When a patient presents with obvious signs of Cushing’s that are confirmed with testing, treatment options can be fairly easy to choose.  Surgery is still the preferred first line of treatment to remove a tumor.  Having a patient whose case is clear to start with doesn’t necessarily mean they will get a one-and-done treatment though.  Research shows that recurrence rates are as high as 27% if patients are followed long enough, and this data comes from expert centers with highly trained doctors who have treated thousands of patients.  Based on that statistic alone, it would not be a waste of time to think about and develop a flexible plan for all the things that could happen after a first surgery.

The majority of patients reach remission and some even have issues with low cortisol after surgery, but many still recur.  This is concerning because even though patients in remission don’t seem to have a higher-than-normal mortality rate, those who experience recurrence see their chance of death increase almost five-fold.  In these cases, the next line of treatment is trickier and more of a complex decision – will the benefits outweigh the risks, and are the risks worth taking?  This is a highly individualized decision that can have a big range of consequences for the patient.  One factor to highlight is the importance of credible, science-backed sources of information to guide your decision-making process.  Personal reasons for choosing one (or two) approaches over the others are never exactly the same for any two patients, and yet the good advice from our peer group can remind us to consider certain real-life scenarios that might not always get addressed when discussing “what next” with a doctor.  We strongly encourage you to consider yourself in your world, as recommended by Dr. Harvey Cushing himself, and proactively become a partner in your healthcare to ensure your best outcome.

The following is pro and con information for some of the treatments available to us.  There is no way to accurately describe these in full detail without writing a book, so please explore each as it interests you.  Look things up online but try to stick to links that come from places of science, education, and medicine such as the NIH, Mayo Clinic, Endocrine Society, UCLA, Harvard, etc.

REPEATED TRANSSPHENOIDAL SURGERY

Pros: seems to be well-tolerated for those who can have it, effects tend to be immediate, provides the only chance for permanent tumor removal

Cons: steroids are usually required afterwards, patient might become hormonally deficient, surgeon might miss tumor cells, patient might not achieve long-term remission

BILATERAL ADRENALECTOMY

Pros: immediate remission from cortisol, usually permanent, well-tolerated, especially when done laparoscopically

Cons: risks of abdominal surgery, lifelong need for glucocorticoids (hydrocortisone) and mineralocorticoids (fludrocortisone), complications from Addison’s Disease and possibly Nelson’s Syndrome, recurrences rare but possible

RADIATION

There are two types of radiation: conventional and fractionated.  Conventional is a strong, one-time treatment.  Examples of this are radiosurgery with a linear accelerator, gamma knife, or proton beam.  Fractionated is radiotherapy over a longer period of time, usually involving a custom made mask to hold you in place during daily treatments.  There do not seem to be any direct comparisons between the two types of radiation at this time; conventional may be faster than fractional, but for Cushing’s there do not seem to be any real differences in outcomes.  Over many years, radiation seems to have a spectrum of 28-86% success rate for biochemical control, with tumor control at a higher rate of 80-100%.

Pros: well-tolerated, possibly a single treatment, tumor and cortisol control

Cons: delayed effectiveness, medication needed until radiation begins working, long-term risks such as pituitary deficiencies, damage to nearby tissue, and secondary tumors, possible but rare recurrence

Things get trickier when you consider the small number of available medical therapies.  Each has a unique personality and it’s likely that more than one will not be a good fit.  The patient and doctor must consider a number of things: severity and urgency of the illness, overall treatment goals, medical history and patient factors, drug-drug interactions, oral vs. injectable delivery, the side effect profile, and cost and availability of the drug.

MEDS THAT WORK AT THE PITUITARY LEVEL

Cabergoline (Dostinex, manufactured by Pfizer, also available as a generic) is fairly well-tolerated but does not seem to be effective in people with very high cortisol levels.  Cabergoline is mainly used for the treatment of prolactin-secreting pituitary tumors, but it has been shown to normalize cortisol levels in 20-40% of patients with Cushing’s. Unfortunately, the effects of cabergoline tend to wear off over time and cortisol levels rise despite continued treatment.

Pasireotide (Signifor, manufactured by Novartis) is an injectable medicine originally developed to treat Acromegaly, another type of pituitary tumor disease.  Trials were done with Cushing’s patients and showed a lot of promise – weight, blood pressure, lipids, and other symptoms improved and cortisol declined.  Based on this data, the FDA approved Signifor as a therapy for Cushing’s.  An updated, once-monthly version of the original drug called Pasireotide LAR just completed an extension study for patients who had success with pasireotide from the original study (see info on Dr. Maria Fleseriu’s late-breaking poster information in our Research Summaries section).  Signifor causes adrenal insufficiency (AI) in only about 8% of users.  Most frequent side effects are gastrointestinal.  This drug can cause hyperglycemia or worsen already-existing diabetes in the patient, but this effect can potentially be managed with additional meds.

