Since the 1970s total body irradiation (TBI) is considered to be a cornerstone of myeloablative conditioning for haematopoietic stem cell transplantation (HSCT) in children. It has been used in combination with chemotherapy as conditioning regimen both in autologous and allogeneic HSCT for malignant and non-malignant diseases (1). However, it gradually became clear that HSCT survivors suffered from various late adverse effects, many of which related to TBI (2–6). As HSCT strategies improved and evolved over time, and reduction of late sequelae was warranted, chemotherapy-only conditioning schedules (chemoconditioning) became the mainstay for most indications; the use of myeloablative TBI was limited mainly to patients with high-risk haematologic malignancies in the allogeneic setting (7–10). For most paediatric acute myeloblastic leukaemia (AML) HSCT indications, chemoconditioning gained preference over TBI-based conditioning (11–14). In children with very-high-risk acute lymphoblastic leukaemia (ALL), studies consistently showed superior survival outcomes of TBI-based conditioning (15–19).

The aspiration to reduce acute and long-term effects after HSCT—especially in developing children—has motivated radiation oncologists to seek out improvements in TBI performance. For many years, myeloablative TBI was mostly given as a single fraction of up to 10 Gy combined with cyclophosphamide (20, 21). Gradually, studies showed decreased toxicities and equal or improved survival with fractionated TBI (22–24), and this has become the standard. However, institutions have developed site-specific TBI setups and techniques, making practises heterogeneous (25–28). With technological advances, general radiation treatments have evolved into highly conformal intensity-modulated techniques delivering high doses to treatment volumes while increasingly sparing the surrounding tissues. For TBI, however, most centres still use two-dimensional (2D) conventional techniques with opposing beams that capture the entire body while shielding certain organs at risk (OAR) (27, 28) (Figure 1). This technique tends to deliver heterogeneous doses throughout the body while shielding also blocks bone marrow compartments. Several centres have introduced highly conformal techniques that offer better dose homogeneity while allowing more options to spare OAR, albeit with higher dose rates than classical setups (29–31). More targeted radiotherapy strategies such as total marrow irradiation (TMI), total lymphoid irradiation (TLI), and total marrow and lymphoid irradiation (TMLI) allow dose escalation to the bone marrow and/or lymphoid volumes of high-risk ALL patients while reducing doses in the remainder of the body. Clinical studies to establish the role of TMLI in HSCT-conditioning are ongoing (32).

Since the superiority of including TBI in conditioning regimens prior to HSCT for very-high-risk ALL paediatric patients has been reinforced by the results of the For Omitting Radiation Under Majority age (FORUM) trial (19), it is timely to review TBI application and rationale for these patients and to gauge future directions.

TBI has been the most frequently applied myeloablative conditioning for HSCT in patients with ALL. Most centres now avoid TBI in children below the age of 3 years because of increased side effects especially on the young developing brain. Prior to the FORUM trial, there was remaining debate over whether non-inferior conditioning in children, adolescents, or young adults could be achieved without TBI (33).

Davies et al. compared HSCT outcomes in children with ALL transplanted from human leukocyte antigen (HLA)-identical siblings who received cyclophosphamide plus TBI conditioning (n = 451) vs. those who received oral busulfan plus cyclophosphamide conditioning (n = 176) (16). The 3-year probability of overall survival (OS) was 55% [95% confidence interval (CI) 50–60%] with TBI and cyclophosphamide and 40% (95% CI 32–48%) with busulfan and cyclophosphamide (p = 0.003), with a higher risk of treatment failure (relapse or death) in the busulfan group [relative risk (RR) 1.39; p = 0.017].

