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Journal of Clinical Oncology : Official... Feb 2021Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.
PATIENTS AND METHODS
FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
RESULTS
Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
CONCLUSION
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Chemoradiotherapy; Child; Child, Preschool; Equivalence Trials as Topic; Etoposide; Female; Follow-Up Studies; Humans; International Agencies; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Thiotepa; Vidarabine; Whole-Body Irradiation
PubMed: 33332189
DOI: 10.1200/JCO.20.02529 -
Journal of Clinical Oncology : Official... Jan 2023It remains controversial whether busulfan-based versus total body irradiation (TBI)-based regimens have comparable outcomes in patients with acute lymphoblastic leukemia... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
It remains controversial whether busulfan-based versus total body irradiation (TBI)-based regimens have comparable outcomes in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We investigated the efficacy and toxicity of busulfan plus cyclophosphamide (BuCy) and TBI plus cyclophosphamide (TBI-Cy) conditioning in allo-HSCT for adult standard-risk B-cell-ALL in first complete remission (CR1).
PATIENTS AND METHODS
We performed an open-label, randomized phase III trial at 13 hospitals in China. Eligible patients (age 14-65 years) had standard-risk ALL in CR1. Patients were randomly assigned (1:1) to BuCy (0.8 mg/kg four times per day on days -7 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2) or TBI-Cy (4.5 Gy TBI on days -5 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2). The primary end point was 2-year overall survival. Analysis was per protocol. This trial is registered with ClinicalTrials.gov (identifier: NCT02670252) and is complete.
RESULTS
Between January 2016 and February 2020, 275 patients were assigned to receive BuCy (273 assessed) and 275 to TBI-Cy (272 assessed). The 2-year overall survival was 76.6% (95% CI, 71.7 to 81.8) and 79.4% (74.7 to 84.4; = .457; difference 2.9%; 95% CI, -4.1 to 9.8; = .022), indicating noninferiority of BuCy. The 2-year relapse was 20.2% (95% CI, 15.6 to 25.1) and 18.4% (14.0 to 23.2; = .616), and the nonrelapse mortality was 11.0% (95% CI, 7.6 to 15.0) and 11.0% (7.7 to 15.1; = .988) in the BuCy and TBI-Cy groups, respectively. There were no differences in regimen-related toxicity, graft-versus-host disease, or late effects between the two groups.
CONCLUSION
The BuCy regimen has noninferior efficiency and safety as TBI-Cy (4.5 Gy × 2) for patients with adult standard-risk B cell-ALL in CR1 undergoing HLA-matched allo-HSCT.
Topics: Adult; Humans; Adolescent; Young Adult; Middle Aged; Aged; Busulfan; Whole-Body Irradiation; Cyclophosphamide; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning
PubMed: 36084276
DOI: 10.1200/JCO.22.00767 -
Cells Apr 2022The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian... (Review)
Review
The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.
Topics: Animals; Disease Models, Animal; Female; Mice; Ovarian Follicle; Ovarian Reserve; Primary Ovarian Insufficiency; Whole-Body Irradiation
PubMed: 35406783
DOI: 10.3390/cells11071219 -
International Journal of Molecular... Feb 2023For widespread cutaneous lymphoma, such as mycosis fungoides or leukemia cutis, in patients with acute myeloid leukemia (AML) and for chronic myeloproliferative... (Review)
Review
For widespread cutaneous lymphoma, such as mycosis fungoides or leukemia cutis, in patients with acute myeloid leukemia (AML) and for chronic myeloproliferative diseases, total skin irradiation is an efficient treatment modality for disease control. Total skin irradiation aims to homogeneously irradiate the skin of the entire body. However, the natural geometric shape and skin folding of the human body pose challenges to treatment. This article introduces treatment techniques and the evolution of total skin irradiation. Articles on total skin irradiation by helical tomotherapy and the advantages of total skin irradiation by helical tomotherapy are reviewed. Differences among each treatment technique and treatment advantages are compared. Adverse treatment effects and clinical care during irradiation and possible dose regimens are mentioned for future prospects of total skin irradiation.
Topics: Humans; Mycosis Fungoides; Skin Neoplasms; Radiotherapy, Intensity-Modulated; Leukemia; Lymphoma, T-Cell, Cutaneous; Radiotherapy Dosage; Whole-Body Irradiation
PubMed: 36901922
DOI: 10.3390/ijms24054492 -
Proceedings of the National Academy of... Jul 2023The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the...
