Citations

Leptomeningeal disease (LMD) is a devastating sequelae of metastatic spread that affects approximately 5% of cancer patients. The incidence of LMD is increasing due to advancements in systemic therapy and enhanced detection methods. The purpose of this review is to provide a detailed overview of the evidence in the detection, prognostication, and treatment of LMD. A comprehensive literature search of PUBMED was conducted to identify articles reporting on LMD including existing data and ongoing clinical trials. We found a wide array of treatment options available for LMD including chemotherapy, targeted agents, and immunotherapy as well as several choices for radiotherapy including whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and craniospinal irradiation (CSI). Despite treatment, the prognosis for patients with LMD is dismal, typically 2–4 months on average. Novel therapies and combination approaches are actively under investigation with the aim of improving outcomes and quality of life for patients with LMD. Recent prospective data on the use of proton CSI for patients with LMD have demonstrated its potential survival benefit with follow-up investigations underway. There is a need for validated metrics to predict prognosis and improve patient selection for patients with LMD in order to optimize treatment approaches.

e15045 Background: Human papillomavirus (HPV) is an oncogenic driver of several human cancers, including those of the anal canal, uterine cervix, and head and neck (predominantly oropharynx). Despite advancements in our understanding of HPV-related cancers, there remains an unmet need for a comprehensive biomarker-driven registry to establish correlations between biomarker detectability and clinicopathologic features in patients diagnosed and treated for HPV-driven cancers. To address this need, the NAVigate-HPV Registry has been established to systematically collect and analyze integrated biomarker and clinical data from many U.S. cancer centers. Methods: NavDx (Naveris, Inc.) is a clinically validated blood-based assay detecting circulating cell-free tumor tissue modified viral (TTMV)-HPV DNA. The NAVigate-HPV Registry is a web-based data platform based on a centrally IRB approved protocol. Participating investigators will include providers that order NavDx tests in the routine clinical care of their patients and agree to the terms and conditions for use of the registry. Eligible subjects will have or have had an HPV-driven cancer (with an initial focus on HPV-driven oropharynx cancer with confirmatory tissue testing) and have received one or more NavDx blood tests during routine clinical care. Clinical data and TTMV-HPV DNA scores will be collected at enrollment and defined intervals over five years or until death. Results: In the initial phase, the registry has enlisted participation and established a steering committee composed of a representative from each of 14 institutions. These institutions are geographically diverse centers ranging from community hospitals to clinics and academic medical facilities. An IRB protocol governing the registry will maintain ethical standards, ensuring compliance and ethical conduct throughout the registry process. Data extraction methods have been previously established to evaluate an initial cohort of 543 patients (Hanna GJ, Roof SA, et. al 2023). Conclusions: Naveris and collaborators have together successfully launched the NAVigate-HPV registry with the aim of creating a robust database linking tumor biomarker results from NavDx with clinical outcomes data for HPV-related cancers. The NAVigate-HPV database is expected to encompass more than 1,000 patients within 1 year and grow to > 5,000 patients within 5 years, serving as a powerful tool for precision cancer medicine in this patient cancer population. Establishing this registry will deepen insights into HPV-related cancers and advance diagnostic and therapeutic approaches to improve patient outcomes.

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy’s potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

PURPOSE The COVID-19 pandemic led to rapid expansion of telemedicine. The implications of telemedicine have not been rigorously studied in radiation oncology, a procedural specialty. This study aimed to evaluate the characteristics of in-person patients (IPPs) and virtual patients (VPs) who presented to a large cancer center before and during the pandemic and to understand variables affecting likelihood of receiving radiotherapy (yield) at our institution. METHODS A total of 17,915 patients presenting for new consultation between 2019 and 2021 were included, stratified by prepandemic and pandemic periods starting March 24, 2020. Telemedicine visits included video and telephone calls. Area deprivation indices (ADIs) were also compared. RESULTS The overall population was 56% male and 93% White with mean age of 63 years. During the pandemic, VPs accounted for 21% of visits, were on average younger than their in-person (IP) counterparts (63.3 years IP v 62.4 VP), and lived further away from clinic (215 miles IP v 402 VP). Among treated VPs, living closer to clinic was associated with higher yield (odds ratio [OR], 0.95; P < .001). This was also seen among IPPs who received treatment (OR, 0.96; P < .001); however, the average distance from clinic was significantly lower for IPPs than VPs (205 miles IP v 349 VP). Specialized radiotherapy (proton and brachytherapy) was used more in VPs. IPPs had higher ADI than VPs. Among VPs, those treated had higher ADI ( P < .001). CONCLUSION Patient characteristics and yield were significantly different between IPPs and VPs. Telemedicine increased reach to patients further away from clinic, including from rural or health care–deprived areas, allowing access to specialized radiation oncology care. Telemedicine has the potential to increase the reach of other technical and procedural specialties.

