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Guidelines| Volume 173, P119-133, August 2022

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ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children

Open AccessPublished:May 30, 2022DOI:https://doi.org/10.1016/j.radonc.2022.05.027

      Highlights

      • Toxicity reduction with outcome preservation is a goal of myeloablative TBI in children.
      • Fractionated TBI of 12–14.4 Gy, in 1.6–2 Gy fractions b.i.d. is advisable for children.
      • When possible, dose reduction to lungs (<8 Gy), kidneys (≤10 Gy) and lenses (<12 Gy) is appropriate.
      • Setup considerations for conventional and highly conformal TBI techniques in children.
      • Cooperation can support new insights, research and implementation of new techniques.

      Abstract

      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.

      Abbreviations:

      AML (acute myeloid leukemia), ALL (acute lymphoblastic leukemia), ALT (alanine aminotransferase), AP (Anterior-Posterior), AST (aspartate aminotransferase), AYA (adolescent and young adults), BED (biologically effective dose), CML (chronic myeloid leukemia), CNS (central nervous system), CRT (cranial radiotherapy), CSI (craniospinal irradiation), CVA (cerebrovascular incident), CVD (cardiovascular disease), DEXA (Dual-energy x-ray absorptiometry), EQD2 (dose delivered in 2-Gy fractions that is biologically equivalent to a total dose), fTBI (fractionated Total Body Irradiation), GVHD (graft versus host disease), HSCT (hematopoietic stem cell transplantation), IMRT (intensity modulated radiation therapy), IP (interstitial pneumonitis), MLC (multileaf collimator), MOSFET (metal–oxide–semiconductor field-effect transistor), MRD (minimal residual disease), NGS (next-generation sequencing), NRM (Non Relapse Mortality), PA (Posterior-Anterior), RT-qPCR (real-time quantitative polymerase chain reaction), SAD (source-axis distance), SSD (source to skin distance), TBI (Total Body Irradiation), TMI (Total Marrow Irradiation), TMLI (Total Marrow and Lymphoid Irradiation), TLD (thermoluminescent dosimeter), TLI (Total Lymphoid Irradiation), TPS (treatment planning system), sfTBI (single fraction Total Body Irradiation), SIOPE (European Society for Paediatric Oncology), SOS (sinusoidal obstruction syndrome)

      Keywords

      Myeloablative Total Body Irradiation (TBI) has long been a cornerstone of the conditioning for hematopoietic stem cell transplantation (HSCT) in children [
      • Storb R.
      History of pediatric stem cell transplantation.
      ], but is associated with considerable late effects [
      • Armenian S.H.
      • Sun C.L.
      • Kawashima T.
      • Arora M.
      • Leisenring W.
      • Sklar C.A.
      • et al.
      Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS).
      ,
      • Bhatia S.
      • Francisco L.
      • Carter A.
      • Sun C.L.
      • Baker K.S.
      • Gurney J.G.
      • et al.
      Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.
      ,
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Lawitschka A.
      • Peters C.
      Long-term effects of myeloablative allogeneic hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia.
      ,
      • Sun C.L.
      • Francisco L.
      • Kawashima T.
      • Leisenring W.
      • Robison L.L.
      • Baker K.S.
      • et al.
      Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study.
      ]. Currently, use of TBI is mainly indicated in allogeneic HSCT for high-risk hematologic malignancy [
      • Copelan E.A.
      Conditioning regimens for allogeneic bone marrow transplantation.
      ,
      • Hong S.
      • Barker C.
      • Klein J.P.
      • Shaw P.
      • Bredeson C.
      • Angelina A.
      • et al.
      Trends in utilization of Total Body Irradiation (Tbi) prior to Hematopoietic Cell Transplantation (Hct) worldwide.
      ,
      • Sureda A.
      • Bader P.
      • Cesaro S.
      • Dreger P.
      • Duarte R.F.
      • Dufour C.
      • et al.
      Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015.
      ,
      • Vettenranta K.
      • Party E.P.W.
      Current European practice in pediatric myeloablative conditioning.
      ,
      • Gupta T.
      • Kannan S.
      • Dantkale V.
      • Laskar S.
      Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: a systematic review and meta-analysis.
      ,
      • Peters C.
      • Dalle J.H.
      • Locatelli F.
      • Poetschger U.
      • Sedlacek P.
      • Buechner J.
      • et al.
      Total body irradiation or chemotherapy conditioning in childhood ALL: a multinational, randomized, noninferiority phase III study.
      ,
      • Hoeben B.A.W.
      • Wong J.Y.C.
      • Fog L.S.
      • Losert C.
      • Filippi A.R.
      • Bentzen S.M.
      • et al.
      Total body irradiation in haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia: review of the literature and future directions.
      ]. Fractionated TBI (fTBI) is standard for pediatric radiotherapy centers, but practices vary [
      • Hoeben B.A.W.
      • Pazos M.
      • Albert M.H.
      • Seravalli E.
      • Bosman M.E.
      • Losert C.
      • et al.
      Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
      ,
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ]. While most centers perform conventional TBI, several institutions have introduced highly conformal TBI techniques or Total Marrow Irradiation (TMI), Total Lymphoid Irradiation (TLI), and Total Marrow and Lymphoid Irradiation (TMLI) [
      • Gruen A.
      • Ebell W.
      • Wlodarczyk W.
      • Neumann O.
      • Kuehl J.S.
      • Stromberger C.
      • et al.
      Total Body Irradiation (TBI) using Helical Tomotherapy in children and young adults undergoing stem cell transplantation.
      ,
      • Losert C.
      • Shpani R.
      • Kiessling R.
      • Freislederer P.
      • Li M.
      • Walter F.
      • et al.
      Novel rotatable tabletop for total-body irradiation using a linac-based VMAT technique.
      ,
      • Symons K.
      • Morrison C.
      • Parry J.
      • Woodings S.
      • Zissiadis Y.
      Volumetric modulated arc therapy for total body irradiation: a feasibility study using Pinnacle(3) treatment planning system and Elekta Agility linac.
      ,
      • Wong J.Y.C.
      • Filippi A.R.
      • Scorsetti M.
      • Hui S.
      • Muren L.P.
      • Mancosu P.
      Total marrow and total lymphoid irradiation in bone marrow transplantation for acute leukaemia.
      ]. After a survey regarding clinical practice of pediatric TBI in European Society for Paediatric Oncology (SIOPE) affiliated centers [
      • Hoeben B.A.W.
      • Pazos M.
      • Albert M.H.
      • Seravalli E.
      • Bosman M.E.
      • Losert C.
      • et al.
      Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
      ], the SIOPE Radiotherapy TBI Working Group together with selected ESTRO experts established recommendations for myeloablative TBI in pediatric patients, for whom optimization of TBI is particularly of importance.

      Methods

      Literature searches were conducted in PubMed regarding fractionated pediatric myeloablative TBI. Search terms were: “tbi”[All Fields] OR (“whole body irradiation”[MeSH Terms] OR (“whole body”[All Fields] AND “irradiation”[All Fields]) OR “whole body irradiation”[All Fields] OR (“total”[All Fields] AND “body”[All Fields] AND “irradiation”[All Fields]) OR “total body irradiation”[All Fields]) OR “TMI”[All Fields] OR (“total”[All Fields] AND “marrow*”[All Fields]) OR ((“total”[All Fields] AND “lymphoid*”[All Fields]) OR “TMLI”[All Fields] OR “TLI”[All Fields]) AND “fraction*”[All Fields] AND (“pediatr*”[All Fields] OR “child*”[All Fields] OR “paediatr*”[All Fields]). Searches focused on conventional and highly conformal techniques of TBI; TMI; TMLI; TLI; technical and radiobiological considerations in publications since 1970. Systematic screening of search results on TBI toxicities in publications since 1980 was conducted using the AI screening tool ASReview LAB (Utrecht University, the Netherlands), and selected full-text analyzed publications were checked for further references. Inclusion criteria and search terms are given in Supplementary Tables 1–6. Members of the ESTRO-SIOPE writing committee held bimonthly virtual meetings to discuss the body of evidence and institutional experiences. Subgroups contributed specific sections and the entire manuscript was reviewed by all members. The Supplement Review provides an extended literature review as background to the recommendations. As exemplified in the Supplementary Tables regarding organ system-specific TBI-related toxicities, most recommendations and considerations are based on Level of Evidence III-IV publications. Considerations regarding boost radiotherapy should be graded as Level V, expert opinion, after evaluation of the literature and peer discussions. We attempted to compile and judge available data, knowing that high-level evidence is lacking for many open questions. All recommendations and considerations were accepted with majority approval.

      Recommendation results

      Indications for TBI-based myeloablative conditioning for HSCT in children

      Myeloablative TBI combined with etoposide is indicated in children ≥4 years of age with high-risk acute lymphoblastic leukemia (ALL) in any remission, who have an indication for allogeneic HSCT, as established in the prospective ALL-SCT-BFM 2003 and the randomized multicenter FORUM trials [
      • Peters C.
      • Dalle J.H.
      • Locatelli F.
      • Poetschger U.
      • Sedlacek P.
      • Buechner J.
      • et al.
      Total body irradiation or chemotherapy conditioning in childhood ALL: a multinational, randomized, noninferiority phase III study.
      ,
      • Peters C.
      • Schrappe M.
      • von Stackelberg A.
      • Schrauder A.
      • Bader P.
      • Ebell W.
      • et al.
      Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial.
      ]. TBI with cyclophosphamide is another traditionally used conditioning schedule. In study protocols, indications for HSCT and TBI are constantly evolving [

      EudraCT Number: 2018-001795-38. ALLTogether1– A Treatment study protocol of the ALLTogether Consortium for children and young adults (0-45 years of age) with newly diagnosed acute lymphoblastic leukaemia (ALL). 2020.

      ].
      In first HSCT for acute myeloid leukemia (AML) or advanced myelodysplastic syndrome, chemotherapy-only-based regimens are the rule, showing equivalent or superior survival as well as leukemia control compared with TBI-based regimens [
      • Lucchini G.
      • Labopin M.
      • Beohou E.
      • Dalissier A.
      • Dalle J.H.
      • Cornish J.
      • et al.
      Impact of conditioning regimen on outcomes for children with acute myeloid leukemia undergoing transplantation in first complete remission. An analysis on behalf of the pediatric disease working party of the European group for Blood and Marrow Transplantation.
      ,

      de Berranger E, Cousien A, Petit A, Peffault de Latour R, Galambrun C, Bertrand Y, et al. Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI+CY versus BU+CY: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Bone Marrow Transplant. 2014;49:382-8.

