Late-onset radiation-induced brain necrosis following allogeneic transplantation for CNS-involved acute myeloid leukemia after whole brain irradiation: two case reports

Radiation-induced brain necrosis (RIBN) is a common adverse event from radiation therapy. We present a case of a 56-year-old man, diagnosed with non-small-cell lung cancer with brain metastases 2years prior, for which he had received whole brain radiotherapy and brain stereotactic radiosurgery, who presented to the oncology unit with headache, dizziness and abnormal gait. MRI of the brain revealed radiological worsening of a cerebellar mass, including edema and mass effect. After a multidisciplinary tumor board meeting, the patient was diagnosed with RIBN and received 4 cycles of high-dose bevacizumab, with complete symptom resolution and significant radiological response. We report the successful use of a high-dose, shorter-duration treatment protocol of bevacizumab for RIBN.

Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation-induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4weeks and a sustained increase in TNF-α, iNOS, and other inflammatory cytokines beginning at 1-week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1-week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation-induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

Introduction: Radiation-induced brain necrosis (RN) is a relatively uncommon (5-20%) but potentially severe adverse effect of stereotactic radiosurgery (SRS) for brain metastasis(BM). We attempted to establish the effect of hypo-fractionation on RN rates by reviewing patients having simultaneous multi-fraction and single fraction treatment of BM at our centre. Methods: Patients receiving simultaneous 1 (20-24Gy) or 3 fraction (21-24Gy) SRS treatments were identified in our institution’s database. Serial post-SRS MRIs were reviewed to determine the lesion quotient (LQ), or maximum cross sectional area on T1 plus gadolinium divided by T2 FLAIR sequences. LQ less than 0.3 was considered RN. Result: Twenty-two patients were followed for a median 320 days. Sixteen patients developed radionecrosis in 21 of 62 lesions (33%), four of which were symptomatic (20%). Eleven of these lesions received 3 fractions and ten received one fraction. RN risk increased with increasing tumor volume (log odds ratio=1.12, p=0.04). There was no difference in incidence of RN in patients who received whole brain radiotherapy (WBRT) (p=0.11), hypo-fractionation (p=0.98) or had a higher maximum dose (p=0.71). Radiographic RN, however, did not clear in any patients who developed it. Eight patients developed a local recurrence (12%), six of which occurred in the single fraction group. Conclusion: Radionecrosis was significantly related to tumor volume but not fractionation, WBRT, or maximum dose. Overall, our results indicate patients receiving SRS for multiple brain metastasis have a higher rate of radionecrosis than the literature and poorer survival despite having equivalent local control.

This study was designed to evaluate the efficacy and safety of brain radiotherapy combined with immune checkpoint inhibitors (ICIs) retrospectively in small-cell lung cancer (SCLC) patients with brain metastases (BMs). A retrospective analysis was conducted on 42 SCLC patients with BMs, who received brain radiotherapy combined with ICIs at our Hospital from 2020 to 2024. They received chemotherapy plus ICIs regimens and brain radiotherapy, and received concurrent/sequential thoracic radiotherapy. This study investigated the forms of WBRT vs. WBRT+ simultaneous integrated boost (SIB, different doses of radiation being delivered simultaneously to different parts of the tumor) combined with ICIs on overall survival (OS), intracranial local control (iLC), and radiotherapy adverse reactions (side effection). The Kaplan-Meier method was used for survival rate analysis. The log-rank test was used to compare the survival curves between different groups, and the chi-square (χ2) test was used to compare categorical data. In all the patients, the median follow-up time was 19.2 (range: 9.79-36.8) months. The 2-year OS rate and iLC rate were 42.3% and 68.8%, respectively. A total of 26 patients died of disease progression; 2 patients developed radiation-induced brain necrosis. The results showed that there was no significant difference in radiation-induced brain necrosis between the two groups. The WBRT patients suffered high rates of headache, dizziness, nausea, and radiodermatitis. The 2-year OS and iLC were brilliant. When brain radiotherapy combined with ICIs, even WBRT or WBRT + SIB had well OS and iLC with tolerable side reactions. Its indications needed to be considered from multiple perspectives. Further evaluation of brain radiotherapy combined with ICIs in SCLC BMs is required. Further prospective studies should be conducted to verify the conclusions.

