DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.

PURPOSE: The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. MATERIALS AND METHODS: For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). CONCLUSION AND RECOMMENDATIONS: Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

Long-term survival in patients with brain metastases-clinical characterization of a rare scenario.

PURPOSE: This study aimed to assess clinical, treatment, and prognostic features in patients with brain metastases (BM) from solid tumors achieving long-term survival (LTS). Further, the accuracy of diagnosis-specific Graded Prognostic Assessment scores (ds-GPA) to predict LTS was evaluated. METHODS: Patients admitted for radiotherapy of BM between 2010 and 2020 at a large tertiary cancer center with survival of at least 3 years from diagnosis of BM were included. Patient, tumor, treatment characteristics and ds-GPA were compiled retrospectively. RESULTS: From a total of 1248 patients with BM, 61 (4.9%) survived ≥ 3 years. In 40 patients, detailed patient charts were available. Among LTS patients, median survival time from diagnosis of BM was 51.5 months. Most frequent primary tumors were lung cancer (45%), melanoma (20%), and breast cancer (17.5%). At the time of diagnosis of BM, 11/40 patients (27.5%) had oligometastatic disease. Estimated mean survival time based on ds-GPA was 19.7 months (in 8 cases estimated survival < 12 months). Resection followed by focal or whole-brain radiotherapy (WBRT) was often applied (60%), followed by primary stereotactic radiotherapy (SRT) (20%) or WBRT (20%). 80% of patients received systemic treatment, appearing particularly active in specifically altered non-small lung cancer (NSCLC), melanoma, and HER2-positive breast cancer. Karnofsky performance score (KPS) and the presence of oligometastatic disease at BM diagnosis were persisting prognostic factors in LTS patients. CONCLUSION: In this monocentric setting reflecting daily pattern of care, LTS with BM is heterogeneous and difficult to predict. Effective local treatment and modern systemic therapies often appear crucial for LTS. The impact of concomitant diseases and frailty is not clear.

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.

Survival outcomes and treatment experience of 124 patients with primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a rare malignancy of the central nervous system with high invasiveness. There is little consensus on the treatment of PCNSL. This study retrospectively studied data from PCNSL patients in a single center to summarize treatment experience and explore prognostic factors. METHODS: Survival curves were drawn using the Kaplan-Meier method and prognostic factors were analyzed using Cox's hazards model. RESULTS: In multivariate analysis, cerebrospinal fluid lactic acid dehydrogenase (CSF LDH; p = 0.005 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.014 and p = 0.038), and completion of four cycles of induction therapy (p < 0.001and p < 0.001) were significant and independent predictors of overall survival (OS) and progression-free survival (PFS), respectively. CONCLUSION: On the basis of this study, we propose that PCNSL patients should receive early induction therapy with sufficient cycles. Subsequent consolidation therapy can prevent relapses and improve survival. In patients with PCNSL, the independent prognostic factors for OS and PFS were CSF LDH level, NLR, and full cycles of induction therapy.

The indication of palliative whole-brain radiotherapy for patients with brain metastases: a simple prognostic scoring system in the era of stereotactic radiosurgery.

BACKGROUND: Stereotactic irradiation has become the mainstay treatment for brain metastases (BM), and whole-brain radiotherapy (WBRT) is often used for symptom palliation. However, the survival time of patients with BM undergoing palliative WBRT (pWBRT) is limited, making it difficult to select patients who should receive treatment. METHODS: We collected patient data from 2016 to 2022 at the Shizuoka Cancer Center and retrospectively analyzed the factors related to survival time. Overall survival (OS) was defined as the survival time after WBRT. RESULTS: A total of 301 patients (median age, 66 years) who underwent pWBRT were included. The primary cancers were lung, breast, gastrointestinal tract, and other cancers in 203 (67%), 38 (13%), 33 (11%), and 27 (9%) patients, respectively. Median OS of all patients was 4.1 months. In the multivariate analysis, male sex (hazard ratio [HR]:1.4), Karnofsky Performance Status (KPS) ≤ 60 (HR:1.7), presence of extracranial metastasis (ECM) (HR:1.6), neutrophil-lymphocyte ratio (NLR) ≥ 5 (HR:1.6), and lactate dehydrogenase (LDH) ≥ upper limit of normal (ULN) (HR:1.3) were significantly associated with shorter OS (all P < 0.05). To predict the OS, we created a prognostic scoring system (PSS). We gave one point to each independent prognostic factor. Median OS for patients with scores of 0-2, 3, and 4-5 were 9.0, 3.5 and 1.7 months, respectively (P < 0.001). CONCLUSIONS: Male sex, KPS ≤ 60, presence of ECM, NLR ≥ 5, and LDH ≥ ULN were poor prognostic factors for patients with BM undergoing pWBRT. By PSS combining these factors, it may be possible to select patients who should undergo pWBRT.

