The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of capecitabine, having considered evidence on the nature of gastric cancer and the value placed on the benefits of capecitabine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from the two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil. The Committee noted that the results of the trials indicated that capecitabine was not inferior to fluorouracil for overall survival (REAL-2 trial) and progression-free survival (ML17032 trial). There was also a trend to improved survival with capecitabine in the published meta-analysis of both trials. The Committee noted the ERG concerns that the ML17032 study was underpowered. The Committee also noted that with non-inferiority trials, it was possible for a treatment to achieve non-inferiority with a worse point estimate than the comparator treatment. Therefore, the Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals. The Committee agreed that the results of the studies showed a trend towards improved survival and concluded that capecitabine was probably at least as effective as intravenously administered fluorouracil.
The Committee noted that the REAL-2 trial was conducted in UK centres, although it included people with cancer involving the gastro-oesophageal junction and distal oesophagus as well as the stomach, and a small minority with squamous cell carcinoma rather than adenocarcinoma. However, the Committee accepted that the two trials were generalisable to people with advanced, inoperable gastric cancer in the UK. In addition, the Committee noted that the people in both trials were relatively young, with good performance status. The clinical specialists highlighted that even though the people in the trials were younger than the median age of death of people with gastric cancer, the trial population was representative of those in UK clinical practice who would be prescribed a chemotherapy regimen. Therefore the Committee concluded that the trials were sufficiently representative of UK practice.
The Committee considered current clinical practice for the first-line treatment of inoperable advanced gastric cancer. It heard about the experience of people receiving treatment and whether people preferred oral treatment with capecitabine or intravenous treatment (via an infusion pump) with fluorouracil. The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to hospital, compared with an infusion pump that has to be replaced weekly. Oral treatment also offers an advantage for people in terms of carrying on with daily physical activities without the continuous presence of a pump. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided. The clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events.
The Committee considered whether there were issues related to equality to be taken into account in its considerations. It acknowledged that some people with inoperable advanced gastric cancer may not be able to swallow oral capecitabine tablets, because of difficulty with swallowing as a result of the cancer, or because of nausea. However the Committee noted that although capecitabine is preferred in most circumstances, fluorouracil remains an alternative where capecitabine is contraindicated or otherwise unsuitable. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.
The Committee then discussed hand–foot syndrome, which is a specific adverse event that occurs more frequently with capecitabine therapy than with intravenously administered fluorouracil. The clinical specialists noted that if reported early it can be successfully treated with emollient cream, vitamin B6 and temporary dose reduction. The Committee concluded that oral capecitabine therapy was the preferred first-line treatment option in most people able to tolerate it.
The Committee heard evidence on the cost effectiveness of capecitabine for the first-line treatment of inoperable advanced gastric cancer. It agreed that in this case the cost-minimisation analysis was an appropriate approach to the economic evaluation based on the clinical evidence that suggested that capecitabine was at least as effective as fluorouracil. The Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in quality of life between capecitabine-based and fluorouracil-based regimens.
The Committee noted that the model assumed that there were no significant differences in the incidence or severity of adverse events between capecitabine and fluorouracil regimens, and so the costs of treatment-related adverse events were not included in the analysis. The Committee agreed that based on the trial data this was acceptable. The Committee then discussed the length of the model. It agreed that the time horizon of 5.5 cycles was a reasonable assumption as this was the mean number of treatment cycles given in the REAL-2 trial and is reflective of UK clinical practice. The Committee concluded that the parameters used in the model were acceptable.
The Committee noted that the model showed that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens. The Committee heard that the ERG had noted some areas of uncertainty and had undertaken exploratory analyses to assess these. However, in all these analyses, capecitabine was still likely to be cost saving compared with fluorouracil. The Committee therefore agreed that capecitabine would be a cost-effective use of NHS resources. The Committee concluded that capecitabine, in combination with a platinum-based regimen, should be recommended for the first-line treatment of inoperable advanced gastric cancer.