Cost-effectiveness analysis of upfront HA-WBRT vs. SRS for treatment of brain metastases due to SCLC

Cost-effectiveness analysis of upfront HA-WBRT vs. SRS for treatment of brain metastases due to SCLC | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cost-effectiveness analysis of upfront HA-WBRT vs. SRS for treatment of brain metastases due to SCLC Keshav Goel, Yushen Qian, Erqi Pollom This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7567773/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Introduction Hippocampal-avoidant whole brain radiation therapy (HA-WBRT) and stereotactic radio surgery (SRS) are standard of care treatments for brain metastases (BM). However, the optimal approach for treating BM originating from small cell lung cancer (SCLC) remains uncertain. We conducted a cost-effectiveness analysis comparing HA-WBRT and SRS for SCLC BMs. Methods We constructed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of SRS versus HA-WBRT. In this model, patients either receive upfront SRS or HA-WBRT. Those receiving SRS may undergo salvage HA-WBRT if they experience salvageable distant recurrences, or progress to non-salvageable local and distant recurrences. We performed over 100,000 Monte Carlo simulations, varying cost and utility parameters using Beta distributions, to analyze the impact of these variations on the ICER. Results The base case ICER for SRS was $2126.88. SRS was more costly and more/less effective in 56.1%/43.9% of Monte Carlo simulations. MRI cost had the greatest positive impact on ICER, and cost of hospice had greatest negative impact. The utility decline of the four-month of neurocognitive decline post-HA-WBRT had the strongest negative impact. The transition probabilities of the controlled state, death, distant recurrence (salvageable), and local recurrence (non-salvageable) had statistically significant impacts on ICER (p<0.001). Discussion SRS was more expensive than HA-WBRT in all simulations and more effective in most. The cost of the MRI and hospice care and the transition probabilities of the controlled state and death had the greatest influence on ICER. As survival increased, ICER decreased, emphasizing the importance of patient selection for SRS. Figures Figure 1 Figure 2 Figure 3 Introduction Small cell lung cancer (SCLC) represents 10–15% of all lung cancer cases in the United States, accounting for approximately 35,000 new cases annually 1 . The average cost of treating SCLC is over $ 45,000 per patient for first and second-line therapy, which is greater than that of non-small cell lung cancer. 2 Cost-effective analysis (CEA) determines the optimal use of resources to maximize health benefits while minimizing cost. 3 Therefore, we can apply CEA to guide cost-effective SCLC treatment. Currently standard of care in the treatment of brain metastases include hippocampal-avoidant whole brain radiation therapy (HA-WBRT), which spares the hippocampus to reduce risk of cognitive deterioration, 4 and stereotactic radio surgery (SRS), which uses a single large dose of radiation delivered via multiple non-coplanar radiation beams to a precisely defined target lesion in the brain, 5 are the standards of care. 4 , 6 – 10 Previous CEA studies have compared SRS to WBRT and have found SRS to be cost-effective, citing incremental cost effectiveness ratios (ICERs) ranging from $ 39,117 - $ 58,903. 7 , 11 – 13 Trials are currently ongoing to evaluate HA-WBRT and SRS as the possible standard of care in the treatment of brain metastases due to SCLC. 14 However, no studies exist currently describing the CEA of HA-WBRT and SRS specifically for SCLC. In this study, we execute a cost-effectiveness analysis of HA-WBRT vs. SRS for brain metastases secondary to SCLC using Markov models with Monte Carlo simulations based on the design of the NRG CC-009 trial. 14 We hope the analysis may help guide future treatment decisions that are both clinically and cost-effective. Methodology Markov Model Patients exist in two treatment arms: upfront SRS and upfront HA-WBRT. Patients in both arms enter the model in the controlled state, or successful treatment of metastases. Patients can remain in controlled , have a local recurrence (which is non-salvageable ) or distant recurrence ( which is only non-salvageable for the HA-WBRT arm or can be non-salvageable or salvageable for the SRS arm), or die from brain metastases, cancer elsewhere in the body, or other causes ( death ). All patients who receive SRS receive HA-WBRT for salvage treatment. Patients cannot die from brain metastases without first having a local or distant recurrence. Patients in the distant brain recurrence (salvageable) states can recover or die. Patients not in the controlled state who received HA-WBRT receive hospice care until they experience death . Patients with a local or distant recurrence may encounter a stopping rule, which results in automatic transition to death if they have already received HA-WBRT. Finally, patients who received upfront SRS receive salvage with HA-WBRT, and no patient can receive repeat HA-WBRT (Fig. 1 ). Model Parameters Transition probability, cost, and utility parameters were calibrated according to previous studies as well as clinical judgement, with Beta distributions applied for the Monte Carlo simulations. Regarding transition parameters, the probability of distant and local recurrences was indexed at 4.68%, and the probability of death was 2% (Table 1 ). The model was calibrated so that there would be no significant survival advantage conferred to SRS or HA-WBRT. 8 , 15 , 16 Table 1 Model Parameters: Transition Parameters. Parameter Base Case 95% CI Distribution Probabilities for 1 mo. transitions Recurrence (distant)* 0.0468 (0.0421–0.0515) 17 β Recurrence (local) 0.0468 (0.0421–0.0515) 18 Calibration parameters (probabilities) Death 0.2 19 β *for salvageable and non-salvageable 17 – 19 Cost parameters were gathered from the 2022 Medicare fee schedule and previous studies, and they were standardized to 2022 US dollars per the Medical Care Consumer Price Index (Table 2). No discounting was needed since most patients in the simulation died within one year. Utility parameters were gathered from previously published studies. 19,25–27 Table 2 Model Parameters: Cost. Parameter HCPCS Code Cost ( $ ) Distribution Occurrence Source Follow-up MRI 70545 246.40 (221.76–271.04) 20 β Every 3 months 20 Hospice - 6109.06 (5498.15–6719.97) 19 Once 19 SRS - 17490.45 (13118.17-21864.04) 21 Once 21 HA-WBRT - 12655.02 (11389.52–13920.52) 19 Once 19 Chemotherapy - 397.9 (358.11–437.69) 22 Monthly 22 Atezolizumab - 10225.13 (9202.62–11247.64) 22 Monthly High complexity level 3 follow up care 99233 102.43 (92.19–112.67) 20 Every 3 months 20 Best supportive care - 3624.15 (3261.74–3986.57) 23 Once 23 Memantine - 4.90/unit (4.41–5.39) 24 (unit = 7mg) Variable per protocol* 24 *assuming the daily dose extended release memantine protocol: week 1–7mg, week 2–14 mg, week 3–21 mg, weeks 4–24–28 mg. 20 – 24 Table 3 Model Parameters: Utility. Parameter Base Case 95% CI Distribution BM controlled 0.83 (0.76–0.9) 25 β Side effects of HA-WBRT: active for 3 mo post-treatment -0.1025 (-0.11275, -0.09225) 26 NCF decline for HA-WBRT: 4mo post-treatment -0.07 27 (-0.095, -0.045) 27 Decline because of progression -0.031 25 Recurrence 0.73 0.66–0.8 25 