Capecitabine for the treatment of advanced gastric cancer
Authors: Norman G , Soares M , Peura P , Rice S , Suh D , Wright K , Sculpher M , Eastwood A 
Published: February 2021

This paper presents a summary of the evidence review group (ERG) report into capecitabine for advanced gastric cancer (aGC). Capecitabine is an oral prodrug of 5-fluorouracil (5-FU). The decision problem addressed was the use of capecitabine (X) compared to 5-FU (F), in combination regimens with platinum agents [cisplatin (C) or oxaliplatin (O)] with or without epirubicin (E), in patients with inoperable aGC. Approximately 7000 new cases of gastric cancer are diagnosed in England and Wales every year. Of these, 80% are candidates for palliative chemotherapy and around 2900 receive such treatment. The standard UK practice for patients with aGC who are considered fit enough has consisted of a triplet regimen comprising intravenous 5-FU in combination with a platinum agent (capecitabine or oxaliplatin) and epirubicin. The manufacturer’s submission (MS) focused on direct evidence from two phase III non-inferiority randomised controlled trials (RCTs), REAL-2 (Randomized ECF for Advanced and Locally advanced oesophagogastric cancer-2;n = 1002) and ML17032 (n = 316). REAL-2 randomised patients to four regimens (ECF, ECX, EOF and EOX) to compare 5-FU with capecitabine and cisplatin with oxaliplatin, whereas ML17032 compared CX with CF. Efficacy outcomes from these trials were pooled in an individual patient data (IPD) meta-analysis. Both RCTs demonstrated statistically significant non-inferiority of capecitabine on the outcome of overall survival (OS) assessed in the per-protocol population; equivalent results were also demonstrated for progression-free survival (PFS). The IPD meta-analysis found a statistically significant benefit in OS for capecitabine compared with 5-FU [unadjusted hazard ratio (HR): 0.87; 95% confidence interval (CI) 0.77 to 0.98,p = 0.027]. There was no evidence of a poorer safety profile for capecitabine overall, nor of any difference in quality of life (QoL) between the two fluoropyrimidines. The MS included a de novo economic evaluation based on a cost-minimisation analysis (CMA), where the costs of capecitabine-based regimens were compared with their equivalent 5-FU-based regimens in aGC. A time horizon of 5.5 cycles (each lasting for 21 days) was used in the base-case analysis, representing the duration of treatment. The results of the manufacturer’s base-case analysis showed that capecitabine regimens are associated with mean net cost savings of £1620 (ECX vs ECF), £1572 (EOX vs EOF) and £4210 (CX vs CF). The manufacturer failed to comment explicitly on the uncertainty around the estimates of efficacy and on the fact that the IPD meta-analysis suggests that capecitabine may actually be more effective on average. Further analyses exploring additional costs incurred by the UK NHS from extending survival duration showed that these are unlikely to have a material effect on conclusions. A full probabilistic analysis was not performed; however, the evidence explored by the MS and ERG is consistent in suggesting that capecitabine has a lower mean cost than 5-FU-based regimens. The submission was considered to contain convincing evidence of the non-inferiority of capecitabine to 5-FU on survival; this evidence was considered to be applicable to UK practice. Although some uncertainty remains, the ERG deemed CMA to be an appropriate framework with which to analyse this decision problem. Overall cost estimates for the CMA were generated appropriately and were robust to uncertainties regarding assumptions and sources. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.