Malouff, Timothy D.

Abstract Background Alpha‐emitting radionuclides enable precise cancer therapy through high linear energy transfer and limited tissue penetration, damaging tumor cells while sparing healthy tissue. Diffusing Alpha‐emitters Radiation Therapy (Alpha DaRT) features Ra‐224 sources that are implanted directly into the tumor and emit alpha particles during radioactive decay. Alpha DaRT has demonstrated efficacy and safety in preclinical and early clinical trials across multiple tumor types, including skin, head and neck, and pancreatic cancers. Purpose Reliable and efficient methods for verifying Alpha DaRT source activity prior to treatment can help support accurate and consistent radiation delivery. The direct measurement of alpha particles from sources within an Alpha DaRT applicator is impractical due to their short range; however, gamma emissions from the Ra‐224 sources can be used to infer radioactivity. This study established a protocol for verifying the source activity within Ra‐224 Alpha DaRT applicators using a reentrant well‐type ionization chamber, providing users with a practical method for detecting errors in source manufacturing or certificate paperwork without compromising applicator sterility. Methods Ra‐224 Alpha DaRT sources in sterile packaging (Flex and Needle applicators with 1–4 sources) were assessed. Source energy spectra and activities were verified using a high‐purity germanium (HPGe) radiation detector. Calibration factors (kBq/pA) were established using an IVB1000 well‐type ionization chamber with measurements conducted by placing single applicator sterile packages into the chamber with sources centered in the chamber's sweet spot and corrected for temperature, pressure, and leakage current. Quality assurance was performed on 26 Flex applicators using the established calibrations before the first clinical procedure. Results HPGe measurements agreed with vendor‐stated activities. The average calibration coefficient using the IVB1000 chamber was 233 ± 3 kBq/pA for Flex and 597 ± 7 kBq/pA for Needle applicators. Calibration coefficients were consistent across two IVB1000 chambers. Source number dependence was observed, with calibration factors increasing by 1.7% ± 0.7% per source (Needle) and 2.7% ± 0.6% per source (Flex). Measurement repeatability was 3.3%. Applying the calibration to 26 Flex applicators before the first patient treatment yielded a 1.1 ± 5.8% (range: −7.5% to 11.4%) difference relative to the vendor's stated activity. Conclusion A reentrant well‐type ionization chamber is suitable for pre‐treatment quality assurance of Ra‐224 Alpha DaRT applicators, enabling verification of the vendor‐stated activity while maintaining sterility within sealed packaging.

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

Abstract OBJECTIVE Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRIC) are a frequently observed clinical manifestation and are commonly classified as radiographic radiation necrosis. However, these findings are not well characterized and may predict for response to SRS and ICI. METHODS The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRIC were determined based upon MRI, PET/CT, or MR spectroscopy and a consensus by local clinical providers was required. RESULTS The analysis included 697 patients with 4,536 brain metastases across 11 institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years, 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% were non-small cell lung cancer, melanoma, and renal cell carcinoma (RCC) histology, respectively. TRIC were observed in 9.8%. On univariable analysis, Karnofsky Performance Status (KPS) (hazard ratio [HR]: 0.98; p < 0.001), presence of TRIC (HR: 0.67; p = 0.03), female sex (HR: 0.67; p < 0.001), and prior resection (HR: 0.60; p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR: 0.98; p < 0.001) and the presence of TRIC (HR: 0.66; p = 0.03) were associated with improved OS. A V12 Gy ≥ 10 cm3 (Odds Ratio [OR]: 2.78; p < 0.001), prior whole brain radiation therapy (OR: 3.46; p = 0.006), and RCC histology (OR: 3.10; p = 0.01) were associated with an increased probability of developing TRIC. The median OS in patients with and without TRIC was 29.0 and 23.1 months, respectively (log-rank p = 0.03). CONCLUSION TRIC following ICI and SRS are associated with a median OS benefit of approximately 6 months. Further prospective study is warranted to further elucidate the role and etiology of this common clinical scenario.

BACKGROUND: Melanoma brain metastases are commonly treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs). However, the toxicity of these 2 treatments is largely unknown when administered concurrently. OBJECTIVE: To evaluate the risk of radiation necrosis (RN) with concurrent and nonconcurrent SRS and ICIs. METHODS: The guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used. Inverse probability of treatment weighting, univariable and multivariable logistic regression, and the Kaplan-Meier method was utilized. RESULTS: There were 203 patients with 1388 brain metastases across 11 international institutions in 4 countries with a median follow-up of 15.6 months. The rates of symptomatic RN were 9.4% and 8.2% in the concurrent and nonconcurrent groups, respectively ( P =.766). On multivariable logistic regression, V12 ≥ 10 cm 3 (odds ratio [OR]: 2.76; P =.006) and presence of BRAF mutation (OR: 2.20; P =.040) were associated with an increased risk of developing symptomatic RN; the use of concurrent over nonconcurrent therapy was not associated with an increased risk (OR: 1.06; P =.877). There were 20 grade 3 toxic events reported, and no grade 4 events reported. One patient experienced a grade 5 intracranial hemorrhage. The median overall survival was 36.1 and 19.8 months for the concurrent and nonconcurrent groups (log-rank P =.051), respectively. CONCLUSION: Concurrent administration of ICIs and SRS are not associated with an increased risk of RN. Tumors harboring BRAF mutation, or perhaps prior exposure to targeted agents, may increase this risk. Radiosurgical optimization to maintain V12 < 10 cm 3 is a potential strategy to reduce the risk of RN.

