Quantitative assessment of background parenchymal enhancement is associated with lifetime breast cancer risk in screening MRI.

OBJECTIVES: To compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI. MATERIALS AND METHODS: This study included screening MRI of 535 women divided into three groups based on lifetime risk: nonhigh-risk women, high-risk women without BRCA mutation, and BRCA1/2 mutation carriers. Six quantitative BPE measurements, including percent enhancement (PE) and signal enhancement ratio (SER), were calculated on DCE-MRI after segmentation of the whole breast and fibroglandular tissue (FGT). The associations between lifetime risk factors and BPE were analyzed via linear regression analysis. We adjusted for risk factors influencing BPE using propensity score matching (PSM) and compared the BPE between different groups. A two-sided Mann-Whitney U-test was used to compare the BPE with a threshold of 0.1 for multiple testing issue-adjusted p values. RESULTS: Age, BMI, menopausal status, and FGT level were significantly correlated with quantitative BPE based on the univariate and multivariable linear regression analyses. After adjusting for age, BMI, menopausal status, hormonal treatment history, and FGT level using PSM, significant differences were observed between high-risk non-BRCA and BRCA groups in PEFGT (11.5 vs. 8.0%, adjusted p = 0.018) and SERFGT (7.2 vs. 9.3%, adjusted p = 0.066). CONCLUSION: Quantitative BPE varies in women with different lifetime breast cancer risks and BRCA mutation status. These differences may be due to the influence of multiple lifetime risk factors. Quantitative BPE differences remained between groups with and without BRCA mutations after adjusting for known risk factors associated with BPE. CLINICAL RELEVANCE STATEMENT: BRCA germline mutations may be associated with quantitative background parenchymal enhancement, excluding the effects of known confounding factors. This finding can provide potential insights into the cancer pathophysiological mechanisms behind lifetime risk models. KEY POINTS: Expanding understanding of breast cancer pathophysiology allows for improved risk stratification and optimized screening protocols. Quantitative BPE is significantly associated with lifetime risk factors and differs between BRCA mutation carriers and noncarriers. This research offers a possible understanding of the physiological mechanisms underlying quantitative BPE and BRCA germline mutations.

Single center experience using stereotactic body radiation therapy (SBRT) on orthotopic liver transplant protocol for unresectable cholangiocarcinoma.

PURPOSE: To evaluate tolerability, pathologic response, and disease outcomes utilizing pre-operative stereotactic body radiation therapy (SBRT) followed by consolidation chemotherapy (CHT) prior to orthotopic liver transplant (OLT) in unresectable cholangiocarcinoma (CCA). METHODS: This was a retrospective chart review of patients treated on OLT protocol at a single tertiary center from 2012 to 2019. Patients received pre-operative SBRT (40-50 Gy in 5 fractions) followed by CHT until progression or OLT. Progression-free survival (PFS) and overall survival (OS) were compared via log-rank test and Cox proportional hazards regression. RESULTS: 26 patients (84.6% hilar, 15.4% intrahepatic) were identified for analysis. Eight patients (30.8%) patients developed acute toxicity after SBRT, mostly grade 1 nausea. Nine (34.6%) patients underwent OLT of which 4 (44.4%) achieved a pathologic complete response (pCR). Five (55.6%) OLT patients, including 2 pCR, developed recurrence at a median time of 49.9 weeks after OLT. 3-year OS for the OLT and dropout cohort was 75% and 9%, respectively (p < 0.0001). OS in hilar tumors only was statistically different for those that achieved a pCR (p = 0.014). CONCLUSIONS: Pre-operative SBRT is a well-tolerated and effective radiation technique as part of OLT protocol for unresectable CCA and conferred in a pCR rate of 44% within our cohort.

Estimating Time-Varying Treatment Switching Effect Using Accelerated Failure Time Model with Application to Vascular Access for Hemodialysis.

