Investigation of autosegmentation techniques on T2-weighted MRI for off-line dose reconstruction in MR-linac workflow for head and neck cancers.

BACKGROUND: In order to accurately accumulate delivered dose for head and neck cancer patients treated with the Adapt to Position workflow on the 1.5T magnetic resonance imaging (MRI)-linear accelerator (MR-linac), the low-resolution T2-weighted MRIs used for daily setup must be segmented to enable reconstruction of the delivered dose at each fraction. PURPOSE: In this pilot study, we evaluate various autosegmentation methods for head and neck organs at risk (OARs) on on-board setup MRIs from the MR-linac for off-line reconstruction of delivered dose. METHODS: Seven OARs (parotid glands, submandibular glands, mandible, spinal cord, and brainstem) were contoured on 43 images by seven observers each. Ground truth contours were generated using a simultaneous truth and performance level estimation (STAPLE) algorithm. Twenty total autosegmentation methods were evaluated in ADMIRE: 1-9) atlas-based autosegmentation using a population atlas library (PAL) of 5/10/15 patients with STAPLE, patch fusion (PF), random forest (RF) for label fusion; 10-19) autosegmentation using images from a patient's 1-4 prior fractions (individualized patient prior [IPP]) using STAPLE/PF/RF; 20) deep learning (DL) (3D ResUNet trained on 43 ground truth structure sets plus 45 contoured by one observer). Execution time was measured for each method. Autosegmented structures were compared to ground truth structures using the Dice similarity coefficient, mean surface distance (MSD), Hausdorff distance (HD), and Jaccard index (JI). For each metric and OAR, performance was compared to the inter-observer variability using Dunn's test with control. Methods were compared pairwise using the Steel-Dwass test for each metric pooled across all OARs. Further dosimetric analysis was performed on three high-performing autosegmentation methods (DL, IPP with RF and 4 fractions [IPP_RF_4], IPP with 1 fraction [IPP_1]), and one low-performing (PAL with STAPLE and 5 atlases [PAL_ST_5]). For five patients, delivered doses from clinical plans were recalculated on setup images with ground truth and autosegmented structure sets. Differences in maximum and mean dose to each structure between the ground truth and autosegmented structures were calculated and correlated with geometric metrics. RESULTS: DL and IPP methods performed best overall, all significantly outperforming inter-observer variability and with no significant difference between methods in pairwise comparison. PAL methods performed worst overall; most were not significantly different from the inter-observer variability or from each other. DL was the fastest method (33 s per case) and PAL methods the slowest (3.7-13.8 min per case). Execution time increased with a number of prior fractions/atlases for IPP and PAL. For DL, IPP_1, and IPP_RF_4, the majority (95%) of dose differences were within ± 250 cGy from ground truth, but outlier differences up to 785 cGy occurred. Dose differences were much higher for PAL_ST_5, with outlier differences up to 1920 cGy. Dose differences showed weak but significant correlations with all geometric metrics (R2 between 0.030 and 0.314). CONCLUSIONS: The autosegmentation methods offering the best combination of performance and execution time are DL and IPP_1. Dose reconstruction on on-board T2-weighted MRIs is feasible with autosegmented structures with minimal dosimetric variation from ground truth, but contours should be visually inspected prior to dose reconstruction in an end-to-end dose accumulation workflow.

Safety and efficacy of salvage conventional re-irradiation following stereotactic radiosurgery for spine metastases.

