Lung Shielding Research Articles

Assessment of lung doses in patients undergoing total body irradiation for haematological malignancies with and without lung shielding.

Total body irradiation (TBI) practices vary considerably amongst centres, and the risk of treatment related toxicities remains unclear. We report lung doses for 142 TBI patients who underwent either standing TBI with lung shield blocks or lying TBI without blocks. Lung doses were calculated for 142 TBI patients treated between June 2016 and June 2021. Patients were planned using Eclipse (Varian Medical Systems) using AAA_15.6.06 for photon dose calculations and EMC_15.6.06 for electron chest wall boost fields. Mean and maximum lung doses were calculated. Thirty-seven patients (26.2%) were treated standing using lung shielding blocks with 104 (73.8%) treated lying down. Lowest relative mean lung doses were achieved using lung shielding blocks in standing TBI, reducing the mean lung doses to 75.2% of prescription (9.9 Gy), ±4.1% (range 68.6-84.1%) for a prescribed dose of 13.2 Gy in 11 fractions, including contributions from electron chest wall boost fields, compared to 12 Gy in 6 fraction lying TBI receiving 101.6% mean lung dose (12.2 Gy) ±2.4% (range 95.2-109.5%) (P ≪ 0.05). Patients treated lying down with 2 Gy single fraction received the highest relative mean lung dose on average, with 108.4% (2.2 Gy) ±2.6% of prescription (range 103.2-114.4%). Lung doses have been reported for 142 TBI patients using the lying and standing techniques described herein. Lung shielding blocks significantly reduced mean lung doses despite the addition of electron boost fields to the chest wall.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review

Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Commissioning and performance evaluation of commercially available mobile imager for image guided total body irradiation.

The setup of lung shield (LS) in total body irradiation (TBI) with the computed radiography (CR) system is a time-consuming task and has not been quantitatively evaluated. The TBI mobile imager (TBI-MI) can solve this problem through real-time monitoring. Therefore, this study aimed to perform commissioning and performance evaluation of TBI-MI to promote its use in clinical practice. The source-axis distance in TBI treatment, TBI-MI (CNERGY TBI, Cablon Medical B.V.), and the LS position were set to 400, 450, and 358cm, respectively. The evaluation items were as follows: accuracy of image scaling and measured displacement error of LS, image quality (linearity, signal-to-noise ratio, and modulation transfer function) using an EPID QC phantom, optimal thresholding to detect intra-fractional motion in the alert function, and the scatter radiation dose from TBI-MI. The accuracy of image scaling and the difference in measured displacement of the LS was<4mm in any displacements and directions. The image quality of TBI imager was slightly inferior to the CR image but was visually acceptable in clinical practice. The signal-to-noise ratio was improved at high dose rate. The optimal thresholding value to detect a 10-mm body displacement was determined to be approximately 5.0%. The maximum fraction of scattering radiation to irradiated dose was 1.7% at patient surface. MI-TBI can quantitatively evaluate LS displacement with acceptable image quality. Furthermore, real-time monitoring with alert function to detect intrafraction patient displacement can contribute to safe TBI treatment.

Impact of chronic graft-versus-host disease on quality of life and cognitive function of long-term transplant survivors after allogeneic hematopoietic stem cell transplantation with total body irradiation

BackgroundTotal body irradiation (TBI)-based-conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is standard of care in patients with acute myeloid leukemia (AML) but can cause long-term morbidity. Data on the impact of chronic Graft-versus-host disease (cGvHD) on cognitive function (CF) and quality of life (QoL) of long-term transplant survivors are sparse.MethodsWe analyzed patient-reported outcomes focusing on progression-free AML patients and 1st allo-HSCT applying a standardized TBI-technique with an average dose rate of 4 cGy/min to the total body and lung shielding in case of doses > 8 Gy. Instruments included the Functional Assessment of Cancer Therapy-Bone marrow transplant (FACT-BMT, version 4), the FACT-Cognition Function (FACT-Cog, version 3) and the Patient Health Questionaire-4 (PHQ-4). We put focus on the impact of cGvHD and compared the results to normative data derived from the general population.ResultsOut of 41 eligible patients contacted, 32 (78.0%) patients with a medium follow-up of 154 months (Interquartile range 113, 191 months) participated in the study. Eleven patients (34.4%) had active cGvHD, 11 (34.4%) resolved cGvHD and 10 (31.3%) never had cGvHD. Patients with active cGvHD had poorer FACT-BMT, FACT-Cog and higher PHQ-4 scores compared to patients with resolved cGvHD or who never had cGvHD. Outcomes were similar in patients with resolved cGvHD and those who never had cGvHD. Patients with active cGvHD had similar FACT-Cog, but lower FACT-BMT in comparison to normative data. However, the overall patient sample had similar FACT-BMT and FACT-Cog in comparison to normative data.ConclusionOur data indicate that CF of long-term survivors upon TBI-based allo-HSCT is not impaired, even in the presence of active cGvHD. However, active cGvHD has a negative impact on QoL.Trial registration The local Ethics Board of the University of Regensburg approved this study (Number 20-1810_1-101).

