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As a component of myeloablative conditioning before allogeneic hematopoietic stem cell transplantation (HSCT), Total Body Irradiation (TBI) is employed in radiotherapy centers all over the world. In recent and coming years, many centers are changing their technical setup from a conventional TBI technique to multi-isocenter conformal arc therapy techniques such as Volumetric Modulated Arc Therapy (VMAT) or Helical Tomotherapy (HT). These techniques allow better homogeneity and control of the target prescription dose, and provide more freedom for individualized organ-at-risk sparing. The technical design of multi-isocenter/multi-plan conformal TBI is complex and should be developed carefully. A group of early adopters with conformal TBI experience using different treatment machines and treatment planning systems came together to develop technical recommendations and share experiences, in order to assist departments wishing to implement conformal TBI, and to provide ideas for standardization of practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children., Material and Methods: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established., Results: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies., Conclusions: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The aim of this study was to determine the feasibility of hypofractionated schedules for metastatic bone/bone marrow lesions in children and to investigate dosimetric differences to the healthy surrounding tissues compared to conventional schedules., Methods: 27 paediatric patients (mean age, 7 years) with 50 metastatic bone/bone marrow lesions (n = 26 cranial, n = 24 extra-cranial) from solid primary tumours (neuroblastoma and sarcoma) were included. The PTV was a 2 mm expansion of the GTV. A prescription dose of 36 and 54 Gy EQD2 α / β =10 was used for neuroblastoma and sarcoma lesions, respectively. VMAT plans were optimized for each single lesion using different fractionation schedules: conventional (30/20 fractions, V 95%  ≥ 99%, D 0.1cm 3  ≤ 107%) and hypofractionated (15/10/5/3 fractions, V 100% ≥ 95%, D 0.1cm 3  ≤ 120%) . Relative EQD2 differences in OARs D mean between the different schedules were compared., Results: PTV coverage was met for all plans independently of the fractionation schedule and for all lesions (V 95% range 95.5-100%, V 100% range 95.1-100%), with exception of the vertebrae (V 100% range 63.5-91.0%). For most OARs, relative mean reduction in the D mean was seen for the hypofractionated plans compared to the conventional plans, with largest sparing in the 5 fractions (< 43%) followed by the 3 fractions schedule (< 40%). In case of PTV overlap with an OAR, a significant increase in dose for the OAR was observed with hypofractionation., Conclusions: For the majority of the cases, iso-effective plans with hypofractionation were feasible with similar or less dose in the OARs. The most suitable fractionation schedule should be personalised depending on the spatial relationship between the PTV and OARs and the prescription dose., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To 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., Methods: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously., Results: From 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., Conclusion: Across 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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Multimodality imaging including 18 F-FDG-PET has improved the detection threshold of nodal metastases in head and neck squamous cell carcinoma (HNSCC). The aim of this retrospective analysis is to investigate the impact of FDG-PET/CT-based nodal target volume definition (FDG-PET/CT-based NTV) on radiotherapy outcomes, compared to conventional CT-based nodal target volume definition (CT-based NTV)., Materials and Methods: Six-hundred-thirty-three patients treated for HNSCC with definitive (chemo)radiotherapy using IMRT/VMAT techniques between 2008 and 2017 were analyzed. FDG-PET/CT-based NTV was performed in 46% of the patients. The median follow-up was 31 months. Diagnostic imaging depicting the regional recurrence was co-registered with the initial CT-scan to reconstruct the exact site of the recurrence. Multivariate Cox regression analysis was performed to identify variables associated with radiotherapy outcome., Results: FDG-PET/CT-based NTV improved control of disease in the CTV elective-nodal (HR: 0.33, p = 0.026), overall regional control (HR: 0.62, p = 0.027) and overall survival (HR: 0.71, p = 0.033) compared to CT-based NTV. The risk for recurrence in the CTV elective-nodal was increased in case of synchronous local recurrence of the primary tumor (HR: 12.4, p < 0.001)., Conclusion: FDG-PET/CT-based NTV significantly improved control of disease in the CTV elective-nodal , overall regional control and overall survival compared to CT-based NTV. A significant proportion of CTV elective-nodal recurrences are potentially new nodal manifestations from a synchronous local recurrent primary tumor. These results support the concept of target volume transformation and give an indication of the potential of FDG-PET to guide gradual radiotherapy dose de-escalation in elective neck treatment in HNSCC., Competing Interests: Declaration of Competing Interest All authors declare having no conflict of interest related to the content of this manuscript., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Hypoxia is a major cause of radio- and chemoresistance. Carbonic anhydrase IX (CAIX) is an endogenous hypoxia-related marker and an important prognostic marker. Assessment of CAIX expression may allow patient selection for hypoxia or CAIX-targeted treatment. The radioactive tracer 111 In-girentuximab-F(ab') 2 targets CAIX and can be used for SPECT imaging. Aim of this study was to validate and optimize 111 In-girentuximab-F(ab') 2 for imaging of CAIX expression in head and neck tumor xenografts., Material and Methods: Affinity and internalization kinetics of 111 In-girentuximab-F(ab') 2 were determined in vitro using CAIX-expressing SK-RC-52 cells. Tumor targeting characteristics were determined in athymic mice with six different head and neck squamous cell carcinoma (SCCNij) xenografts. Tracer uptake was measured by ex vivo radioactivity counting. Intratumoral distribution of tracer uptake was measured using autoradiography and CAIX expression was determined immunohistochemically., Results: 26% of the tracer was internalized into the SK-RC-52 cells within 24h. The half maximal inhibitory concentration (IC 50 ) was 0.69±0.08nM. In biodistribution studies SCCNij153 tumors showed the highest tracer uptake: 4.1±0.8ID/g at 24h p.i. Immunohistochemical and autoradiographic analyses of the xenografts showed a distinct spatial correlation between localization of the tracer and CAIX expression., Conclusion: 111 In-girentuximab-F(ab') 2 has a high affinity for CAIX. In vivo tumor uptake correlated strongly with CAIX expression in different head and neck xenografts. These results suggest that 111 In-girentuximab-F(ab') 2 is a promising tracer for imaging of hypoxia-related CAIX expression., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Immunohistochemical epidermal growth factor receptor (EGFR) expression does not correlate with treatment response in head and neck squamous cell carcinomas (HNSCC). Aim was to apply the tracer (111)In-cetuximab-F(ab')2 for EGFR microSPECT imaging and to investigate if tracer uptake correlated with response to EGFR-inhibition by cetuximab in HNSCC xenografts. Usage of F(ab)2 fragments allows for shorter interval between tracer injection and imaging., Materials and Methods: Mice with HNSCC xenografts, SCCNij202, 153, 185 and 167 were imaged with microSPECT using (111)In-cetuximab-F(ab')2. Subsequently, tumors were analyzed by autoradiography and immunohistochemistry and tracer concentration was determined. Tumor uptake was correlated with previously assessed response to cetuximab treatment., Results: MicroSPECT imaging showed preferential uptake in HNSCC xenografts. Tumor-to-liver ratios were 3.1 ± 0.2 (SCCNij202), 2.8 ± 0.4 (SCCNij153), 2.0 ± 0.8 (SCCNij185), 2.0 ± 0.4 (SCCNij167). Immunohistochemical EGFR fractions (fEGFR) differed significantly between xenografts; 0.77 ± 0.07 (SCCNij202), 0.66 ± 0.11 (SCCNij153), 0.57 ± 0.19 (SCCNij185), 0.16 ± 0.10 (SCCNij167) (p < 0.001). Tumor fEGFR correlated with (111)In-cetuximab-F(ab')2 tumor uptake (r = 0.6, p < 0.01) and tracer autoradiography (r = 0.7, p < 0.0001). Tumor uptake of (111)In-cetuximab-F(ab')2 was proportionally associated with cetuximab treatment response in three out of four xenograft models., Conclusion: (111)In-cetuximab-F(ab')2 showed good tumor-to-background contrast on microSPECT imaging, allowing noninvasive assessment of EGFR expression in vivo, and possibly evaluation of treatment response to EGFR-inhibition., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)