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 Tobias Arkenau
Jan 27, 2016
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)