Radiosurgery in recurrent and persistent Cushing's Disease: a Systematic Review and Meta-Analysis

Cushing's disease (CD) is a severe systemic metabolic disorder caused by elevated levels of cortisol sustained by a pituitary neuroendocrine tumor. Endoscopic trans-sphenoidal surgery (ETS) is the first-line treatment, but does not achieve disease remission in all patients. For patients with persistent or recurrent Cushing's disease, stereotactic radiosurgery (SRS) has been reported as an effective treatment option. This review and meta-analysis assesses the available evidence to systematically highlight the current strengths and limitations of SRS in the treatment of CD. In May 2025, following the PRISMA 2020 statement, a systematic review of Pubmed, Scopus, and Ovid was performed. Of 687 articles screened, 9 were considered eligible, describing a population of 341 patients. Most patients (90%) underwent a single dose of Gamma Knife SRS. The tumor control rate was 97.4% (95% CI: 95.2-99.6%). After a mean follow-up of 61.5 months after the latest SRS cycle, biochemical remission was achieved in 67.1% (95% CI: 58.5-75.7%) of cases in a mean time of 26.4 months. Recurrence post-SRS remission was documented in 21% of cases after a mean time of 39 months. New-onset hypopituitarism was observed in 29.9% of cases, visual impairment and other cranial nerve dysfunction in 1.8% (95% CI: 0.2-3.4%), and 1.9% (95% CI: 0.1-3.7%), respectively. No cases of radionecrosis were seen. After a single cycle of treatment, SRS effectively controls the disease in about half of patients affected by persistent or recurrent CD, with a low percentage of post-treatment complications. Based on the available literature, SRS emerges as a safe and effective treatment, and its implementation in common clinical practice may play a relevant role in the management of CD. Nevertheless, prospective and standardized studies are needed to thoroughly assess its real potential.