Dose-Volume Predictors of Radiation Pneumonitis After Thoracic Hypofractionated Radiation Therapy.

PURPOSE: Hypofractionated radiation therapy (HFRT) is a common treatment for thoracic tumors, typically delivered as 60 Gy in 15 fractions. We aimed to identify dosimetric risk factors associated with radiation pneumonitis in patients receiving HFRT at 4 Gy per fraction, focusing on lung V20, mean lung dose (MLD), and lung V5 as potential predictors of grade ≥2 pneumonitis. METHODS AND MATERIALS: All patients were treated with thoracic HFRT to 60 Gy in 15 fractions or 72 Gy in 18 fractions at a single health care system from 2013 to 2020. Tumors near critical structures (trachea, proximal tracheobronchial tree, esophagus, spinal cord, or heart) were considered central (within 2 cm), and those closer were classified as ultracentral (within 1 cm). The primary endpoint was grade ≥2 pneumonitis. Logistic regression analyses, adjusting for target size and dosimetric variables, were used to establish a dose threshold associated with <20% risk of grade ≥2 pneumonitis. RESULTS: During a median 24.3-month follow-up, 18 patients (16.8%) developed grade ≥2 radiation pneumonitis, with no significant difference between the 2 dose regimens (17.3% vs 16.3%, P = .88). Four patients (3.7%) experienced grade ≥3 pneumonitis, including 2 grade 5 cases. Patients with grade ≥2 pneumonitis had significantly higher lung V20 (mean 23.4% vs 14.5%, P < .001), MLD (mean 13.0 Gy vs 9.5 Gy, P < .001), and lung V5 (mean 49.6% vs 40.6%, P = .01). Dose thresholds for a 20% risk of grade ≥2 pneumonitis were lung V20 <17.7%, MLD <10.6 Gy, and V5 <41.3%. Multivariable analysis revealed a significant association between lung V20 and grade ≥2 pneumonitis (adjusted odds ratio, 1.48, P = .03). CONCLUSIONS: To minimize the risk of grade ≥2 radiation pneumonitis when delivering 4 Gy per fraction at either 60 Gy or 72 Gy, it is advisable to maintain lung V20<17.7%. MLD <10.6 Gy and V5<41.3% can also be considered as lower-priority constraints. However, additional validation is necessary before incorporating these constraints into clinical practice or trial planning guidelines.

Stereotactic ablative radiotherapy for primary renal cell carcinoma.

Stereotactic ablative radiotherapy (SAbR) is an emerging non-invasive definitive treatment option for primary renal cell carcinoma (RCC), particularly when surgery is not ideal. Employing ablative doses, SAbR delivered in one to five fractions to the primary tumor has been shown to achieve high local control rates with favorable toxicity profile in multiple retrospective and prospective series, and has dispelled previous notions of RCC radio-resistance. Moreover, emerging evidence suggests possible immunomodulatory effects, leading to clinical investigations of SAbR in combination with systemic and surgical management in patients with metastatic disease. In this review, we summarize key evidence supporting SAbR delivered to the primary tumor including preclinical rationale, dose escalation studies, recent prospective trials, and outcomes from ongoing multi-institutional registries. We also discuss areas of active clinical investigation including the use of primary SAbR in combination with systemic therapies in patients with metastatic disease. The accumulated body of evidence supports SAbR as promising indication being increasingly incorporated into the multi-disciplinary management of primary RCC.

Comparing Detection Schemes for Adversarial Images against Deep Learning Models for Cancer Imaging.

Deep learning (DL) models have demonstrated state-of-the-art performance in the classification of diagnostic imaging in oncology. However, DL models for medical images can be compromised by adversarial images, where pixel values of input images are manipulated to deceive the DL model. To address this limitation, our study investigates the detectability of adversarial images in oncology using multiple detection schemes. Experiments were conducted on thoracic computed tomography (CT) scans, mammography, and brain magnetic resonance imaging (MRI). For each dataset we trained a convolutional neural network to classify the presence or absence of malignancy. We trained five DL and machine learning (ML)-based detection models and tested their performance in detecting adversarial images. Adversarial images generated using projected gradient descent (PGD) with a perturbation size of 0.004 were detected by the ResNet detection model with an accuracy of 100% for CT, 100% for mammogram, and 90.0% for MRI. Overall, adversarial images were detected with high accuracy in settings where adversarial perturbation was above set thresholds. Adversarial detection should be considered alongside adversarial training as a defense technique to protect DL models for cancer imaging classification from the threat of adversarial images.

