Development of Brain Metastases in Patients With Non-Small Cell Lung Cancer and No Brain Metastases at Initial Staging Evaluation: Cumulative Incidence and Risk Factor Analysis.

BACKGROUND. Although established guidelines give indications for performing staging brain MRI at initial diagnosis of non-small cell lung cancer (NSCLC), guidelines are lacking for performing surveillance brain MRI for patients without brain metastases at presentation. OBJECTIVE. The purpose of this study is to estimate the cumulative incidence of and risk factors for brain metastasis development in patients with NSCLC without brain metastases at initial presentation. METHODS. This retrospective study included 1495 patients with NSCLC (mean [± SD] age, 65 ± 10 years; 920 men and 575 women) without brain metastases at initial evaluation that included brain MRI. Follow-up brain MRI was ordered at the discretion of the referring physicians. MRI examinations were reviewed in combination with clinical records for brain metastasis development; patients not undergoing MRI were deemed to have not had metastases develop through last clinical follow-up. The cumulative incidence of brain metastases was determined, with death considered a competing risk, and was stratified by clinical stage group, cell type, and epidermal growth factor receptor (EGFR) gene mutation status. Univariable and multivariable Cox proportional hazards regression analyses were performed. RESULTS. A total of 258 of 1495 patients (17.3%) underwent follow-up brain MRI, and 72 (4.8%) had brain metastases develop at a median of 12.3 months after initial diagnosis of NSCLC. Of the 72 patients who had metastases develop, 44.4% had no neurologic symptoms, and 58.3% had stable primary thoracic disease. The cumulative incidence of brain metastases at 6, 12, 18, and 24 months after initial evaluation was 0.6%, 2.1%, 4.2%, and 6.8%, respectively. Cumulative incidence at 6, 12, 18, and 24 months was higher (p < .001) in patients with clinical stage III-IV disease (1.3%, 3.9%, 7.7%, and 10.9%, respectively) than in those with clinical stage I-II disease (0.0%, 0.8%, 1.2%, and 2.6%, respectively), and it was higher (p < .001) in patients with EGFR mutation-positive adenocarcinoma (0.7%, 2.5%, 6.3%, and 12.3%, respectively) than in those with EGFR mutation-negative adenocarcinoma (0.4%, 1.8%, 2.9%, and 4.4%, respectively). Among 1109 patients with adenocarcinoma, independent risk factors for the development of brain metastasis were clinical stage III-IV (hazard ratio [HR], 9.39; p < .001) and EGFR mutation-positive status (HR, 1.78; p = .04). The incidence of brain metastasis over the study interval was 8.7% among patients with clinical stage III-IV disease and 17.4% among those with EGFR mutation-positive adenocarcinoma. CONCLUSION. Clinical stage III-IV and EGFR mutation-positive adenocarcinoma are independent risk factors for brain metastasis development. CLINICAL IMPACT. For patients with clinical stage III-IV disease or EGFR mutation-positive adenocarcinoma, surveillance brain MRI performed 12 months after initial evaluation may be warranted.

Diagnostic Yield of Staging Brain MRI in Patients with Newly Diagnosed Non-Small Cell Lung Cancer.