Month of death 0.2 (0.18, 0.22) 19 Not Applicable CHEERS Guidelines As the entire patient population was simulated, no demographic information exists such as age, socioeconomic status, or clinical characteristics beyond the inputs for the model. Similarly, there was no setting or location for the study, nor were there any patient engagement initiatives. For time window, the model assumed monthly cycles of treatment across patients’ lifetimes. Statistical Analysis The Markov models were coded in the statistical software R (Version X) using the “markovchain” package. All statistics were calculated in R (Version X). Results Base Case In the base model, the mean incremental cost effectiveness ratio (ICER) of the SRS treatment arm compared to the HA-WBRT treatment arm was $ 2126.88 (median $ 2720.35). This is not the result of survival differences across the two treatment arms, as patients in both arms experienced identical survival of around 5 months as well as time spent with brain metastases (Table S1). Sensitivity Analyses In the Monte Carlo simulations where the cost and utility parameters were varied, the mean SRS and HA-WBRT Treatment Costs were $ 83,492 and $ 77,241, respectively, and the mean SRS and HA-WBRT Treatment QALYs were 3.10 and 1.98, respectively. When comparing SRS vs. HA-WBRT, SRS was more costly and more effective in 56.1% of the Monte Carlo simulations, and more costly but less effective in 43.9% of simulations. SRS was never less costly (Fig. 2 ). The tornado diagram ordinally ranks which parameters, when varied with a random distribution, have the greatest impact on the ICER. The cost of the MRI had the greatest positive impact on the ICER – as it increased, the ICER of SRS vs. HA-WBRT increased. On the other hand, the cost of hospice care had the greatest negative impact – as it increased, the ICER decreased. On the other end of the spectrum, the utility assigned to the death state had the smallest positive impact on ICER, and the cost of chemotherapy had the smallest negative impact on ICER (Fig. 3 A). When the transition probabilities of entering/exiting each state in the model were varied, the probability of staying in the controlled, or healthy state, had the strongest negative impact on ICER – as the probability of staying healthy increased, ICER decreased. The probability of death had the strongest positive impact on ICER – as the probability of dying increased, ICER increased (Fig. 3 B). The cost-effectiveness ratio of SRS and HA-WBRT was $ 38,202 and $ 49,805, respectively. Most transition probabilities that governed the model – the probabilities of the controlled state, death, distant recurrence (salvageable), distant recurrence (non-salvageable), and local recurrence (non-salvageable) – were statistically significant at the 99.9% confidence interval (Table 4 ). However, the probability of distant recurrence (non-salvageable) was not statistically significant. The odds ratios of the probabilities of controlled and distant recurrence (non-salvageable) were less than one, indicating that as they increased, ICER decreased. The odds ratios of the probabilities of death and local recurrence (non-salvageable) were greater than 1, indicating that as they increased, ICER increased (Table 4 ). Table 4 Odds Ratios of the Transition Probability Parameters on ICER Transition Probabilities OR CI P-value Controlled (Healthy) 0.68 0.65–0.72 2.58x10 − 47*** Death 1.58 1.50–1.67 5.81x10 − 67*** Distant Recurrence (Salvageable) 0.72 0.68–0.76 3.15x10 − 36*** Local Recurrence (Non-salvageable) 1.58 1.50–1.67 5.81x10 − 67*** Distance Recurrence (Non-Salvageable) 0.99 0.94–1.04 2.90x10 − 01 ***p < 0.001, significant at the 99.9% confidence interval For survival sensitivity analyses, simulations were run with forced survivals for both treatment arms of three, six, nine, twelve, and twenty-four months with calculated ICERs. ICERs remained positive -- indicating that SRS remained more expensive than HA-WBRT for increasing QALYs. However, as survival increased, ICERs decreased (Table S2). Discussion To date, several clinical trials have provided key data establishing SRS as non-inferior to WBRT. 28 Most notably, the FIRE-SCLC study, the largest multicenter retrospective study evaluating SRS for SCLC brain metastases, demonstrated that SRS alone achieves similar clinical outcomes—median OS, time to CNS progression, leptomeningeal progression, and salvage therapy rates—to WBRT, with fewer long-term neurocognitive side effects. 28 This was integrated into our model by programming equal survival for the SRS and HA-WBRT treatment arms and less neurocognitive decline for the SRS arm. However, equivalent data for HA-WBRT vs. SRS does not yet exist but will be provided by the ongoing NRG-CC009 trial, the results of which can inform the next iteration of this model. Limitations The main limitations of the study are assumptions underlying the model. First, those who received first line HA-WBRT therapy cannot receive HA-WBRT or SRS salvage therapy – therefore, all brain metastases they experienced were non-salvageable. On the other hand, all patients who received SRS therapy first-line received HA-WBRT for salvage therapy upon experiencing recurrences. This resulted in the SRS treatment arm being more expensive than the HA-WBRT arm in all simulations, and, thus, the results of this study contradicted other Markov model evaluations of the cost-effectiveness of SRS vs. HA-WBRT that found SRS to be more cost-effective with lower ICERs. 29 Second, all local recurrences were non-salvageable. Third, the probability of experiencing local and distant recurrences (salvageable and non-salvageable) were identical. Fourth, and finally, the model did not differentiate causes of death and thus applied one probability of experiencing death from all causes – death from brain metastases, death from cancer elsewhere in the body, and death from other causes. These assumptions greatly simplified the model, but were deemed reasonable as the alternative treatment options that are executed in practice – salvaging local or distant recurrences after HA-WBRT, or salvaging local recurrences after SRS with surgery, repeat SRS, or LITT – have demonstrated poor survival. 30 – 32 Takeaways There are several key takeaways of this study. First, the SRS treatment arm was more expensive than the HA-WBRT treatment arm in all simulations and more effective in most simulations. This is corroborated by existing studies that have found an increased effectiveness of SRS. 29 , 33 Second, the estimated cost-effectiveness ratios of SRS and HA-WBRT was $ 38,202 and $ 49,805, respectively, similar to the cost-effectiveness ratios of SRS calculated from other studies, which ranged from $ 39,117 to $ 58,903. 7 , 11 , 13 , 34 , 35 Third, among the cost and utility parameters, the costs of the MRI and hospice care had the greatest influence on the ICER, and, among the transition probabilities, the probabilities of staying in the controlled state and death had the greatest influence. Fourth, as survival increases, the ICER of SRS vs. HA-WBRT decreases. This, when combined with the third takeaway, suggests that the cost-effectiveness of SRS depends on the projected survival of the patients, which is supported by other studies which have demonstrated greater cost-effectiveness advantage of SRS vs HA-WBRT for worse survival outcomes. 