196 Background: Metastatic thyroid cancer portends a poor prognosis, especially in patients over the age of 55 or in more aggressive histologies, such as anaplastic. Palliative care (PC), which focuses on improving the quality of life in patients with severe disease, may be beneficial to these patients. To our knowledge, there has yet to be a study describing the demographic and usage factors associated with PC in metastatic thyroid cancer. Methods: We conducted a retrospective analysis of the National Cancer Database (NCDB) from 2004-2017 for subjects with metastatic thyroid cancer (n = 5,229) of all histologies. Analysis was completed between patients who utilized PC (n = 826) and patients who did not use PC (n = 4,403). The NCDB defines palliative care as care provided to alleviate or palliate symptoms, including radiation therapy, surgery, pain management, and/or systemic therapy. PC usage and survival were compared between cancer subtypes. Demographic factors were analyzed using Pearson chi-squared tests and t-tests, while survival was estimated using Kaplan-Meier curves. Results: Of the subjects with metastatic thyroid cancer, 50.6% had papillary, 25.2% had anaplastic, 15.9% had follicular, and 8.3% had medullary thyroid cancer. Anaplastic, medullary, follicular, and papillary metastatic cancers had median survivals of 2.4, 19.9, 49.5, and 55.3 months, respectively (p < 0.001). PC usage increased between 2004 (3.4%) and 2017 (11.4%) across all subtypes. The mean age at diagnosis of PC patients was 69.2 years old compared to 66.9 years old for non-PC patients (p < 0.001). Anaplastic thyroid cancer made up the greatest proportion of PC usage (42.5%) compared to other histologies (p < 0.001). Subjects of Spanish/Hispanic origin received PC at lower proportions (p < 0.001). In addition, Asian patients made up a smaller fraction of the PC cohort (4.2%) compared to the non-PC cohort (6.7%) (p = 0.028). Patients with private insurance made up a smaller proportion of PC users (26.5%) compared to non-PC users (35.6%), while subjects with government insurance or no insurance made up a greater proportion of PC usage (p < 0.001). Less PC usage was seen by patients who lived in an area where greater than 17.6% of individuals did not attain a high school degree; these patients made up 25.3% and 19.9% of the non-PC and PC cohorts, respectively (p = 0.006). Patients who received PC tended to live closer to the reporting hospital (p = 0.007). No statistically significant difference was seen between PC and non-PC cohorts for income and facility type. Conclusions: In this study, we highlighted several disparities in PC usage across common types of thyroid cancer. We also compared usage between categories and noted a greater proportion of PC usage in recent years. Our study is a valuable baseline as PC continues to be integrated in cancer care.

OBJECTIVE Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRICs) are a frequently observed clinical manifestation and are commonly classified as imaging-defined radiation necrosis. However, these findings are not well characterized and may predict a response to SRS and ICIs. The objective of this study was to investigate predictors of TRICs and their impact on patient survival. METHODS This retrospective multicenter cohort study was conducted through the International Radiosurgery Research Foundation. Member institutions submitted de-identified clinical and dosimetric data for patients with non–small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) brain metastases that had been treated with SRS and ICIs. Data were collected from March 2020 to February 2021. Univariable and multivariable Cox and logistic regression analyses were performed. The Kaplan-Meier method was used to evaluate overall survival (OS). The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRICs were determined on the basis of MRI, PET/CT, or MR spectroscopy, and consensus by local clinical providers was required. RESULTS The analysis included 697 patients with 4536 brain metastases across 11 international institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years (IQR 58–73 years), 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% of tumors were NSCLC, melanoma, and RCC, respectively. All patients had undergone single-fraction radiosurgery to a median margin dose of 20 Gy (IQR 18–20 Gy). TRICs were observed in 9.8% of patients. The median OS for all patients was 24.5 months. On univariable analysis, Karnofsky Performance Status (KPS; HR 0.98, p < 0.001), TRICs (HR 0.67, p = 0.03), female sex (HR 0.67, p < 0.001), and prior resection (HR 0.60, p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR 0.98, p < 0.001) and TRICs (HR 0.66, p = 0.03) were associated with improved OS. A brain volume receiving ≥ 12 Gy of radiation (V12Gy) ≥ 10 cm3 (OR 2.78, p < 0.001), prior whole-brain radiation therapy (OR 3.46, p = 0.006), and RCC histology (OR 3.10, p = 0.01) were associated with an increased probability of developing TRICs. The median OS rates in patients with and without TRICs were 29.0 and 23.1 months, respectively (p = 0.03, log-rank test). CONCLUSIONS TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study. Further prospective study and additional stratification are needed to validate these findings and further elucidate the role and etiology of this common clinical scenario.

BACKGROUNDPatients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited.METHODSRN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN.RESULTSFifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow‐up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole‐brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06‐42.38 cm3); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27‐111.22 cm3). Any‐grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01‐1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99‐1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17‐2.30; P = .76), prior WBRT, and ICI agents were not statistically significant.CONCLUSIONSSymptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single‐fraction SRS.

Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.

Abstract Pancreatic cancer is the fourth most common cause of cancer-related morality worldwide, and the prognosis remains poor despite aggressive therapy. Carbon ion radiotherapy has favorable radiobiological and physical characteristics in the treatment, including a higher linear energy transfer and higher relative biological effectiveness, which increase the cell kill while potentially reducing toxicities to nearby normal tissues. Although small, early clinical studies have shown promise in both the resectable and unresectable settings to improve local control and overall survival while minimizing toxicities. Currently, there are several trials, including 2 sponsored by institutions in the United States, investigating the role of carbon ion radiotherapy for the treatment of locally advanced pancreatic cancer.