Distinct Patterns in the Reconstitutions of Treg and T-Helper Subsets after Autologous Hematopoietic Stem Cell Transplantation in Juvenile-Onset Systemic Sclerosis Patients

Systemic sclerosis (SSc) is a refractory autoimmune disease characterized by diffuse fibrosis and vasculopathy affecting the skin, joints, and internal organs. Most immunosuppressive drugs have failed to show long-term benefit in randomized trials. In recent years, autologous hematopoietic stem cell transplantation (ASCT) has been performed to treat multiple sclerosis and SSc, however, the reconstitutions of immune components post-ASCT in SSc have not been fully described. Subjects and Methods: We tested a total of 13 samples from 4 consenting SSc patients (3 females, 1 male) receiving IRB-approved immunoablation (TBI 600cGy) with lung shielding and Cytoxan (n=3) or Thiotepa (n=1) +/- Alemtuzumab followed by autologous CD34+ selected, cryopreserved peripheral blood hematopoietic stem cells transplantation. Their median age was 18.5-years-old (range 15.2- to 21.4-years-old). Peripheral blood samples were collected at baseline pre-ASCT, and 3, 6, 12, 24-months post-ASCT. By flow cytometry, we examined lymphocyte and monocyte subset recovery with additional focus on the FOXP3+Treg and T-helper subset reconstitution. Results and Discussion: All 4 subjects experienced significant improvement in several clinical and quality of life parameters, especially in their skin disease evident within weeks after ASCT. T-cell lymphopenia was profound at 3-months; however, the recovery was evident by 6-months reaching pre-ASCT levels by 2-years post-ASCT (Fig 1A). Natural killer (NK) lymphocytes and monocytes attained the normal values by 3-months and after (Fig 1A). The FOXP3+Tregs that appeared post-ASCT displayed distinct features. There was an increased percentage of FOXP3+Tregs in total CD4+T cells during the early stage (3- to 6-months) post-ASCT (Fig 1B), leading to an increase in the ratio of Treg/Tcon (Fig 1B). The higher proportions of proliferating Tregs as measured by Ki67+FOXP3+CD4+/CD25+/CD127- T cells (Fig 1C) likely led to their increased numbers. This trend was sustained until the last evaluation at 2-years post-ASCT (Fig 1C). In contrast, CD4+Tcons showed a relatively lower proliferation rate, leading to a higher ratio of Ki67+Treg/Ki67+Tcon compared to pre-ASCT values (Fig 1C). Notably, there was an increased proportion of Tregs expressing the skin homing marker cutaneous lymphocyte-associated antigen (CLA) at 3-months lasting until the last test at 2-years post-ASCT (Fig 1D), whereas CLA+/CD4+Tcons were less plentiful. The reconstitutions of T-helper (Th) subsets were also examined. Due to lymphopenia at the early stage post-ASCT, Th subsets were identified according to their chemokine receptor expression (Mahnke et alCytometry 2013;83(5):439-440). Gradually decreased numbers of Th2, Th9, and Th17 were observed in the peripheral pool (Fig 1E) contributing to a decline of their proportions in total CD4+T (Fig 1F). Nevertheless, absolute number of Th1 and Th22 cells returned to levels seen pre-ASCT without any recurrence or flare of SSc symptoms. The CD45RO+ memory phenotype was dominant during the early stages post-ASCT in all subsets (data not shown). Summary: Successful reconstitution of lymphocytes and monocytes post-ASCT was observed in available SSc patients. Post-ASCT circulating FOXP3+Tregs displayed distinct features where the increased number led to an elevated Treg/Tcon ratio in the peripheral pool. Amongst Tregs, the skin homing CLA+ subset was further enriched correlating with improved skin scores in all patients. Improved peripheral proliferation and increased expression of CLA+ Tregs may provide protection from skin disease recurrence despite parallel Tcon reconstitution. The decrease of the Th2/Th9/Th17 subsets in the peripheral pool post-ASCT possibly contributes to the clinically less autoimmune phenotype. These results need to be validated in future patients. Acknowledgements: We thank all participating patients, nurses, physicians, and scientists in this study for their contributions. The study was supported by the "Idea Development Award" from the Department of Defense - Scleroderma Research Program (Award number W81XWH-21-1-0782 and W81XWH-21-1-0783). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autologous Stem Cell Transplantation (ASCT) for Refractory Juvenile-Onset Systemic Sclerosis (jSSc) Is Safe and Well Tolerated and Improves Clinical and Patient-Reported Outcomes

