1. Introduction

Brain metastases (BM) affect between 20%-40% of all cancer patients. The incidence and prevalence of BMs are increasing worldwide, due to the advances in diagnostic and therapeutic procedures that transform the disease into a chronic one (1).

Brainstem metastases (BSM), constituting approximately 11% of all BM, often lead to severe neurological deficits and inferior survival (1). Owing to the proximity to critical neurologic structures, treatment options for BSM are limited, and BSM growth can cause acute morbidity or death (2). Due to its location, surgery represents a difficult approach with significant associated morbidity.

Therefore, radiation therapy has been described in the literature as the best solution in these cases, with the concern of potential toxicity in such a sensitive structure. Thus, treating BSM can be challenging for the multidisciplinary team involved.

Stereotactic radiosurgery (SRS) is the precise delivery of focal radiotherapy (RT) to targets within the brain, employing multiple converging narrow RT beams. SRS  has been described as safe and effective for BSM with comparable results to those of SRS for non-brainstem BM (2).

SRS can be delivered in a single fraction or 2 to 5 fractions for larger targets or those near critical normal tissues, such as the brainstem. Regarding recommended doses for treating BSM with SRS, there are no guidelines for dose selection, which currently depends on the institution (3).

Conflicting findings exist regarding the optimum dose, and factors influencing dose selection include tumor volume, tumor histology, and prior radiotherapy. Additionally, there is a dose-volume relationship between the irradiated brainstem and the risk of post-SRS complications. Therefore, determining the ideal dose for SRS should consider both these individual factors and the potential impact on treatment safety and efficacy, given the associated risk of complications (4,5).

Treatment of cerebral metastases located inside the brainstem remains a challenge, as the brainstem is considered to be a neurological organ at risk, whatever the treatment strategy (6).

The goal of treatment is to ensure safety and efficacy while preserving the patient’s quality of life. In literature, toxicity rates are comparable to those of SRS for other brain metastases.

Headache, fatigue, nausea, and vomiting (which are usually self-limited) are the most frequently described toxicities after treatment with SRS for brainstem metastases. Edema, hemorrhage, and radionecrosis are the underlying mechanisms of adverse events following SRS (3,6).

Given the specificity of the location of these tumors, a detailed description of treatment experiences is essential for understanding clinical-pathological behavior. In this context, the authors present a series of 3 cases of BSM treated with SRS at our institution, followed by a literature review for contextualization and foundation of the topic.

2. Case(s) presentation

2.1. Case 1

A 59-year-old male patient who had a solitary brainstem metastasis from non-small cell lung cancer presented with diplopia and occipital headache as initial symptoms. He had no evidence of extracranial disease, and the symptoms improved after taking steroids.

The diagnostic Magnetic Resonance (MRI) scan conducted in September 2022 showed a solitary lesion of 10.4 mm (0.5cm³) with marginal edema, localized in the midbrain. He had an ECOG-Performance Status (ECOG-PS) score of 0. In addition, the Neurologic Assessment in Neuro-Oncology Scale (NANO) and the Mini-Mental State Examination (MMSE) were performed (NANO =0 and MMSE normal = 29). The Lung DS-Graded Prognostic Assessment (Lung-molGPA) calculated an estimated median survival of 26.5 months.

The patient underwent fractionated stereotactic radiosurgery in October 2022. The immobilization device used was an open mask for surface image-guided radiation, following our institution’s protocol. Planning involved fine-slice Computed Tomography (CT) scans (1mm) and MRI (1mm) with contrast injection. Geometric distortion correction was applied during the MRI planning process. A Gross Tumor Volume (GTV) of 0.25cc and a Planning Treatment Volume (PTV) margin of 1mm were delineated, along with critical organs at risk. Constraints were based on the recommendations of the American Association of Physicists in Medicine (7).

The total prescribed dose was 21 Gy administered in 3 fractions. The maximum dose to the brainstem was 25 Gy (in GTV: 119.9%), with a maximum of 23 Gy in the brainstem minus PTV (see Table 1). Treatment was delivered using volumetric modulated arc therapy on a linear accelerator, employing two full arcs and two non-coplanar partial arcs, using 6FFF energy.

Plan evaluation parameters included Paddick conformity index, conformity index, selectivity index, homogeneity index, and gradient measure, with values of 0.93, 1.07, 0.77, 0.15, and 0.34, respectively. For the approval of the treatment plan, the details outlined in Table 3 were considered (Table 3). No toxicity has been observed during or after treatment thus far, and the patient is no longer receiving steroid therapy.

In October 2023, the patient underwent an MRI scan, which showed a complete response after 12 months of treatment (Table 2). In December 2023, the patient experienced progression of cerebral disease, both intracranial and distant, requiring corticosteroid therapy with prednisolone 20mg per day. The patient died in October 2024.

Fig 1. Treatment Images A) Axial MRI showing a brainstem lesion. B) SRS) treatment plan displaying isodose curves. C) Follow-up MRI 30 months post-treatment.

2.2. Case 2

A 57-year-old female patient who was on follow-up for 4 years for breast carcinoma presented with paresthesia and strength deficit in the left hemibody. The symptoms stabilized with corticosteroid therapy. Patient had an MRI in September 2023 that showed a solitary lesion of 19 mm (3.9 cm3) localized in the right side of the medulla oblongata, with marginal vasogenic edema. She had an ECOG-PS score of 0, NANO = 0, and the MMSE = 1 (normal). In addition, the GPA index calculated an estimated median survival of 13 months.

The patient underwent fractionated stereotactic radiosurgery in October 2023 and was subjected to the same institutional protocol as Case 1 for CT and MRI acquisitions, with the same recommendations for organs at risk and margins applied to the volumes.

The total prescribed dose was 21 Gy administered in 3 fractions. The maximum dose to the brainstem was 25 Gy (in GTV: 119.9%), with a maximum of 23 Gy in the brainstem minus PTV (Table 1).

Treatment was delivered using volumetric modulated arc therapy on a linear accelerator, employing one full arc and two non-coplanar partial arcs, using 6FFF energy. Plan evaluation parameters included Paddick conformity index, conformity index, selectivity index, homogeneity index, and gradient measure, with values of 0.93, 1.08, 0.93, 0.06, and 0.54, respectively. For the approval of the treatment plan, the details outlined in Table 3 were considered (Table 3).

The patient received corticosteroid therapy (dexamethasone 4 mg per day), and no toxicity occurred during or after the treatment. In December of 2023, an MRI scan showed lesion stabilization without new neurological deficits. In March of 2024, the patient presented for consult with altered sensation in the right hemiface, dysarthria, and left hemihypesthesia, without other complaints. An increased dose of corticosteroids was necessary, resulting in symptom stabilization. The MRI from June 2024 revealed changes compatible with an increase in the size of the known metastatic lesion. A necrosis caused by prior radiotherapy could not be excluded based on the radiological aspect or clinical symptoms, which were similar.

A perfusion MRI performed in July 2024 indicated possible radionecrosis. During the most recent follow-up in September 2024, the patient reported no symptoms of late toxicity related to the treatment. The patient died in December 2024 due to distant disease progression.

Fig 2. Treatment Images A) Axial MRI showing a brainstem lesion. B) SRS) treatment plan displaying isodose curves. C) Follow-up MRI 11 months post-treatment.

2.3. Case 3

We presented a case of a 59-year-old male patient, ECOG-PS score of 1, with a diagnosis of lung adenocarcinoma, on osimertinib, and with multiple bone metastases. The patient presented with dysarthria, balance, and left-sided muscle strength alterations, and started on dexamethasone.

The patient underwent an MRI scan in September 2022, which revealed a solitary lesion localized in the midbrain, specifically at the right mesopontine transition, measuring 8mm (0.4cm³) in size, associated with marginal edema. NANO and the MMSE scores had normal values (0 and 29, respectively). The Lung-molGPA calculated an estimated median survival of 30 months.

The patient was investigated and treated according to the same institutional protocol as previous cases for CT and MRI acquisition, with the same recommendations for organs at risk and margins applied to the volumes.

He received fractionated SRS in November 2023. The total prescribed dose was 21 Gy administered in 3 fractions. The maximum dose to the brainstem was 22.31 Gy (see Table 1). Treatment was delivered using volumetric modulated arc therapy on a linear accelerator, employing one full arc and three non-coplanar partial arcs, using 6FFF energy.

Plan evaluation parameters included Paddick conformity index, conformity index, selectivity index, homogeneity index, and gradient measure, with values of 0.98, 1.02, 0.93, 0.08, and 0.32, respectively. For the approval of the treatment plan, the details outlined in Table 3 were considered (Table 3). The patient tolerated the treatment well, without complications.