A new updated prognostic index for patients with brain metastases (BMs) treated with palliative whole brain radiotherapy (WBRT) in the era of precision oncology. METASNCore project.

INTRODUCTION: Palliative WBRT is the main treatment for multiple BMs. Recent studies report no benefit in survival after WBRT compared to palliative supportive care in patients (pts) with poor prognosis. A new era of systemic treatment strategies based on targeted therapies are improving the prognosis of patients with BMs. The purpose of this study is to develop a prognostic score in palliative pts with BMs who undergo WBRT in this new setting. METHODS: 239 pts with BMs who received palliative WBRT between 2013-2022 in our center were analyzed retrospectively. The score was designed according to the value of the ß coefficient of each variable with statistical significance in the multivariate model using Cox regression. Once the score was established, a comparison was performed according to Kaplan-Meier and was analyzed by log-rank test. RESULTS: 149 pts (62.3%) were male and median (m) age was 60 years. 139 (58,2%) were lung cancer and 35 (14,6%) breast cancer. All patients received 30Gys in 10 sessions. m overall survival (OS) was 3,74 months (ms). 37 pts (15,5%) had a specific target mutation. We found that 62 pts were in group < 4 points with mOS 6,89 ms (CI 95% 3,18-10,62), 84 in group 4-7 points with mOS 4,01 ms (CI 95% 3,40-4,62) and 92 pts in group > 7 points with mOS 2,72 ms (CI 95% 1,93-3,52) (p < 0,001). CONCLUSIONS: METASNCore items are associated with OS and they could be useful to select palliative pts to receive WBRT. More studies are necessary to corroborate our findings.

Modulated Arc Therapy for hippocampal-avoidance whole brain radiation therapy: planning comparison with intensity modulated Radiation Therapy.

This study aimed to evaluate the modulated arc therapy (mARC) technique as a planning and treatment option for hippocampal sparing whole brain radiotherapy (HS-WBRT) following the Radiation Therapy Oncology Group (RTOG) 0933 dosimetric criteria. Computed tomography (CT) and magnetic resonance imaging (MRI) were selected retrospectively for 15 patients. Two types of plans were created for each patient, namely an intensity-modulated radiation therapy (IMRT) and a mARC plan. IMRT and mARC plans were compared in terms of plan quality indices, absorbed dose to organs at risk (OARs), number of monitor units (MUs), and treatment time. All plans in both techniques were considered clinically acceptable for treatment. However, IMRT plans presented a higher conformity (p = 0.01) as well as a higher homogeneity as compared to mARC plans, but this difference was not statistically significant (p > 0.05). In terms of the preservation of the hippocampus, it was observed that the IMRT plans achieved significantly lower doses for both 100% of its volume and for its maximum dose (p < 0.001). The evaluation of the remaining OARs showed that the IMRT technique resulted in lower doses, and significant differences were observed for the following organs: left cochlea (p < 0.001), left eye (p < 0.001), right eye (p = 0.03), both lenses of the eye (p < 0.001), and right optic nerve (p = 0.02). Despite these differences, the absolute differences in all dosimetric parameters were low enough to bear any clinical relevance. A drastic (close to 65%) and significant (p < 0.001) decrease was observed in the number of MUs for the mARC plans. This resulted in a substantial decrease in treatment time (60.45%, p < 0.001). It is concluded that the mARC technique is a feasible planning and treatment solution for HS-WBRT that meets the RTOG 0933 criteria. The main advantage of using mARC over IMRT for HS-WBRT is the considerable reduction in MUs and treatment time.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Patient reported outcomes following whole brain radiotherapy in patients with brain metastases in NSIA-LUTH Cancer Center.

