Disparities in survival outcomes among Black patients with HPV-associated oropharyngeal cancer.

Patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) have a favorable prognosis and excellent overall survival (OS), and studies have demonstrated these findings in cohorts of predominantly White patients. Racial/ethnic (R/E) minorities, particularly Black patients, with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared with White patients. In this study, we aimed to determine if Black patients with HPV-OPSCC have a similar favorable prognosis to the White population. This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database from 2010 to 2016. We identified patients with Stage I-IV HPV- OPSCC who were treated with radiation, surgery, chemotherapy, or a combination of modalities. Patient outcomes were stratified by R/E groups including White Versus Black patients. The main outcome in this study was OS. Analyses for proportions of categorical variables were performed using a χ2  or Fisher's exact test. Univariate and multivariate time-to-event survival analyses were performed using Kaplan-Meier product limit estimates and log-rank test to test the differences between strata. A Cox proportional hazards regression model was used to assess the association between covariates and risk of death (OS). We identified 9256 OPSCC patients who met inclusion criteria and were treated between 2010 and 2016, of which 7912 were White (85.5%) and 1344 were Black (14.5%). A total of 1727 were HPV-OPSCC, of which 1598 were White (92.5%) and 129 (7.5%) were Black. By race, the 5-year OS for White versus Black OPSCC patients was 42% versus 23%, respectively (log-rank, p < 0.0001). Among HPV-positive OPSCC patients, the 5-year OS for White versus Black patients was 65% versus 39% (log-rank, p < 0.0001). Among HPV-negative patients, the 5-year OS for White versus Black patients was 36% versus 13% (log-rank, p < 0.0001). On multivariate analysis, after accounting for age, sex, insurance status, income, Charlson-Deyo score, receipt of surgery, distance from facility, and total treatment time, Black race trended toward, but was not associated with worse survival. Hazard ratio (HR:1.24, 95% confidence interval [CI] 0.85-1.81, p = 0.255). This national cohort study of OPSCC patients demonstrates that Black patients with HPV-OPSCC have a poor prognosis and OS similar to HPV-negative White patients. This may be partly due to socioeconomic barriers such as insurance and income. Further work is needed to better understand the specific drivers of inferior survival outcomes in this specific patient population.

Outcomes of definitive local therapy with intensity-modulated radiation therapy in elderly patients ≥70 years with HPV-associated oropharyngeal cancer.

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing among elderly (≥70 years) patients and the optimal treatment approach is not known. In this study, we aimed to determine disease and toxicity outcomes in an elderly HPV-OPSCC population primarily treated with a chemoradiation (CRT) approach. We identified 70 elderly HPV-OPSCC patients who were treated with either surgery, radiotherapy, or CRT between 2011 and 2021. Time-to-event analysis for overall survival (OS), progression-free survival (PFS), and local control (LC) were conducted using the Kaplan-Meier method. Univariate and multivariable cox regression models were used to estimate the hazard ratio associated with covariates. The median follow-up for our cohort was 43.9 months. Of the 70 elderly patients, 55 (78.6%) receive CRT and 15 (22.4%) received RT alone. Two patients underwent TORS resection. Of the 55 patients treated with CRT, the most common systemic agents were weekly carboplatin/taxol (n = 18), cetuximab (n = 17), and weekly cisplatin (n = 11). The 5-year OS, PFS, and LC were 57%, 52%, and 91%, respectively. On univariate analysis, Eastern Cooperative Oncology Group performance status and Charlson Comorbidity Index (CCI) were significant predictors of OS, while on multivariate analysis only CCI was a significant predictor of OS (p = 0.006). The rate of late peg tube dependency, osteoradionecrosis, and aspiration was 10%, 4%, and 4%, respectively. Definitive local therapy in elderly HPV-OPSCC patients is associated with excellent LC and a low rate of late toxicities. Prospective studies are needed to further stratify subgroups of elderly patients who may benefit from aggressive definitive local therapy.

Assessment of MRI image distortion based on 6 consecutive years of annual QAs and measurements on 14 MRI scanners used for radiation therapy.

PURPOSE: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning. METHODS AND MATERIALS: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered. RESULTS: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter. CONCLUSION: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners.

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort.

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Fractionated pre-operative stereotactic radiotherapy for patients with brain metastases: a multi-institutional analysis.