      ,
      • Gupta V.
      • Lazarus H.M.
      • Keating A.
      Myeloablative conditioning regimens for AML allografts: 30 years later.
      ]. A potential role of myeloablative TBI in subsequent HSCT for AML and juvenile myelomonocytic leukemia is unclear [
      • Yaniv I.
      • Krauss A.C.
      • Beohou E.
      • Dalissier A.
      • Corbacioglu S.
      • Zecca M.
      • et al.
      Second hematopoietic stem cell transplantation for post-transplantation relapsed acute leukemia in children: a retrospective EBMT-PDWP study.
      ,
      • Yoshimi A.
      • Mohamed M.
      • Bierings M.
      • Urban C.
      • Korthof E.
      • Zecca M.
      • et al.
      Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia.
      ]. No comparative studies on HSCT with TBI in pediatric patients with relapsed Non-Hodgkin (e.g. diffuse large B-cell, primary mediastinal large B-cell, Burkitt, lymphoblastic) lymphomas or anaplastic large cell lymphomas are available, but this treatment can be successful, depending on the histological subtype [
      • Burkhardt B.
      • Taj M.
      • Garnier N.
      • Minard-Colin V.
      • Hazar V.
      • Mellgren K.
      • et al.
      Treatment and outcome analysis of 639 relapsed non-hodgkin lymphomas in children and adolescents and resulting treatment recommendations.
      ,
      • Naik S.
      • Martinez C.A.
      • Omer B.
      • Sasa G.
      • Yassine K.
      • Allen C.E.
      • et al.
      Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients.
      ,
      • Knorr F.
      • Brugieres L.
      • Pillon M.
      • Zimmermann M.
      • Ruf S.
      • Attarbaschi A.
      • et al.
      Stem cell transplantation and vinblastine monotherapy for relapsed pediatric anaplastic large cell lymphoma: results of the international, prospective ALCL-relapse.
      ].
      Myeloablative TBI-based conditioning is not indicated in children with non-malignant diseases such as inborn errors of immunity, metabolism, or bone marrow failure diseases [
      • Lankester A.C.
      • Albert M.H.
      • Booth C.
      • Gennery A.R.
      • Gungor T.
      • Honig M.
      • et al.
      EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity.
      ,
      • Tan E.Y.
      • Boelens J.J.
      • Jones S.A.
      • Wynn R.F.
      Hematopoietic stem cell transplantation in inborn errors of metabolism.
      ,
      • Peffault de Latour R.
      • Peters C.
      • Gibson B.
      • Strahm B.
      • Lankester A.
      • de Heredia C.D.
      • et al.
      Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.
      ]. Non-myeloablative doses of TBI of 2–4 Gy combined with chemotherapy can be employed for their immunosuppressive effect in reduced intensity conditioning [
      • Lawitschka A.
      • Faraci M.
      • Yaniv I.
      • Veys P.
      • Bader P.
      • Wachowiak J.
      • et al.
      Paediatric reduced intensity conditioning: analysis of centre strategies on regimens and definitions by the EBMT Paediatric Diseases and Complications and Quality of Life WP.
      ,
      • Storb R.
      • Sandmaier B.M.
      Nonmyeloablative allogeneic hematopoietic cell transplantation.
      ]. These recommendations focus on myeloablative TBI.

      Patient evaluation before TBI

      Pre-HCST workup should include complete physical examination, a comprehensive series of organ function tests and consultations with members of the HSCT team (Table 1). Disease and complete treatment history, as well as recent outcomes of minimal residual disease (MRD) status and cerebrospinal fluid cytology are mandatory [
      • Bader P.
      • Salzmann-Manrique E.
      • Balduzzi A.
      • Dalle J.H.
      • Woolfrey A.E.
      • Bar M.
      • et al.
      More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.
      ]. Age is a very important factor when deciding about TBI; young children (<3–4 years) are more prone to develop serious late complications [
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ,
      • Vrooman L.M.
      • Millard H.R.
      • Brazauskas R.
      • Majhail N.S.
      • Battiwalla M.
      • Flowers M.E.
      • et al.
      Survival and late effects after allogeneic hematopoietic cell transplantation for hematologic malignancy at less than three years of age.
      ,
      • Perkins J.L.
      • Kunin-Batson A.S.
      • Youngren N.M.
      • Ness K.K.
      • Ulrich K.J.
      • Hansen M.J.
      • et al.
      Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.
      ,
      • Bakker B.
      • Oostdijk W.
      • Geskus R.B.
      • Stokvis-Brantsma W.H.
      • Vossen J.M.
      • Wit J.M.
      Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood.
      ,
      • Smedler A.C.
      • Winiarski J.
      Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning.
      ,
      • Willard V.W.
      • Leung W.
      • Huang Q.
      • Zhang H.
      • Phipps S.
      Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation.
      ].
      Table 1Patient evaluation before allogeneic HSCT conditioning with myeloablative TBI, and long-term follow-up recommendations after TBI.
      Pre-TBI based HSCT conditioning evaluation
      Examination factorTest recommendationReferences
      Age<3 and preferably <4 years old; avoid myeloablative TBI because of increased risk of late effects.

      Consider potential toxicity effects of TBI at specific age and development stage of patients.
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ,
      • Vrooman L.M.
      • Millard H.R.
      • Brazauskas R.
      • Majhail N.S.
      • Battiwalla M.
      • Flowers M.E.
      • et al.
      Survival and late effects after allogeneic hematopoietic cell transplantation for hematologic malignancy at less than three years of age.
      ,
      • Perkins J.L.
      • Kunin-Batson A.S.
      • Youngren N.M.
      • Ness K.K.
      • Ulrich K.J.
      • Hansen M.J.
      • et al.
      Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.
      ,
      • Bakker B.
      • Oostdijk W.
      • Geskus R.B.
      • Stokvis-Brantsma W.H.
      • Vossen J.M.
      • Wit J.M.
      Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood.
      ,
      • Smedler A.C.
      • Winiarski J.
      Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning.
      ,
      • Willard V.W.
      • Leung W.
      • Huang Q.
      • Zhang H.
      • Phipps S.
      Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation.
      Medical historyEvaluate complete disease and treatment history and other relevant medical background details, including family history of malignancies.
      CNS statusCerebrospinal fluid examination for CNS 1-2-3 status; preferably 1-2 before conditioning, otherwise consider CNS boost before TBI.
      • Pinnix C.C.
      • Yahalom J.
      • Specht L.
      • Dabaja B.S.
      Radiation in central nervous system leukemia: guidelines from the International Lymphoma Radiation Oncology Group.
      MRD statusRT-qPCR or NGS MRD negativity related with better prognosis. If positive, discuss potential further treatment to reach MRD negativity before HSCT.
      • Bader P.
      • Salzmann-Manrique E.
      • Balduzzi A.
      • Dalle J.H.
      • Woolfrey A.E.
      • Bar M.
      • et al.
      More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.
      ,
      • Eckert C.
      • Parker C.
      • Moorman A.V.
      • Irving J.A.
      • Kirschner-Schwabe R.
      • Groeneveld-Krentz S.
      • et al.
      Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials.
      ,
      • Merli P.
      • Ifversen M.
      • Truong T.H.
      • Marquart H.V.
      • Buechner J.
      • Wölfl M.
      • et al.
      Minimal residual disease prior to and after haematopoietic stem cell transplantation in children and adolescents with acute lymphoblastic leukaemia: What level of negativity is relevant?.
      Previous radiotherapyCheck cumulative dose and safety of additional TBI.
      Complete physical examinationi.e. lung, heart, abdomen, nodal, testes examination, growth.

      Carreras E., Rambaldi A. Evaluation and counseling of candidates. In: Carreras E., Dufour C., Mohty M., Kröger N., editors. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Cham (CH): Springer Copyright 2019, EBMT and the Author(s). 2019. p. 77-86.

      Lung examinationRadiologic examination of lungs, previous pulmonary problems, respiratory function tests.

      Carreras E., Rambaldi A. Evaluation and counseling of candidates. In: Carreras E., Dufour C., Mohty M., Kröger N., editors. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Cham (CH): Springer Copyright 2019, EBMT and the Author(s). 2019. p. 77-86.

      Cardiac examination and cardiovascular risk profileElectrocardiogram, weight, blood pressure, cardiac ultrasonography or isotopic ventriculography (after previous cardiotoxic treatments e.g. exposure to anthracyclines, previous thoracic radiotherapy), glucose- lipid-, cholesterol- and triglycerides spectrum.

      Carreras E., Rambaldi A. Evaluation and counseling of candidates. In: Carreras E., Dufour C., Mohty M., Kröger N., editors. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Cham (CH): Springer Copyright 2019, EBMT and the Author(s). 2019. p. 77-86.

