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Introduction and Objective: Proton beam therapy (PBT) provides the opportunity for a more localized delivery of high energy protons and may reduce the damage to healthy tissues and vital organs. The aim of this review was to assess the effects of proton therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma treated with mediastinal irradiation., Review Methods: A systematic search of EMBASE, MEDLINE via OVID and Cochrane Library was conducted in May 2022 according to PRISMA guidelines to identify relevant data on the efficacy and toxicity of proton beam therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma., Brief Description of the State of Knowledge: Of 566 screened abstracts (430 after de-duplication) 11 studies with a total of 529 patients were included. All studies were case series published between 2011-2021. Median range of follow-up time was 15-63.6 months. The overall survival (OS) for 2 years varied from 91% - 98% for 5 of the included studies. Three of the included studies had favourable outcomes with 2-year progression-free survival (PFS) ranging from 73% - 94%. Skin reaction, oesophagitis and fatigue were found to be the most common grade 1 and grade 2 toxicities. No acute or late grade 4 and higher toxicities/adverse events were observed., Summary: There are data indicating that PBT may to be an effective treatment against mediastinal Hodgkin and non-Hodgkin lymphoma. Because all the studies were case series, the authors of this review have little confidence in the evidence. There remains a need for well-designed randomized controlled trials to inform about the optimal approach to proton irradiation in HL and NHL.

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 cm 3 (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 cm 3 (D1cm 3 ) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm 3 (D0.1cm 3 ) of heart (p = 0.036), respectively., Conclusion: V95% PTV > 85% and GTV < 90 cm 3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

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., Competing Interests: The authors have declared that no competing interests exist.

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], 5‑field IMRT, and 7‑field 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 7‑field IMRT than in plans using 5‑field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5‑field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7‑field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7‑field IMRT over 5‑field 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 5‑field IMRT than APPA and 0.19% higher in plans using 7‑field IMRT than APPA as well as 0.09% higher in plans using 7‑field IMRT than 5‑field 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.

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 V 5Gy and V 20Gy decreased from 713.2 to 503.6 cm 3 (p = 0.011) and from 338.8 cm 3 to 267.0 cm 3 (p = 0.058), respectively. In the case of VMAT, lung V 5Gy and V 20Gy values decreased from 754.8 to 601.0 cm 3 (p = 0.004) and from 328.5 to 255.7 cm 3 (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.

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 cm 3 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., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

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, n total  = 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.

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.

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.

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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, V 5Gy , V 10Gy , V 20Gy , V 30Gy for lung; D mean , V 7.5Gy , V 15Gy , V 25Gy for heart; D mean , V 3.5Gy , V 10Gy , V 20Gy for breast; D max for spine; D mean , V 10Gy , V 18Gy , V 25Gy , V 30Gy 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 D max (AP-PA/FPIMRT P: 0.012; 4-Field/FPIMRT P: 0.012) for spinal cord and D mean (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., Competing Interests: There are no conflicts of interest

