Recognition and Management of the Long-term Effects of Cranial Radiation.

OPINION STATEMENT: Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and delivery has led to prolongation of survival outcomes. As long-term survivorship improves, we also focus on prevention of permanent side effects of radiation and mitigating the impact when they do occur. Such chronic treatment-related morbidity is a major concern with significant negative impact on patient's and caregiver's respective quality of life. The actual mechanisms responsible for radiation-induced brain injury remain incompletely understood. Multiple interventions have been introduced to potentially prevent, minimize, or reverse the cognitive deterioration. Hippocampal-sparing intensity modulated radiotherapy and memantine represent effective interventions to avoid damage to regions of adult neurogenesis. Radiation necrosis frequently develops in the high radiation dose region encompassing the tumor and surrounding normal tissue. The radiographic findings in addition to the clinical course of the patients' symptoms are taken into consideration to differentiate between tissue necrosis and tumor recurrence. Radiation-induced neuroendocrine dysfunction becomes more pronounced when the hypothalamo-pituitary (HP) axis is included in the radiation treatment field. Baseline and post-treatment evaluation of hormonal profile is warranted. Radiation-induced injury of the cataract and optic system can develop when these structures receive an amount of radiation that exceeds their tolerance. Special attention should always be paid to avoid irradiation of these sensitive structures, if possible, or minimize their dose to the lowest limit.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes?

PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS). A limitation in the application of BMV is it cannot be applied until time of first BM failure after SRS. We developed initial BM velocity (iBMV), a new metric that accounts for the number of BM at first SRS and the time since initial cancer diagnosis. MATERIALS/METHODS: We reviewed patients with BM treated at our institution with upfront SRS without WBRT. iBMV was calculated as the number of BM at initial SRS divided by time (years) from initial cancer diagnosis to first SRS. We performed a linear regression to correlate BMV as a continuous variable and with low, intermediate, and high BMV risk groups. Kaplan-Meier estimation of OS was calculated from time of first SRS to death. iBMV was not calculated for patients who presented with BM at initial cancer diagnosis. RESULTS: 994 patients were treated with upfront SRS without WBRT between 2000 and 2017. Median OS was 8.5 mos. 595 (60%) patients developed BM after cancer diagnosis and median time to first SRS from time of initial diagnosis was 2.2 years. Median iBMV was 0.79 BM/year. iBMV correlated with BMV (ß = 1.57 p = 0.021) and independently predicted for mortality [Cox proportional hazard ratio (HR) 1.11, p = 0.036] after accounting for histology, number of initial brain metastases (HR 1.03, p = 0.32), time from cancer diagnosis to SRS (HR 0.98, p = 0.157) in a multivariate model. CONCLUSION: iBMV correlates with BMV and OS. With further validation, iBMV could serve as a metric to risk stratify patients for WBRT or SRS at time of first BM presentation.

Gender and the Receipt of the Association of Residents in Radiation Oncology Educator of the Year Award.

Purpose: We hypothesized that there may be a gender disparity in the receipt of the Association of Residents in Radiation Oncology (ARRO) Educator of the Year Award and sought to elucidate factors that contribute to differences in award receipt. Methods and Materials: Using a database provided by the American Society for Radiation Oncology, award recipients were identified from 2010 to 2022. Publicly available websites were accessed to obtain data regarding gender, years since residency graduation, percentage of female faculty, size of residency program, and program director designation. A 1-sample Z-test was used to assess whether the proportion of female ARRO award winners, defined as the proportion of female radiation oncology faculty members in the nominating universities that year, was significantly less than the population average. Secondary analyses used univariable binary logistic regression to identify global associations between gender, year since gradation, or program size. Results: The lowest proportion of female awardees occurred in 2013 (14.3%) and the greatest proportion in 2022 (30.6%). Compared with the proportion of female faculty members in nominating programs for the respective year, there were significantly fewer female awardees in 2010 (18% female awardees vs 32% female faculty members; P = .02) and 2013 (14% female awardees vs 31% female faculty members; P = .01). There was a statistically significant increase in female awardees during the study period (P < .01). On logistic regression analysis, large program size (≥10 residents) (odds ratio [OR], 6.86; 95% CI, 2.71-23.1; P < .001) and medium program size (5-9 residents) (OR, 4.05; 95% CI, 1.60-13.7; P < .001) were associated with a greater proportion of female awardees compared with small program size (1-4 residents). There was no association between awardee gender and years since graduation. Conclusions: A gender disparity was present in the receipt of ARRO Educator Awards. Residency chiefs, program directors, and chairs should work to ensure that a diverse slate of faculty is considered annually for the ARRO Educator Award.