29 The survival of patients in our model, and thus the cost-effectiveness of SRS, is influenced greatly by the probability of local and distant recurrences and the probability of death from recurrences; this suggests that SRS may not be as cost-effective for patients with more aggressive cancer subtypes or with multiple metastases causing a greater probability of death upon progression. Fifth, and finally, patients who received first line HA-WBRT received no salvage treatment in our model; thus, in clinical situations where patients who receive first-line HA-WBRT and recur do receive alternative salvage treatment, SRS may be more cost-effective than reported in this study. Still, more research is recommended to ascertain the cost-effectiveness of different methodologies of radiation for the treatment of brain metastases. Declarations Funding Statement: None Conflict of Disclosure: None Author Contribution K.G. and E.P. contributed to the study conceptualization and design. K.G. did the data analysis and prepared figures 1-3 and tables 1-S2. K.G. wrote the abstract and manuscript. E.P. and Y.Q. supervised the data analysis and figures/tables preparation, and edited the manuscript. References American Cancer Society. Key Statistics for Lung Cancer .; 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html Cockrum P, MacEwan JP, Ramirez RA. Treatment patterns and outcomes associated with small cell lung cancer by platinum sensitivity status in a U.S. Medicare population. J Clin Oncol . 2022;40(16_suppl):e20617-e20617. doi:10.1200/JCO.2022.40.16_suppl.e20617 Clement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using Effectiveness and Cost-effectiveness to Make Drug Coverage Decisions: A Comparison of Britain, Australia, and Canada. JAMA . 2009;302(13):1437. doi:10.1001/jama.2009.1409 Brown PD, Gondi V, Pugh S, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol . 2020;38(10):1019-1029. doi:10.1200/JCO.19.02767 Chin LS, Regine WF, eds. Principles and Practice of Stereotactic Radiosurgery . Springer New York; 2008. doi:10.1007/978-0-387-71070-9 Schiff D, Messersmith H, Brastianos PK, et al. Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline. J Clin Oncol . 2022;40(20):2271-2276. doi:10.1200/JCO.22.00333 Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol . 2009;10(11):1037-1044. doi:10.1016/S1470-2045(09)70263-3 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(4):401. doi:10.1001/jama.2016.9839 Jing Li. Stereotactic Radiosurgery Versus Whole-brain Radiation Therapy For Patients With 4-15 Brain Metastases: A Phase III Randomized Controlled Trial. Presented at: ASTRO; 2020; Online. https://www.astro.org/ASTRO/media/ASTRO/News%20and%20Publications/Press%20Kits/PDFs/2020/AM20_PressSlidesLi41.pdf Yamamoto M, Serizawa T, Higuchi Y, et al. A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores. Int J Radiat Oncol . 2017;99(1):31-40. doi:10.1016/j.ijrobp.2017.04.037 Lal LS, Byfield SD, Chang EL, et al. Cost-effectiveness Analysis of a Randomized Study Comparing Radiosurgery With Radiosurgery and Whole Brain Radiation Therapy in Patients With 1 to 3 Brain Metastases. Am J Clin Oncol . 2012;35(1):45-50. doi:10.1097/COC.0b013e3182005a8f Joe Y. Chang, Suresh Senan, Marinus Paul, Reza Mehran, Alexander Louie, Peter Balter. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70168-3/abstract Lester-Coll NH, Dosoretz AP, Magnuson WJ, Laurans MS, Chiang VL, Yu JB. Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases. J Neurosurg . 2016;125(Supplement_1):18-25. doi:10.3171/2016.7.GKS161499 Vinai Gondi. Testing If High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus Is Better at Preventing Loss of Memory and Thinking Ability . Northwestern Feinberg School of Medicine; 2025. https://clinicaltrials.gov/study/NCT04804644 Khan M, Lin J, Liao G, et al. Whole Brain Radiation Therapy Plus Stereotactic Radiosurgery in the Treatment of Brain Metastases Leading to Improved Survival in Patients With Favorable Prognostic Factors. Front Oncol . 2019;9:205. doi:10.3389/fonc.2019.00205 Palmer JD, Klamer BG, Ballman KV, et al. Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial. JAMA Oncol . 2022;8(12):1809. doi:10.1001/jamaoncol.2022.5049 Yomo S, Hayashi M. Is stereotactic radiosurgery a rational treatment option for brain metastases from small cell lung cancer? A retrospective analysis of 70 consecutive patients. BMC Cancer . 2015;15(1):95. doi:10.1186/s12885-015-1103-6 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. The Lancet . 2004;363(9422):1665-1672. doi:10.1016/S0140-6736(04)16250-8 Savitz ST, Chen RC, Sher DJ. Cost‐effectiveness analysis of neurocognitive‐sparing treatments for brain metastases. Cancer . 2015;121(23):4231-4239. doi:10.1002/cncr.29642 CMS.gov. Physician Fee Schedule Menu. Published online October 17, 2024. https://www.cms.gov/medicare/physician-fee-schedule/search?Y=0&T=0&HT=0&CT=3&H1=99233&M=5 Hall MD, McGee JL, McGee MC, et al. Cost-effectiveness of stereotactic radiosurgery with and without whole-brain radiotherapy for the treatment of newly diagnosed brain metastases: Clinical article. J Neurosurg . 2014;121(Suppl_2):84-90. doi:10.3171/2014.7.GKS14972 Zhou K, Zhou J, Huang J, et al. Cost-effectiveness analysis of atezolizumab plus chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer. Lung Cancer . 2019;130:1-4. doi:10.1016/j.lungcan.2019.01.019 Chastek B, Harley C, Kallich J, Newcomer L, Paoli CJ, Teitelbaum AH. Health Care Costs for Patients With Cancer at the End of Life. J Oncol Pract . 2012;8(6S):75s-80s. doi:10.1200/JOP.2011.000469 Drugs.com. Memantine Prices, Coupons, Copay Cards & Patient Assistance. https://www.drugs.com/price-guide/memantine Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess . 2007;11(45). doi:10.3310/hta11450 J Wilson, GL Yao, J Raftery, et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. Published online 2007. https://www.ncbi.nlm.nih.gov/books/NBK62325/ Oremus M, Tarride JE, Clayton N, Raina P. Health Utility Scores in Alzheimer’s Disease: Differences Based on Calculation With American and Canadian Preference Weights. Value Health . 2014;17(1):77-83. doi:10.1016/j.jval.2013.10.009 Rusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study. JAMA Oncol . 2020;6(7):1028. doi:10.1001/jamaoncol.2020.1271 Chen VE, Kim M, Nelson N, Kim IK, Shi W. Cost-effectiveness analysis of 3 radiation treatment strategies for patients with multiple brain metastases. Neuro-Oncol Pract . 2023;10(4):344-351. doi:10.1093/nop/npac093 Mitsuya K, Nakasu Y, Hayashi N, et al. Retrospective analysis of salvage surgery for local progression of brain metastasis previously treated with stereotactic irradiation: diagnostic contribution, functional outcome, and prognostic factors. BMC Cancer . 2020;20(1):331. doi:10.1186/s12885-020-06800-w Rana N, Pendyala P, Cleary RK, et al. Long-term Outcomes after Salvage Stereotactic Radiosurgery (SRS) following In-Field Failure of Initial SRS for Brain Metastases. Front Oncol . 2017;7:279. doi:10.3389/fonc.2017.00279 McKay WH, McTyre ER, Okoukoni C, et al. Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. J Neurosurg . 2017;127(1):148-156. doi:10.3171/2016.5.JNS153051 Desai J, Rajkumar S, Shepard MJ, Wegner RE. National Trends in Radiation Treatment for Small Cell Lung Cancer Brain Metastases in the Modern Era. Adv Radiat Oncol . 