PURPOSE: There has been limited work assessing the use of re-irradiation (re-RT) for local failure following stereotactic spinal radiosurgery (SSRS). We reviewed our institutional experience of conventionally-fractionated external beam radiation (cEBRT) for salvage therapy following SSRS local failure. MATERIALS AND METHODS: We performed a retrospective review of 54 patients that underwent salvage conventional re-RT at previously SSRS-treated sites. Local control following re-RT was defined as the absence of progression at the treated site as determined by magnetic resonance imaging. RESULTS: Competing risk analysis for local failure was performed using a Fine-Gray model. The median follow-up time was 25 months and median overall survival (OS) was 16 months (95% confidence interval [CI], 10.8-24.9 months) following cEBRT re-RT. Multivariable Cox proportional-hazards analysis revealed Karnofsky performance score prior to re-RT (hazard ratio [HR] = 0.95; 95% CI, 0.93-0.98; p = 0.003) and time to local failure (HR = 0.97; 95% CI, 0.94-1.00; p = 0.04) were associated with longer OS, while male sex (HR = 3.92; 95% CI, 1.64-9.33; p = 0.002) was associated with shorter OS. Local control at 12 months was 81% (95% CI, 69.3-94.0). Competing risk multivariable regression revealed radioresistant tumors (subhazard ratio [subHR] = 0.36; 95% CI, 0.15-0.90; p = 0.028) and epidural disease (subHR = 0.31; 95% CI, 0.12-0.78; p =0.013) were associated with increased risk of local failure. At 12 months, 91% of patients maintained ambulatory function. CONCLUSION: Our data suggest that cEBRT following SSRS local failure can be used safely and effectively. Further investigation is needed into optimal patient selection for cEBRT in the retreatment setting.

Feasibility of a novel non-invasive swab technique for serial whole-exome sequencing of cervical tumors during chemoradiation therapy.

BACKGROUND: Clinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to demonstrate the feasibility of a novel noninvasive cervical swab technique to (1) collect tumor DNA with adequate throughput to (2) perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT). METHODS: Cervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were analyzed with whole-exome sequencing (WES) with mutation calling using a custom pipeline optimized for shallow whole-exome sequencing with low tumor purity (TP). Tumor mutation changes over the course of treatment were profiled. RESULTS: 216 samples were collected and successfully sequenced for 70 patients (94% of total number of tumor samples collected). A total of 33 patients had a complete set of samples at all four time points. The mean mapping rate was 98% for all samples, and the mean target coverage was 180. Estimated TP was greater than 5% for all samples. Overall mutation frequency decreased during CRT but mapping rate and mean target coverage remained at >98% and >180 reads at week 5. CONCLUSION: This study demonstrates the feasibility and application of a noninvasive swab-based technique for WES analysis which may be applied to investigate dynamic tumor mutational changes during treatment to identify novel genes which confer radiation resistance.

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16+ Cancers.

Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non-HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.

Linguistic Biases in Letters of Recommendation for Radiation Oncology Residency Applicants from 2015 to 2019.

We aimed to investigate whether implicit linguistic biases exist in letters of recommendation (LORs) for applicants to radiation oncology (RO) residency. LORs (n = 487) written for applicants (n = 125) invited to interview at a single RO residency program from the 2015 to 2019 application cycles were included for analysis. Linguistic Inquiry and Word Count (LIWC) software was used to evaluate LORs for length and a dictionary of predetermined themes. Language was evaluated for gender bias using a publicly available gender bias calculator. Non-parametric tests were used to compare linguistic domain scores. The median number of the LORs per applicant was 4 (range 3-5). No significant differences by applicant gender were detected in LIWC score domains or gender bias calculator (P > 0.05). However, LORs for applicants from racial/ethnic backgrounds underrepresented in medicine were less likely to include standout descriptors (P = 0.008). Male writers were less likely to describe applicant characteristics related to patient care (P < 0.0001) and agentic personality (P = 0.006). LORs written by RO were shorter (P < 0.0001) and included fewer standout descriptors (P = 0.014) but were also more likely to include statements regarding applicant desirability (P = 0.045) and research (P = 0.008). While language was globally male-biased, assistant professors were less likely than associate professors (P = 0.0064) and full professors (P = 0.023) to use male-biased language. Significant linguistic differences were observed in RO residency LORs, suggesting that implicit biases related to both applicants and letter writers may exist. Recognition, and ideally eradication, of such biases are crucial for fair and equitable evaluation of a diverse applicant pool of RO residency candidates.