A retrospective European Society for Blood and Marrow Transplantation (EBMT) study assessed the role of TBI in patients aged 2–18 years who were transplanted for ALL in remission with a bone marrow or peripheral blood graft from a compatible donor, and compared patients who had received TBI-based myeloablative conditioning (n = 1,336) with patients who had been transplanted after chemoconditioning (n = 210) between 2000 and 2012 (18). An inferior outcome was reported after chemoconditioning for patients with ALL in second complete remission (CR2), with a 1.75-fold higher risk of death, 1.86-fold higher risk of any failure and a 1.9-fold higher risk of relapse compared with those receiving TBI-conditioning. Conversely, no difference could be detected for those transplanted in first complete remission (CR1). Nevertheless, as TBI was the standard regimen, a selection bias could have affected regimen allocation, with patients who had experienced severe toxicities and infections prior to HSCT being more likely to being allocated chemoconditioning. Furthermore, logistical issues could have limited timely access to fractionated TBI. Similar results were reported when cord blood units were used as the stem cell source, with TBI being associated with a lower risk of relapse than chemoconditioning (34). Within the Centre for International Blood and Marrow Transplant Research (CIBMTR), attempts to decrease the risk of relapse by intensifying the conditioning of 12 Gy TBI and cyclophosphamide—which included increasing the TBI dose to 13.2–14 Gy and/or adding a second chemotherapeutic agent—were not effective (35).

In the recent international, multicentre, randomised FORUM trial in high-risk ALL patients aged 4–21 years at HSCT, 2-year OS was 91% following conditioning with fractionated 12 Gy TBI and etoposide (n = 212) compared with 75% following chemoconditioning (a combination of fludarabine, thiotepa, and either treosulfan of busulfan; n = 201; p < 0.0001); the 2-year cumulative incidence of relapse and treatment-related mortality were 33 vs. 12% (p < 0.0001) and 9 vs. 2% (p = 0.0269), respectively (19). The median follow-up at interim analysis was relatively short (2.1 years), but the advantage of TBI was striking throughout all subgroups and randomisation was discontinued, as the stopping rule was reached. Whether longer follow-up and associated insights regarding late sequelae will lead to reassessment of the benefit of TBI remains a question.

Efforts to provide equal outcomes with reduced TBI doses, adapted radiotherapy target volumes or the exclusion of TBI are ongoing. For now, however, based on the results of the FORUM study, TBI (12 Gy in six fractions, given twice per day) is the standard of care for ALL patients ≥4 years old who are eligible for HSCT and have no absolute contraindication to radiotherapy.

Minimal residual disease (MRD) consists of a small number of leukaemia cells in the bone marrow detectable by flow cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) or next-generation sequencing (NGS) below a level that can be detected morphologically. MRD is recognised as the strongest independent prognostic factor for disease relapse and survival in frontline and relapse ALL treatment, as well as in the transplant setting (36, 37). Most current protocols stratify patients according to response to treatment, including MRD, which, besides guiding treatment decisions, maintains its predictive value (37–39).

The predictive role of pre- and post-HSCT MRD invariably stands throughout ALL patient groups (38), despite the fact that MRD data are mainly used in real time to modulate immunosuppression tapering and/or discontinuation, possibly associated with the use of cell therapy (donor lymphocyte infusion, cytokine-induced killer cells) (40), or targeted therapy (blinatumomab, chimeric antigen receptor T cells) in the attempt to reduce the relapse risk (41–44). The effectiveness of such immunomodulation cannot be assessed.

It has been suggested that the decision regarding the conditioning regimen could be based on MRD, as defined by means of next generation sequencing (NGS) (45). Such an approach is evaluated in the ongoing prospective study which performs a non-TBI based conditioning regimen in patients ≤25 years old diagnosed with B-cell acute ALL who are pre-HSCT NGS MRD negative (NCT03509961) (46).

The role of the MRD level prior to and after HSCT in children and adolescents is discussed in depth in the publication by Merli et al. (47) in this supplement of Frontiers in Paediatrics.

The rationale for inclusion of TBI in the conditioning regimen before HSCT for ALL is two-fold: 1) to eradicate leukaemic cells, and 2) to prevent rejection of allogeneic engraftment through ablation of the recipient's immune system. Radiotherapy targets leukaemic cells in the entire body, including in sanctuary sites where chemotherapy delivery is hampered by perfusion, diffusion and blood-barrier effects. Optimising the immunosuppressive effect of fractionated TBI schedules while sparing normal tissue from injury where possible requires consideration of the combination of total dose, dose rate, fraction size, and overall treatment time. Advances in the clinical radiobiology of TBI inferred from data originating from trials or retrospective data sets have been limited, in contrast to what is the case for many solid malignancies and the associated OAR. This is, in part, explained by the large variability in patient and treatment characteristics within and between studies, as well as by the difficulties in obtaining reliable patient-level dosimetry for tissues and OAR from TBI. All of these difficulties are compounded by the fact that many institutional TBI protocols included numerous temporal adjustments to planning and delivery as well as to the dose-time-fractionation regimens used, which further hamper direct comparisons of disease control and toxicity between series. The lack of consistency in practise patterns, dosimetry and reporting of TBI doses among institutions is documented in the recent surveys of practise patterns of paediatric TBI from the European Society for Paediatric Oncology (SIOPE) and Children's Oncology Group (COG) (27, 28). As a result of these obstacles, much of the radiobiological rationale for current TBI regimens is derived from in vitro or experimental animal studies, many dating back to the 1970s and 1980s, and only supported qualitatively by clinical data.

