|Investigational drugs may expand medical treatment of Cushing’s syndrome|
Endocrinologists face many challenges when treating patients with Cushing’s syndrome. Diagnosis can be difficult because many of the disease’s characteristics, such as obesity, depression and hypertension, are also common in the general population.
Treating the disease presents hurdles as well. With its potential for total cure, transsphenoidal surgery remains the first-line treatment. However, the problems of achieving permanent remission in all cases demonstrate the need for medical therapies for this condition.
Laurence Katznelson, MD, of Stanford University, Hospital and Clinics, said pasireotide could possibly prevent pituitary tumor growth and promote tumor shrinkage in patients with Cushing’s syndrome.
Visual Arts at Stanford University
Currently, endocrinologists use several medical therapies to treat hypercortisolism, although none have FDA approval for that particular indication. Two new investigational drugs — mifepristone (Korlym, Corcept Therapeutics) and pasireotide (SOM230, Novartis) — have the potential to meet those unmet needs, according to experts interviewed by Endocrine Today.
“Recently completed research studies, which involved innovative medical therapeutic strategies that target the corticotroph adenoma itself or block the effects of cortisol in the periphery, should bring new treatment options in the future,” Maria Fleseriu, MD, associate professor, director of the Northwest Pituitary Center at Oregon Health & Science University, said in an interview.
Manufacturers of both new medications have submitted new drug applications to the FDA. Corcept expects to hear from the FDA on Feb. 17, according to a spokesperson for the company.
Mifepristone has a unique mode of action in that it blocks the cortisol receptor, Robert L. Roe, MD, president of Corcept Therapeutics, said in an interview.
“With that receptor blocked, many of the problems associated with Cushing’s syndrome can be greatly improved, including: obesity, diabetes, insulin resistance, high blood pressure, quality of life and depression,” Roe said.
The SEISMIC trial, a 24-week, multicenter, open-label study, included 50 patients with persistent or recurring Cushing’s disease, metastatic adrenal cortical carcinoma or ectopic adrenocorticotropic hormone (ACTH) syndrome that was not amenable to surgery, according to Fleseriu, who was an investigator on the study. There were two primary endpoints: blood sugar improvement in patients with glucose intolerance and an improvement in BP in patients with a diagnosis of hypertension but without abnormal blood sugar levels. The key secondary endpoint looked for global clinical improvement as determined by a three-member independent data review board.
Results from the phase 3 study showed that, overall, mifepristone yielded significant clinical and metabolic improvement in patients with refractory Cushing’s syndrome, Fleseriu said. Of the glucose-intolerant patients, 60% responded, and BP improved in 38% of patients. The global clinical endpoint was positive in 87% of patients, Roe said.
“In addition, out of 34 patients who completed the main study, 30 elected to continue in the long-term extension study,” Fleseriu said.
She said mifepristone “offers a new approach for the treatment of Cushing’s syndrome that [has] failed other therapies. Keeping in mind that biochemical parameters will not be available for monitoring these patients, close clinical observation is recommended.”
Yet, there are aspects of mifepristone that are still unknown.
“There will be a learning curve with this drug on how to dose it and use it properly to get a good response,” said James Findling, MD, professor of medicine, Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, who was the principal investigator of the study.
Also on the horizon is the investigational agent pasireotide, a multiligand somatostatin analogue with a high affinity for the somatostatin receptor type 5, which is often expressed by corticotroph adenomas in Cushing’s disease. Pasireotide blocks the secretions from ACTH-secreting pituitary tumors.
“Pasireotide works by attacking the pituitary tumor to reduce the ACTH level,” according to Laurence Katznelson, MD, professor of medicine and neurosurgery at Stanford University and medical director of the pituitary program at Stanford Hospital and Clinics. “Possibly, this drug could prevent tumor growth or lead to tumor shrinkage, although we await data to support that.”
Results of the multicenter, phase 3 PASPORT-CUSHINGS trial, presented at the Endocrine Society’s 93rd Annual Meeting & Expo in June, included 162 patients with persistent/recurrent or newly diagnosed Cushing’s disease who were ineligible for surgery. Researchers randomly assigned participants to receive twice-daily subcutaneous pasireotide injections of 600 mcg or 900 mcg. The primary endpoint was urinary-free cortisol levels at 6 months without dose up-titration.