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The risk of aortic valve replacement (AVR) for patients after mediastinal radiation therapy (MRT) remains unaccounted for in traditional risk scores. The aim of this study was to examine perioperative and midterm outcomes in patients undergoing AVR after MRT in the current era., Methods: From 2000 to 2016, 49 consecutive patients previously exposed to MRT underwent AVR with or without concomitant procedures at a single center. Patients were divided into two groups: isolated AVR (n = 18) and AVR with concomitant procedures (n = 31). The logistic European System for Cardiac Operative Risk Evaluation II mean score was 2.8% ± 3.4% and The Society of Thoracic Surgeons mean score was 1.7% ± 1.5%. Median follow-up was 6.6 years and was 90% complete within 12 months of study closure., Results: Overall inhospital mortality was 10% (0% in the isolated group versus 16% in the concomitant group; p = 0.14). A total of 21 patients (47%) died at follow-up. Mean interval to death was 2.0 ± 1.1 years from surgery in the isolated group versus 1.4 ± 1.6 years in the concomitant group (p = 0.18). Actuarial survival was 93% ± 6%, 73% ± 11%, and 65% ± 13%, at 1, 3, and 5 years, respectively, in the isolated group versus 74% ± 8%, 44% ± 11%, and 37% ± 11% in the concomitant group (p = 0.03)., Conclusions: Isolated AVR can be performed safely in patients with MRT-induced disease. In contrast, AVR with concomitant procedures is associated with high mortality, which is vastly underestimated using traditional risk scores. In both groups, survival at 5 years is markedly impaired., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Mediastinal radiation therapy (RT) for Hodgkin lymphoma (HL) is associated with late cardiotoxicity, but there are limited data to indicate which dosimetric parameters are most valuable for predicting this risk. This study investigated which whole heart dosimetric measurements provide the most information regarding late cardiotoxicity, and whether coronary artery dosimetry was more predictive of this outcome than whole heart dosimetry., Methods and Materials: A random sample of 125 HL patients treated with mediastinal RT was selected, and 3-dimensional cardiac dose-volume data were generated from historical plans using validated methods. Cardiac events were determined by linking patients to population-based datasets of inpatient and same-day hospitalizations and same-day procedures. Variables collected for the whole heart and 3 coronary arteries included the following: Dmean, Dmax, Dmin, dose homogeneity, V5, V10, V20, and V30. Multivariable competing risk regression models were generated for the whole heart and coronary arteries., Results: There were 44 cardiac events documented, of which 70% were ischemic. The best multivariable model included the following covariates: whole heart Dmean (hazard ratio [HR] 1.09, P=.0083), dose homogeneity (HR 0.94, P=.0034), male sex (HR 2.31, P=.014), and age (HR 1.03, P=.0049). When any adverse cardiac event was the outcome, models using coronary artery variables did not perform better than models using whole heart variables. However, in a subanalysis of ischemic cardiac events only, the model using coronary artery variables was superior to the whole heart model and included the following covariates: age (HR 1.05, P<.001), volume of left anterior descending artery receiving 5 Gy (HR 0.98, P=.003), and volume of left circumflex artery receiving 20 Gy (HR 1.03, P<.001)., Conclusion: In addition to higher mean heart dose, increasing inhomogeneity in cardiac dose was associated with a greater risk of late cardiac effects. When all types of cardiotoxicity were evaluated, the whole heart variable model outperformed the coronary artery models. However, when events were limited to ischemic cardiotoxicity, the coronary artery-based model was superior., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Cardiac disease after mediastinal radiotherapy for thoracic malignancy (chest radiotherapy [XRT]) often manifests as progressive aortic stenosis. In patients with XRT-induced severe aortic stenosis undergoing surgical aortic valve replacement (SAVR), we sought to: (1) study long-term survival and compare these patients with a matched cohort undergoing SAVR during the same time frame; and (2) identify potential predictors of long-term mortality., Methods and Results: We studied patients with symptomatic severe aortic stenosis undergoing SAVR at our institution, of which there were 172 mediastinal XRT patients (63±13 years, 62% women) matched in a 1:1 fashion (based on age, sex, time of surgery, and aortic valve area) with 172 non-XRT patients (comparison group). Baseline clinical and postoperative data were obtained. Society of Thoracic Surgeons score was calculated and mortality was recorded. In the XRT group, the median Society of Thoracic Surgeons score was 4% (interquartile range 2-13), while mean left ventricular ejection fraction, left ventricular stroke volume index, and mean aortic valve gradient were 54±11%, 38±14 mL/m 2 , and 39±11 mm Hg, respectively. In the entire cohort, 27% and 34% of patients underwent concomitant coronary artery bypass grafting and aortic surgery at the time of SAVR, respectively. Thirty-day/in-hospital deaths occurred in 4 (2%) patients in the XRT group and 0 patients in the comparison group. At 6±3 years of follow-up, on matched group analysis, there were 95 (28%) deaths (83 [48%] in the XRT group versus 12 [7%] in the comparison group (log-rank 89, P <0.001). On multivariable Cox survival analysis, in the whole cohort, higher Society of Thoracic Surgeons score (hazard ratio, 1.14; 95% CI, 1.03-1.26) and mediastinal XRT (hazard ratio, 8.12; 95% CI, 4.26-15.64) were associated with increased longer-term mortality (both P <0.01)., Conclusions: In patients with severe aortic stenosis undergoing SAVR, patients with prior mediastinal XRT have significantly worse longer-term survival versus a matched cohort., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Esophageal symptoms are common during radiation and chemotherapy. It is unclear how often these symptoms persist after therapy. We retrospectively reviewed medical records of 320 adults treated for nonmetastatic breast cancer (84), lung cancer (109), or Hodgkin and non-Hodgkin lymphoma (127) who were disease-free at 10-14 months after therapy. Treatment included chemotherapy with or without nonmediastinal radiation therapy (150 patients), chemotherapy plus sequential mediastinal radiation therapy (MRT) (48 patients), chemotherapy plus concurrent MRT (61 patients), or non-MRT only (61 patients). Proton pump inhibitor use was documented. All treatment groups had similar prevalence of the esophageal symptom of heartburn before therapy. Rates were higher during treatment in those who received MRT with or without chemotherapy, but declined by 10-14 months after treatment. However, low baseline rates of dysphagia (4%) and odynophagia (2%) increased significantly after combined chemotherapy and MRT to 72% for dysphagia and 62% for odynophagia (P < 0.01) during treatment and stayed significantly elevated over baseline with 27% of the patients having dysphagia and 11% having odynophagia at 10-14 months after treatment. The use of proton pump inhibitors by patients who had MRT with chemotherapy was significantly increased during and after treatment (P = 0.002). Dysphagia, odynophagia and the use of proton pump inhibitors were significantly more common both during and after treatment than before treatment in patients who received both chemotherapy and mediastinal radiation. Our data highlight the important challenge for clinicians of managing patients with lung cancer and lymphoma who have persistent esophageal problems, particularly dysphagia and odynophagia, at approximately 1 year after treatment., (© 2016 International Society for Diseases of the Esophagus.)

