Approach to the Cushing's disease patient with persistent/recurrent hypercortisolism after pituitary surgery.

Although it is the ideal treatment, pituitary surgery is not always successful, and success is not always lasting. Close surveillance, clinical and biological, will detect immediate failure or late recurrence. The reason must be thoroughly explored with the somewhat dogmatic rule that the patient should be offered the best surgery in expert hands, and a repeat surgical attempt must be systematically discussed. When repeat pituitary surgery is not indicated or has failed, then comes the difficult task to choose between a number of options directed toward different targets: directly suppress tumor ACTH by pituitary radiotherapy (conventional or stereotaxic) or with medications (somatostatin analog such as pasireotide, or dopaminergic drug such as cabergoline), directly suppress adrenocortical activity with medications (inhibitors of adrenal steroidogenesis such as ketoconazole or metyrapone, or the adrenolytic Lysodren), or by surgery (bilateral adrenalectomy), and finally oppose peripheral cortisol action with the antiglucocorticoid mifepristone. No single option is ideal, able to provide at the same time a high success rate and a rapid onset of action, to restore a normal pituitary adrenal axis, and to have good tolerability. Close follow-up and thorough evaluation of the cortisolic status will eventually dictate a switch in treatment options and/or combination strategies over time. The tumor status and its possible oncogenic threat, the severity of the hypercortisolism, and the patient perspectives (wish of fertility) are among the major parameters that can help a multidisciplinary approach toward the best option.