Outcomes After Breast Radiation Therapy in a Diverse Patient Cohort With a Germline BRCA1/2 Mutation.

PURPOSE: BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations. METHODS AND MATERIALS: This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status. RESULTS: Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively. CONCLUSIONS: Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation.

Use of Specific Duodenal Dose Constraints During Treatment Planning Reduces Toxicity After Definitive Paraaortic Radiation Therapy for Cervical Cancer.

PURPOSE: This study aimed to validate the safety of paraaortic nodal (PAN) radiation therapy (RT) for patients with cervical cancer when the duodenal dose is limited to V55 < 15 cm3 and V60 < 2 cm3. METHODS AND MATERIALS: A total of 97 patients who were treated with RT for cervical cancer between 2010 and 2018 received at least 56 Gy to grossly involved PANs. Patients were treated with concurrent chemoradiation (n = 88; 91%), with 93% of patients (n = 90) receiving intensity modulated RT to the initial PAN field and 98% (n = 95) receiving intensity modulated RT to a sequential PAN boost. The V55 < 15 cm3 and V60 <2 cm3 criteria were implemented in 2014. Normal tissues were contoured on computed tomography (CT) simulation data sets, and the duodenum was contoured from the gastric outlet to the duodenojejunal flexure. Sixty-six patients (68%) had a resimulation scan after approximately 20 fractions. Composite duodenal doses were calculated using the initial CT scan for 50 patients (52%) and the resimulation CT scan for 47 patients (48%) depending on the anatomic changes throughout treatment. RESULTS: The median duodenal V55 was 3.5 cm3 (interquartile range [IQR], 0.2-8.1 cm3) and the median V60 was 0.3 cm3 (IQR, 0.0-1.8). Constraints were exceeded in 18 patients, of whom 16 patients (89%) had been treated before 2014. Treatment for the 2 patients treated after 2014 was complicated by significant weight loss and reduced anterior-posterior diameter, which likely overestimated the true dose on the composite plan. Only 1 patient experienced grade 3 duodenal toxicity (stricture requiring endoscopic balloon dilation 3 months after treatment); however, the stricture was outside of the high-dose boost volume, and the patient had a history of gastritis. Six patients (6%) had a first recurrence within the PAN region. CONCLUSIONS: Limiting the duodenal dose to V55 < 15 cm3 and V60 < 2 cm3 for patients with cervical cancer and PAN involvement is feasible, and minimizes duodenal toxicity while maintaining acceptable local control rates.

Breast Radiation Therapy-Related Treatment Outcomes in Patients With or Without Germline Mutations on Multigene Panel Testing.

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing. METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival, locoregional recurrence, disease-specific death, and radiation-related toxicities in 3 groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations. RESULTS: PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval, 3.8-4.9 years). No differences were found in overall survival, locoregional recurrence, or disease-specific death between groups (P > .1 for all). Acute and late toxicities were comparable across groups. CONCLUSION: Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated.

Single Institution Experience of Proton and Photon-based Postoperative Radiation Therapy for Non-small-cell Lung Cancer.

