Clues to improve the cost-effectiveness of radiotherapy for brain metastases from non-small cell lung cancer: cost reduction, patient selection, and better understanding of neurocognitive deterioration

In September 2018, Girard et al. published the article ‘Extra cost of brain metastases (BM) in patients with non-squamous non-small cell lung cancer (NSCLC): A French national hospital database analysis’ (1). They extracted the data of 2,500 metastatic NSCLC patients from the national medical information database and divided the patients into two groups: those with metastases other than brain (n=1,529), and those with BMs (n=971). The study’s analyses revealed that the presence of BM at diagnosis contributed to the excessive medical cost of €553 per patient-month, and Girard et al. stated that radiotherapy (RT) and palliative care are the principal components of the increased cost.

Their study is of great clinical importance because it provided detailed information on the healthcare costs due to the management of BM from NSCLC. However, we feel that the economic burden of the treatment for BM is emphasized too much, and we are concerned that NSCLC patients with BM might miss the opportunity to receive appropriate treatment. In this editorial, we discuss the cost-effectiveness of cranial RT for BM and we consider several perspectives on the selection of individualized treatment strategies.

The goals of treatment for BM include the relief of neurologic symptoms, the prevention of tumor regrowth, and the maintenance of functional independence. Cranial RT plays an integral role in this context. In the Radiation Therapy Oncology Group (RTOG) 9508 trial by Andrews et al., patients with 1–3 BMs were randomly assigned to either whole-brain RT (WBRT) alone or WBRT followed by a stereotactic radiosurgery (SRS) boost (2). For patients with a single BM, WBRT + SRS significantly improved overall survival (OS) compared to WBRT alone [median survival time (MST) 6.5 vs. 4.9 months, P=0.039]. Patients in the WBRT + SRS group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months’ follow-up compared to the patients assigned to WBRT alone (43% vs. 27%, P=0.03).

Aoyama et al. evaluated the significance of adding WBRT to SRS in the Japanese Radiation Oncology Study Group (JROSG) 99-1 trial, in which patients with 1–4 BMs were randomly assigned to either SRS alone or SRS + WBRT (3). The 12-month brain tumor recurrence rate was significantly lower in the SRS + WBRT group compared to the SRS-alone group (46.8% vs. 76.4%, P<0.001), whereas the OS was not significantly improved with WBRT (MST, 7.5 vs. 8.0 months, P=0.42).

In addition, improved intracranial tumor control is associated with stabilized neurocognitive function (NCF). The average duration until the deterioration of patient’s Mini-Mental State Examination (MMSE) score was longer in the SRS+WBRT group compared to the SRS-alone group (16.5 vs. 7.6 months, P=0.05) (4). However, towards the 24th month post-RT, the SRS + WBRT patients exhibited clinically meaningful declines in their MMSE scores, which could be a manifestation of RT-induced late neurotoxicity.

The impact of WBRT had long been undetermined in BM patients who are not candidates for SRS, until the results of the QUARTZ trial were published (5). The QUARTZ investigators recruited NSCLC patients with BMs that were unsuitable for surgical resection or SRS and randomly assigned them to either WBRT plus supportive care (SC) including dexamethasone, or SC alone. There was no improvement in OS (MST, 9.2 vs. 8.5 weeks, P=0.80) between the two arms. However, it should be highlighted that the subgroup analyses of the QUARTZ study posed a clinically relevant hypothesis; i.e., that the efficacy of WBRT differs based on various clinical factors (6). WBRT significantly improved the OS in younger patients in that study [those <60 years old; hazard ratio (HR) 1.48; 95% confidence interval (CI), 1.01–2.16], and in those with ≥5 BMs (HR 1.37; 95% CI, 1.01–1.86), and in those with high Graded Prognostic Assessment (GPA) scores (2.5–3.0; HR 1.65; 95% CI, 1.04–2.60). The GPA score is calculated based on the patient’s age, KPS, the presence/absence of extracranial metastasis (ECM), and the number of BMs (7). These findings suggest that in patients with controlled systemic cancer, a good general condition and a large intracranial tumor volume, successful treatment for BM leads directly to improved survival.

In 1997, Mehta et al. published the first cost-effectiveness study of various treatment modalities for the management of BM, and their results demonstrated that the cost-effectiveness of SRS was superior to that of surgical resection (8). There are several strategies to further improve the cost-effectiveness of cranial RT, i.e., a reduction of healthcare costs, the identification of the subgroup of patients who will benefit from RT, and the early detection of adverse events.

