Whole brain radiation therapy for patients with brain metastases: survival outcomes and prognostic factors in a contemporary institutional series.

PURPOSE: To study survival outcomes and prognostic factors in patients undergoing whole brain radiation therapy (WBRT) for brain metastases in the contemporary setting. METHODS: Patients undergoing WBRT from 2013-2021 were retrospectively included in an ethics-approved institutional database. Patient and treatment characteristics were assessed, including patient age, primary tumor histology, Karnofsky Performance Status (KPS), extracranial disease, as well as WBRT dose. Overall survival (OS) was calculated from onset of WBRT using the Kaplan-Meier method. RESULTS: A total of 328 patients (median age 63 years) were included. Most patients (52%) had ≥ 10 brain metastases, and 17% had leptomeningeal disease. WBRT was delivered with 10â€¯× 3 Gy (64%), 5â€¯× 4 Gy (25%), or other regimens (11%). Median follow-up was 4.4 months (range, 0.1-154.3), and median OS was 4.7 months (95%CI, 3.8-6.0). OS differed between histologies (p = 0.01), with the longest survival seen in breast cancer (median 7.7 months). Patients with KPS of 90-100 survived for a median of 8.3 months, compared to 4.1 months with KPS 70-80, and 1.7 months with KPS < 70 (p < 0.01). Multivariate analyses revealed that KPS had the largest impact on survival. Patients who received a WBRT dose of ≥ 30 Gy also had a reduced risk of death (HR 0.45; p < 0.001). Survival differed between subgroups reclassified according to the Rades scoring system (p < 0.01). CONCLUSION: Survival outcomes of patients undergoing WBRT in the contemporary era appear comparable to historical cohorts, although individual patient factors need to be considered. Patients with otherwise favorable prognostic factors may benefit from longer-course WBRT.

Treatment Options for Brain Metastases.

OPINION STATEMENT: Therapies for brain metastasis continue to evolve as the life expectancies for patients have continued to prolong. Novel advances include the use of improved technology for radiation delivery, surgical guidance, and response assessment, along with systemic therapies that can pass through the blood brain barrier. With increasing complexity of treatments and the increased need for salvage treatments, multi-disciplinary management has become significantly more important.

Dosimetric and radiobiological comparison of IMRT, VMAT, and helical tomotherapy planning techniques in hippocampal sparing whole brain radiotherapy with simultaneous integrated boost for multiple brain metastases.

To compare treatment planning and dosimetric outcomes for hippocampal sparing whole brain radiotherapy (WBRT) with the simultaneous integrated boost (SIB) in brain metastasis (BM) patients using tumour control probability (TCP) and normal tissue complication probability (NTCP) formalism between IMRT, VMAT, and HT techniques. In this retrospective study, the treatment data of 20 BM patients who typically received whole brain radiation with SIB treatment were used. Prescription doses of 30 Gy and 36 Gy was delivered in 10 fractions for WBRT and SIB, respectively. Niemierko and LKB models were applied for calculating TCP and NTCP. All the plans were evaluated for the RTOG 0933 protocol criteria and found acceptable. Additionally, the homogeneity of the PTV boost is 0.07 ± 0.01, 0.1 ± 0.04, and 0.08 ± 0.02 for IMRT, VMAT, and HT, respectively (P < 0.05). The percentage of TCP for the PTV boost was 99.99 ± 0.003, 99.98 ± 0.004, and 99.99 ± 0.002 of IMRT, VMAT, and HT, respectively, (P < 0.005). The NTCP value of the lenses was higher with the VMAT plan as compared to IMRT and HT Plans. The hippocampal NTCP values are equal in all three planning proficiencies. The techniques like IMRT, VMAT, and HT can reduce the dose received by hippocampus to the dosimetric threshold during the delivery of WBRT with hippocampal sparing and can simultaneously boost multiple metastases. Overall, the high-quality dose distribution, TCP, and NTCP comparison between all three planning techniques show that the HT technique has better results when compared to the VMAT and IMRT techniques.

[Comparative analysis of combined treatment methods for patients with single brain lesions]. / Sravnitel'nyi analiz kombinirovannykh metodov lecheniya patsientov s odinochnym metastaticheskim porazheniem golovnogo mozga.

