Capecitabine (Xeloda)

How Capecitabine Works

Prodrug Mechanism

Capecitabine is a "prodrug" - an inactive medication that your body converts into the active drug through a series of enzymatic steps:

1. Absorption: Capecitabine absorbed from intestine into bloodstream
2. Liver conversion: Enzymes in liver convert capecitabine → 5'-deoxy-5-fluorocytidine (5'-DFCR)
3. Tumor conversion: 5'-DFCR → 5'-deoxy-5-fluorouridine (5'-DFUR)
4. Final activation: Enzyme thymidine phosphorylase (TP) in tumors converts 5'-DFUR → 5-FU (active drug)

Why This Matters

• Tumor-selective: Thymidine phosphorylase (TP) is 3-10 times higher in tumor tissue than normal tissue
• Preferential activation: More 5-FU generated in tumor = potentially fewer side effects, better tumor kill
• Oral convenience: No IV required, can take at home
• Continuous exposure: Mimics continuous infusion 5-FU (which is more effective than bolus)

How 5-FU Kills Cancer Cells

Once converted to 5-FU, capecitabine works as an antimetabolite:

• Blocks thymidylate synthase: Prevents DNA synthesis (cells can't make new DNA)
• Incorporates into RNA: Disrupts RNA function and protein synthesis
• Targets dividing cells: Cancer cells divide rapidly, so are more affected
• Cell death: Unable to divide or function, cancer cells die

FDA-Approved Uses

Colorectal Cancer

• Adjuvant treatment (after surgery): Stage III colon cancer
  • Reduces recurrence risk by ~30%
  • Alternative to IV 5-FU/leucovorin (FOLFOX preferred but capecitabine option)
  • Typical duration: 6 months (8 cycles)
• Metastatic colorectal cancer:
  • First-line in combination with oxaliplatin (XELOX/CAPOX regimen)
  • Alternative to FOLFOX (similar efficacy, oral convenience)
  • Can combine with bevacizumab (Avastin)
  • Monotherapy if patient not candidate for combination therapy

Breast Cancer

• Metastatic breast cancer:
  • After anthracycline and taxane: Approved for patients who progressed on prior chemotherapy
  • Combination with docetaxel: For anthracycline-pretreated patients
  • Response rates: 20-25% as monotherapy, 30-40% with docetaxel
• Neoadjuvant/adjuvant:
  • Off-label but commonly used in certain regimens
  • Can substitute for IV 5-FU in some protocols

Off-Label Uses (Common)

• Gastric/gastroesophageal cancer: Substitute for 5-FU in combination regimens
• Pancreatic cancer: In combination with other agents
• Neuroendocrine tumors: With temozolomide (CAPTEM regimen)
• Hepatobiliary cancers: Various combination regimens

Dosing and Administration

Standard Dosing

• Dose calculation: Based on body surface area (BSA in m²)
  • Standard: 1250 mg/m² twice daily
  • Some protocols: 1000 mg/m² twice daily (reduces side effects)
• Schedule: 14 days on, 7 days off (21-day cycle)
  • Take morning and evening doses 12 hours apart
  • Days 1-14: Take capecitabine
  • Days 15-21: Rest week (no capecitabine)
  • Repeat cycle

Available Strengths

• 150 mg tablets
• 500 mg tablets
• Both strengths may be combined to achieve total dose

How to Take Capecitabine

• With food: Take within 30 minutes after a meal
  • Food improves absorption and reduces nausea
  • Take with water
• Swallow whole: Do not crush, chew, or break tablets
• Timing: Morning and evening doses approximately 12 hours apart
• Consistency: Take at same times each day

Missed Dose

• If you miss a dose, skip it - do NOT double the next dose
• Resume regular schedule with next dose
• Notify your oncologist if you frequently miss doses

Dose Adjustments

For toxicity (side effects):

For renal impairment:

• CrCl 30-50 mL/min: Reduce dose to 75% of starting dose (e.g., 950 mg/m² if starting at 1250 mg/m²)
• CrCl <30 mL/min: Contraindicated (do not use)
• Kidney function monitored before each cycle

For hepatic impairment:

• Mild-moderate: Use with caution, may need dose reduction
• Severe: Limited data, generally avoided

Side Effects

Very Common Side Effects (>30%)