Background Existing guidelines are inconsistent regarding the indications for staging brain MRI in patients with newly diagnosed, early-stage non-small cell lung cancer (NSCLC). Purpose To evaluate the diagnostic yield of staging brain MRI in the initial evaluation of lung cancer. Materials and Methods This retrospective, observational, single-institution study included patients with newly diagnosed NSCLC who underwent staging chest CT and staging brain MRI from November 2017 to October 2018. Diagnostic yield was defined as the proportion of patients with brain metastases among all patients. Yield was stratified into clinical stage groups per the eighth edition of the American Joint Committee on Cancer staging guidelines, based on staging chest CT and in adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation and anaplastic lymphoma kinase (ALK) gene rearrangement. Subgroup analyses were performed on the basis of cell types and molecular markers. The χ2 test was performed to compare the diagnostic yields, and Bonferroni correction was used to account for multiple testing between stage groups. Results A total of 1712 patients (mean age, 64 years ± 10 [standard deviation]; 1035 men) were included. The diagnostic yield of staging brain MRI in newly diagnosed NSCLC was 11.9% (203 of 1712; 95% confidence interval [CI]: 10.4%, 13.5%). In clinical stage IA, IB, and II disease, the diagnostic yields were 0.3% (two of 615; 95% CI: 0.0%, 1.2%), 3.8% (seven of 186; 95% CI: 1.5%, 7.6%), and 4.7% (eight of 171; 95% CI: 2.0%, 9.0%), respectively. The diagnostic yield was higher in patients with adenocarcinoma (13.6%; 176 of 1297; 95% CI: 11.8%, 15.6%) than squamous cell carcinoma (5.9%; 21 of 354; 95% CI: 3.7%, 8.9%) and in patients with EGFR mutation-positive adenocarcinoma (17.5%; 85 of 487; 95% CI: 14.2%, 21.1%) than with EGFR mutation-negative adenocarcinoma (10.6%; 68 of 639; 95% CI: 8.4%, 13.3%) (P < .001 for both). Conclusion The diagnostic yield of staging brain MRI in clinical stage IA non-small cell lung cancer was low, but staging brain MRI had a higher diagnostic yield in clinical stage IB and epidermal growth factor receptor mutation-positive adenocarcinoma. © RSNA, 2020 Online supplemental material is available for this article.

Reevaluating stereotactic radiosurgery for glioblastoma: new potential for targeted dose-escalation.

Countless therapeutic strategies have been explored over many decades to prevent or slow the progression of glioblastoma. Despite radical changes in radiation management in other malignancies, there have been no major advances in the radiotherapeutic approach to glioblastoma in over 30 years. Past hopes to overcome inherent radioresistance with escalating doses have been met with frustration. However, prior clinical trials were performed before temozolomide, a radiosensitizer, altered the standard of care and this has renewed interest in dose escalation. Immunotherapy has led to further excitement, given the substantial responses that have been observed in other cancers when combined with high-dose radiation. In addition, advances in molecular profiling and neuroimaging have created new opportunities to improve patient selection for the most appropriate course of treatment. In this review, we outline past attempts to utilize radiosurgery in glioblastoma and focus on the potential to reintroduce this modality of dose escalation in the setting of modern and emerging systemic agents, molecular studies and imaging analyses.

Trends in the use of immunotherapy to treat soft tissue sarcoma.

BACKGROUND: The role of immune-oncology (IO) therapy in soft tissue sarcoma (STS) is underexplored. This study characterized IO use in STS. METHODS: This is a retrospective analysis of patients with a soft tissue mass in the National Cancer Database, 2011-2021. Patients were categorized by IO receipt status. Groupwise testing and proportional trend tests were performed with Chi-squared tests. Multivariate logistic regression was performed to assess factors associated with IO receipt. RESULTS: Of the 103,092 patients with STS, 1935 (1.9 â€‹%) received or were recommended IO therapy. IO use increased 10-fold (0.24 â€‹%-2.5 â€‹% from 2011 to 2021; p â€‹< â€‹0.0001). Patients had higher odds of receiving IO when having higher grade tumors and metastatic disease, and when treated at an academic research center (all p â€‹< â€‹0.001). CONCLUSIONS: IO use in STS is low but increasing and primarily used in the metastatic setting. Future studies should identify biomarkers of IO response and facilitators for treatment receipt.

Biochemical Safety of SBRT to Multiple Intrahepatic Lesions for Hepatocellular Carcinoma.

