Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer

Two phase 3 randomised controlled trials (RCTs), recruiting 602 and 605 individuals, and 1 pooled analysis of these study data were reviewed. Both RCTs compared capecitabine with a bolus (Mayo) 5-FU/FA regimen and were identical in design. Both studies included individuals with untreated, locally advanced or metastatic colorectal cancer, most of whom had undergone previous surgery. Although neither RCT was undertaken under blinded conditions because of the different routes of administration (oral or intravenous), both studies used an independent committee to review outcomes. The primary outcome measure in both trials was tumour response rate. Both studies were adequately powered to demonstrate equivalence in overall response rates.

Differences in median overall survival were not statistically different at the 5% significance level in either RCT, with values of 12.5 and 13.3 months for capecitabine and 5-FU/FA respectively in 1 study, and 13.2 and 12.1 months respectively in the other study. The pooled study also did not report any statistically significant difference in overall survival.

In both studies, the overall response rate was statistically significantly higher in the capecitabine groups than in the 5-FU/FA groups when outcomes were assessed by study investigators (p=0.005 and p=0.013). However, when the independent review committee assessed outcomes, these response rates were statistically significantly higher in only 1 of the studies (p=0.0001). When the data from both studies were pooled, response rates statistically favoured capecitabine irrespective of who carried out the assessment (p<0.0002 for the investigator assessment and p<0.0001 for the independent review committee assessment).

Neither study reported a statistically significant difference in mean duration of response between the capecitabine and 5-FU/FA groups, nor was a difference reported for the pooled data. Neither study, nor the pooled analysis, reported any statistically significant differences in time to disease progression, death or treatment failure between the capecitabine and 5-FU/FA groups.

Neither of the studies reported any statistically significant difference in global quality of life as measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).

With regard to treatment-related adverse events, the pooled analysis of the 2 trials indicated that individuals in the capecitabine groups reported less diarrhoea (48% versus 58%, p<0.001), stomatitis (24% versus 62%, p<0.001), nausea (38% versus 47%, p<0.001) and alopecia (6% versus 21%, p<0.001) of all grades than those in the 5-FU/FA groups. Patients in the capecitabine groups also had less grade III/IV neutropenia (2% versus 21%, no p-value available) and grade III stomatitis (2% versus 15%, p<0.0001), and less frequent hospitalisation for adverse events (12% versus 18%, p=0.002), but reported more hand–foot syndrome (54% versus 6.0%, no p-value available) and grade III hyperbilirubinaemia (18% versus 3%, p<0.0001). In the pooled analysis, treatment mortality was 1% for each group.

Two large, open, phase 3 RCTs (Studies 011 and 012) were reviewed. These trials recruited 816 and 380 individuals respectively. No independent review committee was used to compensate for the fact that the assessors were aware of treatment allocation. Study 011 compared UFT/FA with 5-FU/FA administered using the Mayo regimen, whereas Study 012 compared UFT/FA with 5-FU/FA administered using a modification of the Mayo regimen, where treatment was repeated every 35 days instead of the standard 28 days. This non-standard variation of the Mayo regimen is a less dose-intensive regimen and has not been tested for efficacy. In Study 011, individuals recruited in the USA received UFT plus FA 75 mg/day, while those in non-USA centres received UFT plus FA 90 mg/day. Study 011 used overall survival as the primary endpoint and was powered to demonstrate equivalence of the 2 treatments as non-inferiority of survival. Study 012 used time to disease progression as the primary endpoint, and was powered to detect a hazard ratio (HR) of 1.4 between the groups. A third study of crossover design was also identified, which assessed patient preference for UFT/FA compared with intravenous 5-FU/FA.

In Study 011, median survival time was 12.4 months in the UFT/FA group and 13.4 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA was 0.96 (95% confidence interval [CI] 0.83 to 1.13). In Study 012, median survival time was 12.2 months in the UFT/FA group and 10.3 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA in this study was 1.14 (95% CI 0.92 to 1.42). A secondary analysis showed that individuals from the USA sites in Study 011, who received lower-dose FA, had worse overall survival than the total study population.

In Study 011 the median time to disease progression was statistically significantly greater in the 5-FU/FA group than in the UFT/FA group (3.8 months versus 3.5 months, p=0.01), although the actual difference was 10 days. No statistically significant difference in time to disease progression was reported in Study 012.

