Should Adrenal Glands be Spared in Radiotherapy? Evidence from Preliminary Clinical Observation and Translational Research

Abstract

Fatigue is a complicated syndrome associated with multiple factors. Development of fatigue after incidental radiotherapy (RT) to adrenal gland was observed in clinical practice. This study aimed to investigate the effect of adrenal RT on fatigue and related physiological impact. Three patients with inevitable RT to adrenal gland after standard optimization for intensity modulated RT were prospectively enrolled. Serum levels of cortisol, aldosterone, dehydroepiandrosterone sulfate (DHEA-S) and adrenocorticotropic hormone (ACTH) were measured before, during and after RT. Fatigue was scored according to validated Fatigue Severity Scale (FSS). Dosimetric parameters were collected by using RT planning systems. Balb/c mice were surgically explored for identification of left adrenal gland with sham operation as controls. Intra-operative RT was delivered by linear accelerator (IX, Varian, Palo Alto, CA) with electron beam (2-Gy single fraction, 6 MeV, 90%, dose rate: 400 MU/min). Exhausted swimming test was applied for endurance assessment to represent fatigue. Plasma levels of stress hormones and histopathological features were examined. In the enrolled patients, the RT dose to unilateral adrenal gland was 33.5 ± 11.8 Gy. The serum baseline (afternoon) cortisol levels declined from 10.4 ± 3.9 (pre-RT) to 5.8 ± 3.9 (interim RT) and 4.6 ± 2.1 (post-RT 1 week) μg/dL. Alterations in levels of morning cortisol and aldosterone showed a similar trend to baseline cortisol whereas the ACTH levels slightly increased, indicating a possible compensatory feedback from hypothalamic-pituitary-adrenal axis. In experimental mice model, the RT to unilateral adrenal gland decreased the time of maximal endurance swimming from 19.91 ± 0.09 to 14.8 ± 2.96 min. In histopathological assessment, the irradiated adrenal glands showed characteristic RT injury features in adrenal cortex including moderate hypertrophy, disorganization, cellular aggregates, increased vasculogenesis, condensed chromatin in nucleus and cytoplasmic swelling which were more prominent in zona fasciculata and medulla. The preliminary clinical observation with fatigue development and characteristic hormone alterations indicated that adrenal glands could be regarded as an organ at risk in RT. This observation was supported by experimental animal model with functional and histopathological evidence.