Temozolomide Effective Against Cushing’s Caused by Aggressive Tumors

The oral chemotherapy temozolomide might be an effective treatment for Cushing’s disease caused by aggressive tumors in the pituitary gland that continue to grow after surgery and taking other medications, a case report suggests.

The study, “Successful reduction of ACTH secretion in a case of intractable Cushing’s disease with pituitary Crooke’s cell adenoma by combined modality therapy including temozolomide,” was published in the journal J-Stage.

Cushing’s disease is often caused by a tumor in the pituitary gland that secretes high levels of adrenocorticotropic hormone (ACTH), leading to high levels of cortisol and other symptoms.

Macroadenomas are aggressive, fast-growing tumors that reach sizes larger than 10 millimeters. Crooke’s cell adenoma is a type of macroadenoma that does not respond to conventional therapies, but has deficient mechanisms of DNA repair. That is why chemotherapeutic agents that damage the DNA, such as temozolomide, might be potential treatments.

Researchers in Japan reported the case of a 56-year-old woman with Cushing’s disease caused by a Crooke’s cell adenoma in the pituitary gland who responded positively to temozolomide.

The patient was diagnosed with Cushing’s disease at age 39 when she went to the hospital complaining of continuous weight gain. She also had excessive production of urine and a loss of vision in the right eye.

The lab tests showed high levels of cortisol and ACTH, and the MRI detected a tumor of 4.5 centimeters in the pituitary gland. The doctors removed a part of the tumor surgically, which initially reduced the levels of ACTH and cortisol.

However, the hormone levels and the size of the residual tumor started to increase gradually after the surgery, despite treatment with several medications.

By the time the patient was 56 years old, she went to the hospital complaining of general fatigue, leg edema (swelling from fluid), high blood pressure, and central obesity (belly fat).

Further examination showed a 5.7 cm tumor, identified as a Crooke’s cell macroadenoma. The patient underwent a second surgery to remove as much tumor as possible, but the levels of ACTH remained high. She took temozolomide for nine months, which normalized the levels of ACTH and cortisol. After the treatment, the patient no longer had high blood pressure or leg edema.

The tumor shrunk considerably in the year following temozolomide treatment. The patient started radiation therapy to control tumor growth. The levels of cortisol and ACHT remained normal, and the tumor did not grow in the seven years following temozolomide treatment.

“These clinical findings suggest that [temozolomide] treatment to patients with Crooke’s cell adenoma accompanied with elevated ACTH may be a good indication to induce lowering ACTH levels and tumor shrinkage,” researchers wrote.

Other cases of Cushing’s disease caused by aggressive macroadenomas showed positive results, such as reduction of tumor size and decrease in plasma ACTH, after temozolomide treatment. However, more studies are needed to establish the ideal course of chemotherapy to treat these tumors, the researchers noted.

From https://cushingsdiseasenews.com/2019/06/18/temozolomide-effective-cushings-disease-aggressive-tumors-case-report/

Novel Therapy Eases Cushing’s Symptoms in Pivotal Trial

by Kristen Monaco, Staff Writer, MedPage Today

LOS ANGELES — An investigational therapy improved quality of life and reduced disease symptoms for patients with endogenous Cushing’s syndrome, according to new findings from the phase III SONICS study.

Patients taking oral levoketoconazole twice daily had significant reductions in mean scores for acne (-1.8), peripheral edema (-0.4), and hirsutism (-2.6), all secondary endpoints of the pivotal trial (P<0.03 for all), reported Maria Fleseriu, MD, of Oregon Health and Science University in Portland.

“We’re looking forward to see the results of further studies and to add this therapy to the landscape of Cushing’s,” Fleseriu said here during a presentation of the findings at AACE 2019, the annual meeting of the American Association of Clinical Endocrinologists. “We have a newer medication and still we cannot make a dent in the outcomes of Cushing’s, especially for patient-reported outcomes.”

Free testosterone levels significantly decreased in women taking levoketoconazole (a ketoconazole stereoisomer and potent steroidogenesis inhibitor), from an average of 0.32 ng/dL down to 0.12 ng/dL (0.011 to 0.004 nmol/L, P<0.0001). Men had a non-significant increase: 5.1 ng/dL up to 5.8 ng/dL (0.177 to 0.202 nmol/L).

