Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of pemetrexed disodium in combination with cisplatin for the treatment of unresectable pleural mesothelioma in chemotherapy-naive patients. DATA SOURCES Electronic databases were searched up to May 2005. REVIEW METHODS The systematic review was conducted following accepted guidelines. An assessment of the economic submission received from the manufacturer of pemetrexed was also carried out. This comprised two sections, each employing an economic model. One of these models was then reformulated in order to carry out a separate exploration of economic performance. RESULTS One randomised controlled trial comparing pemetrexed and cisplatin with cisplatin alone, and involving a total study population of 448 patients, met the inclusion criteria. Pemetrexed in combination with cisplatin in this trial showed a 2.8-month gain in median survival compared with cisplatin alone in an intention-to-treat (ITT) population (12.1 and 9.3 months, respectively, p = 0.020, hazard ratio of 0.77). During the trial, increased reporting of severe toxicity in the pemetrexed arm led to a change in the protocol to add folic acid and vitamin B12 supplementation to therapy. For fully supplemented patients (n = 331) the hazard ratio for median survival in favour of pemetrexed plus cisplatin was also comparable (0.75), but of borderline significance between treatment arms (p = 0.051). The trial inclusion criteria restricted recruitment to those with a Karnofsky performance status of 70 or greater (equivalent to ECOG/WHO 0 or 1 scales more widely used in the UK). Quality of life scores using the Lung Cancer Symptom Scale demonstrated significantly greater improvement for pain and dyspnoea for patients in the combination group compared with those in the cisplatin group. In the ITT population, the incidence of serious toxicities with pemetrexed plus cisplatin was higher compared with cisplatin alone. However, the grade 3/4 toxicities of the combination arm, particularly leucopenia, neutropenia and diarrhoea, were found to be greatly improved by the addition of vitamin B12 and folic acid. The existing published economic literature was very limited. The economic evaluation conducted by the study (and that submitted by the manufacturer) suggested that pemetrexed is unlikely to be considered cost-effective at conventionally accepted thresholds in the UK for all patients, mainly because of the high cost of pemetrexed itself compared with cisplatin. These findings were better for some patient subgroups, e.g. especially for fully supplemented (FS) patients with good performance status (0/1) and advanced disease (AD). These findings seem robust. The estimated cost-effectiveness results were for the FS population, incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained = pound59,600; for the FS with AD population, ICER per QALY = pound47,600; for the FS with performance status 0/1 population, ICER per QALY = pound49,800; and for the FS with performance status 0/1 and AD population, ICER per QALY = pound36,700. CONCLUSIONS The new therapy examined in this document demonstrates an extension of life expectancy and palliation, as measured by time to progression of disease and other end-points. However, the absolute benefit obtained is small, and it needs to be weighed against the benefits of effective palliative care services. The limited benefit was also at the expense of considerable toxicity to patients. The economic evaluation conducted in this study and that of the manufacturers suggest that pemetrexed is not cost-effective at conventional thresholds for all patients. Cost-effectiveness seems better for some patient subgroups, e.g. especially for patients with good performance status and with advanced diseases, where it is estimated the ICER per QALY would be pound36,700. Given the relatively small number of patients with mesothelioma, albeit increasing, the overall budget impact of pemetrexed would be unlikely to be more than pound5 million per year at present costs. Much more research is needed into the optimum chemotherapy for patients with mesothelioma and a clear definition of what constitutes best supportive care.