Introduction: jSSc is a rare autoimmune disease that leads to inflammation, fibrosis, and dysfunction of multiple organ systems which can cause skin sclerosis, interstitial lung disease (ILD), myositis, fasciitis, gastrointestinal and vascular disease. Severe SSc is often refractory to immunomodulatory medications including newer targeted agents. ASCT has demonstrated success in adults with SSc, but experience and data in pediatric patients is limited. Methods: We report our first four consecutive adolescent and young adult ASCT patients. All patients were referred to our scleroderma center at UPMC Children's Hospital of Pittsburgh where they were evaluated by our multidisciplinary team. Baseline patient characteristics are summarized in Table 1. Patients met criteria for ASCT by severity of lung or skin disease, or both. The first 3 patients had severe ILD or musculoskeletal chest wall weakness resulting in pulmonary function tests (PFTs) below traditional cut offs for adult SSc ASCT trials. All four patients had refractory disease and had previously received 3-8 immunomodulatory medications. Autologous stem cells were mobilized with cyclophosphamide and filgrastim and collected via pheresis. Following this, conditioning chemoradiation was administered per an IRB-approved individual treatment plan (Patients 1-3) or on our clinical trial NCT03630211 (Patient 4) with rituximab, anti-thymocyte globulin (ATG), TBI 600 cGy with lung and kidney shielding, and cyclophosphamide or thiotepa +/- alemtuzumab. A CD34+ selected cryopreserved autologous peripheral blood stem cell graft was infused on day 0. Antimicrobial prophylaxis was given per institutional standard and PCRs for EBV, CMV and adenovirus were closely monitored. Steroids were weaned off by 5 weeks post-ASCT. Results: The median cell dose was 5.9 e6 CD34/kg. All patients engrafted, with median neutrophil engraftment on day 11 (range 11-15), and median platelet engraftment (>50K) on day 18.5 (range 16-20). There were infusion-related side effects with equine ATG, but none with rabbit ATG. There were no cases of sinusoidal obstructive syndrome, thrombotic microangiopathy or clinically significant bleeding. No patients required a PCA for pain and received minimal (median=3) doses of narcotics. Patients were discharged from the hospital a median of 19 days after transplant (range 17-21). Only one patient was readmitted, and had a negative 48 hour infectious rule out. Two patients acquired COVID-19 infections at 5 and 19.5 months post-ASCT; both remained outpatient with quick improvement after treatment with best available therapy. There were no viral reactivations, bacterial or fungal infections. There has been no evidence of organ toxicity and there are objective improvements in clinical parameters as well as patient reported outcomes (PROs) over the follow-up visits (Table 2). All patients demonstrated an improvement in their skin involvement, as measured by the modified Rodnan Skin Score (mRSS). There was an improvement in clinical symptoms and exam findings of Raynaud's. The lower esophageal sphincter became less hypotensive; objective measures and symptoms of gastroesophageal reflux were much improved. Despite severely reduced values of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) prior to ASCT, all subjects regained pre-ASCT values. All patients demonstrated an improvement in their PROs and report improvement in fatigue, pain, and the ability to participate in activities of daily living. All patients are off immunomodulatory medications. Tandem serial skin biopsies of the forearm support decreased collagen burden and disappearance of a myofibroblasts population with single cell RNA sequencing (n=3, timepoints 0, 6, 12 mos; data not shown), which correlates with an improvement in the skin score. Conclusions: In refractory jSSc patients, ASCT is well tolerated, even in patients with severe disease who would otherwise not be eligible for clinical trials based on exclusion criteria that were developed for adults with SSc. ASCT can serve as a hard reset to the immune system for patients with this refractory autoimmune disease, with improvements in clinical parameters that reflect disease modification involving the skin, musculoskeletal, vascular, and gastrointestinal systems. Further clinical research treating patients with this rare disease is of great need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A comprehensive method for calculating total body irradiation

Toprovide meansfor calculating the dose received by various tissues of the patient, calculate lung shield, and verify received dose using a phantom as a tool for quality assurance for a planned Total Body Irradiation (TBI) procedure in radiotherapy. Using Microsoft Visual Basic, MATLAB, and Python, a program for Total Body Irradiation Calculation in Radiotherapy (TBICR) is constructed. It uses patient translation and beam zone method for total body irradiation calculations to compute the proper dose received by the patient and determine the lung shield thickness. There are three main user-friendly interfaces in the application. The first one allows the user to upload the TBI topography and estimate the distances needed for TBI calculations. The second one enables the user to count the number of beam zones needed for each point and estimate the effective area (Aeff) for each level. The third interface estimates the velocity required to deliver the relative dose depending on patient separation, Monitor Units (MU), couch speed and travel distance. It allows the user to compute the required lung shield thickness, read any patient's CT DICOM file and acquire dose in any distinct location using machine learning model to predict the dose. The TBICR software has been successfully validated by reproducing all of the manual calculations in an exact and timely manner. TBICR generated more accurate results and confirmed the absorbed dose to patient through measurements on Anderson phantom. A computer program for the calculation of total body irradiation (TBI) is described in full. The dose received at each point on the patient, the calculation of lung shield and the determination of the velocity and time required for the couch movement are all made possible using the software. The ease of use, precision, data storage and printing are some important features of the present software.

Impact of lung block shape on cardiac dose for total body irradiation.