MEDS THAT WORK AT THE ADRENAL LEVEL

Ketoconazole (generic) is an antibiotic used in the treatment of fungal infections and is one of the most, if not the most, commonly used medications in patients with Cushing’s. About 50-75% of patients treated with ketoconazole have their cortisol levels normalized. However, its effectiveness may be limited by side effects including liver damage.  This damage can occur at any dose, and the liver injury may be irreversible even after stopping the drug. The US Food and Drug Administration (FDA) recommends weekly blood testing to monitor liver function for the duration of treatment with ketoconazole.  This drug works by inhibiting several enzyme steps in cortisol production.  Studies have shown cortisol control ranging from 49-99%.  A Phase 3 trial studying a new formulation called levoketoconazole (Strongbridge Biopharma) that hopes to address some of the pitfalls of traditional ketoconazole treatment is almost complete.  Ketoconazole has a lot of drug-drug interactions.

Metyrapone (Metopirone, manufactured by HRA Pharma and available via DSI Pharmacy in the U.S) is currently approved in the US only as a diagnostic drug to test for ACTH function.  It can be used off-label to decrease and stabilize cortisol levels.  Metopirone is currently approved for treatment in Europe.  It inhibits the last enzyme step in cortisol synthesis, with cortisol control reported in about 75% of patients across three studies running from the 1970s-1990s.  Gastrointestinal issues and adrenal insufficiency are the most common side effects in about 25% of patients taking the medication, but overall Metopirone seems to have the best and longest-running satisfactory safety profile of all the medications available.  Although no drug is approved for use in pregnancy, there has been successful use of Metopirone in a pregnant patient who then went on to deliver a healthy baby. 

Mitotane (Lysodren, manufactured by HRA) is primarily used in patients with adrenal gland cancer, but it can also be used to lower cortisol levels. Like ketoconazole, Lysodren blocks production of cortisol, but in higher doses it may also cause destruction of adrenal cells. Studies show it is effective in more than 80% of patients, but nearly as many patients have side effects that can be significant. Many patients may have gastrointestinal problems and some develop problems with confusion and impaired mental function while taking Lysodren. 

Etomidate (Amidate, manufactured by Pfizer, also available as a generic) is an intravenous drug usually used for anesthesia, but it is also used for seriously ill patients with severe hypercortisolemia who cannot take oral medication.  There are only a few cases of its use reported in scientific literature.  Some studies have shown it to inhibit cortisol fairly rapidly at a dose low enough to avoid sedative effects.  The most common side effects are hypnotic effect, hypotension, nausea, and vomiting.  This medication can cause AI which would then cause a need for replacement cortisol products.

MED THAT WORKS ALL OVER

Mifepristone (Korlym, manufactured by Corcept Therapeutics) is the first FDA-approved medication specifically for the treatment of high blood sugar in patients with Cushing’s.  Korlym works differently than the other medications – it blocks the action of cortisol in the body rather than reducing it.  An impressive 60-90% of patients taking Korlym achieve improvement in blood sugars and many of the clinical features of Cushing’s.  Most common side effects include nausea, headaches, swelling (edema), and low potassium levels.  Women taking this drug may also have vaginal bleeding, and Korlym should never be taken for the treatment of Cushing’s in women during pregnancy because of its antiprogestin activity.  In that same vein, it should not be confused with Mifeprex, a different mifepristone drug made by Danco Laboratories for other purposes.  

Some doctors are not familiar with prescribing Korlym and have reservations because cortisol cannot be accurately measured to assess the dangers of AI.  Although Korlym and hydrocortisone cancel each other out, low cortisol can be reversed with dexamethasone.  Dr. Biller feels that the risk of AI is acceptable for this medical therapy vs surgery.  She also stated that in the absence of the ability to precisely measure cortisol levels while taking Korlym, a patient’s clinical response contains sufficient markers to proceed if the medication is a good fit and the patient wants to try it.  There are many potential drug-drug interactions with Korlym, so it is important to tell your doctor about all of the medicines you take including prescription and non-prescription meds, vitamins, and herbal supplements.

Although this list is rather short and full of unfortunate side effects, it is a solid start.  Many rare diseases have zero medical options.  It took a long time to get to the point where there were ANY therapies identified, targeted, or approved for treatment of Cushing’s.  It is encouraging that updated versions of several of these drugs are in Phase 2 or 3 trials now with promising data and fewer adverse effects and/or better cortisol control.

by Leslie Edwin

Author’s Note: this article was based on a lecture given by Dr. Beverly Biller (Mass General, Boston, MA)  at the AACE meeting.  All clinical information comes from her presentation, the information in the review articles Pituitary-Directed Therapies for Cushing’s Disease (Langlois F, Chu J, Fleseriu M.  Front Endocrinol (Lausanne).  2018 May 1;9:164.  doi: 10.3389/fendo.2018.00164.) and Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies (Fleseriu M, Castinetti F.  Pituitary. 2016;19(6):643-653. doi:10.1007/s11102-016-0742-1), and some direct passages about medical therapies from Dr. Ty Carroll’s Doctor’s Answer to the question, “What medications are used to treat Cushing’s?” in the Winter 2013 issue of our newsletter.

Summer, 2018