Background: We aim to better characterize stereotactic body radiation therapy (SBRT)-related hepatic biochemical toxicity in patients with multiple intrahepatic lesions from hepatocellular carcinoma (HCC). Methods: We conducted a retrospective analysis of patients with HCC who underwent SBRT for 2 or more synchronous or metachronous liver lesions. We collected patient characteristics and dosimetric data (mean liver dose [MLD], cumulative effective volume [Veff], cumulative volume of liver receiving 15 Gy [V15Gy], and cumulative planning target volume [PTV]) along with liver-related toxicity (measured by albumin-bilirubin [ALBI] and Child-Pugh [CP] scores). A linear mixed-effects model was used to assess the effect of multi-target SBRT on changes in ALBI. Results: There were 25 patients and 56 lesions with median follow-up of 29 months. Eleven patients had synchronous lesions, and 14 had recurrent lesions treated with separate SBRT courses. Among those receiving multiple SBRT courses, there were 7 lesions with overlap of V15Gy (median V15Gy overlap: 35 mL, range: 0.5-388 mL). There was no association between cumulative MLD, Veff, V15Gy, or PTV and change in ALBI. Four of 25 patients experienced non-classic radiation-induced liver disease (RILD), due to an increase of CP score by ≥2 points 3 to 6 months after SBRT. Sixteen of 25 patients experienced an increase in ALBI grade by 1 or more points 3 to 6 months after SBRT. Comparing the groups that received SBRT in a single course versus multiple courses revealed no statistically significant differences in liver toxicity. Conclusion: Liver SBRT for multiple lesions in a single or in separate courses is feasible and with acceptable risk of hepatotoxicity. Prospective studies with a larger cohort are needed to better characterize safety in this population.

Defining Minimum Treatment Parameters of Ablative Radiation Therapy in Patients With Hepatocellular Carcinoma: An Expert Consensus.

PURPOSE: External beam radiation therapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, the Barcelona Clinic Liver Cancer system does not recommend the use of EBRT in HCC due to a lack of sufficient evidence and intends to perform an individual patient level meta-analysis of ablative EBRT in this population. However, there are many types of EBRT described in the literature with no formal definition of what constitutes "ablative." Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. METHODS AND MATERIALS: Fundamental parameters related to dose, fractionation, radiobiology, target identification, and delivery technique were identified by a steering committee to generate 7 Key Criteria (KC) that would define ablative EBRT for HCC. Using a modified Delphi (mDelphi) method, experts in the use of EBRT in the treatment of HCC were surveyed. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥70% was used to define consensus for answers to each KC. RESULTS: Of 40 invitations extended, 35 (88%) returned responses. In the first round, 3 of 7 KC reached consensus. In the second round, 100% returned responses and consensus was reached in 3 of the remaining 4 KC. The distribution of answers for one KC, which queried the a/b ratio of HCC, was such that consensus was not achieved. Based on this analysis, ablative EBRT for HCC was defined as a BED10 ≥80 Gy with daily imaging and multiphasic contrast used for target delineation. Treatment breaks (eg, for adaptive EBRT) are allowed, but the total treatment time should be ≤6 weeks. Equivalent dose when treating with protons should use a conversion factor of 1.1, but there is no single conversion factor for carbon ions. CONCLUSIONS: Using a mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empirical data are required to define the a/b of HCC.

Outcomes of surgical resection and intraoperative electron radiotherapy for patients with para-aortic recurrences of gastrointestinal and gynecologic malignancies.

BACKGROUND: Para-aortic lymph node (PALN) metastases from primary pelvic malignancies are often treated with resection, but recurrence is common. We report toxicity and oncologic outcomes for patients with PALN metastases from gastrointestinal and gynecologic malignancies treated with resection and intraoperative electron radiotherapy (IORT). METHODS: We retrospectively identified patients with recurrent PALN metastases who underwent resection with IORT. All patients were included in the local recurrence (LR) and toxicity analyses. Only patients with primary colorectal tumors were included in the survival analysis. RESULTS: There were 26 patients with a median follow up of 10.4 months. The rate of para-aortic local control (LC) was 77% (20/26 patients) and the rate of any cancer recurrence was 58% (15/26 patients). Median time from surgery and IORT to any recurrence was 7 months. The LR rate for those with positive/close margins was 58% (7/12 patients) versus 7% (1/14 patients) for those with negative margins (p = 0.009). 15% (4/26 patients) developed surgical wound and/or infectious complications, 8% (2/26 patients) developed lower extremity edema, 8% (2/26 patients) experienced diarrhea, and 19% (5/26 patients) developed an acute kidney injury. There were no reported nerve injuries, bowel perforations, or bowel obstructions. For patients with primary colorectal tumors (n = 19), the median survival (OS) was 23 months. CONCLUSIONS: We report favorable LC and acceptable toxicity for patients receiving surgical resection and IORT for a population that has historically poor outcomes. Our data show disease control rates similar to literature comparisons for patients with strong risk factors for LR, such as positive/close margins.