Oncologic and Functional Outcomes After Stereotactic Body Radiation Therapy for High-Grade Malignant Spinal Cord Compression.

Purpose: Although surgical decompression is the gold standard for metastatic epidural spinal cord compression (MESCC) from solid tumors, not all patients are candidates or undergo successful surgical Bilsky downgrading. We report oncologic and functional outcomes for patients treated with stereotactic body radiation therapy (SBRT) to high-grade MESCC. Methods and Materials: Patients with Bilsky grade 2 to 3 MESCC from solid tumor metastases treated with SBRT at a single institution from 2009 to 2020 were retrospectively reviewed. Patients who received upfront surgery before SBRT were included only if postsurgical Bilsky grade remained ≥2. Neurologic examinations, magnetic resonance imaging, pain assessments, and analgesic usage were assessed every 3 to 4 months post-SBRT. Cumulative incidence of local recurrence was calculated with death as a competing risk, and overall survival was estimated by Kaplan-Meier. Results: One hundred forty-three patients were included. The cumulative incidence of local recurrence was 5.1%, 7.5%, and 14.1% at 6, 12, and 24 months, respectively. At first post-SBRT imaging, 16.2% of patients with initial Bilsky grade 2 improved to grade 1, and 53.8% of patients were stable. Five of 13 patients (38.4%) with initial Bilsky grade 3 improved to grade 1 to 2. Pain response at 3 and 6 months post-SBRT was complete in 45.4% and 55.7%, partial in 26.9% and 13.1%, stable in 24.1% and 27.9%, and worse in 3.7% and 3.3% of patients, respectively. At 3 and 6 months after SBRT, 17.8% and 25.0% of patients had improved ambulatory status and 79.7% and 72.4% had stable status. Conclusions: We report the largest series to date of patients with high-grade MESCC treated with SBRT. The excellent local control and functional outcomes suggest SBRT is a reasonable approach in inoperable patients or cases unable to be successfully surgically downgraded.

Safety and clinical efficacy of immune checkpoint inhibition and stereotactic body radiotherapy in patients with spine metastasis.

OBJECTIVE: Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of patients with many tumor histologies. Simultaneously, stereotactic body radiotherapy (SBRT) provides excellent local control (LC) and plays an important role in the management of spine metastasis. Promising preclinical work suggests the potential therapeutic benefit of combining SBRT with ICI therapy, but the safety profile of combined therapy is unclear. This study aimed to evaluate the toxicity profile associated with ICI in patients receiving SBRT and, secondarily, whether ICI administration sequence with respect to SBRT affects LC or overall survival (OS) outcomes. METHODS: The authors retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI by using Cox proportional hazards analyses. Primary outcomes were long-term sequelae, including radiation-induced spinal cord myelopathy, esophageal stricture, and bowel obstruction. Secondarily, models were created to evaluate OS and LC in the cohort. RESULTS: Two hundred forty patients who received SBRT to 299 spine metastases were included in this study. The most common primary tumor types were non-small cell lung cancer (n = 59 [24.6%]) and renal cell carcinoma (n = 55 [22.9%]). One hundred eight patients received at least 1 dose of ICI, with the most common regimen being single-agent anti-PD-1 (n = 80 [74.1%]), followed by combination CTLA-4/PD-1 inhibitors (n = 19 [17.6%]). Three patients experienced long-term radiation-induced sequelae: 2 had esophageal stricture and 1 had bowel obstruction. No patients developed radiation-induced myelopathy. There was no association between receipt of ICI and development of any of these adverse events (p > 0.9). Similarly, ICI was not significantly associated with either LC (p = 0.3) or OS (p = 0.6). In the entire cohort, patients who received ICI prior to beginning SBRT had worse median survival, but ICI sequence with respect to SBRT was not significantly prognostic of either LC (p > 0.3) or OS (p > 0.07); instead, baseline performance status was most predictive of OS (HR 1.38, 95% CI 1.07-1.78, p = 0.012). CONCLUSIONS: Treatment regimens that combine ICIs before, concurrent with, and after SBRT for spine metastases are safe, with minimal risk for increased rates of long-term toxicity.