• Hand-foot syndrome (palmar-plantar erythrodysesthesia) (50-60%) - see detailed section below
• Diarrhea (40-50%)
• Nausea (30-40%)
• Fatigue (40%)
• Abdominal pain (30%)

Common Side Effects (10-30%)

• Vomiting (15-30%)
• Stomatitis (mouth sores) (20-25%)
• Decreased appetite (20%)
• Constipation (10-15%)
• Hyperbilirubinemia (elevated bilirubin) (20%)
• Dermatitis/rash (10-15%)
• Nail changes (10%)

Less Common But Serious Side Effects

Bone Marrow Suppression (Myelosuppression)

• Neutropenia (low white blood cells): 10-25%
  • Less common than with IV 5-FU
  • Monitor for fever, infections
• Thrombocytopenia (low platelets): 5-10%
• Anemia (low red blood cells): 15-20%
• Blood counts checked regularly

Cardiotoxicity (Rare but Serious)

• Coronary vasospasm: Can cause chest pain, heart attack-like symptoms
  • More common in patients with history of coronary disease
  • Usually occurs during treatment, resolves after stopping
  • Rechallenge NOT recommended
• Cardiomyopathy: Rare
• Report chest pain, shortness of breath, palpitations immediately

Other Serious Side Effects

• Severe diarrhea/dehydration: Can be life-threatening if untreated (see management below)
• Renal impairment: Can worsen kidney function
• Hepatotoxicity: Rare, elevated liver enzymes
• Neurological effects: Confusion, ataxia, dizziness (rare)

Hand-Foot Syndrome (HFS)

Most characteristic side effect of capecitabine (50-60% incidence)

What is Hand-Foot Syndrome?

Also called palmar-plantar erythrodysesthesia (PPE), HFS causes redness, swelling, pain, and sometimes blistering of the palms and soles.

Grading

• Grade 1 (mild):
  • Numbness, tingling, painless swelling or redness
  • No impact on daily activities
  • Management: Continue capecitabine, aggressive prevention
• Grade 2 (moderate):
  • Painful redness and swelling
  • Affects function but doesn't prevent activities
  • Management: Hold capecitabine until improves to grade 0-1, then resume at same dose
• Grade 3 (severe):
  • Moist desquamation (peeling), ulceration, blistering
  • Severe pain preventing activities of daily living
  • Management: Hold capecitabine until improves, reduce dose to 75% when restarting

Prevention Strategies

• Moisturize aggressively:
  • Thick creams (Bag Balm, Udderly Smooth, Eucerin) 2-3 times daily
  • Apply to hands and feet even before symptoms start
  • Especially after washing hands/feet
• Avoid heat and friction:
  • No hot water on hands/feet (use cool/lukewarm)
  • Avoid tight shoes, high heels
  • Wear comfortable, cushioned shoes and cotton socks
  • No prolonged standing or walking
  • Avoid vigorous exercise, jogging
  • Use pot holders when cooking
• Protect skin:
  • Wear gloves for tasks (washing dishes, gardening)
  • Avoid harsh soaps and detergents
  • Pat dry gently, don't rub
• Consider pyridoxine (vitamin B6):
  • Some data suggests 100-200 mg daily may reduce HFS
  • Discuss with oncologist before starting

Treatment of HFS

• Topical steroids: Clobetasol cream for inflamed areas
• Pain management: Acetaminophen, gabapentin for neuropathic pain
• Urea cream: 10-40% urea cream for thick, cracked skin
• Cool compresses: For pain and swelling
• Dose reduction: Often necessary for grade 2-3 HFS

Managing Diarrhea

Diarrhea occurs in 40-50% of patients, can be severe (grade 3-4) in 10-15%.

Prevention

• Avoid dairy products (if lactose intolerant)
• Limit high-fiber, greasy, or spicy foods during treatment
• Stay well-hydrated (8-10 glasses water/day)

First-Line Treatment

• Loperamide (Imodium):
  • Take 4 mg (2 tablets) at first loose stool
  • Then 2 mg (1 tablet) after each loose stool, max 16 mg/day
  • Continue until no diarrhea for 12 hours

If Diarrhea Persists or Severe

• Hold capecitabine
• Contact oncologist
• May need IV fluids, antibiotics (if infectious cause suspected)
• Consider octreotide for severe, refractory diarrhea

Diet for Diarrhea (BRAT Diet)

