Comparison of Total Body Irradiation and Lu-177-DOTATATE Therapy in Pediatric Neuroblastoma: A Dosimetric Analysis of Organ-Specific Radiation Doses

Comparison of Total Body Irradiation and Lu-177-DOTATATE Therapy in Pediatric Neuroblastoma: A Dosimetric Analysis of Organ-Specific Radiation Doses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of Total Body Irradiation and Lu-177-DOTATATE Therapy in Pediatric Neuroblastoma: A Dosimetric Analysis of Organ-Specific Radiation Doses Sevgi Ölmez This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9621891/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: Neuroblastoma is the most common extracranial solid tumor in children. In disseminated disease, total body irradiation (TBI) remains part of conditioning regimens; however, it is associated with severe long-term sequelae including microcephaly, neurocognitive impairment, and skeletal growth arrest. Lu-177-DOTATATE has emerged as a promising molecular radiotherapy option for pediatric neuroblastoma. This study aims to perform a direct dosimetric comparison of TBI and Lu-177-DOTATATE with respect to radiation doses delivered to developmentally critical organs in pediatric patients. Methods: Pediatric patients undergoing TBI as part of myeloablative conditioning and patients receiving Lu-177-DOTATATE for relapsed or refractory high-risk neuroblastoma will be enrolled following ethical approval. Dosimetric evaluation will include organ-absorbed dose calculations for the brain, growth plates, bone marrow, kidneys, and liver. TBI dosimetry will be assessed using thermoluminescent dosimeters (TLDs), and Lu-177 dosimetry will be performed using SPECT/CT-based quantification with the MIRD schema. Expected Results: We hypothesize that Lu-177-DOTATATE delivers significantly lower absorbed doses to developmentally sensitive organs compared to TBI, while maintaining comparable anti-tumor efficacy in somatostatin receptor-positive neuroblastoma. Quantitative dosimetric data will be presented per organ and compared between the two modalities. Conclusion: This dosimetric analysis is intended to provide radiobiological evidence supporting the integration of Lu-177-DOTATATE into standard pediatric oncology protocols as a safer alternative to TBI, particularly for patients with disseminated neuroblastoma expressing somatostatin receptor type 2. Cancer Biology Lu-177-DOTATATE neuroblastoma total body irradiation pediatric dosimetry radionuclide therapy somatostatin receptor Introduction Neuroblastoma is the most common extracranial solid malignancy in children, accounting for approximately 6–10% of all childhood cancers and nearly 15% of pediatric cancer-related mortality [ 1 ]. It arises from neural crest cells of the developing sympathetic nervous system, most frequently in the adrenal medulla, and is classified as a neuroendocrine tumor. While localized disease is often curable with surgery, disseminated high-risk neuroblastoma continues to carry a poor prognosis despite multimodal treatment approaches including high-dose chemotherapy, autologous stem cell transplantation (ASCT), radiation, and immunotherapy [ 2 ]. Total body irradiation (TBI) has historically been used as part of myeloablative conditioning regimens prior to ASCT in high-risk neuroblastoma. By delivering a uniform radiation dose to the entire body, TBI aims to eradicate residual tumor cells and achieve immunosuppression for engraftment [ 3 ]. However, TBI is associated with substantial long-term toxicities, which are particularly severe in the pediatric population. These include growth hormone deficiency, hypothyroidism, neurocognitive impairment, microcephaly, skeletal growth arrest, cataracts, pulmonary fibrosis, and an increased risk of secondary malignancies [ 4 , 5 ]. Recognizing these consequences, contemporary treatment protocols have moved toward TBI-free conditioning regimens; however, TBI continues to be used in selected patients with disseminated disease. Lutetium-177 (Lu-177) is a beta-emitting radionuclide with a physical half-life of 6.7 days and gamma emission energies of 113 keV and 208 keV, making it suitable for both therapeutic and imaging purposes. When conjugated to somatostatin analogs such as DOTATATE, Lu-177 selectively targets somatostatin receptor type 2 (SSTR2)-expressing cells, enabling targeted molecular radiotherapy with a more favorable organ dose profile than external beam radiation [ 6 ]. Lu-177-DOTATATE (Lutathera®) has been approved by the FDA and EMA for the treatment of SSTR2-positive gastroenteropancreatic neuroendocrine tumors in adults following the landmark NETTER-1 trial [ 7 ]. Neuroblastoma cells frequently express SSTR2, providing a rationale for targeting them with Lu-177-DOTATATE. Early clinical experience with Lu-177-DOTATATE in pediatric neuroblastoma demonstrated the safety and feasibility of this approach [ 8 ]. Subsequent clinical trials, including the LuDO and LuDO-N studies, have built upon this foundation, exploring optimized dosing schedules in relapsed and refractory cases [ 9 , 10 ]. Despite these advances, a systematic dosimetric comparison between TBI and Lu-177-DOTATATE—specifically with regard to absorbed doses in developmentally critical organs in children—has not yet been reported in the literature. This gap is clinically significant. Dosimetric evidence is essential to justify the substitution of one treatment modality for another, particularly in a vulnerable pediatric population where developmental toxicities may have lifelong consequences. The present study addresses this gap by performing a direct organ-specific