Gamma knife radiosurgery requires invasive skull fixation with local anesthesia, and the use of less-invasive methods would help decrease the healthcare costs. For this reason, hypofractionated stereotactic radiotherapy (SRT) provided by a linear accelerator using noninvasive thermoplastic shell fixation has become one of the treatment options (9). It is also important to shorten the overall treatment time. When treating multiple BMs with conventional SRT, the isocenters are placed inside each tumor, and it takes time to move the isocenter from one tumor to another. With the use of single-isocentric rotational volumetric modulated arc therapy (VMAT), multiple BMs can be treated at one time, and the treatment time is shortened compared to traditional multi-isocentric RT plans (10).

To improve the efficacy of RT, the selective use of cranial RT is essential (11). Several factors determine the necessity of RT, including the patient’s general condition, ECMs, and epidermal growth factor receptor (EGFR) gene mutations.

In 2012, Sperduto et al. proposed a novel prognostic index, the diagnosis-specific GPA (DS-GPA) (12). It is calculated using different clinical factors such as patient age, KPS, number of BMs, presence of ECM, and molecular subtype, by the primary site. A DS-GPA score of 4.0 correlates with the best prognosis, and a DS-GPA score of 0.0 corresponds to the worst prognosis. For selected BM patients with a good general condition and a limited number of ECMs, the combination of SRS and WBRT has the potential to improve intracranial tumor control and OS.

In the secondary analysis of the RTOG 9508 trial comparing WBRT + SRS with WBRT alone in patients with 1–3 BMs, patients were post-stratified by their DS-GPA scores and NSCLC was the dominant primary tumor (13). The patients with high DS-GPA scores (3.5–4.0) showed improved survival when treated with WBRT + SRS compared to those treated with WBRT alone (P=0.05). In the secondary analysis of the JROSG 99-1 trial, Aoyama et al. post-stratified NSCLC patients according to their DS-GPA scores and reported that the patients with DS-GPA scores of 2.5–4.0 had longer survival when treated with SRS + WBRT compared to those treated with SRS alone (P=0.04) (14). The survival benefit of adding WBRT was not observed in the patients with low DS-GPA scores (0.5–2.0, P=0.86). The positive impact of WBRT on OS could be explained by improved intracranial tumor control. The addition of WBRT significantly ameliorated the BM-recurrence-free rate in the DS-GPA 2.5–4.0 group (P<0.001).

In patients with metastatic NSCLC harboring activating EGFR mutation, BMs as well as systemic metastases are often treated with first-line EGFR-tyrosine kinase inhibitors (TKIs). Magnuson et al. conducted a multi-institutional retrospective analysis and reported that in a multivariate analysis, both first-line SRS (HR 0.39; 95% CI, 0.26–0.58, P<0.001) and first-line WBRT (HR 0.70; 95% CI, 0.50–0.98, P=0.039) significantly improved OS compared to first-line TKI with RT being considered at intracranial progression (15). RT is thus indispensable in the management of EGFR-mutant NSCLC, a distinct biological entity which seems radiosensitive in nature (16).

One of the most clinically relevant late adverse events of WBRT is the deterioration in NCF (4). Among the neurocognitive test batteries used in clinical settings, the MMSE is the most widely used due in part to its convenience. However, the MMSE has several weak points, i.e., a ceiling effect (17) and inadequate sensitivity. In the secondary analysis of the RTOG 0214 trial evaluating prophylactic WBRT for advanced NSCLC, there were greater 12-month declines in the immediate recall (P=0.03) and delayed recall (P=0.008) domains of the Hopkins Verbal Learning Test (HVLT) in the prophylactic WBRT arm compared to the control arm (18). However, there were no significant differences in MMSE scores (P=0.60) between the two arms. The HVLT is superior to the MMSE in detecting subtle changes in NCF. The Response Assessment in Neuro-Oncology (RANO) Working Group has proposed that the revised version of HVLT (HVLT-R) be used in combination with other test batteries to evaluate executive function and processing speed in clinical trials dealing with BMs (19).