Introduction: Isolated nodal failure (INF) without synchronous local or distant failure is an uncommon occurrence after stereotactic body radiation therapy (SBRT) for lung cancer. Here we review the natural history and patterns of failure after post-SBRT INF with or without salvage mediastinal radiotherapy (SvRT)., Methods: Patients treated with SBRT for non-small cell lung cancer with definitive intent were identified. Patients who experienced hilar or mediastinal INF without synchronous distant, lobar, or local failure were included and grouped according to the use of SvRT. The rates of subsequent locoregional control, distant metastases, progression-free survival (PFS), and overall survival were assessed., Results: Of 797 patients treated with definitive SBRT, 24 (3%) experienced INF and 15 (63%) received SvRT. The most common SvRT regimen (53%) was 45 Gy in 15 fractions. The median follow-up after INF was 11.3 months for survivors. There were no grade 3 or higher toxicities after SvRT. The 1-year Kaplan-Meier PFS and overall survival estimates were 33% and 56% for patients not receiving radiotherapy and 75% and 73% with SvRT. After SvRT, the rate of locoregional control at 1 year was 84.4%. Crude rates of distant failure were 20.0% with SvRT and 22.2% with no radiotherapy. Of the 13 deaths observed, five (38%) were related to distant progression of lung cancer, four (31%) to comorbidities, three (23%) to mediastinal progression, and one (8%) to an unknown cause., Conclusions: INF is uncommon after SBRT. Despite the significant comorbidities of this population, intrathoracic progression remains a contributor to morbidity and mortality. SVRT for INF is well tolerated and may improve PFS., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Radiotherapy is one of the cornerstones for treatment of patients with cancer. Although advances in radiotherapy technology have considerably improved radiation delivery, potential adverse effects are still common. Postradiation changes to the mediastinum can include different structures such as the heart, great vessels, and esophagus. The purpose of the article was to illustrate the expected variety of changes to the mediastinum and adjacent lung resulting from external beam radiotherapy and radiotherapy-induced complications to the mediastinum and to discuss different radiotherapy delivery techniques., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Plasmacytomas could involve any organ, and at times might pose a diagnostic challenge when the site of involvement is unusual, or if the presentation is similar to other diseases. We describe a 48-year-old man presenting with worsening shortness of breath and chest discomfort with radiologic evidence of mediastinal enlargement, mimicking a lymphoma with mediastinal involvement. An excisional biopsy of a mediastinal lymph node showed a plasma-cell infiltrate strongly positive for CD138, with a flow-cytometry analysis showing a population of lambda-restricted neoplastic plasma cells. He failed to respond to 50Gy involved-field radiotherapy, but achieved a partial response to combination chemotherapy. He underwent high-dose chemotherapy with melphalan (200mg/m(2)) followed by lenalidomide maintenance, and is in complete remission 18months postautografting. This case illustrates a unique and rare presentation of primary lymph-node plasmacytomas involving the mediastinum potentially mistaken as lymphoid malignancy. Clinicians should be aware of the plasma-cell origin of the mediastinal neoplastic process., (Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

