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ABSTRACT Stereotactic radiotherapy (SRT) is frequently used to treat brain metastases (BMs). The single-isocenter for multiple targets (SIMT) technique allows for faster treatment of large

numbers of BMs, but may adversely affect planning target volume (PTV) coverage due to possible increased positioning uncertainties with an increased isocenter to tumor distance (ITD). This

study aims to investigate the association of ITD with local recurrence (LR) and radionecrosis (RN). Patients treated with SRT using a single isocenter for multiple BMs were retrospectively

analyzed. Previous cranial radiotherapy and inability to undergo MR imaging were exclusion criteria. Patients were irradiated using a Versa HD LINAC with 6 MV flattening filter-free (FFF)

energy and a 6D robotic couch. A non-coplanar volumetric modulated arc technique was used and plans were delivered using 6MV FFF energy. Associations between potential risk factors and LR/RN

were investigated with Cox regression analyses. Seventy-five patients with a total of 357 BMs were included. Median survival after SRT was nine months. LR occurred in 7 (9%) patients and 10

(13%) had RN. After 18 months, LR-free survival was 89% and RN-free survival was 85%, respectively. ITD was not significantly associated with LR and RN. GTV was significantly associated

with both LR (HR 1.10, 95% CI 1.02–1.17, _P_ 0.0079) and RN (HR 1.09, 95% CI 1.01–1.17, _P_ 0.020). LINAC-based SIMT SRT is a safe and effective treatment modality for patients with multiple

BMs. We found no increased risk of LR or RN for BMs located further away from the isocenter. SIMILAR CONTENT BEING VIEWED BY OTHERS RESPONSE OF TREATMENT-NAIVE BRAIN METASTASES TO

STEREOTACTIC RADIOSURGERY Article Open access 02 May 2024 HISTOPATHOLOGY AND SURGICAL OUTCOME OF SYMPTOMATIC TREATMENT-RELATED CHANGES AFTER GAMMA KNIFE RADIOSURGERY IN PATIENTS WITH BRAIN

METASTASES Article Open access 22 February 2022 STEREOTACTIC IRRADIATION OF NON-SMALL CELL LUNG CANCER BRAIN METASTASES: EVALUATION OF LOCAL AND CEREBRAL CONTROL IN A LARGE SERIES Article

Open access 08 July 2020 INTRODUCTION Stereotactic radiotherapy (SRT) is a commonly chosen treatment for patients with one or more brain metastases (BMs), either as sole treatment or in

combination with neurosurgery. In patients with multiple BMs, whole brain radiotherapy (WBRT) used to be the standard of care. However, a shift in treatment strategy from WBRT to SRT has

been observed in these patients, because WBRT is associated with an increased risk of neurotoxicity without survival benefit1,2. Previous research has shown that in patients with metastases

with limited volume, the overall survival and adverse events were similar for patients with 2–4 and for those with 5–10 BMs3. However, one limitation of SRT for a large number of BMs has

been the lengthy treatment time (20 + minutes per lesion, > 1 h for ≥ 3 lesions) due to the need to treat each lesion with a unique radiation isocenter (the point where the radiation

beams converge)4. This makes SRT less practical for the treatment of more than three BMs at the same time. Linear accelerator (LINAC)-based SRT enables the use of the single-isocenter for

multiple targets (SIMT) technique4,5. With SIMT SRT, multiple lesions are treated simultaneously with the same setup based on a single isocenter. The average overall treatment time in this

SIMT SRT is less than 25 min for multiple BMs6. Additionally, hypofractionated SRT becomes more feasible in practice as an alternative to one-fraction SRT due to these shorter treatment

times. Hypofractionated SRT might reduce local tumor recurrence (LR) and radionecrosis (RN) rates, particularly in larger metastases7. The largest potential drawback of SIMT SRT is the

potential risk of planning target volume (PTV) displacement when the isocenter-to-tumor distance (ITD) is longer. Target volumes with longer ITDs are more sensitive to rotational errors and

this may therefore lead to reduced PTV coverage. These errors are caused by residual patient movement during treatment and mechanical limitations in accuracy of couch movement. Collimator

and gantry rotations can also add to rotational uncertainty in SIMT SRT. While small rotational errors would not be relevant in a single-isocenter for single targets technique, these errors