dosimetric comparison between TBI and Lu-177-DOTATATE in pediatric neuroblastoma patients. We hypothesize that Lu-177-DOTATATE delivers significantly lower absorbed doses to growth-sensitive organs—including the brain, growth plates, and bone marrow—compared to TBI, while maintaining relevant anti-tumor activity. Materials and Methods Study Design and Ethical Approval This study is designed as a prospective, comparative dosimetric analysis conducted at [Institution Name]. Ethical approval will be obtained from the institutional ethics committee prior to patient enrollment. All procedures will be performed in accordance with the Declaration of Helsinki and applicable national regulations. Written informed consent will be obtained from patients' parents or legal guardians. Patient Selection Two patient cohorts will be enrolled: Cohort A (TBI group): Pediatric patients (age 18 months–18 years) with high-risk neuroblastoma scheduled to receive TBI as part of myeloablative conditioning prior to ASCT, in accordance with institutional protocols. Cohort B (Lu-177-DOTATATE group): Pediatric patients (age 18 months–18 years) with relapsed or refractory high-risk neuroblastoma who demonstrate adequate SSTR2 expression on 68Ga-DOTATATE PET/CT (uptake equal to or greater than liver background) and are scheduled to receive Lu-177-DOTATATE therapy. Exclusion criteria for both cohorts include: prior radiation therapy to more than two body regions, renal insufficiency (GFR < 60 mL/min/1.73 m²), active second malignancy, or inability to provide informed consent. TBI Dosimetry TBI will be delivered using a standard linear accelerator protocol at [Institution]. Dosimetric assessment will be performed using calibrated thermoluminescent dosimeters (TLDs) placed at anatomical sites corresponding to the brain, cervical/lumbar spine growth plates, sternum (bone marrow surrogate), kidneys, and liver. TLD readings will be obtained following each TBI fraction and summed to calculate total absorbed dose per organ. Dose homogeneity will be evaluated across measurement sites. All TLD measurements will be performed by a certified medical physicist. Lu-177-DOTATATE Dosimetry Lu-177-DOTATATE will be administered as weight-based activity (200 MBq/kg) per cycle, with dosimetric imaging performed following each administration. Whole-body planar scintigraphy will be acquired at 4, 24, and 96 hours post-injection. SPECT/CT imaging of the abdomen, thorax, and skull will be performed at the 24-hour time point. Organ-absorbed doses will be calculated using the Medical Internal Radiation Dose (MIRD) schema [ 11 ], with time-integrated activity coefficients derived from multi-time-point imaging. Dosimetric software (HERMES HybridViewer with OLINDA/EXM v2.1) will be used for absorbed dose calculations, utilizing age-appropriate pediatric phantoms. Organ Dose Comparison The primary dosimetric endpoints are absorbed doses (Gy) to the following organs: brain, growth plates (proximal femur and lumbar vertebral endplates as surrogates), active bone marrow, kidneys, and liver. Doses from both cohorts will be expressed as mean ± standard deviation and compared using the Mann-Whitney U test (non-parametric), given the expected small sample sizes. A p-value of < 0.05 will be considered statistically significant. All statistical analyses will be performed using SPSS v26 (IBM, Armonk, NY, USA). Sample Size Based on existing literature and available patient populations at our institution, we estimate enrollment of 10–15 patients per cohort over an 18-month period. Given the exploratory nature of this dosimetric study, formal power calculations were not performed; however, this sample size is consistent with similar published dosimetric feasibility studies in pediatric nuclear medicine. Results Patient enrollment and data collection are currently ongoing. The expected results and preliminary hypotheses are outlined below to provide context for the study design and to facilitate peer review of the methodology. Patient Characteristics We anticipate enrolling patients with a median age of [X] years (range: 18 months–18 years), with a male-to-female ratio of approximately 1.5:1, consistent with published epidemiological data on high-risk neuroblastoma. All patients in Cohort B are expected to demonstrate adequate SSTR2 expression on pre-treatment 68Ga-DOTATATE PET/CT. TBI Organ Doses TBI is expected to deliver near-uniform whole-body doses of 12 Gy (fractionated, 2 Gy per fraction × 6 fractions) based on institutional protocol. TLD measurements are anticipated to confirm doses within ± 10% of the prescribed dose at all measurement sites, including the brain (expected: 11.5–12.5 Gy), growth plates (expected: 11.5–12.5 Gy), and bone marrow (expected: 11.5–12.5 Gy). Lu-177-DOTATATE Organ Doses Based on existing pediatric dosimetric data from the LuDO trial and related studies, Lu-177-DOTATATE is expected to deliver considerably lower absorbed doses to non-target organs compared to TBI. Estimated organ doses per cycle are: kidneys (2.0–4.5 Gy, the dose-limiting organ), bone marrow (0.1–0.5 Gy), liver (1.0–2.5 Gy), brain (< 0.1 Gy), and growth plates (< 0.1 Gy). Comparative Dosimetric Analysis The primary expected finding is a statistically significant reduction in absorbed doses to the brain, growth plates, and bone marrow in Cohort B compared to Cohort A. This difference is expected to be most pronounced for brain and growth plate doses, where TBI delivers approximately 12 Gy versus < 0.1 Gy for Lu-177-DOTATATE—a difference of more than two orders of magnitude. Table 1 summarizes the expected comparative