Temozolomide May Partially Improve Aggressive Pituitary Tumors Causing Cushing’s Disease

The chemotherapy temozolomide partially improved a case of an aggressive pituitary tumor that caused symptoms of Cushing’s disease (CD), according to a new study in Poland. However, after tumor mass and cortisol levels were stabilized for a few months, the patient experienced rapid progression, suggesting that new methods for extending the effects of temozolomide are needed.

The study, “Temozolomide therapy for aggressive pituitary Crooke’s cells corticotropinoma causing Cushing’s Disease: A case report with literature review,” appeared in the journal Endokrynologia Polska.

Aggressive pituitary tumors are usually invasive macroadenomas, or benign tumors larger than 10 mm.

A very rare subset of pituitary adenoma — particularly corticotropinoma, or tumors with excessive secretion of corticotropin (ACTH) — exhibit Crooke’s cells. These tumors are highly invasive, have a high recurrence rate, and are often resistant to treatment.

Information is not widely available about the effectiveness of treating aggressive pituitary tumors, particularly those that cause Cushing’s disease. The management of these tumors usually requires neurosurgery, followed by radiotherapy, and pharmacotherapy. However, the chemotherapy medication temozolomide has been increasingly used as a first-line treatment after initial evidence of its effectiveness in treating glioblastoma, the most common form of brain cancer.

In this study, researchers at the Jagiellonian University, in Poland, discussed the case of a 61-year-old man with ACTH-dependent Cushing’s syndrome caused by Crooke’s cell corticotropinoma.

The patient first presented with symptoms of severe hypercorticoidism — the excessive secretion of steroid hormones from the adrenal cortex — in December 2011. He also showed advanced heart failure, severe headaches, and impaired vision, which had started two or three years before diagnosis. Examinations revealed osteoporosis and a fracture in the Th5 vertebra.

His morning ACTH levels were high. The same was observed for mean cortisol levels even after dexamethasone treatment, which was suggestive of a pituitary tumor secreting ACTH. MRIs showed the existence of a tumor mass, later identified as a macroadenoma with high cell polymorphism, the presence of Crooke’s cells, and ACTH secretion.

The patient was referred for transsphenoidal nonradical neurosurgery, performed through the nose and the sphenoid sinus, and bilateral adrenalectomy, or the surgical removal of the adrenal glands, in 2012-2013. However, he developed fast, postoperative recurrence of hypercorticoidism and tumor regrowth. This led to three additional transsphenoidal neurosurgeries and radiotherapy.

The patient’s clinical status worsened as he developed severe cardiac insufficiency. Doctors began temozolomide treatment in April 2015, which did not result in adverse effects throughout treatment.

The initial standard dose (150–200 mg/m2) was given once daily in the morning for five consecutive days, in a 28-day cycle. The patient also received 600 mg of ketoconazole, an antifungal medication. Ondansetron was administered to prevent nausea and vomiting.

Subsequent examinations revealed clinical and biochemical improvements, including a reduction in ACTH and cortisol levels. In addition, the patient also showed reduced cardiac insufficiency, less frequent and less severe headaches, visual field improvements, and better physical fitness and mood.

However, clinical symptoms worsened after the eighth temozolomide cycle. The tumor size also suddenly increased after the ninth cycle, reaching the inner ear. Temozolomide was then discontinued and ACTH levels increased by 28 percent one month later. The patient also demonstrated deteriorated vision, hearing loss, and strong headaches.

Clinicians then decided to start treatment with the Cushing’s disease therapy Signifor (pasireotide), but a worsening of diabetes was observed, and the patient died in February 2016.

“The most probable reason for death was compression of the brainstem, which had been observed in the last MRI of the pituitary,” the researchers wrote, adding that “due to the very short duration of treatment, any conclusions on the treatment with Signifor cannot be drawn.”

Overall, “the results of the presented case suggest that [temozolomide] treatment monotherapy could have only partial response in aggressive corticotroph adenoma causing Cushing’s disease, followed by sudden progression,” the investigators wrote. This contrasts with mostly responsive cases reported in research literature, they noted.

“Therefore, further research on the factors of responsiveness and on novel methods to extend the duration of the effect of [temozolomide] should be carried out,” they wrote.

From https://cushingsdiseasenews.com/2018/02/08/cushings-disease-case-study-poland-shows-temozolomide-temporarily-effective-treating-aggressive-pituitary-tumor/

Common Cushing’s Treatment, Somatostatin Analogs, May Sometimes Worsen Disease Course

Doctors often prescribe somatostatin analogs to manage the hormonal imbalance that characterizes Cushing’s syndrome. However, in rare situations these medicines have paradoxically made patients worse than better.

This recently happened with a 48-year-old Spanish woman whose Cushing’s syndrome was caused by an adrenal gland tumor that was producing excess adrenocorticotropic hormone (ACTH). Her case was recently reported in the study “Ectopic Cushing’s syndrome: Paradoxical effect of somatostatin analogs,” and published in the journal Endocrinología, Diabetes y Nutrición.