Factors associated with the use of adjuvant radiation therapy in stage III melanoma.

Objective: The role of radiation therapy (RT) in melanoma has historically been limited to palliative care, with surgery as the primary treatment modality. However, adjuvant RT can be a powerful tool in certain cases and its application in melanoma has been increasingly explored in recent years. The aim of this study is to explore national patterns of care and associations surrounding the use of adjuvant RT for stage III melanoma. Methods: The National Cancer Data Base (NCDB) was used to identify patients who were diagnosed with stage III melanoma between 2004 and 2014. Exclusion criteria included those with distant metastatic disease, in-situ histology, no confirmed positive nodes, palliative intent therapy, and dosing regimens inconsistent with National Comprehensive Cancer Network (NCCN) guidelines for adjuvant RT in melanoma. Patients treated with and without adjuvant RT were compared and factors associated with use of adjuvant RT were identified using multivariable logistic regression analyses. Results: A total of 7,758 cases of stage III melanoma were analyzed, of which 11.7% received adjuvant RT. The mean age of the overall cohort was 58.5 years, and the majority of patients were male (64.7%), white (96.6%), on private insurance (51.3%), and presented to a non-high-volume facility (90.3%). Multivariable regression analyses revealed that patients who present to the hospital in 2009-2014 as compared to 2004-2008 (odds ratio [OR] 1.61, 95% confidence interval [CI] 1.36-1.92), had 4 or more positive nodes (OR 4.30, 95% CI 3.67-5.04), and had microscopic residual tumor (OR 2.11, 95% CI 1.46-3.04) were more likely to receive adjuvant RT. Factors that were negatively associated with receiving adjuvant RT included female gender (OR 0.72, 95% CI 0.61-0.85) and median income of at least $63,000 (OR 0.66, 95% CI 0.52-0.83). Conclusions: This study demonstrates the rising use of RT for stage III melanoma in recent years and identifies demographic, social, clinical, and hospital-specific factors associated with patients receiving adjuvant RT. Further investigation is needed to explore disease benefits to improve guidance on the utilization of RT in melanoma.

Factors Associated With In-Hospital Mortality in Mycosis Fungoides Patients: A Multivariable Analysis.

Background Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Although it often has an indolent course, it can progress to more aggressive CTCL forms. There is sparse data in current literature describing specific clinical factors associated with in-hospital mortality in mycosis fungoides patients. An understanding of patients at greatest risk for in-hospital mortality can aid in developing recommendations for prophylaxis and empirical management. Aim We aim to characterize factors associated with in-hospital mortality in MF patients. Materials and methods The Nationwide Emergency Department Sample (NEDS) was queried for MF cases from 2006 to 2015. Baseline demographic and hospital characteristics were stratified based on survival outcomes. Multivariable logistic regression was used to identify factors associated with in-hospital mortality. Results A total of 57,665 patients with MF presenting to the ED between 2006 and 2015 were identified. Sézary syndrome, sepsis, and advanced age were associated with MF in-hospital mortality, while female sex was inversely associated. There was a downtrend in in-hospital mortality among MF patients presenting to the ED from 2006 to 2015. Conclusions Our study highlights factors crucial for risk-stratification for hospitalized MF patients.

Using Adversarial Images to Assess the Robustness of Deep Learning Models Trained on Diagnostic Images in Oncology.

PURPOSE: Deep learning (DL) models have rapidly become a popular and cost-effective tool for image classification within oncology. A major limitation of DL models is their vulnerability to adversarial images, manipulated input images designed to cause misclassifications by DL models. The purpose of the study is to investigate the robustness of DL models trained on diagnostic images using adversarial images and explore the utility of an iterative adversarial training approach to improve the robustness of DL models against adversarial images. METHODS: We examined the impact of adversarial images on the classification accuracies of DL models trained to classify cancerous lesions across three common oncologic imaging modalities. The computed tomography (CT) model was trained to classify malignant lung nodules. The mammogram model was trained to classify malignant breast lesions. The magnetic resonance imaging (MRI) model was trained to classify brain metastases. RESULTS: Oncologic images showed instability to small pixel-level changes. A pixel-level perturbation of 0.004 (for pixels normalized to the range between 0 and 1) resulted in most oncologic images to be misclassified (CT 25.6%, mammogram 23.9%, and MRI 6.4% accuracy). Adversarial training improved the stability and robustness of DL models trained on oncologic images compared with naive models ([CT 67.7% v 26.9%], mammogram [63.4% vs 27.7%], and MRI [87.2% vs 24.3%]). CONCLUSION: DL models naively trained on oncologic images exhibited dramatic instability to small pixel-level changes resulting in substantial decreases in accuracy. Adversarial training techniques improved the stability and robustness of DL models to such pixel-level changes. Before clinical implementation, adversarial training should be considered to proposed DL models to improve overall performance and safety.

