Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

Fluconazole Found to Be Safe Alternative for Patient with Recurrent Cushing’s

Treatment with fluconazole after cabergoline eased symptoms and normalized cortisol levels in a patient with recurrent Cushing’s disease who failed to respond to ketoconazole, a case study reports.

The case report, “Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing’s Disease: A Case Report,” was published in the International Journal of Endocrinology Metabolism.

Ketoconazole, (brand name Nizoral, among others) is an anti-fungal treatment used off-label for Cushing’s disease to prevent excess cortisol production, a distinct symptom of the disease. However, severe side effects associated with its use often result in treatment discontinuation and have led to its unavailability or restriction in many countries.

Consequently, there is a need for alternative medications that help manage disease activity and clinical symptoms without causing adverse reactions, and that could be given to patients who do not respond to ketoconazole treatment.

In this case report, researchers in Malaysia reported on a 50-year-old woman who fared well with fluconazole treatment after experiencing severe side effects with ketoconazole.

The woman had been in remission for 16 years after a transsphenoidal surgery — a minimally invasive brain surgery to remove a pituitary tumor — but went to the clinic with a three-year history of high blood pressure and gradual weight gain.

She also showed classic symptoms of Cushing’s disease: moon face, fragile skin that bruised easily, and purple stretch marks on her thighs.

Blood and urine analysis confirmed high cortisol levels, consistent with a relapse of the pituitary tumor. Accordingly, magnetic resonance imaging (MRI) of her brain showed the presence of a small tumor on the right side of the pituitary gland, confirming the diagnosis of recurrent Cushing’s disease.

Doctors performed another transsphenoidal surgery to remove the tumor, and a brain MRI then confirmed the success of the surgery. However, her blood and urine cortisol levels remained markedly high, indicating persistent disease activity.

The patient refused radiation therapy or adrenal gland removal surgery, and was thus prescribed ketoconazole twice daily for managing the disease. But after one month on ketoconazole, she experienced low cortisol levels.

Hydrocortisone — a synthetic cortisol hormone — was administered to maintain steady cortisol levels. However, she developed severe skin itching and peeling, which are known side effects of ketoconazole. She also suffered a brain bleeding episode, for which she had to have a craniotomy to remove the blood clot.

Since she experienced adverse effects on ketoconazole, which also hadn’t decreased her disease activity, the doctors switched her to cabergoline. Cabergoline (marketed as Dostinex, among others) is a dopamine receptor agonist that has been shown to be effective in managing Cushing’s disease.

But cabergoline treatment also did not lower the disease activity, and her symptoms persisted.

The doctors then added fluconazole (marketed as Diflucan, among others), an anti-fungal medication, based on studies that showed promising results in managing Cushing’s syndrome. Three months after the addition of fluconazole to her treatment plan, the patient’s clinical symptoms and cortisol levels had responded favorably.

At her next clinical visit 15 months later, her condition remained stable with no adverse events.

“This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing’s disease,” the researchers wrote.

The favorable outcome in this case also “supports the notion that fluconazole is a viable substitute for ketoconazole in the medical management of this rare but serious condition,” they concluded.

From https://cushingsdiseasenews.com/2018/09/27/fluconazole-safe-effective-alternative-recurrent-cushings-patient-case-report/

Transsphenoidal Surgery Is Safe and Effective Treatment for Cushing’s Disease

Transsphenoidal surgery, a minimally invasive surgery to remove tumors in the pituitary gland, is safe and effective to treat Cushing’s disease, a 20-year history of cases in a Belgian hospital shows.

The surgery resulted in high remission rates (83%) in patients. It was also found to be safe, rarely leading to insufficient functioning of the pituitary gland.

The study, “Outcome of transsphenoidal surgery for Cushing’s Disease: a single-center experience over 20 years,” was published in the journal World Neurosurgery.

Surgical removal of tumors in the pituitary gland of the brain remains the gold standard for Cushing’s disease treatment.

Transsphenoidal surgery (TSS) usually leads to good remission rates ranging from 68-95%, depending on the location and type of tumor, the neurosurgeon’s expertise, follow-up period, and the definition of remission.

Today, TSS consists of surgery directed through the nose to get to the bottom of the skull, where the pituitary gland is located. The tumor is reached via the nasal cavity with no need for incisions on the face.

To address the safety and effectiveness of this type of surgery for treating Cushing’s, researchers retrospectively reviewed the outcome of 71 patients who received their first TSS at Saint-Luc Hospital, Belgium, between 1996 and 2017. Patients were followed for an average of 6.8 years (82 months).

Surgeons used a type of TSS that is image-guided with the help of a microscope which magnifies the surgeon’s vision.

Remission was defined as normal fasting cortisol level, normal 24-hour urinary-free cortisol, or prolonged need for hydrocortisone replacement for one year after surgery.

Replacement therapies are sometimes needed when the pituitary is not producing enough cortisol after surgery.

