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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 6  |  Page : 1604-1609

Fractionated stereotactic radiotherapy as a primary or salvage treatment for large brainstem metastasis


1 Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt; Saphir Radiosurgery Center, Frankfurt am Main, Germany
2 Saphir Radiosurgery Center, Frankfurt am Main, Germany
3 Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany

Date of Submission14-Mar-2021
Date of Decision24-Aug-2021
Date of Acceptance25-Aug-2021
Date of Web Publication03-Aug-2022

Correspondence Address:
Georgios Chatzikonstantinou
Department of Radiotherapy and Oncology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590. Frankfurt amMain
Germany
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_426_21

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 > Abstract 


Introduction: This study aimed to determine the efficacy and safety of robotic-based fractionated stereotactic radiotherapy (FSRT) in the treatment of large brainstem metastases (BSMs).
Methods: Ten BSM were treated in ten patients with FSRT between January 2012 and December 2018. The median age was 61 years (range, 53–74 years) with a median Karnofsky Performance Score of 80 (range, 70–90). Four patients (40%) had received whole-brain radiotherapy prior to FSRT. The median tumor volume was 4.2 cm3 (range, 1.35–8.18 cm3) with a median prescription dose of 24 Gy (range, 16–24 Gy) delivered in 3–5 fractions (median three fractions) to the 56%–83% isodose line (median 70.5%).
Results: 1Median follow-up for the entire cohort was 14.1 months (range, 4.6–19.3 months). Five local recurrences were documented. Local control (LC) rate at 6 and 12 months was 90% and 64.2%, respectively. The median tumor volume of patients developing local recurrence was 5.42 cm3. Three patients experienced intracranial out-of-field failure for a 12-month intracranial control rate of 78.7%. Median overall survival and time to extracranial progression were 14.7 and 16.8 months, respectively. Toxicity was low with only one patient developing a new hemiparesis.
Conclusion: Robotic-based FSRT for BSM appears to be safe with favorable LC and low toxicity even for large tumors.

Keywords: Brain metastases, brainstem, hypofractionated radiotherapy, stereotactic radiosurgery


How to cite this article:
Chatzikonstantinou G, Wolff R, Tselis N. Fractionated stereotactic radiotherapy as a primary or salvage treatment for large brainstem metastasis. J Can Res Ther 2022;18:1604-9

How to cite this URL:
Chatzikonstantinou G, Wolff R, Tselis N. Fractionated stereotactic radiotherapy as a primary or salvage treatment for large brainstem metastasis. J Can Res Ther [serial online] 2022 [cited 2022 Dec 2];18:1604-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/6/0/353340




 > Introduction Top


Up to 40% of all cancer patients develop metastatic brain lesions during the course of their disease.[1] Brainstem metastases (BSM) are relative rare, comprising about 5% of all secondary brain malignancies.[2] The treatment of BSM represents a therapeutic challenge and in most of the cases, surgical resection is not feasible due to the risk of severe neurological morbidity. Radiotherapy (RT) treatment options include whole-brain RT (WBRT)[3],[4] and stereotactic radiosurgery (SRS).[5] Although SRS is effective in treating BSM, there has been some concern for high-grade toxicity with increasing lesion volume.[6],[7],[8] Fractionated stereotactic RT (FSRT) in a few sessions has demonstrated efficacy in the treatment of large brain metastases while reducing the risk of radionecrosis.[9],[10],[11],[12] Nevertheless, there are scant data about its role in the treatment of BSM.[13],[14] In this report, we analyze our experience using robotic-based FSRT for the treatment of BSM to provide additional information for this complex clinical setting.