The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T) and P14 circulating memory CD8 T cells (T), with the former being more susceptible to radiation-induced numeric loss. While T cell numbers rapidly recovered, as previously described, the number of P14 T cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 T in irradiated hosts exhibited an inefficient transition to a central memory (CD62L) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with expressing the LCMV GP epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting T, rendering previously protected hosts susceptible to reinfection.
Topics: Mice; Animals; Whole-Body Irradiation; Neoplasm Recurrence, Local; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Immunologic Memory; Mice, Inbred C57BL
PubMed: 37364124
DOI: 10.1073/pnas.2302785120 -
Frontiers in Cellular and Infection... 2021Total body irradiation (TBI) has been demonstrated to alter the intestinal microbiome, but the effects of successful small molecule ionizing radiation mitigators on the...
Total body irradiation (TBI) has been demonstrated to alter the intestinal microbiome, but the effects of successful small molecule ionizing radiation mitigators on the intestinal microbiome are not well-known. Our survival experiments examined the effects of anti-cell death radiation mitigators on and in conjunction with the host's microbiota. Mice received 9.25 Gy TBI and then were administered radiation mitigators 24 hours later. Passed stool were collected pre-irradiation, then on days 1, 3, 5, 7, 10, 14, 21, and 30 post-irradiation for 16S rRNA gene (V4 region) sequencing. The Cox proportional hazards (CPH) model was fit with taxonomic composition (time varying covariates) and treatment as predictors. In the first experiment, mice were administered drugs for "granulocyte stimulation and anti-apoptosis" in four protocol combinations: JP4-039 (anti-apoptosis), granulocyte colony-stimulating factor (G-CSF, granulopoietic precursor cell stimulator), both mitigators, and control. Survival improved relative to control (30.0%) for G-CSF (80%, p-value = 0.025), G-CSF/JP4-039 (70%, p-value = 0.084), but not for JP4-039 (50.0%). In the second experiment, mice were administered mitigation drugs "inhibiting programmed cell death" pathways: JP4-039 (anti-apoptosis), necrostatin-1 (anti-necroptosis), and baicalein (anti-ferroptosis), in eight combinations. The survival of JP4-039/baicalein (60.0%, p-value = 0.010) and JP4-039/baicalein/necrostatin-1 (60.0%, p-value = 0.06) treatment combinations were significantly different from the control (26.7%). The JP4-039/necrostatin-1 (46.7%) and baicalein/necrostatin-1 (40.0%) and singlet treatment combinations (26.7%) were not significantly different from the control. Despite differences between the baseline microbiota compositions of the two experiments, consistent changes in composition after irradiation were found: decreased post-irradiation, relative to baseline. By day 7, microbiota perturbations had incompletely reversed, and no drug-specific differences were identifiable. The CPH model identified and members of , including , as protective and as deleterious. By day 30, the microbiota of surviving mice had not returned to baseline, but the differences between experiments suggest the resultant microbiota composition of the survivors are stochastic or batch specific in nature, rather than a requirement for survival. In conclusion, the study determined that key taxa identified in fecal samples, when applied towards the prediction of TBI survival, improves the survival model relative to treatment information alone.
Topics: Animals; Mice; Mice, Inbred C57BL; Microbiota; RNA, Ribosomal, 16S; Radiation-Protective Agents; Whole-Body Irradiation
PubMed: 34621689
DOI: 10.3389/fcimb.2021.715396 -
Radiotherapy and Oncology : Journal of... Aug 2022Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children...
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.
Topics: Bone Marrow; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 35661674
DOI: 10.1016/j.radonc.2022.05.027 -
British Journal of Haematology Mar 2021Bone marrow damage is an important consequence of exposure to acute high-dose whole-body radiation. As such, haematologists can play an important role in managing this... (Review)
Review
Bone marrow damage is an important consequence of exposure to acute high-dose whole-body radiation. As such, haematologists can play an important role in managing this complication. However, these accident and incident scenarios are complex and often involve injuries to other organs and tissues from heat, projectiles and chemicals. In the case of a large-scale event there will likely be severe infrastructure disruptions and injury or death to medical personnel. Accurate estimates of dose and uniformity of exposure are needed to intelligently direct appropriate interventions, which range from antibiotics, antifungals and anti-virus drugs, molecularly-cloned haematopoietic growth factors and, in rare instances, haematopoietic cell transplants. These therapies are ones that haematologists often use in the context of anti-cancer therapy, especially therapy of haematological cancers like leukaemia. However, most haematologists have little knowledge of radiation biology and should consider updating this aspect of their expertise in continuing medical education. As in other areas of medicine, prevention is better than cure and haematologists should be active in decreasing risks of a nuclear war.
