Focal Radiotherapy of Brain Metastases in Combination With Immunotherapy and Targeted Drug Therapy
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Background: Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review, we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non–small-cell lung cancer, breast cancer, and malignant melanoma.
Methods: This narrative review is based on pertinent original articles, meta-analyses, and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists, neurosurgeons, and oncologists.
Results: There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy, compared to sequential treatment. Two meta-analyses of retrospective data from cohorts consisting mainly of patients with non–small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations, systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals.
Conclusion: Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient.
Patients with brain metastases, if untreated, have a median survival time of approximately one month (e1). Lung cancer, breast cancer, and malignant melanoma are the most common causes of brain metastases, accounting for 67–80% of the total (e2). Advances in neuroimaging, as well as new treatments, particularly targeted and immunotherapeutic drugs, have led both to longer overall survival (OS) and to an increasing incidence of brain metastases (e2, e3, e4). As a result, the median survival of patients with brain metastases rose from five to seven months from 1986–1999 to 2010–2020 (e4). Traditionally, treatment consisted mainly of neurosurgical resection, particularly of solitary metastases with critical space-occupying effect (e5), whole-brain radiation therapy (WBRT), and best supportive care. Further currently available options include stereotactic radiotherapy (local irradiation in multiple fractions) and radiosurgery (RS, i.e., local irradiation in a single session), and new forms of personalized systemic treatment, alongside classic chemotherapy (e6). When used to treat selected cases, these immune therapies and targeted therapies yield markedly higher response rates than classic chemotherapy, for both extra-and intracranial lesions. Predictive molecular markers from tissue and blood can be used to estimate probability of a response (e7).
The optimal multimodal treatment of brain metastases presents a particularly acute challenge at present. In randomized trials, radiosurgery without additional whole-brain radiation therapy led to lasting control of metastases with the same or better OS (e8, e9). These trials, however, generally included patients of heterogeneous tumor histology, and they were performed in an era before effective systemic treatment was introduced. Targeted drugs and immunotherapeutic drugs are likewise evidence-based, standard therapies at present, but, in their approval studies, patients with symptomatic brain metastases were often specifically excluded. High activity in the brain was shown only for certain drugs in secondary analyses. A potential breach in the integrity of the blood-brain barrier and the blood-tumor barrier by radiotherapy is the theoretical basis for improved efficacy, in particular for drugs that ordinarily do not reach the central nervous system (CNS), or do so only to a limited extent (e10). This article provides an overview of the combination of these new systemic and radiooncological treatment options for brain metastases of the most common kinds.
This narrative review is based on publications in English retrieved by a selective search in PubMed, including original articles, meta-analyses, and systematic reviews. The search was for studies on brain metastases of non-small-cell lung cancer (NSCLC), malignant melanoma, and breast cancer that were treated with immunotherapy and/or targeted therapy combined with radiotherapy. Both retrospective and prospective studies were included. They were evaluated by an expert panel consisting of specialists in radiation oncology, neurosurgery, and oncology. The case numbers, radiotherapeutic methods, types of systemic treatment, toxicity, intracranial responses, and overall survival were all considered in the analysis.
Focal radiotherapy for brain metastases
For patients with limited cerebral metastatic disease (up to four brain metastases with a maximal diameter of 4 cm) and without marked clinical manifestations, radiosurgery is the radiotherapeutic method of choice. In radiosurgery, an equivalent radiotherapeutic dose that is much higher than in traditional WBRT enables long-term local tumor control in 70-90% of patients, even in those with radioresistant tumors, such as melanoma or renal-cell carcinoma (e11-e13). The high spatial precision (Figure) of this form of radiotherapy accounts for its favorable side-effect profile; radiation necrosis is a common side effect, appearing after up to one-quarter of all treatments (e14). Radiosurgery alone, i.e., without prior WBRT, is the current standard of treatment, based on the findings of multiple randomized trials (e9, e15). Even though RS alone, compared to RS combined with WBRT, is more often followed by distant cerebral progression (i.e., the appearance of one or more new cerebral metastases outside the treated areas), this is not associated with any worsening of overall survival (e9). The patient’s neurocognitive function is better preserved without WBRT (e16). Follow-up with cranial MRI (cMRI) every 2–3 months is mandatory, so that any new brain metastases can be detected early and treated with either salvage RS or WBRT.