This study aims at optimizing treatment planning in young patients affected by lymphoma (Stage II to III) by using an inclined board (IB) that allows reducing doses to the organs at risk. We evaluated 19 young patients affected by stage I to III lymphomas, referred to our Department for consolidation radiotherapy (RT) treatment on the mediastinum. Patients underwent 2 planning computed tomography (CT) scans performed in different positions: flat standard position and inclined position. A direct comparison between the different treatment plans was carried out analyzing dosimetric parameters obtained from dose-volume histograms generated for each plan. Comparison was performed to evaluate the sparing obtained on breast and heart. Dosimetric evaluation was performed for the following organs at risk (OARs): mammary glands, lungs, and heart. A statistically significant advantage was reported for V 5 , V 20 , and V 30 for the breast when using the inclined board. A similar result was obtained for V 5 and V 10 on the heart. No advantage was observed in lung doses. The use of a simple device, such as an inclined board, allows the optimization of treatment plan, especially in young female patients, by ensuring a significant reduction of the dose delivered to breast and heart., (Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: To prospectively examine the risk of developing Lhermitte's sign (LS) in patients with lymphoma treated with modern-era chemotherapy followed by consolidation intensity-modulated radiation therapy., Methods: We prospectively interviewed all patients with lymphoma who received irradiation to the mediastinum from July 2011 through April 2014. We extracted patient, disease, and treatment-related variables from the medical records of those patients and dosimetric variables from treatment-planning systems and analyzed these factors to identify potential predictors of LS with Pearson chi-square tests., Results: During the study period 106 patients received mediastinal radiation for lymphoma, and 31 (29 %) developed LS. No correlations were found between LS and any of the variables examined, including total radiation dose, maximum point dose to the spinal cord, volume receiving 105 % of the dose, and volumes receiving 5 or 15 Gy., Conclusion: In this group of patients, treatment with chemotherapy followed by intensity-modulated radiation therapy led to 29 % developing LS; this symptom was independent of radiation dose and seemed to be an idiosyncratic reaction. This relatively high incidence could have resulted from prospective use of a structured interview.

Introduction: Reconstruction of radiotherapy (RT) performed decades ago is challenging, but is necessary to address dose-response questions from epidemiological data and may be relevant in re-irradiation scenarios. Here, a novel method to reconstruct extended and involved field RT for patients with Hodgkin lymphoma was used., Materials and Methods: For 46 model patients, 29 organs at risk (OARs) were contoured and seven treatment fields reconstructed (mantle, mediastinal, right/left neck, right/left axillary, and spleen field). Extended and involved field RT were simulated by generating RT plans by superpositions of the seven individual fields. The mean (standard deviation) of the 46 individual mean organ doses were extracted as percent of prescribed dose for each field superposition., Results: The estimated mean doses to the OARs from 17 field combinations were presented. The inter-patient variability was found to be a larger contributor to the uncertainty than the field simulation process. The inter-patient variability depended on the OAR and primarily affected the estimates for OARs located at the edge of the RT field., Conclusions: Dose estimates for 29 OARs were reported from extended and involved field RT. These estimates could be employed when individual reconstruction is not feasible and estimated doses from past treatments are needed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that is putatively derived from a thymic B cell. Accounting for up to 10% of cases of DLBCL, this subtype predominantly affects women in the third and fourth decades of life. Its clinical and molecular characteristics are distinct from other subtypes of DLBCL and, in fact, closely resemble those of nodular sclerosing Hodgkin lymphoma (NSHL). Recently, mediastinal lymphomas with features intermediate between PMBL and NSHL, called mediastinal gray-zone lymphomas, have been described. The optimal management of PMBL is controversial, and most standard approaches include a combination of immunochemotherapy and mediastinal radiation. Recently, the recognition that mediastinal radiation is associated with significant long-term toxicities has led to the development of novel approaches for PMBL that have shown excellent efficacy and challenge the need for routine mediastinal radiation.

Follicular dendritic cell sarcoma is a rare and aggressive tumor and its management is a major clinical challenge. Surgery is considered the mainstay of treatment and no adjuvant approach has demonstrated the ability to reduce the rate of relapses. We report on a case of a man with a 26-year clinical history of mediastinal follicular dendritic cell sarcoma, with several relapses after multiple surgical interventions. The impact of chemotherapy was very small, unlike the radiation therapy that was performed twice, with an interval time of 8 years, through an intensity-modulated technique and an altered fractionation schedule.

