Evaluation of a generalized knowledge-based planning performance for VMAT irradiation of breast and locoregional lymph nodes-Internal mammary and/or supraclavicular regions.

PURPOSE: To evaluate the performance of eleven Knowledge-Based (KB) models for planning optimization (RapidPlantm (RP), Varian) of Volumetric Modulated Arc Therapy (VMAT) applied to whole breast comprehensive of nodal stations, internal mammary and/or supraclavicular regions. METHODS AND MATERIALS: Six RP models have been generated and trained based on 120 VMAT plans data set with different criteria. Two extra-structures were delineated: a PTV for the optimization and a ring structure. Five more models, twins of the previous models, have been created without the need of these structures. RESULTS: All models were successfully validated on an independent cohort of 40 patients, 30 from the same institute that provided the training patients and 10 from an additional institute, with the resulting plans being of equal or better quality compared with the clinical plans. The internal validation shows that the models reduce the heart maximum dose of about 2 Gy, the mean dose of about 1 Gy and the V20Gy of 1.5 Gy on average. Model R and L together with model B without optimization structures ensured the best outcomes in the 20% of the values compared to other models. The external validation observed an average improvement of at least 16% for the V5Gy of lungs in RP plans. The mean heart dose and for the V20Gy for lung IPSI were almost halved. The models reduce the maximum dose for the spinal canal of more than 2 Gy on average. CONCLUSIONS: All KB models allow a homogeneous plan quality and some dosimetric gains, as we saw in both internal and external validation. Sub-KB models, developed by splitting right and left breast cases or including only whole breast with locoregional lymph nodes, have shown good performances, comparable but slightly worse than the general model. Finally, models generated without the optimization structures, performed better than the original ones.

Impact of radiation techniques on lung toxicity in patients with mediastinal Hodgkin's lymphoma.

PURPOSE: Mediastinal radiotherapy (RT), especially when combined with bleomycin, may result in substantial pulmonary morbidity and mortality. The use of modern RT techniques like intensity-modulated radiotherapy (IMRT) is gaining interest to spare organs at risk. METHODS: We evaluated 27 patients who underwent RT for Hodgkin's lymphoma between 2009 and 2013 at our institution. For each patient, three different treatment plans for a 30-Gy involved-field RT (IFRT) were created (anterior-posterior-posterior-anterior setup [APPA], 5­field IMRT, and 7­field IMRT) and analyzed concerning their inherent "normal tissue complication probability" (NTCP) for pneumonitis and secondary pulmonary malignancy. RESULTS: The comparison of different radiation techniques showed a significant difference in favor of standard APPA (p < 0.01). The risk of lung toxicity was significantly higher in plans using 7­field IMRT than in plans using 5­field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5­field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7­field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7­field IMRT over 5­field IMRT (Burman: 0.6%). Further analysis showed an increase in risk for secondary pulmonary malignancies to be statistically significant (p < 0.01); mean induction probability for pulmonary malignoma was 0.1% higher in plans using 5­field IMRT than APPA and 0.19% higher in plans using 7­field IMRT than APPA as well as 0.09% higher in plans using 7­field IMRT than 5­field IMRT. During a median follow-up period of 65 months (95% confidence interval: 53.8-76.2 months), only one patient developed radiation-induced pneumonitis. No secondary pulmonary malignancies have been detected to date. CONCLUSION: Radiation-induced lung toxicity is rare after treatment for Hodgkin lymphoma but may be influenced significantly by the RT technique used. In this study, APPA RT plans demonstrated a decrease in potential radiation pneumonitis and pulmonary malignancies. Biological planning using NTCP may have the potential to define personalized RT strategies.

Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Radiotherapy planning techniques to reduce lung irradiation in head and neck cancer patients with mediastinal involvement.