2025;10(3):101720. doi:10.1016/j.adro.2025.101720 Kimmell KT, LaSota E, Weil RJ, Marko NF. Comparative Effectiveness Analysis of Treatment Options for Single Brain Metastasis. World Neurosurg . 2015;84(5):1316-1332. doi:10.1016/j.wneu.2015.06.021 Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol . 2015;16(6):630-637. doi:10.1016/S1470-2045(15)70168-3 Additional Declarations No competing interests reported. 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08:48:28","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":26774,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/5db94487f6ace04bf6db9490.png"},{"id":91827578,"identity":"c44f81d3-ca89-496b-acbb-3ce014ab93e5","added_by":"auto","created_at":"2025-09-22 08:48:28","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97474,"visible":true,"origin":"","legend":"","description":"","filename":"6116ad483b4646f6ba3ba404498a03071structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/ada4d26804f1afad0c81e05a.xml"},{"id":91827579,"identity":"845f45ac-d470-43ea-98ea-e3a0d29073ac","added_by":"auto","created_at":"2025-09-22 08:48:28","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":104876,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/d1faa84a1675678703dbeb19.html"},{"id":91827563,"identity":"4bc1bfd4-17a4-4719-8398-307f62b563b3","added_by":"auto","created_at":"2025-09-22 08:48:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113786,"visible":true,"origin":"","legend":"\u003cp\u003eMarkov Model State Transition Model\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/4db2b6de4d2acc68e4023ae2.png"},{"id":91827570,"identity":"abf96f85-9ca3-4bdc-b6be-e6561a34574f","added_by":"auto","created_at":"2025-09-22 08:48:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":242116,"visible":true,"origin":"","legend":"\u003cp\u003eCost-Effective Plane: SRS vs. HA-WBRT\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/2ee5b151be0036cab18a2292.png"},{"id":91827564,"identity":"68e2b468-7a13-47ca-b0df-783f2d243c07","added_by":"auto","created_at":"2025-09-22 08:48:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":120652,"visible":true,"origin":"","legend":"\u003cp\u003eTornado Diagram of the A) Cost and Utility Parameters and B) Transition Probabilities\u003c/p\u003e\n\u003cp\u003eud = utility of death state\u003c/p\u003e\n\u003cp\u003echemo = cost of chemotherapy\u003c/p\u003e\n\u003cp\u003eaet = cost of atezolizumab\u003c/p\u003e\n\u003cp\u003ehawbrt = cost of hippocampal-avoidant whole brain radiation therapy\u003c/p\u003e\n\u003cp\u003efollow = cost of follow-up care\u003c/p\u003e\n\u003cp\u003ememantine = cost of memantine\u003c/p\u003e\n\u003cp\u003esupport = cost of supportive care\u003c/p\u003e\n\u003cp\u003eulr = utility of local recurrence (salvageable and non-salvageable) state\u003c/p\u003e\n\u003cp\u003euncf3 = utility decrement for neurocognitive function decline post-HA-WBRT (duration = 3 months)\u003c/p\u003e\n\u003cp\u003euc = utility of control state\u003c/p\u003e\n\u003cp\u003euncf4 = utility decrement for neurocognitive function decline post-HA-WBRT (duration = 4 months)\u003c/p\u003e\n\u003cp\u003esrs = cost of stereotactic radiosurgery\u003c/p\u003e\n\u003cp\u003ehospice = cost of hospice care\u003c/p\u003e\n\u003cp\u003emri = cost of magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003epdr = probability of distant recurrence (salvageable)\u003c/p\u003e\n\u003cp\u003epdrns = probability of distant recurrence (non-salvageable)\u003c/p\u003e\n\u003cp\u003eplrns = probability of local recurrence (non-salvageable)\u003c/p\u003e\n\u003cp\u003epd = probability of death\u003c/p\u003e\n\u003cp\u003epc = probability of controlled state (healthy)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/44ab5da18dda0191a45456bf.png"},{"id":91830549,"identity":"1eaf6f9c-a764-4d23-8505-d7d7ca7af8e3","added_by":"auto","created_at":"2025-09-22 09:04:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1081342,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7567773/v1/c17a1a57-3374-4f77-bbb9-c194fda86f8e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eCost-effectiveness analysis of upfront HA-WBRT vs. SRS for treatment of brain metastases due to SCLC\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSmall cell lung cancer (SCLC) represents 10\u0026ndash;15% of all lung cancer cases in the United States, accounting for approximately 35,000 new cases annually\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The average cost of treating SCLC is over \u003cspan\u003e$\u003c/span\u003e45,000 per patient for first and second-line therapy, which is greater than that of non-small cell lung cancer.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Cost-effective analysis (CEA) determines the optimal use of resources to maximize health benefits while minimizing cost.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Therefore, we can apply CEA to guide cost-effective SCLC treatment. Currently standard of care in the treatment of brain metastases include hippocampal-avoidant whole brain radiation therapy (HA-WBRT), which spares the hippocampus to reduce risk of cognitive deterioration,\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and stereotactic radio surgery (SRS), which uses a single large dose of radiation delivered via multiple non-coplanar radiation beams to a precisely defined target lesion in the brain,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e are the standards of care.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Previous CEA studies have compared SRS to WBRT and have found SRS to be cost-effective, citing incremental cost effectiveness ratios (ICERs) ranging from \u003cspan\u003e$\u003c/span\u003e39,117 - \u003cspan\u003e$\u003c/span\u003e58,903.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Trials are currently ongoing to evaluate HA-WBRT and SRS as the possible standard of care in the treatment of brain metastases due to SCLC.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e However, no studies exist currently describing the CEA of HA-WBRT and SRS specifically for SCLC.\u003c/p\u003e\u003cp\u003eIn this study, we execute a cost-effectiveness analysis of HA-WBRT vs. SRS for brain metastases secondary to SCLC using Markov models with Monte Carlo simulations based on the design of the NRG CC-009 trial.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e We hope the analysis may help guide future treatment decisions that are both clinically and cost-effective.