Introduction: We investigated tolerable doses to organs at risk (OARs) in the mediastinum and pulmonary hilum following stereotactic body radiotherapy for centrally located lung tumors., Methods: Between 2005 and 2012, 381 patients with lung tumors were treated with stereotactic body radiotherapy of 40 to 60 Gy in five fractions. From among these patients, we extracted those who received greater than 25 Gy irradiation to OARs and analyzed dosimetric factors in relation to grade 3 to 5 toxicities., Results: In total, 398 OARs in 133 patients were analyzed, with a median follow-up of 33 (range, 3-87) months. The numbers receiving greater than 25 Gy irradiation to the aorta, vena cava, pulmonary artery, pulmonary vein, bronchus, trachea, heart, and esophagus were 72, 33, 73, 60, 55, 13, 69, and 23, respectively. The corresponding median Dmax 0.5 ml were 43.8, 32.0, 32.2, 29.1, 28.4, 28.7, 41.1, and 21.7 Gy. Of these patients, two developed grade 5 and one grade 3 hemoptysis, and two had grade 3 obstructive pneumonia. Two patients with grade 5 hemoptysis received high doses at the pulmonary artery and bronchus (59.2 and 54.4 Gy, and 61.3 and 59.6 Gy, respectively). No other grade 3 to 5 toxicities occurred., Conclusion: Therapeutic indications and dose-intensity should be carefully determined for patients with central tumors, especially when doses to the pulmonary artery and bronchus in the pulmonary hilum exceed 50 Gy. Tolerable doses for other OARs might, however, be higher than in this study, though longer follow-up is necessary to assess this possibility.

Background: T-cell lymphoblastic lymphoma (T-LBL) is a rare neoplasm of precursor lymphoblast origin, for which there is no standard treatment for adults. Results of current treatment strategies in selected populations do exist but are largely unreported for unselected series. Here, we aimed to investigate treatment outcome in a population-based cohort., Material and Methods: Patients were identified through the Swedish Lymphoma Registry and data was retrospectively collected for all adult (≥ 18 years) Swedish T-LBL patients diagnosed during 2000-2009., Results: A total of 39 patients with median age 40 years (range 18-78) were identified with females being significantly older than males (median age 66 vs. 37, p = 0.027). The five-year overall survival for all patients was 42%. Female gender was associated with shorter survival also when adjusted for treatment strategy and age [hazard ratio (HR) 4.29; p = 0.002]. Thirty patients received intensive chemotherapy, otherwise used for treatment of acute lymphoblastic leukemia (ALL), which resulted in an overall response rate of 97% and a five-year progression-free survival (PFS) of 49%. In this group only CNS involvement at diagnosis predicted shorter PFS (HR 13.3; p = 0.03). Among patients treated with hyper-CVAD the addition of mediastinal irradiation resulted in prolonged time to progression compared to patients receiving only chemotherapy (p = 0.047). The major reason for treatment failure was relapse and in this series 18-fluoro-deoxyglucose positron emission tomography (PET) did not predict this risk., Conclusion: This population-based study indicates that all fit T-LBL patients should be considered for intensive treatment. Our results also suggest a beneficial effect of mediastinal irradiation in combination with hyper-CVAD treatment. Relapsing patients have a dismal outcome irrespective of salvage treatment.

