Transcript 2006_files/Haller ASCO 2006 Cape regional diff

Daniel G. Haller
Tolerability of fluoropyrimidines
differs by region
on behalf of:
Cassidy J, Clarke S, Cunningham D, Van Cutsem E
Hoff P, Rothenberg M, Saltz L, Schmöll H-J, Allegra C
Bertino J, Douillard J-Y, Gustavsson B, Milano G
O'Connell M, Rustum Y, Tabernero J, Fagerberg J
Gilberg F, Sirzen F and Twelves C
Hypothesis Generation
IMPACT analysis and other observations suggest
differences in toxicity for patients receiving adjuvant bolus
5-FU/LV in different countries.1
 Limited information available on regional differences in
fluoropyrimidine tolerability
There is also controversy surrounding the tolerable
capecitabine dose in Europe compared to the US:
 Europe-labeled dose seems acceptable
 Recommended dose in US considered too high
Retrospective analysis of safety data conducted from 3
phase III trials involving 5-FU, capecitabine and oxaliplatin2–4
1. IMPACT investigators. Lancet 1995
to investigate these differences
Hoff P et al. J Clin Oncol 2001
3. Van Cutsem E, et al. J Clin Oncol 2001
Schmöll HJ, et al. J Clin Oncol 2005 (Abst 3523)
2.
4.
Trials Analyzed
Two identical phase III trials
(SO14796, SO14695)
in first-line MCRC:
One phase III trial
(NO16968 XELOXA)
in adjuvant stage III colon cancer:
Prior adjuvant therapy
> 6 months ago
Curative resection < 8 wks
prior to randomization
ECOG PS < 1; No prior chemoradio- or immunotherapy
Capecitabine
(n=596)
5-FU/LV
(n=593)
Endpoints
• Progression-free survival
• Overall survival
• Tolerability
XELOX
(n=938)
5-FU/LV
(n=926)
Endpoints
• Progression-free survival
• Overall survival
• Tolerability
Methodology for regional safety comparison
Regions:
 US compared to non-US (all 3 studies)
 US compared to rest of the world (RoW) and East Asia
(NO16968 only)
Multivariate analysis (logistic regression) adjusted for:
age, gender, BMI, body surface, baseline creatinine
clearance, ECOG PS and treatment (bolus 5-FU/LV,
capecitabine, capecitabine + oxaliplatin)
Interaction term between region and treatment to assess
effect modification. Interaction assessed at p=0.05. If in
adjusted model the interaction term is significant,
stratified relative risks by treatment are compared
Logistic regression SO14796 + SO14695:
comparison US vs. RoW
Relative risk adjusted for age,
gender, BMI, body surface,
creatinine clearance, ECOG
PS and treatment
Relative risk
95% CI
Overall
p-value
for
region
effect
Grade 3/4
1.77
1.35–2.31
<0.001
Grade 4
1.72
0.91–3.24
0.094
Grade 3/4 GI
1.72
1.25–2.36
<0.001
Serious AE
1.20
0.85–1.70
0.291
Grade 3/4 neutropenia
1.51
1.01–2.25
0.044
Grade 3/4 lab neutrophils
1.20
0.78–1.84
0.417
Dose reductions
1.72
1.32–2.25
<0.001
Discontinuations
1.83
1.27–2.65
<0.001
Treatment-related
adverse event
Logistic regression NO16968:
comparison US vs. RoW vs. Asia (1)
Adjusted relative risk
Adverse event
Relative risk
95% CI
Overall
p-value for
region effect
Grade 3/4
US
Rest of World
Asia
1.85
1.29
1.00
1.21–2.83
0.93–1.79
0.013
Grade 4
US
Rest of World
Asia
2.59
1.24
1.00
1.09–6.15
0.62–2.47
0.028
Grade 3/4 GI
US
Rest of World
Asia
3.62
2.38
1.00
2.11–6.20
1.50–3.77
<0.001
Serious AE
US
Rest of World
Asia
2.87
2.10
1.00
1.52–5.39
1.22–3.63
0.005
Logistic regression NO16968:
comparison US vs. RoW vs. Asia (2)
Adjusted relative risk
Adverse event
Relative risk
95% CI
Overall
p-value for
region effect
Grade 3/4
neutropenia
US
Rest of World
Asia
0.96
0.63
1.00
0.53–1.73
0.41–0.95
0.025
Grade 3/4
laboratory
neutrophils
US
Rest of World
Asia
1.09
0.72
1.00
0.58–2.03
0.47–1.11
0.097
Dose
reductions
US
Rest of World
Asia
0.96
0.78
1.00
0.64–1.46
0.56–1.08
0.137
Discontinuation US
Rest of World
Asia
1.84
0.87
1.00
1.14–2.96
0.59–1.28
<0.001
General conclusions
More treatment-related toxicity reported in US
compared to RoW:
 in 1st line MCRC (5-FU/LV or capecitabine)
 in adjuvant setting (5-FU/LV or XELOX)
When comparing East Asia, RoW and US in adjuvant
setting, a ‘gradient’ of fluoropyrimidine toxicity
observed:
 East Asia – low
 US – high
Potential factors explaining regional
differences in fluoropyrimidine tolerability
Methodology

reporting in clinical trials
Baseline prognostic and predictive factors
Food habits

impact of dietary folate
Culture

Potentially influencing drug compliance
Genetic polymorphisms affecting drug metabolism