Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer
- Study type
- Clinical trial
- Study name
- REAL-2
- Design
- Randomised trial with a two-by-two (2×2) factorial design, with non-inferiority in overall survival as the primary aim
- Sample size
- 1002 patients
- Source
- N Engl J Med · 2008
In plain words
In this study, 1002 patients with advanced cancer of the oesophagus or stomach who had not yet been treated received one of four chemotherapy regimens. The results showed that capecitabine tablets can replace infused fluorouracil, and oxaliplatin can replace cisplatin, without making treatment less effective. The side effects of these drugs differ; for example, oxaliplatin caused fewer kidney problems and blood clots, but slightly more diarrhoea and neuropathy (tingling or numbness in the hands and feet).
Key results
Treatment arms and regimens
Epirubicin 50 mg/m² IV (bolus) and cisplatin 60 mg/m² IV with standard hydration every 3 weeks, with fluorouracil 200 mg/m² per day as a continuous IV infusion via a central (Hickman) catheter; warfarin 1 mg per day from the day of catheter insertion to prevent catheter thrombosis. Planned duration 24 weeks (up to 8 cycles of epirubicin and the platinum combination).
Recommended antiemetics in all arms: a 5HT3 antagonist and dexamethasone 8 mg IV before chemotherapy, then dexamethasone 4 mg orally three times daily for 2 days and metoclopramide 10 mg three times daily for 3 days. Dose modifications per the published ECF guidance.
Epirubicin 50 mg/m² IV (bolus) and cisplatin 60 mg/m² IV with standard hydration every 3 weeks, with capecitabine 625 mg/m² twice daily orally, continuously (the starting dose in the first 80 patients was 500 mg/m² twice daily and was increased to 625 after the first interim analysis). Duration 24 weeks (up to 8 cycles).
Capecitabine was interrupted for grade 2 to 3 stomatitis, diarrhoea or nausea and vomiting; recurrence of grade 2: 25% reduction, third occurrence 50% and fourth occurrence discontinuation; grade 3 lasting more than 2 days: 25% reduction (recurrence: 50%, third occurrence discontinuation); grade 4: discontinuation or 50% reduction. Hand–foot syndrome: pyridoxine 50 mg three times daily; grade 2: hold until recovery, then 15% reduction; grade 3: 30% reduction; recurrent grade 3: 50% reduction. Antiemetics as for ECF.
Epirubicin 50 mg/m² IV (bolus) and oxaliplatin 130 mg/m² as a 2-hour IV infusion every 3 weeks, with fluorouracil 200 mg/m² per day as a continuous IV infusion via a central catheter; warfarin 1 mg per day to prevent catheter thrombosis. Duration 24 weeks (up to 8 cycles).
Oxaliplatin was delayed by 1 week for neutrophils below 1.0×109/L, platelets below 75×109/L or persistent grade 1 or 2 neuropathy; after recovery from grade 2 to 4 thrombocytopenia or grade 3 or 4 neutropenia, persistent grade 1 or 2 neuropathy between cycles, grade 3 or 4 neuropathy for 7 to 14 days, or grade 3 or 4 diarrhoea or stomatitis despite fluoropyrimidine dose reduction, the dose was reduced to 100 mg/m²; with persistent grade 3 or 4 neuropathy, oxaliplatin was omitted and substitution with carboplatin was allowed at the investigator's discretion; with laryngeal dysaesthesia, subsequent infusions over 6 hours. Antiemetics as for ECF.
Epirubicin 50 mg/m² IV (bolus) and oxaliplatin 130 mg/m² as a 2-hour IV infusion every 3 weeks, with capecitabine 625 mg/m² twice daily orally, continuously (starting dose in the first 80 patients 500 mg/m² twice daily). Duration 24 weeks (up to 8 cycles). Oxaliplatin dose modifications as for EOF and capecitabine as for ECX; antiemetics as for ECF.
Source of the regimen details: Report of the interim analyses of the same trial with protocol doses (Sumpter et al, Br J Cancer 2005; PMC2361798) and trial registration ISRCTN51678883 (treatment duration and eligibility criteria)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
1002 patients with histologically confirmed adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma of the oesophagus, gastro-oesophageal junction or stomach, locally advanced and unresectable or metastatic; measurable or evaluable disease (RECIST or endoscopy); no prior chemotherapy and no prior radiotherapy (except adjuvant radiotherapy with recurrence outside the radiation field); ECOG 0 to 2; life expectancy of at least 3 months; glomerular filtration rate 60 mL/min or more with normal serum creatinine; bilirubin less than 2 times the upper limit of normal; white cells above 3×109/L, neutrophils above 1.5×109/L and platelets above 100×109/L; no uncontrolled heart disease (if left ventricular dysfunction was suspected, ejection fraction at least at the centre's lower limit of normal).
Endpoints
Primary aim: non-inferiority in overall survival for capecitabine-containing regimens compared with fluorouracil, and for oxaliplatin-containing regimens compared with cisplatin. Secondary aims included progression-free survival, response rate and toxicity.
Safety and side effects
Toxicity of capecitabine and fluorouracil was similar. Compared with cisplatin, oxaliplatin was associated with lower rates of grade 3 or 4 neutropenia, alopecia, renal toxicity and thromboembolism, but slightly higher rates of grade 3 or 4 diarrhoea and neuropathy. In the second interim analysis (204 patients; Br J Cancer 2005), grade 3 or 4 fluoropyrimidine-related toxicity (stomatitis, hand–foot syndrome and diarrhoea) was 13.7% with fluorouracil 200 mg/m² per day and 14.7% with capecitabine 625 mg/m² twice daily. The final percentage for each adverse event was not available in the sources.
Clinical significance and place in guidelines
Based on the abstract, regimens containing capecitabine (instead of infused fluorouracil) and oxaliplatin (instead of cisplatin) have similar efficacy in first-line treatment of advanced oesophagogastric cancer and can be chosen according to the toxicity profile and the patient's condition. The status of these regimens in current guidelines should be checked separately.
Limitations
This card is based on the abstract. Exact adverse event percentages and dose details are not given in the abstract and should be checked in the full text of the paper. The comparison of EOX with ECF was a secondary analysis.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.