could have a substantial effect on PTV coverage in SIMT SRT. Reduced PTV coverage has consequently been associated with a longer ITD, especially in smaller BMs8. In theory, this makes it

more likely that the tumor receives a reduced radiation dose while the surrounding healthy brain tissue is overdosed9. Decreased tumor coverage could lead to higher rates of LR, while

increased radiation dose in healthy brain tissue could increase the likelihood of RN, although clinical evidence has not been reported. The impact of the SIMT technique on local outcomes

such as LR and RN have not been extensively investigated. The purpose of this study was to evaluate the effect of ITD on LR and RN. METHODS AND MATERIALS ETHICS The Medical Ethics Committee

Leiden The Hague Delft gave approval for this study (reference number N24.032) and granted a waiver of informed consent, because it exclusively required retrospectively collected data. All

methods were performed in accordance with the relevant guidelines and regulations. PATIENT SELECTION All adult patients who were treated with SIMT SRT between November 2020 and April 2023

for two or more BMs at our hospital were identified and evaluated for inclusion. Patients were excluded if they had any contraindications for MR imaging or had previously undergone cranial

radiotherapy. Patients were allowed to undergo a neurosurgical resection shortly prior to SRT, but the resected metastases were excluded from the per lesion analyses. TREATMENT PLANNING

Treatment planning for BMs was based on a CT scan with a thermoplastic mask and cerebral 3D MR imaging scans (voxel size 0.9 × 0.9 × 0.9 mm3). All SIMT SRT plans were made using a treatment

planning software (RayStation®, RaySearch Laboratories, Stockholm, Sweden). Patients were irradiated with 6 MV flattening-filter free (FFF) energy of a Versa HD (Elekta, Stockholm, Sweden)

LINAC machine including a 6D robotic couch (Hexapod couch, Elekta, Stockholm, Sweden). All patients were treated using a non-coplanar volumetric modulated arc (VMAT) technique using six arcs

divided over three couch angles. Radiation oncologists delineated the gross tumor volumes (GTVs) based on T1-weighted MR imaging scans. PTVs were generated by creating a 1 mm margin around

the GTV. No margin around the GTV was utilized in BMs in the brainstem. This GTV-PTV margin was used for all BMs based on online Cone Beam CT position verification and a 6D Hexapod couch

correction for translations and rotations10,11. 6D couch correction could be performed before and during the treatment if needed. An additional Cone Beam CT was utilized after the

correction. Q-fix masks (Q-fix, Avondale, USA) with a bite plate were used to reduce rotations. An action level of 1 mm (vector) and 1° was used for position verification. The action level

was applied during the Cone Beam CT with a 0° couch angle. Patients were repositioned when the threshold was violated. In each plan, 99% of the PTV had to be covered by 100% of the

prescribed dose. Small BMs (10 cm3 or smaller) received 21 Gy in one fraction, while BMs > 10 cm3 received 18 Gy in one fraction or 25.5 Gy in three fractions. BMs close to or in the

brainstem were treated with 24 Gy in three fractions. Four patients were treated with 35 Gy in five fractions as part of an ongoing prospective trial12. TREATMENT OUTCOMES After SRT,

three-monthly follow-up MR imaging scans were performed, with increased intervals after at least one year. The Response Assessment in Neuro-oncology Brain Metastases (RANO) criteria were

used to define progression13. LR and RN were evaluated on MR imaging with gadolinium-enhanced T1-weighted images, T2-weighted images, a diffusion weighted series, and (optionally) a

perfusion series. The primary outcome measures were LR and RN. The distinction between LR and RN was made by evaluating RN-specific findings such as absence of perfusion, edema, and an

increased volume followed by loss of volume. This process also included the interpretation of the multidisciplinary tumor board. When available, histology of resected lesions was also

utilized to distinguish between LR and RN. FDG-PET-scans were not routinely used to make the distinction between LR and RN. Regional recurrence was defined as new intracranial solid tumors

outside of the original PTVs. Leptomeningeal disease was diagnosed with cerebrospinal fluid analysis and/or MR imaging. The ITD was calculated in the treatment planning software from the

isocenter of the plan to the center of the BM. Data on patient and tumor characteristics were collected from the treatment planning software or electronic patient dossiers. These included

age, sex, primary tumor histology, number of treated BMs, tumor location, GTV, PTV, presence of extracranial disease, Karnofsky performance status, systemic therapies, treatment dose and

fractionation, Paddick conformity index, and Paddick gradient index14,15. STATISTICS Overall survival was determined from the first day of SRT until the date of death or the last follow-up.

