Total scalp irradiation: A study comparing multiple types of bolus and VMAT optimization techniques.

PURPOSE: To investigate bolus design and VMAT optimization settings for total scalp irradiation. METHODS: Three silicone bolus designs (flat, hat, and custom) from .decimal were evaluated for adherence to five anthropomorphic head phantoms. Flat bolus was cut from a silicone sheet. Generic hat bolus resembles an elongated swim cap while custom bolus is manufactured by injecting silicone into a 3D printed mold. Bolus placement time was recorded. Air gaps between bolus and scalp were quantified on CT images. The dosimetric effect of air gaps on target coverage was evaluated in a treatment planning study where the scalp was planned to 60 Gy in 30 fractions. A noncoplanar VMAT technique based on gEUD penalties was investigated that explored the full range of gEUD alpha values to determine which settings achieve sufficient target coverage while minimizing brain dose. ANOVA and the t-test were used to evaluate statistically significant differences (threshold = 0.05). RESULTS: The flat bolus took 32 ± 5.9 min to construct and place, which was significantly longer (p < 0.001) compared with 0.67 ± 0.2 min for the generic hat bolus or 0.53 ± 0.10 min for the custom bolus. The air gap volumes were 38 ± 9.3 cc, 32 ± 14 cc, and 17 ± 7.0 cc for the flat, hat, and custom boluses, respectively. While the air gap differences between the flat and custom boluses were significant (p = 0.011), there were no significant dosimetric differences in PTV coverage at V57Gy or V60Gy. In the VMAT optimization study, a gEUD alpha of 2 was found to minimize the mean brain dose. CONCLUSIONS: Two challenging aspects of total scalp irradiation were investigated: bolus design and plan optimization. Results from this study show opportunities to shorten bolus fabrication time during simulation and create high quality treatment plans using a straightforward VMAT template with simple optimization settings.

Palliative radiotherapy for children: Symptom response and treatment-associated toxicity according to radiation therapy dose and fractionation.

BACKGROUND/OBJECTIVES: Radiotherapy is an effective palliative treatment in advanced cancer. Shorter palliative treatment courses are recommended for adults, though pediatric data addressing treatment efficacy and toxicity according to radiation therapy (RT) dose and fractionation are limited. DESIGN/METHODS: Total 213 patients aged 21 years or younger receiving 422 palliative radiotherapy treatment courses from 2003 to 2016 were included. Symptom response and treatment-associated toxicity were recorded and analyzed in relationship to demographic and treatment variables. RESULTS: Common diagnoses included sarcoma (32.5%), neuroblastoma (24.9%), leukemia/lymphoma (14.9%), and central nervous system tumors (10.9%). The most common indication for treatment was pain (46.7%). Patients received a median of 10 fractions, 2.5 Gy dose per fraction, and 21 Gy total dose. Number of RT fractions was five or less in 166 (39.3%), six to 10 fractions in 117 (27.2%), and 10 or more fractions in 139 (32.9%) of courses. Complete or partial pain relief was achieved in 85% (151 of 178 evaluable patients), including 77.8% receiving five or less fractions and 89.6% receiving more than five fractions. Highest toxicity was grade 1 in 159 (38.9%), grade 2 in 26 (6.4%), and grade 3 in two (0.5%) treatments. On multivariable analysis, RT delivered 30 or more days from death (OR 12.13, 95% CI: 2.13-69.2, p = .005) and no adjuvant chemotherapy (OR 0.14, 95% CI: 0.03-0.54, p = .005) were significantly associated with pain response, and five or less fractions were significantly associated with lower toxicity (OR 0.24, 95% CI: 0.06-0.97, p = .045). CONCLUSIONS: Palliative RT courses of five or less fractions result in high rates of pain control and are associated with low toxicity in pediatric patients with cancer.

Reduced-volume tumor-bed boost is not associated with inferior local control and survival outcomes in high-risk medulloblastoma.

