Rupesh Kotecha
John H. Suh
Minesh P. Mehta1,2- 1Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
- 2Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
- 3Deparment of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
- 4Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
Editorial on the Research Topic
Effects of radiation therapies on brain metastases
Brain metastasis represents the most common malignancy diagnosed in adults with approximately 15 to 30% of patients with solid tumors at risk of developing intracranial dissemination at some point during their disease course (1). In the multi-disciplinary management of patients with brain metastasis, radiotherapy is often a substantial component of either definitive or adjunctive management. In addition to the development of novel radiotherapy advances, the neurocognitive function has been the subject of contemporary research, with an emphasis on risk mitigation and amelioration of toxicity severity (Lehrer et al.). There have been several recent advances in our understanding of the role of radiotherapy in the management of brain metastasis, including a re-evaluation of the biology of brain metastasis and its impact on treatment decisions, effect on neurocognitive function, and long-term outcome comparisons between stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT), which is the theme of this Research Topic collection.
Khan et al. provide a comprehensive overview of our current understanding of the role of SRS and WBRT in patients with brain metastasis by reviewing the literature specifically for the two most common tumors associated with brain metastasis, lung and breast cancer, as well as radioresistant tumors (i.e. renal cell carcinoma and melanoma); they also focus on the unique scenario of a single brain metastasis. For patients with non-small cell lung cancer (NSCLC), they recommend SRS alone for the majority of patients but also consider WBRT as an upfront diagnosis for selected patients with better-expected prognosis given the results of updated subset analyses from the RTOG 9508 (2) and JROSG 99-1 trials (3). This was also the subject of one of the original research reports in this topic collection by Ni et al., who demonstrated improved survival, especially in those with limited intracranial disease (one to three lesions) or those receiving targeted therapy, in a large series of 684 NSCLC patients treated with or without the combinatorial approach. It is important to note, however, that a subset analysis from N0574 did not recapitulate this benefit (4) and the recent ASTRO (5) and ASCO (6) brain metastasis guidelines do not categorically recommend upfront combined modality treatment, which increases the risk for neurocognitive decline. The identification of patients with central nervous system (CNS) dominant disease, an example of such an exercise evaluated by Trikhirhisthit et al., is clearly needed to better select patients to categorically test the survival benefit hypothesis of combinatorial approaches, especially in the modern era where NSCLC patients receive intracranially active therapies such as immune checkpoint inhibitors and mutation-targeted drugs. In addition, for NSCLC patients with actionable targetable mutations, the lack of level-one comparisons of targeted agents with/without upfront radiotherapy has led to significant variations in clinical practice and deserves specific attention in future trials.
For patients with breast cancer brain metastasis, SRS is commonly used as an upfront treatment given the expected prognosis for this population; recently, combination approaches with molecularly targeted agents, such as Lapatinib and radiotherapy, have been performed (7). As newer systemic therapies become available, categorical data supporting the best possible approaches for integrating local and systemic approaches have become less data-driven and, hence, highly variable. A concept-illustrating example by Ying et al. describes an excellent clinical response with the combination of apatinib (a potent antiangiogenic agent directed at the vascular endothelial growth factor receptor-2) and WBRT. For radioresistant tumors such as renal cell carcinoma and melanoma, SRS is typically recommended given the poor disease control rates with WBRT, and as noted by Khan et al., these also represent a disease site where novel agents such as tyrosine kinase inhibitors with intracranial penetration and immune checkpoint inhibitors are actively being used. Finally, the authors note that although a rare circumstance in the modern era, the optimal approach for a patient with a single brain metastasis currently remains controversial. An “entire compartmental” approach has been recommended, with local therapy such as surgery or SRS, with WBRT. Although not commonly used today, this comprehensive approach was associated with long-term survival in our experience as well (8).
Another topic of interest is the role of SRS or WBRT following the resection of brain metastasis. Currently, national patterns of care data indicate that the majority of patients receive post-operative SRS (9). El Shafie et al. report their long-term outcomes in 101 patients treated with either SRS (n=50) or WBRT (n=51) at a single institution. Not surprisingly, larger cavity volume and incomplete resection were associated with an increased risk of local failure. Yet, overall, local control and survival were longer in patients treated with SRS. This is likely due to the retrospective nature of the study with inherent selection biases with regard to upfront treatment. It is important to note that the long-term outcomes from the N107c randomized trial revealed superior intracranial control with WBRT but less neurocognitive deterioration with SRS (10).
Transitioning to the topic of management of specific brain metastasis categories, the optimal SRS approach for patients with large brain metastasis remains in flux as single fraction SRS local control rates are suboptimal (11). To this end, Putz et al. report on a comparison of lesions larger than 5 mm treated with SRS (18 Gy 1 fraction) or fractionated stereotactic radiotherapy (FSRT, 40 Gy in 10 fractions) in a cohort of 120 patients treated to 190 brain metastasis. A longer time for local progression (22.9 months vs. 14.5 months) and a lower 12-month rate of radiation necrosis (3.4 vs 14.8%) were observed in favor of FSRT. Although the results with this unusual fractionation schedule were favorable compared to single fraction SRS, most clinical practices use fractionated schedules delivered in three to five fractions. Another approach, especially for large lesions, is to perform staged SRS where single fraction SRS is delivered with a 3- to 4-week interval between sessions to allow for tumor shrinkage. In a dosimetric study of staged SRS cases replanned with fractionated SRS (FSRS) equivalent doses, Cui et al. demonstrated that staged SRS allowed for a higher dose to be delivered to the tumor with a comparable dose to the surrounding brain parenchyma. Therefore, prospective comparisons between fractionated approaches, hypofractionated schedules, or staged treatments are clearly needed.