Kaplan–Meier analysis was used to estimate survival rates. Univariable and multivariable Cox regression analyses were performed to evaluate the associations between independent variables and

the rates of LR and RN in all BMs. A nomogram was constructed based on the multivariable Cox regression analyses. Internal validation of the nomogram was performed by calculating the

concordance index (C-index) for a random sample of the study population. A _P_ value of < 0.05 (two-sided) was considered statistically significant. All statistical analyses were

performed using the software R version 4.3.1. After univariable Cox regression analyses, variables with a _P_ value < 0.06 (borderline significant) were included in the multivariable Cox

regression analyses to address potential confounding factors. RESULTS Seventy-five patients with a total of 450 BMs (median 4 per patient) were included. In five patients, not every BM was

treated with SRT, so only the irradiated BMs were included. The median number of irradiated BMs per patient was 3 (range 2–18). In 21 patients (28%), one or two of the largest BMs had been

resected; these resected BMs were excluded from the analyses. This left a total of 357 BMs included for per lesion data analyses. The median follow-up time was 8.4 months (range 0.5–30.3).

The median age during SRT was 67 years (range 31–83). The majority of patients had a primary tumor in the lungs. BMs were symptomatic in 75% of patients. A majority of patients received an

SRT schedule of either a single fraction (21 Gy) or three fractions (8.5 Gy up to a total dose of 25.5 Gy). Detailed patient and tumor characteristics can be found in Table 1. Median ITD was

5.5 cm (range 0.5–8.7) (Fig. 1). LR was found in 12 out of 357 BMs (3%) in 7 out of 75 patients (9%). The LR-free survival rate per BM was 96% at 6 months, 93% at 12 months, and 89% at 18 

months (Fig. 2A). Median time from SRT to LR was 7 months (range 3–13 months). Treatment for LR consisted of surgery, re-SRT, or was not initiated due to regional or extracranial progression

leading to a decision for best supportive care. Symptomatic RN was found in 12 out of 357 BMs (3%) in 10 out of 75 patients (13%). The symptomatic RN-free survival rate per BM was 98% at 6 

months, 94% at 12 months, and 85% at 18 months (Fig. 2B). Median time from SRT to symptomatic RN was 8 months. RN was treated with dexamethasone in all cases. One patient with RN received

treatment with the anti-VEGF monoclonal antibody bevacizumab. Median survival after SRT was 9 months (interquartile range; IQR: 4.4–20.3). Regional recurrence was found in 29 out of 75

patients (39%), while leptomeningeal disease occurred in 7 patients (9%). ITD was not significantly associated with LR or RN in any analysis. GTV was significantly associated with LR (HR

1.10, 95% CI 1.02–1.17, _P_ 0.0079) and with symptomatic RN (HR 1.09, 95% CI 1.01–1.17, _P_ 0.020) in separate uni- and multivariable Cox regression analyses (Table 2). Lung adenocarcinoma

as a primary tumor was associated with higher rates of LR compared to other primary tumors (HR 5.48, 95% CI 1.13–26.7, _P_ 0.035). No significant difference in LR or RN was found between

single and multifraction SRT (Table 2, Fig. 2). Finally, no association between concurrent immunotherapy treatment and other systemic treatment or no systemic treatment was found with LR or

symptomatic RN. A clinical nomogram based on the multivariable Cox regression analysis was created for LR (see Additional File 1). In the internal validation, the C-index of the LR nomogram

was 0.799 (95% CI 0.622–0.976), which indicates adequate discrimination by the model. DISCUSSION LINAC-based SIMT SRT is a novel treatment technique which makes SRT for a large number of BMs

patient-friendly and practically feasible within 30 min. Treatment times are reduced compared to conventional single-isocenter for single targets SRT, Gamma Knife, and CyberKnife6. In this

report, we found no increased risk of LR or RN for BMs located further away from the isocenter. Therefore, this work further supports the use of SIMT SRT for a large number of BMs in

clinical practice. This is to our knowledge the second study to report on the impact of ITD on clinical outcomes. The first study by Kraft et al. also found no association between ITD and

