Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results...
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Transcript of Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results...
Capecitabine versus Bolus Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for 5-FU/Leucovorin as Adjuvant Therapy for
Colon Cancer: X-ACT Trial ResultsColon Cancer: X-ACT Trial Results
James Cassidy, MDColorectal Cancer Update Think Tank Meeting
June 24, 2005
1° endpoint: Disease-free survival (DFS)
2° endpoints Relapse-free survival (RFS) Overall survival Tolerability (NCIC CTC) Pharmacoeconomics QoL
Capecitabine1,250 mg/m2 twice daily,
d1–14, q21d n = 1,004
Bolus 5-FU/LV5-FU 425 mg/m2 plus
LV 20 mg/m2, d1–5, q28dn = 983
Recruitment1998–2001
X-ACT Trial in Adjuvant Treatment of X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon CancerDukes’ C Colon Cancer
Chemo-naïve Dukes’ C,
resection ≤8 weeks
Source: Cassidy J. Presentation. ASCO 2005.
X-ACT Powered to Establish at Least X-ACT Powered to Establish at Least Equivalence of Equivalence of Capecitabine Capecitabine
Sample size to achieve
80% power for at least equivalence in DFS
Noninferiority margin 1.25 for hazard ratio of capecitabine vs 5-FU/LV
Analysis in per-protocol and ITT populations
Secondary analyses
Test for superiority in DFS, RFS, OS
Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.
Standard Eligibility CriteriaStandard Eligibility Criteria
Eligible patients Aged 18–75 years Histologically confirmed
Dukes’ C colon cancer Fully recovered after
surgery ECOG PS: ≤1 Life expectancy
≥ 5 years
Excluded patients Metastatic disease Prior cytotoxic
chemotherapy or organ allografts
Clinically significant cardiac disease
Severe renal impairment
Central nervous system disorders
Pregnant or lactating women
Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.
Protocol-Defined Populations and EndpointsProtocol-Defined Populations and Endpoints
Populations Intent to treat, all randomized patients Per-protocol population excludes major protocol
violations and patients with <12 weeks treatment Time-related endpoints
Disease-free survival• Relapses or new occurrences of colon cancer and
all deaths Relapse-free survival• Relapses/new occurrences of colon cancer and
deaths related to treatment or colon cancer Overall survival
Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.
Bolus 5-FU/LVIV leucovorin
20 mg/m2 +IV 5-FU
425 mg/m2
CapecitabineCapecitabine
1,250 mg/m2 twice daily
Day
Treatment (days 1–14) Rest (days 15–21)
1 2 3 4 5 8 15 21
Repeat cycle x 8(24 weeks)
28
OR
Repeat cycle x 6(24 weeks)
X-ACT Treatment SchedulesX-ACT Treatment Schedules
Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.
X-ACT Treatment Arms Were Well BalancedX-ACT Treatment Arms Were Well Balanced
Capecitabinen = 1,004 (%)
Bolus 5-FU/LVn = 983 (%)
Age, median (range) 62 (25–80) 63 (22–82)
ECOG 0/1 85/15 85/15
Male/Female 54 / 46 54 / 46
Normal CEA 83 84
T1-2 10 10
T3 76 76
T4 14 14
N 1/2 70/30 71/29
Well differentiated 9 10
Moderately differentiated 65 63
Poorly differentiated/anaplastic 17 20
Source: Cassidy J. Presentation. ASCO 2005.
Other Prognostic Factors Were BalancedOther Prognostic Factors Were Balanced
Capecitabinen = 1,004 (%)
Bolus 5-FU/LVn = 983 (%)
Lymph nodes N1 70 71
N2 30 29
T-stage T1-2 10 10
T3 76 76
T4 14 14
Differentiation well 9 10
moderately 65 63
poorly 16 19
anaplastic 1 1
Source: Twelves C. Presentation. ASCO 2005.
Median follow-up 51 months
Strong Trend to Superior DFS (ITT)Strong Trend to Superior DFS (ITT)
1.0
0.8
0.6
0.40 1 2 3 4 5 6
Years
Est
imat
ed p
rob
abil
ity
Capecitabine (n = 1,004) 64.6%5-FU/LV (n = 983) 61%
HR = 0.87 (95% CI: 0.75–1.00)p < 0.0001
Source: Twelves C. Presentation. ASCO 2005.
Capecitabine versus Bolus 5-FU/LV: Capecitabine versus Bolus 5-FU/LV: Superior Relapse-Free Survival (ITT)Superior Relapse-Free Survival (ITT)
Est
imat
ed p
rob
abil
ity
Capecitabine (n = 1,004)5-FU/LV (n = 983)
0 1 2 3 4 5 6
Years
HR = 0.86 (95% CI: 0.74–0.99)p = 0.0407
1.0
0.8
0.6
0.4
Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.
Capecitabine Showed Trend to Improved Capecitabine Showed Trend to Improved Overall Survival (ITT)Overall Survival (ITT)
Est
imat
ed p
rob
abil
ity
Capecitabine (n = 1, 004) 81.7%5-FU/LV (n = 983) 78.3%
0 1 2 3 4 5 6
Years
HR = 0.89 (95% CI: 0.74–1.07)p < 0.001
1.0
0.8
0.6
0.4
Source: Cassidy J. Presentation. ASCO 2005.
