Capecitabine for the treatment of advanced gastric cancer

Evidence-based recommendations on capecitabine for treating advanced gastric cancer in adults.

# Guidance
Capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.# The technology 
Capecitabine (Xeloda, Roche Products) is an orally administered pro-drug of fluorouracil. It is converted to fluorouracil by enzymes that are principally located in the liver and tumour tissue. This leads to a higher concentration of fluorouracil in tumour tissue than in normal tissues. Capecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.
According to the summary of product characteristics (SPC), contraindications include known dihydropyrimidine dehydrogenase deficiency, severe leucopenia, neutropenia or thrombocytopenia, severe hepatic impairment and severe renal impairment. The SPC states that capecitabine has been associated with handfoot syndrome, diarrhoea, neutropenia, peripheral neuropathy, headache and alopecia. For full details of side effects and contraindications, see the SPC.
Capecitabine is administered orally. The recommended dose of capecitabine is 625 mg/m2 twice daily for 21 days if it is used as part of the epirubicin, cisplatin and capecitabine (ECX) regimen, or the epirubicin, oxaliplatin and capecitabine (EOX) regimen. If it is used as part of a capecitabine and cisplatin (CX) regimen, the recommended dose of capecitabine is 1000 mg/m2 twice daily for 14 days in every 21 days. Treatment should be stopped if the disease gets worse or if there is intolerable toxicity. The cost of
60 150-mg tablets of capecitabine is 40.02 and the cost of 120 500-mg tablets is 265.55 (excluding VAT; Monthly Index of Medical Specialities , March 2010). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of capecitabine and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's submission considered the use of capecitabine with epirubicin plus cisplatin or oxaliplatin compared with fluorouracil with epirubicin plus cisplatin or oxaliplatin, and capecitabine plus cisplatin compared with fluorouracil plus cisplatin. The population was people with locally advanced (that is, the disease had spread to regional lymph nodes) or metastatic (that is, the disease had spread beyond the regional lymph nodes to other parts of the body) inoperable gastric cancer. This was in line with the scope, which restricted the population to people with inoperable advanced gastric cancer. The manufacturer reported details of two phase III multicentre randomised controlled trials (REAL-2 and ML17032). These trials assessed the non-inferiority of capecitabine compared with fluorouracil for the treatment of advanced gastric cancer. REAL-2 compared ECX and EOX combinations with epirubicin/cisplatin/fluorouracil (ECF) and epirubicin/oxaliplatin/fluorouracil (EOF) combinations. ML17032 compared CX with cisplatin/fluorouracil (CF).
The REAL-2 trial was an open-label UK multicentre study that enrolled adults with advanced carcinoma of the oesophagus, oesophageal-gastric junction or stomach. People were included in the trial if they had locally advanced or metastatic adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma. In addition the primary tumour had to be classified as inoperable. People were randomised to receive capecitabine plus platinum-based chemotherapy regimens: ECX regimen (n = 241), ECF regimen (n = 249), EOX regimen (n = 239) or EOF regimen (n = 235). The doses were as specified in the individual SPCs of each drug. In all cases treatment was repeated every 3 weeks for 8 cycles in the absence of progressive disease or unacceptable toxicity. The primary endpoint was to determine non-inferiority of overall survival in people receiving capecitabine compared with those receiving fluorouracil, and non-inferiority of overall survival in people receiving oxaliplatin compared with those receiving cisplatin. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95% confidence interval (CI) around the hazard ratio (HR) for overall survival was more than 1.23.
The manufacturer reported that REAL-2 met the two primary non-inferiority endpoints, and that there was a trend towards improved survival in favour of both capecitabine over fluorouracil and oxaliplatin over cisplatin. The manufacturer also reported that the trial showed non-inferiority in terms of overall survival for capecitabine; the HR adjusted for performance status, extent of disease and age was 0.89 (95% CI 0.77 to 1.02) in the per-protocol population. This was based on the comparison of ECF and EOF versus ECX and EOX. The manufacturer also reported that for the secondary endpoints, there was no significant difference in progression-free survival between the capecitabine and the fluorouracil arms or between the cisplatin and the oxaliplatin arms. There was minimal quality-of-life data reported in REAL-2 and there were no differences between the mean scores at baseline and 12 weeks between any of the groups on the General Health Status subscale of the European Organization for Research and Treatment of Cancer (EORTC)-30 questionnaire.
ML17032 was an open-label study that enrolled people with advanced gastric adenocarcinoma. Adults were included in the trial if they had histologically confirmed gastric adenocarcinoma with advanced and/or metastatic disease and at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) that had not been irradiated and a Karnofsky performance status score of 70% or higher. People were randomised to receive cisplatin (80 mg/m2 intravenously, day 1) plus fluorouracil (800 mg/m2 intravenously, days 15 as a continuous infusion) (n = 156) or cisplatin (80 mg/m2 intravenously, day 1) plus capecitabine (1000 mg/m2 orally, twice daily, days 114) (n = 160). The primary endpoint was non-inferiority of progression-free survival. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95% CI around the HR for progression-free survival was more than 1.25.
In the per-protocol population, there was non-inferiority of progression-free survival in people receiving CX compared with those receiving CF (adjusted HR 0.85, 95% CI 0.65 to 1.11). The manufacturer reported that the results showed a trend towards improved progression-free survival with CX compared with CF in the unadjusted analysis. The median overall survival was 10.5 months for CX compared with 9.3 months for CF (HR 0.85, 95% CI 0.64 to1.13). It was also reported by the manufacturer that the trial demonstrated non-inferiority of capecitabine compared with fluorouracil for the secondary end-points of overall survival, response rate, mean time of response and duration of response. No quality of life data were collected in ML17032.
