Medical therapy ‘reasonable option’ vs. surgery in Cushing’s disease

In a large percentage of patients with Cushing’s disease, medical therapy effectively induces cortisol normalization, suggesting the choice may serve as a useful first-line treatment vs. surgery for some, according to findings from a systematic review and meta-analysis published in Pituitary.

Cushing’s syndrome is generally approached by removal of the adrenocorticotropic hormone (ACTH)-producing tumor in ectopic disease and by adrenalectomy in ACTH-independent disease, Leonie H. A. Broersen, MD, of the department of medicine at Leiden University Medical Centre in Leiden, Netherlands, wrote in the study background. However, medical therapy can be used to control cortisol secretion preoperatively and as a “bridge” until control of hypercortisolism is achieved by radiotherapy, whereas use of medical therapy as a first-line treatment is increasing, they noted.

“Medical treatment is a reasonable treatment option for Cushing’s disease patients in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery,” Broersen told Endocrine Today. “In case of side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered.”

Broersen and colleagues analyzed data from 35 studies with 1,520 patients reporting on six medical therapies for Cushing’s disease, including studies assessing pasireotide (n = 2; Signifor LAR, Novartis), mitotane (n = 5; Lysodren, Bristol-Myers Squibb), cabergoline (n = 3), ketoconazole (n = 8), metyrapone (n = 5; Metopirone, HRA Pharma), mifepristone (n = 2; Korlym, Corcept Therapeutics) and multiple medical agents (n = 10), all published between 1971 and 2017. Studies included 11 single-arm trials, two randomized controlled trials with two treatment arms, and 22 cohort studies. In 28 studies, normalization of cortisol was measured by urinary free cortisol, midnight salivary cortisol or a low-dose dexamethasone test, with 25 studies reporting on clinical improvement and three studies reporting on quality of life.

Across studies, medical treatment was effective in normalizing cortisol levels in Cushing’s disease in 35.7% (cabergoline) to 81.8% (mitotane) of patients, according to the researchers. In seven studies reporting data separately for medical therapy as primary (n = 4) or secondary therapy (n = 5), researchers found medication as primary therapy normalized cortisol levels in 58.1% of patients (95% CI, 49.7-66.2), similar to the effect of medication as a secondary therapy (57.8%; 95% CI, 41.3-73.6). In studies in which at least 80% of patients with Cushing’s disease were pretreated with medication before surgery, researchers observed a preoperative normalization of cortisol levels in 32.3% of patients (95% CI, 20-45.8). Patients using medical monotherapy experienced a lower percentage of cortisol normalization vs. patients using multiple agents (49.4% vs. 65.7%), according to researchers, with normalization rates higher among patients with concurrent or previous radiotherapy.

Across studies, 39.9% of patients experienced mild adverse effects, and 15.2% experienced severe adverse effects.

“Importantly, medical agents for hypercortisolism can cause severe side effects, leading to therapy adjustment or withdrawal in 4.8% (cabergoline) to 28.4% (mitotane) of patients,” the researchers wrote. “These results suggest that medical therapy can be considered a reasonable treatment alternative to the first-choice surgical treatment when regarding treatment effectiveness and side effects.” – by Regina Schaffer

For more information: Leonie H. A. Broersen, MD, can be reached at l.h.aA.broersen@lumc.nl.

Disclosure: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B294187ce-3f5e-4d3f-b02e-5023515c3b0b%7D/medical-therapy-reasonable-option-vs-surgery-in-cushings-disease

Fluorescent Metabolite Might Help Surgeons Remove Pituitary Tumors

The resection of microadenomas — small, benign tumors in the pituitary gland underlying Cushing’s disease — could be aided by a fluorescent marker that is naturally produced by the tumor, a new study shows.

The findings were presented recently at the 2018 George Washington Research Days in a poster titled, “Enhanced 5-ALA Induced Fluorescence in Hormone Secreting Pituitary Adenomas.

Cushing’s disease is characterized by high cortisol levels that cause debilitating physical, mental, and hormonal symptoms. The excess cortisol is caused by tiny benign tumors in the pituitary gland, called microadenomas, with a size of less than 10 millimeters.

On account of their small size, these microadenomas pose imaging challenges to physicians. Up to 40 percent of microadenomas remain undetected in the gold-standard magnetic resonance imaging (MRI).

Pituitary adenomas, however, have a characteristic that distinguishes them from the surrounding healthy tissue. They process (metabolize) a natural haemoglobin metabolite, called 5-aminolevulinic acid (5-ALA), into protoporphyrin IX (PpIX) at much higher rates — up to 20 to 50 times higher — than normal tissues.

Importantly, PpIX emits red fluorescence when excited with blue light.

This means that exogenous 5-ALA is taken up by the adenoma cells and rapidly metabolized into the fluorescent metabolite, PpIX, which may establish its use for fluorescence-guided resection of pituitary adenomas.

