Radiation therapy and stereotactic radiosurgery for the treatment of Cushing's disease: an evidence-based review

Current Opinion in Endocrinology, Diabetes & Obesity:

August 2010 - Volume 17 - Issue 4 - p 356–364

doi: 10.1097/MED.0b013e32833ab069

Neuroendocrinology: Edited by William H. Ludlam

 

Starke, Robert M; Williams, Brian J; Vance, Mary Lee; Sheehan, Jason P

Abstract

Purpose of review: The indications, efficacy, and safety of radiation therapy and stereotactic radiosurgery for Cushing's disease are evaluated.

We queried PubMed using the terms, ‘Cushing's disease’, ‘radiotherapy’, and ‘radiosurgery’, then evaluated each study for the number of patients, method of radiation delivery, type of radiation therapy or radiosurgical device used, treatment parameters (e.g. maximal dose, tumor margin dose), length of follow-up, tumor-control rate, complications, rate of hormone normalization, newly onset loss of pituitary function, and method used to assess endocrine remission.

Recent findings: A total of 39 peer-reviewed studies with 731 patients were included. The reported rates of tumor-volume control following radiotherapy and radiosurgery vary considerably from 66–100%. Additionally, the reported rates of endocrine remission vary substantially from 17–100%. The incidence of serious complications following radiosurgery is quite low. Although post-treatment hypopituitarism and disease recurrence were uncommon, they did occur, and this underscores the necessity for long-term follow-up in these patients.

Summary: Radiosurgery and, in the modern era, less commonly, radiation therapy, offer both well tolerated and reasonably effective treatment for recurrent or residual Cushing's adenomas.

 

From http://journals.lww.com/co-endocrinology/Abstract/2010/08000/Radiation_therapy_and_stereotactic_radiosurgery.9.aspx

The 4-mg intravenous dexamethasone suppression test in the diagnosis of Cushing's syndrome

Authors: Jung, Caroline; Alford, Frank P.; Topliss, Duncan J.; Burgess, John R.¹; Long, Fiona²; Gome, James J.; Stockigt, Jim R.; Inder, Warrick J.

Source: Clinical Endocrinology, Volume 73, Number 1, July 2010 , pp. 78-84(7)

Publisher: Blackwell Publishing

Abstract:

Summary

Objective Optimal diagnostic criteria for the 4-mg intravenous dexamethasone suppression test (IVDST) in patients with Cushing's syndrome (CS), compared with normal subjects, have not been established. We evaluated the performance of the 4-mg IVDST for differentiating CS from normal subjects and to define the responses in CS of various aetiologies.

Design, subjects, measurements Thirty-two control subjects [normal and overweight/obese participants with or without type 2 diabetes) were prospectively studied, and data from 66 patients with Cushing's disease (CD), three with ectopic ACTH syndrome (EAS), 14 with adrenal Cushing's (AC)] and 15 with low probability of CS (LPC) from three tertiary hospitals were retrospectively evaluated. Dexamethasone was infused at 1 mg/h for 4 h. Plasma cortisol and ACTH were measured at −60 min (baseline), −5 min, +3 h, +4 h, +5 h and at +23 and +23·5 h on Day 2.

Results Control subjects (including those with type 2 diabetes) exhibited a marked suppression of cortisol which was maintained until Day 2. Two of 15 patients with LPC had Day 2 cortisol results that overlapped with CS. Patients with CD demonstrated partial suppression, with rebound hypercortisolism on Day 2. Patients with AC and EAS did not suppress cortisol levels. Day 2 cortisol level of >130 nmol/l (or >20% of the baseline) diagnosed CS with 100% sensitivity and 96% specificity.

Conclusion While the IVDST allowed complete discrimination between control subjects and CS, 13% of LPC overlapped with CS. Given the small number of EAS, no conclusion can be drawn regarding the utility of this test in the differential diagnosis of CS.

Document Type: Research article

DOI: 10.1111/j.1365-2265.2009.03756.x

Affiliations: 1: Department of Endocrinology and Diabetes, Royal Hobart Hospital and Menzies Research Institute, Tas. 2: Department of Endocrinology and Diabetes, The Alfred Hospital, Vic.