In the 1950s, the discovery that stem cell transplantation could counteract acute mortality from the depletion of blood-forming tissues after TBI injury triggered many studies into the application of HSCT against haematologic malignancies and immunodeficiency diseases in particular (71–73). Experiments in mice showed that extremely high lethal TBI doses of 20–50 Gy or higher were needed to sterilise advanced leukaemia in the body (74), and that the graft-versus-leukaemia effect of infused stem cells was therefore essential for cure when lower TBI doses were applied. The first clinical allogeneic HSCTs were performed with TBI-only conditioning and were largely a disappointment because of disease recurrence, non-engraftment, graft-versus-host-disease- (GvHD) and treatment-related death (75). When up to 10 Gy single-fraction TBI was combined with cyclophosphamide, and immunosuppressive and peri-transplantation care evolved, more patients with acute leukaemia survived (20, 24, 76).

However, the acute and late effects of single-fraction TBI, especially for developing children, became an issue of worry. Peters et al. argued that the therapeutic ratio of the radiosensitive normal tissues vs. the immunosuppressive and anti-leukaemic effects of TBI could be improved by decreasing the single-fraction dose rate (which meant an irradiation lasting up to >10 h for patients) or by dose fractionation (77). The latter was confirmed in a randomised trial (78).

Many different fractionation schedules began to be used (79) and it was difficult to evaluate differences in efficacy because of the multifactorial influence of treatment effects, GvHD and toxicities in cohorts of patients with various diseases and age groups (67). Fractionated doses <9–10 Gy would result in non-engraftment and disease relapse (80, 81). In many instances, lung toxicity was found to be the dose-limiting factor at 2-Gy fractionated 16 Gy TBI (82); it was also diagnosed more frequently after single-fraction TBI than after fractionated TBI in leukaemia patients (83–86). For children, other significant TBI effects such as growth inhibition or cataract formation were reduced by TBI fractionation (23, 87). One fractionation schedule that was applied early on was 12 Gy in six fractions given over 3 or 6 days. To optimise the therapeutic ratio, twice-daily fractionation of doses between 1.5 and 2 Gy to doses ≥12 Gy was estimated to be optimal, while more hyperfractionated schedules with three to four fractions daily seem to have worse anti-leukaemic/immunosuppressive effect as well as being impractical in terms of delivery within working hours while giving healthy tissues the aspired 6-hour recovery period between fractions (54, 88–90). Giving 12 Gy TBI in once-daily fractions of 4 Gy increased acute effects such as mucositis (91, 92). A randomised dose-escalation study comparing 12 Gy TBI over 6 days with 15.75 Gy TBI over 7 days displayed a decreased relapse rate after high-dose TBI but increased rate of non-relapse mortality (NRM), ultimately resulting in equal probabilities of survival (93, 94). In a single-centre ALL HSCT cohort, 12 Gy in six fractions over 3 days was deemed the optimal TBI schedule regarding GvHD occurrence and overall prognosis after variations in TBI dose, dose rate and technical setting had been applied during a span of 12 years (95). Another centre—comparing 10 Gy with 12 and 13.2 Gy TBI given over 3 days—concluded that 10 Gy gave the highest 5-year OS benefit (96). One publication compared 16 TBI studies regarding fractionation and dose rate, the combination of which was recalculated into the biologically effective dose (BED) for leukaemic cells and several OAR (e.g., 6 times 2 Gy with a dose rate 0.16 Gy/min gives a BED_leukaemia of 14.2 Gy and BED_lens of 42.8 Gy) (97). A high BED_leukaemia in the fractionated schedules significantly reduced relapse incidence and increased OS. Shielding for lungs, kidneys and lenses was advised to BEDs ≤15, ≤17, and ≤40–45 Gy, respectively.