 > Methods Top


Between January 2012 and December 2018, all patients with brain metastases at our institution were reviewed to identify patients who received FSRT for BSM. In total, ten patients were identified. Patients with single BSM or with additional brain metastases (maximum 3) all amenable to SRS or FSRT according to physician's discretion were included. Patients were excluded if the BSM was treated with SRS, if WBRT was necessary according to the physician's discretion and if more than one BSM was apparent. Patients with BSM and progressive extracranial disease were excluded if there was no further systemic therapy option and a best supportive care approach was suggested by the treating oncologist. FSRT was offered as a primary or salvage therapeutic modality in all patients upon BSM diagnosis and it was performed using the CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA, USA). All patients were immobilized using a thermoplastic mask. The gross tumor volume (GTV) and the organs at risk were contoured on fused noncontrast-enhanced computed tomography and contrast-enhanced T1-weighted magnetic resonance imaging (MRI) images with 1-mm slice thickness. The planning target volume (PTV) equated to the GTV without further expansion. Treatment planning was performed according to best practice guidelines[15] and the ICRU report 91 on prescribing, recording, and reporting of stereotactic treatments with small photon beams[16] [Figure 1]. Dose–volume histograms for the PTV and the organs at risk were calculated with the Multiplan v 4.6.1 treatment planning system (Accuray Inc., Sunnyvale, CA, USA). Selection of dose and fractionation was based on various factors including prior WBRT and tumor volume. Tumor and treatment characteristics are summarized in [Table 1].
Figure 1: Fractionated stereotactic radiotherapy of a 5.42 cm3 brainstem metastasis located in pons and treated with 24 Gy in three fractions, prescribed on the 60% isodose line. Multiplanar three-dimensional view of the co-registered brain magnetic resonance imaging with overlaid dose distribution in Gy

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Table 1: Tumor and treatment characteristics

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Before treatment initiation, the patient with the thermoplastic mask is positioned on the robotic couch in an identical manner as per CT simulation. Two in-room ceiling-mounted kilovoltage X-ray sources placed at 45° to a vertical axis along with flat-panel detectors provide real-time imaging of the bony anatomy (6-D Skull, Accuray Inc., Sunnyvale, CA, USA) of the patient. The pretreatment images are co-registered with the planning digitally reconstructed radiographs using the two-dimensional–three-dimensional image registration method and necessary setup errors are detected and corrected by couch movement, thus bringing the patient in treatment position. After the treatment starts, real-time setup errors are continuously recorded and adequate adjustments are done by the robotic arm, without moving the patient.

This retrospective analysis was approved by the local institutional review board (Ethics Commission Number: 19-485).

Follow-up

Patients underwent an initial follow-up brain MRI at 3 months following FSRT. Thereafter, serial MRI scans at 3-month intervals were performed. Local control (LC) was defined as the absence of progression and included complete response, partial response, and stable disease as defined by the response evaluation criteria in solid tumors.[17] Intracranial failure was defined as the development of new brain metastases other than those treated. Symptomatic failure was defined as the worsening of existing neurological symptoms or the appearance of new ones. Symptoms attributed to lesions outside the brainstem were excluded. Extracranial progression was determined as the development of new metastases other than brain ones or the progression of already existing extracranial metastases and was assessed through chest/abdomen CT performed every 3 months. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Overall survival (OS) and LC were calculated from the date of last FSRT fraction using the Kaplan–Meier method. Statistical analysis was performed using the WinStat® software (R. Fitch Software, Bad Krozingen, Germany).


 > Results Top


A total of 10 lesions in ten patients were treated. The median age was 61 years (range, 53–74 years). No patient received WBRT in combination with FSRT. Four (40%) patients had undergone prior WBRT for metastatic deposits in other locations. Whole-brain radiotherapy was received between 8 and 48 months before FSRT and the dose applied ranged between 30 and 40 Gy. Three patients (30%) presented with two additional brain metastases apart from the BSM at the time of FSRT, which were treated with the same FSRT dose as the BSM. All other patients presented with a single brainstem lesion. Of the lesions treated, 6 (60%) were located in the midbrain and 4 (40%) in the pons. Primary pathologies included lung (n = 6, 60%), breast (n = 1, 10%), prostate (n = 1, 10%), pancreas (n = 1, 10%), and kidney cancer (n = 1, 10%). The majority of patients (8/10, 80%) had BSM detected on surveillance neuroimaging prior to developing any symptoms. Two patients (20%) presented with BSM-related symptoms, one with dizziness and one with hypoesthesia without manifested cranial nerve palsies.