From http://www.mdlinx.com/EndoLinx/newsl-article.cfm/3199167/ZZ4747461521296427210947/?news_id=561&newsdt=062910

Adrenal Disorders: Cushing's Disease & Cushing's Syndrome

The production of cortisol by the adrenal glands is stimulated by ACTH (Adrenal Cortical Tropic Hormone), which is produced by the pituitary gland in the brain. Thus, overproduction of cortisol can be caused by either a tumor in the pituitary gland (Cushing's disease), or in the adrenal glands (Cushing's syndrome). Less commonly, a tumor producing too much ACTH may be found outside of the pituitary gland. In patients with Cushing's disease, the blood levels of both ACTH and cortisol are elevated. In patients with Cushing's syndrome, the blood level of cortisol is increased in the setting of a low level of ACTH. Rarely, adrenocortical cancers may cause Cushing's syndrome.

Diagnosis

There is a great deal of variability throughout the day in the amounts of cortisol produced by the adrenal glands. For this reason, the most sensitive test measures the amount of cortisol excreted in the urine over a 24-hour period. A 24 hour free cortisol level greater than 100 µg is diagnostic of Cushing's syndrome. Patients suspected of having Cushing's syndrome will also undergo a dexamethasone suppression test which helps to determine the cause of the increased cortisol production. A CT or MRI scan is used to determine the location of the tumor.

Treatment

Patients with Cushing's disease typically have benign tumors of the pituitary gland in the brain. These patients are referred to a neurosurgeon for removal of the tumors. If removal of the pituitary tumor and medications fail to control Cushing's disease, removing both adrenal glands may be indicated. In patients with Cushing's syndrome, an adrenalectomy—surgical removal of the adrenal gland—is curative. This operation is usually performed laparoscopically, through several very small incisions.

From http://www.columbiasurgery.org/pat/adrenal/cushing.html

Corcept Therapeutics Nears Completion of Enrollment in Phase 3 Cushing's Syndrome Study -- Data Announcement Anticipated by Year End

Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's Syndrome can affect every organ system in the body and can be lethal ...
by MarketWatch (press release) [Fri, 25 Jun 2010 10:07:02 GMT+00:00]

 

Corcept Therapeutics Incorporated ("Corcept") /quotes/comstock/15*!cort/quotes/nls/cort (CORT 3.25, -0.28, -7.93%) , a pharmaceutical company engaged in the discovery and development of drugs for the treatment of severe metabolic and psychiatric disorders, today announced that it had enrolled 49 of the planned 50 patients in its Phase 3 trial of CORLUX(R) for the treatment of Cushing's Syndrome and expects the fiftieth patient to begin dosing next week.

"We are near our target of dosing 50 patients in our Phase 3 study of CORLUX for the treatment of Cushing's Syndrome. We remain on track to announce top line results from the trial by the end of this year," said Joseph Belanoff, M.D., Chief Executive Officer of Corcept.

Cushing's Syndrome Phase 3 Trial Nears Completion of Planned Enrollment of 50 Patients

We have dosed 49 of the planned 50 patients in our open-label Phase 3 trial of CORLUX in patients with endogenous Cushing's Syndrome, which is being conducted at 20 leading medical facilities throughout the United States. The final patient is expected to be dosed next week.

The FDA has indicated that this single 50-patient open-label Phase 3 study of CORLUX may provide a reasonable basis for the submission of a New Drug Application ("NDA") for Cushing's Syndrome. In the study, each patient's dose is titrated to clinical benefit by their study investigator and the primary endpoints (either an improvement in glucose tolerance or blood pressure) are measured at the end of 24 weeks.

We expect to announce the top-line results of this study by the end of 2010 and to submit our NDA to the FDA in the first quarter of 2011.

About Cushing's Syndrome

Endogenous Cushing's Syndrome is caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol due to either cortisol or adrenocorticotropic hormone (ACTH) production by tumors. Cushing's Syndrome is an orphan indication which most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients in the United States. An estimated 20,000 patients in the United States have Cushing's Syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's Syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About CORLUX

Corcept's first-generation compound, CORLUX, also known as mifepristone, directly blocks the cortisol (GR-II) receptor and the progesterone (PR) receptor. Intellectual property protection is in place to protect important methods of use for CORLUX. Corcept retains worldwide rights to its intellectual property related to CORLUX.

