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Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard?

Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard?. Prof.dr. C.J.A. Punt afd. Medische Oncologie UMC St. Radboud Nijmegen. Adjuvant therapy for colon cancer hot topics 2004. FOLFOX Capecitabine Stage II Primary endpoint in randomised studies.

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Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard?

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  1. Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard? Prof.dr. C.J.A. Punt afd. Medische Oncologie UMC St. Radboud Nijmegen

  2. Adjuvant therapy for colon cancerhot topics 2004 • FOLFOX • Capecitabine • Stage II • Primary endpoint in randomised studies

  3. Adjuvant therapy for stage III colon cancer - history • 1990: 12 months 5FU/levamisole (absolute reduction of mortality = 13%) • 1990: NIH consensus • 1996: 6 months 5FU/LV is equivalent • 2001: comparable benefit in elderly patients (>70 yrs) • No preference for 5FU/LV schedule

  4. Adjuvant therapy for colon cancer - new developments in 1990s • Locoregional chemotherapy: no benefit • Different schedules of 5FU/LV: no benefit (3 months infusional 5FU  6 months 5FU/LV Mayo Clinic, Ann Oncol, in press) • New modulators of 5FU (IFN!): no benefit

  5. Irinotecan Oxaliplatin Edrecolomab IFN Raltitrexed Capecitabine UFT/LV COX-2 inhibitors Signal transduction inhibitors (EGF-R,VEGF) New drugs for adjuvant therapy in colon cancer since 1998

  6. Irinotecan as adjuvant therapy in stage III colon cancer • Bolus 5FU regimen with irinotecan (IFL) versus weekly 5FU/LV, n = 1254 • No benefit in DFS or OS Data are accumulating that irinotecan should be combined with infusional and not bolus 5FU Saltz et al. ASCO 2004

  7. Primary endpoint in randomised adjuvant studies

  8. Overall survival as primary endpoint in adjuvant studies • considered as gold standard until 2004 Disadvantages: • long duration of studies • poor compliance of investigators • slow implementation of promising new therapies • with inconsistent use of more effective drugs after recurrence, effect of adjuvant Rx difficult to assess

  9. Disease-free survival as endpoint of adjuvant studies in colon cancer • Pooled analysis of > 17.000 patients enrolled in 17 phase III adjuvant 5FU studies 1978 – 1996 • 34% stage II, 65% stage III • 74% of recurrences < 3 years • Excellent correlation between 3-yr DFS and 5-yr OS Sargent et al. ASCO 2004

  10. 3-yrs disease-free survival as endpoint of adjuvant studies in colon cancer Cautions: • Proportion of stage II patients is increasing: overall prognosis will be better • Meta-analysis restricted to 5FU. With new effective drugs available, median survival after recurrence will be longer, DFS in adjuvant setting may be prolonged • DFS at 3 years may not remain the gold standard !!

  11. Adjuvant treatment in stage II colon cancer

  12. Problems in studies with adjuvant therapy in stage II colon cancer Large studies needed: • at this stage relatively few events • elderly population with relatively high incidence of non-cancer related deaths • accrual in 90’s compromised by relatively low incidence of stage II disease

  13. 5FU/LV as adjuvant therapy for stage II colon cancer - history result on survival • IMPACT 6 studies n = 1100 negative • NSABP 4 studies1 n = >2000positive • Mayo ’95 n = 318 negative • CKVO ’012 n = 1029 positive • QUASAR ’04 n = 3239 positive 1 2 studies without observation arm 2 stage II and stage III colon+rectal

  14. Adjuvant treatment in stage II colorectal cancer – QUASAR study • Adjuvant treatment results in absolute 3% overall survival benefit in stage II colorectal cancer • No significant benefit in pts > 70 yrs Gray et al. ASCO 2004

  15. Adjuvant treatment in stage II colon cancer • Data are accumulating that adjuvant treatment may be effective • Absolute survival benefit for fluoropyrimidine treatment is approx. 3 – 4%

  16. Oral fluoropyrimidines as adjuvant treatment for colon cancer

  17. UFT/LV versus 5FU/LV (Roswell Park schedule)in stage II + III colon cancer UFT/LV has equivalent efficacy and toxicity to 5FU/LV Wolmark et al. ASCO 2004

  18. X-ACT trial in adjuvant treatment of stage III colon cancer Capecitabine 1250 mg/m2 twice daily, d1–14, q21d n=1004 • 1° endpoint: DFS • 2° endpoints • OS • tolerability • pharmacoeconomics • QoL Stage III resection <8 weeks 24 weeks Bolus 5-FU/LV 5-FU 425 mg/m2 plus LV 20 mg/m2, d1–5, q28d n=983