LR16. They used a TrueBeam or Edge LINAC (Varian Medical Systems, Palo Alto, USA) to treat patients and they reported local control rates of 94% of BMs after twelve months, similar to the

93% found in this study, where patients were treated with a Versa HD LINAC. Another group, Faccenda et al., also reported a 94% local control rate after twelve months and found no

significant differences between the differences in target coverage and the distance from the isocenter17. This group also found no significant correlation between target coverage and local

recurrence18. Several studies have reported on the safety and efficacy of the SIMT SRT technique for patients with multiple BMs. Alongi et al. reported no acute or subacute toxicities19.

Minniti et al. reported that neurocognitive function did not significantly decline after SIMT SRT while maintaining adequate local tumor control20. Additionally, Kim et al. prospectively

analyzed a cohort of SIMT SRT patients and reported low rates of LR and RN21. No large randomized trials have yet been performed for comparisons with other treatment modalities. Our results

largely support the earlier findings. As BMs which are located further away from the isocenter are not more likely to progress or to develop RN, the largest potential downside of SIMT SRT

has been addressed. This is especially relevant because a recent study reported that patients treated with LINAC-based SIMT SRT had similar overall survival and lower incidence of RN

compared to Gamma Knife treatment, suggesting that SIMT SRT is at least comparable to Gamma Knife in terms of clinical outcomes22. In this study, a PTV margin of 1 mm was utilized in all

patients except for those close to the brainstem. This is largely based on the report of Kirkpatrick et al. who found no significant difference in terms of local control between 1 and 3 mm

GTV-PTV margins for BMs in patients with 1–3 BMs23. Furthermore, Badloe et al. found that PTV-margin reduction from 2 to 0 mm did not reduce local control rates and concluded that margin

reduction is safe in LINAC-based SRT for solitary brain metastases24. The current results of local control rates (89% after 18 months) indicate that margin reduction to 1 mm in patients with

multiple BM (up to 18 metastases) is indeed appropriate when a stable thermoplastic mask is used in combination with 6D couch, which corrects for rotational errors. Lung adenocarcinoma as a

primary tumor, compared to other primary tumors, was associated with higher rates of LR. This may be attributed to relatively high survival rates observed in patients with BMs from these

primary tumors, as opposed to patients with, for instance, SCLC and colorectal cancer25,26,27. Due to the longer survival times, adverse events such as LR are more likely to occur. All

patients in the cohort were treated after immunotherapy had become widely available, which was commonly used in NSCLC adenocarcinoma patients. Our results additionally showed no significant

associations between immunotherapy treatment and symptomatic RN. Existing literature is inconclusive on this topic, as several studies have found a link between immunotherapy and RN,

particularly in melanoma BMs, but other studies are unable to reproduce this association28,29,30,31,32,33. The inhomogeneity of data, namely factors such as different immunotherapy types,

different primary tumor types, and the different time intervals between immunotherapy treatment and SRT, makes it challenging to give a clear answer to the question if immunotherapy in

combination with SRT increases RN rates. The Dutch national guideline for BMs currently allows continuation of immunotherapy during SRT34. The current study had some limitations. Firstly,

selection and information biases are potential concerns due to its retrospective design. Secondly, the number of patients was limited as a result of the relative novelty of SIMT SRT, which

may limit the ability to detect statistical associations (type II error). Finally, the distinction between LR and RN on MR imaging is notoriously difficult without histological confirmation

which was not available in the majority of cases35,36,37. Thirdly, the Cone Beam imaging with a 0° couch can potentially result in misalignment at nonzero couch angles for non-coplanar

irradiation38. Brainlab ExacTrac (Brainlab AG, Munich, Germany) or a surface-guided radiation therapy has been used to mitigate couch walkout of Elekta VersaHD that otherwise would not be

detected by a 0° couch Cone Beam CT39. Finally, it was not possible to do an adequate analysis of neurocognitive outcomes due to missing data. Despite these limitations, this work supports

the existing literature suggesting that SIMT SRT is safe and effective16,17,19,20,21. Our results did not show an association between ITD and LR or RN. SIMT SRT enables much shorter

treatment times for patients with a large number of BMs, addressing a former disadvantage of SRT compared to WBRT. With the lower risk of neurotoxicity and similar survival rates compared to