Yamamoto et al. reported that radiosurgery alone is a treatment option even when there are more than four metastases: in their prospective observational study, the OS of treated patients with 5–10 metastases was no worse than that of patients with 2–4 metastases (1194 patients total) (e17).
One may conclude that radiosurgery alone is a solid therapeutic alternative to WBRT for selected patients with a limited number of metastases and a limited total volume of metastatic tumor.
The surgical resection of brain metastases is also an important tool for local therapy, particularly for large, solitary masses that are symptomatic and surgically accessible, including those located in the posterior fossa (e5, e18). In such cases, it is also important to treat peritumoral cerebral edema (which is largely of vasogenic origin, resulting from a breach in the blood-brain barrier) with drugs, particularly cortico-steroids (e18).
Treatment-associated neurocognitive changes
Most patients who have undergone WBRT suffer a worsening of their neurocognitive function several months after treatment; typically, some degree of functional compromise is already present because of the brain metastasis or metastases themselves (e19). Further deterioration affects these patients’ activities of daily living and their quality of life (e20), produce stress for their families, and limit the benefit of the life-prolonging effect of WBRT, which is often very limited (e21).
The cognition-related neurotoxicity of WBRT is markedly worse than that of radiosurgery alone (e22), especially when structures that are particularly vulnerable in terms of cognitive function, such as the hippocampus, are not specifically spared (e23, e24). A randomized trial revealed a markedly higher likelihood of deficits in learning and memory after RS + WBRT (52%) compared to RS alone (24%) (e19). Thus, the use of RS without WBRT, including as part of combination therapy, can lessen cognition-related neurotoxicity.
Non-small-cell lung cancer
Systemic treatment alone
With regard to systemic treatment, NSCLC with an activating mutation (EGFR, ALK, ROS1, BRAF) can be treated with a tyrosine kinase inhibitor (TKI), while NSCLC without such a mutation cannot. Most Phase 3 trials of targeted TKI have had specific endpoints for brain metastases (Table 1). Higher intracranial response rates have been shown for osimertinib, a third-generation EGFR- and ALK-inhibitor, than for first-generation TKI (1). A further benefit of TKI therapy is that it can prevent the appearance of new brain metastases. It has been shown that fewer new brain metastases arise under treatment with third-generation TKI than with first-generation TKI (4.6% with alectinib vs. 31.5% with crizotinib; 5% with osimertinib vs. 18% with a first-generation TKI) (1, 2).
For patients without an activating mutation, only very limited data are available on monotherapy with immune checkpoint inhibitors (ICI) or chemotherapy. There have been a few small-scale trials of chemotherapy alone for patients with asymptomatic brain metastases, but the results are difficult to interpret because the trials were terminated early (3). A phase 2 trial of treatment with pembrolizumab alone in 18 patients with asymptomatic lung cancer metastases to the brain revealed markedly lower intracranial activity than extracranial activity (4).
Targeted therapy and immunotherapy combined with radiotherapy
No data from randomized trials are yet available concerning the optimal sequence and combination of local radiotherapy with targeted therapy or ICI for NSCLC.
Retrospective studies on patients with an activating EGFR mutation, with study sizes ranging from 176 to 351 patients, have shown better survival with a third-generation TKI such as erlotinib (5), gefinitib (6), or osimertinib (7) and early radiosurgery than with sequential therapy in which radiosurgery is only performed when the tumor progresses (Table 2).
A meta-analysis of the retrospective studies carried out to date supports the hypothesis of improved overall survival after early combined therapy. The survival advantage was greater in patients with symptomatic brain metastases than in patients with asymptomatic ones (8).
Sparse data are available on the optimal sequence of treatment for NSCLC patients with ALK translocations. The retrospective data to date indicate that combined therapy is advantageous (9).
For most NSCLC patients without any activating driver mutation, immunotherapy alone or in combination with chemotherapy is the standard drug treatment. Many retrospective studies and two meta-analyses (10, 11) with data mainly from patients with NSCLC and melanoma indicate that the combination of immunotherapy and early radiosurgery prolongs overall survival (OS at 12 months, for combined versus non-combined treatment: 64.6% and 51.6%, p <0.001 ).
