What are the common side effects of capecitabine, especially in a patient with a history of cancer and diabetes?

Most Common Side Effects of Capecitabine

The most common side effects of capecitabine are hand-foot syndrome (occurring in 50-73% of patients), diarrhea (39-83% depending on combination therapy), and gastrointestinal symptoms including nausea and vomiting, with hand-foot syndrome being the hallmark toxicity requiring dose modification in 11% of patients. 1

Primary Side Effects by Frequency

Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)

• Occurs in 50-73% of patients on capecitabine, with grade 3 events in 11% requiring dose modification 1
• Median time to onset is 79 days (range 11-360 days) after starting treatment 2
• Initial symptoms include tingling, numbness, and paresthesias, progressing to painful erythema, swelling, and in severe cases, desquamation, blisters, ulcers, and bleeding 1, 2
• More common with capecitabine than with other chemotherapy regimens like paclitaxel or CMF 3
• When combined with docetaxel, incidence increases to 25.2% compared to 1.3% with gemcitabine/docetaxel 4

Gastrointestinal Effects

• Diarrhea occurs in 39-83% of patients depending on combination therapy, with grade 3-4 diarrhea in 7.6-24% 5, 1
• When combined with neratinib, diarrhea incidence reaches 83% (24% grade 3-4) 1, 4
• Median time to first occurrence of grade 2-4 diarrhea is 34 days (range 1-369 days), with median duration of grade 3-4 diarrhea being 5 days 6
• Nausea and vomiting are common, with higher incidence (8% vs 3.4%) when combined with docetaxel 4
• Stomatitis/mucositis occurs in 4.4% when combined with docetaxel versus 1.3% with gemcitabine/docetaxel 4

Hematologic Effects

• Neutropenia is relatively uncommon with capecitabine monotherapy (5.5%) compared to combination regimens 5
• Lymphopenia and anemia occur in >25% of patients receiving monotherapy 3
• Thrombocytopenia is especially common when combined with other agents 4

Other Common Effects

• Fatigue occurs frequently (>25% incidence) 3
• Hyperbilirubinemia is a dose-limiting adverse effect 7
• Dermatitis occurs in >25% of patients 3

Critical Considerations for Patients with Diabetes

Metabolic Effects

• Severe hyperglycemia and hypokalemia can occur during long-term capecitabine treatment, though rare 8
• One case report documented fasting plasma glucose increasing from normal to 15.3 mmol/L and hemoglobin A1c to 11.2% after 1.5 years of capecitabine therapy 8
• Serum potassium can drop to dangerously low levels (2.5 mmol/L reported) 8
• These metabolic effects resolved after capecitabine discontinuation, with glucose levels normalizing within 2 months without ongoing insulin therapy 8

Monitoring Requirements for Diabetic Patients

• Monitor blood glucose levels more frequently during capecitabine therapy, particularly during long-term treatment 8
• Check serum potassium levels regularly, as hypokalemia may accompany hyperglycemia 8
• Be prepared to adjust diabetes medications or temporarily discontinue capecitabine if severe metabolic derangements occur 8

Special Population Risks

Elderly Patients (≥65 Years)

• Patients ≥80 years experience 62% incidence of treatment-related grade 3-4 adverse events 6
• In patients ≥80 years: diarrhea (28.6%), nausea (14.3%), hand-foot syndrome (14.3%), and vomiting (9.5%) 6
• Starting dose must be reduced to 1,000 mg/m² twice daily without escalation in patients ≥65 years 1
• Patients ≥65 years have 34% rate of grade 3 or higher toxicity, including treatment-related deaths 1, 4

Cardiovascular Risk

• Patients with prior coronary artery disease face increased risk of myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, and sudden death 1
• Cardiotoxicity incidence ranges from 3-9% with capecitabine, lower than 5-FU (7.6% with high-dose infusions) 1

Renal Impairment

• Patients with moderate renal impairment (CrCl 30-50 mL/min) require 75% dose reduction 6, 7
• Capecitabine is contraindicated if CrCl is <30 mL/min 6, 7
• Elimination is primarily renal, requiring careful monitoring in patients with any degree of renal insufficiency 4, 6

DPD Deficiency

• 3-5% of the population has partial or complete dihydropyrimidine dehydrogenase (DPD) deficiency, leading to potentially life-threatening toxicity 1, 4

Immediate Treatment Interruption Criteria

Stop capecitabine immediately and contact physician if: 1, 6

• Grade 2,3, or 4 diarrhea occurs 6
• Fever ≥100.5°F or signs of infection develop 1
• Hand-foot syndrome worsens 1
• Severe nausea or vomiting occurs 1

Comparison with IV Chemotherapy

Advantages of Capecitabine

• Less stomatitis, alopecia, and neutropenia requiring medical management compared to bolus 5-FU/LV 3, 7
• Better quality of life compared to some IV regimens despite toxicities 5

Disadvantages of Capecitabine

• More hand-foot syndrome than paclitaxel or CMF regimens 3
• More gastrointestinal effects than some IV alternatives 3

Common Pitfalls to Avoid

• Never continue full-dose capecitabine in elderly patients (≥65 years) without dose reduction 1
• Do not underestimate cardiovascular risk in patients with coronary artery disease history 1
• Failure to educate patients on early recognition of hand-foot syndrome and diarrhea can lead to severe toxicity 9
• Not monitoring renal function and adjusting doses appropriately in patients with renal impairment 6
• Overlooking potential drug interactions with warfarin (increased INR) and phenytoin (increased serum levels) 7