Topics: Humans; Radiation Injuries; Radioactive Hazard Release; Whole-Body Irradiation
PubMed: 31388987
DOI: 10.1111/bjh.16138 -
Journal of Cancer Research and Clinical... Aug 2023Total body irradiation (TBI) is often a component of the conditioning regimen prior to hematopoietic stem cell transplantation in patients with hematological...
BACKGROUND
Total body irradiation (TBI) is often a component of the conditioning regimen prior to hematopoietic stem cell transplantation in patients with hematological malignancies. However, total marrow irradiation (TMI) could be an alternative method for reducing radiation therapy-associated toxicity, as it specifically targets the skeleton and thus could better protect organs at risk. Here, we compared dosimetric changes in irradiation received by the target volume and organs at risk between TBI and TMI plans.
MATERIALS AND METHODS
Theoretical TMI plans were calculated for 35 patients with various hematological malignancies who had already received TBI in our clinic. We then statistically compared irradiation doses between the new TMI plans and existing TBI plans. We examined whether TMI provides greater protection of organs at risk while maintaining the prescribed dose in the targeted skeletal area. We also compared beam-on times between TBI and TMI.
RESULTS
TMI planning achieved significant reductions in the mean, minimum, and maximum irradiation doses in the lungs, kidneys, liver, spleen, and body (i.e., remaining tissue except organs and skeleton). In particular, the mean dose was reduced by 49% in the liver and spleen and by 55-59% in the kidneys. Moreover, TMI planning reduced the corpus beam-on time by an average of 217 s.
CONCLUSION
TMI planning achieved significant dose reduction in organs at risk while still achieving the prescribed dose in the target volume. Additionally, TMI planning reduced the beam-on time for corpus plans despite a high modulation factor.
Topics: Humans; Whole-Body Irradiation; Bone Marrow; Radiotherapy, Intensity-Modulated; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Hematologic Neoplasms; Carmustine; Etoposide; Radiation Injuries
PubMed: 36607428
DOI: 10.1007/s00432-022-04565-2 -
Asian Pacific Journal of Cancer... Mar 2019Objective: Hematopoietic stem cell transplant (HSCT) has recently emerged as a cure for previously “incurable” diseases and is being explored and attempted in many... (Meta-Analysis)
Meta-Analysis
Objective: Hematopoietic stem cell transplant (HSCT) has recently emerged as a cure for previously “incurable” diseases and is being explored and attempted in many other fields including congenital and acquired non-malignant diseases. However, the long-term side effect associated with HSCT especially Total Body Irradiation (TBI) is still understudied. Therefore, we attempted to establish association between TBI and risk of developing Diabetes Mellitus (DM) or impaired glucose metabolism (IGM). Methods: We searched for titles of articles in MEDLINE (PubMed), EMBASE, and Cochrane library in August 2018 that evaluated the association between TBI in the setting of HSCT and DM or IGM. We conducted a random effect meta-analysis of 11 studies involving a total of 13,191 participants and reported the pooled MD (mean difference) for the development of DM/IGM after TBI as part of the conditioning regimen for HSCT. Results: We found a significant increase in the risk of developing DM/IGM after TBI is used as part of the conditioning regimen compared to other types of conditioning regimen with the pooled MD being 5.42, 95% Confidence Interval (CI) 2.51-11.71, I2=92.4%. Conclusion: TBI as a conditioning regimen in the setting of HSCT significantly increases the risk of developing DM/IGM. Therefore, we recommend close monitoring and screening for diabetes mellitus in patients who underwent TBI before HSCT.
Topics: Diabetes Mellitus; Hematopoietic Stem Cell Transplantation; Humans; Prognosis; Whole-Body Irradiation
PubMed: 30912408
DOI: 10.31557/APJCP.2019.20.3.885