      ,
      • Armenian S.H.
      • Sun C.L.
      • Vase T.
      • Ness K.K.
      • Blum E.
      • Francisco L.
      • et al.
      Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease.
      ,
      • Friedman D.N.
      • Hilden P.
      • Moskowitz C.S.
      • Suzuki M.
      • Boulad F.
      • Kernan N.A.
      • et al.
      Cardiovascular risk factors in survivors of childhood hematopoietic cell transplantation treated with total body irradiation: a longitudinal analysis.
      Kidney functionBlood pressure, renal function assessment (blood urea nitrogen and creatinine + clearance, urinary protein, and if necessary kidney ultrasonography).
      Liver functionBlood liver function test (bilirubin, AST, ALT), history of cirrhosis or hepatitis.
      Endocrine statusCheck of growth, thyroid, gonadal hormone levels.
      Neurocognitive statusBaseline neurocognitive testing, cognitive development evaluation.
      • Kupst M.J.
      • Penati B.
      • Debban B.
      • Camitta B.
      • Pietryga D.
      • Margolis D.
      • et al.
      Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study.
      ,
      • Buchbinder D.
      • Kelly D.L.
      • Duarte R.F.
      • Auletta J.J.
      • Bhatt N.
      • Byrne M.
      • et al.
      Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT.
      Fertility counselingFertility counseling by specialist, evaluate possibility of gamete storage pre-HSCT conditioning.
      • Salooja N.
      • Shoham Z.
      • Dalle J.H.
      Endocrine disorders, fertility and sexual health.
      ,
      • Borgmann-Staudt A.
      • Rendtorff R.
      • Reinmuth S.
      • Hohmann C.
      • Keil T.
      • Schuster F.R.
      • et al.
      Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence.
      ,
      • Vatanen A.
      • Wilhelmsson M.
      • Borgström B.
      • Gustafsson B.
      • Taskinen M.
      • Saarinen-Pihkala U.M.
      • et al.
      Ovarian function after allogeneic hematopoietic stem cell transplantation in childhood and adolescence.
      ,
      • Couto-Silva A.C.
      • Trivin C.
      • Esperou H.
      • Michon J.
      • Baruchel A.
      • Lemaire P.
      • et al.
      Final height and gonad function after total body irradiation during childhood.
      Ophthalmologic evaluationPre-conditioning inspection by ophthalmologist. Clinical symptoms, visual acuity, fundus exam, lens inspection.
      • Bradfield Y.S.
      • Kushner B.J.
      • Gangnon R.E.
      Ocular complications after organ and bone marrow transplantation in children.
      ,
      • Hall M.D.
      • Schultheiss T.E.
      • Smith D.D.
      • Nguyen K.H.
      • Wong J.Y.
      Dose response for radiation cataractogenesis: a meta-regression of hematopoietic stem cell transplantation regimens.
      Dental evaluationPre-conditioning inspection and preventive care by dental specialist.
      • Majorana A.
      • Schubert M.M.
      • Porta F.
      • Ugazio A.G.
      • Sapelli P.L.
      Oral complications of pediatric hematopoietic cell transplantation: diagnosis and management.
      Cancer predisposition syndromesAvoid radiotherapy for these children if possible.
      Psychosocial and social evaluationPsychological and social burden capacity of patient and caregivers.
      • Kupst M.J.
      • Penati B.
      • Debban B.
      • Camitta B.
      • Pietryga D.
      • Margolis D.
      • et al.
      Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study.
      ,
      • Chardon M.L.
      • Canter K.S.
      • Pai A.L.H.
      • Peugh J.L.
      • Madan-Swain A.
      • Vega G.
      • et al.
      The impact of pediatric hematopoietic stem cell transplant timing and psychosocial factors on family and caregiver adjustment.
      ,
      • Hashmi S.
      • Carpenter P.
      • Khera N.
      • Tichelli A.
      • Savani B.N.
      Lost in transition: the essential need for long-term follow-up clinic for blood and marrow transplantation survivors.
      Long-term follow-up after TBI-based HSCT conditioning
      Examination factorTest recommendationReferences
      Chronic GVHDRegular follow-up with evaluation of GVHD signs and symptoms (skin, mouth, gut, genitourinary system, liver, lungs). Treatment with steroids and other immunosuppressants if necessary.
      • Linhares Y.P.
      • Pavletic S.
      • Gale R.P.
      Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?.
      ,
      • Wolff D.
      • Lawitschka A.
      Chronic graft-versus-host disease.
      ,
      • Penack O.
      • Marchetti M.
      • Ruutu T.
      • Aljurf M.
      • Bacigalupo A.
      • Bonifazi F.
      • et al.
      Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.
      Late respiratory complicationsPulmonary function testing and focused radiologic assessment at 1 and potentially 2 years after HSCT, and regularly thereafter for those with deficits. Regular routine clinical assessment. Discouragement of smoking.
      • Carreras E.
      • Cooke K.R.
      Noninfectious pulmonary complications.
      ,
      • Bruno B.
      • Souillet G.
      • Bertrand Y.
      • Werck-Gallois M.C.
      • So Satta A.
      • Bellon G.
      Effects of allogeneic bone marrow transplantation on pulmonary function in 80 children in a single paediatric centre.
      ,
      • Cerveri I.
      • Zoia M.C.
      • Fulgoni P.
      • Corsico A.
      • Casali L.
      • Tinelli C.
      • et al.
      Late pulmonary sequelae after childhood bone marrow transplantation.
      ,
      • Ferry C.
      • Gemayel G.
      • Rocha V.
      • Labopin M.
      • Esperou H.
      • Robin M.
      • et al.
      Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies.
      ,
      • Hoffmeister P.A.
      • Madtes D.K.
      • Storer B.E.
      • Sanders J.E.
      Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation.
      ,
      • Kunkele A.
      • Engelhard M.
      • Hauffa B.P.
      • Mellies U.
      • Muntjes C.
      • Huer C.
      • et al.
      Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
      ,
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      Metabolic and cardiovascular functionYearly check-ups, e.g. regular evaluation of weight, dyslipidemia, blood pressure and hyperglycemia.
      • DeFilipp Z.
      • Duarte R.F.
      • Snowden J.A.
      • Majhail N.S.
      • Greenfield D.M.
      • Miranda J.L.
      • et al.
      Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT.
      Endocrine functionYearly comprehensive blood screening for endocrine dysfunctions (growth, thyroid, gonadal, adrenocortical). Supplementation by endocrinologist when necessary.
      • Bernard F.
      • Auquier P.
      • Herrmann I.
      • Contet A.
      • Poiree M.
      • Demeocq F.
      • et al.
      Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.
      ,
      • Brennan B.M.
      • Shalet S.M.
      Endocrine late effects after bone marrow transplant.
      ,
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications of hematopoietic stem cell transplantation.
      ,
      • Tauchmanova L.
      • Selleri C.
      • Rosa G.D.
      • Pagano L.
      • Orio F.
      • Lombardi G.
      • et al.
      High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases.
      GrowthEvaluation of growth curve and velocity with checks for influencing factors (hormone depletion, liver dysfunction, chronic GVHD). Supplementation by endocrinologist when necessary.
      • Bakker B.
      • Oostdijk W.
      • Geskus R.B.
      • Stokvis-Brantsma W.H.
      • Vossen J.M.
      • Wit J.M.
      Growth hormone (GH) secretion and response to GH therapy after total body irradiation and haematopoietic stem cell transplantation during childhood.
      ,
      • Isfan F.
      • Kanold J.
      • Merlin E.
      • Contet A.
      • Sirvent N.
      • Rochette E.
      • et al.
      Growth hormone treatment impact on growth rate and final height of patients who received HSCT with TBI or/and cranial irradiation in childhood: a report from the French Leukaemia Long-Term Follow-Up Study (LEA).
      ,
      • Sanders J.E.
      • Guthrie K.A.
      • Hoffmeister P.A.
      • Woolfrey A.E.
      • Carpenter P.A.
      • Appelbaum F.R.
      Final adult height of patients who received hematopoietic cell transplantation in childhood.
      Fertility issuesCounseling and management of post-HSCT fertility issues. Pregnancies after TBI should be monitored by a gynecologist because of higher risk of miscarriages, preterm deliveries, and obstetrical complications.
      • Salooja N.
      • Shoham Z.
      • Dalle J.H.
      Endocrine disorders, fertility and sexual health.
      ,
      • Sanders J.E.
      • Hawley J.
      • Levy W.
      • Gooley T.
      • Buckner C.D.
      • Deeg H.J.
      • et al.
      Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation.
      Bone healthMonitoring of bone health i.e. signs of bone mineral density loss or osteoporosis through biochemical hormone assessments. DEXA scan evaluation at 1 year after HSCT and afterwards based on baseline findings (expert opinion). Counseling by a pediatric endocrinologist, weight-bearing exercise, and use of calcium and vitamin D supplements, hormone replacement in case of hypogonadism, or antiresorptive agents (bisphosphonates or calcitonin) if evidence of abnormalities.
      • Weilbaecher K.N.
      Mechanisms of osteoporosis after hematopoietic cell transplantation.
      ,
      • Stern J.M.
      • Sullivan K.M.
      • Ott S.M.
      • Seidel K.
      • Fink J.C.
      • Longton G.
      • et al.
      Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study.
      ,
      • McClune B.L.
      • Polgreen L.E.
      • Burmeister L.A.
      • Blaes A.H.
      • Mulrooney D.A.
      • Burns L.J.
      • et al.
      Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients.
      Chronic renal dysfunctionYearly screening of renal function (including blood pressure, renal function assessment (blood urea nitrogen and creatinine + clearance, urinary protein, and if necessary kidney ultrasonography).
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      ,
      • Patzer L.
      • Ringelmann F.
      • Kentouche K.
      • Fuchs D.
      • Zintl F.
      • Brandis M.
      • et al.
      Renal function in long-term survivors of stem cell transplantation in childhood. A prospective trial.
      Ocular complicationsYearly inspection by ophthalmologist. Clinical symptoms, visual acuity, fundus examination, lens inspection.
      • Hall M.D.
      • Schultheiss T.E.
      • Smith D.D.
      • Nguyen K.H.
      • Wong J.Y.
      Dose response for radiation cataractogenesis: a meta-regression of hematopoietic stem cell transplantation regimens.
      ,
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      ,
      • Horwitz M.
      • Auquier P.
      • Barlogis V.
      • Contet A.
      • Poiree M.
      • Kanold J.
      • et al.
      Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study.
      Dental evaluationExamination by dentist 6–12 months post-HSCT and yearly thereafter; evaluation of caries and saliva production, dental hygiene, consideration fluoride application. After TBI, awareness of risk for oral malignancies.
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      Neurocognitive functionNeurocognitive testing in children is recommended before and 1 year after HSCT and then at the beginning of each new stage of education.
      • Buchbinder D.
      • Kelly D.L.
      • Duarte R.F.
      • Auletta J.J.
      • Bhatt N.
      • Byrne M.
      • et al.
      Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT.
      Secondary malignanciesRegular clinical assessment at outpatient clinic visits, advise patients and caregivers about the risks of secondary malignancies and encourage routine screening self-examinations, such as breast and skin examination. Consider dermatologic screening by a specialist every 1–2 years. Participation in national cancer screening protocols. Ultrasonography and MRI screening programs for thyroid cancer for all patients and breast cancer in young women ≥ 25 years can be considered. From age 50, annual fecal occult blood testing, or sigmoidoscopy every 5 years with occult blood testing every 3 years, or colonoscopy every 10 years can be considered. Discourage high-risk behaviors such as unprotected skin UV exposure and smoking.
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      ,
      • Socié G.
      • Rizzo J.D.
      Second solid tumors: screening and management guidelines in long-term survivors after allogeneic stem cell transplantation.
      ,
      • Inamoto Y.
      • Shah N.N.
      • Savani B.N.
      • Shaw B.E.
      • Abraham A.A.
      • Ahmed I.A.
      • et al.
      Secondary solid cancer screening following hematopoietic cell transplantation.
      ,
      • Bowers D.C.
      • Verbruggen L.C.
      • Kremer L.C.M.
      • Hudson M.M.
      • Skinner R.
      • Constine L.S.
      • et al.
      Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
      ,
      • Cohen A.
      • Rovelli A.
      • van Lint M.T.
      • Merlo F.
      • Gaiero A.
      • Mulas R.
      • et al.
      Secondary thyroid carcinoma after allogeneic bone marrow transplantation during childhood.
      ,
      • Friedman D.L.
      • Rovo A.
      • Leisenring W.
      • Locasciulli A.
      • Flowers M.E.
      • Tichelli A.
      • et al.
      Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party.
      ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; DEXA = Dual-energy x-ray absorptiometry; GVHD = graft versus host disease; HSCT = hematopoietic stem cell transplantation; MRD = minimal residual disease; MRI = magnetic resonance imaging; NGS = next-generation sequencing; RT-qPCR = real-time quantitative polymerase chain reaction.
      Cancer predisposition syndromes may preclude radiotherapy. In case of known encephalopathy or myelopathy one should consider the potential additional damage of myeloablative TBI. Potential increased toxicity due to previous radiotherapy should be considered before deciding on TBI.