Of the patients in the 900-mcg dose group, 26.3% had normal urinary-free cortisol levels at 6 months; at 12 months, 25% maintained normal levels. The median reduction from baseline in urine-free cortisol after 6 months of treatment was 47.9% for both dose groups.
The researchers noted significant clinical benefit in most patients, including lower BP and total cholesterol, as well as weight loss, Fleseriu said.
“It is noteworthy that while urinary-free cortisol normalization was seen in just a subset of patients, the rate of normalization was higher in patients with lower baseline urinary-free cortisol, making it, in my opinion, an attractive treatment for patients with mild elevations in urinary-free cortisol,” Fleseriu, who was also an investigator for this trial, told Endocrine Today.
Pasireotide was well tolerated in the studies, she added.
“Adverse events were comparable to the other somatostatin analogues, with the exception of a much higher incidence of hyperglycemia,” Fleseriu said. “Patients treated with this drug will require strict monitoring and prompt treatment of hyperglycemia.” The reasons for hyperglycemia are related to inhibition of insulin release from the pancreas by this multiligand somatostatin analogue. The type 5 receptor is abundant on pancreatic insulin secreting cells of the pancreas.
Timely diagnosis, treatment critical
Cushing’s syndrome is the result of chronic exposure to high levels of cortisol. Cortisol, typically released in stressful situations, controls how the body uses carbohydrates, fats and proteins. In addition, it helps decrease the immune system’s response to inflammation.
Untreated, Cushing’s syndrome can have serious consequences, including significant mortality and morbidity. Timely diagnosis and appropriate treatment are critical for this rare disorder, according to Fleseriu, who is also associate professor of medicine/endocrinology and neurological surgery at Oregon Health & Science University.
The endocrinologist uses the following tests to diagnose the disorder: 24-hour urinary-free cortisol levels; late-night salivary cortisol measurements; and low-dose dexamethasone suppression test.
After making the diagnosis of hypercortisolism, the next step is to determine the cause of excess cortisol secretion. There are several tests available for this purpose: corticotropin-releasing hormone (CRH) simulation test; direct radiologic visualization of the pituitary and adrenal glands; and inferior petrosal sinus sampling for ACTH.
The most common cause is long-term synthetic steroid use to treat inflammatory illnesses such as asthma or rheumatoid arthritis, according to Katznelson. In these cases, gradually reduction of the glucocorticoid will reverse the disorder.
Another cause is an ACTH-secreting pituitary adenoma. The excess stimulates the adrenals to produce and secrete excess cortisol release, Katznelson said. This is also known as Cushing’s disease.
Pituitary adenomas are responsible for 70% of Cushing’s syndrome cases, according to information from the National Institute of Diabetes and Digestive and Kidney Diseases.
Surgery is first-line treatment
First-line therapy for Cushing’s disease is transsphenoidal adenomectomy, in which the surgeon approaches the pituitary through the nose and, using either a microscope or endoscope by trained neurosurgeons, according to John Carmichael, MD, assistant professor of medicine, The Pituitary Center, Cedars-Sinai Medical Center, Los Angeles.
The procedure boasts an excellent cure rate.
“In good hands, with a small tumor, you can get cure rates of about 85%,” Carmichael said. “It depends on a number of factors: the skill of the surgeon, the size of the tumor and the level of invasiveness.”
If surgery is curative, the patient will require cortisol replacement.
“Once you remove the tumor, the normal tissue has been suppressed by the activity of the tumor for so long that it takes a long time for patients to recover and start making cortisol on their own,” Carmichael said. “It can take as long as 6 to 12 months for patients to completely recover their normal cortisol secretion once they’ve been cured.”
However, the surgery is associated with risks, including bleeding and infection, although they are “pretty rare,” according to Carmichael. One of the most common risks is a pituitary injury that can cause diabetes insipidus, which is almost always transient. Other postoperative problems include possible cerebrospinal fluid leaks and the possibility of recurrence, said David M. Cook, MD, an endocrinologist in the department of medicine, Oregon Health & Sciences University.
Sometimes the tumor is hard to find during the first surgery, Katznelson said.
“The problem is, in 40% to 50% of patients who have Cushing’s disease, the tumor is very small, if not almost invisible, on the MRI scan,” he said. As a result, the surgeon may remove normal gland or possibly the entire pituitary, resulting in hypopituitarism. The patient would require hormone replacement and would still have Cushing’s syndrome.
Radiation is a possible treatment for these cases.