Primary brain metastases are common in oncology. Preoperative stereotactic radiosurgery followed by surgical resection is a perspective approach. OBJECTIVE: To evaluate own experience of preoperative radiosurgery followed by surgical resection (RS+S) of metastasis regarding local control, leptomeningeal progression, surgical and radiation-induced complications; to compare treatment outcomes with surgical resection and subsequent radiotherapy (S+SRT). MATERIAL AND METHODS. A: Retrospective study included 66 patients with solitary brain metastasis. Two groups of patients were distinguished: group 1 (n=34) - postoperative irradiation, group 2 (n=32) - preoperative irradiation. The median age was 49.5 years (range 36-75). RESULTS: Local 3-, 6- and 12-month control among patients with postoperative irradiation was 88.2%, 79.4% and 42.9%, in the group of preoperative irradiation - 100%, 93.3% and 66.7%, respectively (p=0.021). Leptomeningeal progression developed in 11 patients (8 and 3 ones, respectively). The one-year survival rate was 73.5% and 84.4%, respectively (p=0.33). Long-term surgical and radiation-induced complications occurred in 12 (18.2%) patients. CONCLUSION: Preoperative radiosurgery with subsequent resection provides higher local control and lower incidence of leptomeningeal progression in patients with single brain metastases.

Evaluation of alterations in interstitial fluid dynamics in cases of whole-brain radiation using the diffusion-weighted image analysis along the perivascular space method.

In the current study, we assessed changes in interstitial fluid dynamics resulting after whole-brain radiotherapy using the diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, which is a simplified variation of the diffusion tensor image ALPS (DTI-ALPS) method using diffusion-weighted imaging (DWI) with orthogonal motion-probing gradients (MPGs). This retrospective study included 47 image sets from 22 patients who underwent whole-brain radiotherapy for brain tumors. The data for the normal control group comprised 105 image sets from 105 participants with no pathological changes. DWI was performed with the three MPGs applied in an orthogonal direction to the imaging plane, and apparent diffusion coefficient images for the x-, y-, and z-axes were retrospectively generated. The ALPS index was calculated to quantify interstitial fluid dynamics. The independent t-test was used to compare the ALPS index between normal controls and patients who underwent whole-brain radiotherapy. Patients were compared in all age groups and individual age groups (20-39, 40-59, and 60-84 years). We also examined the correlation between biologically equivalent doses (BEDs) and the ALPS index, as well as the correlation between white matter hyperintensity and the ALPS index. In the comparison of all age groups, the ALPS index was significantly lower (p < 0.001) in the postradiation group (1.32 ± 0.16) than in the control group (1.44 ± 0.17), suggesting that interstitial fluid dynamics were altered in patients following whole-brain radiotherapy. Significant age group differences were found (40-59 years: p < 0.01; 60-84 years: p < 0.001), along with a weak negative correlation between BEDs (r = -0.19) and significant correlations between white matter hyperintensity and the ALPS index (r = -0.46 for periventricular white matter, r = -0.38 for deep white matter). It was concluded that the ALPS method using DWI with orthogonal MPGs suggest alteration in interstitial fluid dynamics in patients after whole-brain radiotherapy. Further systematic prospective studies are required to investigate their association with cognitive symptoms.

Adding simultaneous integrated boost to whole brain radiation therapy improved intracranial tumour control and minimize radiation-induced brain injury risk for the treatment of brain metastases.

BACKGROUND: Brain metastases (BMs) are the most frequent intracranial tumours associated with poor clinical outcomes. Radiotherapy is essential in the treatment of these tumours, although the optimal radiation strategy remains controversial. The present study aimed to assess whether whole brain radiation therapy with a simultaneous integrated boost (WBRT + SIB) provides any therapeutic benefit over WBRT alone. METHODS: We included and retrospectively analysed 82 patients who received WBRT + SIB and 83 who received WBRT alone between January 2012 and June 2021. Intracranial progression-free survival (PFS), local tumour control (LTC), overall survival (OS), and toxicity were compared between the groups. RESULTS: Compared to WBRT alone, WBRT + SIB improved intracranial LTC and PFS, especially in the lung cancer subgroup. Patients with high graded prognostic assessment score or well-controlled extracranial disease receiving WBRT + SIB had improved intracranial PFS and LTC. Moreover, WBRT + SIB also improved the long-term intracranial tumour control of small cell lung cancer patients. When evaluating toxicity, we found that WBRT + SIB might slightly increase the risk of radiation-induced brain injury, and that the risk increased with increasing dosage. However, low-dose WBRT + SIB had a tolerable radiation-induced brain injury risk, which was lower than that in the high-dose group, while it was comparable to that in the WBRT group. CONCLUSIONS: WBRT + SIB can be an efficient therapeutic option for patients with BMs, and is associated with improved intracranial LTC and PFS. Furthermore, low-dose WBRT + SIB (biologically effective dose [BED] ≤ 56 Gy) was recommended, based on the acceptable risk of radiation-induced brain injury and satisfactory tumour control. TRIAL REGISTRATION: Retrospectively registered.