Systemic treatment alone (Table 1)
The treatment options for brain metastases of breast cancer depend on the molecular subtype (12). For triple-negative breast cancer, no data are available on systemic treatment alone after brain metastases arise. Nor are there any prospective data on systemic treatment alone for patients with luminal breast cancer; nonetheless, in this situation, retrospective analyses imply that continuous endocrine therapy may be clinically advantageous for overall survival even after brain metastases arise (13).
The largest number of prospective trials of systemic treatment alone for brain metastases have been carried out on patients with HER2-positive breast cancer (Table 1). These patients have the best prognosis with respect to overall survival after brain metastases are diagnosed (12). The combination of lapatinib, a HER2 tyrosine kinase inhibitor, with capecitabine, a chemotherapeutic drug, for the treatment of multiple oligo- or asymptomatic brain metastases has been shown to prolong the time to progression by eight months (14). In a randomized follow-up trial, tucatinib (another tyrosine kinase inhibitor) combined with trastuzumab + capecitabine was compared with trastuzumab + capecitabine alone. In the tucatinib arm, progression-free survival was 9.9 months, compared to 4.2 months in the control group (15).
The efficacy of T-DM1, a trastuzumab-chemotherapy conjugate, has been shown in small case series (16). Trastuzumab-deruxtecan, another trastuzumab-chemotherapy conjugate, has also been found in initial studies to have a comparably high intracranial efficacy. It is now being studied in a trial specifically concerned with brain metastases (17).
Targeted therapy and immunotherapy combined with radiotherapy
Regarding combined radiotherapy and systemic treatment for brain metastases of breast cancer, there have been retrospective studies of lapatinib and radiosurgery, and of lapatinib and WBRT (Table 3). A meta-analysis on this subject included six studies up to the year 2020 with a total of 843 HER2-positive patients (442 HER2-amplified, 399 luminal B disease) (18). 279 patients were treated with lapatinib in addition to trastuzumab, with or without chemoradiotherapy, while 610 received trastuzumab-based treatment or chemotherapy alone. In all studies, RS was mainly given as local therapy, with or without WBRT (404 patients). Although WBRT was only used in three studies, it was the most common main form of treatment in terms of the number of patients treated (484 patients). All of the included studies were retrospective (19, 20, 21, 22, 23, 24). The combination of trastuzumab and lapatinib yielded a survival advantage compared to either agent alone (hazard ratio [HR]: 0.55; 95% confidence interval: [0.32; 0.92]). RS combined with lapatinib achieved better local tumor control than RS alone (HR: 0.47 [0.33; 0.66]).
In a retrospective comparison, Kim et al. showed statistically significant improvement of intracranial tumor control with lapatinib and concomitant radiotherapy: in 57% of cases, there was a complete response of metastases that were given combined treatment, compared to 38% of metastases that were not. There was no significant increase in the objective response rate per patient (complete remission plus partial remission, 75% vs. 57%) (23). The cumulative 12-month incidence of a distant intracranial recurrence after RS and lapatinib was 48% (95% confidence interval: [28%; 68%]), compared to 49% [40%; 58%] after RS alone. The incidence of radionecrosis was not significantly higher after combination therapy than after RS alone.
Miller et al. reported better distant tumor control after combination therapy than after radiotherapy alone: the 12-month incidence of distant metastases was 9.2% vs. 18.3% (22). Radionecrosis was more common after radiotherapy alone: 1.3% vs. 6.3%. Prospective, randomized trials are now in progress to evaluate modern systemic therapies combined with radiation therapy for brain metastases of breast cancer: pembrolizumab and RS (NCT03449238), atezolizumab and RS for triple-negative breast cancer patients with brain metastases (NCT03483012).