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eMarkov Model\u003c/h2\u003e\n \u003cp\u003ePatients exist in two treatment arms: upfront SRS and upfront HA-WBRT. Patients in both arms enter the model in the \u003cem\u003econtrolled\u003c/em\u003e state, or successful treatment of metastases. Patients can remain in \u003cem\u003econtrolled\u003c/em\u003e, have a \u003cem\u003elocal recurrence\u003c/em\u003e (which is \u003cem\u003enon-salvageable\u003c/em\u003e) or \u003cem\u003edistant recurrence (\u003c/em\u003ewhich is only \u003cem\u003enon-salvageable\u003c/em\u003e for the HA-WBRT arm or can be \u003cem\u003enon-salvageable\u003c/em\u003e or \u003cem\u003esalvageable\u003c/em\u003e for the SRS arm), or die from brain metastases, cancer elsewhere in the body, or other causes (\u003cem\u003edeath\u003c/em\u003e). All patients who receive SRS receive HA-WBRT for salvage treatment. Patients cannot die from brain metastases without first having a local or distant recurrence. Patients in the distant brain recurrence (salvageable) states can recover or die. Patients not in the controlled state who received HA-WBRT receive hospice care until they experience \u003cem\u003edeath\u003c/em\u003e. Patients with a local or distant recurrence may encounter a stopping rule, which results in automatic transition to \u003cem\u003edeath\u003c/em\u003e if they have already received HA-WBRT. Finally, patients who received upfront SRS receive salvage with HA-WBRT, and no patient can receive repeat HA-WBRT (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eModel Parameters\u003c/h3\u003e\n\u003cp\u003eTransition probability, cost, and utility parameters were calibrated according to previous studies as well as clinical judgement, with Beta distributions applied for the Monte Carlo simulations. Regarding transition parameters, the probability of distant and local recurrences was indexed at 4.68%, and the probability of death was 2% (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The model was calibrated so that there would be no significant survival advantage conferred to SRS or HA-WBRT.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eModel Parameters: Transition Parameters.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBase Case\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDistribution\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eProbabilities for 1 mo. transitions\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrence (distant)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0468\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(0.0421\u0026ndash;0.0515)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrence (local)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0468\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(0.0421\u0026ndash;0.0515)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eCalibration parameters (probabilities)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e*for salvageable and non-salvageable\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003eCost parameters were gathered from the 2022 Medicare fee schedule and previous studies, and they were standardized to 2022 US dollars per the Medical Care Consumer Price Index (Table 2). No discounting was needed since most patients in the simulation died within one year. Utility parameters were gathered from previously published studies.\u003csup\u003e19,25\u0026ndash;27\u003c/sup\u003e\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eModel Parameters: Cost.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHCPCS\u003c/p\u003e\n \u003cp\u003eCode\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCost (\u003cspan\u003e$\u003c/span\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDistribution\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOccurrence\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSource\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollow-up MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70545\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e246.40 (221.76\u0026ndash;271.04)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"9\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEvery 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHospice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6109.06 (5498.15\u0026ndash;6719.97)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17490.45 (13118.17-21864.04)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHA-WBRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12655.02 (11389.52\u0026ndash;13920.52)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e397.9 (358.11\u0026ndash;437.69)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonthly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtezolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10225.13 (9202.62\u0026ndash;11247.64)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonthly\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh complexity level 3 follow up care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102.43 (92.19\u0026ndash;112.67)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEvery 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBest supportive care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3624.15 (3261.74\u0026ndash;3986.57)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMemantine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.90/unit (4.41\u0026ndash;5.39) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e (unit\u0026thinsp;=\u0026thinsp;7mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVariable per protocol*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e*assuming the daily dose extended release memantine protocol: week 1\u0026ndash;7mg, week 2\u0026ndash;14 mg, week 3\u0026ndash;21 mg, weeks 4\u0026ndash;24\u0026ndash;28 mg.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable id=\"Tab3\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eModel Parameters: Utility.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBase Case\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDistribution\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(0.76\u0026ndash;0.9)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSide effects of HA-WBRT: active for 3 mo post-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.1025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(-0.11275, -0.09225)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNCF decline for HA-WBRT: 4mo post-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.07\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(-0.095, -0.045)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecline because of progression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.66\u0026ndash;0.8\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth of death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(0.18, 0.22)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eNot Applicable CHEERS Guidelines\u003c/h3\u003e\n\u003cp\u003eAs the entire patient population was simulated, no demographic information exists such as age, socioeconomic status, or clinical characteristics beyond the inputs for the model. Similarly, there was no setting or location for the study, nor were there any patient engagement initiatives. For time window, the model assumed monthly cycles of treatment across patients\u0026rsquo; lifetimes.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eThe Markov models were coded in the statistical software R (Version X) using the \u0026ldquo;markovchain\u0026rdquo; package. All statistics were calculated in R (Version X).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eBase Case\u003c/h2\u003e\n \u003cp\u003eIn the base model, the mean incremental cost effectiveness ratio (ICER) of the SRS treatment arm compared to the HA-WBRT treatment arm was \u003cspan\u003e$\u003c/span\u003e2126.88 (median \u003cspan\u003e$\u003c/span\u003e2720.35). This is not the result of survival differences across the two treatment arms, as patients in both arms experienced identical survival of around 5 months as well as time spent with brain metastases (Table S1).