Advanced Disease Regimens: Epirubicin (E), Cisplatin (C), Fluorouracil (F), Oxaliplatin (O), Capecitabine (X): ECF, ECX, EOF, and EOX
Cunningham D et al. N Engl J Med 2008;358:36–46. Comment in: N Engl J Med 2008;358:1965, Nat Clin Pract
Gastroenterol Hepatol 2008;5:414–415, N Engl J Med 2010;362:858–859
REAL-2 study conclusion: Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer
ECF Regimen
Epirubicin 50 mg/m2; administer intravenously over 3–20 minutes on day 1 before cisplatin, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 50 mg/m2)
Hydration before cisplatin: ≥1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously over a minimum of 3 hours
Cisplatin 60 mg/m2; administer intravenously in 100–500 mL 0.9% NS over 30–60 minutes on day 1, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 60 mg/m2)
Hydration after cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3 hours. Encourage increased oral fluid intake. Goal is to achieve a urine output ≥100 mL/hour. Monitor and replace magnesium and other electrolytes as needed
Fluorouracil 200 mg/m2 per day; administer by continuous intravenous infusion over 24 hours in 50–1000 mL 0.9% NS or 5% dextrose injection (D5W) for 21 consecutive days, on days 1–21, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 4200 mg/m2)
ECX Regimen
Epirubicin 50 mg/m2; administer intravenously over 3–20 minutes on day 1 before cisplatin, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 50 mg/m2)
Hydration before cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3 hours
Cisplatin 60 mg/m2; administer intravenously in 100–500 mL 0.9% NS over 30–60 minutes on day 1, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 60 mg/m2)
Hydration after cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3 hours. Encourage increased oral fluid intake. Goal is to achieve a urine output ≥100 mL/hour. Monitor and replace magnesium and other electrolytes as needed
Capecitabine 625 mg/m2 per dose; administer orally, twice daily for 21 consecutive days, on days 1–21, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 26,250 mg/m2)
EOF Regimen
Epirubicin 50 mg/m2; administer intravenously over 3–20 minutes on day 1 before oxaliplatin, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 50 mg/m2)
Oxaliplatin 130 mg/m2; administer intravenously in 250 mL D5W over 2 hours on day 1, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 130 mg/m2)
Note: Oxaliplatin must not be mixed with sodium chloride solutions
Fluorouracil 200 mg/m2 per day; administer by continuous intravenous infusion in 50–1000 mL 0.9% NS or D5W over 24 hours for 21 consecutive days, on days 1–21, for a maximum of 8 cycles (total dosage/cycle = 4200 mg/m2)
EOX Regimen
Epirubicin 50 mg/m2; administer intravenously over 3–20 minutes on day 1 before oxaliplatin, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 50 mg/m2)
Oxaliplatin 130 mg/m2; administer intravenously in 250 mL D5W over 2 hours on day 1, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 130 mg/m2)
Note: Oxaliplatin must not be mixed with sodium chloride solutions
Capecitabine 625 mg/m2 per dose; administer orally, twice daily for 21 consecutive days, on days 1–21, every 3 weeks, for a maximum of 8 cycles (total dosage/cycle = 26,250 mg/m2)
Supportive Care
Antiemetic prophylaxis for ECF and ECX regimens
Emetogenic potential on day 1 is HIGH. Potential for delayed emetic symptoms
Emetogenic potential on days 2–21 is LOW
Antiemetic prophylaxis for ECF and ECX regimens
Emetogenic potential on day 1 is MODERATE
Emetogenic potential on days 2–21 is LOW
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis
Primary prophylaxis may be indicated
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is LOW
See Chapter 47 for more information
Diarrhea management
Latent or delayed-onset diarrhea✫:
Loperamide 4 mg; administer orally initially after the first loose or liquid stool, then
Loperamide 2 mg; administer orally every 2 hours during waking hours, plus
Loperamide 4 mg; administer orally every 4 hours during hours of sleep
Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration
Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil®)
Oral care
Prophylaxis and treatment for mucositis/stomatitis
General advice:
If mucositis or stomatitis is present:
Use a solution of ¼ teaspoon (1.25 g) each of baking soda and table salt (sodium chloride) in one quart (~950 mL) of warm water. Follow with a plain water rinse
Do not use mouthwashes that contain alcohols
Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)
For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor®), topical or orally administered steroids, antihistamine agents (H1-receptor antagonists), or pyridoxine
Pyridoxine may provide relief; starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day
Patient Population Studied
The REAL-2 study was a trial of 1002 patients with previously untreated advanced esophagogastric cancer who were randomly assigned to 1 of 4 combination chemotherapy regimens, including epirubicin, cisplatin, and fluorouracil (ECF; N = 263); epirubicin, cisplatin, and capecitabine (ECX; N = 250); epirubicin, oxaliplatin, and fluorouracil (EOF; N = 245); and epirubicin, oxaliplatin, and capecitabine (EOX; N = 244). The primary endpoint was noninferiority in overall survival for the triplet therapies containing capecitabine or fluorouracil, and for those containing oxaliplatin or cisplatin. Progression-free survival and response rates did not differ significantly among the regimens. Adverse effects associated with capecitabine and fluorouracil were similar. In comparison with cisplatin, oxaliplatin-containing regimens had less associated G3 or G4 neutropenia, alopecia, renal toxicity, and thromboembolism but higher rates of G3 or G4 diarrhea and peripheral neuropathy. The investigators concluded capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer