Optimal management of brainstem metastases: a narrative review
Review Article on the Modern Approaches to the Management of Brain Metastases

Optimal management of brainstem metastases: a narrative review

Joan Y. Lee1, Danielle A. Cunningham2, Erin S. Murphy3,4, Samuel T. Chao3,4, John H. Suh3,4

1Department of Medicine, MetroHealth Medical Center, Case Western Reserve School of Medicine, Cleveland, OH, USA; 2Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA; 3Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Contributions: (I) Conception and design: JH Suh, JY Lee; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. John H. Suh, MD. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA. Email: suhj@ccf.org.

Background and Objective: Brainstem metastases comprise fewer than 7% of all brain metastases. Nonetheless, they present clinicians with unique clinical challenges in symptom management and treatment. No comprehensive review summarizing the management of brainstem metastases exists. This review aims to summarize epidemiology, anatomy, clinical correlation, prognosis, options for management of symptoms, treatment, treatment toxicity, and dose and fractionation for brainstem stereotactic radiosurgery (SRS) as reported in the literature.

Methods: In July 2021, we searched PubMed and Embase for retrospective studies of brainstem metastasis treatment, as well as case series and case reports describing diagnosis and clinical management of brainstem metastasis. Keywords and MeSH terms searched included “brainstem metastasis”, “symptomatic brainstem metastasis”, “brain metastasis”, “stereotactic radiosurgery brainstem”, “whole brain radiation brainstem”, “brainstem metastasis resection”, “brainstem radiation toxicity”, “brainstem radiosurgery toxicity”, “brainstem radiosurgery dose”, and “radiosurgery dose tolerance”. Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies.

Key Content and Findings: Single-institution studies and multicenter retrospective analyses from 1993 to 2021 reflect a shift from reliance on whole-brain radiation therapy (WBRT) to SRS for primary treatment of brainstem metastases. Recent multicenter retrospective analyses and single-institution case series support the safety and efficacy of SRS of brainstem metastases in symptom management and preservation of quality of life. Incidence of radiation-induced toxicity following SRS of brainstem metastases is comparable to that of SRS for other brain metastases. Complications following brainstem SRS are most strongly associated with prior WBRT.

Conclusions: Radiation oncologists play a central role in the treatment of brainstem metastases due to reliance on SRS. Dose and fractionation of brainstem SRS remain largely institution-dependent. The field would benefit from inclusion of brainstem metastases in prospective trials of SRS and studies of adverse effects of salvage WBRT after prior SRS of brainstem metastases.

Keywords: Brainstem metastasis; stereotactic radiosurgery (SRS); brainstem dose tolerance; brainstem radiation toxicity

Submitted Dec 28, 2021. Accepted for publication Apr 17, 2022.

doi: 10.21037/cco-21-146


Brain metastases represent the most common neurologic complication of cancer patients with fewer than 7% of all brain metastases found in the brainstem. Historically, brainstem metastases were treated with whole-brain radiation therapy (WBRT) alone, as the density of nuclei and white matter tracts in the region rendered surgical resection and early targeted radiation prohibitively high risk for serious adverse effects. Prospective clinical trials of stereotactic radiosurgery (SRS) for brain metastases also excluded brainstem metastases due to caution with SRS radiation doses and the perceived radiosensitivity of brainstem. Nonetheless, single-institution case series of brainstem metastasis SRS emerged with encouraging findings of safety and efficacy. Recent analyses of multicenter retrospective data support the safety and efficacy of SRS for brainstem metastases and shed light on trends in adverse events after brainstem SRS. This review will outline the pathophysiology of brainstem metastases and their clinical manifestations, historical treatment paradigms, and contemporary trends in management. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-146/rc).


PubMed and Embase were used to compile retrospective studies of brainstem metastasis treatment, case series and case reports describing diagnosis of brainstem management, and case series and case reports describing clinical management of brainstem metastasis on July 1, 2021 (Table 1). Keywords and MeSH terms searched included “brainstem metastasis”, “symptomatic brainstem metastasis”, “brain metastasis”, “stereotactic radiosurgery brainstem”, “whole brain radiation brainstem”, “brainstem metastasis resection”, “brainstem radiation toxicity”, “brainstem radiosurgery toxicity”, “brainstem radiosurgery dose”, and “radiosurgery dose tolerance”. Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. Case reports and case series describing symptomatic brainstem metastasis were included only if the symptomatic neurologic deficit was attributed to a brainstem metastasis. Retrospective cohort studies that were conducted before 2007 were excluded. All co-authors contributed, reviewed, and approved the selected literature for this review.

Table 1

Methods for selection of literature included in this review

Items Specification
Date of search July 1, 2022
Databases and other sources searched PubMed, Embase
Search terms used Brainstem metastasis, symptomatic brainstem metastasis, brain metastasis, stereotactic radiosurgery brainstem, whole brain radiation brainstem, brainstem metastasis resection, brainstem radiation toxicity, brainstem radiosurgery toxicity, brainstem radiosurgery dose, radiosurgery dose tolerance
Timeframe For case reports and case series: 1950–2014. For retrospective cohort studies: 2007–2021
Inclusion and exclusion criteria All retrospective cohort studies were English language. All case reports on symptomatic brainstem metastasis must have explicitly attributed a neurological deficit to the brainstem metastasis
Selection process All authors contributed and reviewed the selected literature
Any additional considerations, if applicable None


The literature has reported that 80–85% of brain metastases are located in the cerebral hemisphere, 10–15% in the cerebellum and 3–7% in the brainstem (1-4). The lower incidence of brainstem metastases relative to other brain metastases is attributed to the small volume of the brainstem (less than 3% of the brain by weight) and greater distribution of arterial perfusion to the anterior circulation, which supplies the cerebral hemispheres, over the posterior circulation that supplies the brainstem and cerebellum. High resolution phase contrast magnetic resonance imaging (MRI) studies revealed that 72% of intracranial arterial perfusion is received through the internal carotid arteries (anterior circulation), while 28% is received through the vertebral arteries (posterior circulation) (5).

The pons is the most common location of brainstem metastasis, followed by the midbrain, and then the medulla (6,7). The largest existing analysis of multicenter retrospective data reports that the most frequently associated primary malignancies are lung (44.9%, predominantly non-small cell), followed by breast (20.2%), melanoma (10%), renal cell/genitourinary (7.5%), and gastrointestinal (GI) cancers (4.5%). These incidences are similar to those found in a classical autopsy study of brainstem metastases (46.7% lung, 13.3% breast, 8.9% melanoma, 4.5% renal cell, 4.5% GI), as well as the incidences of primary malignancies for all brain metastases (50% lung cancer, predominantly non-small cell, 15% breast, 7% melanoma, 7% renal cell, and 6% GI) (2,4).

Brainstem anatomy

Superiorly to inferiorly, the brainstem is composed of the diencephalon, midbrain, pons, and medulla oblongata. These structures are densely populated by nuclei and white matter tracts that allow communication among the cerebral hemispheres, cerebellum, and spinal cord. The major white matter tracts that travel through the brainstem are the reticular formation, pontocerebellar tract, corticospinal and corticobulbar motor tracts, spinothalamic tract, dorsal column/medial lemniscus, lateral lemniscus, trigeminal lemniscus, and spinotrigeminal tract.

The diencephalon flanks the third ventricle and contains the epithalamus, subthalamus, hypothalamus, and thalamus. Notable structures include the pineal gland, mammillary bodies, nucleus of Meynert, subthalamic nucleus, lateral geniculate nucleus, and medial geniculate nucleus. The diencephalon is involved in memory consolidation, sensory integration, modulation of motor activity, and regulation of consciousness.

The midbrain envelops the cerebral aqueduct connecting the third and fourth ventricles. Notable structures include the superior and inferior colliculi, medial longitudinal fasciculus, substantia nigra, red nucleus, dorsal raphe nucleus, periaqueductal grey, and the nuclei of cranial nerves (CNs) III and IV. The midbrain is involved in visual and auditory processing, oculomotor reflexes, coordination of eye movements, and motor regulation (substantia nigra, red nucleus).

The pons connects the midbrain with the medulla and cerebellum. Notable structures include the locus coeruleus, pontine nucleus, and the nuclei of CNs V, VI, VII, and VIII. The pontine structures are involved in coordination, autonomic functions, hearing, taste, facial sensation and motor function.

The medulla connects the pons to spinal cord and abuts the fourth ventricle. The nucleus solitarius, cardiovascular, respiratory, vomiting, and vasomotor centers contribute to the autonomic nervous system. The nucleus ambiguus and inferior salivary nucleus regulate swallowing. The gracile and cuneate nuclei, also known as the dorsal column nuclei, integrate sensory input from the dorsal column-medial lemniscus pathway. The medullary pyramids carry motor fibers of the corticobulbar and corticospinal tracts. The olivary bodies and vestibular nucleus regulate coordination and equilibrium. The nuclei of CNs IX, X, XI, and XII are located in the medulla.

Clinical presentation

Nearly half of brainstem metastases are asymptomatic upon discovery, in part due to the sensitivity of MRI and its frequent use in workup and follow-up imaging of patients with cancer. Symptomatic brainstem metastases result from direct impingement of nuclei, tracts, or CNs caused by mass effect or vasogenic edema. In a pooled meta-analysis of 22 single-institution studies, Chen and colleagues reported that 49% of brainstem metastases among 1,104 patients were symptomatic at diagnosis, with a 46.8% median incidence of symptomatic brainstem metastasis among the studies (7). Reports of brainstem-localizing signs in the literature are summarized in Table 2 (8-14). Specifically, involvement of the corticospinal tract can result in hemiparesis while hemisensory loss can result from damage to the medial lemniscus. Ataxia can result from disruption of brainstem-cerebellum communication. CN palsies can be caused by lesions of the CN nuclei, internuclear connections or efferent fibers. Figure 1 demonstrates post-gadolinium MRI imaging of a symptomatic metastatic lesion to the pons.

Table 2

Symptomatic brainstem metastases reported in the literature

Author Presenting symptom(s) No. of patients Location of metastasis Intervention Primary tumor
Awad Headache, tinnitus, ataxia, RUE paresthesia, bilateral dysmetria, hyperreflexia, gait disturbance 1 Pontomedullary Resection and trastuzumab Breast carcinoma
Straube Dysarthria, psychic aura, nystagmus 1 Pontomedullary None Lung carcinoma
Derby Headache, light-headedness, bilateral lower extremity weakness, dysarthria, tremor, horizontal conjugate gaze palsy nausea, vomiting 1 Intra-axial None Renal clear cell
Karampelas Hemiballismus 1 Subthalamic nucleus GKRS 18 Gy to 50% isodose line, topiramate 50 mg BID Breast carcinoma
Glass Hemiballismus 1 Subthalamic nucleus None Lung adenocarcinoma
Moore Hemiballismus 1 Left frontal, right occipital, pontine, cerebellar, and bilateral thalamic Lung
Vale Hemiballismus 1 Left subthalamus WBRT, risperidone Breast carcinoma
Hunter Hemiparesis 11 Unknown Unknown Unknown
Hunter CN III palsy 3 Unknown Unknown Unknown
Hunter CN IV palsy 2 Unknown Unknown Unknown
Hunter CN V palsy 3 Unknown Unknown Unknown
Tomecek CN VI palsy, nystagmus, ataxia, obstructive hydrocephalus 1 Dorsal rostral aspect of the midbrain Dexamethasone, VP shunt, resection, phenytoin Kidney adenocarcinoma
Hunter CN VI palsy 4 Unknown Unknown Unknown
Reyes CN VI palsy (binocular horizontal diplopia) 1 Right pons Radiation Breast carcinoma
Derby CN VII palsy, L sided headache, nausea, vomiting, hemibody weakness, sensory impairment 1 Mesencephalopontine, pontomedullary None Undifferentiated lung
Hunter CN VII palsy 4 Unknown Unknown Unknown
Hunter Dysconjugate gaze 3 Unknown Unknown Unknown
Inci Locked-in syndrome 1 Pontomedullary Resection Melanoma
Pogacar Locked-in syndrome 1 Pontomedullary None Lung adenocarcinoma
Hunter Ataxia 5 Unknown Unknown Unknown
Derby Ataxia, R sided falling, RUE numbness, gaze deviation, unilateral hearing loss 1 Tegmentum None Lung adenocarcinoma
Hunter Hemisensory loss 2 Unknown Unknown Unknown
Hunter Obstructive hydrocephalus 4 Unknown Unknown Unknown

RUE, right upper extremity; CN, cranial nerve; L sided, left sided; R sided, right sided; GKRS, gamma Knife radiosurgery; BID, twice daily; WBRT, whole brain radiation therapy; VP, ventriculo-peritoneal.

Figure 1 Axial T1-weighted MRI of pontine metastasis before and after radiosurgery. (A) Melanoma metastatic to the pons resulting in a 6 mm left pontine lesion causing hemiparesis. (B) This lesion was treated with single fraction linear accelerator-based radiosurgery, and 6 months later, the lesion involuted and resolved. MRI, magnetic resonance imaging.


The median survival time of patients with brainstem metastases left untreated has been reported as 1 month (15,16). The prognosis improves for patients who receive treatment but depends on the intracranial response to treatment as well as control of extracranial disease. On multi-institutional analysis of patients treated with radiosurgery for brainstem metastases, median survival was 5.6 months, and 1-year survival was 32.7%. Chen and colleagues report an objective response rate of 59% in 642 patients across 17 studies (7). The 1-year local control rate was 86% in 1,410 patients across 31 studies who had brainstem metastases treated with SRS. There was a 33% 1-year overall survival in 1,254 patients across 27 studies and 2-year survival of 13% in 959 patients across 22 studies. Only 2.7% of deaths after treatment were attributable to progression of the brainstem metastasis, among 703 patients pooled from 19 studies; 68.6% died from systemic disease, and 18.7% died from non-brainstem intracranial disease (7).

Various studies have associated longer survival with control of extracranial disease, higher Karnofsky performance status (KPS), and class I or II recursive partitioning analysis (RPA) at time of treatment (16-23). Other favorable prognostic factors have been reported without consensus in the literature, including lower number of brain metastases, non-melanoma histology and smaller tumor volume (8,24,25).

Symptom management

Currently, SRS is the definitive mode of alleviating symptomatic brainstem metastasis.

Chen and colleagues reported a 55% symptom improvement rate in 323 patients across 13 studies (7). Some clinical manifestations of brainstem metastasis may require management in the interim before radiosurgery. Corticosteroids and anti-epileptic drugs (AEDs) are the mainstays of symptomatic management of brain metastasis, though some patients may require a shunt. The Congress of Neurological Surgeons Evidence-Based Guidelines recommend starting 4 to 8 mg/d of dexamethasone for mild symptoms of elevated intracranial pressure and peritumoral edema secondary to brain metastases and higher doses such as 16 mg/d for severe symptoms (26). In patients with impaired consciousness or other severe signs of elevated intracranial pressure, Sawaya and colleagues report that headache and neurologic deficits may respond to corticosteroids within 1 day and full effect within 48 hours (27). Steroid doses should be tapered as soon as possible as tolerated to minimize adverse effects of long-term corticosteroid use. The benefits and harms of corticosteroid use must be carefully considered if used concurrently with immune checkpoint inhibitors. Baseline corticosteroid use of ≥10 mg of prednisone equivalent has been associated with inferior outcomes in patients with non-small-cell lung cancer (NSCLC) treated with PD-(L)1 blockade (28,29).

Brainstem seizures are generally rare, brief episodes (15–60 seconds) of sensory and motor disturbance with a tonic-algetic and akinetic-atonic pattern without loss of consciousness. Electroencephalogram (EEG) typically demonstrates a normal pattern with occasional, transient decreases of amplitude. Carbamazepine, valproic acid, and phenytoin are effective AEDs for brainstem seizures (30).


Surgical resection of brainstem metastases is seldom attempted due to high risks of operating on the brainstem, as it is critical for neurologic function and injury can result in severe neurologic symptoms or death (31-33). Brainstem metastases have largely been excluded from prospective trials of SRS for treatment of brain metastases due to concern that brainstem toxicity would result from radiation doses that are acceptable in the remainder of the brain (34,35).

Whole-brain and targeted radiation therapy techniques were initially utilized as the primary treatment options for brainstem metastases. A single-institution study of SRS for metastatic melanoma in 1993 described four cases of brainstem SRS (36). Subsequent case series presented evidence of efficacy and safety of SRS for brainstem metastases (37-39). Single-institution retrospective studies have provided useful information on local control, median survival, and adverse events (8,9,18,24,40-47). Koyfman and colleagues at Cleveland Clinic described a series of 43 patients with single brainstem metastases who underwent SRS as the first local treatment (21 patients) or as salvage after previous WBRT (22 patients) (47). These patients were treated at a median prescription dose of 15 (range, 9.6–24) Gy with a mean conformality index of 1.7 and mean heterogeneity index of 1.9. Of the 33 patients with post-treatment MRI scans, radiographic radionecrosis was demonstrated in 2 (6%) patients. No grade 3 or 4 toxicities were observed. Grade 1 or 2 weakness, ataxia, and bleeding from a pin site were noted in 3 patients.

At the time of this review, two multi-institutional analyses of brainstem metastases treated with SRS have been conducted. Trifiletti and colleagues (47) obtained and analyzed the data of 547 patients with 596 SRS-treated brainstem metastases from collaborators in the International Gamma Knife Research Foundation. This cohort had a median dose of 16 Gy prescribed to the 50% isodose line and a median maximum dose of 30 Gy. At 1 year after SRS, local control was achieved in 81.8% of tumors and overall survival at 1 year after SRS was 32.7%. 7.4% of patients experienced treatment-related grade 3 or higher toxicities (47). Most recently, Chen and colleagues (7) conducted a meta-analysis of data from 32 retrospective studies that included 1,446 patients with 1,590 brainstem metastases, not including the patients described in the 2016 multicenter retrospective study by Trifiletti and colleagues (47). The brainstem metastases were treated with a median marginal dose of 16 (range, 11–39) Gy in a median of 1 (range, 1–13) fraction. Local control was achieved in 86% of lesions at 1 year in 1,410 patients across 31 studies, and the 1-year overall survival rate was 33% in 1,254 patients across 27 studies. Grade 3 to 5 treatment related toxicities were noted in 2.4% of 1,421 patients across 31 studies. The objective response rate was 59% in 642 patients across 17 studies and 55% of patients had improvement in their symptoms in 323 patients across 13 studies (7). Figures 2,3 illustrate treatment plans of solitary brainstem metastases.

Figure 2 T1-weighted MRI images of metastasis in close proximity to midbrain and pons. (A) Sagittal and axial images of patient with melanoma metastatic to the cerebral aqueduct posterior to the midbrain and pons. (B) This lesion was treated with 27 Gy in 3 fractions of linear accelerator-based radiosurgery. MRI, magnetic resonance imaging.
Figure 3 T1-weighted MRI images of patient with a metastatic lesion in midbrain, before and after radiosurgery. (A) Sagittal and axial images of patient with lung adenocarcinoma metastatic to the central midbrain, (B) treated with 27 Gy in 3 fractions of linear accelerator-based radiosurgery. (C) Significant decrease in size and gadolinium enhancement was noted 6 months following radiosurgery. MRI, magnetic resonance imaging.


SRS is often delivered in a single fraction, but may also be given in 2 to 5 fractions for larger targets or those near critical normal tissues such as the brainstem. No guidelines exist for tumor margin dose selection of SRS for brainstem metastases which is currently institution-dependent. Conflicting findings exist regarding the optimum margin dose, with some reports of correlation between higher marginal dose and longer survival (16,42), although this may be at the expense of greater toxicity. Valery and colleagues reported a local control rate of 90% and median survival time of 10 months with a median marginal dose of only 13.4 Gy. Other series have recommended tumor margin doses as low as 12 Gy (48). Factors influencing dose selection include tumor volume, tumor histology, and prior radiotherapy (44,49). Additionally, the radiosurgical technology used (Gamma Knife versus linear accelerator-based radiosurgery) impacts the rate of dose fall-off which influences the margin dose.

Regarding doses for single fraction SRS for brainstem metastases, experts have recommended margin doses of 20 Gy for lesions <1 cc, 18 Gy for 1–2 cc lesions, and 15 Gy for lesions >2 cc. Other regimens in the literature for the tumors in or near the brainstem include 27 Gy in 3 fractions and 25–31 Gy in 5 fractions (50). The brainstem maximum point set by Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC), which was based solely on single-fraction SRS data, indicates that 12.5 Gy in one fraction carries a <5% risk of brainstem injury, though other studies have indicated that a maximum brainstem dose of 15–20 Gy carries a low risk of injury (35). The American Association of Physicists in Medicine (AAPM) Task Group 101 report recommends a maximum brainstem dose of <23.1 Gy in 3 fractions and ≤31 Gy in 5 fractions (51). The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/stereotactic body radiation therapy (SBRT) HyTEC study [2021] explicitly omitted studies that focused on brainstem toxicity and did not report specific recommendations or dose-volume metrics predictive of brainstem toxicity (52).


Edema, hemorrhage, and radionecrosis are the underlying mechanisms of adverse events following SRS. The most frequently reported toxicities after brainstem SRS are postprocedure headache (which may be associated with head frame placement), fatigue, nausea, vomiting, which are usually self-limited or effectively treated with corticosteroids (40,48). Confusion, ataxia, weakness, focal neurologic deficits, and seizures have also been reported (24,41,42,45). Yoo and colleagues reported one death from a hemorrhagic tumor following Gamma Knife SRS to a pontine lesion treated with 14.8 Gy (22). Adverse effects that were reported in the literature are summarized in Table 3. A case of radiation necrosis after WBRT with SRS boost to brainstem metastasis is described in Figure 4. Despite steroids, there was progression of the presumed radiation necrosis. She subsequently passed away with an abrupt decline in her functional and neurologic status.

Table 3

Acute toxicities following brainstem SRS

Author Presenting symptom Radiologic finding Treatment Toxicity grade Tumor histology Prior WBRT Dose (Gy) Toxicity frequency Total patients in study
Kelly Altered mental status Unknown Steroids Grade 3 Unknown Unknown Unknown 1 24
Kilburn Ataxia Radiation necrosis Steroids Grade 1–2 NSCLC No 18 2 44
Kelly Ataxia Unknown Steroids Grade 3 Unknown Unknown Unknown 1 24
Koyfman Ataxia Unknown Unknown Grade 1–2 Unknown Unknown Unknown 1 43
Kilburn Ataxia and diplopia Radiation necrosis Bevacizumab Grade 3 Adenocarcinoma, unknown primary No 18 1 44
Kawabe Ataxia, death Edema Unknown Grade 5 NSCLC No 18 1 200
Kased Ataxia, dysequilibrium, and left facial numbness Radiation necrosis Unknown Grade 3 RCC No 12 1 42
Hatiboglu CN palsy Unknown Unknown Grade 1–2 Unknown Unknown Unknown 2 60
Lin CN V palsy Radiation necrosis Unknown Grade 3 Unknown Unknown 17 1 45
Nakamura CN VI palsy Edema Unknown Grade 1–2 Unknown Unknown Unknown 1 20
Lin CN VII palsy Unknown Unknown Grade 3 Unknown Unknown 12 1 45
Winograd CN VII palsy Unknown Steroids, bevacizumab Grade 3 Endometrial Unknown Unknown 1 41
Kilburn Diplopia Unknown Steroids Grade 3 Ovarian No 18 1 44
Kilburn Diplopia and dysphagia Unknown Steroids Grade 3 NSCLC No 17 1 44
Voong Gait disturbance Edema Steroids Grade 3 Sarcoma Unknown 18 1 74
Voong Gait disturbance Edema Unknown Grade 3 Melanoma Unknown 15 1 74
Voong Headache Edema Unknown Grade 1–2 Melanoma Unknown 14 1 74
Leeman Headache Unknown Steroids Grade 1–2 Unknown Unknown Unknown 2 36
Valery Headache Unknown Steroids Grade 1–2 Unknown Unknown Unknown 4 30
Hatiboglu Headache Unknown Unknown Grade 1–2 Unknown Unknown Unknown 3 60
Voong Headache, vomiting Hemorrhage and radiation necrosis Pentoxifylline Grade 3 Lung Unknown 16 1 74
Joshi Hemiparesis Unknown Unknown Grade 3 NSCLC Unknown 14 1 48
Joshi Hemiparesis Unknown Steroids Grade 3 SCLC Unknown 15 1 48
Hussain Hemiparesis Unknown Unknown Grade 3 Unknown Yes 18 1 22
Winograd Hemiparesis Edema Steroids, bevacizumab Grade 3 Unknown Unknown 16 1 41
Kased Hemiparesis Hemorrhage Unknown Grade 3 RCC Yes 16 1 42
Hatiboglu Hemiparesis Unknown Unknown Grade 1–2 Unknown Unknown Unknown 2 60
Hatiboglu Hemiparesis Unknown Unknown Grade 3 Unknown Unknown Unknown 1 60
Kased Hemiparesis Unknown Unknown Grade 3 Unknown Yes 15 1 42
Hatiboglu Hemiparesis, CN palsy Hemorrhage Unknown Grade 3 Unknown Unknown Unknown 1 60
Trifiletti Hemiplegia, loss of consciousness Radiation necrosis, edema Unknown Grade 3 RCC No 18 1 161
Voong Horner’ syndrome, visual disturbance Radiation necrosis Bevacizumab Grade 3 Breast Unknown 16 1 74
Nakamura ICH Hemorrhage Steroids Grade 3 Melanoma Unknown Unknown 1 20
Trifiletti ICH and death Hemorrhage Steroids Grade 5 Melanoma No 20 1 161
Peterson ICH and death Hemorrhage Steroids Grade 5 Melanoma Unknown Unknown 1 1
Yoo ICH and death Hemorrhage Steroids Grade 5 Melanoma No 14.8 1 32
Murray Leg pain, dizziness, speech difficulty Radiation necrosis Steroids, hyperbaric oxygen Grade 3 Unknown Yes 15 1 44
Voong Leg weakness and imbalance Edema Unknown Grade 3 Thyroid Unknown 20 1 74
Sugimoto Nausea Unknown Steroids Grade 1–2 Unknown Unknown Unknown 1 24
Leeman Nausea Unknown Steroids Grade 1–2 Unknown Unknown Unknown 1 74
Huang Nausea, vomiting, dizziness Unknown Unknown Grade 1–2 Unknown Unknown Unknown 4 26
Hatiboglu Nausea, vomiting Unknown Unknown Grade 1–2 Unknown Unknown Unknown 1 60
Hatiboglu Nausea, vomiting Unknown Unknown Grade 1–2 Unknown Unknown Unknown 1 60
Hatiboglu Nausea, vomiting Unknown Unknown Grade 1–2 Unknown Unknown Unknown 1 60
Guney Pyramidal motor syndrome Unknown Unknown Grade 3 Unknown Unknown Unknown 1 21
Nakamura Pyramidal motor syndrome Edema Unknown Grade 1–2 Unknown Unknown Unknown 2 20
Murray Quadriparesis Radiation necrosis Steroids Grade 3 Unknown Yes 15 1 44
Huang Seizure Unknown AED Grade 3 Unknown Unknown Unknown 3 26
Koyfman Weakness Unknown Unknown Grade 1–2 Unknown Unknown Unknown 1 43

SRS, stereotactic radiosurgery; CN, cranial nerve; ICH, intracranial hemorrhage; AED, anti-epileptic drug; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; SCLC, small-cell lung cancer; WBRT, whole-brain radiation therapy.

Figure 4 A 52-year-old female with 1.2 cm diameter midbrain metastasis from squamous cell lung cancer, treated with WBRT to 37.5 Gy with SRS boost of 15 Gy to the brainstem metastasis. (A) MRI at diagnosis of brain metastasis. (B) MRI at time of SRS boost. (C) MRI 4 months post-SRS shows improvement. (D) MRI and (E) MR perfusion images consistent with radiation necrosis after patient developed worsening headaches (note negative cerebral blood volume). WBRT, whole-brain radiation therapy; SRS, stereotactic radiosurgery; MRI, magnetic resonance imaging; MR, magnetic resonance.

Rates of adverse events after brainstem SRS ranged from 0% to 27% in 31 single-institution retrospective studies analyzed by Chen and colleagues, with an overall 5.6% rate of symptomatic adverse effects and 2.4% rate of grade 3 to 5 toxicities in 1,421 patients (7).

Trifiletti and colleagues (47) reported that 7.4% of their cohort experienced grade 3–5 toxicities. These rates are comparable to the 3–8% toxicity rates reported in prospective randomized/observational trials for SRS for all brain metastases. However, brainstem SRS appears to have a shorter median time to development of toxicity (3 months) compared to cerebral lesions (4.5 months) (53).

Individual risk factors, particularly prior WBRT, may influence the incidence of posttreatment toxicities. Of the 44 patients in the Trifiletti study (47) who developed a severe toxicity, 84% had undergone WBRT before brainstem SRS. The authors also found that an interval of at least 4.5 months between WBRT and brainstem SRS was associated with lower risk of toxicity (odds ratio, 0.116). Increased tumor volume and higher margin dose have also been reported as risk factors (18).


Brainstem metastases pose challenging clinical problems in the setting of various primary malignancies. The radiation oncologist occupies a central role in the treatment of brainstem metastases, perhaps even more than in the treatment of metastatic disease in other regions of the brain, due to the inoperability of the brainstem. Despite the exclusion of brainstem metastases from prospective trials of SRS, single-institution reports on brainstem SRS consistently demonstrated improvement or prevention of symptoms secondary to brainstem lesions, preservation of quality of life, and toxicity rates that are comparable to those of SRS for other brain metastases. A compelling rationale therefore exists for inclusion of brainstem metastases in future prospective trials of SRS to develop optimal dose and fractionation schemes. Dose and fractionation for brainstem SRS remain institution-dependent with some guidelines. The extant literature demonstrates that complications following brainstem SRS are most strongly associated with prior WBRT. As WBRT is used less frequently as the initial mode of treatment for brain metastases, toxicity following brainstem SRS may be of lesser concern. However, future studies may examine adverse effects of WBRT for salvage therapy after prior SRS of brainstem metastases.


Funding: None.