About Corcept Therapeutics Incorporated

Corcept is a pharmaceutical company engaged in the discovery and development of drugs for the treatment of severe metabolic and psychiatric disorders. The company has two ongoing Phase 3 programs: CORLUX for the treatment of Cushing's Syndrome, and CORLUX for the treatment of the psychotic features of psychotic depression. Corcept also has a Phase 1 program for CORT 108297, a selective cortisol receptor antagonist. Corcept has developed an extensive intellectual property portfolio that covers the use of GR-II antagonists in the treatment of a wide variety of psychiatric and metabolic disorders, including the prevention of weight gain caused by the use of antipsychotic medication, as well as composition of matter patents for our selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements, including, for example, statements relating to Corcept's clinical development and research programs, the timing of the introduction of CORLUX and future product candidates, including CORT 108297, estimates of the timing of enrollment or completion of our clinical trials and the anticipated results of those trials, and the timing of submission of the NDA, if submitted at all, the ability to create value from CORLUX or other future product candidates and our estimates regarding our capital requirements, spending plans and needs for additional financing. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances with respect to the cost, rate of spending, completion or success of clinical trials; financial projections may not be accurate; there can be no assurances that Corcept will pursue further activities with respect to the development of CORLUX, CORT 108297, or any of its other selective GR-II antagonists. These and other risk factors are set forth in the Company's SEC filings, all of which are available from our website (www.corcept.com) or from the SEC's website (www.sec.gov). We disclaim any intention or duty to update any forward-looking statement made in this news release.

CONTACT:
Caroline Loewy
Chief Financial Officer
Corcept Therapeutics
650-688-8783
Email Contact
www.corcept.com


From http://www.marketwatch.com/story/corcept-therapeutics-nears-completion-of-enrollment-in-phase-3-cushings-syndrome-study-data-announcement-anticipated-by-year-end-2010-06-25?reflink=MW_news_stmp

CAH (congenital adrenal hyperplasia) and Prenatal Dexamethasone

MountainQueen posted this on the Cushing's Help Boards.  She said:

I came across this article about the clinical use of Dex for CAH carriers. After reading this article I remembered that NO ONE asked me if I was pregnant before I took the Dex test. What would have happened if I had been?
Very interesting article for CAH gene carriers: From Time Magazine on line

Medical Ethics: Prenatal Dexamethasone Use Questioned

By CATHERINE ELTON Catherine Elton – Mon Jun 21, 11:45 pm ET

When Marisa Langford found out she was pregnant again, she called Dr. Maria New, a total stranger, before calling her own mother. New, a prominent pediatric endocrinologist and researcher at Mount Sinai Medical Center in New York City, is one of the world's foremost experts in congenital adrenal hyperplasia, or CAH, a group of inherited disorders of the adrenal gland.

Langford and her husband learned they were silent carriers of the genetic variation that causes CAH when their son was diagnosed with the condition after birth. Their son - like the 1 in 16,000 babies born with CAH each year in the U.S. - faces a lifetime of taking powerful steroid medications to compensate for his faulty adrenal glands. When Langford contacted New about her second pregnancy, New, who was not Langford's regular doctor, called a local pediatric endocrinologist. That doctor prescribed Langford a commonly used medication for CAH. "Dr. New told me I had to start taking dexamethasone immediately," says Langford, 30, who lives in Tampa. "We felt very confident in someone of her stature and that what she was telling us was the right thing to do."(See the most common hospital mishaps.)

The early prenatal use of dexamethasone, or dex, has been shown to prevent some of the symptoms of CAH in girls, namely ambiguous genitalia. Because the condition causes overproduction of male hormones in the womb, girls who are affected tend to have genitals that look more male than female, though internal sex organs are normal. (In boys, in contrast, the condition leads to early signs of puberty, such as deep voice, body hair and enlarged penis by age 2 or 3.) But while the prenatal treatment may address girls' physical symptoms, it does not prevent the underlying, medical condition, which in some severe cases can be life-threatening, nor does it preclude the need for medication throughout life.

Langford says also that neither New nor her prescribing physician mentioned that prenatal dexamethasone treatment is an off-label use of the drug (an application for which it was not specifically approved by the government) or that the medical community is sharply divided over whether dexamethasone should be used during pregnancy at all.

Is It Safe - or Even Necessary?
To date, there has been just one controlled, prospective, long-term trial of prenatal dexamethasone for the prevention of ambiguous genitalia, conducted in Sweden. The results, published in 2007 in the Journal of Clinical Endocrinology & Metabolism - more than two decades after doctors began using the medication in pregnant patients - found some mild behavioral and cognitive deficits in children whose mothers had been treated. But the study, with just 26 participants, was too small to be definitive. "We just don't know what we are doing to these kids," says Dr. Walter Miller, the chief of endocrinology at University of California, San Francisco. "It's not sufficient to say, The baby was born and had all fingers and toes, so it's fine."(See the top 10 medical breakthroughs of 2009.)