Hard conclusions regarding TBI fractionation for ALL specifically are difficult to draw from these studies as they cover different patient and disease categories as well as temporal changes in overall and HSCT-specific treatment protocols. The FORUM trial delivered a conditioning of etoposide combined with TBI as a 6 times 2 Gy TBI schedule given over 3 days and lung shielding at 10 Gy (19). For the moment, fractionated TBI schedules giving doses of 12–14 Gy with lung shielding have been adopted as optimal schedules in ALL HSCT by many paediatric radiation oncology centres (27, 28). Nonetheless, continuous reassessment of TBI optimization is needed as pre-HSCT factors improve and new combinations of chemotherapy with lower doses of TBI are researched (98, 99).

The biologic radiotherapy effect of TBI on cells and tissues depends on their inherent radiosensitivity, the micro-environment, total dose, fractionation, overall treatment time, dose rate, dose homogeneity, TBI setup, patient and disease characteristics, and other therapies. TBI with an extended source-surface distance (SSD) setup is institution specific, precluding normalisation of TBI dose and dose rate (100). Published works may report dose rate at the prescription point of a patient's midplane, in the lung or in air. Reported values may represent measured or calculated data, and measurement and calculation methods can differ between centres. These differences must be considered when comparing and interpreting published data. In older studies, TBI was often delivered with cobalt teletherapy and source decay exposed the analysed cohorts to varying dose rates through time (81). In modern extended SSD TBI, the dose rate is chiefly determined by the SSD (through the inverse square law) and the linear accelerator dose rate.

In the 1970s, the most commonly used TBI schedule was 8–10 Gy given at a low dose rate over several hours, to balance treatment effect against toxicities (101). Fractionated TBI was recommended to improve the therapeutic ratio. For leukaemic cell kill and allogeneic engraftment success, fractionated TBI with a higher dose rate is preferable to a lower dose rate (77, 89). In preclinical studies, increased dose rates during TBI improved allogeneic engraftment (102–104). In clinical studies, dose rates of ≤0.04 Gy/min showed increased leukaemia relapses in patients given TBI doses of 8.4–12.5 Gy in 3 days (81). Bone marrow displays a marginally increased sensitivity for fractionation with 1.2- and 2-Gy fractions, and little effect of higher dose rates of 0.8 Gy/min when compared with 0.05 Gy/min in single-fraction TBI (105). At dose rates >0.3 Gy/min, no extra effect for haematopoietic cell damage is expected (106).

Multiple studies have explored the effect of TBI dose rate on toxicity. In preclinical studies exploring single-fraction TBI, dose rate changes in a lower dose rate range had a much greater influence on toxicity occurrence in late responding tissues (especially the lung, kidney and liver), than dose rate changes in the higher dose rate range (101, 106). For late non-hematopoietic tissue effects, this resulted in e.g., an iso-effective dose factor of ±2.4 for a dose rate of 0.02 Gy/min, ±1.5 for a dose rate of 0.1 Gy/min, and ±1.0 for a dose rate range of 1 to >10 Gy/min. Experiments in mice indicate that average dose rate may be more relevant for lung tissue toxicity than instantaneous dose rate (107). At midplane dose rates ≤0.15 Gy/min, fractionation of total dose had a greater sparing effect on late-responding tissues than reduction of dose rate (23, 106). High dose rates of 0.75 Gy/min induced more gastrointestinal damage in dogs after TBI than dose rates down to 0.021 Gy/min, but this effect could be compensated for by fractionation (108). In dogs given autologous HSCT, acute TBI tolerance doses measured as 50% mortality at 7 days were comparable between single-fraction and fractionated TBI (2 Gy three times daily) at exposure rates of 0.02–0.1 Gy/min, but fractionation benefit occurred at a dose rate of 0.2 Gy/min, with tolerance doses of 10.56 Gy (95% CI 9.39–11.74) vs. 13.2 Gy (95% CI 11.36–15.05), respectively (109). In mice, low dose rates of 0.05 Gy/min as compared with 0.8 Gy/min, had a highly protective effect on late lethality in single dose TBI, but this effect diminished or disappeared when TBI was given in 1.2- or 2-Gy fractions (105). These studies exemplify that influence of dose rate on toxicity induction diminishes through fractionation, that fractionation increases tolerance of normal tissues, that dose rate changes in the lower dose rate range (e.g., <0.15 Gy/min) influence late toxicity effects more than dose rate changes in the higher dose rate range (e.g., >0.3 Gy/min), and that average dose rate may be more relevant for biological effect correlation than instantaneous dose rate.