Provenance and Peer Review: This article was commissioned by the Guest Editors (Simon S. Lo, Balamurugan Vellayappan, Kevin Shiue and Jonathan P. S. Knisely) for the series “The Modern Approaches to the Management of Brain Metastases” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-21-146/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-21-146/coif). The series “The Modern Approaches to the Management of Brain Metastases” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


  1. Delattre JY, Krol G, Thaler HT, et al. Distribution of brain metastases. Arch Neurol 1988;45:741-4. [Crossref] [PubMed]
  2. Suh JH, Kotecha R, Chao ST, et al. Current approaches to the management of brain metastases. Nat Rev Clin Oncol 2020;17:279-99. [Crossref] [PubMed]
  3. Ostrom QT, Wright CH, Barnholtz-Sloan JS. Brain metastases: epidemiology. Handb Clin Neurol 2018;149:27-42. [Crossref] [PubMed]
  4. Hunter KM, Rewcastle NB. Metastatic neoplasms of the brain stem. Can Med Assoc J 1968;98:1-7. [PubMed]
  5. Zarrinkoob L, Ambarki K, Wåhlin A, et al. Blood flow distribution in cerebral arteries. J Cereb Blood Flow Metab 2015;35:648-54. [Crossref] [PubMed]
  6. Patel A, Dong T, Ansari S, et al. Toxicity of Radiosurgery for Brainstem Metastases. World Neurosurg 2018;119:e757-64. [Crossref] [PubMed]
  7. Chen WC, Baal UH, Baal JD, et al. Efficacy and Safety of Stereotactic Radiosurgery for Brainstem Metastases: A Systematic Review and Meta-analysis. JAMA Oncol 2021;7:1033-40. [Crossref] [PubMed]
  8. Voong KR, Farnia B, Wang Q, et al. Gamma knife stereotactic radiosurgery in the treatment of brainstem metastases: The MD Anderson experience. Neurooncol Pract 2015;2:40-7. [Crossref] [PubMed]
  9. Winograd E, Rivers CI, Fenstermaker R, et al. The case for radiosurgery for brainstem metastases. J Neurooncol 2019;143:585-95. [Crossref] [PubMed]
  10. Reyes KB, Lee HY, Ng I, et al. Abducens (sixth) nerve palsy presenting as a rare case of isolated brainstem metastasis from a primary breast carcinoma. Singapore Med J 2011;52:e220-2. [PubMed]
  11. Inci S, Ozgen T. Locked-in syndrome due to metastatic pontomedullary tumor--case report. Neurol Med Chir (Tokyo) 2003;43:497-500. [Crossref] [PubMed]
  12. Straube A, Witt TN. Oculo-bulbar myasthenic symptoms as the sole sign of tumour involving or compressing the brain stem. J Neurol 1990;237:369-71. [Crossref] [PubMed]
  13. Shuto T, Fujino H, Asada H, et al. Gamma knife radiosurgery for metastatic tumours in the brain stem. Acta Neurochir (Wien) 2003;145:755-60. [Crossref] [PubMed]
  14. Karampelas I, Podgorsak MB, Plunkett RJ, et al. Subthalamic nucleus metastasis causing hemichorea-hemiballism treated by gamma knife stereotactic radiosurgery. Acta Neurochir (Wien) 2008;150:395-6; discussion 397. [Crossref] [PubMed]
  15. Coia LR. The role of radiation therapy in the treatment of brain metastases. Int J Radiat Oncol Biol Phys 1992;23:229-38. [Crossref] [PubMed]
  16. Lorenzoni J, Devriendt D, Massager N, et al. Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 2004;60:218-24. [Crossref] [PubMed]
  17. Kawabe T, Yamamoto M, Sato Y, et al. Gamma Knife surgery for patients with brainstem metastases. J Neurosurg 2012;117:23-30. [Crossref] [PubMed]
  18. Kased N, Huang K, Nakamura JL, et al. Gamma knife radiosurgery for brainstem metastases: the UCSF experience. J Neurooncol 2008;86:195-205. [Crossref] [PubMed]
  19. Sneed PK, Mendez J, Vemer-van den Hoek JG, et al. Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg 2015;123:373-86. [Crossref] [PubMed]
  20. Simonová G, Liscák R, Novotný J Jr, et al. Solitary brain metastases treated with the Leksell gamma knife: prognostic factors for patients. Radiother Oncol 2000;57:207-13. [Crossref] [PubMed]
  21. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72. [Crossref] [PubMed]
  22. Yoo TW, Park ES, Kwon DH, et al. Gamma knife radiosurgery for brainstem metastasis. J Korean Neurosurg Soc 2011;50:299-303. [Crossref] [PubMed]
  23. Dea N, Borduas M, Kenny B, et al. Safety and efficacy of Gamma Knife surgery for brain metastases in eloquent locations. J Neurosurg 2010;113:79-83. [Crossref] [PubMed]
  24. Hussain A, Brown PD, Stafford SL, et al. Stereotactic radiosurgery for brainstem metastases: Survival, tumor control, and patient outcomes. Int J Radiat Oncol Biol Phys 2007;67:521-4. [Crossref] [PubMed]
  25. Trifiletti DM, Lee CC, Kano H, et al. Stereotactic Radiosurgery for Brainstem Metastases: An International Cooperative Study to Define Response and Toxicity. Int J Radiat Oncol Biol Phys 2016;96:280-8. [Crossref] [PubMed]
  26. Ryken TC, Kuo JS, Prabhu RS, et al. Neurosurgery 2019;84:E189-91. [Crossref] [PubMed]