Neurocognitive deterioration after WBRT is thought to be caused not only by the toxic effect of irradiation but also by worsening of the patient’s general condition. According to the results of a recent randomized trial, the omission of WBRT appears to lead to the preservation of NCF. Brown et al. reported that there was significantly less cognitive deterioration at 3 months after SRS alone than after SRS + WBRT (63.5% vs. 91.7%, P<0.001) (20). These results should be interpreted with caution. It is of note that the Brown et al. study recruited 213 patients (SRS alone, n=111, SRS + WBRT, n=102), but only 57% (63/111) of the patients in the SRS-alone group and 47% (48/102) of the patients in the SRS + WBRT group underwent HVLT-R at 3 months. The NCF was measured at 3 months post-WBRT, a time point at which RT-induced late neurotoxicity is scarcely observed. The selection of the study endpoint might thus be inappropriate.

The deterioration in NCF at a few months post-WBRT is frequently observed in BM patients with worsened general condition. Saito et al. analyzed the HVLT-R scores after WBRT and reported that a significant deterioration in the HVLT-R scores at 4 months post-WBRT was observed in the patients who dropped out thereafter (21). The most frequent cause of dropping out was a worsened general condition due to systemic cancer. In contrast, the patients who continued their regular visits until the 8-month examination did not exhibit significant NCF deterioration at 4 months post-WBRT. Therefore, NCF deterioration at a few months post-WBRT might be due to worsening of the patient’s general condition and should be distinguished from true RT-induced late neurotoxicity.

In conclusion, RT plays an integral role in the management of BMs from NSCLC. Further efforts should be made to (I) reduce the costs of the use of RT, (II) appropriately select good candidates for RT, and (III) minimize treatment-related toxicities of RT.

Acknowledgements

Funding: This work was partially supported by the Japan Society for Promotion Science (JSPS) KAKENHI (Grant No. 15H04903).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Girard N, Cozzone D, de Leotoing L, et al. Extra cost of brain metastases (BM) in patients with non-squamous non-small cell lung cancer (NSCLC): a French national hospital database analysis. ESMO Open 2018;3:e000414. [Crossref] [PubMed]
2. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72. [Crossref] [PubMed]
3. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483-91. [Crossref] [PubMed]
4. Aoyama H, Tago M, Kato N, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388-95. [Crossref] [PubMed]
5. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388:2004-14. [Crossref] [PubMed]
6. Saito H, Nakano T, Shioi M, et al. Toward the clarification of the role of whole-brain radiation therapy for brain metastases from non-small cell lung cancer: a comment about the QUARTZ trial. Transl Cancer Res 2016.S1465-8. [Crossref]
7. Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510-4. [Crossref] [PubMed]
8. Mehta M, Noyes W, Craig B, et al. A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases. Int J Radiat Oncol Biol Phys 1997;39:445-54. [Crossref] [PubMed]
9. Aoyama H, Shirato H, Onimaru R, et al. Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull. Int J Radiat Oncol Biol Phys 2003;56:793-800. [Crossref] [PubMed]
10. Clark GM, Popple RA, Young PE, et al. Feasibility of single-isocenter volumetric modulated arc radiosurgery for treatment of multiple brain metastases. Int J Radiat Oncol Biol Phys 2010;76:296-302. [Crossref] [PubMed]
11. Mehta MP, Aoyama H, Gondi V. The Changing Role of Whole-Brain Radiotherapy: Demise or Time for Selective Usage? JAMA Oncol 2017;3:1021-2. [Crossref] [PubMed]
12. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30:419-25. [Crossref] [PubMed]
13. Sperduto PW, Shanley R, Luo X, et al. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J Radiat Oncol Biol Phys 2014;90:526-31. [Crossref] [PubMed]
14. Aoyama H, Tago M, Shirato H. Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial. JAMA Oncol 2015;1:457-64. [Crossref] [PubMed]
15. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naive Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol 2017;35:1070-7. [Crossref] [PubMed]
16. Yagishita S, Horinouchi H, Katsui Taniyama T, et al. Epidermal growth factor receptor mutation is associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2015;91:140-8. [Crossref] [PubMed]
17. Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology 2009;73:1738-45. [Crossref] [PubMed]
18. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279-86. [Crossref] [PubMed]
19. Lin NU, Wefel JS, Lee EQ, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol 2013;14:e407-16. [Crossref] [PubMed]
20. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016;316:401-9. [Crossref] [PubMed]
21. Saito H, Tanaka K, Kanemoto A, et al. Factors Affecting the Baseline and Post-Treatment Scores on the Hopkins Verbal Learning Test-Revised Japanese Version before and after Whole-Brain Radiation Therapy. Int J Mol Sci 2016.17. [PubMed]