Safety and efficacy of delivering systemic treatments concomitantly with whole-brain radiotherapy: a prospective, observational, single-institution study

Maria Protopapa , Kalliopi Platoni , Michalis Psarras , Styliani-Theonymfi Nikoloudi , Zoi Liakouli , Despoina Alexiou , Christina Armpilia , Christos Antypas , Christos Papadimitriou , Vasileios Kouloulias , Anna Zygogianni

Exploration of Targeted Anti-tumor Therapy ›› 2026, Vol. 7 ›› Issue (1) : 1002395

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Exploration of Targeted Anti-tumor Therapy ›› 2026, Vol. 7 ›› Issue (1) :1002395 DOI: 10.37349/etat.2026.1002395
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Safety and efficacy of delivering systemic treatments concomitantly with whole-brain radiotherapy: a prospective, observational, single-institution study
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Abstract

Aim: The aim of our study was to evaluate the safety and efficacy of delivering systemic treatments concurrently with whole-brain radiotherapy (WBRT).

Methods: A single-institution, prospective observational study was conducted in Athens, Greece, including 99 patients treated with WBRT for brain metastases from September 2017 until October 2019, and with a follow-up period extending to March 2025. The study endpoints included overall survival (OS) for all causes of death, time to intracranial progression (TTICP), and serious acute toxicities.

Results: The median OS from all causes of death was 6 months [95% confidence interval (CI): 4.7–7.3]. Concomitant systemic therapy reduced the risk of death p = 0.005), and the presence of systemic metastases p = 0.009) increased the risk of death for patients with brain metastases treated with whole brain radiotherapy. The median TTICP was 10 months (95% CI: 3.3–16.6), with a more protracted fractionation and a larger number of brain metastases being prognostic of an increase in the TTICP. Acute severe toxicity was observed in 16.2% of patients, with no statistically significant difference between concurrent and no systemic therapy groups, and with no treatment interruptions in patients treated concurrently.

Conclusions: This study showed that there is no serious toxicity from the combination of systemic therapy with WBRT, and that the OS and the TTICP are not compromised with their concurrent delivery.

Keywords

whole-brain radiotherapy (WBRT) / brain metastases / systemic therapy / concurrent treatment

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Maria Protopapa, Kalliopi Platoni, Michalis Psarras, Styliani-Theonymfi Nikoloudi, Zoi Liakouli, Despoina Alexiou, Christina Armpilia, Christos Antypas, Christos Papadimitriou, Vasileios Kouloulias, Anna Zygogianni. Safety and efficacy of delivering systemic treatments concomitantly with whole-brain radiotherapy: a prospective, observational, single-institution study. Exploration of Targeted Anti-tumor Therapy, 2026, 7 (1) : 1002395 DOI:10.37349/etat.2026.1002395

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References

[1]

Cagney DN, Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017; 19: 1511-21.

[2]

Protopapa M, Kouloulias V, Nikoloudi S, Papadimitriou C, Gogalis G, Zygogianni A. From Whole-Brain Radiotherapy to Immunotherapy: A Multidisciplinary Approach for Patients with Brain Metastases from NSCLC. J Oncol. 2019; 2019: 3267409.

[3]

Chao ST, De Salles A, Hayashi M, Levivier M, Ma L, Martinez R, et al. Stereotactic Radiosurgery in the Management of Limited (1-4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. Neurosurgery. 2018; 83: 345-53.

[4]

Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, 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: 1037-44.

[5]

Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017; 18: 1049-60.

[6]

Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, 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.

[7]

Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011; 29: 134-41.

[8]

Pannullo SC, Julie DAR, Chidambaram S, Balogun OD, Formenti SC, Apuzzo MLJ, et al. Worldwide Access to Stereotactic Radiosurgery. World Neurosurg. 2019; 130: 608-14.

[9]

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375: 1823-33.

[10]

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al.; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015; 372: 2521-32.

[11]

Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015; 372: 724-34.

[12]

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-46.

[13]

Chevli N, Hunt A, Haque W, Farach AM, Messer JA, Sukpraprut-Braaten S, et al. Time Interval to Initiation of Whole-Brain Radiation Therapy in Patients With Small Cell Lung Cancer With Brain Metastasis. Adv Radiat Oncol. 2021; 6: 100783.

[14]

Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al.; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020; 396: 1817-28.

[15]

Mansfield AS, Herbst RS, de Castro G Jr, Hui R, Peled N, Kim DW, et al. Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1-Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042. JTO Clin Res Rep. 2021; 2: 100205.

[16]

Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al.; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367: 1783-91.

[17]

Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.; Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015; 16: e270-8.

[18]

Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, et al. for NRG Oncology. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. 2020; 38: 1019-29.

[19]

Gondi V, Deshmukh S, Brown PD, Wefel JS, Armstrong TS, Tome WA, et al. Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2023; 117: 571-80.

[20]

Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ Jr, Robins HI, et al. A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys. 2008; 71: 79-86.

[21]

Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, 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.

[22]

Andriani R, Tjiptoningsih UM, Hanggrainy OS, Susilodinata A, Wilopo SA. Prognosis of Brain Metastases (BM) Patient Received Whole Brain Radiation Therapy (WBRT) alone or in combination with Surgery at Dharmais National Cancer Center, Indonesia. Asian Pac J Cancer Prev. 2025; 26: 2025-34.

