Radiation therapy in adolescents and young adults (AYA): contemporary evidence on utilization, outcomes, late toxicities, and second malignant neoplasms - A comprehensive systematic review and synthesis.
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Adolescent and young adult (AYA; 15-39 years) cancer survivors face decades of potential life-years, making radiotherapy (RT) modality and technique selection central determinants of long-term health. A PRISMA 2020-reported systematic review was performed using PubMed, Web of Science, and the Cochrane Library (January 2026). Data were synthesised qualitatively using a Synthesis Without Meta-analysis (SWiM) approach. The primary synthesis focused on RT utilization and late outcomes including late toxicity, survivorship morbidity, patient-reported outcomes, and secondary malignant neoplasms (SMN), and model-based estimates of SMN risk where available. Thirty-five primary studies were included in the qualitative synthesis. For tumours of the central nervous system (CNS) and skull base, proton beam therapy (PBT) showed high local control; anterior pituitary dysfunction was frequent (36.3 %), requiring anatomical interpretation. In AYA breast cancer, volumetric modulated arc therapy with a simultaneous integrated boost (VMAT-SIB) achieved a favourable early safety profile, with no reported cardiovascular events at a median follow-up of 86.5 months. In testicular seminoma, PBT significantly reduced acute gastrointestinal (GI) toxicity (0 % vs 29.5 % grade 1-2 diarrhoea, p = 0.039) and was associated with a 50-60 % lower model-estimated SMN risk. Modern RT techniques appear to reduce the burden of late effects in AYAs across the most frequently studied tumour sites. However, evidence on particle therapy for clinically relevant tumour sites, including sarcoma and breast cancer, remains scarce. While clinical safety is improving, the disparity between model-estimated risk and observed SMN latency necessitates long-term registry-based evaluation and standardised, site-specific organ-at-risk and substructure dosimetry to refine survivorship care.