In a BED calculation of 16 clinical studies, it was demonstrated that different dose rates at ≤0.15 Gy/min for fractionated schedules do not induce large BED differences for leukaemic cells and OAR, in contrast to single-fraction schedules (97). Most clinical research into dose rate effects has focused on lung toxicity. In 202 acute leukaemia patients, 8 times 1.65 Gy fractionated TBI given at dose rates of >0.15 Gy/min induced significantly more IP and worse OS than dose rates of ≤0.15 Gy/min when lungs were only shielded by the arms in a bilateral beam setup (IP incidence: 29 vs. 10%, respectively, p < 0.01; 1-year OS: 60 vs. 76%, respectively, p = 0.01) (110). In studies using fractionated conventional TBI, the impact of dose rates up to 0.15 Gy/min becomes negligible for IP development, as long as the registered lung dose does not exceed 8–9 Gy (111–114). At dose rates of 0.15–0.21 Gy/min, IP risk increased with increasing dose rates in studies with lung shielding of 10–12 Gy for TBI schedules of 12 Gy in 6–8 fractions (115, 116). In a meta-analysis including TBI lung dose rates of 0.03–0.41 Gy/min, dose rate was not significantly associated with IP (117). A high dose rate affects late renal damage inasmuch as it can increase BED to levels above tolerance doses, generating the need for kidney shielding (118–120). Cataract development is related to dose rate, with increasing cataract risk at increasing dose rates between 0.02 and 0.56 Gy/min (121, 122). Although not repeated in all publications, clinical studies show that for dose rate ranges of e.g., 0.04–0.4 Gy/min in a conventional SSD TBI setup, increasing the dose rate increases risk of late toxicities in lungs, kidneys and lenses even for fractionated schedules, generating a need for adequate organ shielding.

Momentarily disregarding the numerous influential variables and inconsistent reports regarding the issue of dose rate, dose rates between 0.04 and 0.15 Gy/min seem to be the most frequently reported option for extended-SSD, fractionated conventional TBI schedules in paediatric ALL patients, albeit with appropriate OAR shielding. Regarding immunosuppressive and anti-leukaemic cell effect, the higher end of this spectrum may be preferable. For more staunch multicentre conclusions, we need comparable schedules, uniform specifications, and complete reporting of all relevant parameters including applied dose rates.

Patient comfort is a factor as well. Delivery of 2-Gy fractions at 0.04 Gy/min requires 50 min beam-on time and motionless patient positioning, which would mean more indications for multiple sedations of >1 h in children.

Improved dose homogeneity and specific OAR dose reduction can be achieved with highly conformal TBI techniques. This, along with fractionation, may allow for more favourable toxicity profiles even with a high instantaneous dose rate. Low dose rates are preserved with an image-guided intensity-modulated radiotherapy (IMRT) technique at extended SSD, deriving midplane dose rates of 0.14–0.19 Gy/min (123). First experiences with this technique show encouraging results for outcome and lung/kidney toxicity, with a 15% dose reduction at these organs (124). With highly conformal source-to-axis distance techniques such as TomoTherapy (a device combining a helical computed tomography (CT) scanner and a linear accelerator) and volumetric-modulated arc therapy (VMAT—rotational IMRT delivered on a standard linear accelerator), instantaneous dose rates are inherently higher (e.g., 0.2 to >10 Gy/min) and are variable during treatment (125–127). The first experiences with TomoTherapy and VMAT TBI (with overall instantaneous dose rates of ±13 Gy/min and ±0.31 Gy/min and instantaneous dose rates around the lung of ±8.4 and ±0.11 Gy/min, respectively), showed promising results in 197 children with regard to outcome and toxicity profiles (128). Centres can opt for a decrease of monitor unit output at the level of e.g., the lungs or pelvis to achieve average dose rates of even <0.06 Gy/min if desired (125, 126). Fractionated TMLI, with greater sparing of dose-limiting OAR, may provide a means to preserve immunogenic and anti-leukaemic effects while conveying highly acceptable toxicity profiles with high instantaneous dose rate (32, 129).