To test this, researchers incubated human-derived corticotropinoma, as well as the adjacent normal gland cells with 5-ALA. They did the same with mouse model normal pituitary cells and a mouse model pituitary tumor cell line, called AtT20.

They then analyzed the cells’ fluorescence profile by microscopy and with a technique called flow cytometry.

The analysis showed that compared to normal pituitary tissue, human-derived adenomatous cells had a significant increase of tenfold in 5-ALA-induced PpIX fluorescence intensity.

Similarly, mouse pituitary tumor cells (AtT20 cell line) fluoresced seven times more intensely than normal murine pituitary tissue.

The microscopy analysis revealed that the 5-ALA localized in subcellular organelles called mitochondria.

On June 6, 2017, the U.S. Food and Drug Administration approved the use of 5-ALA (under the brand name Gleolan) as an optical imaging agent for patients with gliomas (brain tumors), as an add-on compound to assist surgeons in identifying the malignant tissue during surgery.

Now, these findings suggest that 5-ALA also may be used for fluorescence-guided surgery of microadenomas in Cushing’s disease.

“The supraphysiological levels of glucocorticoids, as seen in CD [Cushing’s disease], may enhance the 5-ALA fluorescence in corticotropinomas,” researchers wrote.

From https://cushingsdiseasenews.com/2018/04/13/fluorescent-metabolite-might-help-surgeons-removepituitary-tumors/

Cushing’s Patients at Risk for Autoimmune Diseases After Condition Is Resolved

Children with Cushing’s syndrome are at risk of developing new autoimmune and related disorders after being cured of the disease, a new study shows.

The study, “Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children,” was published in Hormone and Metabolic Research.

Patients with Cushing’s syndrome have excess levels of the hormone cortisol, a corticosteroid that inhibits the effects of the immune system. As a result, these patients are protected from autoimmune and related diseases. But it is not known if the risk rises after their disease is resolved.

To address this, researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined 127 children with Cushing’s syndrome at the National Institutes of Health from 1997 until 2017.

Among the participants, 77.5 percent had a pituitary tumor causing the disease, 21.7 percent had ACTH-independent disease, and one patient had ectopic Cushing’s syndrome. All patients underwent surgery to treat their symptoms.

After a mean follow-up of 31.2 months, 7.8 percent of patients developed a new autoimmune or related disorder.

Researchers found no significant differences in age at diagnosis, gender, cortisol levels, and urinary-free cortisol at diagnosis, when comparing those who developed autoimmune disorders with those who didn’t. However, those who developed an immune disorder had a significantly shorter symptom duration of Cushing’s syndrome.

This suggests that increased cortisol levels, even for a short period of time, may contribute to more reactivity of the immune system after treatment.

The new disorder was diagnosed, on average, 9.8 months after Cushing’s treatment. The disorders reported were celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic nerve inflammation, skin hypopigmentation/vitiligo, allergic rhinitis/asthma, and nerve cell damage of unknown origin responsive to glucocorticoids.

“Although the size of our cohort did not allow for comparison of the frequency with the general population, it seems that there was a higher frequency of optic neuritis than expected,” the researchers stated.

It is still unclear why autoimmune disorders tend to develop after Cushing’s resolution, but the researchers hypothesized it could be a consequence of the impact of glucocorticoids on the immune system.

Overall, the study shows that children with Cushing’s syndrome are at risk for autoimmune and related disorders after their condition is managed. “The presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise,” the researchers stated.

Additional studies are warranted to further explore this link and improve care of this specific population.

From https://cushingsdiseasenews.com/2018/03/06/after-cushings-cured-autoimmune-disease-risk-looms-study/

Benefits of Medication Before Surgery for Cushing’s Syndrome Still Unclear

In Europe, nearly 20 percent of patients with Cushing’s syndrome receive some sort of medication for the disease before undergoing surgery, a new study shows.

Six months after surgery, these patients had remission and mortality rates similar to those who received surgery as a first-line treatment, despite having worse disease manifestations when the study began. However, preoperative medication may limit doctors’ ability to determine the immediate success of surgery, researchers said.

A randomized clinical trial is needed to conclusively address if preoperative medication is a good option for Cushing’s patients waiting for surgery, they stated.

The study, “Preoperative medical treatment in Cushing’s syndrome. Frequency of use and its impact on postoperative assessment. Data from ERCUSYN,” was published in the European Journal of Endocrinology. 

Surgery usually is the first-line treatment in patients with Cushing’s syndrome. But patients also may receive preoperative medication to improve cortisol excess and correct severe diseases occurring simultaneously with Cushing’s.

Multiple studies have hypothesized that preoperative medication can have a beneficial effect on patients who undergo surgery. However, data on the beneficial impact of medication on morbidity, and the immediate surgical and long-term outcomes in patients with Cushing’s syndrome, are limited and inconclusive.

