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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 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 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 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) 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 Saltz et al. ASCO 2004 Data are accumulating that irinotecan should be combined with infusional and not bolus 5FU Primary endpoint in randomised adjuvant studies 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 • • • • 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 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 !! Adjuvant treatment in stage II colon cancer 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 5FU/LV as adjuvant therapy for stage II colon cancer - history • • • • • 1 result on survival IMPACT 6 studies n = 1100 negative NSABP 4 studies1 n = >2000 positive Mayo ’95 n = 318 negative CKVO ’012 n = 1029 positive QUASAR ’04 n = 3239 positive 2 studies without observation arm 2 stage II and stage III colon+rectal Adjuvant treatment in stage II colorectal cancer – QUASAR study observation 5FU schedule n 1617 1622 5-yr OS 77.4% 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 Gray et al. ASCO 2004 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% Oral fluoropyrimidines as adjuvant treatment for colon cancer UFT/LV versus 5FU/LV (Roswell Park schedule) in stage II + III colon cancer 5FU/LV UFT/LV n 777 784 5-yr DFS 68.3% 66.9% 5-yr OS 78.7% 78.7% UFT/LV has equivalent efficacy and toxicity to 5FU/LV Wolmark et al. ASCO 2004 X-ACT trial in adjuvant treatment of stage III colon cancer Capecitabine 1 250 mg/m2 twice daily, d1–14, q21d n=1 004 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 • • 1° endpoint: DFS 2° endpoints • OS • tolerability • pharmacoeconomics • QoL 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 X-ACT treatment arms were well balanced Capecitabine (n=1 004) (%) Bolus 5-FU/LV (n=983) (%) 62 (25–80) 63 (22–82) ECOG 0/1 85 / 15 85 / 15 Male/female 54 / 46 54 / 46 CEA: normal / >ULN 83 / 9 84 / 7 T1–2 T3/T4 10 76 / 14 10 76 / 14 Nodal status: N1/2 70 / 30 71 / 29 Tumour differentiation Well/moderate Poor/anaplastic 9 / 65 16 / 1 10 / 63 19 / 1 Age, median (range) Cassidy et al. ASCO 2004 DFS: primary endpoint achieved (ITT) Estimated probability 1.0 Capecitabine (n=1004) 5-FU/LV (n=983) 0.8 0.6 HR = 0.87 (95% CI: 0.75–1.00) 0.4 0 1 2 3 Years 4 5 6 Capecitabine showed trend to superior DFS (ITT) Estimated probability 3-year DFS 1.0 Capecitabine (n=1004) 64.2% 5-FU/LV (n=983) 60.6% 0.8 0.6 p=0.0528 Absolute difference at 3 years: 3.6% 0.4 0 1 2 3 Years 4 5 6 Capecitabine showed trend to improved OS (ITT) Estimated probability 1.0 3-year OS Capecitabine (n=1004) 81.3% 5-FU/LV (n=983) 77.6% 0.8 Absolute difference at 3 years: 3.7% 0.6 HR = 0.84 (95% CI: 0.69–1.01) p=0.0706 0.4 0 1 2 3 Years 4 5 6 Capecitabine consistent benefit in subgroup analysis for DFS capecitabine better Bolus 5-FU/LV better n ITT population 1987 Male Female 1074 912 <40 40–69 years old ≥70 76 1543 396 N1 (1–3 nodes) N2 (4 nodes) 1389 593 Baseline CEA <ULN 1672 Baseline CEA >ULN 155 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Hazard ratio and 95% CI Fewer key grade 3/4 toxicities and later onset with capecitabine Estimated probability of grade 3/4 adverse event 1.0 5-FU/LV capecitabine 0.8 0.6 p<0.001 0.4 0.2 0 0 1 2 3 4 5 6 7 Months Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia 8 Adjuvant chemotherapy needs active management Patients (%) Capecitabine (n=995) Bolus 5-FU/LV (n=974) Completed full course of treatment 84 88 Needed dose reduction 42 44 Needed interruption 15 5 Needed delay 46 29 Needed dose reduction, interruption or delay 57 52 Cassidy et al. ASCO 2004 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 FOLFOX as adjuvant