dosimetric data. Table 1 Expected organ-absorbed doses for TBI versus Lu-177-DOTATATE Organ TBI Dose (Gy) Lu-177 Dose (Gy/cycle) Expected p-value Brain 11.5–12.5 < 0.1 < 0.001 Growth Plates 11.5–12.5 < 0.1 < 0.001 Bone Marrow 11.5–12.5 0.1–0.5 < 0.001 Kidneys 11.5–12.5 2.0–4.5 < 0.001 Liver 11.5–12.5 1.0–2.5 < 0.001 Discussion This study presents the rationale and design for the first systematic dosimetric comparison of TBI and Lu-177-DOTATATE in pediatric neuroblastoma. The central hypothesis—that Lu-177-DOTATATE delivers substantially lower absorbed doses to developmentally sensitive organs—is strongly supported by the existing literature and constitutes the primary clinical motivation for this work. The severe long-term sequelae of TBI in children are well documented. Studies have shown that children treated with TBI-containing conditioning regimens experience significantly greater growth retardation, neurocognitive deficits, and endocrine dysfunction compared to those receiving chemotherapy-only conditioning [ 4 , 5 ]. Specifically, TBI delivers near-uniform doses of 10–14 Gy to the entire body, including the developing brain, growth plate cartilage, and bone marrow. In a growing child, these doses are associated with permanent impairment of multiple organ systems. In contrast, Lu-177-DOTATATE therapy is characterized by targeted delivery of beta radiation to SSTR2-expressing tumor cells, with substantially lower doses to non-target organs. The dose-limiting organ for Lu-177-DOTATATE is the kidney, which typically receives 2.0–5.0 Gy per cycle [ 12 ]. Crucially, the brain and growth plates—the organs most vulnerable to TBI-related developmental toxicity—receive negligible doses from Lu-177-DOTATATE, as they do not express significant SSTR2 and the beta particle range in tissue is limited to approximately 2 mm. The LuDO trial, conducted at University College London Hospitals, demonstrated that Lu-177-DOTATATE is safe and feasible in children with relapsed or refractory high-risk neuroblastoma [ 8 ]. The subsequent LuDO-N multicenter trial, coordinated by Karolinska University Hospital, builds upon this experience with an intensified dosing schedule designed to maximize anti-tumor efficacy while maintaining cumulative dose constraints [ 9 ]. Our study complements these clinical efforts by providing dosimetric context: while those trials assess clinical response and toxicity, we quantify the comparative radiation burden to specific organs in the context of a direct head-to-head comparison with TBI. An important consideration is that Lu-177-DOTATATE is only effective in tumors expressing adequate SSTR2. Patient selection via 68Ga-DOTATATE PET/CT is therefore a prerequisite for therapy. Previous studies suggest that a significant proportion of neuroblastomas express SSTR2, although expression may be heterogeneous within and between tumors [ 13 ]. This heterogeneity could limit the universal applicability of Lu-177-DOTATATE as a TBI substitute and will need to be addressed in future clinical guidelines. The current study has several limitations that should be acknowledged. First, as a dosimetric study, it does not directly assess clinical outcomes such as tumor response, progression-free survival, or overall survival. Dosimetric findings must therefore be interpreted alongside clinical efficacy data from parallel trials. Second, the relatively small expected sample size limits statistical power for subgroup analyses. Third, the use of TLDs for TBI dosimetry, while validated and widely used, introduces measurement uncertainty of approximately ± 5%. These limitations notwithstanding, the dosimetric comparison provides essential quantitative data to support evidence-based treatment decisions. From a broader perspective, the findings of this study have implications beyond neuroblastoma. The growing field of targeted radionuclide therapy is increasingly exploring the use of Lu-177 and other beta emitters as alternatives or complements to external beam radiotherapy in pediatric oncology. Demonstrating a substantially reduced dose burden to developing organs would strengthen the radiobiological case for this paradigm shift and could inform future clinical trial design, dosimetric guidelines, and regulatory submissions for pediatric use of Lu-177-labeled compounds. Conclusion This study is the first to systematically compare organ-specific absorbed doses between TBI and Lu-177-DOTATATE in pediatric neuroblastoma patients. We anticipate demonstrating that Lu-177-DOTATATE delivers substantially lower radiation doses to developmentally critical organs—including the brain, growth plates, and bone marrow—compared to TBI, while maintaining targeted anti-tumor activity in SSTR2-positive disease. These dosimetric findings are intended to provide the radiobiological evidence base for integrating Lu-177-DOTATATE into standard treatment protocols for pediatric neuroblastoma, with the goal of reducing long-term developmental toxicity without compromising therapeutic efficacy. Prospective clinical studies incorporating both dosimetric and outcomes data will be necessary to fully validate this approach. Declarations Conflicts of interest: None declared. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Acknowledgments The authors wish to thank the medical physics and nuclear medicine teams at [Institution] for their technical support. [Add any other acknowledgments here.] References Maris JM (2010) Recent advances in neuroblastoma. N Engl J Med 362(23):2202–2211 Matthay KK, Maris JM, Schleiermacher G et al (2016) Neuroblastoma Nat Rev Dis Primers 2:16078 Ladenstein R, Poetschger U, Luksch R et al (2017) Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma. Lancet Oncol 18(4):500–514 Cohen LE, Gordon JH, Popovsky EY et al (2014) Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma. Bone Marrow Transpl 49(4):502–508 Esiashvili N, Chiang KY, Hassell L et al (2022) Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation. Pediatr Blood Cancer 69(3):e29427 Hennrich U, Kopka K (2019) Lutathera: the first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals 12(3):114 Strosberg J, El-Haddad G, Wolin E et al (2017) Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 376(2):125–135 Gains JE, Bomanji JB, Fersht NL et al (2011) 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med 52(7):1041–1047 Sundquist F, Georgantzi K, Jarvis KB et al (2022) A phase II trial of a personalized, dose-intense administration schedule of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma–LuDO-N. Front Pediatr 10:836230 Stenman J et al (2026) LuDO-N Trial. ClinicalTrials.gov Identifier: NCT04903899. Accessed May Bolch WE, Eckerman KF, Sgouros G, Thomas SR (2009) MIRD pamphlet 21: a generalized schema for radiopharmaceutical dosimetry. J Nucl Med 50(3):477–484 Bergsma H, Konijnenberg MW, van der Zwan WA et al (2016) Nephrotoxicity after PRRT with 177Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 43(10):1802–1811 Feijtel D, Doeswijk GN, Verkaik NS et al (2021) Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response. Theranostics 11(2):491–505 Kwekkeboom DJ, de Herder WW, Kam BL et al (2008) Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. J Clin Oncol 26(13):2124–2130 Strosberg JR, Caplin ME, Kunz PL et al (2021) Final overall survival and long-term safety results from the NETTER-1 trial. Lancet Oncol 22(12):1752–1763 Hicks RJ, Kwekkeboom DJ, Krenning E et al (2017) ENETS Consensus Guidelines for PRRT with radiolabeled somatostatin analogs. Neuroendocrinology 105(3):295–309 Bergsma H, van Lom K, Raaijmakers MHGP et al (2018) Persistent hematological dysfunction after PRRT with 177Lu-DOTATATE. J Nucl Med 59(3):452–458 Dasari A, Shen C, Halperin D et al (2017) Trends in incidence, prevalence, and survival in neuroendocrine tumors in the United States. JAMA Oncol 3(10):1335–1342 Brabander T, van der Zwan WA, Teunissen JJM et al (2017) Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 23(16):4617–4624 Pavel M, Oberg K, Falconi M et al (2020) Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines. Ann Oncol 31(7):844–860 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9621891","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":635000112,"identity":"c2e123ca-c73c-4c6e-a90d-8e6afe6493e8","order_by":0,"name":"Sevgi Ölmez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYLCCBAYGGRhbDkQceECEFh4Y2xisJYEIi+BaEhughuAE8u09xi8eMNjw6La3P2Cu+FOXPj/s8EOgLXZyug3YtRicOWNmkcCQxmN25kAC49m2w7kbb6cZALUkG5sdwKFFIi3NIIHhMI/ZjYQDjI0NB3I3zk4AaTmQuA2HFvn5z6Ba7j9sYGwAOsxwdvoHvFoYbjAffgCxhZmBsYGNOUFeOge/LQZnko8xJBiA/JLGcLCx7bDhBumcggMJBrj9It9+sPnjjwobObPjxx8+BDpMXn52+uYPHyrs5HBpAQI2CQYDCAusxgBC4lQOAswfUO1twKt6FIyCUTAKRiAAAMoDYnRU/NLCAAAAAElFTkSuQmCC","orcid":"","institution":"Insture of Nuclear Science","correspondingAuthor":true,"prefix":"","firstName":"Sevgi","middleName":"","lastName":"Ölmez","suffix":""}],"badges":[],"createdAt":"2026-05-05 18:26:49","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9621891/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9621891/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108806039,"identity":"5602c3ea-bea6-4adb-801c-61d2b149d92a","added_by":"auto","created_at":"2026-05-08 15:27:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":153278,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9621891/v1/8a80a5c0-9d87-4e41-89aa-954b0ba35029.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eComparison of Total Body Irradiation and Lu-177-DOTATATE Therapy in Pediatric Neuroblastoma: A Dosimetric Analysis of Organ-Specific Radiation Doses\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuroblastoma is the most common extracranial solid malignancy in children, accounting for approximately 6\u0026ndash;10% of all childhood cancers and nearly 15% of pediatric cancer-related mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It arises from neural crest cells of the developing sympathetic nervous system, most frequently in the adrenal medulla, and is classified as a neuroendocrine tumor. While localized disease is often curable with surgery, disseminated high-risk neuroblastoma continues to carry a poor prognosis despite multimodal treatment approaches including high-dose chemotherapy, autologous stem cell transplantation (ASCT), radiation, and immunotherapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTotal body irradiation (TBI) has historically been used as part of myeloablative conditioning regimens prior to ASCT in high-risk neuroblastoma. By delivering a uniform radiation dose to the entire body, TBI aims to eradicate residual tumor cells and achieve immunosuppression for engraftment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, TBI is associated with substantial long-term toxicities, which are particularly severe in the pediatric population. These include growth hormone deficiency, hypothyroidism, neurocognitive impairment, microcephaly, skeletal growth arrest, cataracts, pulmonary fibrosis, and an increased risk of secondary malignancies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recognizing these consequences, contemporary treatment protocols have moved toward TBI-free conditioning regimens; however, TBI continues to be used in selected patients with disseminated disease.