BACKGROUND: Brain metastases (BM) are a common complication in advanced cancer patients, and extremely challenging to treat. Consequently, whole brain radiotherapy (WBRT) remains the standard palliative intervention for patients with BM. The present study set to evaluate the clinical benefits of WBRT by assessing the quality of life (QoL) in WBRT-treated patients with BM, in Nigeria. METHODS: This was a prospective, longitudinal, hospital-based single-centre study. Consecutive sampling methodology was used to recruit 52 patients with BM undergoing WBRT. Patients were followed up on days 7, 30, 90 and 180 after WBRT. The EORTC QLQ-C15-PAL and EORTC QLQ-BN20 were employed to report patients' responses. The likert scale responses were linearly converted into 0 - 100 scores, and the descriptive analysis was conducted using IBM SPSS Statistics 29.0, at 95% confidence interval, using the two-tailed t-test for continuous variables or the chi-square test for categorical values. The overall survival was calculated with the Kaplan Maier method and the difference tested with Log-rank method, considering the interval from the baseline until death or end of the study. RESULTS: The study cohort was predominantly females (82.7%), and accordingly, 65.4% of the respondents had a breast primary tumor. A goodness-of-fit test yielded non-significant Chi square Pearson (p = 0.325) and Deviance (p = 1.000) residuals, indicating the best fit. The median overall survival was 180 days (~ 6 months). A total of 20 patients (38%) that survived up to 180 days reported alleviated symptoms and better functioning. A significant improvement in physical functioning (p < 0.001) and emotional functioning (p = 0.031) was reported at 180 days post WBRT, compared to baseline. CONCLUSIONS: WBRT is an effective palliative intervention in patients with BM, resulting in improved QoL. More than 50% of patients that survived ~ 3 months reported alleviation of pain, and 38% of patients that survived for ~ 6 months reported a significantly improved functioning. This demonstrated the clinical benefits of WBRT in palliative care and will add to the body of data on the use of WBRT, from Africa.

Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis.

The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I2  = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I2  = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.

Leukoencephalopathy in patients with brain metastases who received radiosurgery with or without whole brain radiotherapy.

BACKGROUND: Whole brain radiation therapy (WBRT) for brain metastases (BMs) is a common cause of radiation-induced leukoencephalopathy; however the safety of alternative stereotactic radiosurgery (SRS) remains unclear. This study examined the incidence of leukoencephalopathy in patients treated with SRS alone versus WBRT plus SRS for BMs with a focus on the relationship between prognostic factors and leukoencephalopathy. METHODS: Analysis was performed between 2002 and 2021. The total enrollment was 993 patients with the distribution: WBRT plus SRS (n = 291) and SRS only (n = 702). Leukoencephalopathy was graded from 0 to 3 for changes in white matter indicated by the MRI after WBRT or SRS. Patient characteristics and SRS dosimetric parameters were reviewed to identify factors that contributed to the incidence of leukoencephalopathy or overall survival. RESULTS: The incidence of leukoencephalopathy was consistently higher in WBRT plus SRS group than in SRS alone group (p < 0.001). Leukoencephalopathy was also associated with a larger total tumor volume (≧28cm3; p = 0.028) and age (> 77 years; p = 0.025). Nonetheless, the SRS integral dose to skull in the subgroup of WBRT plus SRS treatment was not demonstrated significance in development of leukoencephalopathy (p = 0.986 for integral dose 1-2 J, p = 0.776 for integral dose > 2 J). CONCLUSIONS: This study revealed that SRS is safe for oligo-BMs in terms of leukoencephalopathy development. Patient age and total tumor volume were identified as important factors in assessing the development of leukoencephalopathy. The additional of SRS (even at an integral dose > 2 J) did not increase the incidence of leukoencephalopathy.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

PURPOSE: Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. METHODS: A total of 66 patients were divided into two groups: those treated with 30 Gy (2 Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30 Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6 Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50 Gy (range, 36.0-55.8 Gy). RESULTS: The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. CONCLUSION: Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Retrospective non-inferiority study of stereotactic radiosurgery for more than ten brain metastases.

