Protracted hypocalcaemia foll

Accepted Article
Article Type: Letter to the Editor
Protracted hypocalcaemia following a single dose of denosumab in humoral
hypercalcaemia of malignancy due to PTHrP-secreting neuroendocrine tumour
Authors:
Dr Jessie Teng1, MBBS (Hons), BMedSci
Dr Sally Abell1, MBBS (Hons), BMedSci
Professor Rodney J. Hicks2, MBBS (Hons), MD, FRACP
A/Professor Michael S. Hofman2,3, MBBS (Hons), FRACP, FAANMS
Dr Nirupa Sachithanandan1, MBBS (Hons), FRACP, PhD
A/Professor Penny McKelvie4, MBBS FRCPA D Med Sci.
Professor Richard MacIsaac1,3 , MBBS, FRACP, PhD
1
Department of Endocrinology and Diabetes, St Vincent’s Hospital
Molecular Imaging, Centre for Cancer Imaging, Peter MacCallum Cancer Centre
3
Department of Medicine, University of Melbourne
4
Department of Anatomical Pathology, St Vincent’s Hospital
2
Acknowledgements:
We would like to acknowledge the assistance of Professor TJ Martin (AO MBBS, MD, DSc
(Melb), HonMD (Sheffield), FRACP, FRCPA, FAA, FRS), St Vincent’s Institute,
Melbourne, in reviewing the manuscript.
Corresponding author:
Dr Jessie Teng
Mailing address: Department of Endocrinology & Diabetes, St Vincent’s Hospital, PO Box
2900, Fitzroy VIC 3065, Australia
Telephone: +61 3 9288 3568, fax: +61 3 92883340
E-mail address: [email protected]
Disclosure statement: The authors have nothing to disclose
Dear Editors,
Management of humoral hypercalcaemia of malignancy (HHM) refractory to
bisphosphonates, or where their use is contraindicated, can be challenging. We present a case
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been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cen.12519
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of PTHrP-secreting metastatic pancreatic neuroendocrine tumour (NET) with recurrent
hypercalcaemic crises and renal failure. The challenges of managing hypercalcaemia in the
presence of kidney disease are highlighted in this case.
A 38-year-old man presented with severe hypercalcaemia (calcium 4.50mmol/L, normal
2.12-2.63mmol/L) and renal failure requiring haemodialysis. His medical history was
significant for primary hyperparathyroidism, managed successfully with removal of two
hyperplastic parathyroid glands 14 years prior. HHM was confirmed by undetectable serum
PTH level (<3pg/mL) and elevated PTH-related protein (PTHrP) level of 6.9pmol/L (normal
<1.3pmol/L). Serum 25(OH)-vitamin D was low (<20nmol/L, normal 75-150nmol/L) and
1,25(OH)2-vitamin D was inappropriately normal (165pmol/L, normal 65-175pmol/L).
His serum calcium normalised with a renal-adjusted dose of intravenous pamidronate.
Although he was weaned off haemodialysis, his renal function remained impaired (eGFR 35
mL/min/1.73m2). Abdominal computed tomography showed a large pancreatic tail mass and
multiple bi-lobar hepatic metastases. Core biopsy of a hepatic lesion revealed a welldifferentiated NET, with Ki-67 proliferation index of <2 percent and positive staining for
PTHrP (Figure 1). Chromogranin A levels were elevated (408 U/L; normal <22 U/L ). A
diagnosis of MEN-1 syndrome was made, and confirmed with the detection of a
heterozygous splice site mutation in the MEN-1 gene. Further imaging with F-18
fluorodeoxyglucose (FDG) PET/CT and Ga-68 DOTA-TATE (GaTate) PET/CT revealed
predominantly congruent FDG-avid and somatostatin-receptor-positive disease. His disease
was deemed unresectable and he underwent six cycles of carboplatin/etoposide
chemotherapy.
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His clinical course was complicated by recurrent episodes of hypercalcaemia, requiring
intravenous pamidronate. Six weeks after his last bisphosphonate infusion, he presented with
another hypercalcaemic crisis (serum calcium 4.91mmol/L) and renal failure (eGFR
13mL/min/1.73 m2), which was refractory to rehydration, calcitonin and dexamethasone.