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSensitivity Analyses\u003c/h3\u003e\n\u003cp\u003eIn the Monte Carlo simulations where the cost and utility parameters were varied, the mean SRS and HA-WBRT Treatment Costs were \u003cspan\u003e$\u003c/span\u003e83,492 and \u003cspan\u003e$\u003c/span\u003e77,241, respectively, and the mean SRS and HA-WBRT Treatment QALYs were 3.10 and 1.98, respectively.\u003c/p\u003e\n\u003cp\u003eWhen comparing SRS vs. HA-WBRT, SRS was more costly and more effective in 56.1% of the Monte Carlo simulations, and more costly but less effective in 43.9% of simulations. SRS was never less costly (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe tornado diagram ordinally ranks which parameters, when varied with a random distribution, have the greatest impact on the ICER. The cost of the MRI had the greatest positive impact on the ICER \u0026ndash; as it increased, the ICER of SRS vs. HA-WBRT increased. On the other hand, the cost of hospice care had the greatest negative impact \u0026ndash; as it increased, the ICER decreased. On the other end of the spectrum, the utility assigned to the death state had the smallest positive impact on ICER, and the cost of chemotherapy had the smallest negative impact on ICER (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e\n\u003cp\u003eWhen the transition probabilities of entering/exiting each state in the model were varied, the probability of staying in the controlled, or healthy state, had the strongest negative impact on ICER \u0026ndash; as the probability of staying healthy increased, ICER decreased. The probability of death had the strongest positive impact on ICER \u0026ndash; as the probability of dying increased, ICER increased (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). The cost-effectiveness ratio of SRS and HA-WBRT was \u003cspan\u003e$\u003c/span\u003e38,202 and \u003cspan\u003e$\u003c/span\u003e49,805, respectively.\u003c/p\u003e\n\u003cp\u003eMost transition probabilities that governed the model \u0026ndash; the probabilities of the controlled state, death, distant recurrence (salvageable), distant recurrence (non-salvageable), and local recurrence (non-salvageable) \u0026ndash; were statistically significant at the 99.9% confidence interval (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). However, the probability of distant recurrence (non-salvageable) was not statistically significant. The odds ratios of the probabilities of controlled and distant recurrence (non-salvageable) were less than one, indicating that as they increased, ICER decreased. The odds ratios of the probabilities of death and local recurrence (non-salvageable) were greater than 1, indicating that as they increased, ICER increased (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ctable id=\"Tab4\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOdds Ratios of the Transition Probability Parameters on ICER\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTransition Probabilities\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eControlled (Healthy)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.65\u0026ndash;0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.58x10\u003csup\u003e\u0026minus;\u0026thinsp;47***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.50\u0026ndash;1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.81x10\u003csup\u003e\u0026minus;\u0026thinsp;67***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDistant Recurrence (Salvageable)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.68\u0026ndash;0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.15x10\u003csup\u003e\u0026minus;\u0026thinsp;36***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocal Recurrence (Non-salvageable)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.50\u0026ndash;1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.81x10\u003csup\u003e\u0026minus;\u0026thinsp;67***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDistance Recurrence (Non-Salvageable)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.94\u0026ndash;1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.90x10\u003csup\u003e\u0026minus;\u0026thinsp;01\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e***p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, significant at the 99.9% confidence interval\u003c/p\u003e\n\u003cp\u003eFor survival sensitivity analyses, simulations were run with forced survivals for both treatment arms of three, six, nine, twelve, and twenty-four months with calculated ICERs. ICERs remained positive -- indicating that SRS remained more expensive than HA-WBRT for increasing QALYs. However, as survival increased, ICERs decreased (Table S2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo date, several clinical trials have provided key data establishing SRS as non-inferior to WBRT.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Most notably, the FIRE-SCLC study, the largest multicenter retrospective study evaluating SRS for SCLC brain metastases, demonstrated that SRS alone achieves similar clinical outcomes\u0026mdash;median OS, time to CNS progression, leptomeningeal progression, and salvage therapy rates\u0026mdash;to WBRT, with fewer long-term neurocognitive side effects.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e This was integrated into our model by programming equal survival for the SRS and HA-WBRT treatment arms and less neurocognitive decline for the SRS arm. However, equivalent data for HA-WBRT vs. SRS does not yet exist but will be provided by the ongoing NRG-CC009 trial, the results of which can inform the next iteration of this model.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eLimitations\u003c/h2\u003e\n \u003cp\u003eThe main limitations of the study are assumptions underlying the model. First, those who received first line HA-WBRT therapy cannot receive HA-WBRT or SRS salvage therapy \u0026ndash; therefore, all brain metastases they experienced were non-salvageable. On the other hand, all patients who received SRS therapy first-line received HA-WBRT for salvage therapy upon experiencing recurrences. This resulted in the SRS treatment arm being more expensive than the HA-WBRT arm in all simulations, and, thus, the results of this study contradicted other Markov model evaluations of the cost-effectiveness of SRS vs. HA-WBRT that found SRS to be more cost-effective with lower ICERs.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eSecond, all local recurrences were non-salvageable. Third, the probability of experiencing local and distant recurrences (salvageable and non-salvageable) were identical. Fourth, and finally, the model did not differentiate causes of death and thus applied one probability of experiencing death from all causes \u0026ndash; death from brain metastases, death from cancer elsewhere in the body, and death from other causes. These assumptions greatly simplified the model, but were deemed reasonable as the alternative treatment options that are executed in practice \u0026ndash; salvaging local or distant recurrences after HA-WBRT, or salvaging local recurrences after SRS with surgery, repeat SRS, or LITT \u0026ndash; have demonstrated poor survival.