Systemic treatment alone
In patients with newly diagnosed metastatic melanoma and asymptomatic brain metastases, the combination of ipilimumab and nivolumab has been shown to yield similar intra- and extracranial response rates. A complete intracranial remission was seen in 26% of patients. After one year, 59.5% of patients were free of intracranial progression, and 70.4% were free of extracranial progression (25). In asymptomatic patients (of whom there were 18), the efficacy of the combination was markedly lower, with an intracranial response rate of only 16.6% (26). Similarly, prospective trials of combined BRAF and MEK inhibitors have shown comparable extra- and intracranial activity in asymptomatic patients with newly diagnosed brain metastases. Patients with symptomatic and previously locally treated, but currently progressive brain metastases were included as well and displayed an intracranial response rate of 44% (27).
Prospective trials of systemic treatment alone for malignant melanoma have shown a very good response compared to combined approaches with focal radiotherapy, but patient selection must be considered in the evaluation of these data. The best response rate was seen in asymptomatic patients who did not need cortisone. The size of the brain metastases was restricted as well. At present, trials such as the ABC-X trial (NCT03340129) are in progress that will meet the need for an adequate assessment of the optimal combination and sequence of systemic treatment and local radiotherapy. The results are expected to be published over the next few years.
Targeted therapy and immunotherapy combined with radiotherapy
to date, there have only been retrospective studies on combinations of radiosurgery and immunotherapy or targeted therapy for brain metastases of melanoma. Prospective trials are now being carried out in numerous centers.
Multiple studies have provided evidence for the superiority of RS combined with immune checkpoint inhibitors (ICI) or targeted therapy, compared to monotherapy with systemic treatment alone or with RS (Table 4):
A retrospective analysis of a prospectively acquired registry of 262 patients treated either with ICI or with targeted therapy revealed, after propensity score matching, that patients who received combined radiotherapy (ICI + RS or WBRT) had a significant survival advantage compared to those who did not (28).
In a systematic review of 95 studies on patients with brain metastases of melanoma, tumor control was found to be the best, and survival the longest, after radiotherapy combined with immunotherapy or targeted therapy. As for treatment timing, the best outcome was achieved when radiotherapy was performed before or during systemic treatment (29).
In a meta-analysis, Lehrer et al. studied the combination of RS and ICI for brain metastases on the basis of individual data from 534 patients, most of whom suffered from melanoma. One-year overall survival was better, to a statistically significant extent, after simultaneous therapy, compared to non-simultaneous therapy (64.6% vs. 51.6%). Likewise, with respect to the regional control of brain metastases after one year, the simultaneous administration of ICI and RS was superior to their sequential administration (ICI and then RS; 38.1% vs. 12.3%) (11).
The prognosis of patients with brain metastases with respect to survival has markedly improved in recent years, and thus the quality of life and the avoidance of neurocognitive sequelae of uncontrolled brain metastases, and of the treatment itself, have become important issues. The findings of prospective, randomized trials concerning the optimal combination and temporal sequence of modern radiotherapy and systemic therapies are expected within the next few years.
Aside from potentially indicated neurosurgical intervention, multimodal combined treatment based on the current scientific evidence, consisting of initial local radiotherapy followed by targeted therapy or immunotherapy, is a safe therapeutic strategy that enables the best possible control of brain metastases. Radiosurgery has now replaced whole-brain radiation therapy in many situations, even when multiple metastases are present.
Conflict of interest statement
PD Dr. Kaul has received reimbursement of travel expenses from Accuray.
Prof. Berghoff has been a paid consultant for Roche and Daiichi and has received reimbursement of meeting participation fees and of travel and accommodation expenses from Roche, Amgen, Daiichi, and Abbvie, as well as lecture honoraria from Bristol-Myers Squibb. She has received financial support from Daiichi for a research project that she initiated.
The remaining authors state that they have no conflict of interest.
Manuscript received on 31 March 2021, revised version accepted on 6 September 2021.
Translated from the original German by Ethan Taub, M.D.
PD Dr. med. David Kaul
Charité – Universitätsmedizin Berlin
Augustenburger Platz 1, intern: Südring 5
13353 Berlin, Germany
CIte this as:
Kaul D, Berghoff AS, Grosu AL, Weiss Lucas C, Guckenberger M:
Focal radiotherapy of brain metastases in combination with immunotherapy and targeted drug therapy.
Dtsch Arztebl Int 2021; 118: 759–66. DOI: 10.3238/arztebl.m2021.0332
This article has been certified by the North Rhine Academy for Continuing Medical Education. Participation in the CME certification program is possible only over the internet at cme.aerztebatt.de. The deadline for submission is 11 November 2022.
