Capecitabine and Oxaliplatin Adverse Effects
Overview
The CapeOX regimen (capecitabine plus oxaliplatin) has a predictable toxicity profile dominated by hand-foot syndrome from capecitabine (31% of patients), peripheral sensory neuropathy from oxaliplatin (85% any grade), and gastrointestinal toxicity including diarrhea (10-28%), with minimal myelosuppression compared to infusional 5-FU regimens. 1
Capecitabine-Specific Toxicities
Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)
- Most characteristic adverse effect of capecitabine, occurring in up to 73% of patients, with 11% experiencing grade 3 events 2
- Incidence is 31% in CapeOX regimens 1
- Higher incidence with capecitabine-containing regimens versus bolus or infusional 5-FU/leucovorin 3
- Requires immediate dose modification: patients experiencing grade 2 hand-foot syndrome (painful erythema and swelling affecting activities of daily living) should stop capecitabine immediately 4
- Interestingly, capecitabine-related hand-foot skin reactions are associated with improved overall survival (75.8 vs 41.0 months; HR 0.56) 3
Gastrointestinal Toxicity
- Diarrhea is common, particularly when combined with other agents 2
- Grade 3-4 diarrhea occurs in 27-35% of patients in dose-finding studies 5, 6
- Management protocol: 2
- Mild diarrhea: loperamide 4 mg four times daily
- Persistent diarrhea (>1 week): treat as grade 2
- Severe diarrhea: loperamide every 2 hours; if no improvement after 24-48 hours, consider octreotide 100 μg three times daily
- Grade 3-4 diarrhea with neutropenia, fever, or reduced oral intake requires immediate hospitalization
- Patients experiencing grade 2 diarrhea (4-6 stools/day or nocturnal stools) should stop capecitabine immediately 4
- Stomatitis occurs at grade ≥3 in 9% of patients 5
- Nausea/vomiting: grade 2 or greater requires stopping capecitabine and initiating symptomatic treatment 4
Hematologic Toxicity
- Minimal myelosuppression with CapeOX compared to FOLFOX 3, 1
- Grade 3-4 neutropenia occurs in only 7% of patients with CapeOX versus 41% with FOLFOX 3
- Thrombocytopenia is more common when capecitabine is combined with other agents 2
- Lymphocytopenia (52% of patients) is the most common laboratory abnormality 7
Special Population Considerations
- North American patients experience higher incidence of adverse events at certain doses compared to patients from other countries, necessitating lower starting doses (1,000 mg/m² vs 1,250 mg/m²) 3, 1
- Patients over 65 years have higher risk of severe toxicity (34% grade 3 or higher), including treatment-related deaths 2
- Renal insufficiency: patients with diminished creatinine clearance accumulate the drug and require dose modification 3
- DPD deficiency (3-5% of population): may experience potentially life-threatening toxicity 2
Oxaliplatin-Specific Toxicities
Peripheral Sensory Neuropathy
- Most significant dose-limiting toxicity of oxaliplatin 3
- Occurs in 85% of patients receiving CapeOX (any grade) 1
- Grade 3 sensory neuropathy occurs in 12% with FOLFOX and 8% with FLOX 3
- Grade 3-4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurs in 16% of patients 6
- Acute sensory neuropathy is the most common adverse event (85% of patients) 8
Management of Neuropathy
- Discontinue oxaliplatin after 3-4 months of therapy (or sooner for unacceptable neurotoxicity) to prevent cumulative neurotoxicity, while maintaining capecitabine until disease progression 3, 1
- Patients experiencing neurotoxicity should not receive subsequent oxaliplatin therapy until near-total resolution of that neurotoxicity 3
- Calcium/magnesium infusion is not routinely recommended for prevention of oxaliplatin-related neurotoxicity (insufficient data) 3
Hypersensitivity Reactions
- Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur within minutes of administration and during any cycle 9
- Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions 9
- Oxaliplatin is contraindicated in patients with hypersensitivity to platinum-based drugs 9
Other Oxaliplatin Toxicities
- Posterior reversible encephalopathy syndrome (PRES): requires permanent discontinuation 9
- Interstitial lung disease or pulmonary fibrosis: requires permanent discontinuation if confirmed 9
- Rhabdomyolysis: requires permanent discontinuation 9
- Hematologic toxicity is minimal with oxaliplatin-based regimens 5, 7
Monitoring and Dose Adjustment Protocols
For Adjuvant Treatment (Stage III Colon Cancer)
Peripheral Sensory Neuropathy: 9
- Persistent grade 2: reduce oxaliplatin to 75 mg/m²
- Persistent grade 3: consider discontinuing oxaliplatin
- Grade 4: discontinue oxaliplatin
Myelosuppression: 9
- Grade 4 neutropenia or febrile neutropenia: delay next dose until neutrophils ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L, then reduce oxaliplatin to 75 mg/m²
- Grade 3-4 thrombocytopenia: same approach
Gastrointestinal Toxicity: 9
- Grade 3-4: after recovery, reduce oxaliplatin to 75 mg/m² and fluorouracil to 300 mg/m² bolus and 500 mg/m² continuous infusion
For Advanced/Metastatic Disease
Neuropathy: 9
- Persistent grade 2: reduce oxaliplatin to 65 mg/m²
- Persistent grade 3: consider discontinuing oxaliplatin
- Grade 4: discontinue oxaliplatin
Myelosuppression: 9
- Grade 4 neutropenia or febrile neutropenia: delay next dose until neutrophils ≥1.5 × 10⁹/L and platelets ≥75 × 10⁹/L, then reduce oxaliplatin to 65 mg/m²
- Grade 3-4 thrombocytopenia: same approach
Gastrointestinal Toxicity: 9
- Grade 3-4: after recovery, reduce oxaliplatin to 65 mg/m² and fluorouracil to 300 mg/m² bolus and 500 mg/m² continuous infusion
Capecitabine Dose Modifications
- First-line treatment: 1,000 mg/m² twice daily (North American patients)
- Pretreated patients: consider starting at 1,000 mg/m² twice daily due to higher toxicity risk
Dose Reductions: 6
- Required in 26% of first-line patients and 45% of pretreated patients by the second treatment cycle
- Capecitabine dose reductions were necessary in 35-50% of patients due to diarrhea 6
Critical Monitoring Points
At Each Visit
- Assess for peripheral neuropathy: discontinue oxaliplatin if ≥grade 2 neuropathy develops 10
- Monitor for hand-foot syndrome: adjust capecitabine dose at earliest signs 3, 1
- Evaluate gastrointestinal symptoms: diarrhea, nausea, vomiting, stomatitis 4
Laboratory Monitoring
- Complete blood count: monitor for neutropenia, thrombocytopenia, lymphocytopenia 9, 7
- Renal function: patients with diminished creatinine clearance require dose modification 3
Patient Education
- Instruct patients to stop capecitabine immediately for: 4
- Grade 2 diarrhea (4-6 stools/day)
- Grade 2 nausea (food intake significantly decreased)
- Grade 2 vomiting (2-5 episodes in 24 hours)
- Grade 2 hand-foot syndrome (painful erythema affecting daily activities)
- Grade 2 stomatitis (painful erythema/ulcers but able to eat)
- Fever ≥100.5°F or signs of infection
Drug-Food and Drug-Drug Interactions
- Administer capecitabine within 30 minutes after a meal (all safety/efficacy data based on administration with food) 4
- Warfarin interaction: monitor INR/PT closely with great frequency; S-warfarin AUC increases significantly, maximum INR increased by 91% 4
- Phenytoin: monitor levels carefully; capecitabine inhibits CYP2C9, leading to elevated phenytoin levels 4
Comparative Toxicity Profile
CapeOX versus FOLFOX: 3
- Less myelosuppression with CapeOX (grade 3-4 neutropenia: 7% vs 41%)
- Less alopecia with CapeOX
- More hand-foot syndrome with CapeOX (31% vs lower with FOLFOX)
- Similar neurotoxicity (grade 3 sensory neuropathy: 12% FOLFOX vs 8% FLOX)
- More vomiting with CapeOX
- Similar diarrhea rates overall