“The role of radiation is in the patient who has already had surgery for Cushing’s syndrome. The tumor is visible but cannot be completely removed. Radiation is most useful when there is a target to irradiate,” Katznelson said, adding that even in these cases, radiation cannot promise 100% efficacy.
Unfortunately, radiation takes a significant amount of time to work.
“People are a little reluctant to use radiation because it takes years to help,” Cook said. “It is not curative and patients can relapse from radiation also; it is not foolproof.”
Ectopic ACTH syndrome
Sometimes, tumors located outside the pituitary can produce ACTH, resulting in the ectopic ACTH syndrome. The tumors are usually malignant. In more than half of the cases, the tumors are found in the lungs, according to information from the NIDDK.
“You would need surgery in that location to get rid of the tumor,” Carmichael said.
If an adrenal tumor is stimulating an overabundance of cortisol, the definitive cure is adrenalectomy.
“If we do adrenalectomy, all of the [symptoms of] Cushing’s syndrome go away, but the primary pituitary tumor, which may have been microscopic, can start to become more aggressive and grow and become more difficult to treat in the long run,” Katznelson said. “That is Nelson’s syndrome.”
The adrenal insufficiency that follows adrenalectomy is serious, Cook said.
“It is dangerous to not have your adrenals; it is the most dangerous disease that endocrinologists treat,” he said. “A number of sudden deaths have been reported in patients without adrenals.”
Katznelson also said that managing these patients can be challenging.
“Management of primary adrenal insufficiency is sometimes difficult, because not only does the patient lack cortisol, but will also lack aldosterone, which is important for maintaining electrolytes and volume status,” he said. “Patients often find it quite challenging to manage primary adrenal insufficiency.”
Medical therapies for Cushing’s syndrome
Besides surgery and radiation, endocrinologists can use several medical therapies to treat Cushing’s syndrome; however, to date, none has obtained FDA approval to treat the disorder.
The medical treatment used most often in the United States is ketoconazole, an antifungal agent that blocks the enzymes in the adrenal glands that produce steroids, Findling toldEndocrine Today.
Ketoconazole, administered two to three times daily, is generally successful.
“It is an effective therapy,” Findling said. “Probably 50% to 70% of patients will have a response.”
However, this drug is not the optimal choice for long-term use.
“Ketoconazole has been associated with some toxicity; liver function abnormalities can occur and, in fact, liver failure can occur,” he said.
Another medical treatment option is mitotane (Lysodren, Bristol-Myers Squibb), which blocks adrenal steroid enzymes, Findling said. This toxic agent takes considerable time to work; in fact, it may require roughly 3 or 4 months for cortisol levels to normalize. It is used rarely in the United States.
“Mitotane has a limited future as a therapy for Cushing’s syndrome, except for in patients who have adrenal cancer, at least in the US,” Findling said.
Metyrapone (Metopirone, Novartis), another agent, effectively blocks adrenal steroid enzymes; however, it is not commercially available in the United States, Findling said.
Etomidate is an anesthetic agent that also inhibits adrenal steroidogenesis and is employed successfully in patients with very severe hypercortisolism who are not ready for surgery.
“If etomidate were available in a pill, it would be an excellent medical treatment for Cushing’s syndrome,” Findling said. “With subhypnotic doses, etomidate lowers the cortisol level smoothly down into the normal range. … It is well tolerated, but has to be given as a continuous IV infusion, so it is not practical.”
All of these medications have severe adverse effect profiles, according to Carmichael.
No replacement for surgery … yet
Although mifepristone and pasireotide show some promise as treatments for Cushing’s syndrome, it is not time to put the scalpels in storage, the experts said.
“Neither of these drugs, at least for the foreseeable future, will replace surgical treatment of Cushing’s syndrome,” Findling said. “Like most disorders, if you have a surgical procedure that will resolve the endocrinopathy and restore normal hormonal function, it is usually the treatment of choice.”
However, these medications are a welcome addition to the armamentarium, Carmichael said.
“It remains to be seen exactly what their place will be and how they will be best used. But, certainly, in cases where surgery is not an option or where you need to control the disease in someone who has very severe disease, they would have a role,” he said. Currently, Carmichael sees medical therapy as an adjuvant treatment, which would follow surgery if it was not curative. Also, endocrinologists may use them in place of surgery if surgery was not an option.