The Spectrum of Headache in Leptomeningeal Metastases: A Comprehensive Review with Clinical Management Guidelines.

PURPOSE OF REVIEW: Headaches are a common, oftentimes debilitating symptom in patients with leptomeningeal metastases. RECENT FINDINGS: The third edition of the International Classification of Headache Disorders provides a useful diagnostic framework for headaches secondary to leptomeningeal metastases based on the temporal relationship of headache with disease onset, change in headache severity in correlation with leptomeningeal disease burden, and accompanying neurologic signs such as cranial nerve palsies and encephalopathy. However, headaches in patients with leptomeningeal metastases can be further defined by a wide range of varying cancer- and treatment-related pathophysiologies, each requiring a tailored approach. A thorough review of the literature and expert opinion on five observed headache sub-classifications in patients with leptomeningeal metastases is provided, with attention to necessary diagnostic testing, recommended first-line treatments, and prevention strategies.

Central Nervous System Prophylaxis and Treatment in Acute Leukemias.

OPINION STATEMENT: Improvements in systemic therapy in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved patient outcomes and reduced the incidence of CNS relapse. However, management of patients with CNS disease remains challenging, and relapses in the CNS can be difficult to salvage. In addition to treatment with CNS-penetrant systemic therapy (high-dose methotrexate and cytarabine), intrathecal prophylaxis is indicated in all patients with ALL, however is not uniformly administered in patients with AML without high-risk features. There is a limited role for radiation treatment in CNS prophylaxis; however, radiation should be considered for consolidative treatment in patients with CNS disease, or as an option for palliation of symptoms. Re-examining the role of established treatment paradigms and investigating the role of radiation as bridging therapy in the era of cellular therapy, particularly in chemotherapy refractory patients, is warranted.

Review of the diagnosis and treatment of brain metastases.

Brain metastases (BM) occur in at least 10% of cancer patients, and are one of the main causes of cancer-related deaths and significant deterioration in the quality of life of cancer patients due to the neurological deterioration caused by brain compression and tumor invasion. Whole-brain irradiation has been emphasized as the standard treatment for BM. However, recent clinical trials including the JLGK0901 and JCOG0504 trials conducted in Japan have established therapeutic evidence for the use of stereotactic radiosurgery with regular follow-up with magnetic resonance imaging for BM. In addition to surgery and stereotactic radiotherapy, advances in drug therapy for BM, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, are expected. This review describes the history and the recent evidence of the diagnosis and treatment of BM.

Hybrid split-arc partial-field volumetric modulated arc therapy: an improved beam arrangement for linear accelerator-based hippocampal-avoidance whole brain radiation therapy.