Evaluating cardiac dose during total body irradiation (TBI) is of increasing interest. A three-dimensional beam model for TBI was commissioned and lung shielding was simulated in a treatment planning system with the cardiac silhouette partially blocked and unblocked. When blocked, the median heart dose decreased by 6% (IQR=6%) and the median cardiac V12Gy decreased by 27% (IQR=17%). The median left anterior descending artery dose decreased 20% (IQR=12%) for blocked cases. Because using partial heart shielding may result in considerable changes in dose to cardiac structures, TBI protocols should explicitly consider lung block design parameters and their potential effects.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. <h3>Materials/Methods</h3> Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m²) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. <h3>Results</h3> Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, <i>P</i> = 0.76). <h3>Conclusion</h3> TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

Effect of Lung Blocks Parameters on Lung and Cardiac Doses in Total Body Irradiation Using 3D Dosimetry

Despite being an integral part of stem cell transplant, the technical aspects of classical total body irradiation (TBI) remain relatively crude. In particular, the implementations of lung and cardiac shielding vary widely between institutions. We hypothesize that the block margins away from anatomical landmarks could substantially alter lung and cardiac dose parameters, and thus affecting the likelihood of TBI-related toxicities such as radiation pneumonitis and late cardiotoxicities. This work seeks to utilize a newly commissioned 3D TBI beam model to determine potential dosimetric effects caused by variations in the choice of shielding parameters to better understand the potential for such detrimental effects.We commissioned a TBI beam model in a treatment planning system. CT scans of 3 anonymized patients without gross disease are contoured following typical clinical practice. Patients are planned in the classic standing AP/PA at extended distance technique for a total dose of 1200 cGy in 6 fractions to midline at umbilicus level, with 3/6 fractions delivered with lung blocks. Lung blocks are modeled using automated script in the treatment planning system, with varying superior (from clavicles), inferior (from diaphragms), and lateral margins from 0 to 2 cm, as well as cases for which the cardiac silhouette was blocked or unblocked for the study. Dose to lungs and heart were calculated and compared for the following metrics: mean dose, volume receiving 10 Gy (V10 Gy) and 12 Gy (V12 Gy), and point dose behind the blocks.The results showed that the point dose behind the blocks is approximately 75% of prescription dose for all patients, with insignificant changes with varying block margins. The dose off the block center increases rapidly that much of the tissue under the blocks receives 80% to 90% of prescription dose. Similar results are observed for mean lung dose. In contrast, the lung V10 Gy increases by nearly two-fold, from approximately 30% to 60% over the 0 to 2 cm block margin range. The mean heart dose increased by approximately 7.5% when the cardiac silhouette is unblocked, while the cardiac V12 Gy increased by approximately 25%. The mean dose to left anterior descending artery (LAD) increases significantly in the unblocked case, with as much as 43% difference.This work has shown that margins of lung blocks could affect the dose to lungs and heart substantially, despite the indifference that the commonly used point dose parameter, point dose behind the blocks, indicates. A 3D TBI model could provide more dosimetry data to help future studies to correlate TBI-associated toxicity to the heart and lungs.

Commissioning of a three-dimensional arc-based technique for total body irradiation.

The purpose of this study is to describe the commissioning of a novel three‐dimensional arc‐based technique for total body irradiation (TBI) treatments. The development and implementation of this technique allowed our institution to transition from a bilateral two‐dimensional (2D) technique to a methodology based on volumetric dose calculation. The methodology described in this work is a derivation from the MATBI technique, with the static fields being replaced by four contiguous arc‐fields for each anterior and posterior incidence. The reduced number of fields we employed makes it possible to reach a satisfactory dose uniformity through manual optimization in a straightforward process. We use the Eclipse anisotropic analytical algorithm (AAA) algorithm, commissioned with preconfigured beam data for a 6 MV photon beam, at standard SSD (100 cm). A thorough evaluation of the accuracy of the AAA algorithm at an extended distance (approximately 200 cm) was carried out. For the evaluation, we compared measured and calculated percentage depth–dose and profiles that included open‐field, penumbra, and out‐of‐field regions. The analysis was performed for both static and arc fields, taking into consideration unshielded fields and also in the presence of lung shielding blocks. End‐to‐end tests were carried out for our institutional template plan by two means: with a 2D ion chamber array detector in solid phantom and using Gafchromic films in an anthropomorphic phantom. The results obtained in this work demonstrate that the Eclipse AAA algorithm commissioned for standard treatments can be safely used with our TBI planning technique. Moreover, this technique proved to be a highly efficient path to replace conventional treatment techniques, providing a homogeneous dose distribution, dosimetric robustness, and shorter treatment times. In addition, as inherited from the MATBI technique, our methodology can be implemented in small treatment rooms, with no need for ancillary equipment.