      TBI fractionation

      Fractionated TBI (fTBI) showed equality in disease outcome and reduced toxicity when compared with single-fraction TBI (sfTBI) [
      • Peters L.
      Total body irradiation conference: discussion: the radiobiological bases of TBI.
      ,
      • Peters L.J.
      • Withers H.R.
      • Cundiff J.H.
      • Dicke K.A.
      Radiobiological considerations in the use of total-body irradiation for bone-marrow transplantation.
      ,
      • Cohen A.
      • Rovelli A.
      • Bakker B.
      • Uderzo C.
      • van Lint M.T.
      • Esperou H.
      • et al.
      Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.
      ,
      • Deeg H.J.
      • Flournoy N.
      • Sullivan K.M.
      • Sheehan K.
      • Buckner C.D.
      • Sanders J.E.
      • et al.
      Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation.
      ,
      • Thomas E.D.
      • Clift R.A.
      • Hersman J.
      • Sanders J.E.
      • Stewart P.
      • Buckner C.D.
      • et al.
      Marrow transplantation for acute nonlymphoblastic leukemic in first remission using fractionated or single-dose irradiation.
      ,
      • Deeg H.J.
      • Sullivan K.M.
      • Buckner C.D.
      • Storb R.
      • Appelbaum F.R.
      • Clift R.A.
      • et al.
      Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation.
      ,
      • Clift R.A.
      • Buckner C.D.
      • Thomas E.D.
      • Sanders J.E.
      • Stewart P.S.
      • Sullivan K.M.
      • et al.
      Allogeneic marrow transplantation using fractionated total body irradiation in patients with acute lymphoblastic leukemia in relapse.
      ,
      • Clift R.A.
      • Buckner C.D.
      • Appelbaum F.R.
      • Bearman S.I.
      • Petersen F.B.
      • Fisher L.D.
      • et al.
      Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens.
      ,
      • Clift R.A.
      • Buckner C.D.
      • Appelbaum F.R.
      • Sullivan K.M.
      • Storb R.
      • Thomas E.D.
      Long-term follow-Up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia.
      ,
      • Ozsahin M.
      • Pene F.
      • Touboul E.
      • Gindrey-Vie B.
      • Dominique C.
      • Lefkopoulos D.
      • et al.
      Total-body irradiation before bone marrow transplantation. Results of two randomized instantaneous dose rates in 157 patients.
      ,
      • Belkacemi Y.
      • Labopin M.
      • Vernant J.P.
      • Prentice H.G.
      • Tichelli A.
      • Schattenberg A.
      • et al.
      Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the European Group for Blood and Marrow Transplantation.
      ]. Different fractionation schedules have been used [
      • Quast U.
      Total body irradiation–review of treatment techniques in Europe.
      ] (Supplementary Tables 1–6). Extrapolating exclusive TBI-related effect differences from the literature is precluded by influences of conditioning-protocol variations, previous treatments and GVHD, in patient cohorts with various diseases and age groups. Fractionated TBI with doses of <9–10 Gy resulted in increased non-engraftment and disease-relapse in several reports [
      • Frassoni F.
      • Scarpati D.
      • Bacigalupo A.
      • Vitale V.
      • Corvo R.
      • Miceli S.
      • et al.
      The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation.
      ,
      • Scarpati D.
      • Frassoni F.
      • Vitale V.
      • Corvo R.
      • Franzone P.
      • Barra S.
      • et al.
      Total body irradiation in acute myeloid leukemia and chronic myelogenous leukemia: influence of dose and dose-rate on leukemia relapse.
      ]. Lung and/or liver adverse events were found to be the dose-limiting toxicity for fTBI 15.5–16 Gy [
      • Petersen F.B.
      • Deeg H.J.
      • Buckner C.D.
      • Appelbaum F.R.
      • Storb R.
      • Clift R.A.
      • et al.
      Marrow transplantation following escalating doses of fractionated total body irradiation and cyclophosphamide–a phase I trial.
      ,
      • Bearman S.I.
      • Appelbaum F.R.
      • Buckner C.D.
      • Petersen F.B.
      • Fisher L.D.
      • Clift R.A.
      • et al.
      Regimen-related toxicity in patients undergoing bone marrow transplantation.
      ,
      • Sampath S.
      • Schultheiss T.E.
      • Wong J.
      Dose response and factors related to interstitial pneumonitis after bone marrow transplant.
      ]; non-relapse mortality (NRM) was increased for 15.75-Gy fTBI as compared with 12 Gy [
      • Clift R.A.
      • Buckner C.D.
      • Appelbaum F.R.
      • Bearman S.I.
      • Petersen F.B.
      • Fisher L.D.
      • et al.
      Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens.
      ,
      • Clift R.A.
      • Buckner C.D.
      • Appelbaum F.R.
      • Sullivan K.M.
      • Storb R.
      • Thomas E.D.
      Long-term follow-Up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia.
      ]; and secondary malignancy risk increased with conventionally performed fTBI ≥13–14.4 Gy in large retrospective cohorts [
      • Socie G.
      • Curtis R.E.
      • Deeg H.J.
      • Sobocinski K.A.
      • Filipovich A.H.
      • Travis L.B.
      • et al.
      New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia.
      ,
      • Baker K.S.
      • Leisenring W.M.
      • Goodman P.J.
      • Ermoian R.P.
      • Flowers M.E.
      • Schoch G.
      • et al.
      Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation.
      ]. To optimize the radiobiological therapeutic ratio, twice-daily fractionation of 1.6–2 Gy to total doses ≥12 Gy was advocated by several authors. Strongly hyperfractionated schedules with 3–4 fractions daily seem to have worse anti-leukemic/immunosuppressive effects, and are impractical in terms of delivery [
      • Peters L.J.
      • Withers H.R.
      • Cundiff J.H.
      • Dicke K.A.
      Radiobiological considerations in the use of total-body irradiation for bone-marrow transplantation.
      ,
      • Muller-Runkel R.
      • Vijayakumar S.
      Fractionated total body irradiation: some radiobiological considerations.
      ,
      • O’Donoghue J.A.
      Fractionated versus low dose-rate total body irradiation. Radiobiological considerations in the selection of regimes.
      ,
      • O'Donoghue J.A.
      • Wheldon T.E.
      • Gregor A.
      The implications of in-vitro radiation-survival curves for the optimal scheduling of total-body irradiation with bone marrow rescue in the treatment of leukaemia.
      ]. Giving 12 Gy fTBI in once-daily fractions of 3–4 Gy increases acute effects such as mucositis [
      • Belkacemi Y.
      • Labopin M.
      • Giebel S.
      • Loganadane G.
      • Miszczyk L.
      • Michallet M.
      • et al.
      Single-dose daily fractionation is not inferior to twice-a-day fractionated total-body irradiation before allogeneic stem cell transplantation for acute leukemia: a useful practice simplification resulting from the SARASIN study.
      ,
      • Sengelov H.
      • Petersen P.M.
      • Fog L.
      • Schmidt M.
      • Specht L.
      Less mucositis toxicity after 6 versus 3 fractions of high-dose total body irradiation before allogeneic stem cell transplantation.
      ]. Considering radiobiological early and late effects for children, a maximum fraction dose of 2 Gy is advisable. Interplay between chemotherapy type/dose and TBI can be influential on outcome [
      • Marks D.I.
      • Forman S.J.
      • Blume K.G.
      • Perez W.S.
      • Weisdorf D.J.
      • Keating A.
      • et al.
      A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.
      ], but studies on the finesses are lacking. TBI as 12 Gy in 6 fractions b.i.d. combined with etoposide was employed in the recent randomized FORUM trial, and resulted in generally less NRM and acute toxicity than can be surmised from historical reports [
      • Peters C.
      • Dalle J.H.
      • Locatelli F.
      • Poetschger U.
      • Sedlacek P.
      • Buechner J.
      • et al.
      Total body irradiation or chemotherapy conditioning in childhood ALL: a multinational, randomized, noninferiority phase III study.
      ]. Other common schedules are 13.2 Gy or 14.4 Gy in 8 fractions over 4 days [
      • Hoeben B.A.W.
      • Pazos M.
      • Albert M.H.
      • Seravalli E.
      • Bosman M.E.
      • Losert C.
      • et al.
      Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
      ,
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ]. Currently, in conventional TBI, fTBI schedules of 12–14.4 Gy, in 1.6–2 Gy fractions b.i.d., are customary in pediatric radiation oncology centers [
      • Hoeben B.A.W.
      • Pazos M.
      • Albert M.H.
      • Seravalli E.
      • Bosman M.E.
      • Losert C.
      • et al.
      Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
      ,
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ]. Commonly used schedules are 6×2 Gy, 8×1.8 Gy or 8×1.65 Gy b.i.d. Nonetheless, continuous re-assessment is in order. For example, highly-conformal TBI or TM(L)I techniques, as described further-on, may be beneficial regarding reduction of organ-at-risk (OAR) toxicity and enabling of dose escalation for very high-risk patients [
      • Hui S.
      • Brunstein C.
      • Takahashi Y.
      • DeFor T.
      • Holtan S.G.
      • Bachanova V.
      • et al.
      Dose escalation of total marrow irradiation in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation.
      ].