• Bananas
• Rice (white)
• Applesauce
• Toast
• Also: Plain crackers, boiled potatoes, clear broths

Monitoring During Treatment

Before Each Cycle

• Physical exam: Assess hands/feet for HFS, mucositis
• Complete blood count (CBC): Check blood cell counts
• Renal function: Creatinine, calculate creatinine clearance
• Liver function tests: AST, ALT, bilirubin
• Review side effects: Adjust dose if needed

Tumor Response Assessment

• CT scans every 2-3 months (8-12 weeks) to assess tumor response
• Tumor markers (CEA, CA 19-9) if initially elevated

Patient Self-Monitoring

• Diary: Track doses taken, side effects, bowel movements
• Temperature: Check if feeling ill (call if ≥100.4°F)
• Hands and feet: Daily inspection for early HFS signs
• Mouth: Check for sores

Drug Interactions

Warfarin (Coumadin)

• BLACK BOX WARNING: Capecitabine increases warfarin effect
• Can cause severe, life-threatening bleeding
• Requires frequent INR monitoring (weekly or more often)
• Warfarin dose usually needs reduction
• Consider alternative anticoagulation if possible

Phenytoin (Dilantin)

• Capecitabine increases phenytoin levels
• Can cause phenytoin toxicity (confusion, ataxia)
• Monitor phenytoin levels closely
• May need phenytoin dose reduction

Leucovorin (Folinic Acid)

• Enhances 5-FU (and capecitabine) toxicity
• Combination sometimes used intentionally but increases side effects
• Do not take leucovorin supplements without oncologist approval

Antacids Containing Aluminum/Magnesium

• May increase capecitabine absorption → increased toxicity
• Avoid taking within 2 hours of capecitabine
• Use alternative antacids if needed (calcium carbonate, PPIs)

Other Chemotherapy

• Capecitabine often combined with oxaliplatin (XELOX) or irinotecan
• Combination increases toxicity risk - close monitoring essential

Live Vaccines

• Avoid during capecitabine treatment (weakened immune system)
• Examples: MMR, varicella, yellow fever, rotavirus, nasal flu vaccine
• Inactivated vaccines (flu shot, pneumonia) generally safe

Special Populations

Pregnancy and Breastfeeding

• Pregnancy Category D: Can cause fetal harm
• Effective contraception required during treatment and 6 months after
• Do not breastfeed during treatment
• Male patients should use contraception (may affect sperm)

Elderly Patients (≥65 years)

• Higher risk of grade 3-4 toxicity, especially diarrhea
• More likely to have reduced renal function (dose adjustment needed)
• May benefit from starting at lower dose (1000 mg/m² vs 1250 mg/m²)
• Closer monitoring recommended

Renal Impairment

• Capecitabine and metabolites excreted by kidneys
• Reduced kidney function → drug accumulation → increased toxicity
• CrCl 30-50: Reduce dose to 75%
• CrCl <30: Contraindicated (don't use)
• Monitor creatinine before each cycle

Hepatic Impairment

• Liver converts capecitabine to active metabolites
• Mild-moderate dysfunction: Use caution, may need dose reduction
• Severe dysfunction: Avoid (limited data, unpredictable metabolism)

Patient Tips

Taking Your Medicine

• Set alarms: For morning and evening doses
• Pill organizer: Fill weekly to track doses
• Keep diary: Record each dose taken
• Travel: Bring extra medication, keep in carry-on
• Refills: Order 1 week before running out

Managing Side Effects

• Start prevention early: Don't wait for symptoms (especially HFS)
• Report early: Easier to manage mild side effects than severe ones
• Keep supplies on hand:
  • Thick hand/foot cream
  • Loperamide (Imodium)
  • Thermometer
  • Anti-nausea medication (as prescribed)
• Stay hydrated: Especially if diarrhea or nausea

When to Call Your Oncologist

• Fever ≥100.4°F (38°C)
• Severe diarrhea (4+ stools/day above normal)
• Severe hand-foot syndrome (blisters, can't walk/use hands)
• Chest pain, shortness of breath, palpitations
• Severe mouth sores preventing eating/drinking
• Vomiting preventing taking medication
• Signs of dehydration (dizziness, decreased urine, confusion)
• Any concerning symptoms

Cost and Access

Drug Cost

• Brand name (Xeloda): $4,000-6,000 per month without insurance
• Generic capecitabine: $300-1,000 per month (much more affordable)
• Insurance typically covers with prior authorization
• Medicare Part D covers

Financial Assistance

• Genentech Patient Foundation: For uninsured/underinsured
  • Phone: 1-888-941-3331
  • Website: genentech-access.com
• Co-pay assistance programs: For commercially insured (not Medicare)
• Generic options: Much lower cost, ask pharmacist
• Patient advocacy foundations:
  • PAN Foundation
  • The Assistance Fund
  • CancerCare Co-Payment Assistance

Frequently Asked Questions

How is capecitabine different from IV 5-FU?