The median Karnofsky Performance Score (KPS) was 80 (range, 70–90) with a median follow-up of 14.1 (range, 4.6–19.3) months. Median tumor volume was 4.2 cm3 (range, 1.3–8.1). The median prescribed PTV dose was 24 Gy (range, 16–26 Gy). Nine lesions (80%) were treated in three fractions and one lesion in five fractions. The radiation dose delivered to the PTV was prescribed to the 56%–83% isodose line (median 70.5%), covering ≥95% of the PTV. Conformity and gradient index was median 1.08 (range, 1.02–1.32) and 2.82 (range, 2.68–2.88), respectively. The median Dmean, D98%, and D2% expressed as biological effective dose assuming a tumor a/b ratio of 10 was 54.4 Gy (range, 24.9–68.1), 40.7 Gy (range, 22.2–43.5), and 67.6 Gy, respectively (range, 27.8–100.8). The median maximum brainstem dose was 23.6 Gy (range 16.1–27.3).

Oncological outcomes and toxicity

Five local recurrences were observed during follow-up. The 6- and 12-month LC rates were 90% and 64.2%, respectively [Figure 2]. Tumor progression in the first follow-up MRI scan was observed in one (10%) patient. The median pre-FSRT volume of the BSM lesions that recurred was 5.42 cm3. None of the two additional brain metastases in each of the three patients presented with both brain– and BSM recurred at 12 months. Three patients experienced intracranial failure outside of the PTV for a 12-month intracranial control rate of 78.7%. Median OS and time to extracranial progression were 14.7 and 16.8 months, respectively. One (10%) patient developed a hemiparesis 2 months after treatment. Magnetic resonance imaging showed an enlargement of the cystic component of the BSM without evidence of gross tumor progression. No other new toxicities including radionecrosis were documented.
Figure 2: Kaplan–Meier curve for local control

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 > Discussion Top


Metastases located in the brainstem are an uncommon clinical setting that poses an oncological challenge with evidence-based treatment being very limited. Brainstem metastases are not eligible for resection due to associated morbidity and the role of surgery is usually confined to decompression to avoid local mass effects. As such, RT represents the main lesion-specific treatment option. Whole-brain radiotherapy is often considered in the case of multiple brain metastases, whereas for solitary BSM or BSM along with only a few additional brain deposits, SRS with or without WBRT has been applied.[4],[5],[7],[18],[19],[20]

The majority of published series reporting on RT for BSM consists of results generated by SRS.[21],[22],[23],[24],[25],[26],[27],[28],[29],[30] Exemplarily, Trifiletti et al.[5] analyzed retrospectively 161 patients treated at a single institution. The median age was 60.5 years. By the time of treatment, 51.6% of patients had received prior WBRT. Seventy percent of lesions were located in the pons. The median SRS dose was 18 Gy delivered to the 50% isodose. After a median follow-up of 5.5 months, 1-year LC and OS rates were 84.9% and 30.8%, respectively. A margin dose of at least 16 Gy was the only prognostic factor found to be significantly correlated with improved LC. There were 3 (1.8%) ≥ Grade 3 serious adverse events. One patient with a 0.4 cm3 pontine BSM of melanoma origin treated with 20 Gy developed a lethal intratumoral hemorrhage at 1.7 months following SRS. Similarly, Voong et al.[7] reported on 74 patients with sole SRS for BSM. Eighteen percent of patients had single lesions, whereas the remainder (82%) had one or more synchronous brain metastases. Median follow-up, tumor volume, and treatment dose were 5.5 months, 0.13 cm3 (range, 0.003–5.58 cm3), and 16 Gy (range, 10–20 Gy) prescribed to the 50% isodose line (range, 40%–86%), respectively. Forty-six patients (62%) received WBRT before or after SRS. With the majority of the lesions located in the pons (78%), crude LC was 94% with a median OS of 8.5 months. Symptomatic as well as larger lesions ≥2 cm3 were associated with worse LC and OS. Thirty-six percent of patients were symptomatic with 36% experiencing complete symptom relief, whereas 50% showed stable or improved symptomatology. Toxicity was low (8%) with two patients (2.7%) developing radionecrosis. Lesion size and midbrain location correlated with increased toxicity.

