Adverse radiation effect versus tumor progression following stereotactic radiosurgery for brain metastases: Implications of radiologic uncertainty.

BACKGROUND: Adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases is challenging to distinguish from tumor progression. This study characterizes the clinical implications of radiologic uncertainty (RU). METHODS: Cases reviewed retrospectively at a single-institutional, multi-disciplinary SRS Tumor Board between 2015-2022 for RU following SRS were identified. Treatment history, diagnostic or therapeutic interventions performed upon RU resolution, and development of neurologic deficits surrounding intervention were obtained from the medical record. Differences in lesion volume and maximum diameter at RU onset versus resolution were compared with paired t-tests. Median time from RU onset to resolution was estimated using the Kaplan-Meier method. Univariate and multivariate associations between clinical characteristics and time to RU resolution were assessed with Cox proportional-hazards regression. RESULTS: Among 128 lesions with RU, 23.5% had undergone ≥ 2 courses of radiation. Median maximum diameter (20 vs. 16 mm, p < 0.001) and volume (2.7 vs. 1.5 cc, p < 0.001) were larger upon RU resolution versus onset. RU resolution took > 6 and > 12 months in 25% and 7% of cases, respectively. Higher total EQD2 prior to RU onset (HR = 0.45, p = 0.03) and use of MR perfusion (HR = 0.56, p = 0.001) correlated with shorter time to resolution; larger volume (HR = 1.05, p = 0.006) portended longer time to resolution. Most lesions (57%) were diagnosed as ARE. Most patients (58%) underwent an intervention upon RU resolution; of these, 38% developed a neurologic deficit surrounding intervention. CONCLUSIONS: RU resolution took > 6 months in > 25% of cases. RU may lead to suboptimal outcomes and symptom burden. Improved characterization of post-SRS RU is needed.

Stereotactic radiosurgery for brain metastases from human epidermal receptor 2 positive breast Cancer: an international, multi-center study.

PURPOSE: To report patient outcomes and local tumor control rates in a cohort of patients with biopsy-proven HER-2 positive breast cancer treated with stereotactic radiosurgery (SRS) for brain metastases (BM). METHODS: This international, retrospective, multicenter study, included 195 female patients with 1706 SRS-treated BM. Radiologic and clinical outcomes after SRS were determined and prognostic factors identified. RESULTS: At SRS, median patient age was 55 years [interquartile range (IQR) 47.6-62.0], and 156 (80%) patients had KPS ≥ 80. The median tumor volume was 0.1 cm3 (IQR 0.1-0.5) and the median prescription dose was 16 Gy (IQR 16-18). Local tumor control (LTC) rate was 98%, 94%, 93%, 90%, and 88% at six-, 12-, 24-, 36- and 60-months post-SRS, respectively. On multivariate analysis, tumor volume (p = < 0.001) and concurrent pertuzumab (p = 0.02) improved LTC. Overall survival (OS) rates at six-, 12-, 24-, 36-, 48-, and 60-months were 90%, 69%, 46%, 27%, 22%, and 18%, respectively. Concurrent pertuzumab improved OS (p = 0.032). In this patient subgroup, GPA scores ≥ 2.5 (p = 0.038 and p = 0.003) and rare primary tumor histologies (p = 0.01) were associated with increased and decreased OS, respectively. Asymptomatic adverse radiation events (ARE) occurred in 27 (14.0%) and symptomatic ARE in five (2.6%) patients. Invasive lobular carcinoma primary (p = 0.042) and concurrent pertuzumab (p < 0.001) conferred an increased risk for overall but not for symptomatic ARE. CONCLUSION: SRS affords effective LTC for selected patients with BM from HER-2 positive breast cancer. Concurrent pertuzumab improved LTC and OS but at the same time increased the risk for overall, but not symptomatic, ARE.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Evaluation of a Radiation Oncology Microclerkship as a Component of Medical Student Education.