Significant renal dysfunction precluded the use of intravenous bisphosphonates. A dose of
subcutaneous denosumab 120mg was therefore administered. Ten days later, he developed
symptomatic hypocalcaemia with serum calcium of 1.52mmol/L. The hypocalcaemia
observed post-denosumab proved very difficult to correct. Despite high dose oral calcitriol,
calcium, and cholecalciferol replacement and intermittent intravenous calcium infusions, it
took three months for his hypocalcaemia to resolve. Peptide receptor radionuclide
radiotherapy (PRRT) was then used to target the well-differentiated NET sites and reduce
hormone-overproduction. Interestingly, his calcium levels dropped transiently after each
cycle of PRRT but currently, six months after his last PRRT treatment and 10 months after
denosumab, he is maintaining serum calcium levels on oral calcium supplementation alone
(Figure 2).
Bisphosphonates are used as first-line therapy in the management of HHM. However HHM
refractory to bisphosphonate therapy is not uncommon, perhaps due to inadequate inhibition
of bone resorption and renal calcium reabsorption. Successful use of denosumab, a
monoclonal antibody to receptor activator of nuclear factor kappa-B (RANK) ligand has been
reported in this setting(1,2). A recent study of 15 patients with refractory HHM despite
bisphosphonate therapy showed that 80% responded within two weeks of initiating 120mg
denosumab initially at weekly then 4-weekly intervals(2). In clinical trials, denosumab
rapidly and significantly decreased bone turnover, which is sustained but fully reversible
within
2
years
of
discontinuation
of
therapy(3).
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Unlike
bisphosphonates,
the
Accepted Article
pharmacokinetics of denosumab is reported to be similar in patients with varying degrees of
renal impairment, and no dose adjustment has been recommended(4).
Renal impairment and vitamin D deficiency are known risk factors for hypocalcaemia postdenosumab or bisphosphonates.
However, severe hypocalcaemia after single doses of
denosumab has been reported, even in patients with normal renal function and vitamin D
sufficiency(5). Despite being severely hypercalcaemic, this patient’s calcium levels decreased
dramatically post-denosumab, with a prolonged period of refractory hypocalcaemia. The
causes for his hypocalcaemia were likely multifactorial, including previous bisphosphonate
therapy, renal failure as well as vitamin D deficiency. Current guidelines recommend
adequate vitamin D replacement prior to denosumab or bisphosphonate therapy. However,
this poses a challenge in HHM where acute treatment is often needed to prevent
hypercalcaemic complications, and the possibility of aggravating hypercalcaemia with
vitamin D replacement. We suggest close monitoring of serum calcium levels in this setting,
and initiating vitamin D replacement once serum calcium is corrected to within the normal
range.
PRRT is an emerging treatment in the management of functional NETs. Well-differentiated
NETs retain somatostatin-receptor expression, and thus have high GaTate PET/CT avidity
and PRRT efficacy(6). In this case, our patient presented with two hypercalcaemic crises
within a month of completing chemotherapy, both times with acute on chronic renal failure
(Figure 2). Despite this patient having some sites of discordant FDG+/GaTate- disease, in
view of his limited treatment options, PRRT was administered with the aim of targeting welldifferentiated and likely hormone-producing lesions. The timing of administering PRRT was
also influenced by partial recovery of the patient’s renal function, as poor renal function
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Accepted Article
increases toxicity and adverse effects of PRRT, including bone marrow toxicity,
nephrotoxicity and hormonal crisis due to release of active peptides with cell lysis.
Significant hypocalcaemia (calcium ≤2.10mmol/L) has been reported in 22 percent of
patients undergoing PRRT (7). Whilst the mechanism of post-PRRT hypocalcaemia is
unclear, this phenomenon was also seen in our patient.
In summary, management of HHM can be challenging in the setting of renal impairment.
Treatment goals include normalisation of calcium levels and control of PTHrP hypersecretion
with tumour-directed therapy. Our case extends the available literature on the efficacy of
denosumab in bisphosphonate-refractory HHM. However, in order to avoid problematic
hypocalcaemia, calcium levels should be monitored carefully post-denosumab, with initiation
of vitamin D replacement once serum calcium levels normalise.
Figure 1a.
Figure 1b.
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Figure 1c.
Figure 1d.
Figure 1. Histology of liver biopsy
Figure 1a. Light microscopy showing nests of cells with salt and pepper chromatin
(haematoxylin and eosin, magnification x400). Figure 1b. Immunohistochemistry showed
strong staining for synaptophysin (magnification x400). Figure 1c. Ki-67 staining showed
low proliferation index <2% (magnification x200). Figure 1d. Light microscopy with positive
PTHrP staining.
Figure 2.
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Figure 2.
Graph showing serum corrected calcium levels including therapy administered. Normal range
2.12-2.63mmol/L, denoted by dotted lines.
denotes time period requiring intermittent intravenous calcium replacement whilst on
high dose oral calcium, calcitriol and cholecalciferol
denotes time period on oral calcium, calcitriol and cholecalciferol.
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