Faculty Bibliography

Leptomeningeal disease (LMD) from solid tumors carries a poor prognosis with limited treatment options. Radiotherapy to the involved sites of LMD can provide symptomatic relief in many patients. However, selected patients may derive substantially greater benefit from treating the entire neuroaxis with cerebrospinal irradiation (CSI). Ideal candidates for CSI include patients with good performance status (KPS≥60) and either systemic disease control or effective remaining systemic therapy options. Some patients with LMD, despite being otherwise ideal CSI candidates, may present with neurologic symptoms that require urgent intervention and cannot immediately be treated with CSI. In such cases, it is feasible to urgently deliver 3D radiotherapy to an involved site for urgent symptom palliation as a "bridge" to completion CSI after initial stabilization. Using this approach allows treatment of the entire neuroaxis with minimum elective dose to help minimize the risk of rapid out-of-field recurrence that is characteristic of leptomeningeal disease treated with focal-only radiation therapy. This approach allows for rapid initiation of treatment of neurologic symptoms while a more complex CSI plan is developed.

PURPOSE/UNASSIGNED:Radiation therapy has an increasing role in the management of metastatic cancers. Integrating radiation with surgical and systemic approaches is complex, and inappropriate management can lead to prolonged hospitalizations inconsistent with palliative goals. An inpatient radiation oncology consult (IROC) service was created in January 2020 to provide rapid access to specialized care for hospitalized patients. Here, we report outcomes of the IROC service, focusing on quality-of-care metrics including hospital length of stay (LOS), use of hypofractionated approaches, and treatments for patients discharged to hospice. METHODS AND MATERIALS/UNASSIGNED:= 1509) IROC, from 2019 to 2021. Continuous variables were analyzed using the Mann-Whitney test and categorical variables using Fisher's exact test. RESULTS/UNASSIGNED:= .036). CONCLUSIONS/UNASSIGNED:The IROC service was associated with reduced hospital LOS, increased use of hypofractionated approaches, and decreased treatments for patients discharged to hospice. Our findings demonstrate the value of a dedicated program addressing radiation delivery to hospitalized patients to improve goal-concordant treatments. The financial impact of reducing low-value care is an important subject for future investigations.

IMPORTANCE/UNASSIGNED:Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. OBJECTIVE/UNASSIGNED:To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. INTERVENTION/UNASSIGNED:For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was CNS-PFS. Secondary end points included overall survival (OS). RESULTS/UNASSIGNED:Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04343573.

INTRODUCTION/UNASSIGNED:Gliomas are tumors that arise from glial cells in the central nervous system. Radiation provides local control for low-grade gliomas and improves survival for patients with high-grade gliomas; however, recurrence is common and treatment can be associated with long-term toxicities. Several strategies are under development to improve the anti-tumor efficacy of radiation and limit possible side effects. Novel molecular imaging agents can help diagnose new gliomas, delineate tumors for more accurate radiation planning, and differentiate tumor recurrence from treatment response changes on imaging. Radiotherapeutics provide an alternative method of delivering targeted radiation to tumors by leveraging molecular targets. New generation of radiosensitizers that target DNA damage response and cell cycle pathways aim to enhance radiation-induced cytotoxicity. AREAS COVERED/UNASSIGNED:This review summarizes emerging molecular imaging agents, radiotherapeutics, and radiosensitizers in glioma with a focus on agents currently in the early phase of clinical trials. EXPERT OPINION/UNASSIGNED:The development of new diagnostic and therapeutic agents has the potential of improving outcomes for glioma patients. As new agents are tested in clinical trials, it will be critical to consider questions regarding standardization of methodology in use/interpretation of molecular imaging techniques, appropriate dosimetry of radiotherapeutics, and cumulative toxicities with radiosensitizers.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Bone metastases, affecting more than 4.8% of patients with cancer annually, and particularly spinal metastases require urgent intervention to prevent neurological complications. However, the current process of manually reviewing radiological reports leads to potential delays in specialist referrals. We hypothesized that natural language processing (NLP) review of routine radiology reports could automate the referral process for timely multidisciplinary care of spinal metastases. METHODS:We assessed 3 NLP models-a rule-based regular expression (RegEx) model, GPT-4, and a specialized Bidirectional Encoder Representations from Transformers (BERT) model (NYUTron)-for automated detection and referral of bone metastases. Study inclusion criteria targeted patients with active cancer diagnoses who underwent advanced imaging (computed tomography, MRI, or positron emission tomography) without previous specialist referral. We defined 2 separate tasks: task of identifying clinically significant bone metastatic terms (lexical detection), and identifying cases needing a specialist follow-up (clinical referral). Models were developed using 3754 hand-labeled advanced imaging studies in 2 phases: phase 1 focused on spine metastases, and phase 2 generalized to bone metastases. Standard McRae's line performance metrics were evaluated and compared across all stages and tasks. RESULTS:In the lexical detection, a simple RegEx achieved the highest performance (sensitivity 98.4%, specificity 97.6%, F1 = 0.965), followed by NYUTron (sensitivity 96.8%, specificity 89.9%, and F1 = 0.787). For the clinical referral task, RegEx also demonstrated superior performance (sensitivity 92.3%, specificity 87.5%, and F1 = 0.936), followed by a fine-tuned NYUTron model (sensitivity 90.0%, specificity 66.7%, and F1 = 0.750). CONCLUSION/CONCLUSIONS:An NLP-based automated referral system can accurately identify patients with bone metastases requiring specialist evaluation. A simple RegEx model excels in syntax-based identification and expert-informed rule generation for efficient referral patient recommendation in comparison with advanced NLP models. This system could significantly reduce missed follow-ups and enhance timely intervention for patients with bone metastases.