Prevalence of Missing Data in the National Cancer Database and Association With Overall Survival.

Importance: Cancer registries are important real-world data sources consisting of data abstraction from the medical record; however, patients with unknown or missing data are underrepresented in studies that use such data sources. Objective: To assess the prevalence of missing data and its association with overall survival among patients with cancer. Design, Setting, and Participants: In this retrospective cohort study, all variables within the National Cancer Database were reviewed for missing or unknown values for patients with the 3 most common cancers in the US who received diagnoses from January 1, 2006, to December 31, 2015. The prevalence of patient records with missing data and the association with overall survival were assessed. Data analysis was performed from February to August 2020. Exposures: Any missing data field within a patient record among 63 variables of interest from more than 130 total variables in the National Cancer Database. Main Outcomes and Measures: Prevalence of missing data in the medical records of patients with cancer and associated 2-year overall survival. Results: A total of 1 198 749 patients with non-small cell lung cancer (mean [SD] age, 68.5 [10.9] years; 628 811 men [52.5%]), 2 120 775 patients with breast cancer (mean [SD] age, 61.0 [13.3] years; 2 101 758 women [99.1%]), and 1 158 635 patients with prostate cancer (mean [SD] age, 65.2 [9.0] years; 100% men) were included in the analysis. Among those with non-small cell lung cancer, 851 295 patients (71.0%) were missing data for variables of interest; 2-year overall survival was 33.2% for patients with missing data and 51.6% for patients with complete data (P < .001). Among those with breast cancer, 1 161 096 patients (54.7%) were missing data for variables of interest; 2-year overall survival was 93.2% for patients with missing data and 93.9% for patients with complete data (P < .001). Among those with prostate cancer, 460 167 patients (39.7%) were missing data for variables of interest; 2-year overall survival was 91.0% for patients with missing data and 95.6% for patients with complete data (P < .001). Conclusions and Relevance: This study found that within a large cancer registry-based real-world data source, there was a high prevalence of missing data that were unable to be ascertained from the medical record. The prevalence of missing data among patients with cancer was associated with heterogeneous differences in overall survival. Improvements in documentation and data quality are necessary to make optimal use of real-world data for clinical advancements.

Temporal Trends in Opioid Prescribing Patterns Among Oncologists in the Medicare Population.

BACKGROUND: In the wake of the US opioid epidemic, there have been efforts to curb opioid prescribing. However, it is unknown whether these efforts have affected prescribing among oncologists, whose patients often require opioids for symptom management. We investigated temporal patterns in opioid prescribing for Medicare beneficiaries among oncologists and nononcologists. METHODS: We queried the Centers for Medicare and Medicaid Services Part D prescriber dataset for all physicians between January 1, 2013, and December 31, 2017. We used population-averaged multivariable negative binomial regression to estimate the association between time and per-provider opioid and gabapentinoid prescribing rate, defined as the annual number of drug claims (original prescriptions and refills) per beneficiary, among oncologists and nononcologists on a national and state level. RESULTS: From 2013 to 2017, the national opioid-prescribing rate declined by 20.7% (P < .001) among oncologists and 22.8% (P < .001) among non oncologists. During this time frame, prescribing of gabapentin increased by 5.9% (P < .001) and 23.1% (P < .001) among oncologists and nononcologists, respectively. Among palliative care providers, opioid prescribe increased by 15.3% (P < .001). During the 5-year period, 43 states experienced a decrease (P < .05) in opioid prescribing among oncologists, and in 5 states, opioid prescribing decreased more among oncologists than nononcologists (P < .05). CONCLUSIONS: Between 2013 and 2017, the opioid-prescribing rate statistically significantly decreased nationwide among oncologists and nononcologists, respectively. Given similar declines in opioid prescribing among oncologists and nononcologists, there is concern that opioid-prescribing guidelines intended for the noncancer population are being applied inappropriately to patients with cancer and cancer survivors.