Radiation necrosis of the brain after radiosurgery for vestibular schwannoma

Multivoxel proton magnetic resonance spectroscopy (MRS) was used for differentiation of radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for intracranial metastases in 33 consecutive cases. All patients presented with enlargement of the treated lesion, increase of perilesional brain edema, and aggravation or appearance of neurological signs and symptoms on average 9.3 +/- 4.9 months after primary treatment. Metabolic imaging defined four types of lesions: pure tumor recurrence (11 cases), partial tumor recurrence (11 cases), radiation-induced tumor necrosis (10 cases), and radiation-induced necrosis of the peritumoral brain (1 case). In 1 patient, radiation-induced tumor necrosis was diagnosed 9 months after radiosurgery; however, partial tumor recurrence was identified 6 months later. With the exception of midline shift, which was found to be more typical for radiation-induced necrosis (P < 0.01), no one clinical, radiologic, or radiosurgical parameter either at the time of primary treatment or at the time of deterioration showed a statistically significant association with the type of the lesion. Proton MRS-based diagnosis was confirmed histologically in all surgically treated patients (7 cases) and corresponded well to the clinical course in others. In conclusion, multivoxel proton MRS is an effective diagnostic modality for identification of radiation-induced necrosis and tumor recurrence that can be used for monitoring of metabolic changes in intracranial neoplasms after radiosurgical treatment. It can be also helpful for differentiation of radiation-induced necrosis of the tumor and that of the peritumoral brain, which may have important clinical and medicolegal implications.

Radiation necrosis of normal CNS tissue represents one of the main risk factors of brain irradiation, occurring more frequently and earlier at higher total doses and higher doses per fraction. At present, it is believed that the necrosis results due to increasing capillary permeability caused by cytokine release leading to extracellular edema. This process is sustained by endothelial dysfunction, tissue hypoxia, and subsequent necrosis. Consequently, blocking the vascular endothelial growth factor (VEGF) at an early stage could be an option to reduce the development of radiation necrosis by decreasing the vascular permeability. This might help to reverse the pathological mechanisms, improve the symptoms and prevent further progression. A patient with radiationinduced necrosis was treated with an anti-VEGF antibody (bevacizumab), in whom neurologic signs and symptoms improved in accordance with a decrease in T1-weighted fluid-attenuated inversion recovery signals. Our case report together with the current literature suggests bevacizumab as a treatment option for patients with symptoms and radiological signs of cerebral necrosis induced by radiotherapy.

Brain radiation necrosis is a serious adverse effect of radiotherapy in patients with malignant brain metastases. There is currently no standard treatment for brain radiation necrosis; however, there are advantages to using bevacizumab. Nonetheless, due to the risk of severe bleeding when bevacizumab is used in patients with squamous cell lung carcinoma, relevant clinical studies are lacking; therefore, there is no clear conclusion on the use of bevacizumab to treat brain radiation necrosis in patients with squamous cell carcinoma of the lung with brain metastases. The present study described the case of a patient treated with bevacizumab after brain radiation injury with pathological manifestations diagnosed as squamous cell carcinoma of the lung. Through the evaluation of clinical symptoms and imaging data, the patient was diagnosed with cerebral radiation necrosis a few months after receiving local radiotherapy for intracranial metastatic lesions. After four cycles of treatment with bevacizumab (7.5 mg/kg once every 3 weeks, intravenous drip), the clinical and imaging manifestations of the patient were considerably improved with no significant adverse effects. The favorable efficacy and safety profiles of this patient suggest that bevacizumab holds potential as a future therapeutic option for managing radiation-induced brain necrosis in patients with squamous cell lung cancer.

