Primary adrenal insufficiency in patients with bilateral adrenal metastases treated with curative ablative radiation therapy: A comprehensive review of literature and expert agreements for radiation practice

Abstract Background Bilateral adrenal metastases are rare but clinically significant. While stereotactic body radiotherapy (SBRT) provides excellent local control, the risk of post-treatment primary adrenal insufficiency (PAI) after bilateral irradiation remains poorly defined and lacks standardized management guidelines. Methods We performed a comprehensive literature review following PRISMA principles, using PubMed and Embase databases (January 1956 to June 2025). Studies including patients with bilateral adrenal metastases treated with radiotherapy, or unilateral irradiation in the setting of a solitary adrenal gland, were eligible. Data on treatment characteristics, incidence of PAI, diagnostic approaches, and management were extracted. In parallel, a multidisciplinary expert panel developed expert opinion–based practical recommendations for the screening, treatment, and follow-up of PAI. Results Thirty studies comprising 156 patients treated with bilateral adrenal irradiation (or irradiation of a solitary adrenal gland) were included. PAI was reported in 47 patients (30%), although systematic endocrine evaluation was performed in only a minority of studies, suggesting potential underestimation. Time to onset ranged from 3 to 30 months. Reporting of diagnostic work-up, management, and follow-up was highly heterogeneous, and treatment details were frequently lacking. No study identified reliable dosimetric predictors of PAI, and no association between radiation dose parameters and adrenal insufficiency was demonstrated. Conclusions PAI following bilateral adrenal radiotherapy is likely under-recognized and under-reported, with clinically meaningful incidence and potential life-threatening consequences. In the absence of robust data, systematic hormonal assessment, careful treatment planning, and structured long-term follow-up are essential. We propose practical, expert-based recommendations to guide clinical management, while emphasizing the need for prospective studies to better define incidence, risk factors, and optimal prevention strategies.