Patients were mostly women, ages 15 to 84. Some of them, 32%, required multiple surgeries.

In total, 46 patients out of 71 were in remission after the first surgery, 11 after the second surgery, one after the third, and one after the fourth intervention.

A successful first surgery, resulting in a one-year remission, was a positive indicator for patients, as it was associated with high final remission rates (95%).

However, if the first surgery failed, only 36% of patients achieved a final remission.

“Obtaining a lasting remission after a first TSS could be an interesting parameter to influence future therapeutic decisions [like] performing repeated surgery rather than choosing second-line therapies,” researchers wrote.

Overall, remission was achieved in 83% of patients who underwent a single or multiple TSS intervention, a recurrence rate comparable to previous reports.

Surgery was particularly successful for curing patients with macroadenomas — tumors larger than 10 mm — leading to a 92% remission rate.

Small tumors that were not visible on magnetic resonance imaging (MRI) scans were more difficult to treat, with only 71% of patients being cured. Still, such a remission rate was better than what is commonly reported for MRI-negative tumors. This is likely explained by a higher level of expertise by the surgeon.

Levels of cortisol one day after TSS were significantly lower in patients with long-term remission. However, high levels were still observed in a few patients, especially those who had Cushing’s disease for many years.

“Therefore, high cortisol levels in the postoperative early days do not always indicate persistent disease and later [cortisol] evaluation is warranted,” the researchers wrote.

Most complications from surgery were minor and transient, except for seven patients who developed diabetes. Only 8.8% of patients developed long-term failure of the pituitary gland, likely because physicians favored a less aggressive intervention plan to leave the pituitary gland as intact as possible.

However, such an approach may also explain why some patients had to undergo multiple surgeries to completely remove the tumor.

In addition, a longer duration of Cushing’s disease symptoms and higher cortisol levels before surgery could significantly predict a poorer likelihood of being cured by TSS.

“Neuronavigation-guided microscopic TSS is a safe and effective primary treatment for [Cushing’s disease], allowing high remission rates,” the researchers wrote.

From https://cushingsdiseasenews.com/2018/07/26/transsphenoidal-surgery-safe-effective-treatment-cushings-disease/

Cushing’s Syndrome Eludes Treatment Paradigm or Standard Approach to Care

Results of two systematic reviews indicate that while surgery is the preferred treatment, many patients present with contraindications without an accepted management paradigm leaving clinicians to follow a patient-centric approach to care.

With commentary by Eliza B. Geer, MD

Cushing’s syndrome may arise from an endogenous glucocorticoid excess is either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent; each variation has numerous underlying causes, including pituitary tumor, adrenal tumor, or other unknown causes.

Although rare, ectopic Cushing’s syndrome results from a non-pituitary ACTH-producing source. Cushing’s disease, a type of Cushing’s syndrome, affects an estimated 1.2 to 2.4 million people each year, and is caused by an ACTH-secreting pituitary adenoma.1

While surgery is preferred for treatment of Cushing's syndrome many patients need a medical approach instead.

Gaining insights into treatment preferences and efficacy for Cushing’s syndrome were the focus of two separate systematic reviews and meta-analyses, both published in the journal, Pituitary: one regarding medical treatments for Cushing’s syndrome,2 and the other comparing endoscopic versus microscopic transsphenoidal surgery for Cushing’s disease.3

Assessing Medical Management of Cushing’s Syndrome

The meta-analysis examining medical care of individuals with Cushing’s syndrome encompassed 1520 total patients across 35 studies, most of whom had Cushing’s disease.2 However, only 2 of the 35 studies were randomized trials, highlighting the lack of and clear need for controlled clinical trials on medical therapies for Cushing’s syndrome.

Surgery is typically first-line treatment—whether transsphenoidal pituitary adenomectomy for Cushing’s disease,4 removal of the ACTH-producing tumor in ectopic Cushing’s syndrome or adrenalectomy in ACTH-independent Cushing’s syndrome.5

However, many patients require medical therapy owing to contraindications for surgery, for recurrent disease, or to control cortisol secretion prior to surgery or radiotherapy. Results of the meta-analysis reflected wide-ranging normalization of cortisol levels depending upon the agent used– from 35.7% for cabergoline to nearly 82% for mitotane in Cushing’s disease.2 Combination therapy (medications used either together or sequentially) was shown to increase effectiveness in normalizing cortisol levels.2

In an interview with EndocrineWeb, Eliza B. Geer, MD, medical director of the Multidisciplinary Pituitary and Skull Base Tumor Center at Memorial Sloan Kettering Cancer Center in New York City, noted that most medical therapies for Cushing’s syndrome are used off-label (in the US), and thus may lack clinical trial efficacy and safety data; consequently, this review provides useful information for treatment selection. However, Dr. Geer said there was substantial diversity of treatments reviewed in this paper – including tumor-directed therapies, cortisol synthesis inhibitors, an adrenolytic therapy, and a receptor blocker, used alone or in combination.