Vascular access for hemodialysis is of paramount importance. Although studies have found that central venous catheter (CVC) is often associated with poor outcomes and switching to arteriovenous fistula (AVF) and arteriovenous grafts (AVG) is beneficial, it has not been fully elucidated how the effect of switching of access on outcomes changes over time and whether the effect depends on switching time. In this paper we propose to relate the observed survival time for patients without access change and the counterfactual time for patients with access change using an AFT model with time-varying effects. The flexibility of AFT model allows us to account for baseline effect and the prognostic effect from covariates at access change while estimating the effect of access change. The effect of access change overtime is modeled nonparametrically using a cubic spline function. Simulation studies show excellent performance. Our methods are applied to investigate the effect of vascular access change over time in dialysis patients. It is concluded that the benefit of switching from CVC to AVG depends on the time of switching, the sooner the better.

Predicting Overall Survival for Patients with Malignant Mesothelioma Following Radiotherapy via Interpretable Machine Learning.

PURPOSE/OBJECTIVES: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics. MATERIALS/METHODS: Sixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables. RESULTS: Significant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly. CONCLUSIONS: Clinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice.

M2 isoform of pyruvate kinase rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance.

BACKGROUND: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance. METHODS: Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with M2 isoform of pyruvate kinase (PKM2) activity was tested via gliomasphere formation assays and in vivo human GBM models. RESULTS: Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the PKM2. Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo. CONCLUSIONS: These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.

Current Practice Patterns in Locally Advanced Rectal Cancer at Academic Institutions: A National Survey Among Radiation Oncologists, Medical Oncologists, and Colorectal Surgeons.

PURPOSE: To assess the current treatment patterns in locally advanced rectal cancer (LARC) among radiation oncologists (RO), medical oncologists (MO), and colorectal surgeons (SR) specializing in gastrointestinal (GI) malignancies at academic institutions. MATERIALS AND METHODS: An online survey consisting of 7 LARC clinical vignettes was distributed to GI specialists practicing at ACGME accredited academic institutions. Treatment paradigms consisted of long-course chemoradiation (LC-CRT) and short-course (SCRT) radiotherapy, chemotherapy (CHT), and surgery. The survey was open from January to April 2021. RESULTS: Thirty-six RO, 14 MO and 21 SR (71/508 physicians) replied resulting in a response rate of 14.0%. For low rectal node positive tumors, 88.7% of primary recommendations incorporated TNT (73.1% LC-CRT, 26.9% SCRT). NOM was preferred by 41.3% if a clinical complete response (cCR) was achieved. The presence of high-risk features led 95.8% of physicians to employ TNT (79.4% LC-CRT, 20.6% SCRT). For a cT3N1-2 mid-rectal tumor without high-risk features, 85.9% would primarily recommend TNT (56.6% LC-CRT, 43.4% SCRT). For a cT4bN2a mid-rectal tumor without high-risk features, 97.2% of primary recommendations included TNT (76.9% LC-CRT, 23.1% SCRT). CONCLUSION: Among academic RO, MO, and SR, the traditional regimen of LC-CRT, surgery, and adjuvant CHT is now infrequently recommended for LARC. TNT has been widely adopted for locally advanced node positive rectal tumors with variable patterns of care with respect to sequencing of CHT and RT. Fractionation with LC-CRT remained the majority. Non-operative management after a cCR in low rectal tumors has gained traction transforming LARC from a once classically perceived surgical disease.

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

Characterizing Twitter Influencers in Radiation Oncology.