      TBI dose rate

      The radiobiological effect of TBI depends on many interplaying factors, including radiation dose rate (see the supplement for more elaborate discussion). Preclinical studies have reported influence of TBI dose rate on normal tissues and malignant/hematopoietic cells. Changing the dose rate within the lower range of e.g. 0.5–30 cGy/min had more influence on biological acute and late radiation effects than changes between dose rates within the higher range of e.g. 100–1000 cGy/min [
      • Deeg H.J.
      • Flournoy N.
      • Sullivan K.M.
      • Sheehan K.
      • Buckner C.D.
      • Sanders J.E.
      • et al.
      Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation.
      ,
      • Travis E.L.
      • Peters L.J.
      • McNeill J.
      • Thames Jr., H.D.
      • Karolis C.
      Effect of dose-rate on total body irradiation: lethality and pathologic findings.
      ,
      • Turesson I.
      Radiobiological aspects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation.
      ,
      • Tarbell N.J.
      • Amato D.A.
      • Down J.D.
      • Mauch P.
      • Hellman S.
      Fractionation and dose rate effects in mice: a model for bone marrow transplantation in man.
      ]. Fractionation abrogated increased toxicity effects of high dose rates [
      • Deeg H.J.
      • Flournoy N.
      • Sullivan K.M.
      • Sheehan K.
      • Buckner C.D.
      • Sanders J.E.
      • et al.
      Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation.
      ,
      • Travis E.L.
      • Peters L.J.
      • McNeill J.
      • Thames Jr., H.D.
      • Karolis C.
      Effect of dose-rate on total body irradiation: lethality and pathologic findings.
      ,
      • Turesson I.
      Radiobiological aspects of continuous low dose-rate irradiation and fractionated high dose-rate irradiation.
      ,
      • Tarbell N.J.
      • Amato D.A.
      • Down J.D.
      • Mauch P.
      • Hellman S.
      Fractionation and dose rate effects in mice: a model for bone marrow transplantation in man.
      ]. In the clinical situation, lowering dose rate decreases OAR toxicities in conventional sfTBI, but is less influential for 2-Gy fTBI, especially when OAR shielding is performed [
      • Ozsahin M.
      • Pene F.
      • Touboul E.
      • Gindrey-Vie B.
      • Dominique C.
      • Lefkopoulos D.
      • et al.
      Total-body irradiation before bone marrow transplantation. Results of two randomized instantaneous dose rates in 157 patients.
      ,
      • Sampath S.
      • Schultheiss T.E.
      • Wong J.
      Dose response and factors related to interstitial pneumonitis after bone marrow transplant.
      ,
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      • Heijenbrok-Kal M.H.
      • Struikmans H.
      Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation.
      ,
      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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.
      ,
      • Girinsky T.
      • Benhamou E.
      • Bourhis J.H.
      • Dhermain F.
      • Guillot-Valls D.
      • Ganansia V.
      • et al.
      Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies.
      ,
      • Soejima T.
      • Hirota S.
      • Tsujino K.
      • Yoden E.
      • Fujii O.
      • Ichimiya Y.
      • et al.
      Total body irradiation followed by bone marrow transplantation: comparison of once-daily and twice-daily fractionation regimens.
      ]. However, most clinical studies have been performed at reported patient midplane dose rates ≤15–20 cGy/min. Careful interpretation is needed, since dose rate evaluation and reporting differs between centers, and organ-dose is generally extrapolated from external measurements in 2D techniques. Therefore, unequivocal recommendations regarding dose rate in conventional fTBI cannot be given, other than to stress the importance of international consensus on dose rate reporting. Many pediatric centers report using dose rates of 6–15 cGy/min, with appropriate OAR shielding [
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ,
      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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.
      ]. With the implementation of highly conformal TBI techniques, inherently high fluctuating instantaneous dose rates are applied. The first reports regarding toxicity and outcome with TomoTherapy and VMAT fTBI in 220 children show promising results [
      • Kobyzeva D.
      • Shelikhova L.
      • Loginova A.
      • Kanestri F.
      • Tovmasyan D.
      • Maschan M.
      • et al.
      Optimized conformal total body irradiation among recipients of TCRalphabeta/CD19-depleted grafts in pediatric patients with hematologic malignancies: single-center experience.
      ].