Patient-reported symptoms and interest in symptom monitoring in HCC treated with locoregional therapies: A qualitative study.

BACKGROUND: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system. METHODS: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes. RESULTS: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring. CONCLUSIONS: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC.

Thermal ablation compared to stereotactic body radiation therapy for hepatocellular carcinoma: A multicenter retrospective comparative study.

BACKGROUND AIMS: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort. APPROACH RESULTS: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15-0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13-4.73) and death (aHR 2.04, 95% CI: 1.44-2.88, p < 0.0001). CONCLUSIONS: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.

Practical Challenges of Mask-to-Mask Encounters with Patients with Head and Neck Cancers amid the Coronavirus Disease 2019 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has forced a re-design of care in radiation oncology. Perhaps more than any other disease site we commonly see, the evaluation and treatment of head and neck cancer has posed the greatest risk of COVID-19 transmission between patients and radiotherapy providers. In our early experience with the novel coronavirus, several staff members were exposed to a COVID-positive patient and this caused us to devise policies and procedures to mitigate further risk in a way that could practically be employed across a large health system while not compromising care delivery. Here, we formulate a concise summary of simple steps, including a novel thermoplastic mask fitting technique and procedures for intraoral immobilization devices, to guide practices and provide new layers of protection for both patients and staff.

Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging.

Alternating electric fields have been successfully applied to cancer cells in-vitro to disrupt malignant progression and this antimitotic therapy has now been proven to be efficacious in Phase II and Phase III randomized clinical trials of patients with glioblastoma. With additional clinical trials ongoing in a number of other malignancies, there is a crucial need for a better understanding of the radiographic predictors of response and standardization of surveillance imaging interpretation. However, many radiologists have yet to become familiarized with this emerging cancer therapy and there is little active investigation to develop prognostic or predictive imaging biomarkers. This article provides an overview of the pre-clinical data that elucidate the biologic mechanisms of alternating electric fields as a cancer therapy. Results from clinical trials in patients with glioblastoma are then reviewed while elaborating on the several limitations to adoption of this promising line of treatment. Finally, a proposal for the development of imaging markers as a means of overcoming some of these limitations is made, which may improve treatment utilization by augmenting patient selection not only in glioblastoma, but also other malignant conditions for which this therapy is currently being evaluated.

Challenging AJCC 8 Staging for Soft Tissue Sarcoma Using the NCDB.

PURPOSE: To determine whether the new American Joint Committee on Cancer (AJCC) 8 grouping of soft tissue sarcoma (STS) with nodal disease (N1M0) and metastatic disease (M1) as stage IV correctly represents the prognosis of these previously separate patient groups, using the National Cancer Database. METHODS AND MATERIALS: Adults with STS identified in the 2004 to 2014 National Cancer Database, classified by the World Health Organization 2013 system into 10 histologic subgroups, were grouped according to AJCC 8 staging and analyzed according to demographic characteristics, histology, primary site, disease extent, and adjuvant treatment. Primary retroperitoneal sites, "other/unusual" histologic subgroups, and those with delays in therapy (>180 days from diagnosis) were excluded. We used χ2 tests, Cox proportional hazard models, and propensity-score matched analyses. RESULTS: Of 82,987 patients identified, 55,417 met inclusion criteria; 29,855 (53.9%) were male, and 25,262 (46.1%) were female. Median age was 60 years (range, 18-90 years). Overall survival (OS) of STS of all sites was significantly different between N1M0 and N0-1M1 patients at 5 years (34.4%; [95% confidence interval {CI}, 30.1%-38.8%] vs 10.1% [95% CI, 9%-11%], respectively) and 10 years (27.3% [95% CI, 22.5%- 32.2%] vs 5.4% [95% CI, 4.5%-6.5%], respectively; log-rank test, P < .001). For STS of trunk and extremities in N1M0 and N0-1M1 patients, the N1M0 cohort was associated with significantly greater OS on multivariate Cox proportional hazards models (hazard ratio, 0.48; 95% CI, 0.41-0.58; P < .001), and this OS difference remained significant for propensity-matched cohorts of all primary sites (HR, 0.53; 95% CI, 0.44-0.64; P < .001). CONCLUSIONS: In adult STS, including those of the trunk and extremity, OS is superior with N1M0 compared with N0-1M1 disease. These results suggest that the AJCC 8th edition grouping of N1 and M1 patients into stage IV may obscure the more favorable prognosis of patients with N1M0 disease.