Background: This technical note aims to verify the hippocampus and adjacent organs at risk (OARs) sparing ability of an improved beam arrangement, namely hybrid split-arc partial-field volumetric modulated arc therapy (VMAT) (Hsapf-VMAT) during whole brain radiation therapy (WBRT). Materials and methods: Computed tomography simulation images of 22 patients with brain metastases were retrieved in this retrospective planning study. The hippocampus was manually delineated according to the criterion of RTOG 0933. Plans delivering 30 Gy in 10 fractions were generated for each patient using split-arc partial-field VMAT (sapf-VMAT) and Hsapf-VMAT. The sapf-VMAT plans consisted of 4 arc fields of 179.9° each with reduced field size. The Hsapf-VMAT consisted of 4 arc fields similar to sapf-VMAT in addition to 2 lateral opposing static fields. Statistical comparisons between treatment plans of both techniques were performed using the paired t-test at 5% level significance. Results: The results demonstrated that Hsapf-VMAT can achieve superior dose sparing in hippocampus which is comparable to sapf-VMAT (p > 0.05). In both eyes, Hsapf-VMAT had significantly lower Dmean and Dmax compared to sapf-VMAT (p < 0.005). Decrease in Dmax of both lenses using Hsapf-VMAT (p < 0.005) were statistically significant when compared to sapf-VMAT. Hsapf-VMAT demonstrated significant reduction of Dmean and Dmedian to the optic nerves (p < 0.05). Whole brain planning target volume (PTV) coverage was not compromised in both techniques. Conclusion: The present study adopts a hybrid technique, namely Hsapf-VMAT, for hippocampal sparing WBRT. Hsapf-VMAT can achieve promising dose reduction to the hippocampus, both eyes and lenses. Therefore, Hsapf-VMAT can be considered an improved version of sapf-VMAT.

Updates on Surgical Management and Advances for Brain Tumors.

PURPOSE OF REVIEW: This review summarizes the modern approach to surgical management of malignant brain tumors, highlighting new technology and multimodal treatment paradigms. RECENT FINDINGS: Outcomes in patients with glioblastoma are strongly correlated with extent of initial surgical resection. Intraoperative MRI, 5-ALA, and neuronavigation are surgical tools that can help achieve a maximal safe resection. Stereotactic radiosurgery and brachytherapy can be used to enhance local control for brain metastases in conjunction with surgery, while combinatorial approaches are increasingly employed in patients with multiple metastases. Advances in surgical techniques allow for minimally invasive approaches, including the use of tubular retractors, endoscopes, and laser interstitial thermal therapy. Primary and metastatic brain tumors require a multimodal, multidisciplinary approach to treatment. Surgical resection can be paired with radiation for metastases to maximize tumor control, expanding systemic options. Technological innovations have improved the safety of surgical resection, while expanding the surgical options and indications for treatment.

Multidisciplinary Management of Brain Metastases from Non-Small Cell Lung Cancer in the Era of Immunotherapy.

OPINION STATEMENT: Brain metastases from non-small cell lung cancer often cause neurologic symptoms which lead to initial diagnosis or identification of recurrence. In other patients, they are identified on surveillance imaging or when a patient undergoing treatment develops neurological symptoms. Patients with symptomatic lesions should be started on dexamethasone and evaluated by a neurosurgeon as soon as possible. If feasible, surgery should be offered to decrease intracranial pressure, alleviate symptoms, and prevent irreversible neurological damage. Postoperative stereotactic radiosurgery (SRS) to the resection cavity and any additional brain metastases should follow within 4 weeks of surgery, as early as 2 weeks post-op. Tissue from surgery is used to confirm the diagnosis and test for targetable oncogenic driver mutations. Treatment response and surveillance for development of additional lesions is assessed with MRI of the brain 1 month after SRS and every 3 months thereafter. Patients who are not surgical candidates or who have small, asymptomatic brain metastases should proceed with SRS, the preferred treatment, or sometimes whole-brain radiation therapy (WBRT) if multifocal disease requires more extensive treatment, such as for leptomeningeal spread of disease. The number of brain metastases that warrants use of WBRT over SRS is controversial and a topic of ongoing investigation, and is discussed in this review. When possible, SRS is preferred over WBRT due to reduce morbidity and cognitive side effects. When patients are already on systemic therapy at time of brain metastases diagnosis, systemic therapy should continue, with radiation therapy occurring between cycles. Regarding systemic therapy for new diagnosis at time of brain metastases presentation, molecular testing will guide treatment choice, when available. If there is no neurosurgical intervention, biopsy of another site of disease may provide tissue for molecular testing. If there are no targetable oncogenic driver mutations, concurrent immune checkpoint blockade (ICB) and chemotherapy is preferable for patients who can tolerate it. Single-agent ICB is an alternative option for patients who cannot tolerate chemotherapy. Systemic therapy should start as soon as possible. In some patients with poor performance status, best supportive care may be the most appropriate choice. Treatment decisions should always incorporate patients' goals of care and in many cases should be discussed in a multidisciplinary setting.