The number of patients with head and neck squamous cell carcinoma (HNC) with mediastinal involvement is small, and appropriate treatment techniques have not been widely discussed. This study aimed to compare the efficacy of radiotherapy planning techniques in reducing lung irradiation while retaining target coverage. Among all HNC patients with mediastinal involvement who underwent radiotherapy between 2007 and 2014 at our hospital, seven consecutive patients were included in this study. Four different treatment plans were generated for each patient as follows: seven-field intensity-modulated radiation therapy (IMRT), modified IMRT in which the lateral beams avoided the lungs, three-full-arc volumetric-modulated arc therapy (VMAT), and VMAT with lung avoidance. We compared the outcomes of IMRT and VMAT plans using the paired t-test. After modifications were made to avoid lung irradiation, IMRT values for V5Gy and V20Gy decreased from 713.2 to 503.6 cm3 (p = 0.011) and from 338.8 cm3 to 267.0 cm3 (p = 0.058), respectively. In the case of VMAT, lung V5Gy and V20Gy values decreased from 754.8 to 601.0 cm3 (p = 0.004) and from 328.5 to 255.7 cm3 (p = 0.020), respectively. Other factors did not significantly differ between the plans. In both IMRT and VMAT planning, lung doses were significantly reduced following the modification of the beams that cross the lungs with target coverage maintenance.

Introducing operator characteristic curves to define appropriate frequency of quality control tests: A case study involving whole breast radiotherapy image guidance.

BACKGROUND AND PURPOSE: Sampling theory and operator characteristic curves are methods that can determine an optimal schedule for quality control tests. We apply this method to positional data for whole breast radiotherapy since several surveys report inconsistent image guidance practice for this technique. MATERIALS AND METHODS: Positional errors were defined, for 55 consecutive breast cancer patients, by comparing the central lung distance measured on portal images with that obtained from the corresponding digitally reconstructed radiograph. From the distribution of positional errors, the probability of a setup error >5 mm in the direction of the mediastinum was established. Using operator characteristic curves, we compared the effectiveness of various image-guidance schedules in dealing with such errors. We also calculated the dosimetric impact of undetected errors. RESULTS: Setup errors >5 mm towards the mediastinum for this cohort were unlikely, at 2.7%. Imaging half of the fractions protects most patients against three or more undetected errors. Undetected, such an error increases, on average, the maximum dose to 10 cm3 of the heart by 50 cGy, the mean heart dose by 4 cGy, and the left lung V20Gy by 0.2%; therefore, the clinical impact is minute. Given that detected positional errors outside of tolerance are corrected, their residual likelihood decreases with the ratio of fractions being imaged. CONCLUSIONS: For most tangential breast radiotherapy patients, setup errors >5 mm towards the mediastinum are unlikely, and their dosimetric impact is remote. Imaging half of the fractions of a course of whole breast radiotherapy prevents these errors to occur more than twice.

Dosimetric comparison of incidental radiation to the internal mammary nodes after breast-conserving surgery using 3 techniques-inverse intensity-modulated radiotherapy, field-in-field intensity-modulated radiotherapy, and 3-dimensional conformal radiotherapy: A retrospective clinical study.

BACKGROUND: The study aimed to evaluate and compare the dosimetric parameters of incidental irradiation to internal mammary node (IMN) from inverse intensity-modulated radiotherapy (I-IMRT) and field-in-field IMRT (F-IMRT), and 3-dimensional conformal radiotherapy (3D-CRT) in patients after breast-conservation surgery (BCS). METHODS: Eighty-four patients with BCS were selected. The breast, tumor bed, and IMN, including intercostal spaces (ICS) 1 to 3, were contoured. Three plans were generated. The prescription doses for the breast and tumor bed were 50.4 Gy/28 F and 60.2 Gy/28 F, respectively. If there was no tumor bed boost, patient was treated with 50 Gy/25 F for the whole breast only. The IMN was not included in planning target volume. RESULTS: The median mean dose (Dmean) of the IMNtotal (ICS 1-3) was 2740.2 cGy, 2973.9 cGy, and 2951.4 cGy for I-IMRT, F-IMRT, and 3D-CRT, respectively. Differences were not detected between any of the plans. After separating ICS 1 to 3 for further analysis, neither of the Dmean of ICS 1 to 2 was significantly different between the plans. However, for ICS 3, the median Dmean was highest for I-IMRT, and those for 3D-CRT and F-IMRT were not significantly different. After separating the 3 techniques for further analysis, the median Dmean was highest in ICS 3 and lowest in ICS 1 for all the 3 techniques. CONCLUSION: All 3 techniques failed to attain an adequate dose to cure subclinical disease, and there were no significant differences among the 3 techniques. It is risky to avoid IMN irradiation (IMNI) using any of the 3 techniques during whole-breast radiotherapy in women with indications for elective IMNI. However, in era of systematic therapy, whether the incidental dose could meet clinical acquirements needs further follow-up.

Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model.

A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3 × 5 or 3 × 8 Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n = 15/group, ntotal = 90). Tumors were assigned to volumes receiving 90-107%, 50-90%, 5-50%, and <5% of the target dose and characterized by histology and loss-of-heterozygosity (LOH). Irradiated rats predominantly developed lymphomas and sarcomas in areas receiving 50-107% (n = 26) rather than 5-50% (n = 7) of the target dose. Latency was significantly shortened only after 3 × 8 Gy vs. controls (p < 0.0001). The frequency (14/28 vs. 19/29; p = 0.29) and latency (218 vs. 189 days; p = 0.17) of radiation-associated tumors were similar after VMAT vs. AP/PA. LOH was strongly associated with sarcoma but not with treatment. The results do not support the hypothesis that IMRT increases the risk of second cancer. Thus the current practice of withholding dose-sparing IMRT from young patients may need to be re-evaluated.

Outcomes of Patients With Severe Symptomatic Aortic Valve Stenosis After Chest Radiation: Transcatheter Versus Surgical Aortic Valve Replacement.

Background Patients with symptomatic severe aortic stenosis and a history of chest radiation therapy represent a complex and challenging cohort. It is unknown how transcatheter aortic valve replacement ( TAVR ) compares with surgical aortic valve replacement in this group of patients, which was the objective of this study. Methods and Results We retrospectively reviewed all patients with severe aortic stenosis who underwent either TAVR or surgical aortic valve replacement at our institution with a history of mediastinal radiation (n=55 per group). End points were echocardiographic and clinical outcomes in-hospital, at 30 days, and at 1 year. Inverse propensity weighting analysis was used to account for intergroup baseline differences. TAVR patients had a higher STS score than surgical aortic valve replacement patients (5.1% [3.2, 7.7] versus 1.6% [0.8, 2.6], P<0.001) and more often ( P<0.01 for all) a history of atrial fibrillation (45.5% versus 12.7%), chronic lung disease (47.3% versus 7.3%), peripheral arterial disease (38.2% versus 7.3%), heart failure (58.2% versus 18.2%), and pacemaker therapy (23.6% versus 1.8%). Postoperative atrial fibrillation was less frequent (1.8% versus 27.3%; P<0.001) and hospital stay was shorter in TAVR patients (4.0 [2.0, 5.0] versus 6.0 [5.0, 8.0] days; P<0.001). The ratio of observed-to-expected 30-day mortality was lower after TAVR as was 30-day mortality in inverse propensity weighting-adjusted Kaplan-Meier analyses. Conclusions In patients with severe aortic stenosis and a history of chest radiation therapy, TAVR performs better than predicted along with less adjusted 30-day all-cause mortality, postoperative atrial fibrillation, and shorter hospitalization compared with surgical aortic valve replacement. These data support further studies on the preferred role of TAVR in this unique patient population.

Abscopal effect of radiation on multiple lung metastases of lung adenocarcinoma: a case report.