The effect of brain metastasis location on clinical outcomes: A review of the literature.

It is common clinical practice to consider the location of a brain metastasis when making decisions regarding local therapies and, in some scenarios, estimating clinical outcomes, such as local disease control and patient survival. However, the location of a brain metastasis is not included in any validated prognostic nomogram and it is unclear if this is due to a lack of a relationship or a lack of support from published data. We performed a comprehensive review of the literature focusing on studies that have investigated a relationship between brain metastasis location and clinical outcomes, including patient survival. The vast majority of reports anatomically categorized brain metastases as supratentorial or infratentorial whereas some reports also considered other subdivisions of the brain, including different lobes or with particular areas defined as eloquent cortex. Results were variable across studies, with some finding a relationship between metastasis location and survival, but the majority finding either no relationship or a weak correlation that was not significant in the context of multivariable analysis. Here, we highlight the key findings and limitations of many studies, including how neurosurgical resection might influence the relative importance of metastasis location and in what ways future analyses may improve anatomical categorization and resection status.

A low percentage of metastases in deep brain and temporal lobe structures.

BACKGROUND: Whole-brain radiotherapy (WBRT) in patients with brain metastases (BM) is associated with neurocognitive decline. Given its crucial role in learning and memory, efforts to mitigate this toxicity have mostly focused on sparing radiation to the hippocampus. We hypothesized that BM are not evenly distributed across the brain and that several additional areas may be avoided in WBRT based on a low risk of developing BM. METHODS: We contoured 2757 lesions in a large, single-institution database of patients with newly diagnosed BM. BM centroids were mapped onto a standard brain atlas of 55 anatomic subunits and the observed percentage of BM was compared with what would be expected based on that region's volume. A region of interest (ROI) analysis was performed in a validation cohort of patients from 2 independent institutions using equivalence and one-sample hypothesis tests. RESULTS: The brainstem and bilateral thalami, hippocampi, parahippocampal gyri, amygdala, and temporal poles had a cumulative risk of harboring a BM centroid of 4.83% in the initial cohort. This ROI was tested in 157 patients from the validation cohort and was found to have a 4.1% risk of developing BM, which was statistically equivalent between the 2 groups (P < 1 × 10-6, upper bound). CONCLUSION: Several critical brain structures are at a low risk of developing BM. A risk-adapted approach to WBRT is worthy of further investigation and may mitigate the toxicities of conventional radiation.

Quantitative Analysis of the Spatial Distribution of Metastatic Brain Lesions.

Brain metastases (BMs) are the most common intracranial malignancy and afflict ~10%-20% of patients with cancer. BMs tend to present at the boundaries of gray and white matter because of the distribution of small vessels. In addition, metastases may not be randomly distributed across gross anatomical regions of the brain, but this has not previously been quantified. We retrospectively analyzed a series of 28 patients with recurrent BMs with a total of 150 lesions. Each lesion was manually defined based on T1 gadolinium-enhanced imaging. Standard brain atlases were used to identify the anatomical brain region affected by each BM and the frequency of metastases in each region was compared with the expected probability, which was assumed to be a random distribution based on the brain volume. After correction for multiple comparisons, the paracingulate gyrus was found to have a statistically significant increase (P = 4.731 × 10-9) in the rate of BMs relative to the random spatial distribution. A nonstochastic spatial distribution of metastases may be used to guide partial brain radiotherapy with risk-adapted dose delivery and reduce the risk of neurotoxicity due to overtreatment.