In animal studies, dexamethasone has been shown to cause birth defects, but proponents of the treatment note that no human birth defects have ever been associated with the treatment, and that it is uncertain whether findings in lab animals translate to humans. Meanwhile, the possible benefits are clear: the treatment can spare young girls the potential psychosocial problems associated with having ambiguous genitalia as well as the ordeal of surgery to correct deformities later. "I see potential for benefits and I don't see evidence there's any negatives to this. There are lots of risks associated with surgery, and if this can prevent surgery, then it's a good thing," says Dr. Ingrid Holm, a pediatric endocrinologist at Children's Hospital in Boston.

Research has also suggested that affected women who were treated with dex in the womb show more typical gender behavior than other women with CAH; the latter group tends to behave more tomboyishly and express little interest in having children. New told the Wall Street Journal in 2009 that the treatment further spares parents the "terrifying prospect" of not knowing whether their newborn is a boy or a girl. (Comment on this story.)

It is these very benefits, however, that lead some researchers to question what, exactly, doctors are treating - and whether it needs to be treated at all. Miller believes that prenatal dex is being used to alleviate "parental anxiety," rather than the child's condition. Other doctors and researchers have criticized New for introducing gender behavior into the medical prognosis - in two recent presentations on CAH at medical conferences, New offered medical outcome data on prenatal dex alongside data on typical gender behavior. "Maybe this gives clinicians the idea that the treatment goal is normalizing behavior. To say you want a girl to be less masculine is not a reasonable goal of clinical care," says David E. Sandberg, a University of Michigan pediatric psychologist who treats and conducts research on children with CAH.(Read how postpartum depression can strike fathers.)

Perhaps most controversially, prenatal dex must be given as soon as a woman learns she is pregnant, which is usually several weeks before genetic tests can determine if the fetus is in fact a female affected with CAH - the chance of which is 1 in 8 for parents who already have an affected child or know they are carriers of the genetic disorder. If the baby is healthy, treatment is stopped, but at that point, the fetus has been exposed to the steroid drug for weeks. There is no data on how many mothers receive prenatal dex, but according to the odds, 7 of 8 may be taking medication unnecessarily.

Concerns over Patient Consent
Some critics strongly oppose prenatal dex in large part because of the way it is presented to patients. Guidelines issued by pediatric endocrine societies in Europe and North America recommend that doctors obtain written informed consent from the patient as well as ethics-committee oversight for the treatment, but it is not known how many physicians adhere to these guidelines. Langford says she was not made aware of them. In addition, 2010 practice guidelines from the international Endocrine Society suggest that prenatal dex be administered as part of clinical research, which requires informed consent and ethics-committee oversight.

However, prenatal dex is routinely given outside the research setting, as an off-label treatment. It is common - and perfectly legal - for doctors to use their own discretion when prescribing drugs off-label. Antiseizure drugs like topiramate are commonly prescribed to treat migraine headache pain, for example. The practice allows patients to receive valuable treatment for which the drug may not have been expressly approved and may never be - it takes money and drug-company interest, which are hard to come by, to conduct the large randomized controlled trials required for a new-use the Food and Drug Administration (FDA) approval of a drug that is already on the market.

But as doctors share information about a drug's perceived off-label benefits and lack of harm, it gets even harder to take a step back and launch a formal randomized controlled trial - considered the gold standard in medical research - because patients demand the treatment, and doctors say it would be unethical to withhold it from them or from control groups in clinical trials. "It's a risky and dangerous way to innovate," says prominent University of Pennsylvania bioethicist Arthur Caplan. "There's no systematic collection of information. So, yes, things do get proven this way, and it is a way to innovate, but it also can come at a cost of unnecessary expense and, sometimes, bad side effects."

It also enables doctors to do human research without gaining proper approval. All participants in human medical research are, by law, entitled to the protective oversight of an institutional review board (IRB), a committee that safeguards the interests of research volunteers and ensures they have been fully informed about the potential risks and benefits of an experimental treatment. If doctors are simply treating a patient with an off-label drug, they are not required to obtain written informed consent from patients. But if doctors give treatment with the intent to gain knowledge, they are technically doing research, which must receive IRB approval.

Ethicists say physicians may sometimes treat patients off-label, then decide later to launch a follow-up study; or, they do follow-up research on patients who have been treated by other doctors. In the process, they have converted these patients into unwitting research volunteers. Some doctors game the system this way, Caplan says, to avoid battles with IRBs.