INTRODUCTION: Postoperative radiation therapy (PORT) for non-small-cell lung cancer remains controversial with studies showing no overall survival (OS) benefit in the setting of excessive cardiopulmonary toxicity. Proton beam therapy (PBT) can potentially reduce toxicity with improved organ-at-risk sparing. We evaluated outcomes of PORT patients treated with PBT and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: This is a retrospective review of 136 PORT patients (61 PBT, 75 IMRT) treated from 2003 to 2016. A Kaplan-Meier analysis was performed to assess oncologic outcomes. A Cox regression was conducted to identify associated factors. Total toxicity burden (TTB) was defined as grade ≥ 2 pneumonitis, cardiac, or esophageal toxicity. RESULTS: Median OS was 76 and 46 months for PBT and IMRT with corresponding 1- and 5-year OS of 85.3%, 50.9% and 89.3%, 37.2% (P = .38), respectively. V30 Gy heart (odds ratio [OR], 144.9; 95% confidence interval [CI], 2.91-7214; P = .013) and V5 Gy lung (OR, 15.8; 95% CI, 1.22-202.7; P = .03) were predictive of OS. Organ-at-risk sparing was improved with PBT versus IMRT; mean heart 2.0 versus 7.4 Gy (P < .01), V30 Gy heart 2.6% versus 10.7% (P < .01), mean lung 7.9 versus 10.4 Gy (P = .042), V5 Gy lung 23.4% versus 42.1% (P < .01), and V10 Gy lung 20.4% versus 29.6% (P < .01). TTB was reduced with PBT (OR, 0.35; 95% CI, 0.15-0.83; P = .017). Rates of cardiac toxicity were 14.7% IMRT and 4.9% PBT (P = .09). Rates of ≥ grade 2 pneumonitis were 17.0% IMRT and 4.9% PBT (P = .104). CONCLUSION: PBT improved cardiac and lung sparing and reduced toxicity compared with IMRT. Considering the impact of cardiopulmonary toxicity on PORT outcomes, PBT warrants prospective evaluation.

Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation.

Diversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not have adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation. Our study demonstrates that the diversity of gut microbiota is associated with a favorable response to chemoradiation. Additionally, compositional variation among patients correlated with short term and long-term survival. Short term survivor fecal samples were significantly enriched in Porphyromonas, Porphyromonadaceae, and Dialister, whereas long term survivor samples were significantly enriched in Escherichia Shigella, Enterobacteriaceae, and Enterobacteriales. Moreover, analysis of immune cells from cervical tumor brush samples by flow cytometry revealed that patients with a high microbiome diversity had increased tumor infiltration of CD4+ lymphocytes as well as activated subsets of CD4 cells expressing ki67+ and CD69+ over the course of radiation therapy. Modulation of the gut microbiota before chemoradiation might provide an alternative way to enhance treatment efficacy and improve treatment outcomes in cervical cancer patients.

Postoperative Radiotherapy for Locally Advanced NSCLC: Implications for Shifting to Conformal, High-Risk Fields.

BACKGROUND: To examine the effect of radiotherapy field size on survival outcomes and patterns of recurrence in patients treated with postoperative radiotherapy (PORT) for non-small-cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the records of 216 patients with T1-4 N1-2 NSCLC following surgery and PORT using whole mediastinum (WM) or high-risk (HR) nodal fields from 1998 to 2015. Survival rates were calculated using the Kaplan-Meier method. Univariate and multivariable analyses were conducted using Cox proportional hazards modeling for outcomes and logistic regression analysis for treatment toxicities. RESULTS: Median follow-up was 28 months (interquartile range [IQR] 13-75 months) and 38 months (IQR 19-73 months) for WM (n = 131) and HR (n = 84) groups, respectively. Overall survival (OS) was not significantly different between groups (median OS: HR 49 vs. WM 32 months; P = .08). There was no difference in progression-free survival (PFS), freedom from locoregional recurrence (LRR), or freedom from distant metastasis (P > .2 for all). Field size was not associated with OS, PFS, or LRR (P > .40 for all). LRR rates were 20% for HR and 26% for WM groups (P = .30). There was no significant difference in patterns of initial site of LRR between groups (P > .1). WM fields (OR 3.73, P = .001) and concurrent chemotherapy (odds ratio 3.62, P = .001) were associated with grade ≥2 toxicity. CONCLUSIONS: Locoregional control and survival rates were similar between PORT groups; an improved toxicity profile was observed in the HR group. Results from an ongoing prospective randomized clinical trial will provide further insight into the consequences of HR PORT fields.

