E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Not a Bad Accident After All (#143)

Mimi Wong 1 2 , Usman Malabu 2 3 , Ipeson Korah 4 , YongMong Tan 2 3
  1. School of Medicine, University of Queensland, Brisbane, QLD, Australia
  2. Department of Diabetes & Endocrinology, Townsville University Hospital, Townsville, Queensland, Australia
  3. School of Dentistry & Medicine, James Cook University, Townsville, Queensland, Australia
  4. Department of Radiology, Townsville University Hospital, Townsville, Queensland, Australia

Introduction:

This case describes a 60-year-old female with persistent Cushing’s disease (CD) following transphenoidal surgery, who was treated with subcutaneous (SC) pasireotide for over 10 years, of which 6 years was inadvertently administered at a lower dose than conventionally recommended. Currently there is limited literature on long-term and low-dose pasireotide use in CD.

 

Case Presentation:

A 60-year old female was diagnosed with CD in June 2009. Ten years before that she had a coronary artery bypass graft for ischaemic heart disease, but no history of diabetes or hypertension. She had presented with a two-month history of fluid retention, increased perioral hair, easy bruising, weight gain, proximal muscle weakness, polydipsia and nocturia. On physical examination she was hypertensive with blood pressure (BP) of 150/100 mmHg and showed Cushingoid features of rounded facies, abdominal bruising and peripheral oedema. There was no visual field defect or cranial nerve palsies. Hypercortisolism from CD was confirmed by 24-hour urinary free cortisol (UFC) (4450 nmol/day; reference range 80 – 590 nmol/day), low and high dose dexamethasone suppression test and MRI revealing a right sided pituitary macroadenoma measuring 10.6 x 12.7 x 14.9 mm respectively of height, transverse and anterior-posterior dimensions with pituitary stalk deviation to the left and encompassment of the right internal carotid artery (figure 1A).

Transphenoidal debulking surgery was pursued in August 2009. As the pituitary macroadenoma was in close proximity to the internal carotid artery, complete resection was not possible. Pituitary MRI two months post-surgery showed a residual right-sided non-enhancing heterogeneous mass of 6.6 x 5.5 x 8.5 mm (figure 1B). Post-operatively she had ongoing Cushingoid features and biochemically still had hypercortisolism though it had improved (figure 2) (UFC 860 nmol/day).

In view of ongoing residual CD, in September 2009 she was commenced on SC pasireotide, inadvertently self-administered as 360mcg twice daily (BID). Within one month of pasireotide treatment, her UFC had normalised (240 nmol/day), and within a year she was clinically in remission. She became normotensive with BP of 100/80 mmHg and her Cushingoid features resolved.

She continued with SC pasireotide 360mcg BID from September 2009 to June 2015 when a medication audit discovered the mistaken lower dose and SC pasireotide dose was corrected to 600mcg BID. While on the lower pasireotide dose her diabetes was well controlled on metformin 2g daily and gliclazide modified release (MR) 30mg daily (figure 3). Her HbA1c was 6.8% after one year on low-dose pasireotide and 7.0% in May 2015, just prior to cessation of the low-dose pasireotide. Progress pituitary MRI over the 6 years on low-dose SC pasireotide revealed her residual tumour as measuring 8.2 x 6.6 x 12 mm (figure 1C), and did not show any residual tumour mass reduction despite her normal biochemistry (figure 2).

From June 2015 she started the higher dose SC pasireotide 600mcg BID. She has been on this higher dose for 5 years and remains in clinical and biochemical remission (figure 2). Despite the higher pasireotide dose and the addition of cabergoline 0.5mg twice a week from December 2014, there has not been any reduction in her residual pituitary mass on MRI (figure 1D). The higher dose pasireotide however has worsened her glycaemic control (figure 3) with HbA1c rising to 7.5% within 3 months. Despite increasing her gliclazide MR to 120mg and adding empagliflozin 10mg daily and sitagliptin 100mg daily to her metformin, her HbA1c progressively rose to 8.2% after 5 years of high-dose pasireotide. She has now commenced basal glargine insulin.

 

Discussion:

Cushing’s disease (CD) is rare and the duration patients have hypercortisolism is predictive of morbidity and mortality, therefore achieving remission is important (1). First line treatment for CD is with transphenoidal surgery, with medical therapies suggested in those who are not surgical candidates or have persistent or recurrent disease (2). Corticotroph adenomas express somatostatin receptors (SSTR) and dopamine receptors, and both can be therapeutic targets (1, 2). Pasireotide is a somatostatin analogue, which binds to four of the five SSTR, with the highest affinity to SSTR-5, and can be used in the treatment of CD to improve Cushingoid features, pituitary volume and quality of life. The US Endocrine Society Clinical Guidelines recommends commencing SC pasireotide at 600mcg BID in CD. Pasireotide is generally well tolerated, though common adverse effects include symptoms related to administration, hyperglycaemia, gastrointestinal symptoms, cholelithiasis and liver derangement (2).

Low-dose, 360mcg BID, pasireotide was used to treat our patient for 6 years and she remained in clinical and biochemical remission throughout this period. This dosage appears to be the lowest dose of pasireotide in the literature used initially to treat CD. Feelders et al used 250mcg SC three times daily to treat patients with CD and achieved normalisation of UFC in 29% (3). Additionally there are case reports of low-dose SC pasireotide 150 - 300mcg BID being used in CD to maintain remission following initial treatment with 600 – 900mcg BID (4, 5). In these cases down titration was necessary due to development of adrenal insufficiency.

Amongst studies that compared the safety profile of patients managed with SC pasireotide 600mcg and 900mcg BID, there were increased rates of hyperglycaemia observed with higher doses (6). Pasireotide can bind to SSTR on pancreatic islet cells and K and L cells, reducing insulin, glucagon-like peptide-1 and glucose-independent insulinotropic polypeptide levels, and subsequently lead to hyperglycaemia (7). In our case, on low-dose pasireotide our patient’s glycaemic control was well controlled over the 6 years. Following high-dose, 600mcg BID, pasireotide use her glycaemic control worsened over the 5 years with escalating anti-diabetes medications.

In our case both the low and high doses of pasireotide did not reduce residual pituitary tumour size. Tumour shrinkage appears to have a dose-dependent effect (6), though the mechanism of tumour shrinking following pasireotide use is unclear. There are suggestions that pasireotide may have antiproliferative effects through angiogenesis inhibition and reduction of growth factors and trophic hormones (8).

Currently the literature regarding pasireotide and its long-term efficacy and tolerability is limited. In our case, our patient has been managed with pasireotide for the longest duration in Australia and in the literature. Our patient has sustained benefit for over 10 years and apart from hyperglycaemia, has not had any other adverse effect. An escape phenomenon was not observed, which can be associated with carbergoline (9). Petersenn et al reported data up to 5 years of pasireotide use with normalization of UFC in 11/16 patients, median tumour volume change of -3.5%, and safety profile at 5 years similar to that at 12 and 24 months (10). Following 5 years of pasireotide use though there is limited literature on its long-term use.

 

Learning Points:

  • A lower dose of pasireotide may be effective in the initial treatment of CD than the recommended 600mcg BID dosage, though more studies are required to further explore this.
  • Low-dose pasireotide use has the benefit of minimising adverse effects.
  • In the long-term, pasireotide has a sustained clinical and biochemical effect in the treatment of CD and is well tolerated.

 

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