21 Gy single fraction prostate HDR brachytherapy: 5-year results of a single institution prospective pilot study.

PURPOSE: To present the outcome and toxicity results of a prospective trial of 21 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- or intermediate-risk prostate cancer. METHODS AND MATERIALS: Patients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had low- or intermediate-risk prostate cancer with tumor stage ≤ T2b, PSA ≤ 15, and Gleason score ≤ 7. Patients underwent trans-rectal ultrasound-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy to a dose of 21 Gy. The primary endpoint was grade ≥ 2 urinary/GI toxicity rates. RESULTS: Twenty-six patients were enrolled with a median follow up of 5.1 years and median age of 64 years. 88.5% of patients had T1 disease, 15.4% had Gleason score 6 (84.6% Gleason 7), and median pre-treatment PSA was 5.0 ng/mL. Acute and chronic grade ≥ 2 urinary toxicity rates were 38.5% and 38.5%, respectively. There were no grade ≥ 2 acute or chronic GI toxicities. Six (23.1%) patients experienced biochemical failure, six (23.1%) patients experienced radiographic local failure, and five (19.2%) patients had biopsy-proven local failure. No patients developed regional lymph node recurrence or distant metastasis. 5-year overall survival and cause-specific survival were 96.2% and 100%, respectively. CONCLUSIONS: 21 Gy single fraction HDR brachytherapy was associated with modestly higher-than-anticipated chronic urinary toxicity, as well as high biochemical and local failure rates. The results from this prospective pilot study do not support the use of this regimen in standard clinical practice.

A population-based analysis of chemoradiation versus radiation alone in the definitive treatment of patients with stage I-II squamous cell carcinoma of the anus.

BACKGROUND: The optimal management of patients with stage I-II squamous cell carcinoma (SCC) of the anus is controversial. The current study evaluates the efficacy of combined chemotherapy and radiation therapy (CRT) versus radiation therapy (RT) alone in the treatment of these patients using the Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: SEER 18 Custom Data registries were queried for patients with stage I-II SCC of the anus. Univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. RESULTS: A total of 4,288 patients with stage I-II disease were identified, of whom 3,982 (93%) underwent CRT and 306 (7%) underwent RT. Median follow-up was 42 months. Approximately 30.8% had T1 disease and 69.2% had T2-T3 disease. The IPTW-adjusted 5-year overall survival (OS) was 76.7%, with no significant differences between the CRT and RT groups (77% vs. 73.5%, P=0.33). On multivariate IPTW-adjusted analysis, the lack of association between CRT use and OS was upheld (HR, 0.84, 95% CI, 0.65-1.08, P=0.2). On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I (T1N0) patients, while 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients. CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04). CONCLUSIONS: The current study suggests that omission of concurrent chemotherapy is not associated with inferior OS in patients with stage I SCC of the anus. However, combined chemoradiation was superior to radiation alone in patients with stage II disease. Prospective evidence is needed to optimize clinical decision-making in this patient population.

Higher biologically effective dose is associated with improved survival in patients with squamous cell carcinoma of the lung treated with stereotactic body radiation therapy.

BACKGROUND: Multiple studies have suggested that patients with early-stage SCC of the lung treated with SBRT are more susceptible to local failure compared to other NSCLC histologies. It is unknown if higher BED leads to improved outcomes in this patient population. We evaluated the effect of "high" BED versus "low" BED SBRT on overall survival (OS) in SCC and non-SCC NSCLC patients. METHODS: The National Cancer Database was used to identify patients with cT1-2N0M0 NSCLC diagnosed between 2006-2016 treated with 3-5 fraction SBRT. Patients were grouped by BEDhigh (>150 Gy) and BEDlow (≤132 Gy). Univariate and multivariable analysis using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment (IPTW) weighting was used to account for selection bias. RESULTS: We identified 4,717 eligible SCC patients and 8,807 eligible non-SCC NSCLC patients. In SCC patients, BEDhigh was associated with improved OS in both univariate and multivariate analysis (MVA HR 0.84 95% CI 0.76-0.92, p < 0.001), with estimated IPTW-adjusted 3-year OS of 49% compared to 41% for the BEDlow group. In contrast, BEDhigh was not associated with improved OS compared to BEDlow for non-SCC NSCLC patients (MVA HR 0.94 95% CI 0.86-1.04, p = 0.23), with estimated IPTW-adjusted 3-year OS of 54% and 53%, respectively. CONCLUSIONS: Our analysis suggests that in patients with early-stage NSCLC, SBRT regimens with BED > 150 Gy may confer a survival benefit in patients with SCC histology. Histology-based dose modification should be considered, and prospective validation may be warranted.