      Toxicities and organ-at-risk sparing

      Acute toxicities that can be expected in the days and weeks after TBI include parotitis [
      • Buchali A.
      • Feyer P.
      • Groll J.
      • Massenkeil G.
      • Arnold R.
      • Budach V.
      Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation.
      ,
      • Oya N.
      • Sasai K.
      • Tachiiri S.
      • Sakamoto T.
      • Nagata Y.
      • Okada T.
      • et al.
      Influence of radiation dose rate and lung dose on interstitial pneumonitis after fractionated total body irradiation: acute parotitis may predict interstitial pneumonitis.
      ], nausea, vomiting, diarrhea, xerostomia, mucositis and esophagitis, skin erythema, headache, alopecia, loss of appetite, and fatigue [
      • Buchali A.
      • Feyer P.
      • Groll J.
      • Massenkeil G.
      • Arnold R.
      • Budach V.
      Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation.
      ].
      TBI-based conditioning causes more late sequelae than chemotherapy-only conditioning, although many other factors should be taken into account [
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Lawitschka A.
      • Peters C.
      Long-term effects of myeloablative allogeneic hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia.
      ,
      • Bernard F.
      • Auquier P.
      • Herrmann I.
      • Contet A.
      • Poiree M.
      • Demeocq F.
      • et al.
      Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.
      ,
      • Resbeut M.
      • Cowen D.
      • Blaise D.
      • Gluckman E.
      • Cosset J.M.
      • Rio B.
      • et al.
      Fractionated or single-dose total body irradiation in 171 acute myeloblastic leukemias in first complete remission: is there a best choice? SFGM. Societe Francaise de Greffe de Moelle.
      ]. Young children, especially <3–4 years of age, suffer more profound late effects than older children [
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ,
      • Willard V.W.
      • Leung W.
      • Huang Q.
      • Zhang H.
      • Phipps S.
      Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation.
      ], e.g. negative effects on neurocognition [
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ,
      • Perkins J.L.
      • Kunin-Batson A.S.
      • Youngren N.M.
      • Ness K.K.
      • Ulrich K.J.
      • Hansen M.J.
      • et al.
      Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.
      ,
      • Smedler A.C.
      • Winiarski J.
      Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning.
      ,
      • Willard V.W.
      • Leung W.
      • Huang Q.
      • Zhang H.
      • Phipps S.
      Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation.
      ,
      • Barrera M.
      • Atenafu E.
      • Andrews G.S.
      • Saunders F.
      Factors related to changes in cognitive, educational and visual motor integration in children who undergo hematopoietic stem cell transplant.
      ,
      • Chou R.H.
      • Wong G.B.
      • Kramer J.H.
      • Wara D.W.
      • Matthay K.K.
      • Crittenden M.R.
      • et al.
      Toxicities of total-body irradiation for pediatric bone marrow transplantation.
      ,
      • Parth P.
      • Dunlap W.P.
      • Kennedy R.S.
      • Ordy J.M.
      • Lane N.E.
      Motor and cognitive testing of bone marrow transplant patients after chemoradiotherapy.
      ,
      • Smedler A.C.
      • Ringden K.
      • Bergman H.
      • Bolme P.
      Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation.
      ], growth [
      • Bakker B.
      • Oostdijk W.
      • Geskus R.B.
      • Stokvis-Brantsma W.H.
      • Vossen J.M.
      • Wit J.M.
      Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood.
      ,
      • Couto-Silva A.C.
      • Trivin C.
      • Esperou H.
      • Michon J.
      • Baruchel A.
      • Lemaire P.
      • et al.
      Final height and gonad function after total body irradiation during childhood.
      ,
      • Bernard F.
      • Bordigoni P.
      • Simeoni M.C.
      • Barlogis V.
      • Contet A.
      • Loundou A.
      • et al.
      Height growth during adolescence and final height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning regimen with BU or TBI.
      ,
      • Cohen E.P.
      • Pais P.
      • Moulder J.E.
      Chronic kidney disease after hematopoietic stem cell transplantation.
      ,
      • Thomas B.C.
      • Stanhope R.
      • Plowman P.N.
      • Leiper A.D.
      Growth following single fraction and fractionated total body irradiation for bone marrow transplantation.
      ], and endocrine and metabolic functioning [
      • Bresters D.
      • Lawitschka A.
      • Cugno C.
      • Potschger U.
      • Dalissier A.
      • Michel G.
      • et al.
      Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.
      ,
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ]. Myeloablative TBI in children <3 years, and preferably <4 years, should be avoided. However, individual disease risk and outcome considerations may outweigh potential concerns regarding negative sequelae.
      Although many reports describe TBI-related late sequelae in mostly mixed cohorts of adults and children, the relationship between TBI total dose and fractionation and specific organ toxicities is described sparsely. We provide Supplementary Tables 1–6, summarizing the literature regarding pediatric fTBI-related toxicities of lungs, kidneys, eyes/lenses, liver, cardiovascular and endocrine systems.
      The most evaluated TBI-related lung toxicity is interstitial pneumonitis (IP). IP usually occurs within 4 months post-HSCT. After fTBI in children, the incidence varies from 0–35%, with usually <20% fatal outcome (Supplementary Table 1) [
      • Lucchini G.
      • Labopin M.
      • Beohou E.
      • Dalissier A.
      • Dalle J.H.
      • Cornish J.
      • et al.
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      ,
      • Hoffmeister P.A.
      • Madtes D.K.
      • Storer B.E.
      • Sanders J.E.
      Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation.
      ,
      • Kunkele A.
      • Engelhard M.
      • Hauffa B.P.
      • Mellies U.
      • Muntjes C.
      • Huer C.
      • et al.
      Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
      ,
      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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.
      ,
      • Abugideiri M.
      • Nanda R.H.
      • Butker C.
      • Zhang C.
      • Kim S.
      • Chiang K.Y.
      • et al.
      Factors influencing pulmonary toxicity in children undergoing allogeneic hematopoietic stem cell transplantation in the setting of total body irradiation-based myeloablative conditioning.
      ,
      • Bradley J.
      • Reft C.
      • Goldman S.
      • Rubin C.
      • Nachman J.
      • Larson R.
      • et al.
      High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications.
      ,
      • Demirer T.
      • Petersen F.B.
      • Appelbaum F.R.
      • Barnett T.A.
      • Sanders J.
      • Deeg H.J.
      • et al.
      Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: a Phase I/II trial.
      ,
      • Df F.
      • Grapulin L.
      • Musio D.
      • Pomponi J.
      • Dif C.
      • Iori A.P.
      • et al.
      Treatment complications and long-term outcomes of total body irradiation in patients with acute lymphoblastic leukemia: a single institute experience.
      ,
      • Leung W.
      • Hudson M.M.
      • Strickland D.K.
      • Phipps S.
      • Srivastava D.K.
      • Ribeiro R.C.
      • et al.
      Late effects of treatment in survivors of childhood acute myeloid leukemia.
      ,
      • Linsenmeier C.
      • Thoennessen D.
      • Negretti L.
      • Bourquin J.P.
      • Streller T.
      • Lütolf U.M.
      • et al.
      Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation.
      ,
      • Morgan T.L.
      • Falk P.M.
      • Kogut N.
      • Shah K.H.
      • Tome M.
      • Kagan A.R.
      A comparison of single-dose and fractionated total-body irradiation on the development of pneumonitis following bone marrow transplantation.
      ,
      • Schneider R.A.
      • Schultze J.
      • Jensen J.M.
      • Hebbinghaus D.
      • Galalae R.M.
      Long-term outcome after static intensity-modulated total body radiotherapy using compensators stratified by pediatric and adult cohorts.
      ]. Risk can be decreased by reducing the biologically effective dose (BED), e.g. lowering total doses, use of low dose rates, fractionation and reduction of lung dose i.e. by shielding [
      • Clift R.A.
      • Buckner C.D.
      • Thomas E.D.
      • Sanders J.E.
      • Stewart P.S.
      • Sullivan K.M.
      • et al.
      Allogeneic marrow transplantation using fractionated total body irradiation in patients with acute lymphoblastic leukemia in relapse.
      ,
      • Sampath S.
      • Schultheiss T.E.
      • Wong J.
      Dose response and factors related to interstitial pneumonitis after bone marrow transplant.
      ,
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      • Heijenbrok-Kal M.H.
      • Struikmans H.
      Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation.
      ,
      • Carruthers S.A.
      • Wallington M.M.
      Total body irradiation and pneumonitis risk: a review of outcomes.
      ,
      • Gerrard G.E.
      • Vail A.
      • Taylor R.E.
      • Pitchford W.G.
      • Gilson D.
      • Povall J.M.
      • et al.
      Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique.
      ,
      • Lawton C.A.
      • Barber-Derus S.
      • Murray K.J.
      • Casper J.T.
      • Ash R.C.
      • Gillin M.T.
      • et al.
      Technical modifications in hyperfractionated total body irradiation for T-lymphocyte deplete bone marrow transplant.
      ,
      • Ozsahin M.
      • Belkacémi Y.
      • Pène F.
      • Laporte J.
      • Rio B.
      • Leblond V.
      • et al.
      Interstitial pneumonitis following autologous bone-marrow transplantation conditioned with cyclophosphamide and total-body irradiation.
      ]. Publications describe shielding of the lungs to <40–85% of prescription dose for fractionated TBI doses of 10–16 Gy, or, less frequently, compensatory measures to limit lung dose to within 103–107% of prescription dose (Supplementary Table 1). Careful interpretation of lung dose in reports remains complicated, in view of the inherent inaccuracy of establishing lung doses in 2D conventional TBI techniques. Most pediatric radiotherapy centers perform lung shielding [
      • Hoeben B.A.W.
      • Pazos M.
      • Albert M.H.
      • Seravalli E.
      • Bosman M.E.
      • Losert C.
      • et al.
      Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
      ,
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ]. A multicenter analysis of 127 children with ALL who received allogeneic HSCT after fTBI 12 or 13.2 Gy in 6 or 8 fractions b.i.d. and midplane dose rates 6–15 cGy/min, found significantly worse OS with mean lung doses of ≥8 Gy (HR 1.85, p = 0.043), with lung doses analyzed as reported by participating centers (mean reported lung dose 8.18 Gy (±2.2 SD) for AP-PA field treatments and 11.39 Gy (±1.03 SD) for bilateral field treatments [
      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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.
      ].
      HSCT- and TBI-related chronic renal disease (CRD) occurs in 0–30% of children, and publications inconsistently link CRD incidence to fTBI dose (Supplementary Table 2) [
      • Kunkele A.
      • Engelhard M.
      • Hauffa B.P.
      • Mellies U.
      • Muntjes C.
      • Huer C.
      • et al.
      Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
      ,
      • Chou R.H.
      • Wong G.B.
      • Kramer J.H.
      • Wara D.W.
      • Matthay K.K.
      • Crittenden M.R.
      • et al.
      Toxicities of total-body irradiation for pediatric bone marrow transplantation.
      ,
      • Abboud I.
      • Porcher R.
      • Robin M.
      • de Latour R.P.
      • Glotz D.
      • Socie G.
      • et al.
      Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation.
      ,
      • Cheng J.C.
      • Schultheiss T.E.
      • Wong J.Y.
      Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation.
      ,
      • Delgado J.
      • Cooper N.
      • Thomson K.
      • Duarte R.
      • Jarmulowicz M.
      • Cassoni A.
      • et al.
      The importance of age, fludarabine, and total body irradiation in the incidence and severity of chronic renal failure after allogeneic hematopoietic cell transplantation.
      ,
      • Ellis M.J.
      • Parikh C.R.
      • Inrig J.K.
      • Kanbay M.
      • Patel U.D.
      Chronic kidney disease after hematopoietic cell transplantation: a systematic review.
      ,
      • Esiashvili N.
      • Chiang K.Y.
      • Hasselle M.D.
      • Bryant C.
      • Riffenburgh R.H.
      • Paulino A.C.
      Renal toxicity in children undergoing total body irradiation for bone marrow transplant.
      ,
      • Frisk P.
      • Bratteby L.E.
      • Carlson K.
      • Lonnerholm G.
      Renal function after autologous bone marrow transplantation in children: a long-term prospective study.
      ,
      • Gerstein J.
      • Meyer A.
      • Sykora K.W.
      • Frühauf J.
      • Karstens J.H.
      • Bremer M.
      Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT).
      ,
      • Gronroos M.H.
      • Bolme P.
      • Winiarski J.
      • Berg U.B.
      Long-term renal function following bone marrow transplantation.
      ,
      • Hingorani S.
      • Guthrie K.A.
      • Schoch G.
      • Weiss N.S.
      • McDonald G.B.
      Chronic kidney disease in long-term survivors of hematopoietic cell transplant.
      ,
      • Kist-van Holthe J.E.
      • Bresters D.
      • Ahmed-Ousenkova Y.M.
      • Goedvolk C.A.
      • Abbink F.C.
      • Wolterbeek R.
      • et al.
      Long-term renal function after hemopoietic stem cell transplantation in children.
      ]. fTBI ≥11–12 Gy induces more CRD [
      • Ellis M.J.
      • Parikh C.R.
      • Inrig J.K.
      • Kanbay M.
      • Patel U.D.
      Chronic kidney disease after hematopoietic cell transplantation: a systematic review.
      ,
      • Tarbell N.J.
      • Guinan E.C.
      • Chin L.
      • Mauch P.
      • Weinstein H.J.
      Renal insufficiency after total body irradiation for pediatric bone marrow transplantation.
      ,
      • Igaki H.
      • Karasawa K.
      • Sakamaki H.
      • Saito H.
      • Nakagawa K.
      • Ohtomo K.
      • et al.
      Renal dysfunction after total-body irradiation. Significance of selective renal shielding blocks.
      ,
      • Miralbell R.
      • Bieri S.
      • Mermillod B.
      • Helg C.
      • Sancho G.
      • Pastoors B.
      • et al.
      Renal toxicity after allogeneic bone marrow transplantation: the combined effects of total-body irradiation and graft-versus-host disease.
      ,
      • Lawton C.A.
      • Cohen E.P.
      • Murray K.J.
      • Derus S.W.
      • Casper J.T.
      • Drobyski W.R.
      • et al.
      Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation.
      ]. Kal et al. advised to keep the BED below 16 Gy by shielding the kidneys, to keep CRD risk <3% [
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      • Heijenbrok-Kal M.H.
      • Struikmans H.
      Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation.
      ,
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      Induction of severe cataract and late renal dysfunction following total body irradiation: dose-effect relationships.
      ]. This would mean using kidney shielding for fTBI 12–14.4 Gy at dose rates of ≥6 cGy/min, preferably to ≤10 Gy [
      • Lawton C.A.
      • Cohen E.P.
      • Murray K.J.
      • Derus S.W.
      • Casper J.T.
      • Drobyski W.R.
      • et al.
      Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation.
      ].
      Lens cataract develops less frequently after fTBI of 1.8–2 Gy fractions than after higher doses per fraction, and is related to dose rate (Supplementary Table 3) [
      • Mulcahy Levy J.M.
      • Tello T.
      • Giller R.
      • Wilkening G.
      • Quinones R.
      • Keating A.K.
      • et al.
      Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.
      ,
      • Hall M.D.
      • Schultheiss T.E.
      • Smith D.D.
      • Nguyen K.H.
      • Wong J.Y.
      Dose response for radiation cataractogenesis: a meta-regression of hematopoietic stem cell transplantation regimens.
      ,
      • Horwitz M.
      • Auquier P.
      • Barlogis V.
      • Contet A.
      • Poiree M.
      • Kanold J.
      • et al.
      Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study.
      ,
      • Leung W.
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      • Strickland D.K.
      • Phipps S.
      • Srivastava D.K.
      • Ribeiro R.C.
      • et al.
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      ,
      • Gerrard G.E.
      • Vail A.
      • Taylor R.E.
      • Pitchford W.G.
      • Gilson D.
      • Povall J.M.
      • et al.
      Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique.
      ,
      • Belkacemi Y.
      • Pene F.
      • Touboul E.
      • Rio B.
      • Leblond V.
      • Gorin N.C.
      • et al.
      Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients.
      ,
      • Ozsahin M.
      • Belkacemi Y.
      • Pene F.
      • Dominique C.
      • Schwartz L.H.
      • Uzal C.
      • et al.
      Total-body irradiation and cataract incidence: a randomized comparison of two instantaneous dose rates.
      ,
      • Fahnehjelm K.T.
      • Törnquist A.L.
      • Olsson M.
      • Winiarski J.
      Visual outcome and cataract development after allogeneic stem-cell transplantation in children.
      ,
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      • Miano M.
      • et al.
      Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant.
      ,
      • Lee C.J.
      • Kim S.
      • Tecca H.R.
      • Bo-Subait S.
      • Phelan R.
      • Brazauskas R.
      • et al.
      Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia.
      ,
      • Ricardi U.
      • Filippi A.R.
      • Biasin E.
      • Ciammella P.
      • Botticella A.
      • Franco P.
      • et al.
      Late toxicity in children undergoing hematopoietic stem cell transplantation with TBI-containing conditioning regimens for hematological malignancies.
      ]. After a median follow up of 10 years in 174 pediatric acute leukemia HSCT recipients, cataract incidence was 51.7% after mainly 12 Gy TBI in 6 fractions [
      • Bernard F.
      • Auquier P.
      • Herrmann I.
      • Contet A.
      • Poiree M.
      • Demeocq F.
      • et al.
      Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.
      ]. Using a meta-regression model, Hall et al. extrapolated 5-year risk of cataract after HSCT in children, which was related to TBI total dose and fractionation, and amounted to 60% after 12 Gy in 6 fractions [
      • Hall M.D.
      • Schultheiss T.E.
      • Smith D.D.
      • Nguyen K.H.
      • Wong J.Y.
      Dose response for radiation cataractogenesis: a meta-regression of hematopoietic stem cell transplantation regimens.
      ]. Kal et al. extrapolated a BED of <40 Gy for which risk of severe cataract, needing surgery, will be <10% [
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      Induction of severe cataract and late renal dysfunction following total body irradiation: dose-effect relationships.
      ]. Since BED also depends on dose rate, 6 times 2 Gy with a dose rate >4 Gy would result in a BED > 40 Gy. In a single study, anterior-beam eye shielding to 55–58% of the total dose, reduced cataract incidence significantly while not distinctly increasing risk of CNS recurrence [
      • van Kempen-Harteveld M.L.
      • van Weel-Sipman M.H.
      • Emmens C.
      • Noordijk E.M.
      • van der Tweel I.
      • Revesz T.
      • et al.
      Eye shielding during total body irradiation for bone marrow transplantation in children transplanted for a hematological disorder: risks and benefits.
      ]. Highly conformal TBI techniques make lens sparing without compromising CNS dose attainable [
      • Hoeben B.A.W.
      • Seravalli E.
      • Wood A.M.L.
      • Bosman M.
      • Matysiak W.P.
      • Maduro J.H.
      • et al.
      Influence of eye movement on lens dose and optic nerve target coverage during craniospinal irradiation.
      ].
      Recommendations:
      For fTBI schedules of 12–14.4 Gy in 1.6–2 Gy fractions at dose rates ≥6 cGy/min during conditioning for allogeneic HSCT.
      • Consider limiting the mean lung dose to <8 Gy.
      • Consider limiting the mean kidney dose to ≤10 Gy.
      • Consider reducing the lens dose to <12 Gy to decrease the risk of severe cataracts. For children with a high risk of CNS recurrence*, eye shielding should not be applied during conventional TBI.
      *CNS3 (definite CNS involvement) or intra-ocular/optic leukemic involvement at any time-point, or after CNS recurrence.
      For other toxicities, no recommendations can be made, other than to keep fTBI total dose <16 Gy. If previous irradiation has taken place, consider cumulative dose and related risks of additional fTBI. Further elaboration regarding specific fTBI-related toxicities is given in the Supplement.