Compared to most oncologic subspecialties, radiation oncology (RO) lacks a natural pathway for incorporation into the clinical clerkships, and few students ever complete a formal rotation in RO. The feasibility, and perceived value, of a 1-day "microclerkship" exposure in RO during other related clerkships was evaluated in this study. At a single institution, the RO clerkship director partnered with clerkship directors in medical oncology, palliative care, and radiology so that every 3rd or 4th year student would spend 1 day in RO during those clerkships. Afterwards, students completed an electronic survey containing multiple choice and 5-point Likert-type questions describing their experience. Descriptive statistics are reported. Ninety-seven students completed the RO microclerkship over 2 years, and 81 completed the survey (response rate 84%). Only 8 students (10%) had ever been in a RO department previously. During the microclerkship, 73 students (90%) saw at least one new patient consultation; 77 (95%) were involved in contouring or treatment planning; 76 (94%) saw treatment delivery; and 38 (47%) saw a brachytherapy procedure. Seventy-nine students (98%) felt that the microclerkship was at least moderately valuable (mean Likert-type rating 4.01, SD 0.73). Forty students (49%) were either somewhat or much more interested in participating in a longer (2-4 week) rotation in radiation oncology (mean Likert-type rating 3.59, SD 0.83). This study demonstrated the feasibility of incorporating a 1-day RO microclerkship into other related elective clerkships. Students viewed the experience favorably and found it valuable in their education.

Association of mental health diagnosis with race and all-cause mortality after a cancer diagnosis: Large-scale analysis of electronic health record data.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: A large, retrospective, single tertiary-care institution cohort study was conducted based on deidentified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between January 2012 and September 2019. The exposure of interest was early-onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: There were 8.2% of patients who received a new MHD at a median of 197 days (interquartile range, 61-553) after incident cancer diagnosis; 31.0% received a PM prescription; and 3.7% a mental health-related visit (MHRV). There were 62.6% of patients who were non-Hispanic White (NHW), 10.8% were Asian, 9.8% were Hispanic, and 3.8% were Black. Compared with NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian odds ratio [OR], 0.66, 95% CI, 0.55-0.78; Black OR, 0.60, 95% CI, 0.45-0.79; Hispanic OR, 0.72, 95% CI, 0.61-0.85) and selective serotonin-reuptake inhibitors (Asian OR, 0.43, 95% CI, 0.37-0.50; Black OR, 0.51, 95% CI, 0.40-0.61; Hispanic OR, 0.79, 95% CI, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR], 1.43, 95% CI, 1.25-1.64) that waned by 24 to 36 months (HR, 1.18, 95% CI, 0.95-1.45). CONCLUSIONS: New mental health diagnosis with PM was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of MHDs or treatment, which may represent missed opportunities to identify and treat cancer-related mental health conditions.

Anatomic patterns of relapse and progression following treatment with 131 I-MIBG in relapsed or refractory neuroblastoma.

OBJECTIVES: Patients with metaiodobenzylguanidine (MIBG)-avid relapsed or refractory neuroblastoma after initial therapy may exhibit transient responses to salvage treatment with iodine-131 metaiodobenzylguanidine (131 I-MIBG). It is unclear whether disease progression following 131 I-MIBG treatment occurs in previously involved versus new anatomic sites of disease. Understanding this pattern of relapse will inform the use of consolidation therapy following 131 I-MIBG administration. METHODS: Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma, who received single-agent 131 I-MIBG, had stable or responding disease 6-8 weeks following 131 I-MIBG, but subsequently experienced disease progression were included. MIBG scans were reviewed to establish anatomic and temporal evolution of MIBG-avid disease. RESULTS: A total of 84 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 12 patients. At first progression, a total of 101 MIBG-avid sites were identified, of which 69 (68%) overlapped with pre-treatment disease sites, while 32 (32%) represented anatomically new disease areas. Eight of 12 patients had one or more new MIBG-avid sites at first progression. Of the 69 involved sites at progression that overlapped with pre-treatment disease, 11 represented relapsed sites that had cleared following MIBG therapy, two were persistent but increasingly MIBG-avid, and 56 were stably persistent. CONCLUSIONS: Previously involved anatomic disease sites predominate at disease progression following 131 I-MIBG treatment. Nevertheless, the majority of patients progressed in at least one new anatomic disease site. This suggests that consolidation focal therapies targeting residual disease sites may be of limited benefit in preventing systemic disease progression following 131 I-MIBG treatment of relapsed or refractory neuroblastoma.