Cushing’s syndrome occurs when the body produces too much cortisol. This can happen for many reasons, including an oversupply of ACTH, the hormone responsible for cortisol production, due to a tumor in the pituitary gland.

But sometimes, tumors growing elsewhere can also produce ACTH. This feature, known as ectopic ACTH secretion (EAS), may also cause ACTH-dependent Cushing’s syndrome.

Two-thirds of EAS tumors are located in the thorax, and 8 to 15 percent are in the abdominal cavity. Only 5 percent of EAS tumors are located in the adrenal gland, and up to 15 percent of EAS tumors are never detected.

Doctors usually use cortisol synthesis inhibitors such as ketoconazole or Metopirone (metyrapone) to control EAS, due to their efficacy and safety profiles. But somatostatin analogs (SSAs) such as Somatuline (lanreotide) have also been used to treat these tumors. However, these drugs produce mixed results.

The woman in the case study, reported by researchers at the University Hospital Vall d’Hebron in Barcelona, Spain, had an EAS tumor on the adrenal gland. She experienced s life-threatening cortisol and ACTH increase after receiving high-dose Somatuline.

The patient had been recently diagnosed with hypertension, and complained of intense fatigue, muscular weakness, easy bruising and an absence of menstruation. Laboratory analysis revealed that she had triple the normal levels of free cortisol in the urine, elevated levels of plasma cortisol, and high ACTH levels. In addition, her cortisol levels remained unchanged after receiving dexamethasone. The patient was therefore diagnosed with ACTH-dependent Cushing syndrome.

To determine the origin of her high cortisol levels, the team conducted magnetic resonance imaging (MRI). They found no tumors on the most common places, including the pituitary gland, neck, thorax or abdomen. However, additional evaluation detected a small alteration on the left adrenal gland, suggesting that was the source of ectopic ACTH production.

The team initiated treatment with 120 mg of Somatuline, but a week later, her condition had worsened and become life-threatening. Doctors started Ketoconazole treatment immediately, three times daily. The affected adrenal gland was surgically removed, and tissue analysis confirmed the diagnosis. The patient’s clinical condition improved significantly over the follow-up period.

“We highlight the need to be aware of this rare presentation of EAS, and we remark the difficulties of EAS diagnosis and treatment,”  researchers wrote.

The team could not rule out the possibility that the patient’s clinical development was due to the natural course of the disease. However, they believe “she had a paradoxical response on the basis of her dramatical worsening just after the SSAs administration, associated to an important rise in ACTH and UFC levels.”

For that reason, researchers think a new version of SSAs, such as Signifor (pasireotide) — which has improved receptor affinity — could provide better therapeutic response.

From https://cushingsdiseasenews.com/2017/11/09/paradoxical-effects-of-somatostatin-analogs-on-adrenal-ectopic-acth-tumor/

Long-acting Signifor Has Similar Safety Profiles as Twice-daily Treatment in Cushing’s Patients, Trial Showed

A long-acting, once-a-month treatment of Signifor (pasireotide) normalized cortisol levels in 40% of patients with Cushing’s disease whose disease had recurred after surgery, or who were not candidates for surgery, according to new data from a Phase 3 trial.

The safety profiles of the once-monthly regimen proved to be similar to standard twice-daily Signifor treatments, researchers found.

The study, “Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial,” was published in the journal The Lancet Diabetes & Endocrinology.

Novartis‘ Signifor in its twice-daily injection formulation has already been approved for treating Cushing’s in the U.S. and elsewhere.

The 12-month, Phase 3 trial (NCT01374906) was conducted at 57 sites in 19 countries. The study included 150 patients with Cushing’s whose cortisol levels had risen or not dropped at all after surgery, or who were unable to undergo surgery.

Between Dec. 28, 2011, and Dec. 9, 2014, participants were randomized to receive either 10 mg or 30 mg of Signifor every four weeks, via an injection to the muscle. If, after four months of therapy, cortisol urinary levels (mUFC) were 50% greater than the upper normal limit, the dose could be increased from 10 mg to 30 mg, or from 30 mg to 40 mg. It could also be increased after seven, nine, or 12 months if the mUFC concentration was greater than normal.

The goal was to normalize average concentrations of free cortisol in the urine to less than or equal to the upper normal limit at month seven. It was met by 31 of the 74 patients in the 10 mg group (41.9%) and 31 of the 76 patients in the 30 mg group (40.8%).

The most common adverse events were hyperglycemia (high concentration of blood sugar), diarrhea, cholelithiasis (gall stones), diabetes, and nausea.

The researchers consider this treatment to be a good option for patients whose disease has returned after surgery, or who cannot undergo surgery. The long-lasting treatment schedule of one injection per month is more convenient for patients than the twice-daily subcutaneous injection, making it more likely that they would not discontinue treatment.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” wrote Dr. Andre Lacroix, MD, a professor in the Department of Medicine at the University of Montreal teaching hospital, and colleagues.

“However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

“Long-acting pasireotide normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide,” the team wrote in the study.

