High incidence of radiation-induced brain necrosis in the periventricular deep white matter: Stereotactic radiotherapy for brain metastases using volumetric modulated arc therapy

doi:10.21203/rs.3.rs-4916326/v1

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High incidence of radiation-induced brain necrosis in the periventricular deep white matter: Stereotactic radiotherapy for brain metastases using volumetric modulated arc therapy

https://doi.org/10.21203/rs.3.rs-4916326/v1

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Purpose

In this retrospective study, we aimed to evaluate the efficacy and incidence of radiation-induced brain necrosis (RBN) after volumetric modulated arc therapy (VMAT)-based stereotactic irradiation (STI) for brain metastases.

Methods

In the 220 brain metastatic lesions included between January 2020 and June 2022, there were 1–9 concurrently treated lesions (median 1). A biologically effective dose (BED10) of 80 Gy and a reduced BED10 of 50 Gy were prescribed to the gross tumor volume (GTV) and planning target volume (PTV = GTV + 3 mm) margins, respectively. The number of fractions was adjusted from 3–15 to accommodate different GTV sizes; for larger tumor volumes, this was increased while maintaining the BED10 values comparable to those for GTV and PTV margins.

Results

Of the total patients, 16 (7%) exhibited locally progressive lesions; local tumor recurrence was observed in 2 (1%) patients, while RBN was noted in 14 (6%) patients. RBN was significantly more prevalent in the deep white matter around the lateral ventricles (DWM-LV) than in other sites, occurring in 9/22 (41%) lesions of metastases in the DWM-LV. The 2-year actuarial incidence risk of developing RBN was significantly higher in the DWM-LV (69%) than at other sites (5%).

Conclusion

The recurrence rate of brain metastases was low, and the incidence of RBN was lower in tumor sites other than the DWM-LV. However, the frequency of RBN was significantly higher in the DWM-LV region. Additional VMAT-STI-prescribed dose protocols are necessary to reduce RBN incidence in DWM-LVs.

radiation-induced brain necrosis

stereotactic radiotherapy

volumetric modulated arc therapy

Recent advances in cancer treatment have improved the prognosis of patients with advanced cancer, and radiotherapy for brain metastases is required to provide long-term tumor control and safety. In stereotactic radiotherapy using linear accelerators, volumetric modulated arc therapy (VMAT)-based stereotactic radiotherapy (VMAT-STI) has become popular, allowing a more detailed setting of the dose to the normal brain sur-rounding the tumor and a dose increase inside the tumor, compared with conventional stereotactic radiotherapy using three-dimensional (3D) irradiation. However, the differences in the risk of radiation brain necrosis (RBN) and the optimal dose for each region of the brain are unknown, and uniform treatment is often applied regardless of the metastatic site.

Compared with conventional 3D irradiation and fixed gantry IMRT, VMAT-STI allows for more detailed dose settings from the tumor center to the periphery and can treat multiple brain metastases in a shorter irradiation time. In single-fraction stereo-tactic radiosurgery (SRS), the incidence of symptomatic brain necrosis exceeds 20% when the V12 Gy volume surpasses 5–10 mL [1]. Furthermore, even when the gross tumor volume (GTV) margin dose is reduced to 18 Gy (BEDGy10 of 50 Gy), there re-mains a risk of developing RBNs in tumors of > 2 cm in diameter [1]. Although microscopic infiltration of brain metastases into the surrounding brain tissue is typically estimated to be 1 mm, intraoperative fluorescence diagnosis and pathology reports have documented cases with infiltration depths of ≥ 2–3 mm (2, 3) [2, 3]. Notably, larger brain metastases tend to exhibit deeper invasion of the surrounding brain tissue. Based on these findings, Ohtakara et al. proposed a VMAT-STI protocol utilizing separate prescription doses for the GTV margin and a prophylactic margin of GTV + 2–3 mm [4, 5]. To mitigate the risk of RBN, the protocol also incorporated an increased number of fractions for larger tumor volumes, while maintaining BEDGy10 doses equivalent to both the GTV margin and GTV + 2–3 mm.

In this study, we employed a VMAT-STI protocol involving precise dose and fractionation specifications within, at the limbus of, and surrounding the GTV to treat brain metastases. To the best of our knowledge, there is limited literature on the efficacy of VMAT-STIs with detailed dosimetry as well as on the incidence and risk factors associated with brain necrosis. This study aimed to evaluate the efficacy and toxicity of VMAT-STIs for brain metastases, and the incidence of RBN in relation to the metastatic site.