Deviation from consensus contouring guidelines predicts inferior local control after spine stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To analyze the impact of target delineation on local control (LC) after stereotactic body radiotherapy (SBRT) for spine metastasis. MATERIALS AND METHODS: Patients with de novo metastasis of the spine treated with SBRT, excluding those with prostate or hematologic malignancies, were retrospectively reviewed. Deviations from consensus contouring guidelines included incomplete coverage of involved vertebral compartments, omission of adjacent compartments, or unnecessary circumferential coverage. Univariable and multivariable Cox proportional hazard analyses were performed using death as a competing risk. RESULTS: 283 patients with 360 discrete lesions were included with a median follow up of 14.6 months (range 1.2-131.3). The prescription dose was 24-27 Gy in 2-3 fractions for the majority of lesions. Median survival after SBRT was 18.3 months (95 % confidence interval [CI]: 14.8-22.8). The 1 and 2-year local control (LC) rates were 81.1 % (95 % CI: 75.5-85.6 %) and 70.6 % (95 % CI: 63.2-76.8 %), respectively. In total, 60 deviations (16.7 %) from consensus contouring guidelines were identified. Deviation from guidelines was associated with inferior LC (1-year LC 63.0 % vs 85.5 %, p < 0.001). Gastrointestinal primary, epidural extension, and paraspinal extension were all associated with inferior LC on univariable analyses. After adjusting for confounding factors, deviation from guidelines was the strongest predictor of inferior LC (HR 3.52, 95 % CI: 2.11-5.86, p < 0.001). Among guideline-compliant treatments, progressions were mainly in field (61 %) and/or epidural (49 %), while marginal (42 %) and/or epidural progressions (58 %) were most common for those with deviations. CONCLUSIONS: Adherence to consensus contouring guidelines for spine SBRT is associated with superior LC and fewer marginal misses.

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity.

Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose-response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.

Simple and Rapid Creation of Customized 3-dimensional Printed Bolus Using iPhone X True Depth Camera.

PURPOSE: Three-dimensional printing has produced customized bolus during radiation therapy for superficial tumors along irregular skin surfaces. In comparison, traditional bolus materials are often difficult to manipulate for a proper fit. Current 3-dimensional printed boluses are made from either preexisting computed tomography scans or complex surface scanning methods. Herein, we introduce an inexpensive, convenient approach to generate a 3-dimensional printed bolus from surface scanning technology available in common smartphones. METHODS AND MATERIALS: A three-dimensional printed bolus was designed using surface scans from iPhone X true depth cameras and a low-cost 3-dimensional printer. The percentage density infill was adjusted to achieve tissue equivalence. To evaluate the clinical feasibility, fit against the skin surface and radiation dose distribution were compared with those of the traditional bolus. RESULTS: We fabricated a customized 3-dimensional printed bolus for different areas of the face using an iPhone X camera and inexpensive commercially available 3-dimensional printer. When printed at 100% density, the bolus material approximated soft tissue/water and provided an equivalent dose distribution to that found with standard bolus materials on direct comparison. The bolus material is inexpensive and produces an ideal fit with the scanned anatomy. CONCLUSIONS: We present a simplified method of highly customized bolus production that requires minimal experience with computer modeling programs and can be accomplished with an iPhone true depth camera.

Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique.