Purpose: Both the superstructures of virtual discourse in radiation oncology and the entities occupying influential positions in the social media landscape of radiation oncology remain poorly characterized. Methods and Materials: NodeXL Pro was used to prospectively sample all tweets with the hashtag #radonc every 8 to 10 days during the course of 1 year (December 4, 2018, to November 29, 2019). Twitter handles were grouped into conversational clusters using the Clauset-Newman-Moore community detection algorithm. For each sample period, the top 10 #radonc Twitter influencers, defined using betweenness centrality, were categorized. Influencers were scored in each sample period according to their top 10 influence rank and summarized with descriptive statistics. Linear regression assessed for characteristics that predicted higher influence scores among top influencers. Results: In the study, 684,000 tweets were sampled over 38 periods. #radonc tweets took on the crowd superstructure of a hub-and-spoke broadcast network formed when prominent individuals are widely repeated by many audience members. Professional societies were the most influential category of Twitter handles with an average influence score of 7.63 out of 10 (standard deviation [SD] = 1.94). When industry handles were present among top 10 influencers, they exhibited the second highest average influence scores (6.75, SD = 1.06), followed by individuals with scores of 5.28 (SD = 0.43). The categories of influencers were stable during the course of 1 year. The role of attending physician, radiation oncology specialty, male sex, academic practice, and US-based handles in North America were predictors of higher influence score. Conclusions: Twitter influencers in radiation oncology represent a diverse group of people and organizations, but male academic radiation oncologists based in North America occupy particularly influential positions in virtual communities broadly characterized as "hub and spoke" broadcast networks. Periodic network-based analyses of the social media discourse in radiation oncology are warranted to maintain an awareness of the handles that are influencing discussions on Twitter and ensure that social media utilization continues to contribute to the field of radiation oncology in a meaningful way.

Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition.

Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.

Ablative radiotherapy for liver tumors using stereotactic MRI-guidance: A prospective phase I trial.

BACKGROUND AND PURPOSE: To prospectively determine the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT) to primary and secondary liver tumors with MR-guided radiation therapy (MRgRT). MATERIALS AND METHODS: Treatment plans with a conventional CT-guided linear accelerator and a MRI-guided tri-60Co teletherapy unit (MR-Co) were generated and compared for patients undergoing liver-directed SBRT from 2015 to 2017. If dosimetric parameters were met on MR-Co, patients were treated with MRgRT. The highest priority constraint was >1000 cc or >800 cc of normal liver receiving <15 Gy for single- or multiple-lesion treatments, respectively. Treatment was delivered every other day. RESULTS: Of 23 patients screened, 20 patients (8 primary, 12 secondary) and 25 liver tumors underwent MR-guided SBRT to a median dose of 54 Gy (range 11.5-60) in a median of 3 fractions (range 1-5). With a median follow up of 18.9 months, the 1- and 2-year estimate of local control were 94.7% and 79.6%, respectively. A difference in local control between single and multiple lesions or BED ≥ 100 Gy10 and BED < 100 Gy10, respectively, was observed. The 2-year estimate of overall survival (OS) was 50.7% with a median OS of 29 months. There were no acute grade ≥ 3 toxicities and one late grade 3/4 toxicity from a single patient whose plan exceeded an unrecognized dose constraint at the time. CONCLUSION: MR-guided SBRT is a viable and safe option in the delivery of ultrahypofractionated ablative radiation treatment to primary and secondary liver tumors resulting in high rates of local control and very favorable toxicity profiles.

Linear accelerator-based radiosurgery for trigeminal neuralgia: comparative outcomes of frame-based and mask-based techniques.

OBJECTIVE: Precise and accurate targeting is critical to optimize outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). The aim of this study was to compare the outcomes after SRS for TN in which two different techniques were used: mask-based 4-mm cone versus frame-based 5-mm cone. METHODS: The authors performed a retrospective review of patients who underwent SRS for TN at their institution between 1996 and 2019. The Barrow Neurological Institute (BNI) pain score and facial hypesthesia scale were used to evaluate pain relief and facial numbness. RESULTS: A total of 234 patients were included in this study; the mean age was 67 years. In 97 patients (41.5%) radiation was collimated by a mask-based 4-mm cone, whereas a frame-based 5-mm cone was used in the remaining 137 patients (58.5%). The initial adequate pain control rate (BNI I-III) was 93.4% in the frame-based 5-mm group, compared to 87.6% in the mask-based 4-mm group. This difference between groups lasted, with an adequate pain control rate at ≥ 24 months of 89.9% and 77.8%, respectively. Pain relief was significantly different between groups from initial response until the last follow-up (≥ 24 months, p = 0.02). A new, permanent facial hypesthesia occurred in 30.3% of patients (33.6% in the frame-based 5-mm group vs 25.8% in the mask-based 4-mm group). However, no significant association between the BNI facial hypesthesia score and groups was found. Pain recurrence occurred earlier (median time to recurrence 12 months vs 29 months, p = 0.016) and more frequently (38.1% vs 20.4%, p = 0.003) in the mask-based 4-mm than in the frame-based 5-mm group. CONCLUSIONS: Frame-based 5-mm collimator SRS for TN resulted in a better long-term pain relief with similar toxicity profiles to that seen with mask-based 4-mm collimator SRS.