Patients

From January 2020 to June 2022, patients with brain metastases were prospectively enrolled in the radiotherapy database at the authors’ institution. During the same period, consecutive patients with brain metastases were treated using VMAT-STI. There were 220 brain metastases in 63 patients treated with VMAT-STIs. The inclusion criteria were as follows: (i) patients with metastatic brain tumor(s) treated with VMAT-STI and pathologically confirmed primary malignant tumors, and (ii) patients who had under-gone at least one contrast-enhanced MRI scan 1 month after the end of irradiation. Patient characteristics are shown in Table 1. Written informed consent for the treatment was obtained from all patients. This study was approved by institutional review board of the authors (protocol code UOEHCRB22-078).

VMAT-STI Protocol

VMAT-STI was performed using a linear accelerator (Elekta, Versa HD™). The patients were imaged using high-resolution thin-slice (1.0–2.0 mm) computed tomography (CT) and immobilized in the supine position using a thermoplastic head-mask fixation system. The treatment plans were implemented using Monaco™ (Elekta) in all patients. GTV was contoured using the fusion of CT images for treatment planning and contrast-enhanced MRI. Figure 1 shows a schematic representation of the VMAT-STI protocol for brain metastases. BED10 = 80 Gy was prescribed as the GTV marginal dose, and the marginal dose of the PTV (GTV + 3 mm) was reduced to BED10 = 50 Gy. The central dose of the tumor was increased to more than 125% of the marginal GTV. The number of fractionations was adjusted between 3 and 15 depending on the GTV size. For larger tumor volumes, the number of irradiation fractions increased, and the BED10 values of the GTV margins and GTV + 3 mm were comparable. The relationship between the number of dose fractions and tumor volume is shown in Table 1.

Evaluation of the metastatic sites and RBN

Metastatic sites were classified into the following areas based on anatomical regions observed on MRI images: brain cortical and/or subcortical white matter (BC/SCWM); deep white matter around the lateral ventricles (DWM-LV), defined as lesions bordering the lateral ventricles or located in the deep white matter within 10 mm of their perimeter; and cerebellum, basal ganglia, thalamus, midbrain, and hippocampus.

Assessments using enhanced MRI or CT were scheduled before treatment and every 1–6 months after treatment until treatment failure or death. Local tumor recurrence was assessed using the RANO-BM (Response Assessment in Neuro-Oncology-Brain Metastases) guidelines [6]. Locally progressive lesions of the treated lesion(s) were classified as RBN or tumor recurrence. The diagnosis of RBN and tumor recurrence was confirmed based on temporal MRI images and by considering the me-thionine PET images, the changes in tumor markers in some cases, and pathological findings on excised specimens. Local control rate was defined as the period during which there were no local progressive lesions.

The analyses of certain factors for developing RBN were investigated using Fisher’s exact probability or Mann–Whitney U test. Local control and incidence rates of devel-oping RBN were calculated from the first day of VMAT-STI using the Kaplan–Meier method. Statistical significance of the differences between the actuarial curves was assessed using the log-rank test.

Overall survival was defined as the time from the last day of the first VMATSTI course to death. Distant brain progression-free survival (DPFS) was defined as the time from the last day of the first VMATSTI course to the occurrence of distant brain failure, as indicated by the appearance of new or progressive brain metastases outside the PTV or death.

Local tumor recurrence and RBN

Locally progressive lesions were observed in 16 (7%) of the 220 brain metastases treated with VMAT-STI, and local tumor recurrence of the treated brain metastases was observed in 2 (1%) of the 220 brain metastases and 2 (%) of the 63 patients. RBN was recognized in 14 (6%) of the 220 patients with brain metastases and 14 (22%) of the 63 patients. Table 2 presents the clinical details of the 16 locally progressive lesions. Local tumor recurrence was observed only in two brain metastases. Both lesions had a large tumor volume (9.7cc and 11.9 cc) and underwent tumor removal.

Fourteen (88%) of the sixteen locally progressive lesions were diagnosed as RBN based on clinical findings, including the post-onset course of the disease. The median time to RBN onset after VMAT-STI was 15 months (range, 6–25). Nine of fourteen patients with RBN were administered steroids. No patient experienced poor control with steroid therapy or required explantation. Table 3 shows the incidence of RBN after VMAT-STI for brain metastases among the metastatic sites. RBN was significantly more common in the DWM-LV than in other sites, occurring in 9 (41%) of the 22 lesions in brain metastases from the DWM-LV. The analyses of certain factors for RBN after VMAT-STI are shown in Table 4. Other factors were not significantly associated with the development of RBN. Figure 2 shows the actuarial incidence risk of developing RBN for different meta-static sites and dose fractions. The actuarial incidence risk at 2-year between in the DWM-LV and other sites was 69% and 5%, respectively, and the difference was significant (Fig. 2a, P < 0.0001). Case no. 2 in Table 2, which is associated with RBN, is presented in detail in Fig. 3.

