Tolerability of fluoropyrimidines differs by region

Daniel G. Haller

on behalf of:Cassidy J, Clarke S, Cunningham D, Van Cutsem E

Hoff P, Rothenberg M, Saltz L, Schmöll H-J, Allegra CBertino J, Douillard J-Y, Gustavsson B, Milano GO'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 to investigate these differences 1. IMPACT investigators. Lancet 1995

2. Hoff P et al. J Clin Oncol 20013. Van Cutsem E, et al. J Clin Oncol 2001

4. Schmöll HJ, et al. J Clin Oncol 2005 (Abst 3523)

Two identical phase III trials (SO14796, SO14695) in first-line MCRC:

Trials Analyzed

Prior adjuvant therapy> 6 months ago

Capecitabine (n=596)

5-FU/LV (n=593)

Endpoints• Progression-free survival• Overall survival• Tolerability

Curative resection < 8 wksprior to randomization

ECOG PS < 1; No prior chemo-radio- or immunotherapy

XELOX (n=938)

5-FU/LV (n=926)

Endpoints• Progression-free survival• Overall survival• Tolerability

One phase III trial (NO16968 XELOXA)

in adjuvant stage III colon cancer:

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

Treatment-relatedadverse event

Relative risk adjusted for age, gender, BMI, body

surface, creatinine clearance, ECOG PS and

treatmentOverallp-value

for region effect

Relative risk 95% CI

Grade 3/4 1.77 1.35–2.31 <0.001Grade 4 1.72 0.91–3.24 0.094Grade 3/4 GI 1.72 1.25–2.36 <0.001Serious AE 1.20 0.85–1.70 0.291Grade 3/4 neutropenia 1.51 1.01–2.25 0.044Grade 3/4 lab neutrophils 1.20 0.78–1.84 0.417

Dose reductions 1.72 1.32–2.25 <0.001Discontinuations 1.83 1.27–2.65 <0.001

Logistic regression NO16968: comparison US vs. RoW vs. Asia (1)

Adverse event

Adjusted relative riskOverall

p-value for region effectRelative risk 95% CI

Grade 3/4 USRest of WorldAsia

1.851.291.00

1.21–2.830.93–1.79

0.013

Grade 4 USRest of World

Asia

2.591.241.00

1.09–6.150.62–2.47

0.028

Grade 3/4 GI US Rest of World Asia

3.622.381.00

2.11–6.201.50–3.77

<0.001

Serious AE US Rest of World

Asia

2.872.101.00

1.52–5.391.22–3.63

0.005

Adverse event

Adjusted relative riskOverall

p-value for region effectRelative risk 95% CI

Grade 3/4 USneutropenia Rest of World

Asia

0.960.631.00

0.53–1.730.41–0.95

0.025

Grade 3/4 USlaboratory Rest of Worldneutrophils Asia

1.090.721.00

0.58–2.030.47–1.11

0.097

Dose USreductions Rest of World

Asia

0.960.781.00

0.64–1.460.56–1.08

0.137

Discontinuation US Rest of World

Asia

1.840.871.00

1.14–2.960.59–1.28

<0.001

Logistic regression NO16968: comparison US vs. RoW vs. Asia (2)

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