BACKGROUND: Abscopal effect is the out-of-field response to localized irradiation therapy that results in systemic antitumorigenic effects such as the regression of a tumor distant from the target site. CASE PRESENTATION: A 76-year-old woman was diagnosed with pulmonary adenocarcinoma (cT1bN0M0 stage IA), and right upper lobectomy was performed in November 2015. The pathological stage was pT1bN2M0 stage IIIA. Genomic analysis revealed an EGFR mutation. Immunohistochemical analysis revealed a programmed death-ligand 1 tumor proportion score of < 1%. The patient was under watchful observation without adjuvant chemotherapy. Multiple mediastinal and right hilar lymph node metastases were found in February 2018. Radiation therapy at a total dose of 60.0 Gy distributed in 30 fractions was performed over a period of 6 weeks. A computed tomography (CT) scan performed 6 weeks after irradiation therapy showed a reduction in lymph node metastases. However, left hilar and right supraclavicular lymph node metastases and multiple pulmonary metastases were newly observed outside of the irradiation field. A CT scan performed 6 weeks later showed a dramatic complete disappearance of the previously observed pulmonary metastases. No chemotherapy was administered during the period. CONCLUSION: This was a case of abscopal effect: irradiation of the mediastinum resulted in the disappearance of multiple pulmonary metastases in both lungs.

Dosimetric comparison of anterior posterior-posterior anterior 2-field three-dimensional conformal radiotherapy, 4-field three-dimensional conformal radiotherapy and "forward" plan intensity modulated radiotherapy techniques in female lymphoma patients irradiated to neck and mediastinum.

AIM: Dosimetric comparison of three different techniques in female lymphoma patients who had radiotherapy (RT) to the neck and mediastinum. SETTING AND DESIGN: Retrospective clinical study. MATERIALS AND METHODS: Computerized tomography-simulator images of eight patients were obtained retrospectively. Using 6 MV-X photon energy, RT plans were formed with three different techniques (anterior posterior-posterior anterior 2-field three-dimensional conformal RT [AP-PA 2-field 3D-CRT], 4-field 3D-CRT and "forward" plan intensity modulated RT [FPIMRT]). Comparisons were in terms of homogeneity index (HI), conformity index (CI), and inhomogeneity coefficient for planning target volume (PTV); mean lung dose, V5Gy, V10Gy, V20Gy, V30Gy for lung; Dmean, V7.5Gy, V15Gy, V25Gy for heart; Dmean, V3.5Gy, V10Gy, V20Gy for breast; Dmax for spine; Dmean, V10Gy, V18Gy, V25Gy, V30Gy for thyroid. STATISTICAL ANALYSIS USED: Since nonparametric tests had to be used due to the study population being < 30, Friedman and Wilcoxon signed-rank tests were implemented in trilateral and bilateral comparison of techniques, respectively. For statistical significance, P value was required to be <0.05. RESULTS: When FPIMRT was compared with AP-PA and 4-field techniques with respect to, HI (AP-PA/FPIMRT P: 0.017; 4-field/FPIMRT P: 0.03) and CI (AP-PA/FPIMRT P: 0.018; 4-field/FPIMRT P: 0.042), FPIMRT was more advantageous. In addition, FPIMRT was found more useful in terms of Dmax (AP-PA/FPIMRT P: 0.012; 4-Field/FPIMRT P: 0.012) for spinal cord and Dmean (AP-PA/FPIMRT P: 0.012; 4-field/FPIMRT P: 0.012) for thyroid. CONCLUSION: FPIMRT was superior in terms of PTV homogeneity and conformity. However, it was observed that for normal tissues, FPIMRT was advantageous only for spinal cord and thyroid; but it was not the most advantageous technique for some of the dose-volume parameters of the breast, lung, and heart.

Dose to organs in the supraclavicular region when covering the Internal Mammary Nodes (IMNs) in breast cancer patients: A comparison of Volumetric Modulated Arc Therapy (VMAT) versus 3D and VMAT.