Ultimately, future randomized controlled trials are clearly needed to investigate the optimal combinatorial approach in an era of systemic therapies with CNS penetration and may challenge the long-standing dogma of how SRS is currently being utilized. Given the WBRT data in specific subsets of patients, hippocampal-avoidant WBRT may also remain part of this combinatorial approach.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
RK: Personal fees from Accuray Inc., Elekta AB, ViewRay Inc., Novocure Inc., Elsevier Inc., Brainlab, Kazia Therapeutics, Castle Biosciences, and institutional research funding from Medtronic Inc.; Blue Earth Diagnostics Ltd.; Novocure Inc.; GT Medical Technologies; AstraZeneca; Exelixis; ViewRay Inc.; Brainlab; Cantex Pharmaceuticals; and Kazia Therapeutics. JS: Scientific Advisory Board for Philips, Neutron Therapeutics, EmpNia, and Novocure MM: Consulting Fees from Karyopharm, Sapience, Zap-X, Mevion, Xoft, and Kazia Therapeutics; BOD Oncoceutics; Stock in Chimerix.
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References
1. Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL. Current approaches to the management of brain metastases. Nat Rev Clin Oncol (2020) 17(5):279–99. doi: 10.1038/s41571-019-0320-3
2. Sperduto PW, Shanley R, Luo X, Andrews D, Werner-Wasik M, Valicenti R, et al. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J Radiat Oncol Biol Phys (2014) 90(3):526–31. doi: 10.1016/j.ijrobp.2014.07.002
3. Aoyama H, Tago M, Shirato H, Japanese Radiation Oncology Study Group I. Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA Oncol (2015) 1(4):457–64. doi: 10.1001/jamaoncol.2015.1145
4. Churilla TM, Ballman KV, Brown PD, Twohy EL, Jaeckle K, Farace E, et al. Stereotactic radiosurgery with or without whole-brain radiation therapy for limited brain metastases: a secondary analysis of the north central cancer treatment group N0574 (Alliance) randomized controlled trial. Int J Radiat Oncol Biol Phys (2017) 99(5):1173–8. doi: 10.1016/j.ijrobp.2017.07.045
5. Gondi V, Bauman G, Bradfield L, Burri SH, Cabrera AR, Cunningham DA, et al. Radiation therapy for brain metastases: an ASTRO clinical practice guideline. Pract Radiat Oncol (2022) 12(4):265–82. doi: 10.1016/j.prro.2022.02.003
6. Vogelbaum MA, Brown H, Messersmith PK, Brastianos S, Burri D, Cahill IF, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol (2022) 40(5):492–516. doi: 10.1200/JCO.21.02314
7. Ah Kim I, Winter K, Sperduto P, De Los Santos J, Peereboom D, Ogunleye T, et al. CTNI-05. NRG ONCOLOGY / RTOG 1119: Phase II Randomized study of whole brain radiotherapy / streotactic radiosurgery with concurrent LAPATINIB in patients with Brain metastases from HER2-POSITIVE breast cancer. Neuro-Oncology (2020) 22(Supplement_2):ii42–2. doi: 10.1093/neuonc/noaa215.172
8. Kotecha R, Vogel S, Suh JH, Barnett GH, Murphy ES, Reddy CA, et al. A cure is possible: a study of 10-year survivors of brain metastases. J Neurooncol (2016) 129(3):545–55. doi: 10.1007/s11060-016-2208-8
9. Chin AL, Li G, Gephart MH, Sandhu N, Nagpal S, Soltys SG, et al. Stereotactic radiosurgery after resection of brain metastases: changing patterns of care in the united states. World Neurosurg (2020) 144:e797–806. doi: 10.1016/j.wneu.2020.09.085
10. Palmer JD, Klamer BG, Ballman KV, Brown PD, Cerhan JH, Anderson SK, 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):1809–15. doi: 10.1001/jamaoncol.2022.5049
Keywords: brain metastases, radiation therapy, neurocognition, stereotactic radiosurgery, whole-brain radiotherapy
Citation: Kotecha R, Suh JH and Mehta MP (2023) Editorial: Effects of radiation therapies on brain metastases. Front. Oncol. 13:1196143. doi: 10.3389/fonc.2023.1196143
Received: 29 March 2023; Accepted: 04 April 2023;
Published: 13 April 2023.
Edited and Reviewed by:
Timothy James Kinsella, Brown University, United StatesCopyright © 2023 Kotecha, Suh and Mehta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rupesh Kotecha, rupeshk@baptisthealth.net