A 57 years-old patient presented with back pain, general discomfort, polydipsia, polyuria, fatigue and recent weight loss of 10 kg. Biochemical evaluation showed hypercalcemia (2.85 mmol/l; normal: 2.152.55) with low PTH level (14,2 ng/L; normal 14.956.9 ng/l) excluding primary hyperparathyroidism. The most frequent cause of hypercalcemia with non-elevated PTH levels is an underlying malignancy1. CT-thorax-abdomen showed a pancreatic neuroendocrine tumor (pNET) with multifocal liver metastases, Ki-67 index 15 to 20% (grade 2). Up to 80% of hypercalcemia of malignancy (HCM) are caused by systemic secretion of PTH-related Peptide (PTHrP)2. PTH and PTHrP increase kidney calcium reabsorption and stimulate the maturation of osteoclast precursors, increasing bone resorption3. However, the PTHrP value was normal (≤ 20.0 pg/ml). Osteolysis mediated by local tumor cell secretion of osteoclast activating cytokines accounts for 20% of the cases of HCM. Although our patient had some osteodense skeletal metastases, these bone lesions alone could not explain his marked hypercalcemia. A rare entity (<1%) of HCM is excessive production of calcitriol due to overexpression of 1α-hydroxylase by the tumor cells. This causes ectopic conversion of 25-hydrovitamine D to calcitriol, leading to increased intestinal and bone resorption of calcium4. Patients calcitriol levels were markedly increased up to 134.3 ng/l (normal: 20.080.0), confirming the cause of hypercalcemia. The well-known somatostatin receptor (SSTR) expression in NETs is the foundation of the use of cold (i.e. non-radioactive) somatostatin analogs (SSAs) as a pharmacological treatment. Although initial treatment with the SSA lanreotide 120 mg 1 ×/month and everolimus resulted in stable morphological disease, there was no improvement of the hypercalcemia nor of the associated symptoms. Another strategy exploiting SSTR overexpression are radiolabeled SSAs, for example labeling the peptide vector DOTA-Tyr3-octreotate (DOTATATE) which has high affinity for SSTR2. Due to the specific decay characteristics of the radionuclides, the radiopharmaceutical can be used for diagnostic purposes (molecular imaging by use of gallium68, e.g.) or therapeutic purposes (Peptide Receptor Radionuclide Therapy (PRRT) by use of lutetium-177, e.g.). Currently, PRRT by means of radiolabeled SSAs represents an established, evidence-based treatment modality in case of inoperable/metastatic well-differentiated GEP-NETs4 and its role has been proven by the excellent results obtained in the randomized, controlled NETTER-1 trial5. Based on these data the patient was referred for evaluation the possibility of PRRT with 177Lu-DOTATATE and in the meantime FOLFOX bridging therapy was started. The 68Ga-DOTATATE scan revealed intense SSTR expression in the pancreatic lesion as well as strong uptake in the multifocal liver metastases and the skeletal metastases. All malignant lesions had an uptake intensity above the spleen (Krenning score grade 4). The 18F-FDG-PET/CT showed an intense hypermetabolism in some of the liver metastases (metabolic grade 3). There were no mismatch lesions (18F-FDG+/ SSR−). Evaluation of the renal function showed no contraindication for therapy. Based on this satisfying work-up, four cycles of PRRT were given, with a treatment interval of 8 weeks up to a cumulative activity of 29.6 GBq. Clinical and biochemical follow-up after each therapy showed no major side effects. Three months after the final cycle there was a marked decrease in serum calcium levels up to normal values as well as a resolution of the associated symptoms. Although there was a clear morphologic response, some liver lesions expressed an increase in 18F-FDG uptake compared to baseline suggesting metabolic progression. The patient was started with temozolomide-capecitabine with good tolerance and continuing morphological and biochemical disease stabilization with normal serum calcium levels as well as normal calcitriol values was observed. This case highlights the role of nuclear medicine in patients with hypercalcemia and documents for the first time the potential of PRRT to control inappropriate tumoral secretion of calcitriol, as has been shown with other hormones secreted by NETs.
References: 1. Stewart AF. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373382.
2. Mundy GR, Edwards JR. PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol. 2008;19:672675.
3. Seynour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkins disease and non-Hodgkins lymphomas. Blood. 1993;82:13831394.
4. Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled Somatostatin analogues. Neuroendocrinology 2017; 105: 295309.
5. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376: 12.
21 Oct 2019
Belgian Endocrine Society