BACKGROUND: Radiotherapy boost to the entire posterior fossa (PF) is standard of care for high-risk (H-R) medulloblastoma patients; the utility of tumor bed (TB)-only boost is unclear. The purpose of this study was to examine the impact of PF versus TB boost volume on tumor control and survival in the H-R medulloblastoma population. METHODS: Single-institution records for patients with H-R medulloblastoma were reviewed. The median craniospinal irradiation dose was 36 Gy (range, 23.4-45 Gy), and boost doses to either PF or TB were 54 to 55.8 Gy. PF (local) failures were scored as in-field, marginal (between 80% and 95% isodose lines), or distant. Kaplan-Meier methods and Cox proportional hazards were used to assess the impact of radiation boost technique on local control (LC) and survival endpoints. RESULTS: Thirty-two patients with H-R medulloblastoma were treated between 1990 and 2015, with a median follow-up length of 5.12 years. Twenty-two patients received PF boost, and 10 received TB boost. Patient and disease characteristic were comparable between groups. A total of 11 PF failures occurred, including 3 isolated LFs (2 in the PF and 1 in the TB group). Most PF failures were in-field: three of four in the TB group and six of seven in the PF group; the remainder were marginal failures. TB boost was not associated with inferior LC (hazard ratio [HR] 0.86, log-rank P = 0.81) or overall survival (HR 1.40, P = 0.56) compared with PF boost. CONCLUSION: Reduced-volume radiotherapy boost to the TB does not appear to compromise LC or survival in patients with H-R medulloblastoma; it may reduce the risk of ototoxicity.

Immune microenvironment remodeling after radiation of a progressing brain metastasis.

Radiation is commonly used in the treatment of many cancers. However, its effects on anti-tumor immune responses are incompletely understood. Here, we present a detailed immunological analysis of two tumors from a patient with multiple non-small cell lung cancer metastases to the brain. One tumor was resected without treatment; the second was irradiated to a total dose of 30 Gy and resected following further progression. Comprehensive single-cell analysis reveals a substantially reduced immune cell fraction in the irradiated tumor, including the depletion of tissue-resident macrophages and infiltration of pro-inflammatory monocytes. Despite the presence of similar somatic mutations in both tumors, radiation is associated with the depletion of exhausted, tumor-resident T cell clones and their replacement by circulating clones unlikely to contribute to tumor-specific immunity. These results provide insight into the local effects of radiation on anti-tumor immunity and raise important considerations for the combination of radiation and immunotherapy.

Localization of T cell clonotypes using the Visium spatial transcriptomics platform.

We present a protocol to localize T cell receptor clones using the Visium spatial transcriptomics platform. This approach permits simultaneous localization of both gene expression and T cell clonotypes in situ within tissue sections. T cell receptor sequences identified by this protocol are readily recapitulated by single-cell sequencing. This technique enables detailed studies of the spatial organization of the human T cell repertoire, such as the localization of infiltrating T cell clones within the tumor microenvironment. For complete details on the use and execution of this protocol, please refer to Sudmeier et al. (2022).

Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Recent developments in limited stage small cell lung cancer.

Limited stage small cell lung cancer (LS-SCLC) remains a challenging disease, with 5-year overall survival ranging from 30-35% with current standard of care treatment consisting of thoracic radiation to 45 Gy in 30 fractions delivered twice daily, with concurrent platinum/etoposide chemotherapy, followed by prophylactic cranial irradiation (PCI). The randomized, phase III CONVERT study confirmed 45 Gy delivered twice daily to be the optimal radiation fractionation regimen, without significantly increased toxicity when compared to daily radiation to 66 Gy. Immunotherapy is now being studied in addition to chemoradiation, in both the concurrent and consolidative setting. These randomized trials are ongoing. Additionally, the role of PCI compared to MRI surveillance is being evaluated in patients with LS-SCLC in both the North America and Europe. Ideally these ongoing studies will continue to improve outcomes for LS-SCLC.

Low cardiac and left anterior descending coronary artery dose achieved with left-sided multicatheter interstitial-accelerated partial breast irradiation.