OBJECTIVE Olfactory neuroblastoma (ONB) is a rare, malignant tumor of the sinonasal tract that arises from olfactory epithelium. Although surgery is the preferred first-line treatment, tumor involvement of adjacent structures may preclude the ability to achieve negative margins during initial resection. Herein, the authors examine the oncological outcomes of patients with positive margins after primary resection of ONB, with the aim of determining predictors of disease progression and patterns of recurrence. METHODS The authors performed an institutional review of 25 patients with positive-margin ONB after resection. Cox survival analyses were used to determine any statistically significant predictors of worse progression-free survival (PFS) and overall survival (OS). RESULTS A total of 93 patients who were diagnosed with ONB were identified, of whom 25 patients had positive margins following their primary resection. Eleven (44%) had a delayed finding of positive margins that were initially negative in the operating room but returned as positive on final pathology. Four patients had subtotal resection (STR), whereas the remaining patients underwent gross-total resection. Twenty-four patients received adjuvant radiotherapy (96%), and 15 additionally received adjuvant chemotherapy (60%). Fourteen patients (56%) experienced recurrence/progression at a median time of 35 months following resection (IQR 19–70 months). Local recurrence occurred in 10 patients (40%), regional in 9 (36%), and distant metastasis in 2 (8%). In Cox survival analyses, the 5-year PFS and OS were 55.1% and 79.2%, respectively. Kadish stage D was predictive of worse PFS in univariate (hazard ratio [HR] 15.67, 95% CI 3.38–72.61, p < 0.001) and multivariate (HR 15.46, 95% CI 1.45–164.91, p = 0.023) analyses. Hyams grade, adjuvant chemotherapy, and primary radiotherapy were not associated with PFS. Furthermore, Kadish stage D and STR were predictive of worse OS in univariate analysis (HR 12.64, 95% CI 2.03–78.86, p = 0.007; HR 7.31, 95% CI 1.45–36.84, p = 0.016; respectively). However, local and regional recurrence was not associated with worse OS. CONCLUSIONS Approximately half of patients with positive-margin ONB may experience disease recurrence. Patients with an advanced disease stage (Kadish D) may have a higher likelihood of developing recurrence/progression. Furthermore, patients with tumor burden following resection (STR and Kadish D) may have worse OS. However, in positive-margin ONB with no gross disease following initial resection, the presence of disease recurrence does not significantly alter survival when receiving salvage therapy.

