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
Material and methods
Results
Conclusions
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
- Armenian S.H.
- Sun C.L.
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- Arora M.
- Leisenring W.
- Sklar C.A.
- et al.
- Gupta T.
- Kannan S.
- Dantkale V.
- Laskar S.
Methods
Recommendation results
Indications for TBI-based myeloablative conditioning for HSCT in children
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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.
Patient evaluation before TBI
Pre-TBI based HSCT conditioning evaluation | ||
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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. | 4 , 36 , 37 , 38 , 39 , 40 , 41 |
Medical history | Evaluate complete disease and treatment history and other relevant medical background details, including family history of malignancies. | |
CNS status | Cerebrospinal fluid examination for CNS 1-2-3 status; preferably 1-2 before conditioning, otherwise consider CNS boost before TBI. | [42] |
MRD status | RT-qPCR or NGS MRD negativity related with better prognosis. If positive, discuss potential further treatment to reach MRD negativity before HSCT. | 35 , 43 ,
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. Eur J Cancer. 2021; 151: 175-189 44 |
Previous radiotherapy | Check cumulative dose and safety of additional TBI. | |
Complete physical examination | i.e. lung, heart, abdomen, nodal, testes examination, growth. | [45] |
Lung examination | Radiologic examination of lungs, previous pulmonary problems, respiratory function tests. | [45] |
Cardiac examination and cardiovascular risk profile | Electrocardiogram, 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. | 45 , 46 , 47 |
Kidney function | Blood pressure, renal function assessment (blood urea nitrogen and creatinine + clearance, urinary protein, and if necessary kidney ultrasonography). | |
Liver function | Blood liver function test (bilirubin, AST, ALT), history of cirrhosis or hepatitis. | |
Endocrine status | Check of growth, thyroid, gonadal hormone levels. | |
Neurocognitive status | Baseline neurocognitive testing, cognitive development evaluation. | 48 , 49
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. Bone Marrow Transplant. 2018; 53: 535-555 |
Fertility counseling | Fertility counseling by specialist, evaluate possibility of gamete storage pre-HSCT conditioning. | 50 , 51 , 52 , 53 |
Ophthalmologic evaluation | Pre-conditioning inspection by ophthalmologist. Clinical symptoms, visual acuity, fundus exam, lens inspection. | 54 , 55 |
Dental evaluation | Pre-conditioning inspection and preventive care by dental specialist. | [56] |
Cancer predisposition syndromes | Avoid radiotherapy for these children if possible. | |
Psychosocial and social evaluation | Psychological and social burden capacity of patient and caregivers. | 48 , 57 , 58 |
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. | 59 , 60 , 61
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. Lancet Haematol. 2020; 7: e157-e167 |
Late respiratory complications | 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. | 62 , 63 , 64 , 65 , 66 , 67 , 68
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. Biol Blood Marrow Transplant. 2006; 12: 138-151 |
Metabolic and cardiovascular function | Yearly check-ups, e.g. regular evaluation of weight, dyslipidemia, blood pressure and hyperglycemia. | [69] |
Endocrine function | Yearly comprehensive blood screening for endocrine dysfunctions (growth, thyroid, gonadal, adrenocortical). Supplementation by endocrinologist when necessary. | 70 , 71 , 72 , 73 |
Growth | Evaluation of growth curve and velocity with checks for influencing factors (hormone depletion, liver dysfunction, chronic GVHD). Supplementation by endocrinologist when necessary. | 74 , 75 ,
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). Bone Marrow Transplant. 2012; 47: 684-693 76 |
Fertility issues | 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. | 50 , 77 |
Bone health | 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. | 78 , 79 , 80 |
Chronic renal dysfunction | Yearly screening of renal function (including blood pressure, renal function assessment (blood urea nitrogen and creatinine + clearance, urinary protein, and if necessary kidney ultrasonography). | 68 ,
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. Biol Blood Marrow Transplant. 2006; 12: 138-151 81 |
Ocular complications | Yearly inspection by ophthalmologist. Clinical symptoms, visual acuity, fundus examination, lens inspection. | 55 , 68 ,
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. Biol Blood Marrow Transplant. 2006; 12: 138-151 82 |
Dental evaluation | 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. | [68]
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. Biol Blood Marrow Transplant. 2006; 12: 138-151 |
Neurocognitive function | Neurocognitive testing in children is recommended before and 1 year after HSCT and then at the beginning of each new stage of education. | [49]
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. Bone Marrow Transplant. 2018; 53: 535-555 |
Secondary malignancies | 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. | 68 ,
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. Biol Blood Marrow Transplant. 2006; 12: 138-151 83 , 84 , 85 ,
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. Lancet Oncol. 2021; 22: e196-e206 86 , 87 |
TBI fractionation
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Toxicities and organ-at-risk sparing
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- •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.
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.
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
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Conventional TBI setup for children
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- Ulin K.
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- Kessel S.
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Conventional TBI at extended SSD; setup considerations | References |
---|---|
Beams | |
Setup depends on local technical possibilities. | [15] |
Patient should be placed in the flattened part of the radiation beam (usually over the diagonal of the beam). | [180] |
AP-PA with horizontal beams. | |
Lateral opposing with horizontal beams.
| 118 ,
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. Int J Radiat Oncol Biol Phys. 2019; 104: 513-521 181 , 182 |
[182] | |
Combination of AP-PA and bilateral beams. | [180] |
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. | 178 , 179 |
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. | [183] |
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). | [183] |
AP-PA
| |
Lateral opposing
| |
Sweeping beam and moving couch
| |
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:
| [184] [139] |
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. | [184] |
Beam energy | |
AP-PA setup: 6–10 MV preferable for children
| |
Bilateral setup
| [180] |
Dose reference point | |
International consensus advice:
| [180] |
OAR shielding | |
All shielding should be commissioned for transmission properties. | [183] |
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. | [185] |
Partially transmitting individual lung shielding:
| 186 , 187 , 188 , 189 |
Partially transmitting individual kidney shielding:
| 157 , 190 |
Partially transmitting eye (lens) shielding:
| [165]
Eye shielding during total body irradiation for bone marrow transplantation in children transplanted for a hematological disorder: risks and benefits. Bone Marrow Transplant. |