Trifiletti, Daniel M.

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.

Abstract AIMS In patients with newly-diagnosed glioblastoma, rapid early progression (REP) refers to tumour regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis aimed to appraise published data on REP to better characterise and understand this phenomenon. METHOD Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to 21/10/21. Studies describing the incidence of REP – tumour growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly-diagnosed glioblastoma, were included. The primary outcome was REP incidence. RESULTS From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0- 58.8 years). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1-1.5). The median number of days between MRI scans was 34 days (IQR 18-45 days). The mean incidence rate of REP was 45.9% (range 19.3%-72.0%) and significantly lower in studies employing functional imaging to define REP (p&lt;0.001). REP/non-REP groups were comparable with respect to age (p=0.99), gender (p=0.33) and time between scans (p=0.81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30-2.43, p&lt;0.001), shortened progression-free survival (HR 1.78, 95% CI 1.30-2.43, p&lt;0.001), subtotal resection (OR 6.96, 95% CI 4-51-10.73, p&lt;0.001) and IDH wildtype versus mutant tumours (OR 0.20, 95% CI 0.02-0.38, p=0.03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72-2.28, p=0.39). CONCLUSION REP occurs in almost half of patients with newly-diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.

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.

Brain metastases are a devastating sequela of common primary cancers (e.g., lung, breast, and skin) and have limited effective therapeutic options. Previously, systemic chemotherapy failed to demonstrate significant benefit in patients with brain metastases, but in recent decades, targeted therapies and more recently immune checkpoint inhibitors (ICIs) have yielded promising results in preclinical and clinical studies. Furthermore, there is significant interest in harnessing the immunomodulatory effects of radiotherapy (RT) to synergize with ICIs. Herein, we discuss studies evaluating the impact of RT dose and fractionation on the immune response, early studies supporting the synergistic interaction between RT and ICIs, and ongoing clinical trials assessing the benefit of combination therapy in patients with brain metastases.

BackgroundPatients with high‐risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost.MethodsThe authors compared quality‐adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external‐beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low‐dose‐rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479).ResultsTreatment strategies were compared using the incremental cost‐effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost‐effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost‐effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost.ConclusionsEBRT with LDR brachytherapy boost may be a cost‐effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high‐value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost‐effective care, despite no change in overall survival.

Abstract INTRODUCTION Glioblastomas (GBMs) are highly aggressive tumors. Despite multimodal treatment, its median overall survival ranges between 16 and 20 months. The standard treatment regimen consists of surgical resection followed by concurrent chemoradiotherapy and adjuvant temozolomide. Despite temozolomide’s effectiveness, it may cause the clinical challenge of treatment-related progression also known as pseudoprogression(PsP). Usually, PSP resolves or stabilizes without further treatment, whereas a true progression (TP) requires more aggressive management. Identifying PSP from TP will affect the patient’s treatment plan. Conventional magnetic resonance imaging (MRI) reading techniques cannot distinguish these entities. This study investigated the feasibility of using deep learning to distinguish PsP from TP. METHOD We included GBM patients who met our inclusion criteria. We evaluated all cases to see if they had a new enhancing lesion within the original radiation field or an increase in the size of an existing lesion. The challenging MRIs were collected. Clinical notes regarding tumor and recurrence location, clinical history, and medication were collected. We labeled the ones who stayed stable or improved in the imaging and clinical situation as PSP and those with further imaging and clinical deterioration as TP. We coregistered Contrast-enhanced-T1 MRIs with T2-weighted images for each patient. We performed five-fold cross-validation to generalize the performance. We trained A 3-D Densenet121 model to establish the prediction. We selected the best models with the highest accuracy. RESULT After reviewing 1000 patients, we included 124 patients whose imaging showed suspicious progression and their medicational histories were completely retrievable; 63 PsP, and 61 TP. We developed a deep learning model based on the whole dataset. The 5-fold cross-validation revealed that the mean area under the curve (AUC) was 0.81. CONCLUSION We report the development of a deep learning model that diagnoses PsP from TP in patients who received temozolomide. Further refinement and external validation are required prior to widespread adoption in clinical practice.

Abstract Background Global incidence for brain tumors varies substantially without explanation. Studies correlating radon exposure and incidence are inconclusive. Particulate pollution has been linked to increased tumor incidence. Particulates may disrupt the blood-brain barrier allowing intracranial exposure to oncogenic radon. We investigated the relationship between exposure to residential radon, particulate pollution, and brain tumor incidence in the United States (US). Methods County-level median radon testing results and annual air quality index values were obtained and divided into tertiles. Counties without both values were excluded. Four groups of counties were generated: high particulate/high radon (high/high), high/low, low/high, and low/low. Using incidence data from the Central Brain Tumor Registry of the US (provided by CDC’s National Program of Cancer Registries and NCI’s SEER), annual age-adjusted incidence rates (AAAIRs) by group were generated by behavior. Incidence rate ratios were calculated to examine for significant differences (α = .05). Poisson regression accounting for possible confounders was conducted. Results Counties with available data included 83% of the US population. High/high exposure was significantly associated with increased AAAIR of all non-malignant tumors (up to 26% higher, including most meningiomas) even after accounting for potential confounders. An increased AAAIR was noted for all malignant tumors (up to 10% higher), including glioblastoma, but was negated after accounting for demographic/socioeconomic differences. Conclusions We present the first report suggesting increased non-malignant brain tumor incidence in regions with high particulate and radon exposure. These findings provide insight into unexplained variation in tumor incidence. Future studies are needed to validate these findings in other populations.

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

Abstract Background In patients with newly diagnosed glioblastoma, rapid early progression (REP) refers to tumor regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised previously published data on REP to better characterize and understand it. Methods Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to October 21, 2021. Studies describing the incidence of REP—tumor growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly diagnosed glioblastoma were included. The primary outcome was REP incidence. Results From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0–58.8 y). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1–1.5). The median number of days between MRI scans was 34 days (IQR 18–45 days). The mean incidence rate of REP was 45.9% (range 19.3%–72.0%) and significantly lower in studies employing functional imaging to define REP (P &lt; .001). REP/non-REP groups were comparable with respect to age (P = .99), gender (P = .33) and time between scans (P = .81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30–2.43, P &lt; .001), shortened progression-free survival (HR 1.78, 95% CI 1.30–2.43, P &lt; .001), subtotal resection (OR 6.96, 95% CI 4.51–10.73, P &lt; .001) and IDH wild-type versus mutant tumors (OR 0.20, 95% CI 0.02–0.38, P = .03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72–2.28, P = .39). Conclusions REP occurs in almost half of patients with newly diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.