Int J Radiat Oncol Biol Phys 1998; 42: 581–9.
Department of Medicine 1 and Comprehensive Cancer Center Vienna, Medical University of Vienna: Prof. Dr. med. univ. et scient. med. Anna Sophie Berghoff
Department of Radiation Oncology, University Medical Center Freiburg: Prof. Dr. med. Anca-Ligia Grosu
Center of Neurosurgery, University of Cologne, Faculty of Medicine und University Hospital Cologne: PD Dr. med. Carolin Weiss Lucas
Department of Radiation Oncology, University HospitalZürich, University Zürich: Prof. Dr. med. Matthias Guckenberger
|1.||Reungwetwattana T, Nakagawa K, Cho BC, et al.: CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol 2018; 36: 3290–7 CrossRef MEDLINE|
|2.||Gadgeel S, Peters S, Mok T, et al.: Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018; 29: 2214–22 CrossRef MEDLINE PubMed Central|
|3.||Besse B, Le Moulec S, Mazieres J, et al.: Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study. Clin Cancer Res 2015; 21: 1896–903 CrossRef MEDLINE|
|4.||Goldberg SB, Gettinger SN, Mahajan A, et al.: Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016; 17: 976–83 CrossRef|
|5.||Magnuson WJ, Lester-Coll NH, Wu AJ, et al.: Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol 2017; 35: 1070–7 CrossRef MEDLINE|
|6.||Miyawaki E, Kenmotsu H, Mori K, et al.: Optimal sequence of local and EGFR-TKI therapy for EGFR-mutant non-small cell lung cancer with brain metastases stratified by number of brain metastases. Int J Radiat Oncol Biol Phys 2019; 104: 604–13 CrossRef MEDLINE|
|7.||Lee JH, Chen HY, Hsu FM, et al.: Cranial irradiation for patients with epidermal growth factor receptor (EGFR) mutant lung cancer who have brain metastases in the era of a new generation of EGFR inhibitors. Oncologist 2019; 24: e1417–25 CrossRef|
|8.||Dong K, Liang W, Zhao S, et al.: EGFR-TKI plus brain radiotherapy versus EGFR-TKI alone in the management of EGFR-mutated NSCLC patients with brain metastases. Transl Lung Cancer Res 2019; 8: 268–79 CrossRef MEDLINE PubMed Central|
|9.||Ni J, Li G, Yang X, et al.: Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses. Radiat Oncol 2019; 14: 44 CrossRef MEDLINE PubMed Central|
|10.||Lu VM, Goyal A, Rovin RA, Lee A, McDonald KL: Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: a systematic review and meta-analysis. J Neurooncol 2019; 141: 1–12 CrossRef MEDLINE|
|11.||Lehrer EJ, Peterson J, Brown PD, et al.: Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother Oncol 2019; 130: 104–12 CrossRef MEDLINE|
|12.||Sperduto PW, Mesko S, Li J, et al.: Beyond an updated graded prognostic assessment (Breast GPA): a prognostic index and trends in treatment and survival in breast cancer brain metastases from 1985 to today. Int J Radiat Oncol Biol Phys 2020; 107: 334–43 CrossRef MEDLINE PubMed Central|
|13.||Bergen ES, Berghoff AS, Medjedovic M, et al.: Continued endocrine therapy is associated with improved survival in patients with breast cancer brain metastases. Clin Cancer Res 2019; 25: 2737–44 CrossRef MEDLINE|
|14.||Bachelot T, Romieu G, Campone M, et al.: Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013; 14: 64–71 CrossRef|
|15.||Lin NU, Borges V, Anders C, et al.: Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol 2020; 38: 2610–9 CrossRef MEDLINE PubMed Central|
|16.||Bartsch R, Berghoff AS, Vogl U, et al.: Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis 2015; 32: 729–37 CrossRef MEDLINE|
|17.||Modi S, Saura C, Yamashita T, et al.: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020; 382: 610–21 CrossRef MEDLINE PubMed Central|
|18.||Khan M, Zhao Z, Arooj S, Zheng T, Liao G: Lapatinib plus local radiation therapy for brain metastases from HER-2 positive breast cancer patients and role of trastuzumab: a systematic review and meta-analysis. Front Oncol 2020; 10: 576926 CrossRef MEDLINE PubMed Central|