“Long-acting pasireotide is an efficacious treatment option for some patients with Cushing’s disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule,” researchers concluded.

From https://cushingsdiseasenews.com/2017/10/31/long-acting-signifor-for-cushings-disease-has-similar-efficacy-and-safety-as-twice-daily-treatment/

A Single-Center 10-Year Experience with Pasireotide in Cushing’s Disease: Patients’ Characteristics and Outcome

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing’s disease (CD). Our 10-year experience with pasireotide in CD is reported here.

Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor®; Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months).

Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients.

Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

From http://www.ncbi.nlm.nih.gov/pubmed/27127913

Global Cushing’s Syndrome Market Size 2015

Cushing’s as money makers for drug companies 😦

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Steroidogenesis inhibitors were responsible for approximately 28% of total drug sales in the 6MM in 2013, equating to around $50m. As a consequence of this trend, GlobalData expects overall revenues generated by this drug class to increase by approximately 390% to reach around $247m, encompassing 49% of total drug sales in the 6MM in 2018.

The expansion in this segment of the CS market is fuelled by the introduction of premium-priced pharmacological agents such as Novartis’ LCI699 and Cortendo AB’s NormoCort (COR-003) in the US, as well as the arrival of HRA Pharma’s Ketoconazole HRA (ketoconazole) to the European CS stage. One of the greatest unmet needs in this indication is a lack of effective drugs directed against the underlying cause of Cushing’s disease (the pituitary tumor).

Despite this demand, pharmaceutical companies are continuing to adopt a strategy that simply targets the adrenal glands. As a result, there is a vast amount of room for new or existing players to penetrate the market and capture considerable patient share.

Highlights

Key Questions Answered

Although the current standard of care (ketoconazole) is cheap and reasonably effective in most CS patients, it possesses worrying safety profiles, inconvenient dosing schedules, is difficult to obtain and can display waning efficacy over time. Newer medical treatments, for example, Novartis’ Signifor (pasireotide) and Corcept Therapeutics’ Korlym (mifepristone) address only some of these issues; yet, present their own limitations. The CS market is still marked by the existence of a multitude of unmet needs. What are the main unmet needs in this market? Will the drugs under development fulfil the unmet needs of the CS market?

The late-stage CS pipeline is sparsely populated; however, those drugs in development will be a strong driver of CS market growth. Which of these drugs will attain high sales revenues during 2013-2018? Which of these drugs will have the highest peak sales at the highest CAGR, and why?

Key Findings

One of the main drivers influencing growth in the Cushing’s syndrome market will be the introduction of second-generation steroidogenesis inhibitors, LCI699 and NormoCort (COR-003), in the US, which will rival existing standard of care medical treatments.

Another strong driver will be the arrival of Corcept Therapeutics’ Korlym (mifepristone) and HRA Pharma’s Ketoconazole HRA (ketoconazole) to the European CS market. Both drugs will stimulate significant growth here.

The launch of Novartis’ Signifor LAR (pasireotide) in the 6MM will equip physicians with a less frequently administered formulation of Signifor.

Reasons for inadequate CS treatment include poor physician awareness of the condition, delayed diagnosis, a lack of efficacious drugs for individuals suffering from severe hypersecretion, and a shortage of effective medicines targeting the source of Cushing’s disease.

Scope

Overview of Cushing’s syndrome, including epidemiology, etiology, pathophysiology, symptoms, diagnosis, and treatment guidelines.

Annualized Cushing’s syndrome therapeutics market revenues, annual cost of therapies and treatment usage pattern data from 2013 and forecast for five years to 2018.

Key topics covered include strategic competitor assessment, market characterization, unmet needs, clinical trial mapping and implications for the Cushing’s syndrome therapeutics market.

Pipeline analysis: comprehensive data split across different phases, emerging novel trends under development, and detailed analysis of late-stage pipeline drugs.

Analysis of the current and future market competition in the global Cushing’s syndrome therapeutics market. Insightful review of the key industry drivers, restraints and challenges. Each trend is independently researched to provide qualitative analysis of its implications.

Reasons to buy

Develop and design your in-licensing and out-licensing strategies through a review of pipeline products and technologies, and by identifying the companies with the most robust pipeline. Additionally a list of acquisition targets included in the pipeline product company list.

Develop business strategies by understanding the trends shaping and driving the Cushing’s syndrome therapeutics market.

Drive revenues by understanding the key trends, innovative products and technologies, market segments, and companies likely to impact the Cushing’s syndrome therapeutics market in the future.

Formulate effective sales and marketing strategies by understanding the competitive landscape and by analysing the performance of various competitors.

Identify emerging players with potentially strong product portfolios and create effective counter-strategies to gain a competitive advantage.

Track drug sales in the 6MM Cushing’s syndrome therapeutics market from 2013-2018.

Organize your sales and marketing efforts by identifying the market categories and segments that present maximum opportunities for consolidations, investments and strategic partnerships.

From http://www.medgadget.com/2015/10/global-cushings-syndrome-market-size-2015-share-trend-analysis-price-research-report-forecast.html

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