BACKGROUND AND PURPOSE/OBJECTIVE:Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment. MATERIALS AND METHODS/METHODS:This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility. RESULTS:Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE. CONCLUSION/CONCLUSIONS:Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.

IMPORTANCE/UNASSIGNED:Stereotactic body radiation therapy (SBRT) for spinal metastases improves symptomatic outcomes and local control compared to conventional radiotherapy. Treatment failure most often occurs within the epidural space, where dose is constrained by the risk of radiation myelitis (RM). Current constraints designed to prevent RM after spine SBRT are derived from limited data. OBJECTIVE/UNASSIGNED:To characterize the risk of RM after spine SBRT and to update the dosimetric constraints for preventing it. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study was conducted in a single tertiary cancer care center with patients treated for spinal metastases from 2014 to 2023. All included participants had undergone spine SBRT, had a minimum of 1-month follow-up with magnetic resonance imaging (MRI), a maximal cord dose to a voxel (Dmax) greater than 0 Gy, and no overlapping prior radiotherapy. In all, 2051 patients received SBRT to 2835 spinal metastases (levels C1-L2) during the study period. EXPOSURES/UNASSIGNED:Three-fraction spine SBRT to a prescription dose of 27 to 36 Gy. MAIN OUTCOMES AND MEASURES/UNASSIGNED:RM defined as radiographic evidence of spinal cord injury in the treatment field, classified as grade (G) 1 to G4 or G3 to G4 per the Common Terminology Criteria for Adverse Events, version 5.0. Multiple dosimetric parameters of the true spinal cord structure were assessed for an association with risk of RM to determine the important covariates associated with this toxicity. RESULTS/UNASSIGNED:The analysis included 1423 patients (mean [SD] age, 61.6 [12.9] years; 695 [48.8%] females and 728 [51.1%] males) who received SBRT for 1904 spinal metastases. Among them, 30 cases of RM were identified, 19 of which were classified as G3 to G4. Two years after SBRT, the rate of G1 to G4 RM was 1.8% (95% CI, 1.2%-2.5%) and the rate of G3 to G4 RM was 1.1% (95% CI, 0.7%-1.7%). The minimum dose to the 0.1 cm3 of spinal cord receiving the greatest dose (D0.1cc) was the most important covariate on univariable cause-specific hazards regression for RM (for G3 to G4: hazard ratio, 2.14; 95% CI, 1.68-2.72; P < .001). A true cord D0.1cc of 19.1 Gy and Dmax of 20.8 Gy estimated a 1.0% risk (95% CI, 0.3%-1.6% and 0.4%-1.6%, respectively) of G3 to G4 RM 2 years after SBRT. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of this cohort study indicate that a cord (myelogram or MRI-derived) D0.1cc constraint of 19.1 Gy and a Dmax constraint of 20.8 Gy correspond with a 1.0% risk of G3 to G4 RM at 2 years.

There is a much debate regarding optimal selection in patients with metastatic cancer who should undergo local treatment (surgery or radiation treatment) to the primary tumor and/or metastases. Additionally, the optimal treatment of newly diagnosed metastatic cancer is largely unclear. Current prognostication systems to best inform these clinical scenarios are limited, as all metastatic patients are grouped together as having Stage IV disease without further incorporation of patient and disease-specific covariates that significantly impact patient outcomes. Therefore, improving current prognostic scoring systems and incorporation of these covariates is essential to best individualize treatment for patients with metastatic cancer. In this narrative review article, we provide a detailed review of prognostication systems that can be used for both the site of metastasis and primary site to best tailor treatment in these patients. Additionally, we discuss the incorporation and ongoing developments in radiographic, genomic, and biostatistical techniques that can be used as prognostication tools.

Leptomeningeal metastases are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options and clinical research protocols for patients with leptomeningeal metastases from solid tumors have similarly evolved to improve survival within specific populations. Recent expansion in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multi-modality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of leptomeningeal metastases, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of leptomeningeal metastases and serve as a platform for further discussion and patient advocacy.