      Boost

      A radiotherapy boost to sanctuary sites such as the testes, CNS, or extramedullary disease localizations can be considered. ALL with CNS3 involvement, either at diagnosis or at relapse, predicts a higher risk of post-transplant CNS relapse [
      • Aldoss I.
      • Al Malki M.M.
      • Stiller T.
      • Cao T.
      • Sanchez J.F.
      • Palmer J.
      • et al.
      Implications and management of central nervous system involvement before allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.
      ,
      • Ganem G.
      • Kuentz M.
      • Bernaudin F.
      • Gharbi A.
      • Cordonnier C.
      • Lemerle S.
      • et al.
      Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission.
      ,
      • Oshima K.
      • Kanda Y.
      • Yamashita T.
      • Takahashi S.
      • Mori T.
      • Nakaseko C.
      • et al.
      Central nervous system relapse of leukemia after allogeneic hematopoietic stem cell transplantation.
      ,
      • Vora A.
      • Andreano A.
      • Pui C.H.
      • Hunger S.P.
      • Schrappe M.
      • Moericke A.
      • et al.
      Influence of cranial radiotherapy on outcome in children with acute lymphoblastic leukemia treated with contemporary therapy.
      ]. A CNS-directed radiotherapy boost can be considered for patients with overt CNS leukemia at diagnosis or those who develop CNS leukemia at disease relapse, especially when intrathecal/systemic therapy has failed [
      • Pinnix C.C.
      • Yahalom J.
      • Specht L.
      • Dabaja B.S.
      Radiation in central nervous system leukemia: guidelines from the International Lymphoma Radiation Oncology Group.
      ,
      • Gao R.W.
      • Dusenbery K.E.
      • Cao Q.
      • Smith A.R.
      • Yuan J.
      Augmenting total body irradiation with a cranial boost before stem cell transplantation protects against post-transplant central nervous system relapse in acute lymphoblastic leukemia.
      ].
      It is undetermined what the minimal dose, target volume (cranial radiotherapy (CRT) or craniospinal irradiation (CSI)) and the optimal timing of the boost alongside TBI should be, but in general a cumulative CNS-directed dose of 18–24 Gy is recommended, with the boost given in the days before TBI [
      • Pinnix C.C.
      • Yahalom J.
      • Specht L.
      • Dabaja B.S.
      Radiation in central nervous system leukemia: guidelines from the International Lymphoma Radiation Oncology Group.
      ,
      • Su W.
      • Thompson M.
      • Sheu R.D.
      • Steinberg A.
      • Isola L.
      • Stock R.
      • et al.
      Low-dose cranial boost in high-risk adult acute lymphoblastic leukemia patients undergoing bone marrow transplant.
      ,
      • Cherlow J.M.
      • Sather H.
      • Steinherz P.
      • Gaynon P.
      • Tubergen D.
      • Trigg M.
      • et al.
      Craniospinal irradiation for acute lymphoblastic leukemia with central nervous system disease at diagnosis: a report from the Children's Cancer Group.
      ].
      Considerations for radiotherapy boost:
      • An interval of at least 2 weeks between CNS boost and intrathecal therapy is preferable.
      • Boost fractions should be 1.5–2 Gy, with 1.5-Gy fractions specifically considered for patients <6 years old.
      • Cumulative (EQD2) dose of current CNS boost and TBI should not be >24 Gy.
      • Total (EQD2) cumulative CNS dose for TBI and previous CNS-directed radiotherapy should not be >30 Gy.
      • If previous CRT ≥18 Gy (≥15 Gy for <3 year-old patients) has been given, CNS boost before TBI should be omitted.
      A testicular boost is indicated for patients with a very high risk of testicular relapse, mainly in case of residual disease detected with ultrasound after chemotherapy and after testicular recurrence. This can be done with a cumulative dose of 18–24 Gy in 2-Gy fractions, or single 4-Gy fraction, in the days prior to TBI in case of subclinical or clinical involvement.
      In the case of persistent disease in other extramedullary sites, a local boost to a cumulative dose of 24 Gy can be considered.
      For highly conformal TBI techniques, simultaneous boost to the bone marrow or extramedullary sites is an option [
      • Wong J.Y.C.
      • Filippi A.R.
      • Scorsetti M.
      • Hui S.
      • Muren L.P.
      • Mancosu P.
      Total marrow and total lymphoid irradiation in bone marrow transplantation for acute leukaemia.
      ,
      • Hui S.
      • Brunstein C.
      • Takahashi Y.
      • DeFor T.
      • Holtan S.G.
      • Bachanova V.
      • et al.
      Dose escalation of total marrow irradiation in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation.
      ,
      • Kobyzeva D.
      • Shelikhova L.
      • Loginova A.
      • Kanestri F.
      • Tovmasyan D.
      • Maschan M.
      • et al.
      Optimized conformal total body irradiation among recipients of TCRalphabeta/CD19-depleted grafts in pediatric patients with hematologic malignancies: single-center experience.
      ,
      • Stein A.
      • Palmer J.
      • Tsai N.C.
      • Al Malki M.M.
      • Aldoss I.
      • Ali H.
      • et al.
      Phase I trial of total marrow and lymphoid irradiation transplantation conditioning in patients with relapsed/refractory acute leukemia.
      ,

      Stein A, Tsai N-C, Palmer J, Al Malki M, Aldoss I, Ali H, et al. Total marrow and lymphoid irradiation (TMLI) in combination with cyclophosphamide and Etoposide in patients with relapsed/refractory acute leukemia undergoing allogeneic hematopoietic cell transplantation. Presented at 2019 European Society for Blood and Marrow Transplantation Meeting, Frankfurt, Germany, March 24-27, 2019. 2019.

      ].

      Long-term follow-up of patients after HSCT with TBI conditioning

      Childhood HSCT survivors carry a great risk burden of subsequent morbidity, which calls for life-long monitoring of this population [
      • Armenian S.H.
      • Sun C.L.
      • Kawashima T.
      • Arora M.
      • Leisenring W.
      • Sklar C.A.
      • et al.
      Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS).
      ,
      • Lawitschka A.
      • Peters C.
      Long-term effects of myeloablative allogeneic hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia.
      ,
      • Bernard F.
      • Auquier P.
      • Herrmann I.
      • Contet A.
      • Poiree M.
      • Demeocq F.
      • et al.
      Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.
      ,
      • Cupit M.C.
      • Duncan C.
      • Savani B.N.
      • Hashmi S.K.
      Childhood to adult transition and long-term follow-up after blood and marrow transplantation.
      ,
      • Bevans M.
      • El-Jawahri A.
      • Tierney D.K.
      • Wiener L.
      • Wood W.A.
      • Hoodin F.
      • et al.
      National institutes of health hematopoietic cell transplantation late effects initiative: the patient-centered outcomes working group report.
      ]. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Transplantation and Cellular Therapy (ASTCT) have developed recommendations for long-term screening and preventive practices for HSCT survivors [
      • Rizzo J.D.
      • Wingard J.R.
      • Tichelli A.
      • Lee S.J.
      • Van Lint M.T.
      • Burns L.J.
      • et al.
      Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation.
      ]. General health maintenance is important, and active evaluation of psychosocial and quality of life factors should be part of follow-up programs [
      • Hashmi S.
      • Carpenter P.
      • Khera N.
      • Tichelli A.
      • Savani B.N.
      Lost in transition: the essential need for long-term follow-up clinic for blood and marrow transplantation survivors.
      ]. Table 1 summarizes specific screening recommendations after myeloablative TBI.

      Conventional TBI setup for children

      TBI has historically been delivered using techniques with large fields at extended source-to-skin distance (SSD) [
      • Quast U.
      Total body irradiation–review of treatment techniques in Europe.
      ], and most institutions still use these techniques in a locally designed setup dependent on the technical possibilities [
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      ]. Fig. 1 displays several examples of extended SSD setups, with an example of lung shielding in Fig. 2. TBI at SSD requires the characterization of the beam at extended SSD, careful planning, physics calculations and quality assurance [
      • Wolden S.L.
      • Rabinovitch R.A.
      • Bittner N.H.
      • Galvin J.M.
      • Giap H.B.
      • Schomberg P.J.
      • et al.
      American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) practice guideline for the performance of total body irradiation (TBI).
      ,

      Van Dyk J., Galvin J.M,. Glasgow G.P., Podgorsak E.B. AAPM REPORT NO. 17: The physical aspects of total and half body photon irradiation. 1986.