“There is a lot more room for work,” Carmichael said. “The ideal paradigm of having a medication that is safe and controls the disease and in a sense would replace surgery would be an ideal goal, but we are certainly not there yet.”– by Colleen Owens
Disclosures: Dr. Fleseriu is principal investigator in multiple Cushing’s trials and past consultant for Novartis; she is also the principal investigator on Corcept Cushing’s trials. Dr. Findling is a paid consultant for Corcept Therapeutics. The other doctors in this article did not report any relevant financial disclosures.
Tests are equally accurate, but have limitations
The diagnosis of Cushing’s syndrome is problematic. It is one of the most difficult endocrine diseases to diagnose. Diagnosis includes assessing the symptoms and signs of Cushing’s syndrome because the symptoms and signs overlap with common disorders, including obesity, depression and polycystic ovary syndrome. Many patients consult websites in an attempt to find an explanation for their weight gain, fatigue, depression and other symptoms. They ask frequently after a Web search if their symptoms could be Cushing’s syndrome.
Screening tests for Cushing’s syndrome include three different tests: an 11 p.m. or midnight salivary cortisol level; a 24-hour urine free cortisol level; and an 8 a.m. cortisol level after ingestion of 1 mg of dexamethasone at midnight the previous night. How reliable are these tests? They are equally accurate — approximately 90% to 92% reliable, which is actually good for screening tests.
However, all three tests have limitations. Results of the nighttime salivary cortisol test are affected by laboratory accuracy (not all laboratories are equally reliable) and sleep patterns. In severe depression cases, the results may be falsely elevated. The 24-hour urine free cortisol test is an indicator of overall cortisol production. The most accurate method of measurement — tandem mass spectrometry with concomitant measurement of urine volume and urine creatinine — provides a good measure. It may take several 24-hour urine collections to confirm hypercortisolism. The 1-mg overnight dexamethasone suppression test is reliable, but with several caveats. The test is standardized according to administering dexamethasone at midnight and measurement of serum cortisol promptly at 8 a.m. the following day. However, while the patient may have gone to the lab at 8 a.m., the blood sample may have been obtained later, which invalidates the test. Additionally, if the patient is taking medications that alter dexamethasone metabolism, the results may not be valid. The endocrinologist must measure a serum dexamethasone level to confirm the validity of the test.
The diagnosis of Cushing’s syndrome is dependent upon confirming consistent overproduction of cortisol. The diagnosis may require repeated testing and this should be done in any patient in which there is a suspicion of Cushing’s syndrome.
Mary Lee Vance, MD, is professor of medicine and neurosurgery at University of Virginia Health System, Charlottesville, Va.
Disclosure: Dr. Vance reports no relevant financial disclosures.
Late-night salivary cortisol is best initial test
No test is perfect for all patients. In addition, it is important to remember that some patients will require multiple, different tests to confirm or exclude Cushing’s syndrome. However, that being said, late-night salivary cortisol is the best initial screening for most patients with suspected Cushing’s syndrome.
Late-night salivary cortisol is the most specific test for Cushing’s syndrome. The sensitivity and specificity are very good. Multiple studies have examined late night salivary cortisol testing, and the majority of those studies show sensitivity of more than 95% and a specificity in the range of 90% to 100%. That is comparable to — or better than — other methods to diagnose Cushing’s syndrome.
Also important to note: It is easy for patients to perform late-night salivary testing. Patients are able to do the collection at home and mail in the completed samples to a reference lab, whereas urinary free cortisol and dexamethasone suppression testing can be difficult for some patients to complete. In addition, for the most part, late-night salivary cortisol is not affected by other medications that patients take, unlike dexamethasone suppression testing, which can be affected by several medications that patients often take to treat other conditions.
Ty Carroll, MD, is assistant professor of medicine at Endocrinology Center and Clinics, Menomonee Falls, Wisc.
Disclosure: Dr. Carroll is an investigator in Corcept’s clinical trials of mifepristone.
Thursday, December 22, 2011
We Cushies hope that in 2012, we will see success as more patients to try these drugs.
As you know, my pituitary continues to produce excess ACTH, a hormone that causes my Cushing's. Even after two tumors were removed during two pituitary surgeries, abnormal cells persist. Medication may be a real possibility for Cushies like me. If medication can stop this ACTH production, there will be no need for a life-changing bilateral adrenalectomy (BLA). Click here to see the December 2011 cover story for Endocrine Today.
Posted by Moxie Melissa