  27. Sawaya R, Ligon BL, Bindal RK. Management of metastatic brain tumors. Ann Surg Oncol 1994;1:169-78. [Crossref] [PubMed]
  28. Arbour KC, Mezquita L, Long N, et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:2872-8. [Crossref] [PubMed]
  29. Pan EY, Merl MY, Lin K. The impact of corticosteroid use during anti-PD1 treatment. J Oncol Pharm Pract 2020;26:814-22. [Crossref] [PubMed]
  30. Glötzner FL. Brain stem seizures (author's transl). Fortschr Neurol Psychiatr Grenzgeb 1979;47:538-49. [PubMed]
  31. Gerges MM, Godil SS, Kacker A, et al. Endoscopic Endonasal Transclival Resection of a Pontine Metastasis: Case Report and Operative Video. Oper Neurosurg (Hagerstown) 2020;19:E75-81. [Crossref] [PubMed]
  32. Awad AW, Zaidi HA, Awad AH, et al. Long-term Survival after Resection of HER2+ Infiltrating Ductal Carcinoma Metastasis to the Brainstem. Cureus 2016;8:e462. [Crossref] [PubMed]
  33. Tomecek FJ, Ausman JI, Malik GM. Surgical removal of metastatic renal adenocarcinoma to the midbrain tectum: a case report. Henry Ford Hosp Med J 1990;38:72-5. [PubMed]
  34. Sharma MS, Kondziolka D, Khan A, et al. Radiation tolerance limits of the brainstem. Neurosurgery 2008;63:728-32; discussion 732-3. [Crossref] [PubMed]
  35. Mayo C, Yorke E, Merchant TE. Radiation associated brainstem injury. Int J Radiat Oncol Biol Phys 2010;76:S36-41. [Crossref] [PubMed]
  36. Somaza S, Kondziolka D, Lunsford LD, et al. Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 1993;79:661-6. [Crossref] [PubMed]
  37. Kondziolka D, Lunsford LD, Flickinger JC. Intraparenchymal brain stem radiosurgery. Neurosurg Clin N Am 1993;4:469-79. [Crossref] [PubMed]
  38. Hirato M, Nakamura M, Inoue HK, et al. Gamma Knife radiosurgery for the treatment of brainstem tumors. Stereotact Funct Neurosurg 1995;64:32-41. [Crossref] [PubMed]
  39. Videtic GMM, Gaspar LE, Zamorano L, et al. γ-Knife Radiosurgery for Brainstem Lesions: The Wayne State University Experience. Journal of Radiosurgery 1999;2:135-9. [Crossref]
  40. Huang CF, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for brainstem metastases. J Neurosurg 1999;91:563-8. [Crossref] [PubMed]
  41. Koyfman SA, Tendulkar RD, Chao ST, et al. Stereotactic radiosurgery for single brainstem metastases: the cleveland clinic experience. Int J Radiat Oncol Biol Phys 2010;78:409-14. [Crossref] [PubMed]
  42. Hatiboglu MA, Chang EL, Suki D, et al. Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery. Neurosurgery 2011;69:796-806; discussion 806. [Crossref] [PubMed]
  43. Fuentes S, Delsanti C, Metellus P, et al. Brainstem metastases: management using gamma knife radiosurgery. Neurosurgery 2006;58:37-42; discussion 37-42. [Crossref] [PubMed]
  44. Yen CP, Sheehan J, Patterson G, et al. Gamma knife surgery for metastatic brainstem tumors. J Neurosurg 2006;105:213-9. [Crossref] [PubMed]
  45. Kelly PJ, Lin YB, Yu AY, et al. Linear accelerator-based stereotactic radiosurgery for brainstem metastases: the Dana-Farber/Brigham and Women's Cancer Center experience. J Neurooncol 2011;104:553-7. [Crossref] [PubMed]
  46. Peterson HE, Larson EW, Fairbanks RK, et al. Gamma knife treatment of brainstem metastases. Int J Mol Sci 2014;15:9748-61. [Crossref] [PubMed]
  47. Trifiletti DM, Lee CC, Winardi W, et al. Brainstem metastases treated with stereotactic radiosurgery: safety, efficacy, and dose response. J Neurooncol 2015;125:385-92. [Crossref] [PubMed]
  48. Valery CA, Boskos C, Boisserie G, et al. Minimized doses for linear accelerator radiosurgery of brainstem metastasis. Int J Radiat Oncol Biol Phys 2011;80:362-8. [Crossref] [PubMed]
  49. Vogelbaum MA, Angelov L, Lee SY, et al. Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. J Neurosurg 2006;104:907-12. [Crossref] [PubMed]
  50. Morimoto M, Yoshioka Y, Kotsuma T, et al. Hypofractionated stereotactic radiation therapy in three to five fractions for vestibular schwannoma. Jpn J Clin Oncol 2013;43:805-12. [Crossref] [PubMed]
  51. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys 2010;37:4078-101. [Crossref] [PubMed]
  52. Milano MT, Grimm J, Niemierko A, et al. Single- and Multifraction Stereotactic Radiosurgery Dose/Volume Tolerances of the Brain. Int J Radiat Oncol Biol Phys 2021;110:68-86. [Crossref] [PubMed]
  53. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000;47:291-8. [Crossref] [PubMed]
Cite this article as: Lee JY, Cunningham DA, Murphy ES, Chao ST, Suh JH. Optimal management of brainstem metastases: a narrative review. Chin Clin Oncol 2022;11(2):15. doi: 10.21037/cco-21-146

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