Clinical outcomes of stereotactic magnetic resonance image-guided adaptive radiotherapy for primary and metastatic tumors in the abdomen and pelvis.

PURPOSE: Stereotactic body radiotherapy (SBRT) delivers ablative doses with excellent local control. However, implementing SBRT for abdominal and pelvic tumors has been limited by the risk for treatment-related gastrointestinal toxicity. MRI-guided radiotherapy may ameliorate these risks and increase the therapeutic ratio. We report the clinical outcomes of stereotactic MRI-guided adaptive radiotherapy (SMART) for primary and metastatic tumors in the abdomen and pelvis. METHODS: From November 2014 to August 2017, the first 106 consecutive patients with 121 tumors in the abdomen and pelvis were treated with SMART at a single institution. Of the cohort, 41.5%, 15.1%, and 43.4% had primary, locally recurrent, and oligometastatic tumors, respectively. SMART was delivered using a tri-cobalt-60 gantry with on-board 0.35 Tesla MRI with respiratory breath-hold and daily adaptive re-planning when anatomically necessary. A median of 40Gy in five fractions was prescribed. The Common Terminology Criteria for Adverse Events v.4.03 was used to score treatment-related toxicities. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method. RESULTS: Of the 510 treatments, seventy-one (13.9%) were adapted. Fatigue, nausea, and pain were the most common acute toxicities. 0.9 and 0% of patients experienced acute grade three and four toxicities, respectively. 5.2 and 2.1% of patients experienced late grade three and four toxicities, respectively. After a median follow-up of 20.4 months, the 2-year LC rate was 74% on a per-lesion basis. Two-year LC was 96% for lesions that were treated with BED10 ≥100 versus 69% for BED10 <100 (p = 0.02). PFS was significantly different between patients with and without locally controlled tumors (2-year PFS 21 vs. 8%, p = 0.03). Two-year OS was 57% for the entire cohort. CONCLUSIONS: Favorable LC and PFS outcomes were observed with minimal morbidity for tumors in the abdomen and pelvis treated with SMART. Future prospective clinical trials to validate these findings are warranted.

National variation in the delivery of radiation oncology procedures in the non-facility-based setting.