BACKGROUND: Treatment options are limited for large, unresectable brain metastases. OBJECTIVE: To report a single institution series of staged stereotactic radiosurgery (SRS) that allows for tumor response between treatments in order to optimize the therapeutic ratio. METHODS: Patients were treated with staged SRS separated by 1 mo with a median dose at first SRS of 15 Gy (range 10-21 Gy) and a median dose at second SRS of 14 Gy (range 10-18 Gy). Overall survival was evaluated using the Kaplan-Meier method. Cumulative incidences were estimated for neurological death, radiation necrosis, local failure (marginal or central), and distant brain failure. Absolute cumulative dose-volume histogram was created for each treated lesion. Logistic regression and competing risks regression were performed for each discrete dose received by a certain volume. RESULTS: Thirty-three patients with 39 lesions were treated with staged radiosurgery. Overall survival at 6 and 12 mo was 65.0% and 60.0%, respectively. Cumulative incidence of local failure at 6 and 12 mo was 3.2% and 13.3%, respectively. Of the patients who received staged therapy, 4 of 33 experienced local failure. Radiation necrosis was seen in 4 of 39 lesions. Two of 33 patients experienced a Radiation Therapy Oncology Group toxicity grade > 2 (2 patients had grade 4 toxicities). Dosimetric analysis revealed that dose (Gy) received by volume of brain (ie, VDose(Gy)) was associated with radiation necrosis, including the range V44.5Gy to V87.8Gy. CONCLUSION: Staged radiosurgery is a safe and effective option for large, unresectable brain metastases. Prospective studies are required to validate the findings in this study.

Impact of diabetes mellitus on outcomes in patients with brain metastasis treated with stereotactic radiosurgery.

PURPOSE: To determine the influence of diabetes mellitus (DM) on outcomes in patients with brain metastasis treated with stereotactic radiosurgery (SRS). METHODS: We retrospectively reviewed 498 patients with brain metastasis treated at our institution with SRS between January 2012 and March 2017. RESULTS: Eight-four patients (16.9%) held a diagnosis of DM prior to SRS treatment. Diabetics compared to nondiabetics had worse overall survival (OS). DM was found to be a significant predictor of OS on multivariate analysis (HR: 1.41, CI: 1.03-1.92, p = 0.03). When stratified by DM diagnosis, there were no significant differences in incidence of radiation necrosis (p = 0.82), radiation-induced edema (p = 0.88), cerebrospinal fluid leak (p = 0.49), or postoperative infection (p = 0.68). CONCLUSIONS: DM diagnosis was a significant predictor of poorer OS in patients treated for brain metastasis with SRS. Diabetics and nondiabetics experienced similar rates of radiation-associated brain toxicities.

Survival and Failure Outcomes Predicted by Brain Metastasis Volumetric Kinetics in Melanoma Patients Following Upfront Treatment with Stereotactic Radiosurgery Alone.

Introduction The roles of early whole brain radiotherapy (WBRT) and upfront stereotactic radiosurgery (SRS) alone in the treatment of melanoma patients with brain metastasis remain uncertain. We investigated the volumetric kinetics of brain metastasis development and associations with clinical outcomes for melanoma patients who received upfront SRS alone. Methods Volumetric brain metastasis velocity (vBMV) was defined as the volume of new intracranial disease at the time of distant brain failure (DBF) for the first DBF (DBF1) and second DBF (DBF2) averaged over the time since initial or most recent SRS. Non-volumetric brain metastasis velocity (BMV) was calculated for comparison. Results Median overall survival (OS) for all patients was 7.7 months. Increasing vBMVDBF1 was associated with worsened OS (hazard ratio (HR): 1.10, confidence interval (CI): 1.02 - 1.18, p = .01). Non-volumetric BMVDBF1 was not predictive of OS after DBF1 (HR: 1.00, CI: 0.97 - 1.02, p = .77). Cumulative incidence of DBF2 at three months after DBF1 was 50.0% for vBMVDBF1 > 4 cc/yr versus (vs) 15.1% for vBMVDBF1 ≤ 4 cc/yr, (Gray's p-value = .02). Cumulative incidence of salvage WBRT at three months after DBF1 was 50.0% for vBMVDBF1 > 4 cc/yr vs 2.3% for vBMVDBF1 ≤ 4 cc/yr (Gray's p-value < .001). Conclusion In melanoma patients with brain metastasis, volumetric BMV was predictive of survival, shorter time to second DBF, and the need for salvage WBRT. Non-volumetric BMV, however, did not predict for these outcomes, suggesting that vBMV is a stronger predictor in melanoma.