Outcome of patients with newly diagnosed primary CNS lymphoma after high-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine: an 8-year cohort study.

BACKGROUND: Addition of cytarabine to high-dose methotrexate (HD-MTX) chemotherapy improves outcome of primary CNS lymphoma (PCNSL); however, the combination therapy increases toxicity. Sequential chemotherapy and cranial radiation may decrease toxicity without altering efficacy. METHODS: This was a single-center, retrospective cohort study of consecutive newly diagnosed immunocompetent PCNSL patients treated with HD-MTX (5 cycles of 3 g/m2 every 2 weeks) followed by consolidation whole-brain radiotherapy (WBRT) and cytarabine (2 cycles of 3 g/m2/d for 2 days every 3 weeks) from January 2013 to December 2020. Initial WBRT before HD-MTX was allowed in patients with significant disability or brain edema at presentation. Primary outcome was progression-free survival (PFS). Key secondary outcomes were response rate, treatment-related toxicity, and overall survival (OS). RESULTS: Of 41 patients, 25 patients had a complete response (CR) and ten patients had a partial response, inferring an overall response rate (ORR) of 85.4% and a CR rate of 60.9%. More than 90% of patients were able to tolerate and complete the HD-MTX. The incidence of ≥ grade 3 hematologic and non-hematologic toxicities were 4.8% and 17.1%, respectively. Treatment-related mortality rate was 2.4%. There was no difference in toxicity between patients with age < 60 and ≥ 60 years. At the median follow-up duration of 39.8 months, the median PFS was 35.2 months (95% CI 12.4-69.3) and median OS was 46.5 months (95% CI 21.8-NR). CONCLUSION: High-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine has acceptable efficacy, great tolerability, and low toxicity in newly diagnosed PCNSL patients.

Feasibility of automated planning for whole-brain radiation therapy using deep learning.

PURPOSE: The purpose of this study was to develop automated planning for whole-brain radiation therapy (WBRT) using a U-net-based deep-learning model for predicting the multileaf collimator (MLC) shape bypassing the contouring processes. METHODS: A dataset of 55 cases, including 40 training sets, five validation sets, and 10 test sets, was used to predict the static MLC shape. The digitally reconstructed radiograph (DRR) reconstructed from planning CT images as an input layer and the MLC shape as an output layer are connected one-to-one via the U-net modeling. The Dice similarity coefficient (DSC) was used as the loss function in the training and ninefold cross-validation. Dose-volume-histogram (DVH) curves were constructed for assessing the automatic MLC shaping performance. Deep-learning (DL) and manually optimized (MO) approaches were compared based on the DVH curves and dose distributions. RESULTS: The ninefold cross-validation ensemble test results were consistent with DSC values of 94.6 ± 0.4 and 94.7 ± 0.9 in training and validation learnings, respectively. The dose coverages of 95% target volume were (98.0 ± 0.7)% and (98.3 ± 0.8)%, and the maximum doses for the lens as critical organ-at-risk were 2.9 Gy and 3.9 Gy for DL and MO, respectively. The DL technique shows the consistent results in terms of the DVH parameter except for MLC shaping prediction for dose saving of small organs such as lens. CONCLUSIONS: Comparable with the MO plan result, the WBRT plan quality obtained using the DL approach is clinically acceptable. Moreover, the DL approach enables WBRT auto-planning without the time-consuming manual MLC shaping and target contouring.

Cyberknife radiosurgery on the brainstem metastases of non-small cell lung cancer.

OBJECTIVE: Management of brainstem metastatic tumor is challenging. This study aimed to evaluate overall survival and quality-of-life in patients with non-small cell lung cancer (NSCLC) brainstem metastases who were treated with the Cyberknife stereotactic radiosurgery. METHODS: From August 2007 through August 2016, a total of 32 patients with 34 brainstem metastases of NSCLC were consecutively enrolled and treated with the Cyberknife radiosurgery (CKRS) at The Huashan Hospital. The study was limited to patients with NSCLC, which was confirmed by postoperative pathological examination. Patients were treated by CKRS as an initial treatment or a second treatment after whole-brain radiation therapy (WBRT). Quality of life was assessed by the SF-12 score and neurological examination. RESULTS: Four out of the 32 (12.5%) patients received WBRT before or concurrent with CKRS treatment. The mean survival time after CKRS was 10.0 (95%CI: 6.0-14.0) months. Karnofsky performance score was not the independent predictor of survival after radiosurgery as analyzed by log-rank test (p = 0.392). Age, however, was a significant predictor of improved survival as analyzed by multivariate analysis (p = 0.024). SF-12 physical component scores demonstrated no significant change after treatment. CONCLUSIONS: The CKSR is a non-invasive, safe, and effective modality in the treatment of patients with brainstem metastases of NSCLC. Better therapeutic outcomes of CKSR for brainstem metastasis might be achieved in the patients older than 65 years old.

Hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost for multiple brain metastases.

BACKGROUND: The current study was aimed at investigating the feasibility of hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost (HA-WBRT+SIB) for metastases and at assessing tumor control in comparison with conventional whole-brain radiation therapy (WBRT) in patients with multiple brain metastases. METHODS: Between August 2012 and December 2016, 66 patients were treated within a monocentric feasibility trial with HA-WBRT+SIB: hippocampus-avoidance WBRT (30 Gy in 12 fractions, dose to 98% of the hippocampal volume ≤ 9 Gy) and a simultaneous integrated boost (51 or 42 Gy in 12 fractions) for metastases/resection cavities. Intracranial tumor control, hippocampal failure, and survival were subsequently compared with a retrospective cohort treated with WBRT via propensity score matching analysis. RESULTS: After 1:1 propensity score matching, there were 62 HA-WBRT+SIB patients and 62 WBRT patients. Local tumor control (LTC) of existing metastases was significantly higher after HA-WBRT+SIB (98% vs 82% at 1 year; P = .007), whereas distant intracranial tumor control was significantly higher after WBRT (82% vs 69% at 1 year; P = .016); this corresponded to higher biologically effective doses. Intracranial progression-free survival (PFS; 13.5 vs 6.4 months; P = .03) and overall survival (9.9 vs 6.2 months; P = .001) were significantly better in the HA-WBRT+SIB cohort. Four patients (6.5%) developed hippocampal metastases after hippocampus avoidance. The neurologic death rate after HA-WBRT+SIB was 27.4%. CONCLUSIONS: HA-WBRT+SIB can be an efficient therapeutic option for patients with multiple brain metastases and is associated with improved LTC of existing metastases, higher intracranial PFS, a reduction of the neurologic death rate, and an acceptable risk of radiation necrosis. The therapy has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicenter, phase 2 HIPPORAD trial.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) - a phase II prospective randomized multicenter trial (NOA-14, ARO 2015-3, DKTK-ROG).

BACKGROUND: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). METHODS: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. DISCUSSION: This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. TRIAL REGISTRATION: The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

The neurocognitive function change criteria after whole-brain radiation therapy for brain metastasis, in reference to health-related quality of life changes: a prospective observation study.

BACKGROUND: We sought to construct the optimal neurocognitive function (NCF) change criteria sensitive to health-related quality of life (HR-QOL) in patients who have undergone whole-brain radiation therapy (WBRT) for brain metastasis. METHODS: We categorized the patients by the changes of NCF into groups of improvement versus deterioration if at least one domain showed changes that exceeded the cut-off while other domains remained stable. The remaining patients were categorized as stable, and the patients who showed both significant improvement and deterioration were categorized as 'both.' We examined the clinical meaning of NCF changes using the cut-off values 1.0, 1.5, and 2.0 SD based on the percentage of patients whose HR-QOL changes were ≥ 10 points. RESULTS: Baseline, 4-month and 8-month data were available in 78, 41 (compliance; 85%), and 29 (81%) patients, respectively. At 4 months, improvement/stable/deterioration/both was seen in 15%/12%/41%/32% of the patients when 1.0 SD was used; 19%/22%/37%/22% with 1.5 SD, and 17%/37%/37%/9% with 2.0 SD. The HR-QOL scores on the QLQ-C30 functional scale were significantly worse in the deterioration group versus the others with 1.0 SD (p = 0.013) and 1.5 SD (p = 0.015). With 1.5 SD, the HR-QOL scores on the QLQ-BN20 was significantly better in the improvement group versus the others (p = 0.033). However, when 'both' was included in 'improvement' or 'deterioration,' no significant difference in HR-QOL was detected. CONCLUSIONS: The NCF cut-off of 1.5 SD and the exclusion of 'both' patients from the 'deterioration' and 'improvement' groups best reflects HR-QOL changes.

