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Corresponding author at: Department of Radiation Oncology, Q.00.311, University Medical Center Utrecht and Princess Máxima Center for Pediatric Oncology, PO Box 85500, 3508 GA Utrecht, The Netherlands.
Dept. of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, University of Maryland School of Medicine, Baltimore, United States
Toxicity reduction with outcome preservation is a goal of myeloablative TBI in children.
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Fractionated TBI of 12–14.4 Gy, in 1.6–2 Gy fractions b.i.d. is advisable for children.
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When possible, dose reduction to lungs (<8 Gy), kidneys (≤10 Gy) and lenses (<12 Gy) is appropriate.
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Setup considerations for conventional and highly conformal TBI techniques in children.
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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.
Myeloablative Total Body Irradiation (TBI) has long been a cornerstone of the conditioning for hematopoietic stem cell transplantation (HSCT) in children [
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).
Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.
Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study.
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.
Total body irradiation in haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia: review of the literature and future directions.
Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
]. 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) [
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 [
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 [
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.
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 [
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 [
]. Non-myeloablative doses of TBI of 2–4 Gy combined with chemotherapy can be employed for their immunosuppressive effect in reduced intensity conditioning [
Paediatric reduced intensity conditioning: analysis of centre strategies on regimens and definitions by the EBMT Paediatric Diseases and Complications and Quality of Life WP.
]. 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 [
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 factor
Test recommendation
References
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.
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.
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?.
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.
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.
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.
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.
in: Carreras E. Dufour C. Mohty M. Kröger N. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. CH): Springer International Publishing,
Cham2019: 421-427
Long-term follow-up after TBI-based HSCT conditioning
Examination factor
Test recommendation
References
Chronic GVHD
Regular follow-up with evaluation of GVHD signs and symptoms (skin, mouth, gut, genitourinary system, liver, lungs). Treatment with steroids and other immunosuppressants if necessary.
in: Carreras E. Dufour C. Mohty M. Kröger N. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. CH): Springer International Publishing,
Cham2019: 331-345
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.
Pulmonary 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.
in: Carreras E. Dufour C. Mohty M. Kröger N. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. CH): Springer International Publishing,
Cham2019: 393-401
Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
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 syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT.
Evaluation of growth curve and velocity with checks for influencing factors (hormone depletion, liver dysfunction, chronic GVHD). Supplementation by endocrinologist when necessary.
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).
Counseling 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.
in: Carreras E. Dufour C. Mohty M. Kröger N. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. CH): Springer International Publishing,
Cham2019: 421-427
Monitoring 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.
Yearly screening of renal function (including blood pressure, renal function assessment (blood urea nitrogen and creatinine + clearance, urinary protein, and if necessary kidney ultrasonography).
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.
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.
Examination 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.
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 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.
Regular 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.
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.
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.
Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party.
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) [
Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.
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.
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.
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.
] (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 [
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.
]. 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 [
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.
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.
]. 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 [
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 [
Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
]. 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 [
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 [
]. 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 [
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.
]. 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 [
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 [
Optimized conformal total body irradiation among recipients of TCRalphabeta/CD19-depleted grafts in pediatric patients with hematologic malignancies: single-center experience.
Influence of radiation dose rate and lung dose on interstitial pneumonitis after fractionated total body irradiation: acute parotitis may predict interstitial pneumonitis.
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.
Height growth during adolescence and final height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning regimen with BU or TBI.
]. 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) [
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.
Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
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.
Factors influencing pulmonary toxicity in children undergoing allogeneic hematopoietic stem cell transplantation in the setting of total body irradiation-based myeloablative conditioning.
Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: a Phase I/II trial.
]. 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 [
Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique.
Clin Oncol (Royal College of Radiologists (Great Britain)).1998; 10: 379-383
]. 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 [
Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.
]. 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 [
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) [
Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years.
The importance of age, fludarabine, and total body irradiation in the incidence and severity of chronic renal failure after allogeneic hematopoietic cell 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) [
Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique.
Clin Oncol (Royal College of Radiologists (Great Britain)).1998; 10: 379-383
Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients.
]. 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 [
]. 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 [
]. 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 [
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 [
Implications and management of central nervous system involvement before allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.
]. 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 [
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 [
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 [
Optimized conformal total body irradiation among recipients of TCRalphabeta/CD19-depleted grafts in pediatric patients with hematologic malignancies: single-center experience.
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 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).
]. 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 [
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.
]. 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 [
American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) practice guideline for the performance of total body irradiation (TBI).
]. 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 [
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.
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).
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).
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.
American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) practice guideline for the performance of total body irradiation (TBI).
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).
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.
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
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.
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