Background: Cardiovascular diseases are the most common nonmalignant cause of death in Hodgkin lymphoma (HL) survivors, especially after mediastinal irradiation. We investigated the role of computed tomographic coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, and related CTA findings to exercise testing and subsequent interventions., Patients and Methods: Patients were eligible for this phase II study if at least 10 years disease-free and treated with mediastinal radiotherapy. Screening consisted of electrocardiogram, exercise testing and CTA. Primary end point was significant CAD (stenosis >50%) on CTA. CTA screening was considered to be indicated for testing in a larger population if ≥6 of 50 CTA scanned patients (12%) would need revascularization. Screening was evaluated with a questionnaire before and after screening., Results: Fifty-two patients were included, and 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. There were 45 evaluable scans. Significant CAD on CTA was found in 20% (N = 9), significantly increased compared with the 7% expected abnormalities (P = 0.01, 95% confidence interval 8.3% to 31.7%). In 11% (N = 5), significant stenosis was confirmed at coronary angiography, and revascularization was carried out. Additionally, two patients were treated with optimal medical therapy. Ninety percent of patients were content with screening, regardless whether the CTA showed abnormalities., Conclusions: Prevalence of significant CAD among HL survivors is high, while asymptomatic even in the presence of life-threatening CAD. This might justify screening by CTA in asymptomatic HL survivors who had mediastinal radiotherapy, but needs to be evaluated in a larger cohort. The trial protocol was approved by the Ethics Committee of the LUMC and registered with ClinicalTrials.gov, NCT01271127., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To analyze patterns of local-regional failure (LRF) for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients treated in our hospital and to propose a clinical target volume (CTV) for postoperative radiation therapy (PORT) in these patients., Methods and Materials: From 2005 to 2011, consecutive patients with pT1-3N2 NSCLC who underwent complete resection in our hospital but who did not receive PORT were identified. The patterns of first LRF were assessed and evaluated as to whether these areas would be encompassed by our proposed PORT CTV., Results: With a median follow-up of 24 months, 173 of 250 patients (69.2%) experienced disease recurrence. Of the 54 patients with LRF as the first event, 48 (89%) had recurrence within the proposed PORT CTV, and 6 (11%) had failures occurring both within and outside the proposed CTV (all of which occurred in patients with right-lung cancer). Ninety-three percent of failure sites (104 of 112) would have been contained within the proposed PORT CTV. For left-sided lung cancer, the most common lymph node station failure site was 4R, followed by 7, 4L, 6, 10L, and 5. For right-sided lung cancer, the most common site was station 2R, followed by 10R, 4R, and 7., Conclusions: LRF following complete surgery was an important and potentially preventable pattern of failure in stage IIIA(N2) patients. Ipsilateral superior mediastinal recurrences dominated for right-sided tumors, whereas left-sided tumors frequently involved the bilateral superior mediastinum. Most of the LRF sites would have been covered by the proposed PORT CTV. A prospective investigation of patterns of failure after PORT (following our proposed CTV delineation guideline) is presently underway and will be reported in a separate analysis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Electron radiotherapy is applied to treat the chest wall close to the mediastinum. The performance of the GGPB and eMC algorithms implemented in the Varian Eclipse treatment planning system (TPS) was studied in this region for 9 and 16 MeV beams, against Monte Carlo (MC) simulations, point dosimetry in a water phantom and dose distributions calculated in virtual phantoms. For the 16 MeV beam, the accuracy of these algorithms was also compared over the lung-mediastinum interface region of an anthropomorphic phantom, against MC calculations and thermoluminescence dosimetry (TLD). In the phantom with a lung-equivalent slab the results were generally congruent, the eMC results for the 9 MeV beam slightly overestimating the lung dose, and the GGPB results for the 16 MeV beam underestimating the lung dose. Over the lung-mediastinum interface, for 9 and 16 MeV beams, the GGPB code underestimated the lung dose and overestimated the dose in water close to the lung, compared to the congruent eMC and MC results. In the anthropomorphic phantom, results of TLD measurements and MC and eMC calculations agreed, while the GGPB code underestimated the lung dose. Good agreement between TLD measurements and MC calculations attests to the accuracy of "full" MC simulations as a reference for benchmarking TPS codes. Application of the GGPB code in chest wall radiotherapy may result in significant underestimation of the lung dose and overestimation of dose to the mediastinum, affecting plan optimization over volumes close to the lung-mediastinum interface, such as the lung or heart., (Copyright © 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The results of treatment of 23 patients, suffering primary angiosarcoma (AS), and 7--having mediastinal hemangiopericytoma, were analyzed. Primary mediastinal AS constitutes a quite rare tumor, for its recognition it is necessary to do differential diagnosis from tumors with possible localization in anterior mediastinum. AS differs by more aggressive course and, accordingly, by poorer results of treatment and poorer prognosis as well. Surgical treatment was conducted in 15 patients, including radical operations in 13 (in 7--for AS, in 6--hemangiopericytoma), the combined--in 4. The total survival indices during 3 - 5 yrs after radical operations for AS have had constituted, accordingly, 57.1 and 28.6%, and of recurrence-free survival--42.8 and 28.6%. Chemotherapy as a single method of treatment was conducted in 11 patients, radiation therapy--4. The total survival indices in 3 and 5 yrs follow-up have had constituted 26.6 and 7.1%. Application of taxans in the treatment of AS permits to achieve better results. Radiation therapy is applied in a chemotherapy resistant and recurrent tumors. Surgery constitutes the main method of treatment of mediastinal AS. The standard schemes of chemotherapy are lacking efficacy, the taxans are characterized by higher antitumoral activity.

Background: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB., Methods: In the treatment plans, each patient's heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed., Results: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors., Conclusions: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study.