The Role of Postoperative Radiation Therapy for pN2 Non-small-cell Lung Cancer.

BACKGROUND: The role for postoperative radiation therapy (PORT) for patients with non-small-cell lung cancer (NSCLC) with mediastinal lymph node (LN) involvement (pN2 disease) is controversial. We compared surgery alone with PORT among patients with pN2 NSCLC. We then performed subset analyses to better delineate patients that might benefit from PORT. PATIENTS AND METHODS: We conducted a propensity score (PS)-matched, inverse probability of treatment weighting (IPTW) Surveillance, Epidemiology, and End Results (SEER) analysis of patients with pN2 disease from 1989 to 2016 with surgery alone or PORT. Multiple imputation with chained equations was used for missing LN data. RESULTS: A total of 8631 patients were included in this analysis; 4579 underwent surgery alone, and 4052 underwent PORT. Following PS matching and IPTW, there was no difference in overall survival (OS) (hazard ratio [HR], 0.99; P = .76). However, PORT improved OS among a subset of patients with a LN positive to sampled ratio ≥ 50% (HR, 0.90; P = .01). Moreover, there was a trend towards improved OS among this subset, even with chemotherapy (HR, 0.91; P = .09). CONCLUSION: PORT is not associated with an improvement or detriment in OS for all patients with pN2 NSCLC. However, patients with a positive to sampled LN ratio ≥ 50% may benefit, regardless of chemotherapy status. Nevertheless, PORT will remain the standard of care as we await the results of the ongoing LUNG ART trial.

Left anterior descending artery avoidance in patients receiving breast irradiation.

PURPOSE: Dose to the left anterior descending artery (LAD) may be significant in patients receiving left-sided irradiation for breast cancer. We investigated if prospective contouring and avoidance of the LAD during treatment planning were associated with lower LAD dose. METHODS AND MATERIALS: We reviewed dosimetric plans for 323 patients who received left whole breast or chest wall irradiation with or without internal mammary node (IMLN) coverage between 1/2014 and 1/2019 at a single institution. The LAD was contoured prospectively for 155 cases, and techniques were utilized to minimize LAD dose. Dose-volume-histograms from these patients were compared to those of 168 patients for whom the LAD was contoured retrospectively after treatment completion. EQD2 was calculated to account for fractionation differences. RESULTS: Compared to cases where the LAD was contoured retrospectively (n = 126), prospective LAD contouring (n = 124) was associated with lower unadjusted median max and mean LAD doses for 250 patients receiving whole-breast irradiation (WBI) without IMLN coverage: 8.5 Gy vs 5.2 Gy (p < 0.0001) and 3.6 Gy vs 2.7 Gy (p < 0.0001), respectively. EQD2 median max and mean LAD doses were also lower with prospective LAD contouring: 5.2 Gy vs 3.0 Gy (p < 0.0001) and 1.9 Gy vs 1.5 Gy (p < 0.0001), respectively. Compared to cases where the LAD was contoured retrospectively (n = 42), prospective LAD contouring (n = 31) was associated with lower max LAD doses for 73 patients with IMLN coverage: 20.4 Gy vs 14.3 Gy (p = 0.042). There was a nonsignificant reduction in median mean LAD dose: 6.2 Gy vs 6.1 Gy (p = 0.33). LAD doses were reduced while maintaining IMLN coverage (mean V90%Rx >90%). CONCLUSIONS: Prospective contouring and avoidance of the LAD were associated with lower max and mean LAD doses in patients receiving WBI and with lower max LAD doses in patients receiving IMLN treatment. Further reduction in LAD dose may require stricter optimization weighting or compromise in IMLN coverage.

Deep convolutional neural networks for automatic segmentation of thoracic organs-at-risk in radiation oncology - use of non-domain transfer learning.

PURPOSE: Segmentation of organs-at-risk (OARs) is an essential component of the radiation oncology workflow. Commonly segmented thoracic OARs include the heart, esophagus, spinal cord, and lungs. This study evaluated a convolutional neural network (CNN) for automatic segmentation of these OARs. METHODS: The dataset was created retrospectively from consecutive radiotherapy plans containing all five OARs of interest, including 22,411 CT slices from 168 patients. Patients were divided into training, validation, and test datasets according to a 66%/17%/17% split. We trained a modified U-Net, applying transfer learning from a VGG16 image classification model trained on ImageNet. The Dice coefficient and 95% Hausdorff distance on the test set for each organ was compared to a commercial atlas-based segmentation model using the Wilcoxon signed-rank test. RESULTS: On the test dataset, the median Dice coefficients for the CNN model vs. the multi-atlas model were 71% vs. 67% for the spinal cord, 96% vs. 94% for the right lung, 96%vs. 94% for the left lung, 91% vs. 85% for the heart, and 63% vs. 37% for the esophagus. The median 95% Hausdorff distances were 9.5  mm vs. 25.3 mm, 5.1  mm vs. 8.1 mm, 4.0  mm vs. 8.0 mm, 9.8  mm vs. 15.8 mm, and 9.2 mm vs. 20.0 mm for the respective organs. The results all favored the CNN model (P < 0.05). CONCLUSIONS: A 2D CNN can achieve superior results to commercial atlas-based software for OAR segmentation utilizing non-domain transfer learning, which has potential utility for quality assurance and expediting patient care.

Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM. METHODS: We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM. RESULTS: 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 - 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 - 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease. CONCLUSIONS: These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

Post-mastectomy radiotherapy is associated with improved overall survival in T3N0 patients who do not receive chemotherapy.

BACKGROUND AND PURPOSE: There is limited retrospective evidence addressing the utility of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer. We performed a retrospective analysis of the National Cancer Database (NCDB) comparing overall survival (OS) in T3N0 patients treated with mastectomy alone (MTX) or with PMRT. MATERIALS AND METHODS: We performed a matched-cohort analysis of NCDB breast cancer patients with pT3N0 disease who did not receive NAC, or cT3N0 patients who received NAC treated between 2006 and 2014. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. RESULTS: We identified 13,901 eligible patients. In the pT3N0 cohort, median follow-up was 47 months for the MTX group and 50 months for the PMRT group. In the cT3N0 cohort, median follow-up was 44 months for the MTX group and 46 months for the PMRT group. OS was higher in pT3N0 patients treated with PMRT compared to MTX: 7-year OS of 74% vs. 65% (P < 0.001). Doubly robust multivariable analysis showed an association between PMRT and improved OS (HR 0.78, 95% CI 0.68-0.89, P < 0.001). There was no benefit to PMRT in patients who received adjuvant chemotherapy (AC). In the NAC cohort, PMRT did not change OS, with 7-year OS of 78% with MTX and 79% with PMRT. There was a trend of improved OS with PMRT in patients with residual disease in the breast and lymph nodes (HR 0.70, 95% CI 0.46-1.07). CONCLUSION: PMRT improves OS in patients with pT3N0 disease, but the benefit appears limited to those who do not receive AC. PMRT does not improve OS in patients with cT3N0 disease who receive NAC, but there might be a benefit in patients with a poor response to chemotherapy. However, longer follow-up may be needed to make a definitive conclusion about the benefit of PMRT in patients who receive chemotherapy.

Trimodality therapy for atypical teratoid/rhabdoid tumor is associated with improved overall survival: A surveillance, epidemiology, and end results analysis.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS: The majority of patients were <3 years old (75.8%). Patients <3 were more likely to be treated without RT as compared with older patients (62% vs 38%). Doubly robust MVA identified distant disease as a negative prognostic factor (HR 2.1, P = 0.003), whereas trimodality therapy was strongly protective (HR 0.39, P < 0.001). Infants (<1), toddlers (1-2), and older children (3+) all benefited from trimodality therapy, with largest benefit for infants (HR 0.34, P = 0.02) and toddlers (HR 0.31, P < 0.001). CONCLUSION: The current study provides further evidence that trimodality therapy improves clinical outcomes among patients with AT/RT. This finding was most pronounced for younger patients; therefore, further studies are needed to confirm this finding in this vulnerable population.

Very low dose bevacizumab for the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. The genetic mutations that cause this disease result in elevated levels of vascular endothelial growth factor, which is inhibited by bevacizumab. Previous studies have shown bevacizumab treatment to be effective in reducing symptoms, but study protocols have all used oncological dosing parameters, which carry several well-described serious side effects. This study investigates whether drastically lower dosages of bevacizumab than normally used in oncological treatment could control epistaxis in patients with HHT and medically refractory epistaxis. A prospective, open-label, noncomparative study enrolled six patients receiving 0.125-mg/kg infusions of bevacizumab once every 4 weeks for a total of six infusions. Severity of epistaxis was assessed with the epistaxis severity score, and quality-of-life measures were followed with the 20-item Sino-Nasal Outcome Test and 36-item Short Form surveys. A statistically significant improvement was seen in the control of epistaxis severity and frequency, with minimal negative side effects and high patient satisfaction. Very low dose bevacizumab treatment is an effective method of controlling medically refractory epistaxis in patients with HHT and additional investigation to optimize dosing guidelines is warranted.