Critics suspect that Mount Sinai's New, who has long championed prenatal dex and bills it as safe on her foundation website, has gamed the system. In a letter dated Feb. 2, 2010, a group of 36 bioethicists, including Alice Dreger, a professor of bioethics at Northwestern University, asked the FDA and the federal Office for Human Research Protections to investigate New's practices; the authors contend that the doctor has conducted follow-up studies on prenatal dex patients without receiving IRB approval for treatment trials. Dreger says she has also asked Weill Cornell Medical College, where New previously worked, and Mount Sinai Medical Center to investigate the matter.

New, who declined to be interviewed for this article, does not administer the treatment in her current practice - according to Mount Sinai Medical Center, she has prescribed it only once since joining the hospital in 2004 - but ethical concerns remain, Dreger says, if the doctor consults with patients, resulting in their being prescribed dex elsewhere, then follows up with them for research purposes. At a medical conference in January, where New presented data from her research on prenatal dex, the doctor refused to answer a fellow researcher's questions regarding her process of informed consent.

Clinical Trials vs. Legal Trials
For Langford's part, she says she is grateful to New for her help, even though her daughter, now 4 and healthy, was found not to have CAH.

But Jenny Westphal, 24, who took dexamethasone throughout her pregnancy at the recommendation of another doctor, says she feels misled. Like Langford she was not asked to give informed consent. Unlike Langford, however, her daughter, now 3, who has CAH, has also had serious and mysterious health problems since birth, including feeding disorders, that are not commonly associated with her adrenal-gland disorder.

In April, Westphal, who lives in Wisconsin, started doing research online and discovered there was some controversy over the treatment. "I was outraged, frustrated and confused. Confused, because no one had ever warned me about this. I wasn't given the chance to decide for myself, based on the risks and benefits, if I wanted the treatment or not," she says.

Westphal may never know whether her daughter's problems were caused by dexamethasone, though she will likely always believe they were. That is why so many similar situations, in which experimental drugs are prescribed off-label without informed consent rather than in clinical trials, wind up becoming case studies - not in scientific journals, but exactly where Westphal and her husband are considering taking theirs: to court.

Originally from http://news.yahoo.com/s/time/20100622/hl_time/08599199645300

Peri-operative management of Cushing’s disease

PDF (180.7 KB) | HTML

Dima AbdelMannan1, Warren R. Selman2  and Baha M. Arafah1, 3 Contact Information
(1)      Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland, Case Medical Center, Louis Stokes Cleveland VA Medical Center and Case Western Reserve University, Cleveland, OH, USA
(2)      Department of Neurosurgery, University Hospitals of Cleveland, Case Medical Center, and Case Western Reserve University, Cleveland, OH, USA
(3)      Division of Endocrinology, University Hospitals/ Case Medical Center, and Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA

Published online: 17 June 2010

Abstract 
Management of patients with ACTH producing pituitary adenoma remains to be challenging. Removal of the pituitary adenoma through transsphenoidal surgery is the main stay of treatment.

Complete resection of the adenoma is followed by the development of ACTH deficiency since the normal corticotrophs are suppressed by the pre-existing hypercortisolemia. The concern for ACTH deficiency has led many centers to advocate the use glucocorticoids before, during and after surgery. We provide evidence that such coverage with glucocorticoids is unnecessary until clinical or biochemical documentation of need is established. Given that patients are closely monitored, they are immediately treated with glucocorticoids once they exhibit any clinical and/or biochemical evidence of adrenal insufficiency.

Defining remission in the immediate postoperative period has been rather difficult despite using different biochemical markers. Serum cortisol continues to be the best determinant of disease activity after surgical adenomectomy. However it needs to be interpreted with caution as a biochemical marker of remission in patients given glucocorticoids during and after surgery. Other biochemical markers are also used in the peri-operative period to determine the possibility of remission. These include the dexamethasone suppression test, CRH stimulation without dexamethasone, urinary free cortisol measurements, desmopressin stimulation test, the determination of salivary cortisol and / or plasma ACTH concentrations. Each test has its own advantages and limitations. The simplest and most informative approach is to measure serum cortisol levels repeatedly after surgery without the administration of exogenous glucocorticoids. Low serum cortisol levels (less than 2 ug/dL) in the peri-operative period are highly indicative of surgical success and a high likelihood for clinical remission. Higher serum cortisol levels require careful interpretation and further planning and discussions between the patient and the management team.

Keywords  Cushing’s disease - Cushing’s syndrome - Hypercortisolism - ACTH - Cortisol - Adrenal insufficiency - Peri-operative management - Glucocorticoids - Pituitary adenoma - Transsphenoidal surgery - Pituitary adenomectomy

Contact Information     Baha M. Arafah
Email: baha.arafah@case.edu

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From http://www.springerlink.com/content/e3k81t7825750nh4/