During breast/chest wall and regional nodal irradiation (RNI), standard 3D conformal techniques can fail to meet the dosimetric constraints for the heart and ipsilateral lung. VMAT can improve the dosimetric sparing of the heart and lungs. However the unnecessary increase in dose to the organs in the supraclavicular region as a result of using VMAT can be avoided. In this work we investigate potential dosimetric advantages of combining 3D with VMAT to improve sparing of these organs. Ten breast cancer patients requiring radiation therapy to the breast/chest wall and RNI including the IMNs, and who did not have a viable 3D conformal plan were chosen for the study. Each patient was planned with VMAT and with a combination of 3D for the supraclavicular region and VMAT for the breast/chest wall followed by a dosimetric comparison. Prescription dose was 50.4 Gy in 28 fractions. For similar coverage to the PTV and IMNs, doses to the esophagus and cord were reduced by 17.8 Gy and 15.5 Gy while mean dose to the thyroid and larynx were also reduced by 16.5 Gy and 11.7 Gy respectively. Maximum brachial plexus dose was the same in both techniques. The ipsilateral lung V20Gy increased by 3.1% but was still < 30%. No significant differences were noted in doses to the heart, total lung and contralateral breast. However V5Gy to the contralateral lung was reduced by 8.5% with the combined plan. Using 3D conformal planning for the supraclavicular region and VMAT over the breast/chest wall improves sparing of the esophagus, cord, thyroid and larynx while reducing low dose exposure to the contralateral lung and does not compromise doses to the heart, ipsilateral lung and total lung.

Lymphoblastic Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group (ILROG).

Presentation with a large mediastinal mass is a hallmark of acute lymphoblastic lymphoma, a disease that is treated in the same way as acute lymphoblastic leukemia even in the absence of marrow involvement. The role of mediastinal radiation for patients who achieve complete remission after chemotherapy has been overlooked and controversial. This document presents current knowledge on the role of radiation for lymphoblastic lymphoma and best practices for addressing how to deliver mediastinal radiation with modern technology.

Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer.

PURPOSE: Recent data indicate consolidative radiation therapy improves progression-free survival (PFS) for patients with oligometastatic non-small cell lung cancer (NSCLC). Data on long-term outcomes are limited. METHODS AND MATERIALS: This prospective, multicenter, single-arm, phase 2 trial was initiated in 2010 and enrolled patients with oligometastatic NSCLC. Oligometastatic disease was defined as a maximum of 5 metastatic lesions for all disease sites, including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Patients achieving a partial response or stable disease after 3 to 6 cycles of platinum-based chemotherapy were treated with CRT to the primary and metastatic sites of disease, followed by observation alone. The primary endpoint was PFS, with secondary endpoints of local control, overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled between October 2010 and October 2015, and 27 were eligible for consolidative radiation therapy. The study was closed early because of slow accrual but met its primary endpoint for success, which was PFS >6 months (P < .0001). The median PFS (95% confidence interval) was 11.2 months (7.6-15.9 months), and the median OS was 28.4 months (14.5-45.8 months). Survival outcomes were not significantly different for patients with brain metastases (P = .87 for PFS; P = .12 for OS) or lymph node involvement (P = .74 for PFS; P = .86 for OS). CONCLUSIONS: For patients with oligometastatic NSCLC, chemotherapy followed by consolidative radiation therapy without maintenance chemotherapy was associated with encouraging long-term outcomes.

Plan optimization for mediastinal radiotherapy: Estimation of coronary arteries motion with ECG-gated cardiac imaging and creation of compensatory expansion margins.

BACKGROUND AND PURPOSE: Inadvertent heart and coronary arteries (CA) irradiation may increase the risk of coronary artery disease (CAD) in patients receiving thoracic irradiation. To date, the entity of cardiac-related CA displacement and the possible margins to be used for planning organs at risk volume (PRV) have been poorly described. Aim of this study was to quantify CA displacement and to estimate PRV through the use of ECG-gated computed tomography (CT) scans. MATERIAL AND METHODS: Eight patients received an ECG-gated intravenous contrast enhanced CT for non-cancer related reasons. Nine data sets were reconstructed over the entire R-R cycle with a dedicated retrospective algorithm and the following structures were delineated: Left main trunk (LM), left anterior descending (LAD), left circumflex (CX) and right coronary artery (RCA). CA displacements across the different cardiac phases were evaluated in left-right (X), cranio-caudal (Y) and anteroposterior (Z) directions using the McKenzie-van Herk formula (1.3 * Σ + 0.5 * σ). RESULTS: The following CA displacements were found in X, Y and Z coordinates: 3.6, 2.7 and 2.7 mm for LMT, respectively; 2.6, 5.0 and 6.8 mm for LAD, respectively; 3.5, 4.5 and 3.7 mm for CX, respectively; 3.6, 4.6 and 6.9 mm for RCA, respectively. Based on the mean displacements, we created a PRV of 3 mm for LM, 4 mm for CX and 5 mm for LAD and RCA. CONCLUSION: CA showed relevant displacements over the heart cycle, suggesting the need for a specific PRV margin to accurately estimate the dose received by these structures and optimize the planning process.