PURPOSE: Though utilization of medical procedures has been shown to vary considerably across the United States, similar efforts to characterize variation in the delivery of radiation therapy (RT) procedures have not been forthcoming. Our aim was to characterize variation in the delivery of common RT procedures in the Medicare population. We hypothesized that delivery would vary significantly based on provider characteristics. METHODS: The Centers for Medicare and Medicaid Services (CMS) Physician and Other Supplier Public Use File was linked to the CMS Physician Compare (PC) database by physician NPI to identify and sum all treatment delivery charges submitted by individual radiation oncologists in the non-facility-based (NFB) setting in 2016. Multivariable logistic regression analysis was carried out to determine provider characteristics (gender, practice rurality, practice region, and years since graduation) that predicted for the delivery of 3D conformal RT (3DCRT), intensity modulated RT (IMRT), stereotactic body RT (SBRT), stereotactic radiosurgery (SRS), low dose rate (LDR) brachytherapy, and high dose rate (HDR) brachytherapy delivery in the Medicare patient population. The overall significance of categorical variables in the multivariable logistic regression model was assessed by the likelihood ratio test (LRT). RESULTS: In total, 1,802 physicians from the NFB practice setting were analyzed. Male gender predicted for greater LDR brachytherapy delivery (OR 8.19, 95% CI 2.58-26.05, p < 0.001), but not greater delivery of other technologies. Metropolitan practice was the only predictor for greater HDR brachytherapy utilization (OR 12.95, 95% CI 1.81-92.60, p = 0.01). Practice region was predictive of the delivery of 3DCRT, SRS and SBRT (p < 0.01, p < 0.001, and p < 0.001, respectively). With the Northeast as the reference region, 3DCRT was more likely to be delivered by providers in the South (OR 1.33, 95% CI 1.09-1.62, p < 0.01) and the West (OR 1.38, 95% CI 1.11-1.71, p < 0.01). At the same time, SRS use was less likely in the Midwest (OR 0.71, 95% CI 0.55-0.91, p < 0.01), South (OR 0.49, 95% CI 0.40-0.61, p < 0.001), and West (OR 0.43, 95% CI 0.34-0.55, p < 0.001). SBRT, on the other hand, was more commonly utilized in the Midwest (OR 2.63, 95% CI 1.13-6.13, p = 0.03), South (OR 3.44, 95% CI 1.58-7.49, p < 0.01), and West (OR 4.87, 95% CI 2.21-10.72, p < 0.001). HDR brachytherapy use was also more likely in the Midwest (OR 1.97, 95% CI 1.11-3.49, p = 0.02) and West (OR 1.87, 95% CI 1.08-3.24, p = 0.03). While the degree held by the billing physician did not predict for delivery of a given procedure, greater years since graduation was related to decreased likelihood of SBRT use (OR 0.98, 95% CI 0.96-0.99, p < 0.001) and increased likelihood of LDR brachytherapy use (OR 1.02, 95% CI 1.00-1.04, p = 0.02). CONCLUSIONS: Substantial geographic variation in the use of specific RT technologies was identified. The degree to which this variation reflects effective care, preference-sensitive care, or supply-sensitive care warrants further investigation.

Dosimetric impact from cardiac motion to heart substructures in thoracic cancer patients treated with a magnetic resonance guided radiotherapy system.

Few studies have examined the cardiac volume and radiation dose differences among cardiac phases during radiation therapy (RT). Such information is crucial to dose reconstruction and understanding of RT related cardiac toxicity. In a cohort of nine patients, we studied the changes in the volume and doses of several cardiac substructures between the end-diastolic and end-systolic phases based on the clinical magnetic resonance-guided RT (MRgRT) treatment plans. Significant differences in the volume and dose between the two phases were observed. Onboard cardiac cine MRI holds promise for patient-specific cardiac sparing treatment designs.

Dosimetric Quality of Online Adapted Pancreatic Cancer Treatment Plans on an MRI-Guided Radiation Therapy System.

PURPOSE: Stereotactic magnetic resonance image-guided adaptive radiation therapy (SMART) is an emerging technique that shows promise in the treatment of pancreatic cancer and other abdominopelvic malignancies. However, it is unknown whether the time-limited nature of on-table adaptive planning may result in dosimetrically suboptimal plans. The purpose of this study was to quantitatively address that question through systemic retrospective replanning of treated on-table adaptive pancreatic cancer cases. METHODS AND MATERIALS: Of 74 consecutive adapted fractions, 30 were retrospectively replanned based on deficiencies in planning target volume (PTV) and gross tumor volume (GTV) coverage or doses to organs-at-risk (OARs) that exceeded ideal constraints. Retrospective plans were created by adjusting dose-volume objectives in an iterative fashion until deemed optimized. The goal of replanning was to improve PTV/GTV coverage while keeping the dose to gastrointestinal OARs the same or lower or to reduce OAR doses while keeping PTV coverage the same or higher. The global maximum dose was required to be maintained within 2% of that of the treated adaptive plan to eliminate it as a confounding factor. A threshold of 5% improvement in PTV coverage or 5% decrease in OAR dose was used to define a clinically significant improvement. RESULTS: Of the 30 replans, 7 obtained at least 5% PTV coverage improvement. The average increase in PTV coverage for these plans was 11%. No plans were clinically significantly improved in terms of OAR sparing. Changes in beam-on time did not show any correlation. Statistical analysis via a linear mixed-effects model with a nested random effect suggested that both GTV and PTV coverage were improved over SMART process plans by 0.91 cc (P = .02) and 2.03 cc (P < .001), respectively. CONCLUSIONS: Dosimetric plan quality of at least 10% of SMART fractions may be improved through more extensive replanning than is currently performed on-table. Further work is needed to develop an automated replanning workflow to streamline the in-depth replanning process to better fit into an on-table adaptive workflow.