Quantitative 3-Dimensional Photographic Assessment of Breast Cosmesis After Whole Breast Irradiation for Early Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

PURPOSE: Our purpose was to use 3-dimensional (3D) surface photography to quantitatively measure breast cosmesis within the framework of a randomized clinical trial of conventionally fractionated (CF) and hypofractionated (HF) whole breast irradiation (WBI); to identify how 3D measurements are associated with patient- and physician-reported cosmesis; and to determine whether objective measures of breast symmetry varied by WBI treatment arm or transforming growth factor ß 1 (TGFß1) status. METHODS AND MATERIALS: From 2011 to 2014, 287 women age ≥40 with ductal carcinoma in situ or early-stage invasive breast cancer were enrolled in a multicenter trial and randomized to HF-WBI or CF-WBI with a boost. Three-dimensional surface photography was performed at 3 years posttreatment. Patient-reported cosmetic outcomes were recorded with the Breast Cancer Treatment Outcome Scale. Physician-reported cosmetic outcomes were assessed by the Radiation Therapy Oncology Group scale. Volume ratios and 6 quantitative measures of breast symmetry, termed F1-6C, were calculated using the breast contour and fiducial points assessed on 3D surface images. Associations between all metrics, patient- and physician-reported cosmesis, treatment arm, and TGFß1 genotype were performed using the Kruskal-Wallis test and multivariable logistic regression models. RESULTS: Among 77 (39 CF-WBI and 38 HF-WBI) evaluable patients, both patient- and physician-reported cosmetic outcomes were significantly associated with the F1C vertical symmetry measure (both P < .05). Higher dichotomized F1C and volumetric symmetry measures were associated with improved patient- and physician-reported cosmesis on multivariable logistic regression (both P ≤ .05). There were no statistically significant differences in vertical symmetry or volume measures between treatment arms. Increased F6C horizontal symmetry was observed in the CF-WBI arm (P = .05). Patients with the TGFß1 C-509T variant allele had lower F2C vertical symmetry measures (P = .02). CONCLUSIONS: Quantitative 3D image-derived measures revealed comparable cosmetic outcomes with HF-WBI compared with CF-WBI. Our findings suggest that 3D surface imaging may be a more sensitive method for measuring subtle cosmetic changes than global patient- or physician-reported assessments.

Development, implementation, and outcomes of a simulation-based medical education (SBME) prostate brachytherapy workshop for radiation oncology residents.

PURPOSE: Despite a preponderance of data demonstrating strong clinical outcomes and cost-effectiveness, prostate brachytherapy use and competency continue to decline. Enhanced resident education may help reverse this trend. We therefore developed and implemented a simulation-based medical education course for low-dose-rate prostate brachytherapy (LDR-PB). MATERIALS AND METHODS: A 1-week LDR-PB course comprised four 1-h lectures on clinical outcomes, physics, radiobiology, and anatomy/contouring, followed by a 4.5-h simulation session on ultrasound-guided prostate phantom implantation, was developed for radiation oncology residents at an academic institution. A 10-statement Likert-scale survey and 20-question multiple-choice test were administered 1 week before and 4 weeks after the course. RESULTS: Precourse and postcourse instruments were completed by 24 and 20 residents, respectively. The median number of prior LDR-PB cases after at least one genitourinary rotation was 10.5 (range 5-20). Overall mean test scores were significantly improved (55% before the course vs 68% after the course; p = 0.010). Mean Likert scores significantly increased on nine of 10 survey statements and were significantly increased overall (2.4 before the course vs 3.3 after the course, p < 0.001). When asked about interest in performing brachytherapy after residency, 37.5% of residents "agreed" or "strongly agreed" before the course vs 50% after the course (p = 0.41). Those with higher postresidency brachytherapy interest (scores of 4-5 vs 1-3) had significantly more LDR-PB cases (11.2 vs 5.3 cases; p = 0.005). CONCLUSIONS: A 1-week simulation-based medical education course for LDR-PB can improve didactic performance and self-reported technical competence/confidence, and may increase overall enthusiasm for brachytherapy. Future studies at our institution will incorporate evaluation of implant quality and assessment of procedural competence into this framework. Residency programs should dedicate resources to this essential component of radiation oncology.