Photons, protons or carbon ions for stage I non-small cell lung cancer - Results of the multicentric ROCOCO in silico study.

PURPOSE: To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. METHODS: For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. RESULTS: The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. CONCLUSION: On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient.

Prophylactic use of colchicine in preventing radiation induced coronary artery disease.

Radiation therapy is one of the primary treatments in fighting breast cancer, one of the most common cancers in the US. One of the dose limiting factors of this therapy is radiation induced heart damage that results from mediastinal radiation. Recently statins, a medication typically used to lower cholesterol levels, have been suggested as a prophylactic treatment to potentially mitigate this process. Similarly, we hypothesized whether colchicine, an anti-inflammatory medication that is presently used in the treatment of gout and pericarditis, might be used to prevent coronary artery disease induced by radiation therapy. We hypothesize that colchicine may help prevent the deleterious effect on coronary arteries induced by radiation therapy by inhibiting inflammation and platelet aggregation. The pathophysiology of radiation induced coronary artery disease is similar to that of coronary artery disease in the general population. Inflammation, fibrosis and platelet aggregation play a key role in this process. After radiation therapy, inflammation occurs, recruiting leukocytes, particularly neutrophils and monocytes. Neutrophils are fibrotic mediators, and macrophages form foam cells in the intimal layer of the vessel wall, leading to the build-up of atherosclerotic plaques. Platelet aggregation, both initially and upon plaque rupture, is also a culprit in exacerbating radiation damage. Colchicine is known to inhibit microtubule polymerization and therefore inhibits mitosis, neutrophil motility and has been shown to decrease platelet aggregation. Its anti-inflammatory properties have been attributed to several different effects based on microtubule dysfunction. Colchicine has also been shown to affect the expression of adhesion molecules on endothelial cells, leukocytes, and to decrease activation of thrombin induced platelet aggregation. There is evidence to suggest that colchicine may be beneficial in the treatment of radiation induced coronary artery disease due to its anti-inflammatory and anti-coagulant properties. This idea would be beneficial for future studies.

Stereotactic body radiation therapy for isolated hilar and mediastinal non-small cell lung cancers.

OBJECTIVES: The seminal phase II trial for pulmonary stereotactic body radiation therapy (SBRT) suggested that SBRT to central lesions resulted in unacceptable toxicity. Alternative dose-fractionation schemes have been proposed which may improve safety without compromise of efficacy. We report our institutional outcomes of SBRT for hilar/mediastinal non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective review was conducted of patients with NSCLC in a hilar or mediastinal nodal station which was treated with SBRT. Patients presented with a lesion involving the hilum or mediastinum from primary or oligorecurrent NSCLC. Kaplan-Meier with log-rank testing and Cox analysis were utilized for outcomes analysis. RESULTS: From 2008-2015, 40 patients with median age of 70 were treated with SBRT for primary/oligorecurrent hilar/mediastinal NSCLC with median follow-up of 16.4 months. 85% presented with oligorecurrent disease at a median of 22.4 months following definitive therapy. The aortico-pulmonary window was the target in 40%, the hilum in 25%, lower paratracheal in 20%, subcarinal in 10%, and prevascular in 5%. The median dose was 48Gy in 4 fractions (range: 35-48Gy in 4-5 fractions). Median overall (OS) and progression-free (PFS) survivals were 22.7 and 13.1 months, respectively. Two-year local control was 87.7% and not significantly different between hilar and mediastinal targets. Median PFS was significantly improved in patients with hilar vs mediastinal nodal targets: 33.3 vs 8.4 months, respectively (p=0.031). OS was not statistically different between hilar and mediastinal targets (p=0.359). On multivariable analysis, hilar vs mediastinal target predicted for PFS (HR 3.045 95%CI [1.044-8.833], p=0.042), as did shorter time to presentation in patients with oligorecurrence (HR 0.983 [95%CI 0.967-1.000], p=0.049). Acute grade 3+ morbidity was seen in 3 patients (hemoptysis, pericardial/pleural effusion, heart failure) and late grade 3+ morbidity (hemoptysis) in 1 patient. CONCLUSION: Hilar/mediastinal SBRT appears to be a safe technique for the local control of isolated nodal disease with limited toxicity from the fractionation schemes utilized.