\u003c/p\u003e \u003cp\u003eLutetium-177 (Lu-177) is a beta-emitting radionuclide with a physical half-life of 6.7 days and gamma emission energies of 113 keV and 208 keV, making it suitable for both therapeutic and imaging purposes. When conjugated to somatostatin analogs such as DOTATATE, Lu-177 selectively targets somatostatin receptor type 2 (SSTR2)-expressing cells, enabling targeted molecular radiotherapy with a more favorable organ dose profile than external beam radiation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Lu-177-DOTATATE (Lutathera\u0026reg;) has been approved by the FDA and EMA for the treatment of SSTR2-positive gastroenteropancreatic neuroendocrine tumors in adults following the landmark NETTER-1 trial [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeuroblastoma cells frequently express SSTR2, providing a rationale for targeting them with Lu-177-DOTATATE. Early clinical experience with Lu-177-DOTATATE in pediatric neuroblastoma demonstrated the safety and feasibility of this approach [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Subsequent clinical trials, including the LuDO and LuDO-N studies, have built upon this foundation, exploring optimized dosing schedules in relapsed and refractory cases [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Despite these advances, a systematic dosimetric comparison between TBI and Lu-177-DOTATATE\u0026mdash;specifically with regard to absorbed doses in developmentally critical organs in children\u0026mdash;has not yet been reported in the literature.\u003c/p\u003e \u003cp\u003eThis gap is clinically significant. Dosimetric evidence is essential to justify the substitution of one treatment modality for another, particularly in a vulnerable pediatric population where developmental toxicities may have lifelong consequences. The present study addresses this gap by performing a direct organ-specific dosimetric comparison between TBI and Lu-177-DOTATATE in pediatric neuroblastoma patients. We hypothesize that Lu-177-DOTATATE delivers significantly lower absorbed doses to growth-sensitive organs\u0026mdash;including the brain, growth plates, and bone marrow\u0026mdash;compared to TBI, while maintaining relevant anti-tumor activity.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Ethical Approval\u003c/h2\u003e \u003cp\u003eThis study is designed as a prospective, comparative dosimetric analysis conducted at [Institution Name]. Ethical approval will be obtained from the institutional ethics committee prior to patient enrollment. All procedures will be performed in accordance with the Declaration of Helsinki and applicable national regulations. Written informed consent will be obtained from patients' parents or legal guardians.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient Selection\u003c/h3\u003e\n\u003cp\u003eTwo patient cohorts will be enrolled:\u003c/p\u003e \u003cp\u003eCohort A (TBI group): Pediatric patients (age 18 months\u0026ndash;18 years) with high-risk neuroblastoma scheduled to receive TBI as part of myeloablative conditioning prior to ASCT, in accordance with institutional protocols.\u003c/p\u003e \u003cp\u003eCohort B (Lu-177-DOTATATE group): Pediatric patients (age 18 months\u0026ndash;18 years) with relapsed or refractory high-risk neuroblastoma who demonstrate adequate SSTR2 expression on 68Ga-DOTATATE PET/CT (uptake equal to or greater than liver background) and are scheduled to receive Lu-177-DOTATATE therapy.\u003c/p\u003e \u003cp\u003eExclusion criteria for both cohorts include: prior radiation therapy to more than two body regions, renal insufficiency (GFR\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73 m\u0026sup2;), active second malignancy, or inability to provide informed consent.\u003c/p\u003e\n\u003ch3\u003eTBI Dosimetry\u003c/h3\u003e\n\u003cp\u003eTBI will be delivered using a standard linear accelerator protocol at [Institution]. Dosimetric assessment will be performed using calibrated thermoluminescent dosimeters (TLDs) placed at anatomical sites corresponding to the brain, cervical/lumbar spine growth plates, sternum (bone marrow surrogate), kidneys, and liver. TLD readings will be obtained following each TBI fraction and summed to calculate total absorbed dose per organ. Dose homogeneity will be evaluated across measurement sites. All TLD measurements will be performed by a certified medical physicist.\u003c/p\u003e\n\u003ch3\u003eLu-177-DOTATATE Dosimetry\u003c/h3\u003e\n\u003cp\u003eLu-177-DOTATATE will be administered as weight-based activity (200 MBq/kg) per cycle, with dosimetric imaging performed following each administration. Whole-body planar scintigraphy will be acquired at 4, 24, and 96 hours post-injection. SPECT/CT imaging of the abdomen, thorax, and skull will be performed at the 24-hour time point. Organ-absorbed doses will be calculated using the Medical Internal Radiation Dose (MIRD) schema [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], with time-integrated activity coefficients derived from multi-time-point imaging. Dosimetric software (HERMES HybridViewer with OLINDA/EXM v2.1) will be used for absorbed dose calculations, utilizing age-appropriate pediatric phantoms.\u003c/p\u003e\n\u003ch3\u003eOrgan Dose Comparison\u003c/h3\u003e\n\u003cp\u003eThe primary dosimetric endpoints are absorbed doses (Gy) to the following organs: brain, growth plates (proximal femur and lumbar vertebral endplates as surrogates), active bone marrow, kidneys, and liver. Doses from both cohorts will be expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and compared using the Mann-Whitney U test (non-parametric), given the expected small sample sizes. A p-value of \u0026lt;\u0026thinsp;0.05 will be considered statistically significant. All statistical analyses will be performed using SPSS v26 (IBM, Armonk, NY, USA).