A randomised phase III study evaluating whether XELOX (capecitabine plus oxaliplatin) is noninferior to FOLFOX 4 (fluorouracil, folinic acid and oxaliplatin) as first-line therapy in metastatic colorectal cancer was reported by Cassidy et al.rr
Between July 2003 and May 2004, 634 patients were randomly assigned in the two-arm portion of the study. Between February 2004 and February 2005, an additional 1,401 patients were randomly assigned in the 2 x 2 factorial part of the study where patients were assigned to either receive bevacizumab or placebo. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately.
The primary end point for the noninferiority analysis was progression-free survival (PFS) and secondary efficacy end points were overall survival (OS), overall response rate (ORR), duration of response, and time to treatment failure.r
A meta-analysis of 6 randomised phase II and III trials comparing the efficacy of XELOX with infusional FU/OX was reported by Arkenau et al.r XELOX resulted in in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different fluorouracil schedules, with thrombocytopenia and hand and foot syndrome consistently more prominent in the regimens with capecitabine.r
Efficacy
Cassidyr |
XELOX (ITT population) (%) |
95% CI (range) |
Objective response |
55 |
45 to 65 |
Stable disease |
31 |
22 to 42 |
Progressive disease |
6 |
2 to 13 |
Not assessable |
7 |
3 to 14 |
Time to progression (months) |
7.7 |
6.4 to 8.6 |
Median overall survival (months) |
19.5 |
15.3 to 21.6 |
Overall survival at 1 year |
70 |
- |
Overall survival at 2 years |
30 |
- |
Cassidy et al 2008r
The median follow-up times were 17.7 (for PFS) and 29.7 months (for OS). The median PFS (ITT analysis) was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4–containing arms (HR, 1.04; 97.5% CI, 0.93 to 1.16).
Progression-free survival (ITT population)r
© J Clin Oncol 2008
ORR for the two regimens, as assessed both by investigators (XELOX 47% v FOLFOX 48%) and the independent response review committee (37% in each arm), were essentially the same. The median OS in the ITT population was 19.8 months in the pooled XELOX arms and 19.6 months in the pooled FOLFOX-4 arms, with a corresponding HR of 0.99 (97.5% CI, 0.88 to 1.12).
Overall survival (ITT population)r
© J Clin Oncol 2008
Toxicity
Adverse eventsr
Toxicity |
XELOX (%) |
Neutropenia grade 3 |
7 |
Thrombocytopenia grade 3 |
4 |
Hyperbilirubinaemia grade 3 |
4 |
Sensory neuropathy |
17 |
Diarrhoea grade 3 or 4 |
16 |
Nausea or vomiting grade 3 or 4 |
13 |
Hand and foot syndrome grade 1-2 |
36 |
Hand and foot syndrome grade 3 |
3 |
Cassidy et al 2008r
While the overall rates of grade 3/4 adverse events were fairly similar with both FOLFOX-4 and XELOX, grade 4 adverse events were more common with FOLFOX-4 (25% and 12%, respectively), this difference being predominantly due to grade 4 neutropenia.
FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia (44% v 7%), febrile neutropenia (4.8% v 0.9%), and grade 3/4 venous thromboembolic events (6.3% v 3.8%) than XELOX. XELOX was associated with more grade 3 diarrhoea (19% v 11%) and grade 3 hand-foot syndrome (6% v 1%). Rates of grade 3/4 neurosensory toxicity were similar with both regimens (approximately 17%). Grade 3/4 cardiac disorders were reported in nine FOLFOX-4 recipients (1.4%) and six XELOX recipients (0.9%).r
Hochster et al 2018r
In the TREE-2 study, the capecitabine dose was reduced to 850 mg/m² twice per day (650 mg/m² twice per day for patients with a creatinine clearance of 30 to 50 mL/min). The incidence of grade 3/4 dehydration and diarrhoea was reduced compared to the TREE-1 study (capecitabine 1000 mg/m² twice per day).r
|
TREE-1r |
TREE-2r |
Capecitabine dose BD D1-14 |
1000 mg/m² |
850 mg/m² |
Bevacizumab |
N |
Y |
Grade 3/4 Diarrhoea (%) |
31 |
19 |
Grade 3/4 Dehydration (%) |
27 |
8 |
ORR (%) |
27 |
46 |
TTF (months) |
4.4 |
5.5 |
TTP (months) |
5.9 |
10.3 |
OS (months) |
17.2 |
24.6 |
1 year survival |
65.0 |
77.8 |