There were no significant changes from baseline to the end of maintenance for other secondary endpoints in the analysis: moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation, and dysmenorrhea. However, significant improvements after 6 months of therapy were seen in patient-reported quality of life compared with baseline (mean 10.6 change on the Cushing QOL questionnaire) as well as a significant reduction in depressive symptoms (mean -4.3 change on the Beck Depression Inventory II).

The open-label, multicenter SONICS (Study of Levoketoconazole in Cushing’s Syndrome) trial included 94 adult men and women with a confirmed diagnosis of Cushing’s syndrome and elevated 24-hour mean urinary free cortisol (mUFC) levels at least 1.5 times the upper limit of normal.

In the dose-titration phase of the study (weeks 2 to 21), patients were titrated up to a max dose of 600 mg levoketoconazole twice daily until mUFC normalization. A 6-month maintenance phase followed with no dose increases, but decreases were allowed if adverse events emerged. An additional 6-month extended evaluation phase followed thereafter.

The study met it’s previously reported primary endpoint, with 30% of patients achieving normalized mUFC levels after 6 months of maintenance therapy without a dose increase (95% CI 21%-40%, P=0.0154).

Levoketoconazole was well tolerated, with only 12.8% of patients discontinuing treatment due to adverse events. The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17%), and fatigue (16%), some of which were expected due to steroid withdrawal, Fleseriu said.

Serious adverse events were reported in 14 patients, including prolonged QTc interval in two patients, elevated liver function in one patient, and adrenal insufficiency in another, events similar to those seen with ketoconazole (Nizoral) therapy.

Fleseriu explained that drug-drug interaction is a problem in Cushing’s, as all of the available medications prolong QT interval.

She noted that in SONICS, QT prolongation with levoketoconazole was observed in few patients. It’s still a “concern,” said Fleseriu, especially for patients on other drugs that prolong QT.

Although not yet approved, levoketoconazole has received orphan drug designation from the FDA and the European Medicines Agency for endogenous Cushing’s syndrome. The tentative brand name is Recorlev.

The study was supported by Strongbridge Biopharma.

Fleseriu reported relationships with Strongbridge, Millendo Therapeutics, and Novartis. Co-authors also disclosed relevant relationships with industry.

From https://www.medpagetoday.com/meetingcoverage/aace/79465

Pregnant Women with Hypertension and Hypercortisolism May Have Cushing’s

Pregnant woman with hypertension and significant signs of hypercortisolism (high cortisol levels) may have Cushing’s disease, according to a new case report.

The report, titled “A Case of Cushing’s Syndrome in Pregnancy,” was published in the Iranian Journal of Medical Sciences.

While Cushing’s rarely occurs in women during pregnancy, high cortisol levels can lead to major complications for both the mother and the fetus, such as premature birth and high fetal mortality.

However, it can be difficult to diagnose pathological hypercortisolism in these women as the symptoms might resemble other diseases that commonly occur during pregnancy, such as preeclampsia (high blood pressure during pregnancy) and gestational diabetes.

Unfortunately, there are no effective long-term medical therapies for Cushing’s. The most definitive therapy is the surgical removal of the pituitary or adrenal adenoma, if that is the case of hypercortisolism.

The case report details that a 29-year old women in the 27th week of pregnancy presented to the Ghaem Hospital clinic in Mashhad, Iran, with edema, weakness, and hypertension. Her symptoms also included truncal obesity, moon face (her face had a rounded appearance), purple steria on her upper and lower limbs and abdomen, excessive edema, and wet skin.

At first, she was hospitalized for suspected preeclampsia, but the diagnosis was later excluded.

The patient’s hormonal profile showed high levels of 24-hour urine cortisol. There were also low levels of adrenocorticotropic hormone (ACTH), which results from a negative feedback due to excessive cortisol. However, plasma cortisol is generally elevated during pregnancy, and therefore may not be the best method for diagnosis.

An abdominal ultrasonography revealed a well-defined mass in the right adrenal gland.

While hospitalized, the patient experienced two crises of blood pressure, and while preeclampsia was ruled out, the physicians could find no more plausible explanation than eclampsia (the onset of seizures in a women with preeclampsia).