The manufacturer also reported a published meta-analysis that combined the individual data from 1318 people taking part in the REAL-2 and ML17032 trials. The aim of the meta-analysis was to test whether capecitabine was superior to fluorouracil within the double and triple combination chemotherapy regimens for people with advanced oesophago-gastric cancer. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and response rate. The median overall survival for the intention-to-treat population was 285 days (95% CI 265 to 305 days) for people treated with fluorouracil (n = 664) and 322 days (95% CI 300 to 343 days) for people treated with capecitabine (n = 654). This resulted in an unadjusted HR of 0.87 (95% CI 0.77 to 0.98, p = 0.027) in favour of capecitabine. There was no evidence of any statistically significant heterogeneity of treatment effect according to baseline patient characteristics (such as age, disease site and histology). The meta-analysis reported that superiority of capecitabine over fluorouracil was maintained with multivariate analyses (adjusted HR 0.87, 95% CI 0.77 to 0.98, p = 0.02).The meta-analysis also reported a non statistically significant trend towards improved progression-free survival in people receiving capecitabine (unadjusted HR 0.91, 95% CI 0.81 to 1.02, p = 0.093).
In REAL-2, grade 3 and 4 neutropenia was more common in the ECX arm compared with the ECF arm and there was an increased level of fatigue in the EOF arm compared with the EOX arm. Stomatitis occurred more frequently and with greater severity in the CF arm than in the CX arm in ML17032, while handfoot syndrome was more common in the CX arm. The ML17032 trial also reported that adverse events leading to dose modification were more common in the CX arm (62%) compared with the CF arm (48%).
On the basis of equivalent clinical effectiveness, similar safety and improved patient convenience, a cost-minimisation model was developed to evaluate the costs for each regimen. The manufacturer reported that this captured all significant incremental direct costs relating to switching from fluorouracil-based therapies to capecitabine-based therapies. The model considered both the drug acquisition and drug administration costs for all the regimens evaluated. People entered the model at the start of treatment when they received either capecitabine or fluorouracil and left the model after 5.5 cycles (21 days per cycle), which was the time horizon of the model. The costs of treatment-related adverse events were not included. The overall tolerability profile of capecitabine was considered by the manufacturer to be similar and at least as good as fluorouracil. The manufacturer also stated that the adverse events associated with the method by which fluorouracil is administered, such as central-line complications, can be expensive to manage. This meant that the costs associated with the management of adverse events with capecitabine were unlikely to be higher than those associated with fluorouracil. Therefore, the non-inclusion of adverse events costs in the model would be expected to favour fluorouracil.
The manufacturer stated that the economic evaluation of capecitabine was undertaken within its licensed indication for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen. There were three sets of analyses: a comparison of ECX with ECF, EOX with EOF, and CX with CF. A total of six regimens were therefore analysed in the cost-minimisation model. The dosages in each regimen were analysed according to the SPC for each treatment and no drug wastage was taken into account. The manufacturer also conducted some additional sensitivity analyses that included one-way sensitivity analyses, scenario analyses, a worst case scenario analysis and threshold analyses.
The base-case results included all the drug acquisition and administration costs for all the regimens considered in the submission. All capecitabine-based regimens were shown to be cost saving compared with equivalent fluorouracil-based regimens. The overall NHS cost saving for switching from ECF to ECX regimens was 1620. The overall NHS cost saving for switching from EOF to EOX regimens was 1572. For the double combination chemotherapy regimens the overall NHS saving of switching from CF to CX was 4210. All the results of the sensitivity and scenario analyses conducted by the manufacturer supported the base case and suggested that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens.
The ERG considered that the clinical-effectiveness evidence presented by the manufacturer reflected the available relevant evidence. It noted that the ML17032 trial was underpowered since the trial had only 50% power to detect statistically significant non-inferiority. The REAL-2 and the ML17032 trials used appropriate outcomes, but there were limited data on health-related quality of life. The ERG also noted that in clinical practice, fluorouracil and capecitabine would be administered in lower doses in the double combination chemotherapy regimen compared with the doses used in ML17032.
Overall, the ERG considered the manufacturer's approach to the economic evaluation reasonable and that the cost-minimisation analysis used in the submission was acceptable. The ERG stated that there was minimal change to the savings when many of the assumptions used were explored. The ERG pointed out that treatments cannot be considered to be exactly equivalent due to uncertainty in estimating their effectiveness. By conducting a cost-minimisation analysis, the manufacturer did not address the uncertainty around the estimates of efficacy. However, they performed a threshold analysis but the ERG noted that modelling a scenario in which fluorouracil was more effective was unlikely to be relevant to the determination of capecitabine's cost effectiveness. The ERG noted that adverse events had not been included in the cost-minimisation model because the manufacturer assumed that the costs associated with adverse event management were unlikely to be higher for capecitabine than fluorouracil. The ERG highlighted that rare adverse events may not have been identified because of the large sample sizes needed to detect these. Therefore, the ERG felt that some uncertainty remained about treatment-related adverse events associated with capecitabine and fluorouracil regimens. The ERG also noted that number of cycles used in the model did not represent the number used in UK clinical practice: the maximum number of cycles in clinical practice is usually six, but in REAL-2 the median (rather than the maximum) number of cycles received was six.
The ERG noted some additional areas of uncertainty. In the model, the manufacturer calculated capecitabine costs based on milligrams used. The ERG considered that in clinical practice, this would be rounded to match the available tablets. It also considered that in calculating fluorouracil costs, wastage had not been taken into account. The ERG noted that when calculating epirubicin, cisplatin and oxaliplatin costs, the manufacturer used an average of the NHS list prices. In practice, the NHS is likely to prefer the cheapest product. The ERG also considered that, in practice, the dose of capecitabine may be reduced by 2550% because of toxicity. The ERG undertook exploratory analyses that took into account many of the above areas of uncertainty. In all analyses capecitabine was cost saving compared with fluorouracil.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
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.