Mortality of early treatment for radiation-induced brain necrosis in head and neck cancer survivors: A multicentre, retrospective, registry-based cohort study

GB (Glioblastoma WHO Grade 4) is the most aggressive type of brain tumor in adults that has a short survival rate even after aggressive treatment with surgery and radiation therapy. The changes in magnetic resonance imaging (MRI) for patients with GB after radiotherapy are indicative of either radiation-induced necrosis (RN) or recurrent brain tumor (rBT). Screening for rBT and RN at an early stage is crucial for facilitating faster treatment and better outcomes for the patients. Differentiating rBT from RN is challenging as both may present with similar radiological and clinical characteristics on MRI. Moreover, learning-based rBT versus RN classification using MRI may suffer from class imbalance due to a lack of patient data. While synthetic data generation using generative models has shown promise to address class imbalances, the underlying data representation may be different in synthetic or augmented data. This study proposes computational modeling with statistically rigorous repeated random sub-sampling to balance the subset sample size for rBT and RN classification. The proposed pipeline includes multiresolution radiomic feature (MRF) extraction followed by feature selection with statistical significance testing (p<0.05). The five-fold cross validation results show the proposed model with MRF features classifies rBT from RN with an area under the curve (AUC) of 0.892±0.055. Moreover, considering the dependence between survival time and censoring time (where patients are not followed up until death), the feasibility of using MRF radiomic features as a non-invasive biomarker to identify patients who are at higher risk of recurrence or radiation necrosis is demonstrated. The cross-validated results show that the MRF model provides the best overall survival prediction with an AUC of 0.77±0.032. Comparison with state-of-the-art methods suggest the proposed method is effective in RN versus rBT classification and patient survivability prediction.

It's Not All in the Conditioning or the Perils of Early Trial Cessation

To analyze the therapeutic effect of bevacizumab on radiation-induced brain necrosis. Four radiation-induced brain necrosis patients, administered with bevacizumab at a dose of 7.5 mg/kg every 3 weeks, 2 times. One case of brain metastasis of lung cancer and one case of nasopharyngeal carcinoma with brain necrosis after radiotherapy. However, their physical signs disappeared after the treatment with bevacizumab. One case of brainstem lesion and one case of brain glioma patient showed a transient improvement in signs and symptoms after treatment with bevacizumab. Bevacizumab can significantly alleviate the radiation-induced brain edema, and can improve the symptoms successively.

Non-small cell lung cancer (NSCLC) is the second most common cancer worldwide, resulting in 1.8 million deaths per year. Most patients are diagnosed with a metastatic disease. Brain metastases are one of the most common metastatic sites and are associated with severe neurological symptoms, shorter survival, and the worst clinical outcomes. Brain radiotherapy and systemic oncological therapies are currently used for controlling both cancer progression and neurological symptoms. Brain radiotherapy includes stereotactic brain ablative radiotherapy (SBRT) or whole brain radiotherapy (WBRT). SBRT is applied for single or multiple (up to ten) small (diameter less than 4 cm) lesions, whereas WBRT is usually applied for multiple (more than ten) and large (diameter greater than 4 cm) brain metastases. In both cases, radiotherapy application may be viewed as an overtreatment which causes severe toxicities without achieving a significant clinical benefit. Thus far, a number of scoring systems to define the potential clinical benefits derived from brain radiotherapy have been proposed. However, most are not well established in clinical practice. In this article, we present a clinical case of a patient with advanced NSCLC carrying a BRAFV600E mutation and brain metastases. We review the variables in addition to applicable scoring systems considered to have potential for predicting clinical outcomes and benefits of brain radiotherapy in patients with advanced NSCLC and brain metastases. Lastly, we highlight the unmet need of specific scoring systems for advanced NSCLC patients with brain metastases carrying oncogene alterations including BRAFV600E mutations.

A GSK-3β Inhibitor Protects Against Radiation Necrosis in Mouse Brain

Cystic brain necrosis (CBN) is a rare form of BN. It typically occurs as a very late complication, and no standard treatment has been established. We report a case of a 59-year-old man who developed CBN 10 years after radiation therapy for metastatic brain tumors. The therapy consisted of whole brain radiotherapy followed by linac-based stereotactic radiosurgery as a boost. Initially, the CBN continued to expand despite treatment with corticosteroids and bevacizumab. Therefore, we resected the tumor and implanted an Ommaya reservoir, which successfully stabilized the lesion. Although the prognosis of patients with brain metastases is generally poor, some patients, like the one reported here, achieve long survival. Therefore, we should follow such cases carefully, considering the possibility of developing CBN as a late complication.