Background: Our goal was to define the prevalence of radiation-induced valvular heart (RIVD) disease among patients undergoing cardiac valve surgery in a community-based, regional academic medical center. Mediastinal radiation is a treatment modality for various hematologic and solid malignancies; however, long-term cardiac complications, including radiation-induced valvular heart disease, can occur years after the radiation treatments., Hypothesis: Mediastinal radiation exposure is an independent risk factor for valvular heart disease often necessitating valve replacement in patients without other risk factors for valve disease., Methods: Between January 1, 1998 and September 1, 2007, we retrospectively analyzed our institution's cardiac surgical database over a 10 year period and identified 189 consecutive patients ≤ 50 years of age who underwent valve surgery. Using case-control matching, we assessed the prevalence of mediastinal radiation among these young patients with valve disease necessitating surgery and to their matched controls from all patients admitted to the hospital., Results: Nine individuals (4.8%) were identified as having received previous mediastinal radiation, significantly increased from controls (p<0.0001), and 8 of whom had surgical or pathologic findings consistent with radiation damage. Compared with a matched case-control population, individuals who had severe valve disease and underwent valve replacement had a markedly increased prevalence of prior mediastinal radiation therapy., Conclusions: In conclusion, cardiologists must remain aware of the potential long term valvular complications in patients treated with mediastinal radiation. Increased surveillance for RIVD may be considered in the decades following radiation therapy., (© 2013 Wiley Periodicals, Inc.)

In this prospective study, the effects of mediastinal radiation therapy (RT) on autonomic nervous system (ANS) were investigated by heart rate variability (HRV) analysis that is accepted as a non-invasive indicator of ANS. Study was performed with the eligible patients had a histopathologically confirmed diagnosis of malignant disease with no known congestive heart failure, coronary heart disease, hypertension, valvular cardiac disease or arrhythmia history. Electrocardiograms of 14 voluntary patients were recorded for duration of 5 min just before and after irradiation for the first and the 15th fractions. ANS-related HRV analysis parameters were calculated as which were recommended by Task Force of ESC/NASPE (Circulation 93:1043-1065, 1996). HRV parameters that belong to pre- and post-RT treatment of patients were compared statistically. We found that there is not effect of single-dose radiation on HRV parameter. The mean RRI (782.29 ± 115.65-738.93 ± 111.01, P < 0.014) and HF power of HRVs PSD (156.94 ± 229.37-60.71 ± 77.99, P < 0.045) decreased, and LF/HF ratio (1.38 ± 0.79-2.03 ± 1.25, P < 0.039) increased significantly with 28-Gy external radiation dose. As the effect of cumulative dose was investigated on HRV parameters, the above changes were continued to increase with 30-Gy external radiation dose. We found that mediastinal RT involving heart directly in the radiation field decreased vagal and sympathetic ANS activities, and autonomic balance shifted toward sympathetic dominance.

Background: Proton-beam therapy (PBT) provides therapeutic advantages over conformal x-ray therapy in sparing organs at risk when treating esophageal cancer because of the fundamental physical dose distribution of the proton-beam. However, cases with extended esophageal lesions are difficult to treat with conventional PBT with a single isocentric field, as the length of the planning target volume (PTV) is longer than the available PBT field size in many facilities. In this study, the feasibility of a practical technique to effectively match PBT fields for esophageal cancer with a larger regional field beyond the available PBT field size was investigated., Methods: Twenty esophageal cancer patients with a larger regional field than the available PBT single-field size (15 cm in our facility) were analyzed. The PTV was divided into two sections to be covered by a single PBT field. Subsequently, each PTV isocenter was aligned in a cranial-caudal (CC) axis to rule out any influence by the movement of the treatment couch in anterior-posterior and left-right directions. To obtain the appropriate dose distributions, a designed-seamless irradiation technique (D-SLIT) was proposed. This technique requires the following two adjustments: (A) blocking a part of the PTV by multi-leaf collimator(s) (MLCs); and (B) fine-tuning the isocenter distance by the half-width of the MLC leaf (2.5 mm in our facility). After these steps, the inferior border of the cranial field was designed to match the superior border of the caudal field. Dose distributions along the CC axis around the field junction were evaluated by the treatment-planning system. Dose profiles were validated with imaging plates in all cases., Results: The average and standard deviation of minimum dose, maximum dose, and dose range between maximum and minimum doses around the field junction by the treatment-planning system were 95.9 ± 3.2%, 105.3 ± 4.1%, and 9.4 ± 5.2%. The dose profile validated by the imaging plate correlated with the results of the treatment-planning system in each case, with an error range within 4.3%., Conclusions: Dose distributions around the field junction were applied using D-SLIT. D-SLIT can be a useful treatment strategy for PBT of extended esophageal cancer.