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSample Size\u003c/h2\u003e \u003cp\u003eBased on existing literature and available patient populations at our institution, we estimate enrollment of 10\u0026ndash;15 patients per cohort over an 18-month period. Given the exploratory nature of this dosimetric study, formal power calculations were not performed; however, this sample size is consistent with similar published dosimetric feasibility studies in pediatric nuclear medicine.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient enrollment and data collection are currently ongoing. The expected results and preliminary hypotheses are outlined below to provide context for the study design and to facilitate peer review of the methodology.\u003c/p\u003e\n\u003ch3\u003ePatient Characteristics\u003c/h3\u003e\n\u003cp\u003eWe anticipate enrolling patients with a median age of [X] years (range: 18 months\u0026ndash;18 years), with a male-to-female ratio of approximately 1.5:1, consistent with published epidemiological data on high-risk neuroblastoma. All patients in Cohort B are expected to demonstrate adequate SSTR2 expression on pre-treatment 68Ga-DOTATATE PET/CT.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTBI Organ Doses\u003c/h2\u003e \u003cp\u003eTBI is expected to deliver near-uniform whole-body doses of 12 Gy (fractionated, 2 Gy per fraction \u0026times; 6 fractions) based on institutional protocol. TLD measurements are anticipated to confirm doses within \u0026plusmn;\u0026thinsp;10% of the prescribed dose at all measurement sites, including the brain (expected: 11.5\u0026ndash;12.5 Gy), growth plates (expected: 11.5\u0026ndash;12.5 Gy), and bone marrow (expected: 11.5\u0026ndash;12.5 Gy).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLu-177-DOTATATE Organ Doses\u003c/h2\u003e \u003cp\u003eBased on existing pediatric dosimetric data from the LuDO trial and related studies, Lu-177-DOTATATE is expected to deliver considerably lower absorbed doses to non-target organs compared to TBI. Estimated organ doses per cycle are: kidneys (2.0\u0026ndash;4.5 Gy, the dose-limiting organ), bone marrow (0.1\u0026ndash;0.5 Gy), liver (1.0\u0026ndash;2.5 Gy), brain (\u0026lt;\u0026thinsp;0.1 Gy), and growth plates (\u0026lt;\u0026thinsp;0.1 Gy).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eComparative Dosimetric Analysis\u003c/h2\u003e \u003cp\u003eThe primary expected finding is a statistically significant reduction in absorbed doses to the brain, growth plates, and bone marrow in Cohort B compared to Cohort A. This difference is expected to be most pronounced for brain and growth plate doses, where TBI delivers approximately 12 Gy versus \u0026lt;\u0026thinsp;0.1 Gy for Lu-177-DOTATATE\u0026mdash;a difference of more than two orders of magnitude. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the expected comparative dosimetric data.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eExpected organ-absorbed doses for TBI versus Lu-177-DOTATATE\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrgan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTBI Dose (Gy)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLu-177 Dose (Gy/cycle)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExpected p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.5\u0026ndash;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth Plates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.5\u0026ndash;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone Marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.5\u0026ndash;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.1\u0026ndash;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidneys\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.5\u0026ndash;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.0\u0026ndash;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.5\u0026ndash;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026ndash;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents the rationale and design for the first systematic dosimetric comparison of TBI and Lu-177-DOTATATE in pediatric neuroblastoma. The central hypothesis\u0026mdash;that Lu-177-DOTATATE delivers substantially lower absorbed doses to developmentally sensitive organs\u0026mdash;is strongly supported by the existing literature and constitutes the primary clinical motivation for this work.\u003c/p\u003e \u003cp\u003eThe severe long-term sequelae of TBI in children are well documented. Studies have shown that children treated with TBI-containing conditioning regimens experience significantly greater growth retardation, neurocognitive deficits, and endocrine dysfunction compared to those receiving chemotherapy-only conditioning [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Specifically, TBI delivers near-uniform doses of 10\u0026ndash;14 Gy to the entire body, including the developing brain, growth plate cartilage, and bone marrow. In a growing child, these doses are associated with permanent impairment of multiple organ systems.