BACKGROUND: The current standard of care for patients with a large brain metastasis and limited intracranial disease burden is surgical resection and post-operative single fraction stereotactic radiosurgery (SRS). However, post-operative SRS can still lead to substantial rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) can minimize rates of LF, RN, and MD. METHODS: A retrospective, multi-institutional analysis was conducted and included patients who had pre-operative FSRT for a large or symptomatic brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. A primary measurement was the rate of a composite endpoint of (1) LF, (2) MD, and/or (3) Grade 2 or higher (symptomatic) RN. RESULTS: 53 patients with 55 lesions were eligible for analysis. FSRT was prescribed to a dose of 24-25 Gy in 3-5 fractions. There were 0 LFs, 3 Grade 2-3 RN events, and 1 MD occurrence, which corresponded to an 8% per-patient composite endpoint event rate. CONCLUSIONS: In this study, the composite endpoint of 8% for pre-operative FSRT was improved compared to previously reported rates with post-operative SRS of 49-60% (N107C, Mahajan etal. JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe, effective, and may decrease the incidence of adverse outcomes. Prospective validation is needed.

Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.

BACKGROUND: The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. METHODS: Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed. RESULTS: Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis. CONCLUSIONS: Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.

Association between Tumor Microbiome and Hypoxia across Anatomic Subsites of Head and Neck Cancers.

Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78], of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package "tmesig" was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the "stats" package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted.

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Platinum-based regimens versus cetuximab in definitive chemoradiation for human papillomavirus-unrelated head and neck cancer.

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT.

CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET.

A negative interim positron emission tomography/computerized tomography (PET/CT) after 1 to 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, nonbulky stage I or II Hodgkin lymphoma (HL) predicts a low relapse rate. This phase 2 trial was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without radiation therapy (RT) on the basis of a negative interim PET/CT, thereby limiting the risks of treatment. Between 15 May 2010 and 21 February 2013, 164 previously untreated patients with nonbulky stage I/II HL were enrolled, and 149 were included in the final analysis. Patients received 2 cycles of ABVD followed by PET. Deauville scores 1 to 3 were negative (≤ liver uptake) based on central review. PET- patients received 2 more cycles of ABVD, and PET+ patients received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus 3060-cGy involved-field RT. The primary objective was to determine 3-year progression-free survival (PFS) for the PET- group. One hundred thirty-five patients (91%) were interim PET-, and 14 patients (9%) were PET+ With median follow-up time of 3.8 years, the estimated 3-year PFS was 91% for the PET- group and 66% for the PET+ group (hazard ratio, 3.84; 95% confidence interval, 1.50-9.84; P = .011). There was 1 death as a result of suicide. Four cycles of ABVD resulted in durable remissions for a majority of patients with early-stage nonbulky HL and a negative interim PET. This trial was registered at www.clinicaltrials.gov as #NCT01132807.

NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018.

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

Palliative Quad Shot Radiation Therapy with or without Concurrent Immune Checkpoint Inhibition for Head and Neck Cancer.

OBJECTIVES: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. 'QuadShot' (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. MATERIALS AND METHODS: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. RESULTS: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9-77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60-70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073-0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. CONCLUSIONS: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation.

Volumetric Modulated Arc Therapy Craniospinal Irradiation Utilizing a Vertebral Body Sparing Approach: An Alternative Approach to Improve Access and Minimize Toxicity.

Introduction: Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral body sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS CSI using volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs at risk, minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI. Methods and Materials: Consecutive patients with LMD received VMAT VBS CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to 2 spine isocenters for the upper and lower spine were created using limited posterior arcs. To further decrease the vertebral body dose, an avoid entry and exit contour was created. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events v5. Results: Ten adult patients were treated in this cohort. One patient experienced grade 2 neutropenia with the remaining 9 experiencing grade 1 hematologic toxicity. Three patients experienced grade 2 gastrointestinal toxicity with the remaining 7 experiencing grade 1 nausea. No patient experienced grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay. Conclusions: In this study, VMAT VBS CSI led to acceptable toxicity compared with patients treated with proton CSI on a phase 2 clinical trial. Given its promising early results, future prospective evaluation of the technique is warranted.

Safety and Feasibility of Stereotactic Radiosurgery for Patients with 15 or more Brain Metastases.