PURPOSE: Studies have shown that an additional mean dose of 1 Gy to the heart can increase the relative risk of cardiac events. The purpose of this study was to quantify the dose delivered to the heart and left anterior descending artery (LAD) in a series of patients with left-sided breast cancer (BC) or ductal carcinoma in situ treated with multicatheter-accelerated partial breast irradiation (MC-APBI) at a single institution. METHODS AND MATERIALS: Patients with left-sided BC or ductal carcinoma in situ treated consecutively from 2005 to 2011 with MC-APBI were retrospectively identified. Cardiac and LAD contours were generated for each patient. Cardiac dosimetry and distance to the planning target volume were recorded. Patient health records were reviewed and cardiac events were recorded based on Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty consecutive patients with left-sided BC treated with MC-APBI were retrospectively identified. Median followup was 41.4 months. Mean equivalent dose in 2 Gy fractions delivered to the heart and LAD were 1.3 (standard deviation: 0.7, range: 0.2-2.9) and 3.8 (standard deviation: 3.0, range: 0.4-11.3) Gy, respectively. There was an inverse linear relationship (R2 = 0.52) between heart-to-lumpectomy cavity distance and mean heart equivalent dose in 2 Gy fractions. One patient (5%) experienced symptomatic cardiac toxicity. CONCLUSIONS: MC-APBI consistently delivers average doses to the heart and LAD that are similar to those achieved in most series with deep inspiration breath-hold and lower than free-breathing radiotherapy techniques. Distance from the heart to the lumpectomy cavity and the availability of other heart-sparing technologies should be considered to minimize the risk of cardiac toxicity.

A Drosophila model to investigate the neurotoxic side effects of radiation exposure.

Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. Wild-type third-instar larvae were irradiated with single doses of γ-radiation, and the percentage that survived to adulthood was determined. Motor function of surviving adults was examined with a climbing assay, and longevity was assessed by measuring lifespan. Neuronal cell death was assayed by using immunohistochemistry in adult brains. We also tested the sensitivity at different developmental stages by irradiating larvae at various time points. Irradiating late third-instar larvae at a dose of 20 Gy or higher impaired the motor activity of surviving adults. A dose of 40 Gy or higher resulted in a precipitous reduction in the percentage of larvae that survive to adulthood. A dose-dependent decrease in adult longevity was paralleled by a dose-dependent increase in activated Death caspase-1 (Dcp1) in adult brains. Survival to adulthood and adult lifespan were more severely impaired with decreasing larval age at the time of irradiation. Our initial survey of the Drosophila Genetic Reference Panel demonstrated that differences in genotype can confer phenotypic differences in radio-sensitivity for developmental survival and motor function. This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions.

Persistent Activation of the Innate Immune Response in Adult Drosophila Following Radiation Exposure During Larval Development.

Cranial radiation therapy (CRT) is an effective treatment for pediatric central nervous system malignancies, but survivors often suffer from neurological and neurocognitive side effects that occur many years after radiation exposure. Although the biological mechanisms underlying these deleterious side effects are incompletely understood, radiation exposure triggers an acute inflammatory response that may evolve into chronic inflammation, offering one avenue of investigation. Recently, we developed a Drosophila model of the neurotoxic side effects of radiation exposure. Here we use this model to investigate the role of the innate immune system in response to radiation exposure. We show that the innate immune response and NF-ĸB target gene expression is activated in the adult Drosophila brain following radiation exposure during larval development, and that this response is sustained in adult flies weeks after radiation exposure. We also present preliminary data suggesting that innate immunity is radioprotective during Drosophila development. Together our data suggest that activation of the innate immune response may be beneficial initially for survival following radiation exposure but result in long-term deleterious consequences, with chronic inflammation leading to impaired neuronal function and viability at later stages. This work lays the foundation for future studies of how the innate immune response is triggered by radiation exposure and its role in mediating the biological responses to radiation. These studies may facilitate the development of strategies to reduce the deleterious side effects of CRT.