Hypoxia as a cause of radioresistance is a well-known problem in rapidly proliferating solid tumours which outgrow their blood supply. It has not gained much attention in leukaemia research. However, it turns out that the microenvironment in the deeper peri-sinusoidal bone marrow regions (where most of the long-term haematopoietic stem cells reside) is hypoxic, with O₂ levels <10 mmHg (130–132). Moreover, leukaemic cells have been shown to be markedly hypoxic; hypoxia inducible factor-1α (HIF-1α), a molecular marker of hypoxia, was shown to be overexpressed in leukaemic cells in the bone marrow in paediatric patients with ALL (132, 133). Hypoxia induces chemoresistance and may play a role in the maintenance of MRD (134). The level of hypoxia in some leukaemic cells in the bone marrow is sufficient to cause hypoxic radioresistance. However, there are no data to support that this is a significant clinical problem, and, so far, no interventions directed at modifying the hypoxia of leukaemic cells have been proposed.

The central nervous system (CNS) and the testes are protected by barriers that are difficult to penetrate by systemic treatment and have been shown to act as sanctuaries for leukaemic cells with a high risk of local recurrence. Including TBI in the conditioning regimen has the distinct advantage of reaching these sites with the planned treatment.

Radiotherapy can also deliver a higher dose to precisely defined volumes: a so-called boost. Adding a radiation boost to the sanctuary sites in order to reduce the recurrence risk was performed often in the past. However, the effectiveness of the systemic regimens has improved very significantly, making radiation boosts unnecessary in most cases (135–141).

The risk of CNS relapse after HSCT is very high in patients with residual CNS leukaemia after chemotherapy or in patients who develop a relapse involving the CNS. For these patients, additional CNS-directed radiotherapy is often considered (140, 142). Most often, whole brain radiotherapy has been applied to a cumulative cranial dose of 18–24 Gy (140). However, data indicate that craniospinal irradiation (CSI) may be more effective, which seems logical with leukaemic cells circulating in the cerebrospinal fluid. CSI is given to a cumulative dose of 18 in 2 Gy fractions (143). CNS-directed radiotherapy is given in the days immediately prior to TBI.

With modern systemic therapy for ALL, testicular relapses are rare. A boost is only considered for patients with a very high risk of testicular relapse, typically patients with residual disease after chemotherapy or who develop testicular recurrence. The scrotal content including both testes (or the contralateral testis after orchiectomy) is irradiated. If only the contralateral testicle with no evidence of disease is present, a single dose of 4 Gy is often given; however, if one or both testes are clinically involved, the cumulative dose (together with TBI) is 18–24 Gy given in 2 Gy fractions in the days immediately prior to TBI.

Survivors after HSCT can develop morbidities in any organ system and have higher morbidity and mortality rates than those observed in the general population or in non-transplanted childhood cancer survivors (5, 6, 144–146). Very young children (aged below 3–4 years) are more prone to developing serious side effects from HSCT and TBI-based conditioning (4, 147, 148). Concerns are i.e., more negative effects on neurocognition, growth, endocrine and metabolic functioning and second malignancies, and many centres now avoid TBI in these young patients (27). Radiotherapy can cause toxicities depending on patient-, tissue-, disease-, treatment-, dose-, and location-related factors (149). Although many factors are at play in the establishment of HSCT sequelae, TBI-based conditioning causes more late effects than chemoconditioning (4, 5, 150). Within the French Leucémies de l'Enfant et l'Adolescent (LEA) cohort, at a median follow-up of 10.1 years, the 174 patients who received TBI reported more complications than the 66 patients conditioned with busulfan during the same time period (3.01 vs. 2.35, respectively, p = 0.03) (151).

Since late effects of HSCT will be explored in another review within the current Frontiers in Paediatrics supplement, this chapter will focus on fractionated TBI effects. Table 1 narrates several fractionated TBI-related sequelae. General observations from the literature are given as well as noteworthy specific articles. Consequences/recommendations for TBI, or consequences after TBI are remarked upon.