# Clinical effectiveness
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 handfoot 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.

# Cost effectiveness
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.

# Summary of the Appraisal Committee's key conclusions
Key conclusion
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.
Current practice
Clinical need
The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the hospital, compared with an infusion pump that has to be replaced weekly. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided.
Availability of alternative treatments
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 clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events.
The position of the treatment in the pathway of care for the condition
Capecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.
The technology
Proposed benefits of the technology from the manufacturer, clinician and patient perspective
The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the 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.
Distinguishing features of the technology
Capecitabine is an orally administered pro-drug of fluorouracil.
Adverse effects
The Committee discussed handfoot 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.
Evidence for clinical effectiveness
Availability and nature of evidence
The Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil.
Quality of the evidence
The Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals, noting the ERG concerns that one of the studies was underpowered. 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.
Relevance to general clinical practice in the NHS
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 trials were sufficiently representative of UK clinical practice.
Uncertainties generated by the evidence
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.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None
Evidence for cost effectiveness
Availability and nature of evidence
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.
Uncertainties around and plausibility of assumptions and inputs in the economic model
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.
Incorporation of health-related quality-of-life benefits and utility values
The Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in the quality of life between capecitabine-based and fluorouracil-based regimens.
Are there specific groups of people for whom the technology is particularly cost effective?
None
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that the model showed that there were likely to be cost savings with capecitabine-based regimens compared with fluorouracil-based regimens.
Additional factors taken into account
Patient access scheme
(Pharmaceutical Price Regulation Programme)
No patient access scheme was submitted for the technology being appraised.
End of life considerations (supplementary advice on end of life)
Because the most plausible ICER was not more than 30,000 per QALY gained, the supplementary advice was not relevant.
Equalities considerations, social value judgement
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 agreed 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.

# Related NICE guidance
Trastuzumab for the treatment of HER2-positive metastatic gastric cancer. NICE technology appraisal guidance 208 (2010)# Review of guidance
The guidance on this technology will be considered for review in May 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJuly 2010# Changes after publication
February 2014: minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
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 National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.