Safe & Effective Reduced Intensity Conditioning Regimen in Patients with Dyskeratosis Congenita

Background: Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by telomerase dysfunction leading to shortened telomeres.1 Recent literature shows only a 23% estimated 10-year survival, secondary to death from pulmonary complications.2 Currently, hematopoietic cell transplantation (HCT) is the only curative therapy for marrow failure but has been limited by mortality related to infection, sinusoidal obstructive syndrome (SOS), graft-versus-host disease (GVHD) and respiratory failure.3,4 The ideal conditioning regimen that optimizes engraftment while maximizing long-term survival is yet to be determined. Methods: We describe three consecutive patients with DC who underwent matched unrelated donor (MUD) allogeneic HCT following a reduced-intensity conditioning regimen similar to protocol NCT03330795 that uses a reduced intensity conditioning (RIC) while maximizing the benefits of shielding vulnerable organs in this populations. These three patients received a RIC regimen of rituximab, alemtuzumab, hydroxyurea, thiotepa, fludarabine, and 250 cGy total body irradiation; patients 1 and 2 received 85% lung shielding and 50% liver shielding. Results: Patient 1 is a 17-year-old male with reduced diffusing capacity of the lungs for carbon monoxide (DLCO), splenomegaly, splenic varices and nodular regenerative hyperplasia (NRH) who presented with pancytopenia. Testing revealed telomeres below the 1st percentile in all WBC subtypes, a PARN c.1257dup heterozygous mutation and a TERC c.17_31 mutation. He underwent a 12/12 MUD HCT and engrafted on Day +18. His course was complicated by poor adherence to medications and visits, and development of skin and GI GVHD, which responded to steroids. He was weaned off of immunosuppression by 11 months post-transplant. Twenty-eight months post-transplant, he remains 100% donor engrafted with no chronic GVHD or organ toxicity, including stable pulmonary function tests (PFT). See figure 1 and 2. Patient 2 is a 16-year-old male with reduced DLCO, splenomegaly and NRH who was diagnosed after his brother (Patient 1). He was found to have very short telomeres in all testable WBC subtypes and the same mutations as his brother. After marrow failure, he underwent a 12/12 MUD HCT, with neutrophil engraftment on Day +16. His course was complicated by sudden noncompliance with tacrolimus at day +100, after which he suffered GI GVHD which responded to steroids. He then developed disseminated adenovirus infection which responded to an adenovirus-specific T-cell infusion. He is now Day +356 after transplant and has been off all immunosuppression for 4 months. He remains &amp;gt;98% donor-engrafted without evidence of GVHD or organ toxicity, and his PFTs have remained stable. Patient 3 is a 16-year-old male with a history of antibody-negative autoimmune hepatitis who later developed pancytopenia. Telomere testing revealed very short telomeres in 4 of the 5 evaluable WBC subtypes. His genetic testing did not uncover a mutation yet identified as pathogenic in DC. He received a 12/12 MUD HCT and engrafted on Day +12. He had skin GVHD which responded to ruxolitinib. He remains 100% donor-engrafted, most recently at 9 months post-transplant without organ toxicity. Conclusions: All patients had timely neutrophil engraftment without SOS or other organ toxicity, despite being at increased risk for organ morbidity due to preexisting liver and lung disease. GVHD was noted, although two of the cases were related to poor adherence, and all responded to treatment. There is sustained donor-engraftment at a median of 637 days (range 356-1186 days) post-transplant.

Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group

Background and purposeTo reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. MethodsAn electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. ResultsFrom over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1–2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8–10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. ConclusionAcross SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

Dose to Lungs and Kidneys during Total Body Irradiation: Are We Delivering the Expected Dose?

Total Body irradiation (TBI)-based conditioning is key component for hemopoietic stem cell transplantation. TBI dose calculation is traditionally based on point-dose calculations based on estimates of body separation at different levels with the umbilicus as a reference point, an approach followed as standard protocol at most institutions. This homogenous dose calculation technique does not take into account tissue heterogeneity. Limited data exists for TPS-based TBI planning systems especially in the setting of lung and kidney partial transmission blocks, which is a void in our understanding of TBI dose delivery and is explored in this study. Primary objective of the study was to assess differences between radiation treatment planning software (TPS) estimated doses with heterogeneity correction and point calculation estimated doses when delivering TBI. Secondary objective was to validate accurate treatment delivery through optically stimulated luminescent dosimetry (OSLD) measurements at umbilicus obtained at first TBI fraction. Our retrospective study involved virtual dosimetric simulation of total body CT scan datasets in patients treated with a prescribed dose of 12 Gy in six fractions delivered twice daily over three days. Patients received TBI using a translating couch AP/PA technique with lung and kidney shielding (transmission blocks to achieve < 7 Gy point dose). The Varian Eclipse TPS was used to calculate the 3D dose distribution to the lungs, kidneys, and heart. Paired t-test with a significance value of 0.05 was used to compare means. 24 patients (Male-11, female-13; Age range: 23-60 years; Diagnosis: AML-7, ALL-8, HL-1, NHL-6, MDS-2) with total body CT scan datasets available were included in the analysis. Contrary to expected dose with shielding (< 7 Gy), the TPS simulated mean dose to lungs was 11.08 Gy (SD: 0.61, p= 9.66E-22) and to kidneys was 8.98 Gy (SD: 0.62, p: 2.31E-14). TPS mean dose to the unshielded heart was 11.38 Gy. Compared to the point dose calculation of 2 Gy at the midpoint of the umbilicus, the mean OSLD dose measured during the first fraction of treatment was 2.08 Gy (SD: 0.058, p: 2.07E-9). Using TPS of total body CT scan data, we demonstrated much higher than expected dose to lungs and kidneys than expected from point-based calculations. This study has triggered a comprehensive outcomes analysis of institutional data for assessing toxicities in patients receiving TBI 12 Gy-based conditioning prior to SCT with the goal to revisit the 7-Gy dose limit to the lungs and kidneys. Institutions are encouraged to pursue similar analyses of their TBI systems to refine dose to critical organs. (Supported by the Radiation Oncology Summer Research Fellowship and the Office of Student Research at the University of Maryland School of Medicine).