Background: Current standard of care treatment for patients with ≥15 brain metastases (BM) is whole brain radiation therapy (WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery (SRS), with the aim of evaluating safety, cognitive outcomes, and survival metrics. Methods: Patients who received SRS for ≥15 BMs in 1 to 5 fractions from 2014 to 2022 were included. Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System (PROMIS) scores. The Kaplan-Meier method was used for survival analysis and log-rank test for intergroup comparisons. Results: Overall, 118 patients underwent 124 courses of LINAC-based SRS. The median number of lesions treated per course was 20 (range, 15-94). Most patients received fractionated SRS to a dose of 24 Gy in 3 fractions (81.5%). At the time of SRS, 19.4% patients had received prior WBRT, and 24.2% had received prior SRS. The rate of any grade radiation necrosis (RN) and grade ≥3 RN were 15.3% and 3.2%, respectively. When evaluating longitudinal PROMIS score trends, 25 of 31 patients had a stable/improved PROMIS score. Patients who did not receive prior brain RT had a longer median survival (7.4 months vs 4.6 months, P = .034). The 12m local control was 97.6%, and the cumulative incidence of distant intracranial failure, with death as a competing event, was 46% (95% CI, 36%, 55%). One year freedom from neurologic death, leptomeningeal disease, and salvage WBRT were 89%, 94.6%, and 84%, respectively. Conclusion: We present here one of the largest studies evaluating SRS for patients with ≥15 BMs. SRS was safe, had favorable cognitive outcomes, and had comparable survival outcomes to contemporary studies evaluating WBRT in this population. Treatment-naïve patients had a median survival of >6 months, long enough to benefit from cognitive sparing with SRS. Our study supports randomized studies comparing SRS and hippocampal avoidance WBRT approaches for these patients.

Advancing Beyond the Hippocampus to Preserve Cognition for Patients With Brain Metastases: Dosimetric Results From a Phase 2 Trial of Memory-Avoidance Whole Brain Radiation Therapy.

Purpose: Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery, hippocampal avoidance whole brain radiation therapy (WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a "memory-avoidance" WBRT (MA-WBRT) approach that spares these substructures for patients with >15 brain metastases. Methods and Materials: Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory-avoidance region was created using a 5-mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9 Gy and D0.03 cm3 ≤ 16 Gy (variation acceptable to 20 Gy). LINAC-based volumetric modulated arc therapy plans were generated for a prescription dose of 30 Gy in 10 fractions. Results: On average, the memory avoidance structure volume was 37.1 cm3 (range, 25.2-44.6 cm3), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8 of 10 plans met the D0.03 cm3 constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% > 25 Gy) and homogeneity (D2% ≤ 37.5 Gy) were achieved for all plans. Conclusions: Modern volumetric modulated arc therapy techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.

Comparative analysis of the tumor microbiome, molecular profiles, and immune cell abundances by HPV status in mucosal head and neck cancers and their impact on survival.

Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40-0.89, p = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (p < .001) and M2 macrophages (p = .035), while HPV+ tumors had more T regulatory cells (p < .001) and CD8+ T-cells (p < .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.

Scalp Irradiation with 3D-Milled Bolus: Initial Dosimetric and Clinical Experience.

BACKGROUND AND PURPOSE: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. MATERIALS AND METHODS: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0-69.96). RESULTS: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25-90%). The median dose homogeneity index was 1.07 (range: 1.03-1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0-75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. CONCLUSIONS: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

Vertebral Compression Fracture After Spine Stereotactic Body Radiotherapy: The Role of Vertebral Endplate Disruption.

BACKGROUND AND OBJECTIVES: Vertebral compression fracture (VCF) is a common, but serious toxicity of spinal stereotactic body radiotherapy (SBRT). Several variables that place patients at high risk of VCF have previously been identified, including advanced Spinal Instability Neoplastic Score (SINS), a widely adopted clinical decision criterion to assess spinal instability. We examine the role of tumoral endplate (EP) disruption in the risk of VCF and attempt to incorporate it into a simple risk stratification system. METHODS: This study was a retrospective cohort study from a single institution. Demographic and treatment information was collected for patients who received spinal SBRT between 2013 and 2019. EP disruption was noted on pre-SBRT computed tomography scan. The primary end point of 1-year cumulative incidence of VCF was assessed on follow-up MRI and computed tomography scans at 3-month intervals after treatment. RESULTS: A total of 111 patients were included. The median follow-up was 18 months. Approximately 48 patients (43%) had at least one EP disruption. Twenty patients (18%) experienced a VCF at a median of 5.2 months from SBRT. Patients with at least one EP disruption were more likely to experience VCF than those with no EP disruption (29% vs 6%, P < .001). A nomogram was created using the variables of EP disruption, a SINS of ≥7, and adverse histology. Patients were stratified into groups at low and high risk of VCF, which were associated with 2% and 38% risk of VCF ( P < .001). CONCLUSION: EP disruption is a novel risk factor for VCF in patients who will undergo spinal SBRT. A simple nomogram incorporating EP disruption, adverse histology, and SINS score is effective for quickly assessing risk of VCF. These data require validation in prospective studies and could be helpful in counseling patients regarding VCF risk and referring for prophylactic interventions in high-risk populations.