In both studies there were no statistically significant differences between treatment arms with regard to overall tumour response rates. The rates in the UFT/FA and 5-FU/FA groups were 11.7% and 14.5% respectively in Study 011, and 10.5% and 9.0% respectively in Study 012. No statistically significant differences in duration of response were reported (actual values were not reported).

In Study 011, compared with 5-FU/FA, UFT/FA was associated with statistically significantly less diarrhoea (67% versus 76%, p=0.006), nausea/vomiting (67% versus 75%, p=0.02), mucositis (24% versus 75%, p<0.001), neutropenia (13% versus 77%, p<0.001) and thrombocytopenia (21% versus 31%, p<0.001) of all toxicity severity grades. UFT/FA was also associated with less grade III/IV mucositis (1% versus 20%, p<0.001), neutropenia (1% versus 56%, p<0.001), thrombocytopenia (0% versus 2%, p=0.003) and anaemia (3% versus 7%, p=0.03). Increased bilirubin, without other liver function abnormalities, was statistically significantly more common in individuals treated with UFT/FA than in those treated with 5-FU/FA (39% versus 22%, p<0.001). In Study 012, UFT/FA treatment resulted in statistically significantly fewer episodes of stomatitis/mucositis (18% versus 55%, p<0.001), neutropenia (11% versus 67%, p<0.001), thrombocytopenia (18% versus 28%, p=0.025) and anaemia (76% versus 89%, p=0.002) of any grade than 5-FU/FA treatment. UFT/FA treatment resulted in statistically significantly less grade III/IV stomatitis/mucositis (2% versus 16%, p<0.001) and neutropenia (3% versus 31%, p<0.001). In all, 127 individuals were hospitalised during the study: 59 (31%) in the UFT/FA group and 68 (37%) in the 5-FU/FA group (p-values not reported).

Health-related quality of life was measured in both studies using either the Functional Living Index-Cancer or EORTC QLQ-C30; no statistically significant differences in outcomes were reported between the treatment groups in either study. An unpublished preliminary report of a phase 2 randomised study in 202 individuals indicated that scores for functional and symptom scales were either improved or unchanged in the UFT/FA group but worse in the 5-FU/FA group.

The only information available on preferences for treatment was a 37-patient crossover study in which individuals received either UFT (300 mg/m²/day) plus FA (90 mg/m²/day) for 28 days every 5 weeks, or intravenous FU (425 mg/m²/day) plus FA (20 mg/m²/day) for 5 days every 4 weeks. They were then crossed-over to the other treatment regimen for the second treatment cycle. Therapy preference questionnaires were completed before the first and after the second treatment cycle. Of the 31 individuals who completed the questionnaire, 84% preferred the UFT/FA regimen. The reasons for this preference included being able to take medication at home, experiencing less stomatitis and diarrhoea, and being able to use a tablet instead of having an injection.

Two economic evaluations of capecitabine compared with 5-FU/FA were identified, 1 conducted by the manufacturer and the other by the assessment group. Both evaluations assumed equivalent effectiveness, and thus only evaluated associated costs from an NHS perspective. Both models included costs associated with drug acquisition, chemotherapy administration (including inpatient stays) and adverse event management.

The manufacturer estimated the costs of capecitabine and 5-FU/FA (using the Mayo bolus regimen) to be approximately £2,700 and £5,000, respectively. The assessment group estimated these costs to be £2,100 and £3,600, respectively. The assessment group also estimated the cost of 5-FU/FA to be £6,300 when the de Gramont infusional regimen was used and £3,500 when the modified de Gramont infusional method, which does not generally require inpatient administration, was used. In all instances, capecitabine was the least costly treatment option.

Both the manufacturer and the assessment group conducted economic analyses that compared UFT/FA with 5-FU/FA; both assessed costs from an NHS perspective and included categories of costs such as drug acquisition, chemotherapy administration (including inpatient stays), and adverse event management. A cost-minimisation study was also identified, although it was of limited use because it was from a non-UK perspective and did not specify the comparator regimen (for example Mayo or de Gramont).

The manufacturer's cost-effectiveness analysis compared UFT/FA with 5-FU/FA based on a Mayo regimen. The analysis used adverse events as the health outcome of interest although the evaluation was conducted separately for the 2 RCTs, and the costs of UFT/FA and 5-FU/FA were found to be £3,600 and £6,100 respectively for Study 011, and £3,200 and £4,900 respectively for Study 012.

The assessment group's cost-minimisation analysis showed a cost of approximately £3,500 both for UFT/FA and for 5-FU/FA, administered using either the Mayo or modified de Gramont outpatient-based regimen.