{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:11:58Z","timestamp":1792789918786,"version":"4.5.0"},"reference-count":72,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Background: Osteosarcoma remains a biologically complex and clinically challenging malignancy, with survival gains plateauing despite decades of multimodal therapy incorporating surgery and cytotoxic chemotherapy. Unlike cancers in which mutation-centric precision oncology has yielded transformative advances, osteosarcoma is characterized by profound structural variation, copy number alteration dominance, and dynamic clonal evolution, limiting the effectiveness of single-target approaches. These realities motivate alternative strategy-level frameworks that better align treatment selection with evolving disease behavior. Methods: This narrative educational review synthesizes contemporary evidence from osteosarcoma biology, radiobiology, and translational oncology to propose a state-based framework for integrating radiotherapy\u2014particularly stereotactic body radiotherapy (SBRT\/SABR) and spatially fractionated radiotherapy (SFRT)\u2014into osteosarcoma management and clinical trial design. Rather than relying solely on static anatomic stage, this framework emphasizes clinically actionable, time-varying state variables, including disease burden patterns (localized, oligometastatic, polymetastatic), tempo of progression, prior systemic response, and feasibility of complete local control. Results: Within this context, radiotherapy is presented not only as a local control modality but also as a hypothesis-generating biologic intervention, capable of perturbing tumor vasculature, inflammatory signaling, innate DNA-sensing pathways, and immune\/myeloid programs in a dose-, fractionation-, and spatial-distribution-dependent manner. The review critically examines both the potential opportunities (e.g., local eradication, immune modulation) and limitations (e.g., rarity of abscopal responses, risk of unintended systemic signaling) of radiobiotherapy combinations, emphasizing the need for cautious interpretation and prospective validation. Conclusions: Finally, the article outlines practical implications for state-stratified, biomarker-embedded clinical trials, highlighting endpoints beyond conventional response criteria, including circulating tumor DNA dynamics, immune and myeloid signatures, and long-term patterns of disease progression. Overall, this review frames radiobiotherapy as an educational and investigational paradigm intended to support rational hypothesis generation, multidisciplinary decision-making, and learning-oriented trial designs in osteosarcoma, rather than as definitive clinical guidance.<\/jats:p>","DOI":"10.3390\/curroncol33060342","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:25:16Z","timestamp":1780935916000},"page":"342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Radiobiotherapy in Osteosarcoma: A State-Based Educational Framework for Strategy Selection and Trial Design"],"prefix":"10.3390","volume":"33","author":[{"given":"Srinivasan","family":"Vijayakumar","sequence":"first","affiliation":[{"name":"Department of Radiology, Ochsner Clinic Foundation and Xavier Ochsner College of Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Radiation Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India"},{"name":"Cancer Care Advisors and Consultants, LLC, Ridgeland, MS 39157, USA"},{"name":"Mississippi Comprehensive Cancer Control Program, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Matrana","sequence":"additional","affiliation":[{"name":"The Gayle and Tom Benson Cancer Center, Jefferson, LA 70121, USA"},{"name":"Precision Medicine, Ochsner Health, Jefferson, LA 70121, USA"},{"name":"Physician Research Steering Committee and Physician Research Council, Lincoln, NE 68516, USA"},{"name":"Clinical Cancer Research, Ochsner MD Anderson Cancer Center, New Orleans, LA 70121, USA"},{"name":"Experimental Therapeutics, Ochsner Health, Houston, TX 77054, USA"},{"name":"Hematology and Oncology, Xavier Ochsner College of Medicine (XOCOM), New Orleans, LA 70112, USA"},{"name":"Faculty of Medicine, The University of Queensland Medical School, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Pediatric Stem Cell Transplant and Adolescent and Young Adult Cancer and Survivor Programs, Ochsner Health, New Orleans, LA 70112, USA"},{"name":"Division of Pediatric Hematology-Oncology, Ochsner Children\u2019s Hospital, New Orleans, LA 70118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshul","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Duesbery","sequence":"additional","affiliation":[{"name":"Research, Ochsner Health, Jefferson, LA 70121, USA"},{"name":"Ochsner Center for Outcomes Research, New Orleans, LA 70121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anderson B.","family":"Collier","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Nemours Children\u2019s Health, Jacksonville, FL 32207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Larned","sequence":"additional","affiliation":[{"name":"Clinical Cancer Research, Ochsner MD Anderson Cancer Center, New Orleans, LA 70121, USA"},{"name":"Hematology\/Oncology, Ochsner Health, New Orleans, LA 70121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3510-8962","authenticated-orcid":false,"given":"Jennifer","family":"Barr","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Rehabilitation, Orthopaedic Oncology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne R.","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Surgery, Surgical Oncology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9755-5672","authenticated-orcid":false,"given":"Mary R.","family":"Nittala","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vani","family":"Vijayakumar","sequence":"additional","affiliation":[{"name":"Nuclear Medicine, Diagnostic Radiology, Ochsner Health, New Orleans, LA 70115, USA"},{"name":"Ochsner Medical Center\u2014New Orleans, New Orleans, LA 70121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","unstructured":"PDQ Pediatric Treatment Editorial Board (2026, May 29). 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