FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
New clinical practice guidelines for the treatment of Cushing’s syndrome stress coordinated care and patient involvement, and solidify an evidence-based treatment path for surgical and medical treatment options. The Endocrine Society released the guidelines, which were developed in conjunction with the European Society of Endocrinology ( J Clin Endocrinol Metab. 2015 Aug;100[8]:2807-2831 ).
Dr. Lynette Nieman, chair of the task force that developed the guidelines, commented in an interview that the guidelines don’t really contain new or controversial elements, but they do help clarify existing best practices. “This is not a common diagnosis, but it is very important to understand how to handle this disorder,” said Dr. Nieman of the program in reproductive and adult endocrinology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md. “Cushing’s syndrome really needs to be treated with a team approach and by expert surgeons and expert endocrinologists,” she said.
In establishing treatment goals, the guidelines emphasize clinically based treatment, only recommending normalization of cortisol levels or action when overt Cushing’s syndrome (CS) and an established diagnosis exist (grade 1 recommendation). “Surgical resection of the causal lesion(s) is generally the first-line approach,” said Dr. Nieman and coauthors (grade 1 recommendation). Medical management of comorbidities and sequelae of hypercortisolism should always accompany any medical or surgical treatment. The guidelines also provide for emergent surgical or medical management of hypercortisolism if life-threatening complications are present (grade 1 recommendation).
Adjunctive management is directed at a patient-centered, multidisciplinary approach to address potential cortisol-dependent comorbidities. These may include hypertension and dyslipidemia, diabetes, electrolyte disturbances, increased infection risk, osteoporosis and deconditioning, and psychiatric illnesses (ungraded best practice recommendation). Additionally, the guidelines recommend perioperative prophylaxis for venous thromboembolism for CS patients (grade 2 recommendation).
For Cushing’s disease (CD), the guidelines recommend excision of ectopic and adrenal lesions, barring contraindications or low likelihood of successful surgery, with unilateral adrenal resection by an experienced adrenal surgeon recommended in benign unilateral disease. Ectopic adrenocorticotropic hormone (ACTH)–secreting tumors should be resected, with local node dissection as appropriate. Transsphenoidal selective adenomectomy is the recommended treatment for CD in adults and children, and should be performed by an experienced pituitary surgeon. Serum sodium should be measured several times during the first 2 weeks after surgery, and free T4 and prolactin by no more than 2 weeks after surgery (all grade 1 recommendations).
The task force recommends an MRI by 3 months after transsphenoidal surgery (ungraded best practice recommendation). When adrenal disorders are bilateral, the task force recommends surgical resection and medical therapy to block aberrant hormone receptors (grade 2 recommendation).
Carrying through the theme of an individualized, patient-centered approach, the task force recommends individualized postoperative management depending on postoperative cortisol levels. Persistent and overt postsurgical hypercortisolism should be treated, while patients with eucortisolism should have serum or salivary cortisol measured late at night. Patients with ACTH-dependent CS should be screened for recurrence of hypercortisolism (all grade 1 recommendations).
Glucocorticoid replacement, when required for hypocortisolemic patients, should be accompanied by appropriate patient education. When patients have an intact adrenal gland remaining, hypothalamic-pituitary-adrenal (HPA) axis recovery should be assessed at follow-up, so glucocorticoids can be stopped when recovery occurs. Other pituitary hormone deficiencies may occur, and care should include assessing the need to treat these deficiencies as well (all grade 1 recommendations).
In the difficult cases where surgery is not possible or does not cure ACTH-dependent CS, shared patient decision making is recommended to choose among the various second-line therapies that may be of benefit (grade 2 recommendation).
Therapy choices may include bilateral adrenalectomy, reserved for occult or metastatic ectopic ACTH secretion, or in an emergency situation where the procedure may be lifesaving (grade 2 recommendation); repeat transsphenoidal surgery when imaging or the clinical picture points to a new lesion or incomplete resection (grade 2 recommendation); radiation therapy or radiosurgery for those who fail transsphenoidal surgery or whose CD recurs, or where mass effect may be of concern (grade 1-2 recommendations; and medical treatment with steroidogenesis inhibitors in limited circumstances (grade 1 recommendation).
Specific medical treatment recommendations include the use of steroidogenesis inhibitors after transsphenoidal surgery for patients with CD or to treat occult or metastatic cases of ectopic ACTH secretion, and as an adjunct in adrenocortical carcinoma (grade 1 recommendation). The task force, in the discussion accompanying the guidelines, lists pros and cons of the various medical choices in order to present a balanced view of medical treatment options, said Dr. Nieman.
The long-term follow-up of individuals with CS should include screening and treating for the comorbidities that may persist even after successful surgery. Follow-up should be lifelong, with each comorbidity followed to resolution and ongoing vigilance for recurrence (except in patients with successfully resected low-attenuation adrenal adenomas – grade 1 recommendation).
In an interview, Dr. Rebecca S. Sippel of the University of Wisconsin–Madison brought an endocrine surgeon’s perspective to the guidelines, agreeing that the document generally reflects accepted practice. She also agreed that the interdisciplinary approach advocated by the task force is critical. “It’s important that discharge planning is done in a systematic way, so there’s systematic follow-up of patients after excision,” she said. She noted that CS patients on her service all receive an endocrine consult while they are inpatients to ensure adequate discharge planning.
Future research directions recommended by Dr. Nieman and the task force coauthors include identification of markers that will “explain the variable clinical effect of steroids among individuals,” with the goal of achieving better quantification of treatment effect and tracking response and remission. Health care–related quality of life is negatively affected by CS even after resolution to eucortisolism in many patients, so the guidelines recommend further research into quality of life and cognitive problems experienced by individuals with CS. Dr. Nieman specifically called for more multisite research, noting that diagnoses of Cushing’s disease and Cushing’s syndrome are rare, and etiologies are varied. “In order to get the numbers we need to do good research, we will need to cooperate,” she said.
All authors of the clinical practice guidelines had financial disclosures; a complete listing of disclosures and the task force’s methodology for resolving conflicts may be found in the downloadable guidelines .
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