AIM: This study aimed to investigate the clinical benefits of stereotactic radiosurgery (SRS) in patients with > 10 brain metastases (BM) compared to patients with 2-10 BM. METHODS: The study included multiple BM patients who underwent SRS between 2014 and 2022, excluding patients who underwent whole brain radiotherapy, had a Karnofsky Performance Status score < 60, suspected leptomeningeal disease, or a single BM lesion. Patients were divided into two groups (2-10 and > 10 BM groups) and matched 2:1 based on propensity scores. The primary endpoint was overall survival (OS) in the matched dataset, with intracranial progression-free survival (PFS) as the secondary endpoint. Non-inferiority was established if the upper limit of the 95% confidence interval (CI) of the adjusted hazard ratio was below 1.3. RESULTS: Of the 1042 patients identified, 434 met eligibility criteria. After propensity score matching, 240 patients were analyzed (160 in the BM 2-10 group and 80 in the > 10 BM group). The median OS was 18.2 months in the 2-10 BM group and 19.4 months in the > 10 BM group (P = 0.60). The adjusted hazard ratio was 0.86 (95% CI: 0.59-1.24), indicating non-inferiority. PFS was not significantly different between the groups (4.8 months vs. 4.8 months, P = 0.94). The number of BM did not significantly impact OS or PFS. CONCLUSIONS: SRS for selected patients with > 10 BM was non-inferior in terms of OS compared to those with 2-10 BM in a propensity score-matched dataset.

Psychological distress as risk factor for the efficacy of whole-brain radiotherapy in brain metastasis patients.

Aim: To evaluate the relationship between psychological distress and the efficacy of whole-brain radiotherapy (WBRT) in advanced brain metastasis patients. Methods: Brain metastasis patients (40 with psychological distress and 47 without psychological distress) completed distress thermometer tests before WBRT, and progression-free survival (PFS) was acquired during the follow-up period. Results: Psychological distress was a risk factor for poorer PFS in patients treated with WBRT (p < 0.01). The PFS of survivors who underwent WBRT was superior for those without psychological distress (hazard ratio: 0.295; 95% CI: 0.173-0.500; p < 0.01). Conclusion: The survival of brain metastasis patients receiving WBRT was influenced by psychological distress, which negatively affected the treatment outcome and is likely to be a potential risk indicator in advanced cancer patients receiving WBRT.

Distress thermometer tests were carried out 1 week before whole-brain radiotherapy to assess psychological distress in 87 brain metastasis patients. The results demonstrated that the progression-free survival of brain metastasis patients with psychological distress was obviously inferior to that of patients without psychological distress. The negative effects of psychological distress could be recognized in advanced patients with brain metastases after whole-brain radiotherapy. Psychological distress is likely to be a potential risk indicator for radiotherapy in brain metastasis patients.

Prognostic factors associated with the transition in treatment methods for brain metastases from colorectal cancer.

BACKGROUND: Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC. METHODS: We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997-2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997-2013 ("first period") and 2014-2018 ("second period"). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates. RESULTS: Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5 months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods. CONCLUSION: Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy.

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma.

