BACKGROUND: Folate level was proposed to be a predictor for 
fluoropyrimidine-related toxicity. We conducted a prospective study to determine 
the association between serum and red-cell folate and capecitabine-related 
toxicity in patients with colorectal cancers.
MATERIALS AND METHODS: Eligibility criteria included diagnosis of colorectal 
cancers; eligible patients who were scheduled to undergo capecitabine 
monotherapy or capecitabine-oxaliplatin (CAPOX) for adjuvant or palliative 
purposes. Exclusion criteria included concomitant radiotherapy or chemotherapy 
other than capecitabine or CAPOX and creatinine clearance <30 mL/min. Fasting 
serum and red-cell folate were measured prior to chemotherapy. Capecitabine was 
administered at 2,500 mg/m2 per day (monotherapy) or 2,000 mg/m2 per day (CAPOX) 
for 14 days every 3 weeks. The toxicity of the first four cycles was documented 
by clinical investigators who were blinded to folate levels.
RESULTS: A total of 144 patients were recruited, of whom 126 were eligible; 40 
patients had capecitabine alone, and 86 patients received CAPOX. The rates of 
grade 2 and grade 3 toxicity were 63.5% and 14.3%, respectively. Nausea and 
vomiting were the most common grade ≥2 adverse event (47.7%), followed by 
hand-foot syndrome (25.4%), diarrhea (23.1%), and neutropenia (22.3%). 
Combination with oxaliplatin (odds ratio [OR], 2.77; p = .043) and serum folate 
(OR, 10.33; p = .002) were independent predictors of grade ≥2 toxicity. Red-cell 
folate was not predictive of toxicity. For every 10 nmol/L increment in serum 
folate, the risk of grade ≥2 toxicity increased by 9%.
CONCLUSION: Serum folate level, but not red-cell folate, was associated with 
higher rate of grade ≥2 toxicity during capecitabine-based treatment. Excessive 
folate intake may be avoided before and during capecitabine-based chemotherapy.
IMPLICATIONS FOR PRACTICE: This is the first prospective study to evaluate the 
association between serum folate level and capecitabine-related toxicity in 
patients with colon cancers. It shows that higher serum folate level is 
associated with increased risks of moderate to severe toxicity during 
capecitabine-based treatment. Excessive folate intake should be avoided before 
and during capecitabine-based chemotherapy.