Patient-reported outcomes, physician-reported toxicities, and treatment outcomes in a modern cohort of patients with sinonasal cancer treated using proton beam therapy.

BACKGROUND AND PURPOSE: To report physician-assessed toxicities (PATs) and patient-reported outcomes (PROs) in a prospective cohort of patients treated using proton beam therapy (PBT). METHODS AND MATERIALS: From 2011 to 2019, PBT-treated patients with a sinonasal malignancy were enrolled with a primary endpoint of toxicity assessment. PATs and PROs were assessed at baseline, acute (during PBT), subacute (within 90 days after PBT), and chronic time points. PATs were graded with the Common Terminology Criteria for Adverse Events V4.0. PROs were assessed with the Xerostomia-Related Quality-of-Life Scale (XeQoLS), MD Anderson Dysphagia Inventory (MDADI), and Functional Assessment of Cancer Therapy (FACT). PRO changes from baseline to follow-up were defined as significantly different based on a paired t-test plus a minimal clinically important difference. RESULTS: Sixty-four patients had a median follow-up time of 33 months (interquartile range: 10-52 months). The most common histology was olfactory neuroblastoma (28%) and most patients had T4 disease (46%). One acute G3 neurologic PAT (blurred vision) resolved, and no late G3-4 neurologic PATs were observed. Feeding tube placement occurred in 6% of patients. No significant changes were noted in PROs from baseline to the chronic period. Significant worsening from baseline was noted in the XeQoLS acute-subacute physical functioning, pain, personal/psychological distress, and social function; acute-subacute MDADI physical function; and acute-subacute FACT head/neck subscale. The 3-year local control, disease-free survival, and overall survival rates were 88%, 76%, and 82%, respectively. CONCLUSIONS: We demonstrate low grade ≥3 toxicity and encouraging disease outcomes with PBT. PROs suggest significant changes in the acute-subacute period but no chronic sequelae.

Estimating PTV Margins in Head and Neck Stereotactic Ablative Radiation Therapy (SABR) Through Target Site Analysis of Positioning and Intrafractional Accuracy.

PURPOSE: Recurrent or previously irradiated head and neck cancers (HNC) are therapeutically challenging and may benefit from high-dose, highly accurate radiation techniques, such as stereotactic ablative radiation therapy (SABR). Here, we compare set-up and positioning accuracy across HNC subsites to further optimize the treatment process and planning target volume (PTV) margin recommendations for head and neck SABR. METHODS AND MATERIALS: We prospectively collected data on 405 treatment fractions across 79 patients treated with SABR for recurrent/previously irradiated HNC. First, interfractional error was determined by comparing ExacTrac x-ray to the treatment plan. Patients were then shifted and residual error was measured with repeat x-ray. Next, cone beam computed tomography (CBCT) was compared with ExacTrac for positioning agreement, and final shifts were applied. Lastly, intrafractional error was measured with x-ray before each arc. Results were stratified by treatment site into skull base, neck/parotid, and mucosal. RESULTS: Most patients (66.7%) were treated to 45 Gy in 5 fractions (range, 21-47.5 Gy in 3-5 fractions). The initial mean ± standard deviation interfractional errors were -0.2 ± 1.4 mm (anteroposterior), 0.2 ± 1.8 mm (craniocaudal), and -0.1 ± 1.7 mm (left-right). Interfractional 3-dimensional vector error was 2.48 ± 1.44, with skull base significantly lower than other sites (2.22 vs 2.77; P = .0016). All interfractional errors were corrected to within 1.3 mm and 1.8°. CBCT agreed with ExacTrac to within 3.6 mm and 3.4°. CBCT disagreements and intrafractional errors of >1 mm or >1° occurred at significantly lower rates in skull base sites (CBCT: 16.4% vs 50.0% neck, 52.0% mucosal, P < .0001; intrafractional: 22.0% vs 48.7% all others, P < .0001). Final PTVs were 1.5 mm (skull base), 2.0 mm (neck/parotid), and 1.8 mm (mucosal). CONCLUSIONS: Head and neck SABR PTV margins should be optimized by target site. PTV margins of 1.5 to 2 mm may be sufficient in the skull base, whereas 2 to 2.5 mm may be necessary for neck and mucosal targets. When using ExacTrac, skull base sites show significantly fewer uncertainties throughout the treatment process, but neck/mucosal targets may require the addition of CBCT to account for positioning errors and internal organ motion.

