XELOX is a new option for patients with stage III colon cancer </li></ul>XELOXA (NO16968): conclusions

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