Pattern and predictors of sites of relapse in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

PURPOSE: We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma. PATIENTS AND METHODS: Children <21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse. RESULTS: Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p < .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p < .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p < .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p < .001) remained at decreased risk for death as compared to patients with combined failure. CONCLUSION: Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse.

Radiation Oncology Education Collaborative Study Group Annual Spring Symposium: Initial Impact and Feedback.

The Radiation Oncology Education Collaborative Study Group (ROECSG) is an international collaborative network of radiation oncology (RO) professionals with the goal of improving RO education. This report summarizes the first two ROECSG annual symposia including an overview of presentations and analysis of participant feedback. One-day symposia were held in June 2018 and May 2019. Programs included oral and poster presentations, RO education leadership perspectives, and keynote addresses. Post-symposia surveys were collected. Research presentations were recorded and made available online. The 2018 symposium was had 36 attendees from 25 institutions in three countries. The 2019 symposium had 76 individuals from 41 institutions in five countries. Attendees represented diverse backgrounds including attending physicians (46%), residents (13%), medical students (14%), physicists (2%), nurses (1%), and program coordinators (1%). Fifty-five oral presentations were given with 53 released online. Ninety percent of attendees rated the symposium as improving their knowledge of RO educational scholarship, 98% felt the symposium provided the opportunity to receive feedback on RO education scholarship, and 99% felt that the symposium fostered the development of collaborative RO education projects. ROECSG was rated higher than professional organizations in fostering educational scholarship (p<0.001). All attendees felt that the symposium produced new RO education scholarship ideas and provided unique networking opportunities. The first two ROECSG symposia drew a diverse population of attendees and provided unique opportunities for presentation of RO education scholarship. Future ROECSG symposia will be designed to enhance opportunities to present RO education scholarship and to facilitate networking.

Relationship between 7T MR-angiography features of vascular injury and cognitive decline in young brain tumor patients treated with radiation therapy.

PURPOSE: Although radiation therapy (RT) is a common treatment for pediatric brain tumors, it is associated with detrimental long-term effects such as impaired cognition, vascular injury, and increased stroke risk. This study aimed to develop metrics that describe vascular injury and relate them to the presence of cerebral microbleeds (CMBs) and cognitive performance scores. METHODS: Twenty-five young adult survivors of pediatric brain tumors treated with either whole-brain (n = 12), whole-ventricular (n = 7), or no RT (n = 6) underwent 7T MRI and neurocognitive testing. Simultaneously acquired MR angiography and susceptibility-weighted images were used to segment CMBs and vessels and quantify their radii and volume. RESULTS: Patients treated with whole-brain RT had significantly lower arterial volumes (p = 0.003) and a higher proportion of smaller vessels (p = 0.003) compared to the whole-ventricular RT and non-irradiated control patients. Normalized arterial volume decreased with increasing CMB count (R = - 0.66, p = 0.003), and decreasing trends were observed with time since RT and at longitudinal follow-up. Global cognition and verbal memory significantly decreased with smaller normalized arterial volume (p ≤ 0.05). CONCLUSIONS: Arterial volume is reduced with increasing CMB presence and is influenced by the total brain volume exposed to radiation. This work highlights the potential use of vascular-derived metrics as non-invasive markers of treatment-induced injury and cognitive impairment in pediatric brain tumor patients.

A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma.

INTRODUCTION: Anaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity. METHODS: We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. RESULTS: 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival. CONCLUSIONS: Initial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.