  19. X-ACT powered to establish at least equivalence of capecitabine to 5-FU/LV • Primary endpoint DFS • 80% power for at least equivalence • primary endpoint met if upper limit 95% CI HR <1.25 • Secondary analyses • tests for superiority • RFS, OS • multivariate and subgroup analyses • All analyses shown were prospectively planned

  20. X-ACT treatment arms were well balanced Cassidy et al. ASCO 2004

  21. DFS: primary endpoint achieved (ITT) Estimated probability Capecitabine (n=1004) 5-FU/LV (n=983) 1.0 0.8 0.6 0.4 HR = 0.87 (95% CI: 0.75–1.00) 0 1 2 3 4 5 6 Years

  22. Absolute difference at 3 years: 3.6% Capecitabine showed trend to superior DFS (ITT) Estimated probability 3-year DFS Capecitabine (n=1004) 64.2% 5-FU/LV (n=983) 60.6% 1.0 0.8 0.6 0.4 p=0.0528 0 1 2 3 4 5 6 Years

  23. Absolute difference at 3 years: 3.7% Capecitabine showed trend to improved OS (ITT) Estimated probability 3-year OS Capecitabine (n=1004) 81.3% 5-FU/LV (n=983) 77.6% 1.0 0.8 0.6 0.4 HR = 0.84 (95% CI: 0.69–1.01)p=0.0706 0 1 2 3 4 5 6 Years

  24. Capecitabine consistent benefit in subgroup analysis for DFS capecitabine better Bolus 5-FU/LV better n ITT population Male Female <40 40–69 years old ≥70 N1 (1–3 nodes) N2 (³4 nodes) Baseline CEA <ULN Baseline CEA >ULN 1987 1074 912 76 1543 396 1389 593 1672 155 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Hazard ratio and 95% CI

  25. Fewer key grade 3/4 toxicities and later onset with capecitabine Estimated probability of grade 3/4 adverse event 1.0 0.8 0.6 0.4 0.2 0 5-FU/LV capecitabine p<0.001 0 1 2 3 4 5 6 7 8 Months Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia

  26. Adjuvant chemotherapy needs active management Cassidy et al. ASCO 2004

  27. Capecitabine as adjuvant treatment in stage III colon cancer Compared to 5FU/LV, capecitabine has: • trend towards better DFS • trend towards better OS • improved safety (but is still cytotoxic treatment!) Capecitabine should replace 5FU/LV as adjuvant treatment in stage III colon cancer

  28. FOLFOX as adjuvant treatment for colon cancer

  29. FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² LV5FU2 R MOSAIC: Study Design stage II + III colon cancer Endpoints • Primary: • Disease-Free Survival (DFS) • Secondary: • Safety (including long-term) • Overall Survival (OS)

  30. D1 D2 5-FU bolus 5-FU bolus 5-FU infusion 5-FU infusion LV LV MOSAIC Rationale 1: LV5FU2 in metastatic colon cancer • Compared to monthly bolus 5-FU/LV: • improved progression-free survival • decreased toxicity de Gramont et al. J Clin Oncol, 1997

  31. D1 D2 5-FU bolus 5-FU bolus 5-FU infusion 5-FU infusion LV LV MOSAIC Rationale 2: LV5FU2 in adjuvant colon cancer • Compared to monthly bolus 5-FU/LV: • same efficacy: 73% 3-year DFS • decreased toxicity André et al. J Clin Oncol, 2003

  32. D1 D2 5-FU bolus 5-FU bolus 5-FU infusion 5-FU infusion LV LV OXA MOSAIC Rationale 3: FOLFOX4 in metastatic coloreactal cancer • Improved PFS compared to: • LV5FU2 de Gramont et al. J Clin Oncol 2000 • IFL Goldberg et al. J Clin Oncol 2004

  33. D1 D1 D2 D2 5-FU bolus 5-FU bolus 5-FU bolus 5-FU bolus 5-FU infusion* 5-FU infusion* 5-FU infusion* 5-FU infusion* LV LV LV LV R MOSAIC: Treatment arms FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² LV OXA LV5FU2 Every 2 weeks, 6 months of treatment (12 cycles) *ambulatory infusion

  34. FOLFOX4 LV5FU2(n=1123) (n=1123) Median age, years 61 60 Male/Female % 56 /44 52 /48 KPS 80-100 % 86.2 87.6 Stage II/ III % 40 /60 40 /60 Bowel obstruction %18 19 Perforation % 7 7 MOSAIC: Patient characteristics Stratification for TNM stage, bowel obstruction/perforation, center Median time surgery – start chemo: 5.7 wks (range 1.1 – 17)