Since eclampsia was suspected, the physicians terminated the pregnancy at 28th week of gestation using misoprostol. The woman delivered a male infant weighing 1.94 pounds.

Two days after birth, the physicians conducted a computed tomography (CT) scan and again found a mass in the right adrenal gland.

As a result, the patient underwent a laparoscopic right adrenalectomy to remove the mass one week after giving birth. The patient’s blood pressure normalized and cortisol levels declined. Her condition remained stable after surgery.

“Cushing’s syndrome should be considered in hypertensive pregnant patients with remarkable signs of hypercortisolism,” the researchers concluded. “The best results would be achieved through a collaboration between obstetricians, endocrinologists, and surgeons.”

From https://cushingsdiseasenews.com/2017/12/19/pregnant-women-hypertension-hypercortisolism-may-have-cushings-disease/

Ectopic Cushing’s syndrome associated with thoracic tumors

Results of a retrospective review conducted in southern India demonstrate that ectopic Cushing’s syndrome occurred most commonly in association with thoracic tumors.

Researchers added that early control over hypercortisolemia was necessary to prevent metabolic complications and infections, both of which had the potential to be life-threatening.

“As compared to patients with pituitary-dependent Cushing’s syndrome, patients with [ectopic Cushing Syndrome] present with a rapid progression of symptoms,” Nihal Thomas, MD, MNAMS, DNB, FRACP, professor in the department of endocrinology, diabetes and metabolism at Christian Medical College, Vellore, India, and colleagues wrote. “It is also associated with typical features of proximal muscle weakness, severe hypokalaemic metabolic alkalosis, hyperpigmentation, edema, hypertension and glucose intolerance. Early diagnosis and localization of the ectopic source of [adrenocorticotrophic hormone] is crucial, because the treatment of choice in most of these patients is complete excision of the tumor. Localizing the source of excess ACTH continues to be a challenge in most patients.”

Thomas and colleagues reviewed the records of 21 patients treated at a tertiary care center in southern India from 2006 to 2015. The researchers documented patients’ clinical features, history and images from radiological findings and PET scans, as well as details of management, follow-up and outcomes. They also compared those with ectopic Cushing’s syndrome with 20 patients who had Cushing’s disease.

Median age was 34 years. Thomas and colleagues reported that one patient demonstrated “an occult source of ACTH.” The rest had a variety of tumors: bronchial carcinoid (n = 7), thymic carcinoid (n = 7), lung malignancies (n = 3), medullary thyroid carcinoma (n = 2) and pancreatic neuroendocrine tumor (n = 1).

At presentation, muscle weakness was the most common clinical feature (95%), followed by hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%) and striae (52%). Slightly less than half (43%) showed extensive acne. Central obesity in ectopic Cushing’s syndrome was uncommon and occurred in 14% of patients (n = 3), according to Thomas and colleagues; however, it was more prevalent (n = 18) in those with Cushing’s disease.

Median cortisol at 8 a.m. was 55.5 mcg/dL, the researchers wrote, while median 8 a.m. ACTH was 207 pg/mL. The median 24-hour urinary free cortisol level was 2,484 mcg.

Compared with patients with Cushing’s disease, those with ectopic Cushing’s syndrome had “markedly higher” midnight cortisol and ACTH, as well as basal cortisol and ACTH.

During follow-up, more than half of patients (12 of 21) with ectopic Cushing’s syndrome developed life-threatening infections. Although nine patients received surgery for their tumors, only one patient achieved a complete cure during the study period, the researchers wrote.

“In our series, patients with [ectopic Cushing’s syndrome] have more profound hypokalemia, and hypercortisolemia with higher levels of ACTH,” Thomas and colleagues wrote. “The prognosis of patients with [ectopic Cushing’s syndrome] was dependent on tumor histology. The role of a timely adrenalectomy needs to be considered in patients with hypercortisolemia unresponsive to medical management, and in patients with metastatic or recurrent disease.” – by Andy Polhamus

Disclosure: Endocrine Today was unable to confirm any relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Be42c81a5-fd5b-4313-9b2b-9bcbdec7f8ce%7D/ectopic-cushings-syndrome-associated-with-thoracic-tumors

When to think Cushing’s syndrome in type 2 diabetes

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

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