Further, treatments used in the studies addressed a range of Cushing’s etiologies and reflected heterogeneous study designs (for example follow-up ranged from 2 weeks to 11.5 years).2  As such, she said, “findings provided by this review should be viewed in the context of a broader clinical understanding of Cushing’s treatment.”

Specifically, Dr. Geer said, “Dr. Broersen’s analysis found that efficacy of medical therapy was improved by prior radiotherapy. But we know that radiotherapy is recommended on an individualized basis in only a fraction of Cushing’s patients, depending on tumor behavior and treatment history. Also, the fact that mitotane was shown here to have the highest efficacy of all therapies does not make this the appropriate treatment for all, or even most, Cushing’s patients; mitotane is adrenolytic and has a high rate of significant adverse effects.”

Too Many Questions Persist, Necessitating Focus on Attaining Management Paradigm

Dr. Geer also highlighted the need for answers to basic questions when investigating Cushing’s treatments: How do we define ‘successful’ treatment? What goals of care can patients expect? Which cortisol measurements and cut-offs can be used? How do we define clinical remission—resolution of which symptoms and comorbidities? She said Cushing’s syndrome is one of the most challenging endocrine diseases to treat because of the lack of an accepted, universal treatment or management paradigm.

Treatment is often multimodal and always multidisciplinary, with patient-specific decision trees that must consider many factors, including goals of care, treatment history, disease etiology and severity, tumor behavior, and individual responses to medical therapies, she told EndocrineWeb.

She concluded, “While Broersen et al’s study provides a useful review of available medical therapies, it reinforces something we already know about the treatment of Cushing’s: Expertise is required.”

Pituitary surgery is first-line treatment for Cushing’s disease. Currently, there are two main techniques for transsphenoidal pituitary surgery: microscopic and endoscopic. The operating microscope provides three-dimensional vision and may be advantageous in identifying small tumors; the broader field of vision afforded by the endoscope may be advantageous for complete resection of large tumors.3  Generally, despite an absence of studies directly comparing relative remission and complication rates between microscopic versus endoscopic approaches, most surgical centers choose to use one or the other; few have both.3

Examining the Surgical Options to Manage Cushing’s Disease

The second systematic review is the first to compare remission and recurrence rates, and mortality after microscopic versus endoscopic transsphenoidal pituitary surgery for Cushing’s disease.3 The review included 97 studies of 6695 patients: 5711 individuals having the microscopic procedure and 984 undergoing endoscopic surgery.

Results of the meta-analysis found no clear difference between the two techniques in overall remission (80%) or recurrence (10%).3 Short-term mortality for both techniques was < 0.5%. However, endoscopic surgery was associated with a greater occurrence of cerebrospinal fluid leak (12.9 vs 4.0%) but a lesser occurrence of transient diabetes insipidus (11.3 vs 21.7%).3

The authors reported a higher percentage of patients in remission (76.3 vs. 59.9%) and lower percentage recurrence rates (1.5 vs 17.0%) among patients undergoing endoscopic surgery for macroadenomas.3

When interviewed regarding the second meta-analysis,3 Dr. Geer said that the potential benefit of endoscopy over microscopy has been questioned for ACTH-secreting tumors specifically since most are microadenomas.

“With the caveat that few studies (four of the 97 reviewed) compared techniques directly, Broersen et al3 found that endoscopic surgery was associated with higher remission rates compared to microscopic surgery for large tumors, but the two techniques were comparable for small tumors,” said Dr. Geer, however, “one limitation of these data is the lack of standardized criteria to define diagnosis and remission of Cushing’s among the studies reviewed.”

Need for Consistency in Clinical Trials and Surgical Expertise

The study investigators concluded, “endoscopic surgery for patients with Cushing’s disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery,” despite the greater learning curve associated with endoscopic surgery.3 As such, based on their findings, the authors concluded that “endoscopic surgery may thus be considered the current standard of care. Microscopic surgery can be used based on neurosurgeon’s preference.” They did not respond to EndocrineWeb for a request for comment.

As more neurosurgeons receiving training with the endoscope, the preferred technique for pituitary surgery is changing. Dr. Geer said, “Broersen’s review provides reassurance that the newer endoscopic technique is at least equal to the microscope for microadenomas and may be preferred for macroadenomas.”

“However, [conclusions based on the systematic review] do not change our role as endocrinologists treating Cushing’s disease, which is to refer, when indicated, to the available neurosurgeon with the most favorable outcomes and lowest rate of complications, both of which depend directly on level of experience with the procedure and the instrument being used, whether endoscope or microscope,” she said.

The authors had no financial conflicts to declare.

From https://www.endocrineweb.com/professional/cushings/cushings-syndrome-eludes-treatment-paradigm-standard-approach-care

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