INTRODUCTION: Memantine is used for neurocognitive protection in patients undergoing cranial radiotherapy for central nervous system tumors and is reported to be well-tolerated. CASE REPORT: Presented is a case of memantine-induced altered mental status requiring an intensive care unit admission. An 18-year-old male with relapsed, progressive medulloblastoma presented with severe altered mental status shortly after the first fraction of palliative whole brain radiotherapy. At the time, the patient was on day five of memantine therapy, which had been prescribed to reduce neurocognitive toxicity risk. MANAGEMENT & OUTCOME: Memantine was withheld while dexamethasone, valproate, and morphine were continued for headache. Approximately 50 h after admission, the patient's confusion significantly improved. Evaluation of acute altered mental status was unrevealing, including but not limited to negative urinary toxicology screen and lack of disease progression on imaging. Whole brain radiotherapy was resumed after a two-day cessation and he was discharged home after four days with complete resolution of symptoms. DISCUSSION: Clinicians should be aware of and consider the risk of altered mental status with memantine, given the increased utilization and upcoming clinical trials in pediatric patients.

Customizable landmark-based field aperture design for automated whole-brain radiotherapy treatment planning.

PURPOSE: To develop and evaluate an automated whole-brain radiotherapy (WBRT) treatment planning pipeline with a deep learning-based auto-contouring and customizable landmark-based field aperture design. METHODS: The pipeline consisted of the following steps: (1) Auto-contour normal structures on computed tomography scans and digitally reconstructed radiographs using deep learning techniques, (2) locate the landmark structures using the beam's-eye-view, (3) generate field apertures based on eight different landmark rules addressing different clinical purposes and physician preferences. Two parallel approaches for generating field apertures were developed for quality control. The performance of the generated field shapes and dose distributions were compared with the original clinical plans. The clinical acceptability of the plans was assessed by five radiation oncologists from four hospitals. RESULTS: The performance of the generated field apertures was evaluated by the Hausdorff distance (HD) and mean surface distance (MSD) from 182 patients' field apertures used in the clinic. The average HD and MSD for the generated field apertures were 16 ± 7 and 7 ± 3 mm for the first approach, respectively, and 17 ± 7 and 7 ± 3 mm, respectively, for the second approach. The differences regarding HD and MSD between the first and the second approaches were 1 ± 2 and 1 ± 3 mm, respectively. A clinical review of the field aperture design, conducted using 30 patients, achieved a 100% acceptance rate for both the first and second approaches, and the plan review achieved a 100% acceptance rate for the first approach and a 93% acceptance rate for the second approach. The average acceptance rate for meeting lens dosimetric recommendations was 80% (left lens) and 77% (right lens) for the first approach, and 70% (both left and right lenses) for the second approach, compared with 50% (left lens) and 53% (right lens) for the clinical plans. CONCLUSION: This study provided an automated pipeline with two field aperture generation approaches to automatically generate WBRT treatment plans. Both quantitative and qualitative evaluations demonstrated that our novel pipeline was comparable with the original clinical plans.

Automated field-in-field whole brain radiotherapy planning.

PURPOSE: We developed and tested an automatic field-in-field (FIF) solution for whole-brain radiotherapy (WBRT) planning that creates a homogeneous dose distribution by minimizing hotspots, resulting in clinically acceptable plans. METHODS: A configurable auto-planning algorithm was developed to automatically generate FIF WBRT plans independent of the treatment planning system. Configurable parameters include the definition of hotspots, target volume, maximum number of subfields, and minimum number of monitor units per field. This algorithm iteratively identifies a hotspot, creates two opposing subfields, calculates the dose, and optimizes the beam weight based on user-configured constraints of dose-volume histogram coverage and least-squared cost functions. The algorithm was retrospectively tested on 17 whole-brain patients. First, an in-house landmark-based automated beam aperture technique was used to generate the treatment fields and initial plans. Second, the FIF algorithm was employed to optimize the plans using physician-defined goals of 99.9% of the brain volume receiving 100% of the prescription dose (30 Gy in 10 fractions) and a target hotspot definition of 107% of the prescription dose. The final auto-optimized plans were assessed for clinical acceptability by an experienced radiation oncologist using a five-point scale. RESULTS: The FIF algorithm reduced the mean (± SD) plan hotspot percentage dose from 35.0 Gy (116.6%) ± 0.6 Gy (2.0%) to 32.6 Gy (108.8%) ± 0.4 Gy (1.2%). Also, it decreased the mean (± SD) hotspot V107% [cm3 ] from 959 ± 498 cm3 to 145 ± 224 cm3 . On average, plans were produced in 16 min without any user intervention. Furthermore, 76.5% of the auto-plans were clinically acceptable (needing no or minor stylistic edits), and all of them were clinically acceptable after minor clinically necessary edits. CONCLUSIONS: This algorithm successfully produced high-quality WBRT plans and can improve treatment planning efficiency when incorporated into an automatic planning workflow.