Local control rate and survivals

The 3-year local control rate was 82% in all 220 patients with brain metastases (Fig. 4a). The local control rates for different radiation dose fractions are shown in Fig. 4b. There was no significant difference in the local control rates between brain metastatic lesions treated with 36 Gy/3 and 43 Gy/5 fractions. However, the brain met-astatic lesions were treated with 50–59 Gy/8–15 fractions. exhibits significantly lower local control rates. The local control rate in the DWM-LV region was significantly lower than that in the other sites (P < 0.0001). The 3-year local control rate was 31% in DWM-LV and 89% in the other sites (Fig. 4c).

Overall survival rate and DPFS rates are shown in Fig. 4d. The 3-year overall survival rate was 52% for all 63 patients. The median overall survival time was 39.5 months. The 3-year DPFS was 17%, with a median DPFS of 7.7 months.

To our knowledge, this is the first study to investigate the impact of VMAT-STI treatment, characterized by a detailed dose prescription within, at the limbus, and surrounding the GTV, as well as dose fraction adjustment based on tumor size while maintaining BEDGy10, on treatment efficacy and site-specific brain necrosis incidence for brain metastasis. The strength of this study was that it was conducted using a uniform prescription protocol. Our prescription protocol for VMAT-STIs for brain metastases showed a low incidence of tumor recurrence. However, there was a significantly higher risk of RBN only at the DWM-LV sites.

Linac-based stereotactic radiotherapy with fractionated irradiation using 3D con-formal radiation therapy has been reported to be safer than SRS, which is a single-dose irradiation. Kim et al. compared SRS and fractionated stereotactic radiotherapy (FSRT) for brain metastases and found that the incidence of toxicity was three times higher in the SRS group than in the FSRT group [7]. However, the 1-year local control rate after FSRT was only 69%, and the prescribed dose in the FSRT group (36 Gy/6 fractions, BED 58.7 Gy10) to the GTV + 1 mm margin was lower than the prescribed dose. Saito et al. reported a better 1-year local control rate of 86% with FSRT using 3D conformal radiation therapy at 35.1–37.8 Gy/3 fractions (BED 76.2–85.4 Gy10) to the GTV + 3 mm margin [8], while also noted brain necrosis in 12% of cases [9]. Our dose prescription more clearly defined the GTV margin and GTV + 3 mm doses as well as the maximum dose at the tumor center using the VMAT technique. The antitumor effect was satisfactory, with only two cases of local tumor recurrence. The incidence of brain necrosis was low at only 2.5% (5/198 lesions) of the tumor sites, except for DWM-LV. However, brain necrosis occurred significantly more frequently in the DWM-LV group (41%, 9/22). To reduce the incidence of cerebral necrosis further, we believe that it is necessary to develop a pre-scription protocol specifically for DWM-LV.

Previous studies have indicated that the risk factors for RBN in brain metastases include radiation dose, prior whole-brain radiotherapy, metastasis size, and previous surgery [10, 11]. Few studies have investigated the anatomical location of RBN. A clinical study has reported a high incidence of brain necrosis following stereotactic radiotherapy for brain metastases located in the deep white matter; in a retrospective study of 137 cases with 311 lesions treated with SRS (16–22 Gy, BEDGy10 of 41.6–70.4 Gy) for brain metastases of malignant melanoma, the overall RBN incidence was 17/137 (12.4%) [9]. The incidence of RBN in the deep white matter was 7/19 (36.8%), which was significantly higher than that in other regions. Ohtakara et al. also suggested that lesion lo-cation is important in predicting RBN after stereotactic radiosurgery, especially in depth from the brain surface [1]. Shallow lesions cause less damage to the surrounding tissues, whereas deeper lesions increase the risk of radiation injury.

Research has shown that following radiation therapy, the white matter can exhibit a range of pathological changes, including the development of small necrotic foci, vacuolation, and punctate hemorrhages [12]. The severity and progression of these lesions are influenced by factors, such as patient age and cumulative radiation dose. Over months to years, these initial changes may evolve into more extensive and severe neurodestructive lesions characterized by coagulative necrosis. This progression can lead to clinical symptoms that mimic those of recurrent intracranial neoplasms, making it challenging to differentiate radiation-induced lesions from recurrent or residual tumors using CT imaging. Radiation preferentially damages the white matter, potentially due to direct injury to myelin and oligodendrocytes, increased vulnerability of glial cells, and exacerbated hypoxia in deep white matter regions [13]. The periventricular and deep white matter areas are particularly susceptible to ischemic changes secondary to vascular injury and may contribute to a higher incidence of RBN than other brain regions.