Fewer Relapses in Liver and Lymph Nodes Fewer Relapses in Liver and Lymph Nodes with with Capecitabine Capecitabine
Number of relapses
Capecitabinen = 1,004
Bolus 5-FU/LVn = 983
TotalAs only
site TotalAs only
site
Total number of relapses 323 357
Colon, rectum 58 41 60 43
Lymph nodes 44 20 57 35
Liver 126 93 145 110
Lung 58 35 58 39
Other 101 68 99 65
* Data points from KM curves
Sources: 1 Haller DG et al. J Clin Oncol 2004; In Press2 André T et al. J Clin Oncol 2003;15:2896–9033 IMPACT. Lancet 1995;345(8955):939–44
X-ACT Mayo Comparable to Mayo in Other Trials X-ACT Mayo Comparable to Mayo in Other Trials (Dukes’ C, Colon Only)(Dukes’ C, Colon Only)
INT0089*n = 7691
Andre*n = 2562
IMPACTn = 3133
X-ACTn = 983
Mayo3-year DFS
63 61 62 61
Mayo3-year OS
73 81 78 78
Treatment ExposureTreatment Exposure
Median dose intensity
Capecitabine 93% (quartiles 77-100%)
Bolus 5-FU/LV 92% (quartiles 78-100%)
Patients completing >12 weeks treatment at full dose
Capecitabine 75%
Bolus 5-FU/LV 67%
Majority of patients completed the full course of treatment
Capecitabine 84% completed all 8 cycles
Bolus 5-FU/LV 89% completed all 6 cycles
Fewer Key Grade III/IV Toxicities and Fewer Key Grade III/IV Toxicities and Later Onset with CapecitabineLater Onset with Capecitabine
1.0
0.8
0.6
0.4
0.2
0
p < 0.001
0 1 2 3 4 5 6 7 8Months
5-FU/LVCapecitabine
Overall safety profile: Grade III to IV diarrhea, stomatitis, nausea, vomiting, alopecia, HFS, neutropenia
Source: Cassidy J. Presentation. ASCO 2005.
Est
imat
ed p
rob
abil
ity
of
Gra
de
III/
IV a
dve
rse
even
t
* p < 0.001† Laboratory value
Treatment-related AEs
*
*
*
*
Diarrhea Stomatitis Hand-foot Neutropenia† Nausea/ Alopecia syndrome vomiting
100
80
60
40
20
0
Capecitabine (n = 993)
Bolus 5-FU/LV (n = 974)
*
*
Pat
ien
ts (
%)ToxicityToxicity
Nu
mb
er o
f cy
cles
Before After Before After Before After
Hand-foot syndrome Diarrhea Stomatitis
Grade II
Grade III
Grade IV
20
15
10
5
0
Capecitabine Dose Modification Reduces the Capecitabine Dose Modification Reduces the Recurrence of Adverse EventsRecurrence of Adverse Events
Improved Tolerability Profile of Capecitabine Improved Tolerability Profile of Capecitabine Maintained in ElderlyMaintained in Elderly
All grades
Capecitabine (%) Bolus 5-FU/LV (%)
≥70 years(n = 186)
≥70 years(n = 205)
Diarrhea 52 68
Stomatitis 23 67
Hand-foot syndrome 63 8
Nausea 33 47
Fatigue 17 19
Neutropenia 4 31
1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed p
rob
abili
ty
0 12 24 36 48 60 72Months
Full dose capecitabineInter dose capecitabineLow dose capecitabine
Capecitabine Efficacy Maintained with Appropriate Capecitabine Efficacy Maintained with Appropriate Dose ReductionDose Reduction: DFS: DFS
532 510 459 403 332 280 194 113 61 12 4 0 0343 323 293 265 218 174 122 81 37 13 5 0 0120 90 77 70 60 50 34 20 10 3 1 0 0
No. at riskFull doseInter doseLow dose
X-ACT: Quality of Life Maintained Over Time X-ACT: Quality of Life Maintained Over Time (QLQ C-30)(QLQ C-30)
5-FU / LVCapecitabine
100
80
60
40
20
0Baseline 7 9 16 17 25
Weeks (of trial treatment)
889 817 894 912841 746 838 865
n = n =
Glo
bal
hea
lth
sta
tus
sco
re
Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.
*Also balanced first- versus second-line chemotherapy
Poststudy Chemotherapy after RelapsePoststudy Chemotherapy after RelapseSimilar in Both ArmsSimilar in Both Arms
Percent patients with chemotherapy*
Capecitabinen = 372
5-FU/LVn = 404
Regimens based on:
5-FU 17 16
Irinotecan 39 35
Oxaliplatin 32 29
Capecitabine 4 10
Others 9 6
-1864
1450
-3004
-57 -259
7
Net costs per patient versus 5-FU/LV (£)
4 000
2 000
0
–2 000
–4 000
Total Drugs Administration Hospital Medications Consultations use
Sources: Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl 3):iii73; Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.
Replacement of 5-FU/LV with Xeloda is Net Cost Replacement of 5-FU/LV with Xeloda is Net Cost Saving: Direct Payer CostsSaving: Direct Payer Costs
X-ACT Trial ConclusionsX-ACT Trial Conclusions
Disease-free survival for capecitabine at least equivalent to 5-FU/leucovorin
Capecitabine improved relapse-free survival
Capecitabine associated with significantly fewer adverse events
Capecitabine is an effective alternative to IV 5-FU/leucovorin as adjuvant therapy in patients with Stage III disease