Estimation of radiation-induced, organ-specific, secondary solid-tumor occurrence rates with total body irradiation and total marrow irradiation treatments

PurposeWe aimed to predict and compare radiation-induced, organ-specific, secondary solid-tumor occurrence risks from conventional total body irradiation (TBI) and total marrow irradiation (TMI) for patients undergoing hematopoietic cell transplant. Methods and MaterialsWe retrospectively selected 20 patients who received TMI treatments before hematopoietic cell transplant. Ten patients (5 men; 5 women) received 12 Gy to the skeletal bones, lymph nodes, and spleen, and the other 10 patients (5 men; 5 women) received an escalated dose of 20 Gy to the same targets and 12 Gy to the brain and liver. A conventional TBI treatment plan was generated for each patient with a prescription dose of 12 Gy, using anterior-posterior and posterior-anterior photon beams with lung shielding and a chest wall boost with electron beams. Secondary cancer risks were estimated using linear-exponential and plateau models for major organs. ResultsAt the 12 Gy dose level, using the linear-exponential model, the total radiation-induced secondary solid-tumor risks for major organs were 159.3 ± 8.7 for men and 221.5 ± 14.4 for women per 10,000 people per year with the TMI plans, which is a reduction of 38.8% and 32.9%, respectively, compared with those with the TBI plans. At the 20 Gy dose level, the risks were 220.3 ± 8.3 for men and 298.5 ± 9.3 for women with the TMI plans, which is a reduction of 14.6% and 9.2%, respectively, compared with those with the 12 Gy TBI plans. Significant risk reductions were also found with the TMI plans using the plateau risk model. ConclusionsAt both the 12 Gy and 20 Gy prescription dose levels, a conditioning regimen using TMI could significantly lower overall radiation-induced secondary solid-tumor risks for major organs compared with a conditioning regimen with standard 12 Gy TBI. Clinical data from long-term follow-up studies are needed to verify the model predictions.

Image-guided total-body irradiation with a movable electronic portal imaging device for bone marrow transplant conditioning

IntroductionTo prevent radiation pneumonitis following total body irradiation (TBI) clinicians usually use lung shield blocks. The correct position of these shields relative to the patient's lungs is usually verified via mega-voltage imaging and computed radiographic (CR) films. In order to improve this time-consuming procedure, we developed in our department a dedicated, movable, real-time imaging system for image-guided TBI. Material & MethodsThe system consists of an electronic portal imaging device (EPID) mounted on a dedicated support whose motion along a rail can be controlled from the linac console outside the bunker room. Images are acquired online using a stand-alone console. To test the system efficacy we retrospectively analyzed data of lung blocks positioning from two groups of 10 patients imaged with EPID or CR-films, respectively. ResultsThe median number of portal images per fraction was 2 (range 1-5) and 1 (range 1-2) for the EPID and the CR-film system, respectively. The minimum time required for an EPID image acquisition, without interpretation and no need of patient position correction in the bunker, was 20seconds against 214seconds for the CR-film. Lung shielding positioning in the right-left and superior-inferior directions was improved using the EPID system (p<0.01). ConclusionsCompared to CR-films, our movable real-time imaging EPID system is a simple technical solution able to reduce the minimum imaging time for lung shielding by a factor of 10. With the increased possibility to acquire more images as compared to CR-film system the EPID system has the potential to improve patient alignment, as well as patient's comfort and overall setup time.