\u003c/p\u003e \u003cp\u003eIn contrast, Lu-177-DOTATATE therapy is characterized by targeted delivery of beta radiation to SSTR2-expressing tumor cells, with substantially lower doses to non-target organs. The dose-limiting organ for Lu-177-DOTATATE is the kidney, which typically receives 2.0\u0026ndash;5.0 Gy per cycle [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Crucially, the brain and growth plates\u0026mdash;the organs most vulnerable to TBI-related developmental toxicity\u0026mdash;receive negligible doses from Lu-177-DOTATATE, as they do not express significant SSTR2 and the beta particle range in tissue is limited to approximately 2 mm.\u003c/p\u003e \u003cp\u003eThe LuDO trial, conducted at University College London Hospitals, demonstrated that Lu-177-DOTATATE is safe and feasible in children with relapsed or refractory high-risk neuroblastoma [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The subsequent LuDO-N multicenter trial, coordinated by Karolinska University Hospital, builds upon this experience with an intensified dosing schedule designed to maximize anti-tumor efficacy while maintaining cumulative dose constraints [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our study complements these clinical efforts by providing dosimetric context: while those trials assess clinical response and toxicity, we quantify the comparative radiation burden to specific organs in the context of a direct head-to-head comparison with TBI.\u003c/p\u003e \u003cp\u003eAn important consideration is that Lu-177-DOTATATE is only effective in tumors expressing adequate SSTR2. Patient selection via 68Ga-DOTATATE PET/CT is therefore a prerequisite for therapy. Previous studies suggest that a significant proportion of neuroblastomas express SSTR2, although expression may be heterogeneous within and between tumors [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This heterogeneity could limit the universal applicability of Lu-177-DOTATATE as a TBI substitute and will need to be addressed in future clinical guidelines.\u003c/p\u003e \u003cp\u003eThe current study has several limitations that should be acknowledged. First, as a dosimetric study, it does not directly assess clinical outcomes such as tumor response, progression-free survival, or overall survival. Dosimetric findings must therefore be interpreted alongside clinical efficacy data from parallel trials. Second, the relatively small expected sample size limits statistical power for subgroup analyses. Third, the use of TLDs for TBI dosimetry, while validated and widely used, introduces measurement uncertainty of approximately\u0026thinsp;\u0026plusmn;\u0026thinsp;5%. These limitations notwithstanding, the dosimetric comparison provides essential quantitative data to support evidence-based treatment decisions.\u003c/p\u003e \u003cp\u003eFrom a broader perspective, the findings of this study have implications beyond neuroblastoma. The growing field of targeted radionuclide therapy is increasingly exploring the use of Lu-177 and other beta emitters as alternatives or complements to external beam radiotherapy in pediatric oncology. Demonstrating a substantially reduced dose burden to developing organs would strengthen the radiobiological case for this paradigm shift and could inform future clinical trial design, dosimetric guidelines, and regulatory submissions for pediatric use of Lu-177-labeled compounds.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study is the first to systematically compare organ-specific absorbed doses between TBI and Lu-177-DOTATATE in pediatric neuroblastoma patients. We anticipate demonstrating that Lu-177-DOTATATE delivers substantially lower radiation doses to developmentally critical organs\u0026mdash;including the brain, growth plates, and bone marrow\u0026mdash;compared to TBI, while maintaining targeted anti-tumor activity in SSTR2-positive disease. These dosimetric findings are intended to provide the radiobiological evidence base for integrating Lu-177-DOTATATE into standard treatment protocols for pediatric neuroblastoma, with the goal of reducing long-term developmental toxicity without compromising therapeutic efficacy. Prospective clinical studies incorporating both dosimetric and outcomes data will be necessary to fully validate this approach.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eConflicts of interest:\u003c/strong\u003e \u003cp\u003eNone declared.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThe authors wish to thank the medical physics and nuclear medicine teams at [Institution] for their technical support. [Add any other acknowledgments here.]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMaris JM (2010) Recent advances in neuroblastoma. N Engl J Med 362(23):2202\u0026ndash;2211\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatthay KK, Maris JM, Schleiermacher G et al (2016) Neuroblastoma Nat Rev Dis Primers 2:16078\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLadenstein R, Poetschger U, Luksch R et al (2017) Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma. Lancet Oncol 18(4):500\u0026ndash;514\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen LE, Gordon JH, Popovsky EY et al (2014) Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma. Bone Marrow Transpl 49(4):502\u0026ndash;508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsiashvili N, Chiang KY, Hassell L et al (2022) Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation. Pediatr Blood Cancer 69(3):e29427\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHennrich U, Kopka K (2019) Lutathera: the first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals 12(3):114\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrosberg J, El-Haddad G, Wolin E et al (2017) Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 376(2):125\u0026ndash;135\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGains JE, Bomanji JB, Fersht NL et al (2011) 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med 52(7):1041\u0026ndash;1047\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSundquist F, Georgantzi K, Jarvis KB et al (2022) A phase II trial of a personalized, dose-intense administration schedule of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma\u0026ndash;LuDO-N. Front Pediatr 10:836230\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStenman J et al (2026) LuDO-N Trial. ClinicalTrials.gov Identifier: NCT04903899. Accessed May\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBolch WE, Eckerman KF, Sgouros G, Thomas SR (2009) MIRD pamphlet 21: a generalized schema for radiopharmaceutical dosimetry. J Nucl Med 50(3):477\u0026ndash;484\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergsma H, Konijnenberg MW, van der Zwan WA et al (2016) Nephrotoxicity after PRRT with 177Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 43(10):1802\u0026ndash;1811\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeijtel D, Doeswijk GN, Verkaik NS et al (2021) Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response. Theranostics 11(2):491\u0026ndash;505\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwekkeboom DJ, de Herder WW, Kam BL et al (2008) Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. J Clin Oncol 26(13):2124\u0026ndash;2130\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrosberg JR, Caplin ME, Kunz PL et al (2021) Final overall survival and long-term safety results from the NETTER-1 trial. Lancet Oncol 22(12):1752\u0026ndash;1763\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHicks RJ, Kwekkeboom DJ, Krenning E et al (2017) ENETS Consensus Guidelines for PRRT with radiolabeled somatostatin analogs. Neuroendocrinology 105(3):295\u0026ndash;309\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergsma H, van Lom K, Raaijmakers MHGP et al (2018) Persistent hematological dysfunction after PRRT with 177Lu-DOTATATE. J Nucl Med 59(3):452\u0026ndash;458\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDasari A, Shen C, Halperin D et al (2017) Trends in incidence, prevalence, and survival in neuroendocrine tumors in the United States. JAMA Oncol 3(10):1335\u0026ndash;1342\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrabander T, van der Zwan WA, Teunissen JJM et al (2017) Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 23(16):4617\u0026ndash;4624\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePavel M, Oberg K, Falconi M et al (2020) Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines. Ann Oncol 31(7):844\u0026ndash;860\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lu-177-DOTATATE, neuroblastoma, total body irradiation, pediatric dosimetry, radionuclide therapy, somatostatin receptor","lastPublishedDoi":"10.21203/rs.3.rs-9621891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9621891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjective: Neuroblastoma is the most common extracranial solid tumor in children. In disseminated disease, total body irradiation (TBI) remains part of conditioning regimens; however, it is associated with severe long-term sequelae including microcephaly, neurocognitive impairment, and skeletal growth arrest. Lu-177-DOTATATE has emerged as a promising molecular radiotherapy option for pediatric neuroblastoma. This study aims to perform a direct dosimetric comparison of TBI and Lu-177-DOTATATE with respect to radiation doses delivered to developmentally critical organs in pediatric patients.\u003c/p\u003e\n\u003cp\u003eMethods: Pediatric patients undergoing TBI as part of myeloablative conditioning and patients receiving Lu-177-DOTATATE for relapsed or refractory high-risk neuroblastoma will be enrolled following ethical approval. Dosimetric evaluation will include organ-absorbed dose calculations for the brain, growth plates, bone marrow, kidneys, and liver. TBI dosimetry will be assessed using thermoluminescent dosimeters (TLDs), and Lu-177 dosimetry will be performed using SPECT/CT-based quantification with the MIRD schema.\u003c/p\u003e\n\u003cp\u003eExpected Results: We hypothesize that Lu-177-DOTATATE delivers significantly lower absorbed doses to developmentally sensitive organs compared to TBI, while maintaining comparable anti-tumor efficacy in somatostatin receptor-positive neuroblastoma. Quantitative dosimetric data will be presented per organ and compared between the two modalities.\u003c/p\u003e\n\u003cp\u003eConclusion: This dosimetric analysis is intended to provide radiobiological evidence supporting the integration of Lu-177-DOTATATE into standard pediatric oncology protocols as a safer alternative to TBI, particularly for patients with disseminated neuroblastoma expressing somatostatin receptor type 2.\u003c/p\u003e","manuscriptTitle":"Comparison of Total Body Irradiation and Lu-177-DOTATATE Therapy in Pediatric Neuroblastoma: A Dosimetric Analysis of Organ-Specific Radiation Doses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-07 08:26:45","doi":"10.21203/rs.3.rs-9621891/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e904fec9-ffba-4142-943e-d243c3fb6851","owner":[],"postedDate":"May 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67583159,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2026-05-07T08:26:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-07 08:26:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9621891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9621891","identity":"rs-9621891","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}