|19.||Bartsch R, Bago-Horvath Z, Berghoff A, et al.: Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer. Eur J Cancer 2012; 48: 1932–8 CrossRef CrossRef MEDLINE|
|20.||Yap YS, Cornelio GH, Devi BC, et al.: Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival. Br J Cancer 2012; 107: 1075–82 CrossRef MEDLINE PubMed Central|
|21.||Yomo S, Hayashi M, Cho N: Impacts of HER2-overexpression and molecular targeting therapy on the efficacy of stereotactic radiosurgery for brain metastases from breast cancer. J Neurooncol 2013; 112: 199–207 CrossRef MEDLINE|
|22.||Miller JA, Kotecha R, Ahluwalia MS, et al.: Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies. Cancer 2017; 123: 2283–93 CrossRef MEDLINE|
|23.||Kim JM, Miller JA, Kotecha R, et al.: Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis. Neuro Oncol 2019; 21: 659–68 CrossRef MEDLINE PubMed Central|
|24.||Parsai S, Miller JA, Juloori A, et al.: Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases. J Neurosurg 2019; 132: 503–11 CrossRef MEDLINE|
|25.||Tawbi HAH, Forsyth PA, Algazi A, et al.: Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018; 379: 722–30 CrossRef MEDLINE PubMed Central|
|26.||Tawbi HAH, Forsyth PAJ, Hodi FS, et al.: Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). Journal of Clinical Oncology 2019; 37: 9501 CrossRef|
|27.||Davies MA, Saiag P, Robert C, et al.: Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017; 18: 863–73 CrossRef|
|28.||Tétu P, Allayous C, Oriano B, et al.: Impact of radiotherapy administered simultaneously with systemic treatment in patients with melanoma brain metastases within MelBase, a French multicentric prospective cohort. Eur J Cancer 2019; 112: 38–46 CrossRef MEDLINE|
|29.||van Opijnen MP, Dirven L, Coremans IEM, Taphoorn MJB, Kapiteijn EHW: The impact of current treatment modalities on the outcomes of patients with melanoma brain metastases: a systematic review. Int J Cancer 2020; 146: 1479–89 CrossRef MEDLINE PubMed Central|
|30.||Schuler M, Wu YL, Hirsh V, et al.: First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol 2016; 11: 380–90 CrossRef MEDLINE|
|31.||Bartsch R, Berghoff A, Pluschnig U, et al.: Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer 2012; 106: 25–31 CrossRef MEDLINE PubMed Central|
|32.||Kotecha R, Kim JM, Miller JA, et al.: The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol 2019; 21: 1060–8 CrossRef CrossRef MEDLINE PubMed Central|
|33.||Mathew M, Tam M, Ott PA, et al.: Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res 2013; 23: 191–5 CrossRef MEDLINE|
|34.||Kiess AP, Wolchok JD, Barker CA, et al.: Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 2015; 92: 368–75 CrossRef MEDLINE PubMed Central|
|35.||Diao K, Bian SX, Routman DM, et al.: Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. J Neurooncol 2018; 139: 421–9 CrossRef MEDLINE PubMed Central|
|36.||Ahmed KA, Stallworth DG, Kim Y, et al.: Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 2016; 27: 434–41 CrossRef CrossRef|
|37.||Ahmed KA, Freilich JM, Sloot S, et al.: LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases. J Neurooncol 2015; 122: 121–6 CrossRef MEDLINE|
|e1.||Lang EF, Slater J: Metastatic brain tumors. Results of surgical and nonsurgical treatment. Surg Clin North Am 1964; 44: 865–72 CrossRef|
|e2.||Nayak L, Lee EQ, Wen PY: Epidemiology of brain metastases. Curr Oncol Rep 2012; 14: 48–54 CrossRef MEDLINE|
|e3.||Schellinger PD, Meinck HM, Thron A: Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999; 44: 275–81 CrossRef MEDLINE|
|e4.||Steindl A, Kreminger J, Moor E, et al.: Clinical characterization of a real-life cohort of 6001 patients with brain metastases from solid cancers treated between 1986–2020. Profferred Paper, ESMO Virtual Congress 2020. Ann Oncol 2020; 31 (suppl. 4): S397–408 CrossRef|