Low-dose radiation (4 Gy) with/without concurrent chemotherapy is highly effective for relapsed, refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) generally exhibits an aggressive disease course with poor outcomes. Despite inherent radiosensitivity, radiation therapy (RT) is not commonly used for MCL. This study assesses the role of low-dose RT (LDRT) with concurrent chemotherapy in relapsed, multiply refractory MCL. From 2014 through 2018, 19 patients with relapsed, refractory MCL had 98 sites treated with 4 Gy. Median follow-up from initial LDRT was 15.4 months. Patients had received a median 7 courses of chemotherapy since diagnosis, and 58% were ibrutinib-refractory. Of the 98 sites, 76% were refractory to ongoing chemotherapy, and LDRT was delivered with concurrent chemotherapy for 76%. The complete response (CR) rate was 81% at a median 2.7 months post-LDRT. There were no differences in CR despite ibrutinib-refractory disease, prior chemotherapy courses (>5), or tumor size (>3 cm). There were no RT-related toxicities. Overall survival at 1 year following initial LDRT was 90%, and 1-year progression-free survival following last course was 55%. In summary, LDRT is effective for relapsed, multiply refractory MCL, and may be safely delivered with chemotherapy, to multiple sites, and repeatedly without issue. By treating active sites of disease, LDRT can provide durable local control, help achieve remission, and potentially bridge patients to subsequent novel therapies.

Spine Stereotactic Radiosurgery for Metastatic Pheochromocytoma.

PURPOSE:  Despite aggressive primary treatment, up to 13.5% of patients diagnosed with pheochromocytoma may develop metastases, most often affecting the axial skeleton. Given that systemic therapy options are often inadequate, local therapy remains the cornerstone of palliation for these patients. Historically poor responses to standard fractionated radiotherapy have led to the consideration of stereotactic radiosurgery as an option to overcome potential radioresistance and provide durable local control of these tumors. Here we report our institutional experience in treating spine metastases from pheochromocytoma with spine stereotactic radiosurgery (SSRS). METHODS AND MATERIALS: Our clinical databases were retrospectively reviewed for patients with metastatic pheochromocytoma treated with SSRS from 2000-2017. Seven patients with 16 treated metastatic spinal lesions were identified. Local control was evaluated using magnetic resonance imaging (MRI). Pain and symptom data were assessed to evaluate toxicity using Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The Kaplan-Meier method was used to assess local control and overall survival (OS). RESULTS: Median follow-up for treated lesions was 11 months (range 2.2 - 70.8). Most lesions were treated to a dose of 27 Gy in three fractions (62.5%). Other fractionation schemes included 24 Gy in one fraction (25%), 16 Gy in one fraction (6.3%), and 18 Gy in three fractions (6.3%). Treatment sites included the cervical spine (18.8%), thoracic spine (37.5%), lumbar spine (31.3%), and sacrum (12.5%). The crude local control rate was 93.7%, with one thoracic spine lesion progressing 20.7 months after treatment with 24 Gy in one fraction. Kaplan-Meier OS rates at 1 and 2 years after SSRS were 71.4% and 42.9%, respectively. Most common toxicities included acute grade 1-2 pain and fatigue. There was one case of vertebral fracture in a cervical spine lesion treated to 27 Gy in three fractions, which was managed non-surgically. CONCLUSION: Very few studies have explored the use of SSRS in metastatic pheochromocytoma. Our data suggest this modern radiation modality is effective, safe, and provides durable local control to palliate symptoms and potentially limit further metastatic seeding. Larger patient numbers and longer follow-up will further define the role of SSRS as a treatment option in these patients.