WBRT, SRT should be considered in the majority of patients regardless of number of metastases1,2. CONCLUSION With single-isocenter LINAC-based SRT for multiple brain metastases, we found no

correlation between the distance of the isocenter and the incidence of radionecrosis or local recurrence. Single-isocenter SRT using a 6D robotic couch is a safe and effective treatment

option. DATA AVAILABILITY The datasets supporting the conclusions of the article are stored in an institutional repository and are available from the corresponding author on reasonable

request. ABBREVIATIONS * BM(s): Brain metastasis/metastases * C-index: Concordance index * FFF: Flattening filter-free * GTV: Gross tumor volume * ITD: Isocenter-to-tumor distance * LINAC:

Linear accelerator * LR: Local recurrence * MRI: Magnetic resonance imaging * NSCLC: Non-small cell lung cancer * PTV: Planning target volume * RN: Radionecrosis * SCLC: Small cell lung

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(2025). Article  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Marc de Goede and Xander Staal for their help with collecting the treatment planning data. FUNDING This

work was supported by the Jacobusstichting (the Hague, the Netherlands). They were not involved in the conceptualization, design, data collection, analysis, decision to publish, or

preparation of the manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Radiotherapy, Haaglanden Medical Center, Lijnbaan 32, 2512 VA, The Hague, The Netherlands J. A.

Crouzen, J. D. Zindler, M. E. Mast, M. C. Versluis, M. Hashimzadah, M. Kiderlen & N. C. M. G. van der Voort van Zyp * Department of Radiotherapy, HollandPTC, Huismansingel 4, 2629 JH,

Delft, The Netherlands J. D. Zindler * Department of Medical Physics, Haaglanden Medical Center, Lijnbaan 32, 2512 VA, The Hague, The Netherlands J. J. E. Kleijnen & A. L. Petoukhova *

Department of Neurosurgery, Haaglanden Medical Center, Lijnbaan 32, 2512 VA, The Hague, The Netherlands M. L. D. Broekman * Department of Neurosurgery, Leiden University Medical Center,

Albinusdreef 2, 2333 ZA, Leiden, The Netherlands M. L. D. Broekman * Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The

Netherlands M. L. D. Broekman Authors * J. A. Crouzen View author publications You can also search for this author inPubMed Google Scholar * J. D. Zindler View author publications You can

also search for this author inPubMed Google Scholar * M. E. Mast View author publications You can also search for this author inPubMed Google Scholar * J. J. E. Kleijnen View author

publications You can also search for this author inPubMed Google Scholar * M. C. Versluis View author publications You can also search for this author inPubMed Google Scholar * M.

Hashimzadah View author publications You can also search for this author inPubMed Google Scholar * M. Kiderlen View author publications You can also search for this author inPubMed Google

Scholar * N. C. M. G. van der Voort van Zyp View author publications You can also search for this author inPubMed Google Scholar * M. L. D. Broekman View author publications You can also

search for this author inPubMed Google Scholar * A. L. Petoukhova View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.C., J.Z., M.M., and

A.P. came up with the concept and methodology of the study. J.C. wrote the main manuscript text along with J.Z, M.M. and A.P. J.C. prepared all figures. J.C. and M.M. did the formal data

analysis. All authors reviewed and edited the manuscript. CORRESPONDING AUTHOR Correspondence to J. D. Zindler. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

interests. ETHICS APPROVAL The Medical Ethics Committee Leiden The Hague Delft gave approval for this study (reference number N24.032) and granted a waiver of informed consent, because it

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licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Crouzen, J.A., Zindler, J.D., Mast, M.E. _et al._ Local

recurrence and radionecrosis after single-isocenter multiple targets stereotactic radiotherapy for brain metastases. _Sci Rep_ 15, 15722 (2025). https://doi.org/10.1038/s41598-025-01034-x

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Nature SharedIt content-sharing initiative KEYWORDS * Brain metastases * Single-isocenter multiple targets technique * Stereotactic radiotherapy * Radionecrosis * Local recurrence