Radiation Dose to the Rectum With Definitive Radiation Therapy and Hydrogel Spacer Versus Postprostatectomy Radiation Therapy.

PURPOSE: Management options for localized prostate cancer include definitive radiation therapy (RT) or radical prostatectomy, with a subset of surgical patients requiring adjuvant or salvage RT after prostatectomy. The use of a peri-rectal hydrogel spacer in patients receiving definitive RT has been shown to reduce rectal doses and toxicity. However, in the postprostatectomy setting, a hydrogel spacer cannot be routinely placed. Therefore, we sought to compare rectal dosimetry between definitive RT with a hydrogel spacer versus postoperative RT. METHODS AND MATERIALS: We identified patients with prostate cancer who underwent conventionally fractionated RT. Rectal dosimetry was evaluated between 2 groups: definitive RT with a hydrogel spacer (79.2 Gy, group 1) and postoperative RT (70.2 Gy, group 2). Rectal dosimetry values were tabulated and compared using Mann-Whitney U test. We implemented a Bonferroni correction to account for multiple comparisons (threshold P < .005). Linear regression analysis evaluated predictors of candidate rectal dose-volume parameters. RESULTS: We identified 51 patients treated during years 2017 to 2018; 16 (31%) and 35 (69%) patients were included in groups 1 and 2, respectively. The rectal volume receiving ≥65 Gy (V65) was significantly lower in group 1 (median, 2.1%; interquartile range, 0.9%-3.1%) than in group 2 (10.7%, 6.6%-14.5%) (P < .001). Use of a hydrogel spacer in the definitive setting was independently associated with lower V65 (P < .001). Similar results were found for V60, V55, V50, and V45 (P < .005 for all). CONCLUSIONS: Rectal dosimetry is more favorable for definitive RT (79.2 Gy) with a hydrogel spacer compared with postoperative RT (70.2 or 66.6 Gy). This may inform shared decision-making regarding primary management of prostate cancer, especially among patients at high risk of needing postoperative RT after prostatectomy.

National Patterns in Prescription Opioid Use and Misuse Among Cancer Survivors in the United States.

Importance: Prescription opioids are frequently prescribed to treat cancer-related pain. However, limited information exists regarding rates of prescription opioid use and misuse in populations with cancer. Objectives: To estimate the prevalence and likelihood of prescription opioid use and misuse in adult cancer survivors compared with respondents without cancer and to identify characteristics associated with prescription opioid use and misuse in adult cancer survivors. Design, Setting, and Participants: This cross-sectional study is a retrospective, population-based study using data from 169 162 respondents to the National Survey on Drug Use and Health from January 2015 to December 2018. Survey data sets were queried for all respondents aged 18 years or older. Those with a reported history of cancer were termed cancer survivors and further divided into more recent (had cancer within 12 months of survey) and less recent (had cancer more than 12 months prior to survey) cohorts. Respondents with nonmelanoma skin cancer were excluded. Main Outcomes and Measures: Prescription opioid use and misuse within the past 12 months. Results: Among 169 162 respondents, 5139 (5.2%) were cancer survivors, with 1243 (1.2%) and 3896 (4.0%) reporting having more recent and less recent cancer histories, respectively. Higher rates of prescription opioid use were observed among more recent cancer survivors (54.3%; 95% CI, 50.2%-58.4%; odds ratio [OR], 1.86; 95% CI, 1.57-2.20; P < .001) and less recent cancer survivors (39.2%; 95% CI, 37.3%-41.2%; OR, 1.18; 95% CI, 1.08-1.28; P < .001) compared with respondents without cancer (30.5%, reference group). Rates of prescription opioid misuse were similar among more recent (3.5%; 95% CI, 2.4%-5.2%; OR, 1.27; 95% CI, 0.82-1.96; P = .36) and less recent (3.0%; 95% CI, 2.4%-3.6%; OR, 1.03; 95% CI, 0.83-1.28; P = .76) survivors compared with respondents without cancer (4.3%, reference group). Younger age (aged 18-34 years vs ≥65 years: OR, 7.06; 95% CI, 3.03-16.41; P < .001), alcohol use disorder (OR, 3.22; 95% CI, 1.45-7.14; P = .005), and nonopioid drug use disorder (OR, 14.76; 95% CI, 7.40-29.44; P < .001) were associated with prescription opioid misuse among cancer survivors. Conclusions and Relevance: In this study, prescription opioid use was higher among more and less recent cancer survivors compared with the population without a history of cancer. Rates of prescription opioid misuse were low and similar among all 3 cohorts. These findings suggest that higher prescription opioid use among cancer survivors may not correspond to increased short-term or long-term misuse.