treatment for colon cancer MOSAIC: Study Design stage II + III colon cancer FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² R LV5FU2 Endpoints Primary: – Disease-Free Survival (DFS) Secondary: – Safety (including long-term) – Overall Survival (OS) MOSAIC Rationale 1: LV5FU2 in metastatic colon cancer D1 5-FU bolus LV 5-FU infusion D2 5-FU bolus LV 5-FU infusion Compared to monthly bolus 5-FU/LV: improved progression-free survival decreased toxicity de Gramont et al. J Clin Oncol, 1997 MOSAIC Rationale 2: LV5FU2 in adjuvant colon cancer D1 5-FU bolus LV 5-FU infusion D2 5-FU bolus LV 5-FU infusion Compared to monthly bolus 5-FU/LV: same efficacy: 73% 3-year DFS decreased toxicity André et al. J Clin Oncol, 2003 MOSAIC Rationale 3: FOLFOX4 in metastatic coloreactal cancer D1 5-FU bolus LV D2 5-FU bolus 5-FU infusion LV 5-FU infusion OXA Improved PFS compared to: LV5FU2 IFL de Gramont et al. J Clin Oncol 2000 Goldberg et al. J Clin Oncol 2004 MOSAIC: Treatment arms FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² D1 5-FU bolus LV 5-FU infusion* D2 5-FU bolus LV LV 5-FU infusion* OXA R D1 5-FU bolus LV5FU2 LV 5-FU infusion* D2 5-FU bolus LV 5-FU infusion* Every 2 weeks, 6 months of treatment (12 cycles) *ambulatory infusion MOSAIC: Patient characteristics FOLFOX4 (n=1123) Median age, years Male/Female % LV5FU2 (n=1123) 61 56 /44 60 52 /48 86.2 87.6 40 /60 40 /60 Bowel obstruction % 18 19 Perforation % 7 7 KPS 80-100 % Stage II/ III % Stratification for TNM stage, bowel obstruction/perforation, center Median time surgery – start chemo: 5.7 wks (range 1.1 – 17) DFS by treatment arm (ITT) 3-year DFS Probability 1 FOLFOX4 (n=1123) 78.7% LV5FU2 (n=1123) 73.3% abs. difference = 5.4% 0,9 0,8 0,7 0,6 Hazard ratio: 0.76 [0.64 – 0.89] p =0.0008 0,5 0 10 20 30 40 50 months 24% risk reduction in the FOLFOX4 arm Probability 1 Disease-Free Survival Stage III patients 3-year DFS FOLFOX4 (n=672) 72.8% LV5FU2 (n=675) 65.8% abs. difference = 7.0% 0,9 0,8 0,7 0,6 Hazard ratio: 0.75 [0.62-0.90] p=0.002 0,5 0 10 20 30 40 50 months 25% risk reduction for stage III patients Probability Disease-Free Survival Stage II patients 1 0,9 3-year DFS 0,8 FOLFOX4 (n=451) 87.4% LV5FU2 (n=448) 84.3% abs. difference = 3.1% 0,7 0,6 Hazard ratio: 0.79 [0.57-1.09] p=0.151 0,5 0 10 20 30 40 50 months 21% risk reduction for stage II patients 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 MOSAIC: Safety results, toxicity per patient NCI Gr 3 % Thrombocytopenia Neutropenia FOLFOX4 LV5FU2 (n=1108) (n=1111) 1.7 0.4 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 MOSAIC: Peripheral sensory neuropathy Paresthesias (NCI version 1) FOLFOX4 arm Per patient (n=1108) One year after Grade 0 8% 70 % Grade 1 48.1 % 24 % Grade 2 31.5 % 5% Grade 3 12.4 % 1% Overall 82% 30% 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 MOSAIC study in stage II/III colon cancer Patients (n) 5FU/LV FOLFOX 1123 1123 Stage III 675 (60%) 672 (60%) Stage II 448 (40%) 451 (40%) High-risk stage II 290 (26%) 286 (25%) total Hickish et al. ASCO/ESMO 2004 Disease-Free Survival High-risk stage II patients 3-year DFS FOLFOX4 (n=286) 84.9% LV5FU2 (n=290) 79.8% Probability 1.0 abs. difference 5.1% 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 0 6 12 18 24 30 36 42 48 months MOSAIC study in subgroups of colon cancer Hazard ratio for relapse (95% CI) Decrease in Absolute relative risk difference in of recurrence 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% 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 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 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 New standards for adjuvant treatment in stage II and III colon cancer 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) 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 ? • 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