Low incidence of late failure and toxicity after spine stereotactic radiosurgery: Secondary analysis of phase I/II trials with long-term follow-up.

BACKGROUND AND PURPOSE: To characterize local control and late toxicity in long-term survivors prospectively-treated with spine stereotactic radiosurgery (SSRS). MATERIALS AND METHODS: From 2002 to 2011, 228 patients were prospectively-treated on protocol for metastatic disease of 261 vertebral sites. A subset of 52 patients surviving >4 years following treatment were collectively treated for 58 sites (encompassing 69 vertebrae) and underwent secondary analysis. Of all sites, 9% received prior radiation, and 16% encompassed multiple contiguous vertebrae. Radiation prescriptions were most commonly 24 Gy in 1 and 27 Gy in 3 fractions. Outcomes were evaluated via Kaplan-Meier, and associations analyzed via logistic regression. RESULTS: Median follow-up was 6.7 years (range: 49-142 months). Five-year local control by site was 91%, with late failures (>2 years) occurring in 3%. Overall and Grade ≥3 late toxicities (>2 years) were observed in 5% and 2% of sites. The last known neurologic event (grade 2 radiculopathy) was noted 2.1 years post-treatment, while the last documented fracture occurred at 4.1 years. No Grade ≥3 events were witnessed after 3.1 years post-SSRS, and no toxicities were noted after 4.1 years through end of follow-up. Re-irradiation, number of segments treated per site (1 vs. 2-3), and fractionation (1 vs. 3-5) were not associated with failure or toxicity. CONCLUSION: SSRS maintains excellent disease control and a favorable late toxicity profile even among long-term survivors, with very few failures or toxicities after 2 years in this prospectively-treated population. Overall, these data support the durable control and long-term safety of SSRS with extended follow-up.

Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.

OBJECTIVE: To identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer. METHODS: We retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method. RESULTS: The 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ±â€¯CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001). CONCLUSIONS: Combined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer.

The Insurance Approval Process for Proton Radiation Therapy: A Significant Barrier to Patient Care.

PURPOSE: Proton therapy is increasingly prescribed for cancer treatment, given its potential for improvements in clinical outcomes and toxicity reduction; however, insurance coverage continues to be a barrier to patient access. This study examined insurance approval and appeal outcomes at a large-volume proton therapy center to clarify the process and identify areas for improvement. METHODS AND MATERIALS: In 2013 to 2016, 1753 patients with thoracic or head and neck cancer were considered for proton therapy; 903 (553 thoracic, 350 head and neck) entered the insurance process. Rates of and times to approval and successful appeal after initial denial were calculated. Clinical factors were evaluated for association with insurance outcomes via logistic regression. RESULTS: Approval rates by Medicare (n = 538) and private insurance (n = 365) were 91% and 30% on initial request, at a median 3 days and 14 days from inquiry to determination. Of the 306 patients initially denied coverage, 276 appealed the decision, and denial was overturned for 189 patients (68%; median time, 21 days from initial inquiry). On multivariable analysis, Medicare (odds ratio [OR], 14.20; P < .001) was the strongest predictor of initial approval. Approval rates decreased from 2013 to 2014 versus 2015 to 2016 (OR 0.54; P = .001). For patients who appealed denial, multivariable analysis found no associations between approval and trial enrollment or tumor type. Submission of a comparison treatment plan (proton vs photon) indicating dosimetric advantage to normal tissues was associated with decreased likelihood of approval (OR 0.43; P = .006), as was a prescribed dose of ≥66 Gy (OR 0.48; P = .019). CONCLUSIONS: Despite an 87% ultimate approval rate for proton therapy, the insurance process is a resource-intensive barrier to patient access associated with significant time delays to cancer treatment. These findings, plus the lack of clinical correlates with insurance outcomes, highlight a need for increased efficiency, transparency, and collaboration among stakeholders to promote timely patient care and research.