According to current data from the Particle Therapy Co-operative Group, only 1 proton center is in operation for the 1.4 billion Chinese population in China, and at least 10 new proton centers will start to treat patients in next 3 years due to huge demands [21]. However, PBT related costs are not yet covered by public medical insurance in China due to limited medical resources. Therefore, cost-effectiveness evaluation of this advanced but costly radiotherapy modality is of urgent need for the clinical decision making regarding prescribing PBT or IMRT. To our knowledge, this is the first study on CEA modeling of PBT which was designed specifically for China.
Due to deficiency of valid data and lacking of a uniform model pattern, effective and reliable CEA studies of PBT are rare worldwide [22]. Some classical studies such as a 3-state Markov model designed for breast cancer, which focused on the advantages of IMPT in reducing the incidence of irradiation-induced coronary heart disease, concluded that IMPT was cost-effective for patients with 1 cardiac risk factors when photon are unable to achieve mean dose of heart < 5 Gy [23]. Another 6-state Markov model designed for Stage IVa oropharynx cancer, which was based on a hypothesis that IMPT could make a 25% reduction of xerostomia, dysgeusia and the need for gastrostomy tube, concluded that IMPT was cost-effective only in younger patients who could benefit from profound reductions of long-term morbidity [24]. These two Markov models focused on the late toxicities’ reduction of IMPT and could hardly be popularized to the tumor types for which IMPT could obviously improve tumor control compared with IMRT. Due to the anatomical location and a relatively low radiosensitivity of paranasal sinus and nasal cavity cancer, the advantage of IMPT compared with IMRT mainly lies in the improvement of tumor control, and no significant reduction of common toxicities was found in report of Samir H Patel et al. [7]. Therefore, late toxicities and complications were assumed to be identical between the two strategies in our model building. This 3-state Markov model could be easily applied to the tumor types with similar behavior.
For validating model robustness, probabilistic sensitivity analyses were used to evaluate the uncertainties of parameters by their value variations. The Tornado diagram showed that only the probability of IMPT eradicating cancer, the probability of IMRT eradicating cancer and the cost of IMPT had significant impact on ICER. These results did correspond to our model design in which we focused on the advantage of IMPT in improving tumor control compared with IMRT so that the difference in probabilities for eradicating tumor between the two strategies would be the source of the difference in effectiveness and cost. Furthermore, the 2-, 5- and 10-year overall survival rates of the model were calculated and found to be within the ranges of previously published survival data of paranasal sinus and nasal cavity cancer, which demonstrated that our proposed model did abide with the natural process of this disease.
The specific scenarios that may benefit from IMPT were further analyzed, and results of CEA further supported that the application of IMPT for this type of tumor was reasonable from the perspective of the daily Chinese clinical practice. For the base case, IMPT should at least achieve a 0.859 probability of eradicating cancer. This probability is readily achieved as the actual 5-year locoregional control rate of paranasal sinus and nasal cavity cancer treated by PBT is 89.5% [7]. On the other hand, IMRT could hardly obtain the expected eradication probability of 0.771 in general. Hence, the specific scenarios in favor of IMPT in clinical practice would be when IMRT is considered as inability to well eradicate the tumor. The threshold of maximum cost of IMPT ($52,163.9) demonstrated the current price ($50,000) as reasonable considering the economic situation of China. Stratified analyses of different age levels showed that IMPT was considered as cost-effective only in patients ≤ 56-years old using the current WTP threshold of China. And this age threshold would increase with the growth of WTP threshold (the growth of GDP per capita) and the cost reduction of IMPT. With an assumption of a 20% cost reduction (with a cost of IMPT $40,000), IMPT could be cost-effective in patients ≤ 63-year-old at the WTP of China, in patients ≤ 69-year-old at a WTP of $50,000 / QALY, and in patients ≤ 72-year-old at a WTP of $100,000 / QALY. Therefore, we presume that IMPT would be more recommended in the future.
There are three main limitations to this model. First, the HSUVs applied in our model were derived from previously published studies for head and neck cancer because of the lack of specific HSUVs for paranasal sinus and nasal cavity cancer. As previously reported, the overall mean HSUV of head and neck cancer survivors after radiotherapy was consistently considered as 0.7 [25, 26]. In this study, the survivors after radiotherapy had two different states, namely as “alive with cancer” and “no cancer”. Therefore, we chose 0.47 as HSUV of “alive with cancer” for describing the utility of salvage treatment relative to chemotherapy, as reported by Ward MC et al. [16]; and HSUV of “no cancer” was assumed as 0.94 for describing the situation of no cancer and no need of treatment, as reported by Noel CW et al. [18]. Second, our CEA results indicated that the benefits obtained from IMPT (the improvement of tumor control in comparison with IMRT) was a principal consideration for the clinical decision of prescribing IMPT, but the current analyses with base case setting had not involved evaluating such benefits of an individual patient. So, we plan to use model-based approaches (such as tumor control probability model) to estimate personal benefits from IMPT for supporting individualized decision making in the future [27]. Third, due to the current deficiency of valid data of late toxicities of IMPT for paranasal sinus and nasal cavity cancer, the effectiveness gain of IMPT in reducing long-term adverse events were not taken into the effectiveness calculation. We assumed that this limitation might be the cause of the negative results in trials of Monte Carlo simulations (only 13.5% of trials favored IMPT to IMRT), which were more susceptible to long-term differences [28]. With more data from clinical trials evaluating the late toxicities (such as NCT00797498 (photon/proton radiation therapy for cancers of the nasal cavity and/or paranasal sinuses)), IMPT for this tumor type could be further evaluated and IMPT might be more recommended with respect to patient’s life quality after radiotherapy.