Characterizing and quantifying the temporal relationship between structural and functional change in glaucoma.

PURPOSE: To characterize and quantify the temporal relationship between structural and functional change in glaucoma. METHODS: 120 eyes of 120 patients with ocular hypertension or primary open-angle glaucoma were selected from the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study. Patients had 11 visits, separated by at least 3 months over 5 to 10 years. Each visit had rim area (RA) and mean sensitivity (MS) measurements taken within a 30-day period. The structure-function (SF) relationship was summarized using conventional and modified cross-correlation functions (CCFs), which identified the strongest absolute and positive correlation, respectively. Patients were categorized in one of the following three groups: RA and MS evolved simultaneously (lag = 0), RA preceded MS (lag<0), and MS preceded RA (lag>0). Lagging regression analysis was used to examine the variations of the SF relationship within groups. RESULTS: The number of participants, mean visit lag, and mean correlation (standard deviation) were, for the conventional and modified CCFs, respectively: lag = 0 [16, 0, 0.53 (0.10) and 16, 0, 0.46 (0.11)]; lag<0 [50, -2.94, 0.51 (0.11) and 55, -3.45, 0.44 (0.12)], and lag>0 [54, 3.35, 0.53 (0.13) and 49, 3.78, 0.45 (0.12)]. A significant difference of the visit lag relation within groups was identified using lagging regression analysis (p<0.0001). CONCLUSIONS: The strongest relationship between structure and function was obtained at different visit lags in different patients. This finding also suggests that the SF relationship should be addressed at the subject level when using both measurements jointly to model glaucoma progression.

Assessment of Toxic Effects Associated With Dose-Fractionated Radiotherapy Among Patients With Cancer and Comorbid Collagen Vascular Disease.

Importance: The adoption of alternative fractionated radiotherapy regimens for the treatment of patients with cancer and comorbid collagen vascular disease (CVD) is controversial among oncologists because of concerns about potentially severe toxic effects; however, the association between fractionated radiotherapy and toxic effects in the modern era has not been well studied. Objective: To compare acute and late toxic effects among patients with cancer and comorbid CVD who received dose-fractionated radiotherapy. Design, Setting, and Participants: This retrospective cohort study examined 197 adult patients with cancer and CVD who received radiotherapy at a single-institution tertiary academic center over a 12-year period (February 1, 2007, to April 30, 2019), with a median follow-up of 23 months (range, 0-108 months). Data were analyzed from February 1 to August 31, 2020. Exposures: Three dose-fractionated radiotherapy regimens: conventional fractionation (CF; ≤2 Gy per fraction), moderate hypofractionation (MH; >2 Gy to <5 Gy per fraction), and ultrahypofractionation (UH; ≥5 Gy per fraction). Main Outcomes and Measures: The main outcomes were the incidence and severity of acute and late radiotherapy-associated toxic effects, which were assessed separately by dose-fractionation regimen. Toxic effects occurring within 90 days after radiotherapy completion were considered acute, and toxic effects occurring after that 90-day period were considered late. Secondary goals were to identify covariates associated with toxic effects and to characterize the incidence of CVD symptom flares (defined as worsening clinical symptoms and/or worsening results [transient or permanent] on associated blood tests compared with baseline, as documented by managing physicians) after radiotherapy. Results: Of 197 patients with cancer and comorbid CVD (mean [SD] age, 69 [12] years; 134 women [68.0%]; and 149 White participants [75.6%]), 80 patients (40.6%) received CF radiotherapy, 55 patients (27.9%) received MH radiotherapy, and 62 patients (31.5%) received UH radiotherapy. The most common CVD diagnoses were rheumatoid arthritis (74 patients [37.6%]), psoriasis (54 patients [27.4%]), systemic lupus erythematosus (34 patients [17.3%]), and scleroderma (8 patients [4.1%]). The most common radiotherapy sites were the breast (48 patients [24.4%]), thorax (25 patients [12.7%]), central nervous system (24 patients [12.2%]), and prostate (23 patients [11.7%]). Data on acute toxic effects were available for 188 patients (95.4%) and missing for 9 patients (4.6%). Data on late toxic effects were available for 142 patients (72.1%) and missing for 55 patients (27.9%). Over 12 years, the unadjusted incidences of severe acute toxic effects associated with CF, MH, and UH radiotherapy were 5.4% (95% CI, 0.3%-10.5%), 7.4% (95% CI, 0.4%-14.4%), and 1.7% (95% CI, 0%-5.0%), respectively. The incidences of severe late toxic effects associated with CF, MH, and UH radiotherapy were 8.3% (95% CI, 1.3%-15.3%), 0%, and 2.2% (95% CI, 0%-6.4%), respectively. No significant associations were found between severe acute or late toxic effects by dose fractionation regimen. In the multivariable analysis, MH radiotherapy was associated with a lower likelihood of developing late toxic effects (odds ratio [OR], 0.21; 95% CI, 0.05-0.83; P = .03) compared with CF radiotherapy. Those who received UH radiotherapy had a lower likelihood of experiencing late toxic effects (OR, 0.22; 95% CI, 0.04-1.21; P = .08). A total of 19 of 80 patients (23.8%), 15 of 55 patients (27.3%), and 10 of 62 patients (16.1%) experienced CVD symptom flares after receiving CF, MH, and UH radiotherapy, respectively (P = .33). Conclusions and Relevance: In this study, the incidences of unadjusted severe toxic effects over 12 years were less than 10% and were not significantly associated with dose fractionation. When clinically indicated, patients with cancer and comorbid CVD may not require immediate exclusion from the receipt of currently used hypofractionated radiotherapy regimens.

