Management of patients with persistent or recurrent Cushing’s disease after initial pituitary surgery

ABSTRACT

Introduction

Treatment options for persistent and recurrent Cushing’s disease (CD) include an individualized approach for repeat surgery, medical treatment, radiation therapy (RT), and bilateral adrenalectomy (BLA).

Areas covered

In this expert opinion perspective, the authors review the latest treatment(s) for persistent/recurrent CD. A PubMed search was undertaken (English articles through May 2020) and relevant articles discussed. Repeat pituitary surgery should be considered in most patients with proven hypercortisolism; there is potential for cure with low risk of major complications. Medical therapy is valuable either alone, while awaiting the effects of RT, or in preparation for BLA. Medical therapy includes steroidogenesis inhibitors, agents that act at the pituitary or glucocorticoid receptor level, and novel agents in development. Radiation therapy has been used successfully to treat CD, but hypopituitarism risk and delayed efficacy (improved with radiosurgery) are major drawbacks. Laparoscopic BLA is safe and effective in patients with severe, difficult-to-manage hypercortisolism, but long-term follow-up is required as corticotroph tumor progression can develop.

Expert opinion

Treatment of persistent/recurrent CD is challenging. Most patients require >1 therapy to achieve long-lasting remission. There is currently no ideal single treatment option that provides high and rapid efficacy, low adverse effects, and preserves normal pituitary-adrenal axis function.

KEYWORDS:

• Cushing’s disease
• persistence
• recurrence
• repeat surgery
• radiotherapy
• medical therapy
• adrenalectomy

Article highlights

• Despite a high surgical success rate, at least a quarter of CD patients will experience recurrence (as measured by long follow-up periods).

• Repeat transsphenoidal surgery has a lower success rate than the initial surgery and should be considered in cases with proven persistent hypercortisolism. The availability of an expert neurosurgeon should be also taken into consideration. The incidence of major complications is low overall (with the exception of hypopituitarism).

• Medical therapy has been used successfully (some drugs are approved for use and some are used off-label, or are under investigation in clinical trials). Medical therapy includes steroidogenesis inhibitors (osilodrostat, ketoconazole, mitotane, metyrapone, and etomidate), pituitary-directed drugs (pasireotide, cabergoline, and temozolomide), glucocorticoid-receptors blockers (mifepristone), and numerous other novel agents that are in development.

• Radiation therapy is effective in achieving disease remission but with a high risk of hypopituitarism, delayed efficacy, and low but possible risks of other long-term consequences (such as cranial nerve neuropathies, cerebrovascular disease, and secondary tumor). There are no prospective studies that compare RT methods; however, use of radiosurgery is promising.

• Bilateral adrenalectomy is highly effective in patients with severe refractory hypercortisolism in whom rapid improvement is needed. However, there are concerns regarding immediate postoperative morbidity, adrenal insufficiency and possible development of Nelson syndrome, which collectively limit BLA widespread use. Additionally, long-term follow-up for early detection of Nelson syndrome is needed (for at least 7 years after BLA).

• Persistent/recurrent CD requires individualized and tailored clinical management by experienced multidisciplinary CD teams.

• Individual factors such as tumor and disease characteristics, comorbidities, and local resource availability are important considerations. Care in a Pituitary Center of Excellence is preferred for all CD patients, but especially for patients who fail initial pituitary surgery.

Acknowledgments

The authors wish to acknowledge editorial assistance received from Shirley McCartney, PhD, of Oregon Health & Science University.

Declaration of interest

M Fleseriu has received research funding to OHSU as a Principal Investigator from Novartis and Strongbridge Biopharma, and has received scientific consulting fees from Novartis and Strongbridge Biopharma. C Poiana has received research funding to Carol Davila University of Medicine and Pharmacy as a Principal Investigator from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.