Ultracentral Tumors Treated With Stereotactic Body Radiotherapy: Single-Institution Experience.

INTRODUCTION: Patients with ultracentral lung tumors, whose planning target volume directly contacts or overlaps the proximal bronchial tree, trachea, esophagus, pulmonary vein, or pulmonary artery, may be at higher risk of toxicity when treated with stereotactic body radiotherapy (SBRT). We reviewed the outcomes and toxicities of ultracentral lung tumors and compared the results with central lung tumors. PATIENTS AND METHODS: A review of our institutional prospective database of patients treated with lung SBRT from January 2006 to December 2015 was conducted. Patients with central tumors (RTOG 0813 definition) and ultracentral tumors were included. RESULTS: In total, 180 central and 26 ultracentral tumors were analyzed. The majority of patients received 60 Gy in 8 fractions (53.9%) or 48 Gy in 4 fractions (29.1%). The rates of any grade 2 or higher toxicity were 8.4% (n = 16) in the central group and 7.9% (n = 2) in the ultracentral group (P = .88). There were no observed grade 4 or 5 toxicities. In the nonmetastatic primary lung cancer cohort (n = 182), the median overall survival was 39.4 months versus 23.8 months (P = .40) and cause-specific survival was 55.5 months versus 28.2 months (P = .34) for central and ultracentral tumors, respectively. The 2-year cumulative local, regional, and distant failure rates were 3.3% versus 0 (P = .36), 9.1% versus 5.0% (P = .5), and 17.7% versus 18.7% (P = .63) in the central and ultracentral groups, respectively. CONCLUSION: In our experience, with strict adherence to planning parameters, SBRT to ultracentral tumors resulted in effective local control and no excessive risk of toxicity compared to central tumors.

SUNSET: Stereotactic Radiation for Ultracentral Non-Small-Cell Lung Cancer-A Safety and Efficacy Trial.

BACKGROUND: Lung stereotactic body radiotherapy (SBRT) is considered a standard curative treatment for medically inoperable early stage non-small-cell lung cancer (NSCLC). Patients with ultracentral tumors (signifying tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, or pulmonary artery) may be at higher risk of serious toxicities such as bronchial stricture and collapse, esophageal strictures, tracheal-esophageal fistula, and hemorrhage. The primary objective of the study is to determine the maximum tolerated dose of radiotherapy for ultracentral NSCLC. METHODS: This multicenter phase 1 dose-escalation study will use a time-to-event continual reassessment method (TITE-CRM). Accrual will start at level 1 (60 Gy in 8 fractions delivered daily). The model will use all available information from previously accrued patients to assign the highest dose with a predicted risk of grade 3-5 toxicity of 30% or less. All patients with newly diagnosed stage T1-3 N0M0 NSCLC (International Union Against Cancer, 8th edition) with tumor size ≤ 6 cm and meeting the criteria for ultracentral location (ie, tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery) will be eligible for this study. DISCUSSION: It is important to identify a safe dose-fractionation regimen for treating ultracentral tumors with SBRT. In addition, the data from this study may be informative in guiding future studies on the use of SBRT in treating malignancies within the mediastinum-for example, for salvage treatment of mediastinal lymph nodes for recurrent NSCLC or mediastinal oligometastases.

Low Incidence of Esophageal Toxicity After Lung Stereotactic Body Radiation Therapy: Are Current Esophageal Dose Constraints Too Conservative?

PURPOSE: To explore and quantify the relationship between esophageal dose and toxicity in the setting of lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: This analysis was conducted on the basis of a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54 Gy/3 fractions, 48 Gy/4 fractions alternate days, or 60 Gy/8 fractions daily. Toxicity was prospectively graded using Common Terminology Criteria for Adverse Events version 3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiation therapy dose, in 2-Gy-equivalent dose, using an α/ß ratio of 3 Gy in the linear-quadratic model. RESULTS: A total of 632 patients were analyzed. The median follow-up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute grade ≥1 esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n = 21). The median (range) esophageal doses were 11.8 Gy (0.2-48.2 Gy), 10.34 Gy (0.17-44.5 Gy), and 9.63 Gy (0.08-43 Gy) for Dmax, D1cc, and D2cc, respectively. A 15% risk of esophageal toxicity was associated with a 2-Gy-equivalent dose of Dmax 141.6 Gy, D1cc 123.61 Gy, and D2cc 117.6 Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity, and the remainder had grade 2 or lower toxicity. CONCLUSIONS: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumors, may provide more accurate dose-toxicity parameters.

Survival Impact of Cardiac Dose Following Lung Stereotactic Body Radiotherapy.