A Simple Technique for Partial Transmission Lung Shielding in Pediatric Patients Undergoing TBI for HSCT

Total Body Irradiation (TBI) is generally administered as part of the preparative regimen for pediatric patients undergoing Hematopoietic Stem Cell Transplant (HSCT). In this study, we propose a simple partial transmission lung shielding technique for achieving lung dose reduction to ≤ 8-Gy, as mandated in the COG AALL1331 protocol, while conveniently treating patient in a lateral decubitus position on a stretcher at an extended distance using parallel opposed-pair beam arrangement. A CT-sim with the patient in the lateral decubitus position is performed. The ipsilateral arm is tucked folded under and raised over the head and the contralateral arm is rested along the body. Straight patient lateral body geometry, perpendicular with respect to beam direction (Anterior (A)-Posterior (P) beams) is maintained. The legs are bent at the knees so as to encompass the entire body length in the CT- scan. Right and left lungs are contoured separately on the CT-images and the contours are then converted to multi-leaf-collimation (MLC) shapes simulating lung shields. Treatment fields (AP and PA) are inserted with cross-hair centered at the umbilicus. Beam's-eye-view projection of the MLC shapes at source-to-focus distance of 65.4 cm is printed to custom fabricate the lung shields. The shields are constructed from thin lead sheets (0.4 mm thick) each cut to patient lung shape and stacked to the required thickness. The lung blocks are mounted on a blocking tray and positioned in the accessory mount at the gantry of the linac during treatment. Patients are treated in lateral decubitus position on a stretcher positioned at 515 cm distance to mid-umbilicus from the radiation source, using 15 MV photons and AP/PA oriented beams. Lung shields are positioned by aligning the shadow of lung shield made (by using light field) with lung apexes marked on the patient’s skin (anteriorly and posteriorly). Stretcher is turned around for the 2nd field and the lung shield realigned with lung apex. A 1cm-perspex beam spoiler is positioned along the edge of the stretcher to increase skin dose. A total dose of 12 Gy is prescribed to mid-umbilicus depth at 2 Gy BID administered over 3 days. OSLD in-vivo dose measurements are performed during treatments. In-phantom measurements suggested that 9 mm of lead thickness is required to achieve 70-75% transmission in lung for the 15-MV beam. Additional 1 mm of lead thickness is added for safety. Two pediatric patients (ages 10 and 12) were successfully treated using our lung shielding technique. The average dimensions (mm) of lead shields for each lung were 20 (l) × 12 (w) × 10 (t). Measured fractional doses under the lung shield were in the 1.50-1.55 Gy range. Our method of lung shielding provides a simple solution for achieving partial lung dose reduction during pediatric TBI treatments. The shield size is greatly reduced by positioning the lung shields on a tray at the linac gantry accessory mount level compared to shields placed on or close to patient’s body.

Total Body Irradiation – Comparison of Outcome after Various Techniques of Irradiation and Shielding: A Polish Lymphoma Research Group (PLRG) Multicenter Study

The aim of the study was to compare the efficiency and side effects of total body irradiation (TBI) performed with various techniques in hematology and radiotherapy centers across the country. Three radiotherapy departments performing TBI and five hematology centers performing hematopoietic stem-cell transplantation (HSCT) responded to invitation to the study. Patients conditioned with TBI before HSCT between 2005 and 2010 irrespective of diagnosis were included. Technique of irradiation, dosage, dose rate and usage of lung and lens shields were recorded and analyzed in the context of occurrence of radiation-induced pneumonitis, lung fibrosis, cataract and localization of the recurrence on relation to shields. Patients in whom follow-up data were not available were excluded from the study leaving 138 subjects for further analysis. Three TBI techniques were analyzed: a pair of AP-PA fields with lung and lens shielding, and two variations of four-field box technique, one with standard lung shielding and electron boosts to supplement the chest dose and the other with lung dose reduction to 11 Gy; both without lens shielding. The total dose was 12 Gy: 4 Gy/fx once daily (lung dose approximately 6 Gy) in the first scheme, in the other two 2 Gy/fx bid with approximate lung dose of 11 and 8.5 Gy, respectively. Pneumonitis within the first 6 months after TBI was reported in 15.2% of patients: in 42% with minimum shielding and in 11.1% with standard shielding (p<0.05), lung fibrosis in 3.6% (2.5 and 10.4%, respectively, ns.). The incidence of pneumonitis did not differ between children and adults. In 12.3% of patients a recurrence within the 1st year after TBI was reported, in two in the brain only, and both had lens shielding. Only one case of cataract was reported in a patient with lens shielding. The purposefulness of lens shields application demands reevaluation as they do not seem to significantly reduce the cataract rate whereas partial shielding of the brain can be associated with isolated CNS recurrence in lymphoma patients. Utilization of TBI techniques with more strict lung sparing is associated with reduced pneumonitis rate and does not jeopardize the outcome.

Higher Reported Lung Dose Received During Total Body Irradiation for Allogeneic Hematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukemia Is Associated With Inferior Survival: A Report from the Children's Oncology Group

To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia on the Children's Oncology Group trial. TBI (1200 or 1320cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens, allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality, relapse-free survival, and overall survival (OS) was examined using the Cox proportional hazards regression model controlling for the following variables: TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease level. Of a total of 143 eligible patients, 127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5cGy (standard deviation, ±232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800cGy(P<.001). The influence of lung dose ≥800cGy on transplant-related mortality was not significant (hazard ratio [HR], 1.78; P=.21). On univariate analysis, lung dose ≥800cGy was associated with inferior relapse-free survival (HR, 1.76; P=.04) and OS (HR, 1.85; P=.03). In the multivariate analysis, OS maintained statistical significance (HR, 1.85; P=.04). The variability in TBI techniques resulted in uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, and thus they should be avoided. Patients treated with lung dose <800cGy in this study had better outcomes. This approach is currently being investigated in the Children's Oncology Group AALL1331 study. Additionally, the Imaging and Radiation Oncology Core Group is evaluating effects of TBI techniques on lung doses using a phantom.

