Capecitabine Maintenance After First-Line Therapy for Metastatic Colorectal Cancer

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In the FOCUS4-N trial reported in the Journal of Clinical Oncology, Adams et al found that capecitabine maintenance improved progression-free—but not overall—survival vs active monitoring in patients with stable disease or objective response after first-line therapy for metastatic colorectal cancer.  

As stated by the investigators, “Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer, they are not universally offered to patients despite improvements in quality of life without detriment to overall survival. FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy.”

Study Details

FOCUS4 is a molecularly stratified trial program evaluating novel treatments in biomarker subgroups of patients with metastatic colorectal cancer in phase II or III trials. The FOCUS4-N trial enrolled patients with no available targeted subtrial or who had negative biomarker tests.

In the multicenter trial, 254 patients with stable disease or response after 16 weeks of first-line treatment (most commonly doublet chemotherapy; irinotecan-based in 57%) were randomly assigned between March 2014 and March 2020 to receive a standard-dosage regimen of capecitabine (n = 127) or active monitoring (n = 127) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival.

Progression-Free Survival

Median progression-free survival was 3.88 months (95% confidence interval [CI] = 3.65­–4.37 months) in the capecitabine group vs 1.87 months (95% CI = 1.81–2.14 months) in the active monitoring group (adjusted hazard ratio [HR] = 0.40, 95% CI = 0.21–0.75, P < .0001). Median overall survival was 14.8 months (95% CI = 13.7–18.6 months) in the capecitabine group vs 15.2 months (95% CI = 12.1–18.5 months) in the active monitoring group (adjusted HR = 0.93, 95% CI = 0.69–1.27, P = .66).  


  • Maintenance capecitabine improved progression-free survival vs active monitoring.
  • No difference in overall survival was observed.

Preplanned subgroup analyses suggested that maintenance treatment performed better in patients with left-sided vs right-sided tumors for both progression-free survival (HRs = 0.38 vs 0.56, interaction P = .13) and overall survival (HRs = 0.82 vs 1.37, interaction P = .076).

Adverse Events

Adverse events of ≥ grade 2 that were more common in the capecitabine group included fatigue (25% vs 12%), diarrhea (23% vs 13%), and hand-foot syndrome (26% vs 3%). Proportions of patients with grade 0 toxicity were 67% vs 74% for nausea, 46% vs 72% for diarrhea, 77% vs 90% for stomatitis, 77% vs 83% for dry skin, 44% vs 87% for hand-foot syndrome, and 54% vs 69% for anemia. No notable differences in quality-of-life measures were observed between groups.

The investigators concluded, “Despite strong evidence of disease control with maintenance therapy, overall survival remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for metastatic colorectal cancer. Capecitabine without bevacizumab may be used to extend progression-free survival in the interval after 16 weeks of first-line therapy.”

Louise C. Brown, PhD, of University College London, MRC Clinical Trials Unit, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Cancer Research UK and the National Institute for Health Research. For full disclosures of the study authors, visit

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