Pneumonitis is a complication of high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) regimens containing BCNU. Our goal was to define the incidence and risk factors for pneumonitis in patients with lymphoma receiving a uniform conditioning regimen in the modern era. We studied 222 patients who received HDC-ASCT using cyclophosphamide, BCNU and VP-16 (CBV). Pneumonitis incidence was 22%, with 19% receiving systemic corticosteroid treatment and 8% requiring inpatient hospitalization for pneumonitis. Three patients died secondary to pneumonitis-related complications. The following variables were independently associated with pneumonitis: prior mediastinal radiation (odds ratio [OR] 6.5, 95% confidence interval [CI] 2.3-18.9, p = 0.0005), total BCNU dose above 1000 mg (OR 3.4, 95% CI 1.3-8.7, p = 0.012) and age less than 54 (OR 3.0, 95% CI 1.4-6.5, p = 0.0037). Increased vigilance for symptoms of pneumonitis is warranted for patients with prior mediastinal radiation and for younger patients, and dose reduction may be considered for patients who would receive greater than 1000 mg of BCNU.

Purpose: To report clinical and pathologic characteristics and outcome of breast cancer (BC) after irradiation for Hodgkin's lymphoma (HL) in women treated at the Institut Curie, with a special focus on the breast-conserving option., Methods and Materials: Medical records of 72 women who developed either ductal carcinoma in situ or Stage I-III invasive carcinoma of the breast after HL between 1978 and 2009 were retrospectively reviewed., Results: Median age at HL diagnosis was 23 years (range, 14-53 years). Median total dose received by the mediastinum was 40 Gy, mostly by a mantle-field technique. Breast cancers occurred after a median interval of 21 years (range, 5-40 years). Ductal invasive carcinoma and ductal carcinoma in situ represented, respectively, 51 cases (71%) and 14 cases (19%). Invasive BCs consisted of 47 cT0-2 tumors (82%), 5 cN1-3 tumors (9%), and 20 Grade 3 tumors (35%). Locoregional treatment for BCs consisted of mastectomy with (3) or without (36) radiotherapy in 39 patients and lumpectomy with (30) or without (2) adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast-conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were, respectively, 74.5% (95% confidence interval [CI], 64-88%) and 82% (95% CI, 72-93%) for invasive carcinoma and 100% (95% CI, 100 -100%) and 92% (95% CI, 79-100%) for in situ carcinoma. In patients with invasive tumors, the 5-year distant disease-free survival rate was 79% (95% CI, 69-91%), and 13 patients died of progressive BC. Contralateral BC was diagnosed in 10 patients (14%)., Conclusions: Breast-conserving treatment can be an option for BCs that occur after HL, despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position, to protect the underlying heart and lung., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The therapeutic role of mediastinal radiotherapy and stem cell transplantation (SCT) in lymphoblastic lymphoma (LL) remains controversial. In a risk-oriented design, we adopted a flexible treatment program in which (1) patients with persistent mediastinal abnormality, evaluated by post-induction computed chest tomography, received mediastinal irradiation; and (2) those with persistence of minimal residual disease (MRD), evaluated by MRD analysis of the bone marrow, underwent SCT. Twenty-eight out of 30 patients (T-lineage, n = 24; B-lineage, n = 6) achieved a complete response. Of 21 patients with mediastinal mass, 13 (62%) achieved a complete response after chemotherapy alone, while 6 (28.5%) required additional irradiation. Eleven patients were evaluated for MRD: 6 were negative and 5 positive. On the basis of MRD findings and clinical risk characteristics, 14 patients underwent SCT, 13 received maintenance chemotherapy, and 1 had local radiotherapy. Five patients relapsed. Among the 14 non-irradiated patients with T-LL, the mediastinal recurrence rate was only 7%. After a median follow-up of 3.9 years, 21 patients who responded were alive without recurrence (75%). The projected 5-year survival, disease-free survival, and relapse rate were 72%, 77%, and 18%, respectively. This program induced high remission and survival rates, indicating the feasibility and the benefits potentially associated with a selective, response-oriented policy of mediastinal irradiation and a concurrent MRD-based strategy to assign adult LL patients to SCT.

Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENI(off)) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENI(on)). Nodal stations were contoured using published guidelines, then placed into 4 "bins" (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENI(on) plans demonstrated a statistically significant degradation in dose coverage compared with the ENI(off) plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the "1 echelon away" nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to anatomically distant lymph nodes within the mediastinum. The ENI(on) plans demonstrate that intergroup-style treatments, as actually delivered, had statistically reduced coverage to the mediastinum and tumor volumes than was reported. Furthermore, SNI leads to improved tumor coverage and reduced esophageal/spinal cord dose, which suggests the possibility of dose escalation using SNI., (Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)