At present, chemotherapy is still an important method for clinical treatment of patients with metastatic breast cancer, but most of the traditional chemotherapy programs use "maximum tolerated dose (MTD)" to treat patients. Although MTD has a good killing effect on tumor cells, due to its high toxicity, many patients have adverse reactions, and some patients even terminate treatment because they can’t tolerate toxic side effects. Moreover, in traditional chemotherapy, there is a long interval between two chemotherapy cycles, which can easily cause tumor cells to regrow, disease progression, and even lead to tumor cell resistance(Kerbel 2015). In recent years, the metronomic chemotherapy model that uses low-dose, low toxicity, and continuous application of anti-tumor drugs to inhibit tumor angiogenesis and promote tumor cell apoptosis has received much attention(Di Desidero et al. 2015). Metronomic chemotherapy has better anti angiogenic effects and does not increase toxic side effects(Cazzaniga et al. 2016). Taking Vinorelbine as an example, previous basic research has shown that compared to traditional chemotherapy, Vinorelbine metronomic chemotherapy can significantly downregulate the expression of pro angiogenic genes and upregulate the expression of antiangiogenic genes(Biziota et al. 2016). In addition, the study by Mavroeidis L et al. confirmed that the blood drug concentration of Vinorelbine metronomic chemotherapy can effectively inhibit the proliferation of vascular endothelial cells(Mavroeidis et al. 2015). Vitro experiments have shown that metronomic chemotherapy combined with antiangiogenic drugs can effectively reduce tumor stem cell generation(Vives et al. 2013; Folkins et al. 2007).
The METEORA-II trial showed that compared with weekly intravenous paclitaxel chemotherapy, oral vinorelbine + cyclophosphamide + capecitabine metronomic chemotherapy significantly prolonged TTF and PFS, and had a higher disease control rate(Munzone et al. 2023). The OS of the two groups was similar. Although the toxic reactions of VEX increased, they were basically controllable. However, in the adjuvant treatment of metastatic breast cancer, patients bear a great financial burden. The economic evaluation of postoperative adjuvant therapy is crucial for maintaining a balance between clinical benefits and medical costs, especially in developing countries such as resource- limited China(Huang et al. 2018). Therefore, we have established a cost- effectiveness analysis of vinorelbine + cyclophosphamide + capecitabine (VEX regimen) and weekly intravenous paclitaxel (P regimen) for the treatment of metastatic breast cancer patients in China. This is the first time to analyze ER+/HER2 adjuvant treatment strategies for metastatic breast cancer from the perspective of efficacy and cost-effectiveness.
Different countries use different WTP thresholds for medical cost-effectiveness analysis. The cost effectiveness threshold range recommended by the United States is $50000 to $200000 per QALY(Neumann, Cohen, and Weinstein 2014). Although China has not set a cost-effectiveness threshold, the Chinese Pharmacoeconomic Evaluation Guidelines suggest that if the ICER is below the threshold of per capita GDP (approximately $34240 in 2015), the additional cost of new therapies is worthwhile; If the ICER is between three times the per capita GDP and per capita GDP, the additional cost of the new therapy is acceptable; If the ICER is greater than three times the per capita GDP, then the additional cost of this new therapy is not worth it. In China, the most widely used cost-effectiveness threshold when evaluating new therapies is three times the per capita GDP(Liao et al. 2019). In our analysis, the ICER of the VEX regimen is $40 333.69/QALY, which is higher than per capita GDP but much lower than three times per capita GDP. Therefore, according to the Chinese Pharmacoeconomic Guidelines, VEX is acceptable as a treatment for advanced breast cancer. The ICER of P regimen is $4 152.09/QALY, which is lower than the per capita GDP. Although the VEX regimen improves patient TTF and PFS, it requires significant additional costs. Even with additional sensitivity analysis indicating that the VEX regimen improves AEs management, we cannot determine whether the high cost of the VEX regimen is reasonable. Therefore, in China, the P regimen may be a more cost-effective option.
The high prices of anti-cancer drugs have led to a sharp increase in the consumption of medical resources, which has troubled clinical doctors and medical managers. The healthcare expenditures of high-income countries such as the United States and Europe have been increasing year by year, and they have explored potential methods for pricing cancer treatment drugs, hoping to maintain a sustainable impact on healthcare systems(Godman et al. 2021). Low and middle-income countries are also actively addressing the issue of rising cancer treatment costs. Especially with the diversification of cancer treatment methods, choosing new anti-tumor drugs such as Vinorelbine may not be cost-effective in low and middle-income countries(Gershon et al. 2019). Therefore, it is of great significance to evaluate treatment plans economically and make reasonable and effective use of limited medical resources. However, to our knowledge, China's medical insurance has already covered as many people as possible. Although there are significant differences in the reimbursement ratios of different regions and types of medical insurance, choosing a treatment plan with better results and lower costs is beneficial for the rational use of medical insurance.
Therefore, we believe that properly increasing the reimbursement proportion of VEX regimen in patients with metastatic breast cancer will help to save medical expenses and benefit more patients. In general, from the perspective of Chinese payers, P regimen is a cost-effective strategy for first-line systemic treatment of metastatic breast cancer.
Due to data availability and model assumptions, our economic model has some limitations. Firstly, the clinical data comes from the METEORA-II trial(Munzone et al. 2023), where the majority of patients were from Italy and the proportion of Asians was small and unavailable, which may have a slight impact on our results. Due to the lack of research results on the health effects of breast cancer in different states in China, this limitation cannot be avoided at present. Updating the clinical data of metastatic breast cancer patients in the Chinese population may improve the accuracy in the future. Secondly, in this study, we assume that the transition probability of the Markov model remains unchanged during the study period. However, in the actual processing process, the transition probability between different states varies over time. Thirdly, the incidence of adverse reactions in different disease states of breast cancer is different, and the incidence of adverse reactions generally changes with time. The clinical real data relied on by this study only provides the incidence of adverse reactions for the entire treatment group, and does not provide the incidence of adverse reactions for different disease states. Our study also did not discuss the decrease in utility value caused by adverse effects. However, sensitivity analysis indicates that changes in utility values do not alter the results in terms of quality. Fourthly, in our analysis, we did not consider indirect costs such as income loss caused by discontinuation of treatment and premature death, as the high variability of the condition makes it difficult to accurately calculate. Fifthly, drug prices and treatment costs are derived from previously published literature or local data and may not be applicable to all regions. To avoid the impact of these costs on the model, we changed the treatment costs within a considerable range (± 20%) in the one-way sensitivity analysis. Variation is mediated by these factors and is limited. Although our research has certain limitations, after sensitivity analysis, these variables do not affect the final results.