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

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 = 1100negative NSABP 4 studies 1 n = >2000positive Mayo ’95 n = 318negative CKVO ’01 2 n = 1029 positive QUASAR ’04 n = 3239positive 1 2 studies without observation arm 2 stage II and stage III colon+rectal

14. Adjuvant treatment in stage II colorectal cancer – QUASAR study Gray et al. ASCO 2004 observation5FU schedule n16171622 5-yr OS77.4%80.3% (p.02) Adjuvant treatment results in absolute 3% overall survival benefit in stage II colorectal cancer No significant benefit in pts > 70 yrs

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 Wolmark et al. ASCO 2004 5FU/LVUFT/LV n777784 5-yr DFS68.3%66.9% 5-yr OS78.7% UFT/LV has equivalent efficacy and toxicity to 5FU/LV

18. X-ACT trial in adjuvant treatment of stage III colon cancer 1° endpoint: DFS 2° endpoints OS tolerability pharmacoeconomics QoL Stage III resection <8 weeks Capecitabine 1 250 mg/m 2 twice daily, d1–14, q21d n=1 004 Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20 mg/m 2, d1–5, q28d n=983 24 weeks

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) HR = 0.87 (95% CI: 0.75–1.00) Capecitabine (n=1 004) 5-FU/LV (n=983) Estimated probability 01234560123456 1.0 0.8 0.6 0.4 Years

22. Capecitabine showed trend to superior DFS (ITT) Estimated probability 01234560123456 1.0 0.8 0.6 0.4 Absolute difference at 3 years: 3.6% p=0.0528 3-year DFS Capecitabine (n=1 004)64.2% 5-FU/LV (n=983) 60.6% Years

23. Capecitabine showed trend to improved OS (ITT) Estimated probability 01234560123456 Years Absolute difference at 3 years: 3.7% 1.0 0.8 0.6 0.4 3-year OS Capecitabine (n=1 004)81.3% 5-FU/LV (n=983) 77.6% HR = 0.84 (95% CI: 0.69–1.01) p=0.0706

24. Capecitabine consistent benefit in subgroup analysis for DFS Hazard ratio and 95% CI capecitabine better Bolus 5-FU/LV better 0.40.60.81.01.21.41.61.8 ITT population Male Female <40 40–69 years old ≥70 N1 (1–3 nodes) N2 (  4 nodes) Baseline CEA <ULN Baseline CEA >ULN 1 987 1 074 912 76 1 543 396 1 389 593 1 672 155 n

25. 1.0 0.8 0.6 0.4 0.2 0 Estimated probability of grade 3/4 adverse event 012345678012345678 Months 5-FU/LV capecitabine Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia p<0.001 Fewer key grade 3/4 toxicities and later onset with capecitabine

26. Adjuvant chemotherapy needs active management Patients (%) Capecitabine (n=995) Bolus 5-FU/LV (n=974) Completed full course of treatment 8488 Needed dose reduction4244 Needed interruption155 Needed delay4629 Needed dose reduction, interruption or delay 5752 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. MOSAIC: Study Design stage II + III colon cancer R LV5FU2 FOLFOX4 : LV5FU2 + Oxaliplatin 85mg/m² n Primary: – Disease-Free Survival (DFS) n Secondary: – Safety (including long-term) – Overall Survival (OS) Endpoints

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

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

32. 5-FU infusion D1 5-FU bolus D2 LV 5-FU bolus 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. LV OXA R MOSAIC: Treatment arms *ambulatory infusion LV5FU2 FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² Every 2 weeks, 6 months of treatment (12 cycles) D1 5-FU bolus D2 5-FU bolus LV 5-FU infusion* D1 5-FU bolus D2 5-FU bolus LV 5-FU infusion*

34. MOSAIC: Patient characteristics FOLFOX4 LV5FU2 (n=1123)(n=1123) Median age, years6160 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 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) months Probability Hazard ratio: 0.76 [0.64 – 0.89] p =0.0008 24% risk reduction in the FOLFOX4 arm 3-year DFS FOLFOX4 (n=1123)78.7% LV5FU2 (n=1123)73.3% abs. difference = 5.4%

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

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

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 sepsis1.10.1 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 Paresthesias FOLFOX4 arm Per patientOne year (n=1108)after Grade 08 %70 % Grade 148.1 %24 % Grade 231.5 %5 % Grade 312.4 %1 % Overall82%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 Patients (n)5FU/LVFOLFOX total1123 Stage III675 (60%)672 (60%) Stage II448 (40%)451 (40%) High-risk stage II290 (26%)286 (25%) Hickish et al. ASCO/ESMO 2004

43. 0612182430364248 3-year DFS FOLFOX4 (n=286)84.9% LV5FU2 (n=290)79.8% abs. difference 5.1% 28% risk reduction in the FOLFOX4 arm 1.0 0.9 0.8 0.7 0.6 months Probability Disease-Free Survival High-risk stage II patients Hazard ratio 0.72 [0.48-1.08] N.S.

44. MOSAIC study in subgroups of colon cancer Hazard ratio for relapse (95% CI) Decrease in relative risk of recurrence Absolute difference in 3-yr DFS Overall n = 2246 0.76 (0.64-0.89) p.0008 24%5.4% # Stage III n = 1247 0.76 (0.62-0.92) p.002 25%7.0% Stage II n = 899 0.80 (0.56-1.15) NS 21%3.1% High-risk stage II n = 576 0.72 (0.48-1.08) NS 28%5.1% # 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 ?

51. Adjuvant treatment in colon cancer: which option is best for our patients? patients must be informed about:  the reality of treatment  the associated risks/benefits Information should be provided by a physician with experience in chemotherapy