What is the real-world incremental cost-effectiveness ratio of combination chemotherapy over sequential chemotherapy in the treatment of metastatic colorectal cancer patients that are eligible for curative treatment?

Background Treatment of mCRC patients has evolved from 5-FU monotherapy as the only accepted therapy in the 1960s, till 2012 were a combination of chemotherapy regimens and targeted therapy is the standard. In this thesis only mCRC patients that are ineligible for curative treatment are included. These patients were treated with the chemotherapeutic drugs fluoropirimidine, oxaliplatin or irinotecan in 2003 and 2004. There are different common combination with these drugs which can be divided in the sequential and the combination treatment arms. Cost-effectiveness The CAIRO trial was a non-inferiority open-label, phase III randomised controlled trial done by the DCCG. Sequential versus combination chemotherapy in mCRC was tested. Median OS was longer for combination therapy and it was associated with an improvement in PFS in first line treatment compared to sequential therapy, but both differences were not significant. A higher percentage of the sequential treatment group did not receive all the different drugs than of the combination treatment group, which would favour upfront combination therapy. The oxaliplatin pilot outcome research was a retrospective daily-practice outcome research done by the iMTA at the request of the CVZ. This study investigated the appropriate use and cost-effectiveness of oxaliplatin in Dutch daily practice for the treatment of mCRC. The aim of this research was to investigate the appropriate use of oxaliplatin in daily practice. Methods The data source was patient level data, collected for the oxaliplatin outcome research of newly diagnosed stage IV colorectal patients in 2003 and 2004 in the Netherlands. The incremental cost-effectiveness ratio of combination chemotherapy over sequential chemotherapy was investigated. The transition probabilities were calculated from the patient level data that were available. The chemotherapy costs are calculated using the patient level treatment information. As patient level data of costs was not available, these were calculated as a weighted average from the total costs reported in the outcome research. Costs related to end-of-life care were calculated based on literature. The retrospective design of this study made it impossible to collect quality-of-life data. This data was abstracted from the oxaliplatin outcome research which used the data collected in the CAIRO trial. Results The median OS in the sequential treatment arm was 11.2 months and 19.1 months in the combination treatment. The ICER of combination treatment compared to sequential treatment was € 49,172 per QALY gained and € 39,373 per LY gained. The combination treatment arm was 0.53 QALY more effective than the sequential treatment arm but also € 26,022 more expensive. The impact of the model parameters on the model were evaluated using a USA and a PSA. The OSA showed that chemotherapy costs of combination treatment was the parameter that effected the ICER the most, followed by the total other costs of combination treatment. In the PSA 71% of the 10.000 iterations the ICERs of the combination treatment are stayed under the WTP of € 50.000 per QALY gained. Discussion In both the CAIRO trial and the outcome research no ICERs were calculated for stage IV patients. Comparison therefore will focus on OS and costs. In this thesis eligible and ineligible patients were combined, resulting in a median OS of 11.2 months for sequential and 19.1 months for combination treatment. The median OS for sequential therapy was the highest in the CAIRO trial (16.3 months), followed by the median OS of this thesis and the outcome research (both 11.2 months). For combination treatment the OS of this thesis was the highest (19.1 months), followed by the CAIRO trial (17.4 month) and lowest for the outcome research (15.1 month). The difference in OS for combination treatment between this thesis and the outcome research was already expected, since the OS of the patient population used as this thesis input was already higher. The total mean costs for the outcome research were € 19,812 for monotherapy, € 28,200 for oxaliplatin combination treatment, € 44,664 for irinotecan combination treatment and € 13,899 for ineligible patients. The total costs as in this thesis were € 24,336 for sequential and € 50,358 for combination treatment arm. The costs in this thesis are higher than the costs in the outcome research. The effects of this thesis were also higher than found in the outcome research. Since there was no ICER calculated in the CAIRO trial or outcome research no comparison can be made. Conclusion The aim of this thesis was to investigate the real-world ICER of combination over sequential chemotherapy in the treatment of mCRC patients that are ineligible for curative treatment. In the CAIRO trial there was concluded that it is more important that patients are exposed to all three types of chemotherapeutic drugs, than that they are treated in the combination or sequential treatment arm. In this thesis there is shown that combination treatment has an higher median OS than sequential treatment. This increase in OS comes with higher costs, but the ICER of combination over sequential treatment does not exceeds the WTP of € 50,000 per QALY gained. Since the higher OS increases the change that patients are exposed to all three chemotherapeutic drugs, upfront combination treatment is preferred.