Geographic-Level Association of Contemporary Changes in Localized and Metastatic Prostate Cancer Incidence in the Era of Decreasing PSA Screening.

Decreased prostate-specific antigen screening since 2008 has generated much concern, including report of recent increase in metastatic prostate cancer incidence among older men. Although increased metastatic disease was temporally proceeded by decreased screening and decreased localized prostate cancer at diagnosis, it is unclear whether the 2 trends are geographically connected. We therefore used the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database to assess geographic-specific associations between changes in localized (2008-2011) and later changes in metastatic prostate cancer incidence (2012-2015). We examined trends from 200 health-care service areas (HSAs) within SEER 18 registries. While on average for each HSA, localized incidence decreased by 27.4 and metastatic incidence increased by 2.3 per 100 000 men per year, individual HSA-level changes in localized incidence did not correlate with later changes in metastatic disease. Decreased detection of localized disease may not fully explain the recent increase in metastatic disease at diagnosis.

Emergency Department Visits for Opioid Overdoses Among Patients With Cancer.

BACKGROUND: Patients with cancer may be at risk of high opioid use due to physical and psychosocial factors, although little data exist to inform providers and policymakers. Our aim is to examine overdoses from opioids leading to emergency department (ED) visits among patients with cancer in the United States. METHODS: The Healthcare Cost and Utilization Project Nationwide Emergency Department Sample was queried for all adult cancer-related patient visits with a primary diagnosis of opioid overdose between 2006 and 2015. Temporal trends and baseline differences between patients with and without opioid-related ED visits were evaluated. Multivariable logistic regression analysis was used to identify risk factors associated with opioid overdose. All statistical tests were two-sided. RESULTS: Between 2006 and 2015, there were a weighted total of 35 339 opioid-related ED visits among patients with cancer. During this time frame, the incidence of opioid-related ED visits for overdose increased twofold (P < .001). On multivariable regression (P < .001), comorbid diagnoses of chronic pain (odds ratio [OR] 4.51, 95% confidence interval [CI] = 4.13 to 4.93), substance use disorder (OR = 3.54, 95% CI = 3.28 to 3.82), and mood disorder (OR = 3.40, 95% CI = 3.16 to 3.65) were strongly associated with an opioid-related visit. Patients with head and neck cancer (OR = 2.04, 95% CI = 1.82 to 2.28) and multiple myeloma (OR = 1.73, 95% CI = 1.32 to 2.26) were also at risk for overdose. CONCLUSIONS: Over the study period, the incidence of opioid-related ED visits in patients with cancer increased approximately twofold. Comorbid diagnoses and primary disease site may predict risk for opioid overdose.

Impact of Widespread Cervical Cancer Screening: Number of Cancers Prevented and Changes in Race-specific Incidence.

OBJECTIVES: With recent approval of standalone HPV testing and increasing uptake of HPV vaccination, some have postulated that we are moving toward a "post-Pap" era of cervical cancer prevention. However, the total number cases that have been prevented by Pap smear screening as well as its impact on racial disparities are unknown. METHODS: We estimated national cervical cancer incidence from 1976 to 2009 using the Surveillance, Epidemiology, and End Result database. Screening data were obtained from the literature and National Cancer Institute Progress Reports. We examined early, late, and race-specific trends in cancer incidence, and calculated the estimated number of cancers prevented over the past 3 decades. RESULTS: From 1976 to 2009, there was a significant decrease in the incidence of early-stage cervical cancer, from 9.8 to 4.9 cases per 100,000 women (P<0.001). Late-stage disease incidence also decreased, from 5.3 to 3.7 cases per 100,000 women (P<0.001). The incidence among black women decreased from 26.9 to 9.7 cases per 100,000 women (P<0.001), a greater decline compared with that of white women and women of other races. After adjusting for "prescreening era" rates of cervical cancer, we estimate that Pap smears were associated with a reduction of between 105,000 and 492,000 cases of cervical cancer over the past 3 decades in the United States. CONCLUSIONS: A large number of early-stage and late-stage cervical cancers were prevented and racial disparity in cancer rates were reduced during an era of widespread Pap smear screening.