Stereotactic radiosurgery with whole brain radiotherapy combined with bevacizumab in the treatment of brain metastases from NSCLC.

OBJECTIVE: Non-small cell lung cancer (NSCLC) patients who experience brain metastases are usually associated with poor prognostic outcomes. Whole-brain radiotherapy (WBRT) is one of the standard treatment strategies for NSCLC. It is interesting to combine angiogenesis inhibitors such as bevacizumab with radiation therapy. This study aimed to explore the efficacy and safety of stereotactic radiosurgery (SRS) with WBRT combined with bevacizumab in the treatment of brain metastases. METHODS: A total of 21 patients with brain metastases from NSCLC were treated with bevacizumab and WBRT-SRS, while 28 patients were treated with WBRT-SRS only. The bevacizumab average dose was 5-7.5 mg/kg, approximately 2 cycles during radiotherapy. Tumor responses were evaluated every 3 months based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: The median follow-up time was 13.5 months (range 2.7-88.4 months). The ORR and DCR of patients who received WBRT-SRS with or without bevacizumab were similar (p = 0.458, p = 0.382). OS(42.63 years VS 25.23 years, p = 0.02)and LPFS (39.53 years VS 23 years, p = 0.047)were better in WBRT-SRS with bevacizumab groups. After radiotherapy and 3 months after radiotherapy, the volume of peritumoral edema was significantly reduced in WBRT-SRS with bevacizumab groups(45.62 ± 24.03 cm3 vs 63.03 ± 25.44 cm3, p = 0.036;8.63 ± 6.87 cm3 vs 15.62 ± 10.58 cm3, p = 0.021). The main adverse reactions were similar in the two groups except for Venous thrombosis with bevacizumab (0 patients vs 5 patients, p = 0.006). CONCLUSION: Bevacizumab with radiotherapy improved the overall efficacy and reduced the peritumoral edema of BM from NSCLC.

How many brain metastases can be treated with stereotactic radiosurgery before the radiation dose delivered to normal brain tissue rivals that associated with standard whole brain radiotherapy?

INTRODUCTION: Clinical trial data comparing outcomes after administration of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) to patients with brain metastases (BM) suggest that SRS better preserves cognitive function and quality of life without negatively impacting overall survival. Here, we estimate the maximum number of BM that can be treated using single and multi-session SRS while limiting the dose of radiation delivered to normal brain tissue to that associated with WBRT. METHODS: Multiple-tumor SRS was simulated using a Monte Carlo - type approach and a pre-calculated dose kernel method. Tumors with diameters ≤36 mm were randomly placed throughout the contoured brain parenchyma until the brain mean dose reached 3 Gy, equivalent to the radiation dose delivered during a single fraction of a standard course of WBRT (a total dose of 30 Gy in 10 daily fractions of 3 Gy). Distribution of tumor sizes, dose coverage, selectivity, normalization, and maximum dose data used in the simulations were based on institutional clinical metastases data. RESULTS: The mean number of tumors treated, mean volume of healthy brain tissue receiving > 12 Gy (V12) per tumor, and total tumor volume treated using mixed tumor size distributions were 12.7 ± 4.2, 2.2 cc, and 12.9 cc, respectively. Thus, we estimate that treating 12-13 tumors per day over 10 days would deliver the dose of radiation to healthy brain tissue typically associated with a standard course of WBRT. CONCLUSION: Although in clinical practice, treatment with SRS is often limited to patients with ≤15 BM, our findings suggest that many more lesions could be targeted while still minimizing the negative impacts on quality of life and neurocognition often associated with WBRT. Results from this in silico analysis require clinical validation.