In addition to exclusive SRS, there are also published data with mixed results by the implementation of both SRS and FSRT.[13],[30] Leeman et al.[13] retrospectively reviewed 36 patients with 38 BSM receiving SRS or FSRT. Twenty (56%) of them were treated with one fraction and 16 (46%) with 2–5 fractions. Topographically, 25 (66%) lesions were identified in the pons, 11 (29%) in the midbrain, and 2 (5%) in the medulla. At the time of treatment, 25 patients (69%) were symptomatic. Furthermore, 29 (76%) patients had additional brain metastases. Median age, KPS, tumor volume, and prescription dose were 62 years, 80%, 0.94 cm3, and 17 Gy, respectively. With a median follow-up of 3.2 months, the actuarial 6-month LC and OS rates were 93% and 27%, respectively. No Grade 3 or higher toxicities were documented. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that resolved with a short course of dexamethasone.

Although there is sufficient evidence for the efficacy and safety of FSRT for brain metastases, only one study so far focused specifically on its role for lesion-targeted RT of BSM. Nakamura et al.[14] treated 26 lesions in 20 patients reflecting the Japanese experience on this approach. Median age and KPS were 69 years and 90%, respectively. The distribution of the lesions within the brainstem was 18 (70%) in the pons, 4 (15%) in the medulla, and 4 (15%) in the midbrain. Five lesions (19%) were treated with WBRT prior to FSRT. The median follow-up was 6.5 months. Median tumor volume was 0.33 cm3 and median GTV dose 24.7 Gy (range, 18.6–29.6 Gy) delivered over 3 (73% of the lesions) or 5 (27% of the lesions) fractions. Of the 23 (88%) lesions for which follow-up MRI data were available, only one lesion had locally failed within 8 months of FSRT for a 1-year LC of 90%. One (3.8%) Grade 3 intracranial hemorrhage and 4 (15.8%) Grade 2 adverse events, consisting of two pyramidal tract syndromes, one radiation necrosis and one abducens nerve disorder, were documented. [Table 2] summarizes the available literature on SRS and FSRT for the treatment of BSM.
Table 2: Literature review for patients with brainstem metastases treated with stereotactic radiosurgery or fractionated stereotactic radiotherapy

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Notwithstanding the efficacy of SRS for the highly conformal RT of BSM, there have been some concerns regarding inferior LC[7],[24] and higher toxicity with increasing PTV.[6],[7],[8] In the SRS series reviewed by Murray et al.,[4] median tumor volume was ≤1.0 cm3 in all but one, whereas in our analysis, all treated patients had a tumor volume of ≥1.0 cm3 for a median of 4.2 cm3. Despite the large volumes treated, our toxicity profile is encouraging with only one patient developing a hemiparesis after treatment of a 5.42 cm3 large lesion. Our 6-month LC is comparable to the current literature, whereas the corresponding LC at 1 year is inferior compared to other reviewed SRS series.[4] One possible explanation for this finding could be the lower tumor volumes treated in those series, as tumor volume represents a factor strongly correlated with LC.[7],[18],[30]

The limitations of our analysis included its retrospective nature, the relatively small patient number, and the comparatively short follow-up. Nonetheless, our LC is comparable to results in the current literature for though smaller reported tumor volumes. Our experience indicates that even larger BSM can be safely treated by FSRT with encouraging oncological outcomes.


 > Conclusion Top


Robotic-based FSRT for BSM appears to be safe and could achieve favorable LC with low toxicity even for large tumors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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