Estimating the magnitude of colorectal cancers prevented during the era of screening: 1976 to 2009.

BACKGROUND: Ideally, screening detects cancer at a more curable stage and, as a result, decreases the rate of subsequent diagnosis at a late stage. Although it is suggested that some cancer screening tests have led to substantial increases in early-stage incidence with only marginal reductions in late-stage incidence (eg mammography), the association between temporal trends in colorectal cancer screening and its cumulative impact on colorectal cancer incidence is unknown. METHODS: Colorectal cancer incidence data spanning over 3 decades (1976-2009) were collected from the Surveillance, Epidemiology, and End Results database. Data on screening use spanning the period from 1986 to 2010 were collected from the National Cancer Institute Cancer Trends Progress Report, and trends in the incidence of early-stage (in situ, local) and late-stage (regional, distant) colorectal cancer were examined among adults aged ≥50 years. RESULTS: From 1987 to 2010--the years for which screening data were available--the percentage of adults aged ≥50 years who underwent screening rose from 34.8% to 66.1% (which included increases in colonoscopy). During that time, the incidence of late-stage colorectal cancer decreased from 118 to 74 cases per 100,000 population (P < .001). The incidence of early-stage colorectal cancer also decreased, from 77 to 67 cases per 100,000 population (P < .001). After adjusting for underlying trends in cancer incidence, colorectal screening was associated with a reduction of approximately 550,000 cases of colorectal cancer over the past 3 decades in the United States. CONCLUSIONS: There has been a significant decline in the incidence of colorectal cancer in the United States, particularly for late-stage disease, during a time of increasing rates of screening.

Helping science and drug development to succeed through pharma-academia partnerships: Yale Healthcare Conference 2013.

The theme of the 2013 Yale Healthcare Conference was "Partnerships in Healthcare: Cultivating Collaborative Solutions." The April conference brought together leaders across several sectors of health care, including academic research, pharmaceuticals, information technology, policy, and life sciences investing. In particular, the breakout session titled "Taking R&D Back to School: The Rise of Pharma-Academia Alliances" centered on the partnerships between academic institutions and pharmaceutical companies. Attendees of the session included members of the pharmaceutical industry, academic researchers, and physicians, as well as graduate and professional students. The discussion was led by Dr. Thomas Lynch of Yale University. Several topics emerged from the discussion, including resources for scientific discovery and the management of competing interests in collaborations between academia and the pharmaceutical industry.

Genotype-dependent cooperation of ionizing radiation with BRAF inhibition in BRAF V600E-mutated carcinomas.

BACKGROUND: A substantial proportion of solid tumors carry the BRAF V600E mutation, which causes activation of the MEK/MAPK pathway and is a poor prognostic indicator. Patients with locally advanced human cancers are often treated with external beam radiation therapy. Given the association of Raf overactivation with radioresistance, we hypothesized that, in BRAF V600E-mutated carcinomas, there would be combinatorial activity between radiation and PLX4720, a specific BRAF V600E-inhibitor. METHODS: Two BRAF V600E-mutated cancer cell lines and one BRAF-V600E wildtype (WT) cancer cell line were obtained. We performed cell viability assays and clonogenic assays using combinations of radiation and PLX4720. We assessed MEK and MAPK phosphorylation at different PLX4720 concentrations with western blotting, and cell cycle progression was evaluated by flow cytometry. RESULTS: Our results show combinatorial, additive activity between radiation and PLX4720 in BRAF V600E-mutated cell lines, but not in the BRAF WT line. In BRAF V600E-mutated cells, there was a PLX4720 concentration-dependent decrease in MEK and MAPK phosphorylation. In cells with BRAF V600E mutations, PLX4720 caused cell cycle arrest at G1, and, when combined with radiation, caused a combined G1 and G2 cell cycle arrest; this pattern of cell cycle effects was not seen in the BRAF WT cell line. CONCLUSIONS: These data suggest additive, combinatorial activity between radiation and PLX4720 in cancers carrying BRAF V600E mutations. Our data has potential for translation into the multimodality treatment of BRAF V600E-mutated cancers.