  35. DFS by treatment arm (ITT) 3-year DFS Probability FOLFOX4 (n=1123) 78.7% LV5FU2 (n=1123) 73.3% abs. difference = 5.4% Hazard ratio: 0.76 [0.64 – 0.89] p =0.0008 months 24% risk reduction in the FOLFOX4 arm

  36. Disease-Free Survival Stage III patients Probability 3-year DFS FOLFOX4 (n=672) 72.8% LV5FU2 (n=675) 65.8% abs. difference = 7.0% Hazard ratio: 0.75 [0.62-0.90] p=0.002 months 25% risk reduction for stage III patients

  37. Disease-Free Survival Stage II patients Probability 3-year DFS FOLFOX4 (n=451) 87.4% LV5FU2 (n=448) 84.3% abs. difference = 3.1% Hazard ratio: 0.79 [0.57-1.09] p=0.151 months 21% risk reduction for stage II patients

  38. DFS analysis according to prognostic factors ITT population Male Female > 65 years old < 65 years old T4 T1,T2,T3 N2 N0,N1 Stage III Stage II Bowel obstruction No obstruction Tumour perforation No perforation Baseline CEA > 5 Baseline CEA < 5 Well/moderately differentiated Poorly differentiated Venous invasion No venous invasion FOLFOX better LV5FU2 better

  39. MOSAIC: Safety results, toxicity per patient NCI  Gr 3 % FOLFOX4 LV5FU2 (n=1108) (n=1111) Thrombocytopenia 1.7 0.4 Neutropenia 41.1 (Gr 4: 12.2) 4.7 Febrile neutropenia 0.7 0.1 Neutropenic sepsis 1.1 0.1 Diarrhoea 10.8 6.7 Stomatitis 2.7 2.2 Vomiting 5.9 1.4 Allergy 3.0 0.2 Alopecia (Gr 2) 5.0 5.0 All cause mortality 0.5 0.5

  40. MOSAIC:Peripheral sensory neuropathy ParesthesiasFOLFOX4 arm Per patient One year (n=1108) after Grade 0 8 % 70 % Grade 1 48.1 % 24 % Grade 2 31.5 % 5 % Grade 3 12.4 % 1 % Overall 82% 30% (NCI version 1)

  41. High-risk stage II colon cancer Either of the following characteristics: • Stage T4 • < 10 regional lymphnodes examined • Bowel obstruction • Tumor perforation • Poorly differentiated histology • Venous invasion

  42. MOSAIC study in stage II/III colon cancer Hickish et al. ASCO/ESMO 2004

  43. Disease-Free Survival High-risk stage II patients 3-year DFSFOLFOX4 (n=286)84.9%LV5FU2 (n=290) 79.8% abs. difference 5.1% Probability 1.0 0.9 0.8 0.7 Hazard ratio 0.72 [0.48-1.08] N.S. 28% risk reduction in the FOLFOX4 arm 0.6 months 0 6 12 18 24 30 36 42 48

  44. MOSAIC study in subgroups of colon cancer # 4-yr DFS 75.9% vs. 69.1%, abs. diff. 6.8%

  45. FOLFOX as adjuvant treatment in colon cancer • Significant DFS benefit overall (stage II + III) • MOSAIC study not designed for stage II – III subgroups • Significant benefit in stage III, overall increasing after longer follow-up (DFS 3yrs. 5.4%  4-yrs. 6.8%) • With so many effective drugs available, overall survival as endpoint becomes less reliable

  46. FOLFOX as adjuvant treatment in stage II colon cancer • Benefit in stage II is small, non-significant • Benefit in high-risk stage II seems comparable to stage III but non-significant (underpowered) • Prospective studies in high-risk stage II will probably never be performed

  47. FOLFOX as adjuvant treatment in stage II colon cancer • Relapse rate in stage II  20% • Absolute benefit of 5FU/LV  4% To cure 1 patient, 25 patients have to be treated • Additional benefit of FOLFOX 3% (extrapolation!) To cure 1 patient, 14 patients have to be treated One out of 25 overall will not relapse if treated by FOLFOX instead of 5FU/LV

  48. New standards for adjuvant treatment in stage II and III colon cancer

  49. Proposal for new standard adjuvant treatment in stage III colon cancer • FOLFOX 12 cycles q 2 weeks • For patients refusing or ineligible for FOLFOX: capecitabine 8 cycles q 3 weeks • Capecitabine + oxaliplatin should not be administered outside adjuvant trials (ongoing)

  50. Proposal for new standard adjuvant treatment in stage II colon cancer Stage II overall • capecitabine 8 cycles q 3 weeks, or observation ? Stage II high-risk: • FOLFOX or capecitabine ?

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