Randomized Trials of Autologous Hematopoietic Stem Cell Transplantation for Diffuse Cutaneous Systemic Sclerosis: Systematic Review and Meta-Analysis with Trial Sequential Analysis of Overall Mortality

Background. Diffuse cutaneous systemic sclerosis (SSc) is a multi-system chronically progressive and debilitating autoimmune connective tissue disease affecting internal organs, characterized by a dysregulated immune system and the production of autoantibodies. Patients experience progressive cumulative mortality despite currently available immunosuppressive therapies.Objective. To assess the safety and efficacy of hematopoietic stem cell transplantation (SCT) with the research question: “what is the relative effect on overall mortality in patients with SSc and internal organ involvement treated with SCT compared to those treated with other available immunosuppressive therapies?”Design. Systematic review with meta-analysis of randomized controlled trials (RCTs), with trial sequential analysis (TSA) adjustment for random error and repetitive testing of sparse and accumulating data (Patel A et al BMJ 2014;349:g4561).Data sources. PubMed, PubMed Central, Web of Science, OvidSP, Cochrane central register of controlled trials (CENTRAL), clinicaltrials.gov, eudract.ema.europa.eu, controlled-trials.com, free Google search, relevant conference proceedings, hand searching of reference lists, and contact with authors as necessary. Search terms “systemic sclerosis” and “transplant”. The search was last updated on 21 July 2018.Eligibility criteria. RCTs of adult patients with SSc randomized to receive SCT compared with those who were randomized to receive a non-SCT treatment were included, if overall mortality outcome data were available.Data extraction. Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk (RR) of overall mortality was calculated using a random effects model accounting for clinical heterogeneity.Primary outcome measure. Overall mortality, using intension to treat (ITT) and per protocol (PP) analyses.Risk of Bias. Assessed using the Cochrane Risk of Bias Assessment Tool.Results. There were three eligible RCTs (ASSIST 2011, ASTIS 2014, SCOT 2018), including 250 patients followed for up to 7.8 years (156 patients in Europe and 94 in North America). All trials were open label and assessed as at unclear risk of bias. Peripheral blood stem cell collection: 2-4 g/m2 cyclophosphamide before reinfusion of thawed cryopreserved 2 million CD34+ cells/kg, or GCSF and CD34+ cell enrichment before reinfusion of thawed cells (median of 5.6 million cells/kg). Conditioning was cyclophosphamide 200 mg/kg with 6.5-7.5 mg/kg rabbit anti-thymocyte globulin (ATG) or 120 mg/kg with 8 Gy total body irradiation (TBI) (lung and kidney shielding with 2 Gy limit) and 90 mg/kg equine ATG. Supportive care included corticosteroids, angiotensin converting enzyme inhibitors (usually lisinopril), and aciclovir. Control group treatments comprised monthly cyclophosphamide, 0.5-1 g/m2, 6-12 infusions.Significant overall mortality benefit was observed in the SCT group, with both an ITT (RR 0.60, 95% confidence interval (CI) 0.40-0.90; P=0.01) and PP analysis (RR 0.52, 95% CI 0.33-0.83; P=0.006). Statistical heterogeneity was absent (I2=0%). SCT benefit was robust to TSA adjustment for both the ITT (RR 0.60, 95% CI 0.36-0.98; P=0.014; diversity adjusted information size (D2=0%) and PP analyses (RR 0.51, 95% CI 0.31-0.86; P=0.004; D2=0%). The information size for an ITT model had >70% power (Fig 1), while the PP model had >90% power (Fig 2). The corresponding number needed to treat (NNT) to prevent 1 death was 7 (95% CI 4-29) for the ITT analysis and 5 (95% CI 3-11) for the PP analysis.However, significantly higher CTCAE grade 3-4 infective (P<0.01) and hematological (P<0.01) adverse events were reported in the SCT group compared to control, with no difference for cardiovascular (P=0.92) and respiratory (P=0.24) events. More viral infection or reactivation events were reported in the SCT group compared to control (P=0.05): CMV (P=0.01), EBV (P=0.08), HSV (P=0.59). Importantly, subsequent malignancy was similar for both groups (P=0.96), 4-5%.Conclusions. Our analysis has sufficient information size to indicate that autologous SCT for patients with SSc and internal organ involvement is safe and efficacious. The magnitude of the reduction in long-term mortality of autologous SCT over other available therapies may be practice changing. DisclosuresNo relevant conflicts of interest to declare.