      ]. Generally, doses are assessed using in vivo dosimetry. Table 2 gives considerations for conventional TBI setup in children. Differences in techniques preclude reliable comparison of TBI effectivity between centers and publications, and it is not clear if there is an optimal setup that can be recommended for all children, although AP-PA beam directions seem preferable [
      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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 enable comparison of TBI data between centers, we need comprehensive standardized reporting of all relevant parameters. The reported information should include: beam setup, prescribed target volume dose in Gy and prescription point (e.g. midplane at the level of umbilicus), fraction dose, fractions per day and minimum interval between fractions, treatment time per fraction, instantaneous (and, if possible, also average) dose rate at midplane in the patient and in the lungs, shielding/dose reduction to specified organs.
      Figure thumbnail gr1
      Fig. 1Examples of setup for conventional TBI and highly conformal TBI. Setup with “chair” construction for AP-PA irradiation, with beam spoilers and blocks for lungs, kidneys and lenses in this setting (A). Setup with stool-sitting position for AP-PA irradiation, with beam spoilers and blocks for lungs, in vivo dosimetry diodes attached (red circles) (B). Setup with “bed” construction for AP-PA irradiation in lateral decubitus position, with beam spoilers and blocks for lungs and kidneys in this setting (C). Setup in “standing” position for AP-PA irradiation, with beam spoilers and blocks for lungs (D). Setup with “bed” construction for AP-PA irradiation, with patient in supine and prone position during treatment (E-F). Patient with diodes attached for in vivo dosimetry during irradiation; homogeneity check diodes circled green, dose verification check diode at prescription point circled blue (G + H). Patient in treatment position for VMAT TBI on rotatable tabletop (I + J). Patient is distracted with movie on smartphone. 3D CT reconstruction image of patient >150 cm with 6 isodose planes and Head First/Feet First planning area for VMAT TBI indicated (K). Patient in treatment position for TomoTherapy TBI (L).
      Figure thumbnail gr2
      Fig. 2Lung blocks. Block delineation on PA X-ray image in lateral decubitus position (A). Verification of block position with megavoltage X-ray image during treatment (B).
      Table 2Conventional TBI at extended SSD setup in children; considerations.
      Conventional TBI at extended SSD; setup considerationsReferences
      Beams
      Setup depends on local technical possibilities.
      • Rassiah P.
      • Esiashvili N.
      • Olch A.J.
      • Hua C.H.
      • Ulin K.
      • Molineu A.
      • et al.
      Practice patterns of pediatric total body irradiation techniques: a children's oncology group survey.
      Patient should be placed in the flattened part of the radiation beam (usually over the diagonal of the beam).
      • Quast U.
      Whole body radiotherapy: A TBI-guideline.
      AP-PA with horizontal beams.
      Lateral opposing with horizontal beams.
      • Disadvantageous in children because of higher lung doses.
      • Dose calculations without lung density corrections are incorrect in the thorax by 16–24%, depending on beam energy.


      • Esiashvili N.
      • Lu X.
      • Ulin K.
      • Laurie F.
      • Kessel S.
      • Kalapurakal J.A.
      • et al.
      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.
      ,
      • Hui S.K.
      • Das R.K.
      • Thomadsen B.
      • Henderson D.
      CT-based analysis of dose homogeneity in total body irradiation using lateral beam.
      ,
      • Bailey D.W.
      • Wang I.Z.
      • Lakeman T.
      • Hales L.D.
      • Singh A.K.
      • Podgorsak M.B.
      TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections.
      • Bailey D.W.
      • Wang I.Z.
      • Lakeman T.
      • Hales L.D.
      • Singh A.K.
      • Podgorsak M.B.
      TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections.
      Combination of AP-PA and bilateral beams.
      • Quast U.
      Whole body radiotherapy: A TBI-guideline.
      Sweeping beam.
      Moving couch underneath a static beam.
      Dose homogeneity
      Effort should be made to maintain target volume dose homogeneity within 90–110% of prescription dose.
      • Wolden S.L.
      • Rabinovitch R.A.
      • Bittner N.H.
      • Galvin J.M.
      • Giap H.B.
      • Schomberg P.J.
      • et al.
      American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) practice guideline for the performance of total body irradiation (TBI).
      ,

      Van Dyk J., Galvin J.M,. Glasgow G.P., Podgorsak E.B. AAPM REPORT NO. 17: The physical aspects of total and half body photon irradiation. 1986.

      Field-in-field techniques can help to achieve a more homogeneous dose distribution; stable patient positioning is more vital.
      Regular quality assurance of the TBI technique should take place.
      • Murrer L.H.P.
      • van der Hulst P.C.
      • Jansen W.
      • van Leeuwen R.G.H.
      • Koken P.W.
      • Dumont D.
      • et al.
      Code of practice and recommendations for total body irradiation and total skin irradiation.
      Patient positioning
      Markings on the patient should be used to ensure stable positioning on each fraction.
      Effort should be made to equalize patient diameter over body sections; compensators can be used for narrower parts of the body (head/neck, lower legs).
      • Murrer L.H.P.
      • van der Hulst P.C.
      • Jansen W.
      • van Leeuwen R.G.H.
      • Koken P.W.
      • Dumont D.
      • et al.
      Code of practice and recommendations for total body irradiation and total skin irradiation.
      AP-PA
      • Lateral decubitus position: patient in lateral decubitus, support with vacuum bag, stable tilted head position, drawn up knees, one arm extended along 1 side and the other encircling the head.
      • Standing / leaning position: dedicated support, stable tilted head, bended legs.
      • Supine and prone for sweeping beam technique. Use compensators.
      Lateral opposing
      • Supine position: arms close to the side, stable head position. Use compensators.
      • Sitting position on dedicated chair design: arms close to the side, stable head position. Use compensators.
      Sweeping beam and moving couch
      • Supine and prone position: stable position, arms close to the side. Use compensators.
      Tissue compensators
      Compensators should be used to ensure homogeneous dose over narrow body parts depending on patient positioning (often head/neck, lower legs). Compensation can be achieved by:
      • increasing the thickness of the acrylic barrier that is placed in front of the patient in the beam
      • attaching metal plates of appropriate thickness to the acrylic barrier that is placed in front of the patient in the beam
      • positioning tissue-equivalent materials (bags or blocks) close to the body
      • metal individual hemibody compensators made in styrodur moulds after calculating appropriate dimensions using a planning-CT




      • Wong J.Y.C.
      • Filippi A.R.
      • Dabaja B.S.
      • Yahalom J.
      • Specht L.
      Total Body irradiation: guidelines from the International Lymphoma Radiation Oncology Group (ILROG).
























      • Schneider R.A.
      • Schultze J.
      • Jensen J.M.
      • Hebbinghaus D.
      • Galalae R.M.
      Long-term outcome after static intensity-modulated total body radiotherapy using compensators stratified by pediatric and adult cohorts.
      Beam spoilers
      Beam spoilers counter skin- and subcutaneous tissue sparing effect of photon beams. Spoilers are typically made of 1–2 cm thick acrylic screens, to produce electrons that increase surface doses to at least 90% of prescription dose.
      • Wong J.Y.C.
      • Filippi A.R.
      • Dabaja B.S.
      • Yahalom J.
      • Specht L.
      Total Body irradiation: guidelines from the International Lymphoma Radiation Oncology Group (ILROG).
      Beam energy
      AP-PA setup: 6–10 MV preferable for children
      • no additional neutron production
      • more homogeneity than lower energies
      Bilateral setup
      • depth dose inhomogeneities of ±10% – ±30% including skin dose arise in the bilateral setup with 10 MV


      • Quast U.
      Whole body radiotherapy: A TBI-guideline.
      Dose reference point
      International consensus advice:
      • reference dose prescription point in the midplane at the level of the umbilicus
      • lung dose reference point: mean dose at midpoint of both lungs
      • Quast U.
      Whole body radiotherapy: A TBI-guideline.
      OAR shielding
      All shielding should be commissioned for transmission properties.
      • Murrer L.H.P.
      • van der Hulst P.C.
      • Jansen W.
      • van Leeuwen R.G.H.
      • Koken P.W.
      • Dumont D.
      • et al.
      Code of practice and recommendations for total body irradiation and total skin irradiation.
      Placement of shielding needs to be verified before each beam delivery.
      Awareness of electron scatter behind the blocks. Compensation e.g. with bolus material or thickness of the block mount.
      • Narayanasamy G.
      • Cruz W.
      • Saenz D.L.
      • Stathakis S.
      • Papanikolaou N.
      • Kirby N.
      Effect of electron contamination on in vivo dosimetry for lung block shielding during TBI.
      Partially transmitting individual lung shielding:
      • shaped from metal alloy/cerrobend using X-ray images of the patient in treatment position
        manual positioning
      • individually positioned MLC’s
      • Bloemen-van Gurp E.J.
      • Mijnheer B.J.
      • Verschueren T.A.
      • Lambin P.
      Total body irradiation, toward optimal individual delivery: dose evaluation with metal oxide field effect transistors, thermoluminescence detectors, and a treatment planning system.
      ,
      • Ekstrand K.
      • Greven K.
      • Wu Q.
      The influence of x-ray energy on lung dose uniformity in total-body irradiation.
      ,
      • Ho A.
      • Kishel S.
      • Proulx G.
      Partial lung shield for TBI.
      ,
      • Fog L.S.
      • Hansen V.N.
      • Kjaer-Kristoffersen F.
      • Berlon T.E.
      • Petersen P.M.
      • Mandeville H.
      • et al.
      A step and shoot intensity modulated technique for total body irradiation.
      Partially transmitting individual kidney shielding:
      • shaped from metal alloy / cerrobend using kidney outline in the skin made with ultrasonography performed in the TBI treatment position
      • manual positioning
      • Lawton C.A.
      • Cohen E.P.
      • Murray K.J.
      • Derus S.W.
      • Casper J.T.
      • Drobyski W.R.
      • et al.
      Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation.
      ,
      • Kal H.B.
      • van Kempen-Harteveld M.L.
      Renal dysfunction after total body irradiation: dose-effect relationship.
      Partially transmitting eye (lens) shielding:
      • standard thickness based on local TBI setup properties and measurements
      • van Kempen-Harteveld M.L.
      • van Weel-Sipman M.H.
      • Emmens C.
      • Noordijk E.M.
      • van der Tweel I.
      • Revesz T.
      • et al.
      Eye shielding during total body irradiation for bone marrow transplantation in children transplanted for a hematological disorder: risks and benefits.