Systematic intrafraction shifts of mediastinal lymph node targets between setup imaging and radiation treatment delivery in lung cancer patients.

BACKGROUND AND PURPOSE: Internal target motion results in geometrical uncertainties in lung cancer radiotherapy. In this study, we determined the intrafraction motion and baseline shifts of mediastinal lymph node (LN) targets between setup imaging and treatment delivery. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received intensity-modulated radiotherapy with a daily setup cone-beam CT (CBCT) scan used for online soft-tissue match on the primary tumor. At a total of 122 fractions, 5 Hz fluoroscopic kV images were acquired orthogonal to the MV treatment beam during treatment delivery. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections and in the intra-treatment kV images. Baseline shifts and changes in the respiratory motion amplitude between CBCT and treatment delivery were determined from the 3D trajectories. RESULTS: Systematic mean LN baseline shifts of 2.2 mm in the cranial direction (standard deviation (SD): 1.8 mm) and 1.0 mm in the posterior direction (SD: 1.2 mm) occurred between CBCT imaging and treatment delivery. The mean motion amplitudes during CBCT and treatment delivery agreed within 0.2 mm in all directions. CONCLUSIONS: Systematic cranial and posterior intrafraction baseline shifts between CBCT and treatment delivery were observed for mediastinal LN targets. Intrafraction motion amplitudes were stable.

Different manifestation of irradiation induced coronary artery disease detected with coronary computed tomography compared with matched non-irradiated controls.

BACKGROUND AND PURPOSE: Patients who received chest irradiation for treatment of a malignancy are at increased risk for the development of coronary artery atherosclerosis. Little is known about the anatomical coronary artery plaque characteristics of irradiation induced coronary artery disease (CAD). This study aimed to evaluate potential differences in the presence, extent, severity, composition and location of CAD in patients treated with mediastinal irradiation compared with non-irradiated controls matched on age, gender and cardiovascular risk factors. MATERIAL AND METHODS: Seventy-nine asymptomatic Hodgkin and non-Hodgkin lymphoma survivors, all treated with mediastinal irradiation with or without chemotherapy, who underwent coronary computed tomography angiography (CTA) to exclude or detect CAD were included. Patients were 1:3 matched with non-irradiated controls (n=237) for age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD and currently smoking. Mean age at cancer diagnosis was 26±9years and age at the time of coronary CTA was 45±11years. RESULTS: More patients had an abnormal CTA (defined as any coronary artery atherosclerosis): 59% vs. 36% (P<0.001) and significantly more patients had two vessel CAD: 10% vs. 6% and three vessel/left main CAD: 24% vs. 9% compared with controls (overall P<0.001). The maximum stenosis severity among patients was less often <30% (53% vs. 68%) and more often >70% (7% vs. 0%) (overall P=0.001). Patients had more coronary artery plaques in proximal coronary artery segments: left main (17% vs. 6%, P=0.004), proximal left anterior descending artery (30% vs. 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001) and proximal left circumflex artery (14% vs 6%, P=0.022), whereas the number of plaques in non-proximal segments did not differ between groups. CONCLUSIONS: Hodgkin and non-Hodgkin lymphoma survivors treated with mediastinal irradiation with or without chemotherapy showed a higher presence, greater severity, larger extent and more proximally located CAD compared with age, gender and risk factor matched non-irradiated controls. These findings represent features of higher risk CAD and may explain the worse cardiovascular outcome after chest irradiation.