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eTakeaways\u003c/h2\u003e\n \u003cp\u003eThere are several key takeaways of this study. First, the SRS treatment arm was more expensive than the HA-WBRT treatment arm in all simulations and more effective in most simulations. This is corroborated by existing studies that have found an increased effectiveness of SRS.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Second, the estimated cost-effectiveness ratios of SRS and HA-WBRT was \u003cspan\u003e$\u003c/span\u003e38,202 and \u003cspan\u003e$\u003c/span\u003e49,805, respectively, similar to the cost-effectiveness ratios of SRS calculated from other studies, which ranged from \u003cspan\u003e$\u003c/span\u003e39,117 to \u003cspan\u003e$\u003c/span\u003e58,903.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eThird, among the cost and utility parameters, the costs of the MRI and hospice care had the greatest influence on the ICER, and, among the transition probabilities, the probabilities of staying in the controlled state and death had the greatest influence. Fourth, as survival increases, the ICER of SRS vs. HA-WBRT decreases. This, when combined with the third takeaway, suggests that the cost-effectiveness of SRS depends on the projected survival of the patients, which is supported by other studies which have demonstrated greater cost-effectiveness advantage of SRS vs HA-WBRT for worse survival outcomes.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The survival of patients in our model, and thus the cost-effectiveness of SRS, is influenced greatly by the probability of local and distant recurrences and the probability of death from recurrences; this suggests that SRS may not be as cost-effective for patients with more aggressive cancer subtypes or with multiple metastases causing a greater probability of death upon progression.\u003c/p\u003e\n \u003cp\u003eFifth, and finally, patients who received first line HA-WBRT received no salvage treatment in our model; thus, in clinical situations where patients who receive first-line HA-WBRT and recur do receive alternative salvage treatment, SRS may be more cost-effective than reported in this study. Still, more research is recommended to ascertain the cost-effectiveness of different methodologies of radiation for the treatment of brain metastases.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding Statement:\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003ch2\u003eConflict of Disclosure:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eK.G. and E.P. contributed to the study conceptualization and design. K.G. did the data analysis and prepared figures 1-3 and tables 1-S2. K.G. wrote the abstract and manuscript. E.P. and Y.Q. supervised the data analysis and figures/tables preparation, and edited the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmerican Cancer Society. \u003cem\u003eKey Statistics for Lung Cancer\u003c/em\u003e.; 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html\u003c/li\u003e\n\u003cli\u003eCockrum P, MacEwan JP, Ramirez RA. Treatment patterns and outcomes associated with small cell lung cancer by platinum sensitivity status in a U.S. Medicare population. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2022;40(16_suppl):e20617-e20617. doi:10.1200/JCO.2022.40.16_suppl.e20617\u003c/li\u003e\n\u003cli\u003eClement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using Effectiveness and Cost-effectiveness to Make Drug Coverage Decisions: A Comparison of Britain, Australia, and Canada. \u003cem\u003eJAMA\u003c/em\u003e. 2009;302(13):1437. doi:10.1001/jama.2009.1409\u003c/li\u003e\n\u003cli\u003eBrown PD, Gondi V, Pugh S, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2020;38(10):1019-1029. doi:10.1200/JCO.19.02767\u003c/li\u003e\n\u003cli\u003eChin LS, Regine WF, eds. \u003cem\u003ePrinciples and Practice of Stereotactic Radiosurgery\u003c/em\u003e. Springer New York; 2008. doi:10.1007/978-0-387-71070-9\u003c/li\u003e\n\u003cli\u003eSchiff D, Messersmith H, Brastianos PK, et al. Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2022;40(20):2271-2276. doi:10.1200/JCO.22.00333\u003c/li\u003e\n\u003cli\u003eChang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2009;10(11):1037-1044. doi:10.1016/S1470-2045(09)70263-3\u003c/li\u003e\n\u003cli\u003eBrown 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. \u003cem\u003eJAMA\u003c/em\u003e. 2016;316(4):401. doi:10.1001/jama.2016.9839\u003c/li\u003e\n\u003cli\u003eJing Li. Stereotactic Radiosurgery Versus Whole-brain Radiation Therapy For Patients With 4-15 Brain Metastases: A Phase III Randomized Controlled Trial. Presented at: ASTRO; 2020; Online. https://www.astro.org/ASTRO/media/ASTRO/News%20and%20Publications/Press%20Kits/PDFs/2020/AM20_PressSlidesLi41.pdf\u003c/li\u003e\n\u003cli\u003eYamamoto M, Serizawa T, Higuchi Y, et al. A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores. \u003cem\u003eInt J Radiat Oncol\u003c/em\u003e. 2017;99(1):31-40. doi:10.1016/j.ijrobp.2017.04.037\u003c/li\u003e\n\u003cli\u003eLal LS, Byfield SD, Chang EL, et al. Cost-effectiveness Analysis of a Randomized Study Comparing Radiosurgery With Radiosurgery and Whole Brain Radiation Therapy in Patients With 1 to 3 Brain Metastases. \u003cem\u003eAm J Clin Oncol\u003c/em\u003e. 2012;35(1):45-50. doi:10.1097/COC.0b013e3182005a8f\u003c/li\u003e\n\u003cli\u003eJoe Y. Chang, Suresh Senan, Marinus Paul, Reza Mehran, Alexander Louie, Peter Balter. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70168-3/abstract\u003c/li\u003e\n\u003cli\u003eLester-Coll NH, Dosoretz AP, Magnuson WJ, Laurans MS, Chiang VL, Yu JB. Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2016;125(Supplement_1):18-25. doi:10.3171/2016.7.GKS161499\u003c/li\u003e\n\u003cli\u003eVinai Gondi. \u003cem\u003eTesting If High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus Is Better at Preventing Loss of Memory and Thinking Ability\u003c/em\u003e. Northwestern Feinberg School of Medicine; 2025. https://clinicaltrials.gov/study/NCT04804644\u003c/li\u003e\n\u003cli\u003eKhan M, Lin J, Liao G, et al. Whole Brain Radiation Therapy Plus Stereotactic Radiosurgery in the Treatment of Brain Metastases Leading to Improved Survival in Patients With Favorable Prognostic Factors. \u003cem\u003eFront Oncol\u003c/em\u003e. 2019;9:205. doi:10.3389/fonc.2019.00205\u003c/li\u003e\n\u003cli\u003ePalmer JD, Klamer BG, Ballman KV, et al. Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial. \u003cem\u003eJAMA Oncol\u003c/em\u003e. 2022;8(12):1809. doi:10.1001/jamaoncol.2022.5049\u003c/li\u003e\n\u003cli\u003eYomo S, Hayashi M. Is stereotactic radiosurgery a rational treatment option for brain metastases from small cell lung cancer? A retrospective analysis of 70 consecutive patients. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2015;15(1):95. doi:10.1186/s12885-015-1103-6\u003c/li\u003e\n\u003cli\u003eAndrews 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. \u003cem\u003eThe Lancet\u003c/em\u003e. 2004;363(9422):1665-1672. doi:10.1016/S0140-6736(04)16250-8\u003c/li\u003e\n\u003cli\u003eSavitz ST, Chen RC, Sher DJ. Cost‐effectiveness analysis of neurocognitive‐sparing treatments for brain metastases. \u003cem\u003eCancer\u003c/em\u003e. 2015;121(23):4231-4239. doi:10.1002/cncr.29642\u003c/li\u003e\n\u003cli\u003eCMS.gov. Physician Fee Schedule Menu. Published online October 17, 2024. https://www.cms.gov/medicare/physician-fee-schedule/search?Y=0\u0026amp;T=0\u0026amp;HT=0\u0026amp;CT=3\u0026amp;H1=99233\u0026amp;M=5\u003c/li\u003e\n\u003cli\u003eHall MD, McGee JL, McGee MC, et al. Cost-effectiveness of stereotactic radiosurgery with and without whole-brain radiotherapy for the treatment of newly diagnosed brain metastases: Clinical article. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2014;121(Suppl_2):84-90. doi:10.3171/2014.7.GKS14972\u003c/li\u003e\n\u003cli\u003eZhou K, Zhou J, Huang J, et al. Cost-effectiveness analysis of atezolizumab plus chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer. \u003cem\u003eLung Cancer\u003c/em\u003e. 2019;130:1-4. doi:10.1016/j.lungcan.2019.01.019\u003c/li\u003e\n\u003cli\u003eChastek B, Harley C, Kallich J, Newcomer L, Paoli CJ, Teitelbaum AH. Health Care Costs for Patients With Cancer at the End of Life. \u003cem\u003eJ Oncol Pract\u003c/em\u003e. 2012;8(6S):75s-80s. doi:10.1200/JOP.2011.000469\u003c/li\u003e\n\u003cli\u003eDrugs.com. Memantine Prices, Coupons, Copay Cards \u0026amp; Patient Assistance. https://www.drugs.com/price-guide/memantine\u003c/li\u003e\n\u003cli\u003eGarside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. \u003cem\u003eHealth Technol Assess\u003c/em\u003e. 2007;11(45). doi:10.3310/hta11450\u003c/li\u003e\n\u003cli\u003eJ Wilson, GL Yao, J Raftery, et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. Published online 2007. https://www.ncbi.nlm.nih.gov/books/NBK62325/\u003c/li\u003e\n\u003cli\u003eOremus M, Tarride JE, Clayton N, Raina P. Health Utility Scores in Alzheimer\u0026rsquo;s Disease: Differences Based on Calculation With American and Canadian Preference Weights. \u003cem\u003eValue Health\u003c/em\u003e. 2014;17(1):77-83. doi:10.1016/j.jval.2013.10.009\u003c/li\u003e\n\u003cli\u003eRusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study. \u003cem\u003eJAMA Oncol\u003c/em\u003e. 2020;6(7):1028. doi:10.1001/jamaoncol.2020.1271\u003c/li\u003e\n\u003cli\u003eChen VE, Kim M, Nelson N, Kim IK, Shi W. Cost-effectiveness analysis of 3 radiation treatment strategies for patients with multiple brain metastases. \u003cem\u003eNeuro-Oncol Pract\u003c/em\u003e. 2023;10(4):344-351. doi:10.1093/nop/npac093\u003c/li\u003e\n\u003cli\u003eMitsuya K, Nakasu Y, Hayashi N, et al. Retrospective analysis of salvage surgery for local progression of brain metastasis previously treated with stereotactic irradiation: diagnostic contribution, functional outcome, and prognostic factors. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2020;20(1):331. doi:10.1186/s12885-020-06800-w\u003c/li\u003e\n\u003cli\u003eRana N, Pendyala P, Cleary RK, et al. Long-term Outcomes after Salvage Stereotactic Radiosurgery (SRS) following In-Field Failure of Initial SRS for Brain Metastases. \u003cem\u003eFront Oncol\u003c/em\u003e. 2017;7:279. doi:10.3389/fonc.2017.00279\u003c/li\u003e\n\u003cli\u003eMcKay WH, McTyre ER, Okoukoni C, et al. Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2017;127(1):148-156. doi:10.3171/2016.5.JNS153051\u003c/li\u003e\n\u003cli\u003eDesai J, Rajkumar S, Shepard MJ, Wegner RE. National Trends in Radiation Treatment for Small Cell Lung Cancer Brain Metastases in the Modern Era. \u003cem\u003eAdv Radiat Oncol\u003c/em\u003e. 2025;10(3):101720. doi:10.1016/j.adro.2025.101720\u003c/li\u003e\n\u003cli\u003eKimmell KT, LaSota E, Weil RJ, Marko NF. Comparative Effectiveness Analysis of Treatment Options for Single Brain Metastasis. \u003cem\u003eWorld Neurosurg\u003c/em\u003e. 2015;84(5):1316-1332. doi:10.1016/j.wneu.2015.06.021\u003c/li\u003e\n\u003cli\u003eChang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2015;16(6):630-637. doi:10.1016/S1470-2045(15)70168-3\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7567773/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7567773/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHippocampal-avoidant whole brain radiation therapy (HA-WBRT) and stereotactic radio surgery (SRS) are standard of care treatments for brain metastases (BM). \u0026nbsp;However, the optimal approach for treating BM originating from small cell lung cancer (SCLC) remains uncertain. We conducted a cost-effectiveness analysis comparing HA-WBRT and SRS for SCLC BMs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe constructed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of SRS versus HA-WBRT. In this model, patients either receive upfront SRS or HA-WBRT. Those receiving SRS may undergo salvage HA-WBRT if they experience salvageable distant recurrences, or progress to non-salvageable local and distant recurrences. We performed over 100,000 Monte Carlo simulations, varying cost and utility parameters using Beta distributions, to analyze the impact of these variations on the ICER.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe base case ICER for SRS was $2126.88. SRS was more costly and more/less effective in 56.1%/43.9% of Monte Carlo simulations. MRI cost had the greatest positive impact on ICER, and cost of hospice had greatest negative impact. The utility decline of the four-month of neurocognitive decline post-HA-WBRT had the strongest negative impact. The transition probabilities of the controlled state, death, distant recurrence (salvageable), and local recurrence (non-salvageable) had statistically significant impacts on ICER (p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSRS was more expensive than HA-WBRT in all simulations and more effective in most. The cost of the MRI and hospice care and the transition probabilities of the controlled state and death had the greatest influence on ICER. As survival increased, ICER decreased, emphasizing the importance of patient selection for SRS.\u003c/p\u003e","manuscriptTitle":"Cost-effectiveness analysis of upfront HA-WBRT vs. SRS for treatment of brain metastases due to SCLC","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:48:23","doi":"10.21203/rs.3.rs-7567773/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-26T13:42:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-26T01:16:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-23T16:08:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54648739785961176937225579431949923386","date":"2025-09-15T12:58:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"243106166132312895697519541905662717610","date":"2025-09-15T01:34:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218793639732095014252723827434123825381","date":"2025-09-14T18:54:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170372950750402492261835033490088777749","date":"2025-09-13T13:45:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T14:38:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-10T14:04:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-10T14:04:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-09-08T22:36:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3d43aa26-54e9-4018-a475-545b367c5669","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:25:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 08:48:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7567773","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7567773","identity":"rs-7567773","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}