|e5.||DGN - Deutsche Gesellschaft für Neurologie: Leitlinie Hirnmetastasen und Meningeosis neoplastica. www.awmf.org/uploads/tx_szleitlinien/030-060l_S2k_Hirnmetastasen_Meningeosis_neoplastica_ 2015-06-abgelaufen.pdf (last accessed on 11 July 2021).|
|e6.||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: 279–99 CrossRef MEDLINE|
|e7.||Berghoff AS, Bartsch R, Wohrer A, et al.: Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues. Acta Neuropathol 2014; 128: 879–91 CrossRef MEDLINE|
|e8.||Andrews DW, Scott CB, Sperduto PW, et al.: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665–72 CrossRef|
|e9.||Kocher M, Soffietti R, Abacioglu U, 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 CrossRef MEDLINE PubMed Central|
|e10.||Arvanitis CD, Ferraro GB, Jain RK: The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer 2020; 20: 26–41 CrossRef MEDLINE PubMed Central|
|e11.||Mori Y, Kondziolka D, Flickinger JC, Kirkwood JM, Agarwala S, Lunsford LD: Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. |
Int J Radiat Oncol Biol Phys 1998; 42: 581–9.
|e12.||Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD: Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 1998; 83: 344–53 CrossRef|
|e13.||Lesueur P, Lequesne J, Barraux V, et al.: Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer). Radiat Oncol 2018; 13: 138 CrossRef MEDLINE PubMed Central|
|e14.||Kohutek ZA, Yamada Y, Chan TA, et al.: Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol 2015; 125: 149–56 CrossRef MEDLINE PubMed Central|
|e15.||Aoyama H, Shirato H, Tago M, et al.: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91 CrossRef MEDLINE|
|e16.||Li J, Ludmir EB, Wang Y, et al.: Stereotactic radiosurgery versus whole-brain radiation therapy for patients with 4–15 brain metastases: a phase III randomized controlled trial. International Journal of Radiation Oncology*Biology*Physics 2020; 108: S21-22 CrossRef|
|e17.||Yamamoto M, Serizawa T, Shuto T, et al.: Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95 CrossRef CrossRef|
|e18.||Proescholdt MA, Schodel P, Doenitz C, et al.: The management of brain metastases-systematic review of neurosurgical aspects. Cancers (Basel) 2021; 13 CrossRef MEDLINE PubMed Central|
|e19.||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: 1037–44 CrossRef|
|e20.||Li J, Bentzen SM, Li J, Renschler M, Mehta MP: Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys 2008; 71: 64–70 CrossRef MEDLINE|
|e21.||Pinkham MB, Sanghera P, Wall GK, Dawson BD, Whitfield GA: Neurocognitive effects following cranial irradiation for brain metastases. Clin Oncol (R Coll Radiol) 2015; 27: 630–9 CrossRef MEDLINE|
|e22.||Tsao MN, Xu W, Wong RK, et al.: Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2018; 1: CD003869 CrossRef MEDLINE PubMed Central|
|e23.||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: 1019–29 CrossRef MEDLINE PubMed Central|
|e24.||Grosu AL, Frings L, Bentsalo I, et al.: Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD)—a phase II prospective randomized multicenter trial (NOA-14, ARO 2015–3, DKTK-ROG). BMC Cancer 2020; 20: 532 CrossRef MEDLINE PubMed Central|
|e25.||Lange M, Joly F, Vardy J, et al.: Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors. Ann Oncol 2019; 30: 1925–40 CrossRef MEDLINE PubMed Central|
|e26.||Joly F, Castel H, Tron L, Lange M, Vardy J: Potential effect of immunotherapy agents on cognitive function in cancer patients. J Natl Cancer Inst 2020; 112: 123–7 CrossRef MEDLINE PubMed Central|
Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical ResectionJAMA Network Open, 202210.1001/jamanetworkopen.2022.9553
Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting SubgroupsCancers, 202210.3390/cancers14051240