[23]

Steindl A, Zach C, Berchtold L, Grisold A, Gatterbauer B, Eckert F, et al. Prognostic relevance of the neurological symptom burden in brain metastases from breast cancer. Br J Cancer. 2025; 132: 733-43.

[24]

Steindl A, Yadavalli S, Gruber KA, Seiwald M, Gatterbauer B, Dieckmann K, et al. Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases. Cancer. 2020; 126: 4341-52.

[25]

Steindl A, Heimbach K, Ressler J, Gatterbauer B, Dieckmann K, Widhalm G, et al. P11.23.B Neurological symptoms independently associate with overall survival in patients with melanoma brain metastases. Neuro Oncol. 2022; 24: ii61.

[26]

Steindl A, Schlieter F, Klikovits T, Leber E, Gatterbauer B, Frischer JM, et al. Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort. J Neurooncol. 2019; 145: 85-95.

[27]

Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010; 77: 655-61.

[28]

Wei Y, Li R, Liu X, Shi Y, Xu Y, Zhao J, et al. Clinical outcomes and predictive factors of immunotherapy efficacy in non-small-cell lung cancer brain metastases: a comparative study. BMC Cancer. 2025; 26: 198.

[29]

Bartsch R, Fromm S, Rudas M, Wenzel C, Harbauer S, Roessler K, et al. Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer - a retrospective analysis. Radiother Oncol. 2006; 80: 313-7.

[30]

Rosner D, Nemoto T, Lane WW. Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer. 1986; 58: 832-9.

[31]

Czogalla M, Stöhr J, Gleim N, Papsdorf K, Klagges S, Hambsch P, et al. Short-term survivors with brain metastases have modest benefits from focal and systemic therapies and remain frequent despite improving treatment landscape. Clin Transl Radiat Oncol. 2025; 51: 100919.

[32]

Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013; 85: 1312-8.

[33]

Chua D, Krzakowski M, Chouaid C, Pallotta MG, Martinez JI, Gottfried M, et al. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study. Clin Lung Cancer. 2010; 11: 176-81.

[34]

Qin H, Pan F, Li J, Zhang X, Liang H, Ruan Z. Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis. PLoS One. 2014; 9: e111475.

[35]

Lehrer EJ, McGee HM, Sheehan JP, Trifiletti DM. Integration of immuno-oncology with stereotactic radiosurgery in the management of brain metastases. J Neurooncol. 2021; 151: 75-84.

[36]

Lehrer EJ, Khosla AA, Ozair A, Gurewitz J, Bernstein K, Kondziolka D, et al. Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients. J Neurooncol. 2023; 165: 63-77.

[37]

Gerber NK, Young RJ, Barker CA, Wolchok JD, Chan TA, Yamada Y, et al. Ipilimumab and whole brain radiation therapy for melanoma brain metastases. J Neurooncol. 2015; 121: 159-65.

[38]

Williams NL, Wuthrick EJ, Kim H, Palmer JD, Garg S, Eldredge-Hindy H, et al. Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. Int J Radiat Oncol Biol Phys. 2017; 99: 22-30.

[39]

Christodoulou C, Kalogera-Fountzila A, Karavasilis V, Kouvatseas G, Papandreou CN, Samantas E, et al. Lapatinib with whole brain radiotherapy in patients with brain metastases from breast and non-small cell lung cancer: a phase II study of the Hellenic Cooperative Oncology Group (HeCOG). J Neurooncol. 2017; 134: 443-51.

[40]

Meattini I, Becherini C, Caini S, Coles CE, Cortes J, Curigliano G, et al.; Consensus Panellist Group. International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. Lancet Oncol. 2024; 25: e73-83.

[41]

Zhang Q, Chen J, Yu X, Cai G, Yang Z, Cao L, et al. Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis. Breast Cancer. 2016; 23: 732-9.

[42]

Li S, Xu S, Li L, Xue Z, He L. Efficacy and safety of EGFR-TKI combined with WBRT vs. WBRT alone in the treatment of brain metastases from NSCLC: a systematic review and meta-analysis. Front Neurol. 2024; 15: 1362061.

[43]

Rades D, Schild SE, Lohynska R, Veninga T, Stalpers LJ, Dunst J. Two radiation regimens and prognostic factors for brain metastases in nonsmall cell lung cancer patients. Cancer. 2007; 110: 1077-82.

[44]

Botturi M, Fariselli L. Clinical results of unconventional fractionation radiotherapy in central nervous system tumors. Tumori. 1998; 84: 176-87.

[45]

Baschnagel AM, Meyer KD, Chen PY, Krauss DJ, Olson RE, Pieper DR, et al. Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg. 2013; 119: 1139-44.

[46]

Blattmann LM, Shafie RE, Bendrich S, Donath S, Knaus O, Hille A, et al. Radiotherapy for patients with brain metastases and leptomeningeal carcinomatosis: prognostic factors and clinical outcomes. Clin Exp Metastasis. 2025; 42: 33.

[47]

Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg. 2010; 126: 2234-42.

[48]

Palmer JD, Dawson E, Dibs K, Ritter A, Sun Y, Boulter D, et al. An Initial Report of Memory Avoidance Whole Brain Radiotherapy to Treat Brain Metastases: A Prospective Phase 2 Trial. Int J Radiat Oncol Biol Phys. 2025; 123: S35-6.

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