So, researchers made use of the European Registry on Cushing’s Syndrome (ERCUSYN), the largest database that collects information on diagnosis, management, and long-term follow-up in Cushing’s patients.

The team set out to collect information of the prevalence of preoperative medication in Cushing’s patients throughout Europe, and whether it influences patients’ outcomes after surgery. It also aimed to determine the differences between patients who receive preoperative medication versus those who undergo surgery directly.

Researchers analyzed 1,143 patients in the ERCUSYN database from 57 centers in 26 countries. Depending on what was causing the disease, patients were included in four major groups: pituitary-dependent Cushing’s syndrome (68%), adrenal-dependent Cushing’s syndrome (25%), Cushing’s syndrome from an ectopic source (5%), and Cushing’s syndrome from other causes (1%).

Overall, 20 percent of patients received medication – ketoconazole, metyrapone, or a combination of both – before surgery. Patients with ectopic and pituitary disease were more likely to receive medication compared to patients whose disease stemmed from the adrenal glands. Preoperative treatment lasted for a median of 109 days.

Patients in the pituitary group who were prescribed preoperative medication had more severe clinical features at diagnosis and poorer quality of life compared to those who received surgery as first-line treatment. No differences were found in the other groups.

But patients with pituitary-dependent disease receiving medication were more likely to have normal cortisol within seven days of surgery, or the immediate postoperative period, compared to patients who had surgery without prior medication. These patients also had a lower remission rate.

Within six months of surgery, however, there were no differences in morbidity or remission rates observed between each group. Also, no differences were seen in perioperative mortality rates – within one month of surgery.

Interestingly, researchers noted that patients who took medication prior to surgery were less likely to be in remission immediately after surgery. The reason, they suggest, might be because the medication already had begun to improve the clinical and biochemical signs of the disease, “so changes that take place in the first week after surgery may be less dramatic.”

“A randomized trial assessing simple endpoints, such as length of hospital stay, surgical impression and adverse effects of surgery, is needed to conclusively demonstrate that [preoperative medication] is a valid option in patients waiting for surgical correction of hypercortisolism,” the team concluded.

From https://cushingsdiseasenews.com/2018/02/22/benefits-cushings-syndrome-pre-surgery-medication-unclear-study/

Endoscopic and Microscopic Surgery Equally Effective in Cushing’s Disease

Using endoscopic or microscopic techniques to surgically remove the pituitary glands leads to similar remission and recurrence rates in Cushing’s disease patients, a review of 24 studies shows.

The study, titled “Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing’s disease,” was published in the journal Endocrine Connections.

In endoscopic transsphenoidal surgery, a surgeon uses a tiny camera as a guide, allowing for a panoramic surgical view with increased illumination of anatomic structures. In microsurgical transsphenoidal resection, a surgeon views through a microscope and uses minute instruments or lasers. Both procedures are used in transsphenoidal (TS) surgery to remove pituitary gland tumors, the root cause of Cushing’s disease. In transsphenoidal surgery, a surgeon accesses the pituitary gland through the nose and sinuses.

While endoscopic surgery seems to lead to better patient outcomes, it was unclear before this study if it has any advantages in patients with Cushing’s disease.

To gain more insight into the remission and recurrence rates of both techniques, researchers examined a total of 24 studies that included 1,670 adult patients with Cushing’s syndrome. Of these patients, 702 underwent endoscopic TS, and 968 underwent microsurgical TS.

The study’s authors found that remission rates were similar in both groups. In the endoscopic group, an average of 79.7 percent of patients experienced remission versus 76.9 percent in the microscopic group.

Patients who underwent endoscopic surgery experienced recurrence less often than those who underwent microscopic surgery, with recurrence rates of 11 percent and 15.9 percent, respectively. But researchers pointed out that follow-up times in the studies varied, making comparisons unreliable.

When recurrence rates were calculated by person per year, which takes follow-up time into account, both groups had a recurrence rate of approximately 4 percent per person per year.

Previous studies have shown that complications following either type of surgery occurred at comparable rates. These complications include hypothyroidism (underactivity of the thyroid gland), diabetes insipidus (a condition characterized by increased thirst), CSF leakage (leakage of fluid that normally bathes the brain and spinal cord), visual defects, hypocortisolemia (low cortisol blood levels), and hypogonadism (little or no hormones produced by the sex glands).

“We found that overall remission proportion was the same in CD patients who underwent endoscopic TS compared to patients who underwent microscopic TS. However, patients treated with the endoscopic approach for micro-adenomas were more likely to achieve remission than those treated microsurgically. Patients treated endoscopically were less likely to experience recurrence; however, when follow-up time is taken into account, this advantage disappears,” the researchers concluded.

 

From https://cushingsdiseasenews.com/2018/02/01/cushings-disease-transsphenoidal-surgery-study-finds-endoscopic-microscopic-procedures-equally-effective/

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