Provider-Level Variation in Treatment Planning of Radiation Oncology Procedures in the United States.

PURPOSE: Variation in the use of radiation oncology procedures and technologies is poorly characterized. We sought to identify associations between the treatment planning codes used to bill for radiotherapy procedures and the demographic characteristics of the radiation oncologists submitting them. METHODS: The Physician and Other Supplier Public Use File was linked to the Physician Compare database by using the physician National Provider Identifier for the year 2016. Analysis was stratified by practice setting, considering both the freestanding non-facility-based (NFB) setting and the facility-based (FB) setting. Multivariable logistic regression was used to determine provider characteristics (gender, practice rurality, and years since graduation) that predicted for the use of 3D-conformal RT (3DCRT) planning, intensity-modulated RT (IMRT) planning, and brachytherapy planning in the Medicare population. RESULTS: Three thousand twenty-nine physicians were linked for analysis. In both the FB and NFB settings together, male gender predicted for decreased likelihood of 3DCRT planning (OR, 0.70, 95% CI, 0.62 to 0.80, P < .001) and increased likelihood of IMRT planning (OR, 1.35, 95% CI, 1.19 to 1.54, P < .001). Brachytherapy planning was also more likely with increasing years since medical school graduation (OR, 1.03, 95% CI, 1.01 to 1.04, P < .001) in the combined FB and NFB settings. These significant associations persisted when examining the NFB and FB settings individually. In both settings overall, brachytherapy planning was more likely in male providers (OR, 1.75, 95% CI, 1.10 to 2.76, P = .02) and also more likely for providers practicing in metropolitan regions compared with those practicing in rural areas (OR, 3.01, 95% CI, 1.23 to 7.39, P = .02). CONCLUSION: Male gender predicts for utilization of IMRT planning, whereas female gender predicts for utilization of 3DCRT planning. Future research is warranted to better understand the role that provider gender and rurality play in the selection of radiation planning techniques for Medicare patients.

Underutilization of Androgen Deprivation Therapy with External Beam Radiotherapy in Men with High-grade Prostate Cancer.

Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving <24mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men. PATIENT SUMMARY: In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.