Financial toxicity of radiotherapy for multiple brain metastases: Will it get worse or better? Free

For many decades, radiotherapy (RT) has been the primary treatment for patients with limited as well as extended brain metastases. Whole brain radiotherapy (WBRT) was practically the only method often used even in the case of a single brain metastasis (BM), depending on the availability of special RT systems such as the gamma knife. Also nowadays, the availability of modern RT methods is often a decisive factor. In recent years, however, we have witnessed almost revolutionary changes with many new studies in patients with BM defining quality of life and neurocognitive function as important outcomes.¹ For many decades we have rather witnessed a lack of interest in multiple BM patients who dogmatically had a very poor prognosis and no treatment method had even the theoretical potential to be superior to WBRT. Thus, it is not surprising that there was not much interest in these studies. The greater the ignorance, the greater the dogmatism (Sir William Osler, 1849–1919).

In the case of the current development of RT in the treatment of BM, we can observe some general characteristics of the development of local treatment methods (RT, surgery). It can be stated that it tends towards smaller and smaller interventions to show how much can we afford to slow down while achieving the expected therapeutic effect. A parallel in surgery may be axillary dissection in breast cancer, initially indicated in all patients with clinically suspected axillary lymphadenopathy, then only in patients with positive sentinel node and now even omitted in someone with sentinel node micrometastases, or at least performed as targeted axillary dissection. For RT of BM, WBRT has long been the standard (even up to a dose of 50.4 Gy as postoperative WBRT in Patchell et al. trial from 1998)² with current usual doses of 10 × 3.0 Gy. After that, the gradual transition to standard local stereotactic RT for a limited as well as extended number of BM is accompanied by special hippocampal avoiding HA-WBRT techniques.³ In the case of new drugs, we are seeing rather the opposite, with more and more drugs being added to the already established standards of care (just as in glioblastoma studies). Overall, we can conclude that for all local treatments, we are addressing the trade-off between toxicity and tumor control. Both of these variables must be considered when deciding on a treatment recommendation for a particular patient.

At present, we have a wide portfolio of RT techniques available for patients with multiple BM (defined here as 5–15 BM). In addition to conventional WBRT, these include HA-WBRT or HA-WBRT with simultaneous integrated boost, stereotactic radiosurgery (SRS) delivered by gamma knife or more or less specialized linear accelerators, fractionated stereotactic radiotherapy (eg, 3 × 9Gy or 5 × 6Gy), or various combinations with surgery. To recommend the optimal therapy in patient-oriented care, the referring physician must take into account a large number of variables, including the availability (or waiting time) of special RT systems, prognostic indicators (eg, https://brainmetgpa.com/), or including financial toxicity (generally defined as financial burden and distress for patient related to the cost of the treatment. In other words, it describes the harmful effect of high cost of treatment on a person’s quality of life).⁴

The cost-effectiveness of three different RT techniques (WBRT, HA-WBRT, and SRS) in the treatment of multiple BM (5–15 BM) is discussed in an article published in this issue of Neuro-oncology Practice. Victor Eric Chen and colleagues present the robust analysis of financial toxicities associated with radiotherapy for multiple BM.⁵ The authors constructed a Markov model (probability theory) using data from previously published studies to simulate the disease course of patients with 5 to 15 BM to determine the cost-effectiveness of HA-WBRT and SRS relative to standard WBRT. A key metric is the incremental cost-effectiveness ratio (ICER) expressing the difference in costs divided by the difference in outcomes (Cost_experimental − Cost_control)/(QALY_experimental/QALY_control). If the calculated ICER is lower than the predefined willingness-to-pay threshold (set to $100 000 per quality-adjusted life year [QALY] in this study),⁵ then the RT technique is cost-effective. SRS met the threshold for cost-effectiveness, with ICERs ranging from $41 198 to $54 852 for patients with five to fifteen BM; however, HA-WBRT did not, with an ICER of $163 915.⁵

The need for similar analyses can be expected to grow as the portfolio of clinical trials combining RT and systemic treatment of BM continues to expand. Similarly, recalculation and remodeling of the currently presented data were necessary to take into account the evolution of willingness-to-pay values and also to take into account the cheapening of individual RT techniques (eg, with the wider use of dedicated software for rapid AI-based RT contouring and planning). At present, it is almost impossible to predict whether the financial toxicity of initial RT for multiple BM will be better or worse, as the expanding portfolio of treatment modalities in the case of local BM recurrence will also have to be taken into account. There are also significant differences within countries with differently set reimbursement rates for pertinent RT procedures.

The presented work⁵ is an excellent example of a detailed cost-effectiveness analysis that should be part of all modern studies dealing with BM therapy. For comparison, a similar analysis was recently published concerning tucatinib in HER2-positive breast cancer patients with BM.⁶ In this study from January 2022, the willingness-to-pay threshold was determined to be $200 000/QALY (from this perspective, HA-WBRT with an ICER of $163 915 would emerge as cost-effective). The ICER obtained by the investigated combination of tucatinib plus trastuzumab plus capecitabine was $418 007/QALY.⁶ In conclusion, optimizing the quality of life remains a critical issue for patients with multiple BM despite the poor prognosis associated with this disease; it is of utmost importance to ensure that radiation therapy administered to these patients to alleviate the burden of their disease does not cause significant adverse effects.⁵

Funding

This work is supported by the Ministry of Health of the Czech Republic, grant NV18-03-00469

References