TBI practise worldwide remains varied, with radiotherapy centres typically developing site-specific setups and techniques (25–28, 79, 269, 270). Conventional TBI is mostly delivered using extended SSD techniques (79), where the radiation beam covers a patient's entire body, and delivers a relatively low dose rate in the patient as a consequence of linear accelerator dose rate adjustability and the inverse square dose reduction with distance (Figure 1). Other setups can be multiple parallel or adjacent beams, sweeping beams, a moving couch underneath a static beam, and field-in-field techniques (271–273).

Many large, open-field conventional techniques result in rather heterogeneous dose distributions, delivering between <80% to even >120% of prescribed doses (Figure 2B), although efforts are made to reduce heterogeneity to within 10%, according to guidelines (e.g., the American Association of Physicists in Medicine guidelines, Report No. 17) (274). The last decade has seen nascent implementation of highly conformal isocentric techniques (where the radiation gantry rotates around the patient on the treatment couch), with the intention to improve dose distribution homogeneity and to reduce the dose to OAR.

Image guided highly conformal delivery of TBI allows the radiation oncology and the transplant teams to define what critical organs to spare, what anatomic structures to target, and the dose that each organ and target structure should receive. This offers the advantage to reduce acute and long-term toxicities (305), the potential to reduce risk of secondary malignancies (306), and the ability to dose escalate to target structures with acceptable toxicities and improved outcomes (307). This is particularly relevant to the paediatric population where, in patients with ALL receiving fractionated TBI, mean lung dose ≥8 Gy was associated with a statistically significant decrease in overall survival (111).

TMI (Figure 4A) and TMLI (Figure 4B) are defined as highly conformal organ sparing forms of TBI delivered to the bone marrow, lymph nodes, and spleen (308–310), while sparing lungs, kidneys, heart, oral cavity, GI tract, and other critical organs. In some studies the liver, brain and testes are included as target regions (Figure 4C) (311). Today the terms TMI/TMLI can be broadly applied to a spectrum of highly conformal IMRT TBI dose distributions, including TBI with only lung sparing, which has been shown to result superior dose reduction to the lungs compared to conventional TBI delivery using lung blocks (312).

The advantages of IMRT based delivery of TBI and TMI/TMLI are clinically important for both adult and paediatric patients, particularly in patients with co-morbidities who cannot tolerate standard myeloablative TBI regimens, in paediatric patients to limit short and long term toxicities, and in patients with relapsed or refractory (R/R) disease who have no standard transplant options. Figure 5 and Table 2 provide an example of a TMLI plan of a 5 year old patient with ALL, with superior organ dose reduction compared to conventional SSD TBI.

TMI and TMLI are feasible because of advances in IMRT that have made targeted irradiation of large body regions possible (308, 310, 313–316). The first attempts to cover the whole bone marrow with a very conformal dose distribution were performed with helical TomoTherapy (HT) (308). The first planning studies of HT-based TMI showed that the technique was feasible and that good target coverage could be achieved while reducing doses to key normal tissues by 35–70% compared with conventional TBI (308, 310).

This was followed by the use of a standard linear accelerator to deliver TMI with a number of static (so-called “step and shoot”) IMRT fields (313, 314), with a dose reduction of 29–65% to various OARs in comparison with conventional TBI (314). VMAT-based TMI was shown to obtain comparable target coverage to that obtained with HT and IMRT, with similar dose reduction to normal tissues (314–316).

Myeloablative fractionated TBI delivered together with chemotherapy remains the standard for conditioning prior to HSCT in paediatric patients with high-risk or relapsed/refractory ALL. Since its introduction, TBI has undergone developments to decrease the risks of late sequelae. Still, survivors typically develop serious late effects and efforts to improve the balance between outcomes and toxicity need to continue. While TBI performance between different radiotherapy centres is heterogeneous, with many centres not changing practises for a long time, new techniques may have the potential to mitigate adverse effects while preserving efficacy. To properly evaluate real-world data, we need comparable TBI schedules, uniform specifications, and comprehensive standardised reporting of all relevant parameters. Cooperation between treatment centres and research groups can support new insights, implementation of new techniques and research regarding the potential to reduce the need for TBI, lower TBI doses, or decrease radiotherapy treatment volumes within the body. Future studies must identify whether highly conformal TBI or TMI/TMLI techniques offer equal disease outcomes while reducing toxicity.

All authors fulfil the criteria for authorship, wrote significant sections of this review, and reviewed and approved the entire manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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