What is the appropriate treatment approach for a patient being considered for Xeloda (capecitabine) in cancer treatment?

Xeloda (Capecitabine) Treatment Approach in Cancer

Primary Indications and FDA-Approved Uses

Xeloda is FDA-approved for three specific cancer indications: adjuvant treatment of Dukes' C (Stage III) colon cancer after complete resection, first-line treatment of metastatic colorectal cancer when fluoropyrimidine monotherapy is preferred, and metastatic breast cancer either in combination with docetaxel after anthracycline failure or as monotherapy after both anthracycline and taxane resistance. 1

Colorectal Cancer Applications

Adjuvant Stage III Colon Cancer:

• For Stage III colon cancer, capecitabine 1,250 mg/m² orally twice daily for 2 weeks followed by 1-week rest (3-week cycles) for 8 cycles (total 6 months) is the standard regimen 1
• Capecitabine monotherapy is appropriate when fluoropyrimidine therapy alone is preferred, though combination chemotherapy (FOLFOX or XELOX) has demonstrated superior disease-free survival compared to single-agent therapy 2, 1
• XELOX (capecitabine plus oxaliplatin) is preferred over FOLFOX based on the IDEA study results for high-risk stage II and low-risk stage III patients, with the option of 3-month duration instead of 6 months 2

Metastatic Colorectal Cancer:

• Capecitabine can safely substitute intravenous 5-FU/leucovorin in combination with oxaliplatin without impairment in progression-free survival or overall survival 2
• For first-line metastatic disease, combination chemotherapy has shown survival benefit compared to 5-FU/LV alone, though capecitabine monotherapy has not demonstrated this survival advantage 1
• The combination of capecitabine with irinotecan (CAPIRI) should be avoided or used with dose reduction due to high rates (27%) of grade 3/4 diarrhea 2

Breast Cancer Applications

Metastatic Breast Cancer - Combination Therapy:

• Capecitabine 1,250 mg/m² twice daily for 2 weeks followed by 1-week rest, combined with docetaxel 75 mg/m² IV on day 1 of each 3-week cycle, is indicated after failure of anthracycline-containing chemotherapy 1
• This combination showed 36% response rate versus 26% with docetaxel monotherapy in anthracycline-resistant disease 3

Metastatic Breast Cancer - Monotherapy:

• Indicated for patients resistant to both paclitaxel and anthracycline-containing regimens, or when further anthracycline therapy is contraindicated (e.g., cumulative doxorubicin doses ≥400 mg/m²) 1
• Response rates of 20-29% have been demonstrated in paclitaxel-refractory patients 4, 5, 3

Thymic Neuroendocrine Tumors

For intermediate-grade thymic NETs (atypical carcinoid) with clinically significant tumor burden or disease progression:

• Temozolomide ± capecitabine can be considered for tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum 2

Dosing and Administration

Standard Dosing:

• Starting dose: 1,250 mg/m² orally twice daily (morning and evening) for 2 weeks followed by 1-week rest period 1
• Tablets should be taken within 30 minutes after a meal with water 1
• Total daily dose is calculated based on body surface area and divided into equal morning and evening doses 1

Elderly Patients (≥70 years):

• An upfront dose reduction to 80% (1,000 mg/m² twice daily) is recommended for elderly patients, though not formally studied in randomized trials 2
• Single-agent capecitabine is the treatment of choice for elderly patients with Stage III colon cancer, as oxaliplatin combinations show decreased to absent survival benefit in this population 2, 6
• Capecitabine demonstrates equal efficacy with comparable toxicity versus bolus 5-FU/FA in patients ≥65 years 2, 6

Dose Modifications for Toxicity

Grade 2 Toxicity:

• 1st appearance: Interrupt until resolved to grade 0-1, resume at 100% dose during cycle 1
• 2nd appearance: Interrupt until resolved, resume at 75% of original dose 1
• 3rd appearance: Interrupt until resolved, resume at 50% of original dose 1
• 4th appearance: Discontinue treatment 1

Grade 3 Toxicity:

• 1st appearance: Interrupt until resolved, resume at 75% of original dose 1
• 2nd appearance: Interrupt until resolved, resume at 50% of original dose 1
• 3rd appearance: Discontinue treatment permanently 1

Grade 4 Toxicity:

• Discontinue permanently, or if physician deems continuation in patient's best interest, interrupt until resolved and resume at 50% dose 1

Critical Rule: Once dose has been reduced, it should not be increased at a later time 1

Special Populations and Precautions

Renal Impairment:

• Dose adjustments are mandatory for renal impairment, which is particularly common in elderly patients 6
• Close monitoring of renal function is essential throughout treatment 6

Patients with Inflammatory Bowel Disease:

• Capecitabine should be used with extreme caution in patients with ulcerative colitis or Crohn's disease, as it may exacerbate diarrhea and trigger disease flares 7

Drug Interactions:

• Phenytoin and coumarin-derivative anticoagulant doses may need reduction when administered concomitantly with capecitabine 1

Timing and Duration

Adjuvant Colon Cancer:

• Treatment should start between 3 weeks and maximum 8-12 weeks after surgery 2, 6
• If delayed beyond 12 weeks, treatment should be given based on individual decision considering limited benefit likelihood against potential toxicity 2
• Total duration: 6 months (8 cycles of 3 weeks each) 2, 6, 1
• For high-risk stage II and low-risk stage III patients (T1-3N1), 3-month CAPEOX may be considered based on IDEA study 2

Metastatic Disease:

• Treatment continues until disease progression, unacceptable toxicity, or achievement of treatment goals 8

Common Adverse Events and Management

Most Frequent Toxicities:

• Hand-foot syndrome (palmar-plantar erythrodysesthesia): 57-60% incidence, mostly grade 1-2 1, 4, 9
• Diarrhea, nausea, vomiting 1, 4, 5
• Skin pigmentation and dermatitis 1, 4
• Fatigue and anorexia 1, 4, 5

Hematologic Toxicity:

• Myelotoxicity is generally mild compared to IV 5-FU regimens 5
• Neutropenia: 26% total incidence, 22% grade 3-4 1
• Lymphopenia: 94% total incidence, 44% grade 3-4 1

Hand-Foot Syndrome Prevention:

• High-dose vitamin B6 prophylaxis may reduce severity, though evidence is mixed 9
• Dose modifications per protocol are essential when grade 2-3 occurs 1

Unusual Adverse Effects:

• Hypertriglyceridemia observed in approximately 40% of tested patients 5

Critical Clinical Pitfalls to Avoid

Do Not:

• Use capecitabine in combination with irinotecan without dose reduction due to excessive diarrhea risk 2
• Prescribe to patients with active inflammatory bowel disease without extreme caution 7
• Increase dose after reduction has been made 1
• Neglect renal function monitoring, especially in elderly patients 6
• Undertreat elderly patients based on age alone—comprehensive assessment of comorbidities and functional status should guide decisions 6

Do:

• Provide clear instructions about managing diarrhea and hand-foot syndrome 6
• Monitor for drug interactions, particularly with warfarin and phenytoin 1
• Consider oral fluoropyrimidine preference over IV 5-FU to avoid central venous access complications 2
• Evaluate response every 2 months in metastatic disease to assess resectability 7