Capecitabine is an oral prodrug that your body converts to 5-FU. It offers similar effectiveness to IV 5-FU with the convenience of taking pills at home instead of hospital infusions. The conversion happens preferentially in tumor tissue, potentially reducing some side effects. However, capecitabine causes more hand-foot syndrome, while IV 5-FU causes more neutropenia and mucositis. Overall survival and tumor response are comparable.

Why do I need to stop for a week every cycle?

The "2 weeks on, 1 week off" schedule allows your body to recover from side effects while maintaining drug effectiveness. The rest week lets blood counts recover, hand-foot syndrome improve, and GI symptoms resolve. Studies show this schedule balances efficacy with tolerability better than continuous dosing. Always take the full week off - don't restart early even if feeling better.

Can I cut the tablets in half?

No, do not cut, crush, or chew capecitabine tablets. They should be swallowed whole. The tablets have a special coating designed for proper absorption. If you have trouble swallowing large pills, talk to your doctor - they can adjust your dose using different combinations of the 150 mg and 500 mg tablets.

What if I vomit shortly after taking capecitabine?

If you vomit within 30 minutes of taking a dose, you may retake that dose. If more than 30 minutes have passed, skip that dose and take the next scheduled dose - do not double up. If vomiting is frequent, tell your oncologist - you may need anti-nausea medication or dose adjustment.

How long will I be on capecitabine?

Duration depends on your situation. For adjuvant (after surgery) colon cancer, typical duration is 6 months (8 cycles). For metastatic cancer, treatment continues as long as it's working and side effects are tolerable - this could be months to years. Your oncologist will order scans every 2-3 months to assess if treatment is working.

Will I lose my hair?

Hair loss is uncommon with capecitabine alone (occurs in <10% of patients and is usually mild thinning, not complete loss). This is very different from many IV chemotherapy drugs that cause complete hair loss. However, if capecitabine is combined with other chemotherapy drugs (like docetaxel), hair loss is more likely.

Can I drink alcohol while taking capecitabine?

Small amounts of alcohol are generally okay, but discuss with your oncologist. Alcohol can worsen some side effects (nausea, diarrhea, dehydration) and may affect liver function. Avoid alcohol if you're taking pain medications or anti-nausea drugs. Never drink alcohol if you're also on warfarin (blood thinner). Moderation is key - ideally no more than 1 drink occasionally.

My hands and feet are starting to turn red. Should I stop capecitabine?

Contact your oncologist to assess the severity. Mild redness without pain (grade 1) can usually be managed while continuing treatment with aggressive moisturizing and avoiding heat/friction. Moderate symptoms with pain affecting function (grade 2) typically require holding capecitabine until improvement, then restarting at the same dose. Severe symptoms with blistering or inability to use hands/feet (grade 3) require holding the drug and dose reduction when restarting. Early intervention prevents progression.

Do I need to take any special precautions since this is chemotherapy?

Yes, capecitabine is chemotherapy and appears in body fluids. For 48 hours after each dose: use a separate toilet if possible or close lid and flush twice; wash hands thoroughly; wash clothing separately if contaminated with body fluids. Caregivers should wear gloves when handling pills or body fluids. If you're sexually active, use condoms during treatment and for 1 week after stopping (protects partner from drug exposure and prevents pregnancy).

Can capecitabine be combined with radiation therapy?

Yes, capecitabine is often used as a radiosensitizer - it makes radiation therapy more effective. This is common for rectal cancer, esophageal cancer, and some other cancers. When combined with radiation, capecitabine is typically given at a lower dose than when used alone. The combination increases effectiveness but also increases side effects, especially diarrhea, hand-foot syndrome, and skin reactions in the radiation field.