Adrenal Insufficiency During Treatment With Immune-Checkpoint Inhibitors: How to Simplify the Diagnostic Pathway?

Objective and background: Early identification of adrenal insufficiency (AI) during immune-checkpoint inhibitors (ICIs) is crucial to prevent life-threatening consequences; however, the diagnosis is challenging.

Design, patients and measurement: In this prospective observational study, ICI-treated cancer patients with morning serum cortisol (SC) within the grey zone (83-414 nmol/L) were enroled. A low-dose adrenocorticotropic hormone (ACTH) stimulation test was performed to assess peak stimulated SC, preceded by re-evaluation of morning SC. The analysis aimed to refine morning SC cut-offs to minimize the diagnostic grey zone reducing the need for ACTH stimulation. To interpret the results of ACTH test, it was employed both the threshold for peak stimulated SC provided by the Endocrine Society guidelines (500 nmol/L) and an assay-specific cut-off for the Abbott platform recently proposed in literature (414 nmol/L). Moreover, the utility of salivary cortisol and cortisone upon awakening was explored.

Results: In 30 ICI-treated patients, a good positive correlation between morning and peak stimulated SC was confirmed (r = 0.72, p < 0.001); peak stimulated SC ≤ 500 nmol/L and ≤ 414 nmol/L was detected in 36.7% and 20% of subjects, respectively; all cases were secondary AI. ROC curve analysis identified optimal morning SC thresholds for AI prediction and exclusion (> 196 nmol/L and ≤ 397 nmol/L in case of pathological peak stimulated SC ≤ 500 nmol/L; > 163 nmol/L and ≤ 251 nmol/L in case of pathological peak stimulated SC ≤ 414 nmol/L). Salivary cortisol and cortisone upon awakening positively correlated with peak stimulated SC (r = 0.49 and r = 0.56, respectively, p < 0.01).

Conclusions: Morning SC is a reliable tool for the screening of ICI-related AI; the need for dynamic stimulation would be reduced by the application of assay-specific cut-offs. Salivary hormone analysis of cortisol and cortisone upon awakening may represent a viable alternative in selected cases.