A major limitation of this study is its retrospective design, which raises the possibility of selection bias in predictive factors. Differentiating between RBN and tumor recurrence based solely on imaging findings is challenging and potentially inaccurate. While both tumor recurrence cases in our study were confirmed through tissue resection, the RBN cases were followed up for at least three months after steroid administration, excluding the possibility of tumor recurrence. Therefore, we believe that the clinical diagnostic accuracy in our cases was maintained.

The antitumor effect of our VMAT-STI treatment protocol, characterized by a precise dose prescription within, at the limbus, and around the GTV as well as dose fractionation adjustment based on tumor size while maintaining BEDGy10, was satisfactory, with only two cases of local tumor recurrence. Additionally, the incidence of brain necrosis was lower at tumor sites other than the DWM-LV. However, the frequency of brain necrosis was significantly higher in the DWM-LV group, suggesting the need for a DWM-LV-specific prescription protocol to reduce the incidence of brain necrosis in these lesions.

BED

Biologically effective dose

DPFS

Distant brain progression-free survival

DWM-LV

Deep white matter around the lateral ventricles

FSRT

Fractionated stereotactic radiotherapy

GTV

Gross tumor volume

Overall survival

PTV

Planning target volume

RBN

Radiation brain necrosis

SRS

Single-fraction stereotactic radiosurgery

STI

Stereotactic irradiation

VMAT

Volumetric modulated arc therapy

Three-dimensional

Data availability

No datasets were generated or analysed during the current study.

Ethics declarations

Ethics approval and consent to participate

Our study was reviewed and approved by the Ethics Committee of University of　Occupational and Environmental health.

This is a retrospective study using data from a database that does not identify patients, and the Ethics Committee has waived the need to obtain consent.

Human Ethics declaration

Not applicable

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Ohtakara K, Hayashi S, Nakayama N, et al. Significance of target location relative to the depth from the brain surface and high-dose irradiated volume in the development of brain radionecrosis after micromultileaf collimator-based stereotactic radiosurgery for brain metastases. J Neurooncol. 2012;108(1): 201-209.
Yagi R, Kawabata S, Ikeda N, et al. Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis. World J Surg Oncol. 2017;15(1): 179.
Matsuyama T, Kogo K and Oya N Clinical outcomes of biological effective dose-based fractionated stereotactic radiation therapy for metastatic brain tumors from non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2013;85(4): 984-990.
Ohtakara K, Nakao M, Muramatsu H, et al. Nineteen-month immunity to adverse radiation effects following 5-fraction re-radiosurgery with 43.6 gy for local progression after prior 3-fraction radiosurgery for brain metastasis from pan-negative lung adenocarcinoma. Cureus. 2023;15(10): e46374.
Ohtakara K, Kondo T, Obata Y, et al. Five-fraction radiosurgery using a biologically equivalent dose of a single fraction of 24 gy for a 3-cm parasagittal para-central sulcus brain metastasis from adenocarcinoma of the cecum. Cureus. 2023;15(11): e48799.
Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: Proposal from the rano group. Lancet Oncol. 2015;16(6): e270-278.
Kim YJ, Cho KH, Kim JY, et al. Single-dose versus fractionated stereotactic radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys. 2011;81(2): 483-489.
Saitoh J, Saito Y, Kazumoto T, et al. Therapeutic effect of linac-based stereotactic radiotherapy with a micro-multileaf collimator for the treatment of patients with brain metastases from lung cancer. Jpn J Clin Oncol. 2010;40(2): 119-124.
Choi S, Hong A, Wang T, et al. Risk of radiation necrosis after stereotactic radiosurgery for melanoma brain metastasis by anatomical location. Strahlenther Onkol. 2021;197(12): 1104-1112.
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(2): 373-386.
Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: Analysis of outcome and risk of brain radionecrosis. Radiat Oncol. 2011;6(48.
Tsuruda JS, Kortman KE, Bradley WG, et al. Radiation effects on cerebral white matter: Mr evaluation. AJR Am J Roentgenol. 1987;149(1): 165-171.
Fukutomi A, Mizusawa J, Katayama H, et al. Randomized phase ii study of s-1 and concurrent radiotherapy with versus without induction chemotherapy of gemcitabine for locally advanced pancreatic cancer (jcog1106). J Clin Oncol 2015 33(suppl; abstr 4116)(

Tables 1 to 4 are available in the Supplementary Files section

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You are reading this latest preprint version

High incidence of radiation-induced brain necrosis in the periventricular deep white matter: Stereotactic radiotherapy for brain metastases using volumetric modulated arc therapy

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Materials and Methods

Patients

VMAT-STI Protocol

Evaluation of the metastatic sites and RBN

Results

Local tumor recurrence and RBN

Local control rate and survivals

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1