INTRODUCTION: The purpose of this study was to determine the impact of radiation dose to substructures of the heart in lung stereotactic body radiotherapy (SBRT) patients on non-cancer-related deaths. METHODS: Patients treated with lung SBRT at a single institution from 2005 to 2013 were included. The heart and its substructures were contoured, and dose was calculated including mean, max, and max 10 cc dose. Clinical variables including stage, histology, age, gender, Charlson comorbidity index (CCI), preexisting cardiac disease, pulmonary function (forced expiratory volume in 1 second, diffusion capacity), and smoking status were explored for association with non-cancer-related deaths in univariable (UVA) and multivariable (MVA) analyses. Heart dosimetric parameters were correlated with the risk of radiation pneumonitis (RP) using UVA and MVA. RESULTS: A total of 189 patients were included with median age of 76 years (range, 48-93 years). Of these patients, 45.5% were female, 27.5% were T2, 16.9% were current smokers, 64% had preexisting cardiac risk factors, and 34.5% had CCI score of ≥ 3. Mean lung dose ± SD was 456 ± 231 cGy. Heart max, mean, and 10 cc doses were 1867 ± 1712 cGy, 265 ± 269 cGy, and 1150 ± 1075 cGy, respectively. There were 14 (7.4%) ≥ Grade 2 RP and 3 (1.6%) were ≥ Grade 3. The median overall survival was 37.3 months (95% confidence interval, 29.8-45.3 months). On UVA, female gender (P < .01), higher Eastern Cooperative Oncology Group (P = .01), cardiac risk (P < .01), CCI (P < .01), and bilateral ventricles max dose (P = .02) were associated with non-cancer-related deaths; on MVA, bilateral ventricles max dose was significant (P = .05). No heart parameters were associated with RP. CONCLUSIONS: Higher bilateral ventricles max dose is associated with poorer survival. Heart dose parameters should be considered when planning patients for SBRT.

Debate: single-fraction treatment should be standard in the retreatment of uncomplicated bone metastases.

There is controversy surrounding the optimal radiotherapy dose-fractionation for retreatment of painful bone metastases. Two commonly used regimens are 8 Gy in a single-fraction or 20 Gy in five or eight fractions. Randomized evidence, including the NCIC SC.20 randomized clinical trial, has failed to standardize clinical practice. Practitioners who use single-fraction regimens cite patient convenience, fewer acute adverse effects, and better cost-effectiveness. Practitioners who prefer multiple fractions raise questions about the interpretation of data that justifies single-fraction treatment, and the possibility that single-fraction treatment may provide inferior pain relief. Given this clinical controversy, should single-fraction irradiation be standard in retreatment of uncomplicated bone metastases? In this article, two teams debate both sides of the argument with commentary to summarize the relevant issues. The conclusion from the debate is that the "standard" treatment should be individualized to the patient with shared-decision making between the oncologist, patient and family members. In a cancer patient with poor performance status and short life expectancy, single-fraction repeat radiotherapy may be preferred; in a patient with a prolonged disease course, perhaps multiple fraction retreatments would be preferred. The choice between different fractionation schemes depends on an assessment of individual patient factors, tumour factors and unique patient circumstances.

Reasons for poor accrual in palliative radiation therapy research studies.

BACKGROUND: Patients with advanced-stage cancer commonly have multiple symptoms, poor performance status, and limited life expectancies. Despite the need for evidence-based practice and guidelines for palliative radiation therapy (RT), conducting clinical palliative research has proven to be a challenge in the past because of low accrual rates and high patient attrition. We explore the change in accrual rates, reasons for nonparticipation in palliative RT clinical research trials, and factors that contributed to the increase in accrual over a 3-year period. PATIENTS AND METHODS: A record was kept for all patients seen at the Rapid Response Radiotherapy Program between 2002 and 2005, including information on patient demographics, disease characteristics, and whether patients were accrued into >/=1 palliative research study at the time of clinic visit. If a patient did not participate in a study, the reason for nonaccrual was recorded. RESULTS: Despite previous difficulties, changes to the methods of conducting palliative research and study design have resulted in an increase in patient accrual, from 14% to an average of approximately 60%. The implementation of a full-time clinical research assistant and a simple study design with realistic eligibility criteria contributed to the increase in patient participation. CONCLUSION: Difficulties in conducting palliative clinical research trials were improved through changes in study design and research administration. Future clinics should use a dedicated clinical research assistant responsible for patient recruitment and study management. Studies should be designed specifically for the patient population receiving palliative care and should involve clearly defined and realistic eligibility criteria and brief assessments.

Role of clathrin-mediated endocytosis during vesicular stomatitis virus entry into host cells.

Vesicular stomatitis virus (VSV) is well established to enter cells by pH-dependent endocytosis, but mechanistic aspects of its internalization have remained unclear. Here, we examined the functional role of clathrin in VSV entry by expression of a dominant-negative mutant of Eps15 (GFP-Eps15Delta95/295), a protein essential for clathrin-mediated endocytosis. Whereas expression of GFP alone had no effect on VSV infection, expression of GFP-Eps15Delta95/295 severely limited infection. As independent ways to examine clathrin function, we also examined cells that had been treated with chlorpromazine and utilized small interfering RNA (siRNA) techniques. Inhibition of clathrin-mediated endocytosis by chlorpromazine treatment, as well as clathrin knock-down using siRNA duplexes directed against the clathrin heavy chain, also prevented VSV infection. In combination with previous morphological approaches, these experiments establish clathrin as an essential component needed for endocytosis of VSV.