Effect of Exposure to Gadodiamide and Brain Irradiation on T1 -Weighted Images and ADC Maps of the Dentate Nucleus.

BACKGROUND: Brain irradiation is considered a cofactor influencing the dentate nucleus (DN) signal intensity (SI) on unenhanced T1 -weighted images in patients exposed to gadolinium-based contrast agents (GBCAs). PURPOSE: To assess the effect of gadodiamide and whole-brain radiation therapy (WBRT) on T1 -weighted images and on apparent diffusion coefficient (ADC) maps of DN. STUDY TYPE: Single-center retrospective. POPULATION: In all, 125 patients who underwent brain MRIs were classified into four groups: 1) patients who did neither receive intravenous GBCAs injections nor irradiation (controls); 2) patients having ≥3 GBCAs-enhanced scans and no WBRT; 3) patients having WBRT and < 3 GBCAs-enhanced scans; and 4) patients having WBRT and ≥ 3 GBCAs-enhanced scans. FIELD STRENGTH/SEQUENCE: 1.5T magnet, echo-planar diffusion weighted imaging (DWI) and unenhanced T1 -weighted sequences. ASSESSMENT: The DN-to-pons SI ratio on unenhanced T1 -weighted images and ADC values of the DN were calculated. Values were compared between groups and relative to the cumulative gadolinium dose and to the time delay after WBRT. STATISTICAL TESTS: Statistical analysis included the Mann-Whitney U-test and Spearman's rank-order correlation. RESULTS: DN ADC values were not significantly different (P = 0.34) between patients exposed to gadodiamide (0.81 ± 0.06) and controls (0.83 ± 0.07). There were no differences in DN ADC values (P = 0.28) and DN-to-pons SI ratios (P = 0.42) between patients exposed to WBRT (ADC values: 0.85 ± 0.09; SI ratio: 1.11 ± 0.10) and controls (ADC values: 0.83 ± 0.06; SI ratio: 1.09 ± 0.06). There was a significant negative correlation between DN ADC values and the time (days) since the end of WBRT (r = - 0.33; 95% confidence interval [CI]: -0.55, -0.06; P < 0.05). DATA CONCLUSION: We did not find changes suggestive of gadolinium-related tissue microstructural damage of the DN. The ADC values of the DN are associated with the time from WBRT. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 5.

Prescription of memantine during non-stereotactic, brain-directed radiation among patients with brain metastases: a population-based study.

PURPOSE: Whole brain radiation therapy (WBRT) remains an important component of treatment for patients with multiple brain metastases (BrM) but is associated with significant neurotoxicity and memory impairment. Although RTOG 0614 demonstrated that administration of memantine to patients receiving WBRT may reduce radiation-associated cognitive decline, prior literature has suggested that radiation oncologists are hesitant to prescribe memantine. We sought to assess the frequency of memantine prescription in patients managed with non-stereotactic, brain-directed radiation for BrM. METHODS: Patients > 65 years old with newly diagnosed BrM between 2007 and 2016 receiving non-stereotactic, brain-directed radiation (including WBRT) were identified using the SEER-Medicare database. Receipt of memantine with non-stereotactic, brain-directed radiation was defined as any Part D claim for memantine 30 days before or after initiation of non-stereotactic, brain-directed radiation. Clinical and demographic variables among patients who did and did not receive memantine were compared. RESULTS: Between 2007 and 2016, we identified 6220 patients with BrM receiving non-stereotactic, brain-directed radiation. Only 2.20% of patients (n = 137) received memantine with radiation. Rates were 1.10% versus 5.14% in the period preceding (2007-2013) and following (2014-2016) the publication of RTOG 0614, respectively. Overall utilization of memantine remained low across several clinical, demographic, and prognostic variables. CONCLUSION: Despite phase 3 evidence supporting memantine utilization among patients receiving WBRT, our population-based study indicates that rates of memantine prescription are strikingly low, although memantine utilization seems to be increasing since publication of RTOG 0614. Further investigation is needed to identify provider and practice-related barriers preventing incorporation of memantine into management paradigms.