Abstract Background: Analyzing interactions and the microanatomical distribution of the tumor immune microenvironment (TIME) is essential for a comprehensive understanding of tumor progression. Imaging Mass Cytometry (IMC) is a high-dimensional tissue imaging system that enables the deeper and multiparametric in situ exploration of tumor microenvironments at a single-cell level. This study describes a pipeline for analyzing 39-plex IMC images of human HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) tumor sections, elucidating immune cells' nature, functions, and interactions with tumor cells. The IMC data analysis provides valuable information for clinical studies that could be used for the identification of prognostic biomarkers and mechanisms of resistance to current immunotherapies. Methods: A retrospective study was conducted on (N=20) patients (10 progressors and 10 non-progressors) with HPV(+) OPSCC. The dataset comprises paired hematoxylin and eosin (H&E) images with IMC data from multiple Regions of Interest (ROIs) (N=82), enabling the in-situ profiling of 39 proteins in primary tumor tissue. Cell segmentation was followed by employing original images and their segmentation masks for cell phenotype identification using a probabilistic neural network method to spatially profile cancer cells, macrophages, NK-M cells, B-cells, and distinct T-cell populations. We identified protein expression at single-cell resolution and investigated the impact of multicellular spatial organization on the disease progression. The spatial neighborhood interaction score of tumor cells with various other cells was computed for all the ROIs across the two groups. Results: The markers showed varying expression levels of intensity distribution, likely due to differences in tissue sample composition. Specifically, CD3, CD4, CD8, CD19, CD20, and CD68 showed significantly higher intensity in non-progressors. Interestingly, FoxP3 also had a significantly higher intensity level in non-progressors. Cell phenotyping emphasized that non-progressors generally have increased levels of NK-M cell markers. Spatial analysis revealed a significant increase in interaction between CD3 cells and tumor cells in non-progressors (p-value=0.07, Mann-Whitney U test). Furthermore, a significant rise in the interaction between B-cells and FoxP3+ cells was observed in non-progressors (p-value&lt;0.05, Mann-Whitney U test) suggesting a coordinated suppression of tumor growth. Conclusion: We developed a deep learning-based pipeline to analyze spatial relationships in the TIME of IMC data, demonstrating its clinical relevance in predicting disease progression. Our findings emphasize the importance of spatial relationships in the TME for response and suggest that proximity between either CD3+ T-cells to cancer cells or B-cells to FoxP3+ cells are candidate biomarkers. Citation Format: Sumanth Reddy Nakkireddy, Routman David, Kathleen Bartemes, Daniel Ma, Tae Hyun Hwang, Kathryn Van Abel, Chadi Nimeh Abdel-Halim. AI-enhanced spatial proteomics reveals B-cells & FoxP3+ cells interactions in HPV(+) oropharyngeal squamous cell carcinoma Progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5488.

Abstract Background This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18–66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54–55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P &lt; .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus –2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41–63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Background: Approximately 75% of all head and neck cancer patients are treated with radiotherapy (RT). RT to the oral cavity results in acute and late adverse events which can be severe and detrimental to a patient’s quality of life and function. The purpose of this study was to explore associations between RT dose to a defined oral cavity organ-at-risk (OAR) avoidance structure, provider- and patient-reported outcomes (PROs), opioid use, and hospitalization. Methods: This was a retrospective analysis of prospectively obtained outcomes using multivariable modeling. The study included 196 patients treated with RT involving the oral cavity for a head and neck tumor. A defined oral cavity OAR avoidance structure was used in all patients for RT treatment planning. Validated PROs were collected prospectively. Opioid use and hospitalization were abstracted electronically from medical records. Results: Multivariable modeling revealed the mean dose to the oral cavity OAR was significantly associated with opioid use (p = 0.0082) and hospitalization (p = 0.0356) during and within 30 days of completing RT. Conclusions: The findings of this study may be valuable in RT treatment planning for patients with tumors of the head and neck region to reduce the need for opioid use and hospitalization during treatment.

Abstract Although the majority of HPV (+) oropharyngeal squamous cell carcinoma (OPSCC) patients exhibit a favorable prognosis, approximately 20% face recurrent or metastatic disease, posing management challenges. Therefore, the identification of robust prognostic markers for risk stratification is essential. Our study focused on the comprehensive characterization of intratumor heterogeneity within the tumor immune microenvironment (TME) in both primary tumors and metastatic lymph nodes. Utilizing computational approaches, we integrated hematoxylin and eosin (H&E) and 11 adjacent immunohistochemistry (IHC)-stained slides to investigate the cellular composition and functional characteristics across different regions within the TME. Based on these detailed immune characteristics, we classified patients into specific immune subtypes. Our integrative TME analysis indicated that patients with high tumor-infiltrating lymphocytes (TIL), increased CD8 + levels, and reduced CD163 + cell counts within their primary tumors were likely to have a more favorable progression-free survival outcome. The integration of H&E and IHC data enhances the functional characterization of immune phenotypes of the TME with biological interpretability and improves patient stratification in HPV(+) OPSCC.

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.