In April 2024, the patient underwent an MRI scan, which showed a slightly more necrotic-cystic center in the treated lesion, the dimensions and mass effect of the right paramedian expansile lesion at the mesencephalon-protuberance transition, and the area of accompanying vasogenic edema overlapping. It also showed new lesions (cingulate gyrus, at the transition of the pre- and postcentral gyrus to the right, and the white matter-gray matter interface of the ipsilateral cerebellar hemisphere). At this time, the patient also showed extracranial progression.

The patient started chemotherapy in July 2024 while maintaining osimertinib and subsequently underwent whole-brain radiotherapy (30 Gy in 10 fractions). The last follow-up in our department was in July 2024.

Fig 3. Treatment Images A) Axial MRI showing a brainstem lesion. B) SRS) treatment plan displaying isodose curves. C) Follow-up MRI 5 months post-treatment.

Table 1  – Clinical and Treatment Characteristics of the Cases

Table 2 – Follow-up, Toxicity, and MRI Response to Treated Metastases

Table 3 – Details for radiotherapy plan approval, including normal tissue tolerance, dose constraints, maximum dose, and volume constraints (8)

3. Discussion

Metastatic tumors are the most frequent type of CNS tumor in adults, and the incidence of metastasis is increasing. This increase has been due to advances in diagnosis and a significant improvement in the control of extracranial disease by new systemic therapies. In the adult population, the primary tumors most frequently associated with the development of CNS metastases are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, in descending order (9).

In the present case series, two patients had pulmonary adenocarcinoma as the primary tumor, while one had breast carcinoma, all exhibiting controlled extracranial disease prior to treatment. Regarding pathogenesis, the most common mechanism of CNS metastasis is haematogenous dissemination. BM typically presents as single or multiple contrast-enhancing space-occupying lesions, often with surrounding brain oedema (9). Clinical manifestations vary according to the number, volume, and location of the metastases. The main symptoms described are headache, nausea, vomiting, focal neurological dysfunction, and cognitive dysfunction (9,10). The brainstem includes sensory and motor pathways, as well as multiple nuclei responsible for reflexes and cranial nerves. Therefore, when referring to BSM, the main symptoms result from the direct compression of nuclei, tracts, or cranial nerves (CN) caused by mass effect/vasogenic oedema.

Due to the intracranial anatomy and its concealed central location, brainstem surgery is challenging. Given the high risk of morbidity and mortality, resection for BSM is seldom considered (1,2,3). RT plays a central role in the treatment of brainstem metastases due to its inoperability. Historically, BSM were treated solely with whole-brain radiation therapy (WBRT) (2,3,9,10).

According to the review by Lee, the local control rates (LC) were reported in the range of 93% to 95.2% and 86% to 90.4% after 6 and 12 months, respectively (3).

The systematic review and meta-analysis published by Chen et al. demonstrate that SRS for BSM were associated with effectiveness, safety, and improved symptoms (2). Also, Chen et al mentioned LC 86%, a high therapeutic ratio of symptom relief and tumor response (50%-60%) when compared with targeted therapy (17%-56%), rare significant toxic effects (2.4%), and rare death from BSM progression (2.7%) (2,4).

Nevertheless, the efficacy and safety of SRS in BSM remain incompletely characterized, as patients with BSM are excluded from most clinical trials (2,3). However, the literature review supports that SRS delivered at centers with advanced technology and experienced practitioners is a suitable and effective treatment option for patients with BSM.

When the authors researched aspects regarding the dose, safety, and toxicity of SRS, they found that 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 (1,5).

Several treatment regimens have been proposed for BSM, but standardized guidelines for SRS dosing remain lacking. In a review, John et al. highlighted that, for single-fraction SRS, expert consensus recommends margin doses of 20 Gy for lesions smaller than one cc, 18 Gy for lesions measuring 1–2 cc, and 15 Gy for those larger than two cc. For tumors located in or near the brainstem, alternative fractionated regimens have also been described, including 27 Gy in three fractions and 25–31 Gy in five fractions (3,11). These recommendations underscore the importance of tailoring dose prescriptions to lesion size and location in order to minimize treatment-related risks.

Supporting this approach, a study by Milano et al. (2021) demonstrated a clear relationship between tissue volume receiving high radiation doses and the risk of symptomatic radionecrosis. In single-fraction SRS for BM, a V12 (volume receiving 12 Gy) of 5 cm³, 10 cm³, and over 15 cm³ was associated with approximately 10%, 15%, and 20% risk of radionecrosis, respectively. In the context the fSRS, delivering V20 over three fractions or V24 over five fractions to a total brain and target volume of less than 20 cm³ resulted in a risk of necrosis or edema below 10%, and under 4% for radionecrosis requiring surgical resection. These findings suggest that both the dose and the irradiated tissue volume are critical determinants of toxicity, and that fSRS may allow safer treatment of larger lesions without compromising local tumor control (12).

