BC is the most commonly diagnosed cancer worldwide and it is also a potential target for proton beam therapy [9, 10, 36]. This is the first CEA study stratifying both irradiated and non-irradiated (preexisting) cardiac risks to assess the cost-effectiveness of IMPT versus IMRT in BC patients. Upon assumption-based CEA modeling, our analyses demonstrated that the patient’s preexisting cardiac risk level contributed a substantial impact on the cost-effectiveness of protons and should be a main consideration for the clinical decision of using protons; further, patients in appropriate risk groups were identified to facilitate proton decision making from the perspective of cost-effectiveness and the potential future trends.
Model robustness examinations were performed with the baseline set-ups (50-year-old, no preexisting CRF, a photon MHD of 5Gy). Markov cohort analysis was applied as a calibration tool, it confirmed that the cancer-related survival rates in IMPT strategy and IMRT strategy were identical, and the model-predicted IHD death risk and total IHD risk corresponded to the natural process previously reported ; tornado diagram evaluating the model parameter uncertainty showed that only the IMPT cost had an obvious impact on the ICER value. As such, the benefits of IMPT over IMRT in reducing IHD risk and the cost difference between the two radiotherapy modalities would be the determinants of the cost-effectiveness (ICERs) in the CEA modeling, which indicated that the CEA model was robust.
A similar CEA study conducted by Mailhot Vega et al. also evaluated the IHD risk difference between protons and photons by using the data of Darby et al., but the effect of preexisting cardiac risk was only evaluated as presence/absence of a CRF in that study . In our modeling, both the photon MHD and the patient’s preexisting cardiac risk have been quantified to estimate the absolute IHD risk reduction from IMPT. Using the baseline set-ups as a contrast, our analyses showed that either an increase in photon MHD or an increase in preexisting cardiac risk would cause the IE value increased and ICER value decreased, and the impact of the preexisting cardiac risk was even greater than the impact of photon MHD (Fig. 2). In BC radiotherapy practice, the increasing use of prone positioning and breath-holding techniques makes a high photon MHD less common , so we supposed that preexisting cardiac risk level should be a main consideration in clinical decision making of using protons.
To facilitate proton decision making, we identified the cost-effective scenarios in the form of the minimum photon MHDs for BC patients at different preexisting cardiac risk levels, using different set-ups for proton cost and WTP (Fig. 3). Further, we applied the general-population cardiac risk data from the Framingham Heart Study to estimate the cost-effective scenarios from a Chinese perspective. In China, there is currently only 1 operational proton center on the mainland of China and the proton costs is not yet covered by the Chinese public medical insurance. Meanwhile, the Chinese government has authorized 16 new licenses for operating proton centers in 2021, and more than 70 proton centers are in the planning stage. Applying the current unfavorable settings (a WTP of $33,558 / QALY and a IMPT cost of $50,000), we found that for the BC patients having non-irradiated general-population cardiac risk, the cost-effective scenarios existed in 40-year-old women patients who received anthracycline-based chemotherapy or special breast irradiation (IMC/SBBC). But considering the potential future trends, such as market competition, proton technology upgrades, hypofractionated schedule, the introduction of newly China-made compact proton treatment system, the gradual coverage of medical insurance as well as the economic growth [38, 39], substantial reduction in proton cost or gradual increase in WTP may occur in the near future. Of particular note, it has been observed in our study that the cost-effective scenarios would be extended to the general-level BC patients (40- and 50-year-old women BC patients having non-irradiated general-population cardiac risk) if the current IMPT cost reduced to $20,000. Such indicated the huge market potential of protons in BC patients in China.
There were several limitations in this study worth mentioning. First, the benefits of protons in reducing the irradiation-related pneumonia and secondary cancer were not evaluated in this study, considering the relatively low absolute incidences and the opportunistic occurrences of the two events . Second, due to the current data limitation, our analyses only involved 40-, 50- and 60-year-old women patients. Theoretically, younger (< 40-year-old) BC patients could benefit more from protons compared to those ≥ 40-year-old, because they usually have higher cumulative lifetime IHD risk and more Markov cycles in the CEA modeling; and protons should be more cost-effective to men BC patients than women BC patients because of their higher preexisting IHD risk level . Third, the IEs in 40-year-old patients were not greater than that in the 50-year-old patients in our CEA modeling, especially in those at low levels of preexisting cardiac risk (Fig. 2). This phenomenon had also been observed in the study of Mailhot Vega et al. , it should be attributed to the survey of Darby et al. which excluded the patients with only an angina in counting the total IHD risk . Lastly, as our study suggests, BC patient’s preexisting cardiac risk should be individually assessed prior to proton decision making, but the current cardiac risk prediction algorithms, such as the Framingham Heart Study who applied traditional risk factors (sex, blood pressure, lipoprotein cholesterol, smoking, and diabetes) , could hardly accurately estimate the cardiac risk for BC patients who had received cardiotoxic anticancer agents. In this study, based on the survey of Boekel et al. , we assumed that the BC patients who received anthracycline-based chemotherapy experienced 1.5-fold preexisting IHD risk compared with those who did not receive, but the potential impacts of the other cardiotoxic agents (such as paclitaxel, trastuzumab or taxanes) have not been evaluated in Boekel’s study nor in our study. Besides, it has been reported that the IHD death risk in non-irradiated BC population might be lower than that in general population , the risk inconsistency between BC population and general population may affect our estimation for general-level cost-effective scenarios. Therefore, we call for the establishment of a cardiac risk prediction algorithm dedicated to BC patients in future studies .