Are people with Cushing’s disease refractory to surgery and radiotherapy better served with long-term pharmacotherapy or bilateral adrenalectomy?
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If you can control the patient’s symptoms with medication, you can prolong their life as well as with bilateral adrenalectomy.
The Endocrine Society recommends medical management with a moderate level of evidence; in particular, steroidogenesis inhibitors as a second-line treatment after surgery for people with Cushing’s disease, either with or without radiotherapy, and as primary treatment for ectopic adrenocorticotropic hormone (ACTH) secretion. The guideline also recommends pituitary-directed medical treatments for patients who are not surgical candidates or who have persistent disease after surgery. The choice of medical therapy should be guided by efficacy, individual patient factors and cost.
Available drugs target three things. Therapies like ketoconazole, metyrapone (Metopirone, HRA Pharma) and mitotane (Lysodren, Bristol-Myers Squibb) target the adrenal. Pituitary-directed therapy, such as pasireotide (Signifor, Novartis), can shrink the tumor, and cabergoline is another option if cost is an issue, as is the glucocorticoid receptor-directed therapy mifepristone, to control the symptoms.
Surgery brings with it several complications, such as infection and bleeding. Bilateral adrenalectomy resolves the patient’s hypercortisolism; however, the pituitary tumor may continue to grow, leading to the development of Nelson’s syndrome. Additionally, bilateral adrenalectomy necessitates lifelong gluco- and mineralocorticoid replacement for the patient.
There are times when surgery is warranted. If the person has uncontrolled disease, high ACTH production or an extremely high excess of cortisol, or ectopic Cushing’s disease, surgery is better. However, anytime you put a person into adrenal insufficiency with bilateral adrenalectomy or with medication, life expectancy decreases approximately 5 years. If the patient has relapsed after surgery and radiation therapy, first, I start medication.
Other drug therapies for Cushing’s disease currently in the pipeline are going to further change the picture for patients in the coming years. This is something to be considered on a case-by-case basis. Evidence comparing medical therapy vs. bilateral adrenalectomy is low. This is a rare condition, and it is difficult to conduct a randomized controlled trial comparing one option vs. another. People can do very well on a therapy like mifepristone, and their symptoms — diabetes and hypertension — are well controlled, although potassium levels must be carefully monitored. For those with refractory disease with multiple comorbidities when cortisol production is high enough to cause damage, but not too high, medication is the better option.
Ricardo Correa, MD, EsD, FACE, FACP, CMQ, is program director of the endocrinology fellowship at the University of Arizona College of Medicine-Phoenix. Disclosure: Correa reports no relevant financial disclosures.
There is a window of opportunity where the patient has clearly proved that they are medically refractory and would benefit from surgery, but they are not too sick to undergo the surgery.
This situation also applies to people with neuroendocrine tumors producing ACTH and causing Cushing’s syndrome. In these cases, there is going to be continued cortisol production, really indefinitely, because we can’t cure the underlying disease. In those cases, it is important to first try treating with medical therapies; ketoconazole and metyrapone are usually the first-line treatments. Bilateral adrenalectomy is considered a somewhat drastic step, and it is not the immediate first step one should take.
That said, when we can’t control the Cushing’s for these patients, their mortality comes from the Cushing’s syndrome, not the underlying tumor in most cases. These people can live for decades with metastatic disease. The morbidity or mortality comes from the Cushing’s syndrome.
The benefit of surgery is it absolutely cures the Cushing’s syndrome because you no longer have the end organ producing the cortisol, and it is a fast resolution of the Cushing’s syndrome. Even as the disease progresses, you still have the Cushing’s under control forever. The major downsides are the risks that come with surgery for these already high-risk patients; however, there have been many advances in surgical techniques to decrease the surgical complications. I do the surgery laparoscopically with a retroperitoneal approach through the back. With this approach, we can remove both adrenal glands at the same time. The whole operation can take about 2 hours. This decreases risks for mortality and morbidity and makes surgery much more feasible. Of course, the downside is the patient no longer has adrenal glands and needs to be put on lifelong steroid therapy.
Timing is key. At our institution, we have monthly endocrine tumor boards where we discuss these cases with our endocrinologists, and that is always the question — what is the right window? If you don’t perform the surgery at the right time, the person becomes too sick from the Cushing’s syndrome. As much as we don’t want to jump to surgery too early, because it is so drastic and you have the downside of adrenal insufficiency, it is equally bad to wait too long. One has to strike that balance.
Masha Livhits, MD, FACS, is assistant professor of surgery in the section of endocrine surgery at UCLA. Disclosure: Livhits reports no relevant financial disclosures.