Transcript Adjuvante therapie van het coloncarcinoom anno 2004
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
• • • • • IMPACT 6 studies n = 1100 NSABP 4 studies
1
Mayo ’95 n = 318 CKVO ’01
2
n = >2000 n = 1029 QUASAR ’04 n = 3239 result on survival negative positive negative positive positive
1
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 5-yr OS 1617 77.4% 1622 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 5-yr DFS 5-yr OS 777 68.3% 78.7% 784 66.9% 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 Stage III resection <8 weeks Capecitabine 1 250 mg/m 2 twice daily, d1 –14, q21d n=1 004 24 weeks
• •
Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20 mg/m 2 , 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 Age, median (range) ECOG 0
/
1 Male/female CEA: normal / >ULN T1 –2 T3/T4 Nodal status: N1/2 Tumour differentiation Well/moderate Poor/anaplastic Capecitabine (n=1 004) (%) 62 (25 –80) 85 / 15 54 / 46 83 / 9 10 76 / 14 70 / 30 Bolus 5-FU/LV (n=983) (%) 63 (22 –82) 85 / 15 54 / 46 84 / 7 10 76 / 14 71 / 29 9 / 65 16 / 1 10 / 63 19 / 1
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
0.4
0 HR = 0.87 (95% CI: 0.75
–1.00) 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
0.4
0 Absolute difference at 3 years: 3.6% 1 2 3 Years 4 p=0.0528
5 6
Capecitabine showed trend to improved OS (ITT) Estimated probability 1.0
Capecitabine (n=1004) 3-year OS 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 ITT population n 1987 Male Female 1074 912 <40 40 –69 years old ≥70 N1 (1 –3 nodes) N2 (
4 nodes) 76 1543 396 1389 593 Baseline CEA
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
0.4
p<0.001
0.2
0 0 1 2 3 4 Months 5 6 7 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 Needed dose reduction Needed interruption Needed delay Needed dose reduction, interruption or delay 84 42 15 46 57 88 44 5 29 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 D2 5-FU bolus LV OXA
5-FU infusion
LV
Improved PFS compared to: LV5FU2 IFL 5-FU infusion
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 D2 5-FU bolus LV OXA 5-FU infusion* 5-FU infusion* R D1 5-FU bolus D2 5-FU bolus
LV5FU2
LV 5-FU infusion* LV 5-FU infusion*
Every 2 weeks, 6 months of treatment (12 cycles) *ambulatory infusion
MOSAIC: Patient characteristics FOLFOX4 (n=1123) LV5FU2 (n=1123) Median age, years Male/Female % KPS 80-100 % Stage II/ III % Bowel obstruction % Perforation % 61 56 /44 86.2 40 /60 18 7 60 52 /48 87.6 40 /60 19 7
Stratification for TNM stage, bowel obstruction/perforation, center Median time surgery – start chemo: 5.7 wks (range 1.1 – 17)
Probability 1 0,9 DFS by treatment arm (ITT) 3-year DFS FOLFOX4 (n=1123) LV5FU2 (n=1123) 78.7% 73.3% abs. difference = 5.4% 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 0,9 Disease-Free Survival Stage III patients 3-year DFS FOLFOX4 (n=672) LV5FU2 (n=675) 72.8% 65.8% abs. difference = 7.0% 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
Disease-Free Survival Stage II patients Probability 1 0,9 0,8 0,7 0,6 3-year DFS FOLFOX4 (n=451) LV5FU2 (n=448) 87.4% 84.3% abs. difference = 3.1% 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 % FOLFOX4 (n=1108) LV5FU2 (n=1111) Thrombocytopenia Neutropenia Febrile neutropenia Neutropenic sepsis 1.7
0.4
41.1 (Gr 4: 12.2) 4.7 0.7 1.1
0.1 0.1
Diarrhoea 10.8 Stomatitis 2.7 Vomiting 5.9 Allergy 3.0 6.7
2.2
1.4
0.2
Alopecia (Gr 2) 5.0
5.0
All cause mortality 0.5 0.5
MOSAIC: Peripheral sensory neuropathy Paresthesias (NCI version 1) Grade 0 Grade 1 Grade 2 Grade 3 Overall FOLFOX4 arm Per patient (n=1108) 8 % One year after 70 % 48.1 % 31.5 % 12.4 % 82% 24 % 5 % 1 % 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) total Stage III Stage II High-risk stage II 5FU/LV 1123 675 (60%) 448 (40%) 290 (26%) FOLFOX 1123 672 (60%) 451 (40%) 286 (25%)
Hickish et al. ASCO/ESMO 2004
Disease-Free Survival Probability High-risk stage II patients 3-year DFS FOLFOX4 (n=286) 84.9% 1.0
LV5FU2 (n=290) 79.8% abs. difference 5.1% 0.9
0.8
0.7
0.6
Hazard ratio 0.72 [0.48-1.08] N.S.
28% risk reduction in the FOLFOX4 arm 0 6 12 18 24 30 36 42 48 months
MOSAIC study in subgroups of colon cancer Overall n = 2246 Hazard ratio for relapse (95% CI) Decrease in relative risk of recurrence Absolute difference in 3-yr DFS 0.76
(0.64-0.89) p.0008
24% 5.4% # 25% 7.0% Stage III n = 1247 Stage II n = 899 High-risk stage II n = 576 0.76
(0.62-0.92) p.002
0.80
(0.56-1.15) NS 0.72
(0.48-1.08) NS 21% 28% 3.1% 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