The recent findings by Toshiki Ikawa (2024) indicate that fSRS using an inhomogeneous dose distribution may further enhance local control while reducing toxicity, particularly in brainstem lesions (13).

The literature remains inconclusive regarding the optimal margin dose for BSM. Some studies suggest that higher marginal doses may be associated with improved survival; however, this potential benefit must be weighed against the increased risk of toxicity.

The most frequently reported toxicities after brainstem SRS are headache, fatigue, nausea, and vomiting, which are usually self-limited or effectively treated with corticosteroids. Edema, hemorrhage, and radionecrosis are the underlying mechanisms of adverse events following SRS, which can be minimized through the administration of corticosteroids. Severe toxicity after brainstem SRS was rare (3,4,5,14).

In our series, all three patients showed initial positive responses to SRS, with no acute toxicity observed during or immediately after treatment. Our results are in line with existing literature, suggesting that SRS for BSM can be both safe and effective, offering comparable outcomes to non-brainstem metastases.

In case 1, the patient had a solitary midbrain metastasis from non-small cell lung cancer, and he received single-fraction SRS with a total dose of 21 Gy. The patient showed a complete response on MRI 12 months post-treatment, with no evidence of toxicity, acute or delayed. This case highlights the potential for SRS to achieve durable local control in BSM.

Case 2 involved a patient with a solitary BSM from breast carcinoma. The lesion was controlled post-SRS; however, the patient later developed symptoms suggestive of radionecrosis. This observation underlines the importance of long-term monitoring and the potential for delayed complications.

The third case presented had a midbrain lesion secondary to lung adenocarcinoma. Despite initial positive responses, the patient developed new intracranial lesions and extracranial progression, necessitating whole-brain irradiation. This case illustrates the complexity of managing patients with advanced disease and multiple metastatic sites.

The absence of standardized guidelines for SRS dosing in BSM increases the complexity of treatment planning.

Our institution followed a protocol that considered the location, tumor volume, histology, and previous treatments, prescribing a total dose of 21 Gy in three fractions. This regimen aimed to balance efficacy and safety, reducing the risk of complications such as edema, hemorrhage, and radionecrosis.

4. Conclusion

This case series supports the use of fSRS as a safe and effective treatment for BSM, providing good LC and manageable toxicity profiles. However, long-term follow-up and comprehensive management of potential complications remain crucial. Further research is needed to establish standardized dosing guidelines and to explore the integration of SRS with systemic therapies for optimal patient outcomes. The detailed descriptions of these cases contribute to a better understanding of the clinical-pathological behavior of BSM and reinforce the role of SRS in their management.

ABBREVIATIONS

6FFF – 6 MV Flattening Filter Free

BM – Brain Metastases

BSMs – Brainstem Metastases

CN – Cranial Nerves

CT – Computed Tomography

ECOG-PS – Eastern Cooperative Oncology Group – Performance Status

fSRS – fractionated Stereotactic Radiosurgery

GPA – Graded Prognostic Assessment

GTV – Gross Tumor Volume

LC – Local Control

Lung-molGPA – Lung cancer-specific molecular Graded Prognostic Assessment

MMSE – Mini-Mental State Examination

MRI – Magnetic Resonance Imaging

NANO – Neurologic Assessment in Neuro-Oncology

PTV – Planning Target Volume

RT – Radiotherapy

SRS – Stereotactic Radiosurgery

WBRT – Whole Brain Radiation Therapy

STATEMENTS

Authors’ contribution: AA, FA, PS, RT, PAS, and LO conceived and planned the analysis and contributed to the interpretation of the results. PF, FC, DS, and AM contributed to the dosimetric planning. AG and RP executed the treatment in the linac. VS, CT, and LS contributed to the acquisition of MRI images for planning and follow-up of the patients. RF and GF were responsible for patient-specific QA and treatment plan validation. LO and PS were the radiation oncologists responsible for planning approval and treatment evaluation. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Informed Consent Statement: Written informed consent was obtained from all patients involved in this case series for the publication of their anonymized clinical data and imaging findings.

Conflict of Interest Statement: The authors declare no conflicts of interest related to this work.

Funding: Not applicable

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