Infusional 5-FU/FA plus Oxaliplatin (FUFOX)vs.

Capecitabine plus Oxaliplatin (CAPOX)

as first-line treatment for metastatic colorectal cancer: safety and efficacy analysis

from a phase III trial of the German AIO

TobiasArkenau

Rationale for CAPOX in 1st-line ACRC

Addition of oxaliplatin to i.v. 5-FU/LV (FOLFOX/FUFOX) significantly improves efficacy

Capecitabine provides superior response rates and safety vs. bolus 5-FU/LV

In phase II trials, XELOX/CAPOX showed clear antitumor efficacy and good tolerability

Prospective, randomized, multicenter phase III study of CAPOX vs. FUFOX

Metastatic CRC, no prior chemotherapy for metastatic CRC, adjuvant treatment > 6 months,

Measurable disease (RECIST), Age >18 years; ECOG PS 2

Normal renal, hepatic and hematological parameters

Randomization (n=476)08/02 – 08/04

69 German centers

Stratification: WBC, Alk. Phos., No. of sites, ECOG PS, Center

Patient disposition

242 CAPOX

476 pts randomized

234 FUFOX

Median # cycles 6 (1–21)

3-week cycles

Median # cycles 4 (1–13)

5-week cycles

Treatment schedules

Day 1 8 15 22 29 36 43

Capecitabine1000 mg/m2 bid

Oxaliplatin70 mg/m2

CAPOX

5-FU2000 mg/m2

Oxaliplatin50 mg/m2

FUFOXFA500 mg/m2

Endpoints/statistical design

Primary endpoint: progression-free survival (PFS)

Secondary endpoints: OS, RR, toxicity, TTF, QOL

Statistical design: 440 patients needed to exclude inferiority of 41% vs. 50%

PFS rate at 9 months calculating a one-sided 95% CI for

the HR (power: 80%)

The study was monitored by an external review committee

Baseline characteristics

CAPOX

n=242

FUFOX

n=234

Age, median (range) 66 (32–81) 64 (34–86)

ECOG 0–1 / 2 (%) 92 / 8 93 / 7

Male / Female (%) 62 / 38 64 / 36

Metastatic sites 1 / 1 (%) 49 / 51 49 / 51

Prior adjuvant chemo (%) 32 29

Most common (20%) treatment-relatedclinical adverse events (all grades)

Diarrhea Nausea Vomiting HFS Neurosensory

100

80

60

40

20

0

CAPOX (n=235)

FUFOX (n=229)

% of patients

Most common (>5%) treatment-relatedgrade 3/4 clinical adverse events

Diarrhea Nausea Vomiting Mucositis HFS Neurosensory grade 2/3

50

40

30

20

10

0

CAPOX (n=235)

FUFOX (n=229)

% of patients

*

*p<0.01

Most common treatment-relatedgrade 3/4 hematological adverse events

Anemia Leukopenia Neutropenia Thrombocytopenia

CAPOX (n=235)

FUFOX (n=229)

% of patients

50

40

30

20

10

0

Efficacy analysis: response rates

CAPOX

n=238 (%)

FUFOX

n=230 (%)

Overall response

p=0.70

47

95% CI, 41–54

49

95% CI, 43–56

Complete response 2 5

Partial response 45 44

Stable disease 27 24

Progression-free survival

1.0

0.8

0.6

0.4

0.2

00 20 40 60 80 100 120 140

Weeks

Estimated probability Median

CAPOX (n=238) 7.0 monthsFUFOX (n=230) 8.0 months

HR = 1.19 (95% CI: 0.97–1.48)p=0.11 (Log-rank)

PFS: multivariate analysis (n=474)

Hazard ratio (95% CI)

CAPOX 1.16 (0.94–1.44)

p=0.17

ECOG 2 1.73 (1.15–2.59)

p=0.009

Metastatic sites >1 1.36 (1.10–1.70)

p=0.006

Leukocytes >8000/µL 1.33 (1.06–1.66)

p=0.012

Alk. Phos. >300 U/I 1.40 (1.02–1.91)

p=0.038

Overall survival

1.0

0.8

0.6

0.4

0.2

00 20 40 60 80 100 120 140

Weeks

Estimated probability Median

CAPOX (n=238) 16.3 monthsFUFOX (n=230) 17.2 months

HR = 1.05 (95% CI: 0.79–1.41)p=0.72 (Log-rank)

Conclusions

Similar safety profile for CAPOX and FUFOX:– significantly higher HFS grade 2/3 with CAPOX

CAPOX shows no inferiority compared to FUFOX within our statistical assumptions:– response rate: 47% vs. 49%

– median PFS: 7.0 vs. 8.0 months (p=0.11)

– median OS: 16.3 vs. 17.2 months (p=0.72)

Acknowledgements

Thanks to all of the investigators, patients and their families who participated in the studyParticipating investigators:

Aachen (Tummes); Ansbach (Hahn); Aschersleben (Deist); Augsburg (Heinrich); Aurich (Langer); Bad Homburg (Rohwedder); Bad Soden (Seipelt); Berlin (Zuchold, Reichardt, Kretzschmar); Bietigheim-Bissingen (Dietrich); Bochum (Andre, Ansorge, Behringer,

Schmiegel); Bonn (Fronshoff, Ko); Bremen (Arkenau, Doering, Porschen); Bremerhaven (Ahlf); Dernbach (Hoffknecht); Dortmund (Hagen); Duisburg (Selbach, Petrasch); Eschweiler (Fuchs);

Flensburg (Hartwigsen); Frankfurt (Trojan); Geilenkirchen (Schardt, Zeidler); Goch (Runde); Göttingen (Hilden); Greven (Nischik); Grevenbroich (Prangischvili); Hagen (Lindemann,

Zinngrebe); Halle (Arnold, Behrens, Steudel, Schmoll); Hamburg (Lipp); Hannover (Kubicka, Greten); Hildesheim (Freier); Homburg (Lubomierski); Jena (Eigendorff); Karlsruhe (Ebenezer);

Koblenz (Hermesdorf); Kronach (Stauch); Leer (Köchling); Leipzig (Abelius); Lemgo (Constantin); Lüneburg (Heinkele); Magdeburg (Kröning); Mainz (Höhler, Möhler); Marburg (Balser); Mönchengladbach (Koch, Graeven); Münster (Bremer, Wehmeyer); Nordhausen

(Keppler, Parchim, Hesse); Recklinghausen (Heer); Riedlingen (Pernice); Rinteln (Krause); Rotenburg (Schlichting); Rüsselsheim (Fried-Proell); Saarbrücken (Jacobs, Preiß); Salzburg

(Greil, Hausmaninger); Salzwedel (Roth); Siegen (Gaska); Stuttgart (Hiller); Troisdorf (Forstbauer); Ulm (Seufferlein, Hahn, Adler); (Unna, Steinmeister); Vechta (Diers); Velbert

(Nusch); Weiden (Weiß); Weißenfels (Bornschein); Werningerode (Wilhelm); Wuppertal (Papavasiliou)