Therapy of Parathyroid Carcinoma

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This entry is adapted from the peer-reviewed paper 10.3390/endocrines4010018

Parathyroid carcinoma (PC) is an extremely rare endocrine malignancy of the parathyroid glands, representing about 1% of all parathyroid tumors and one of the rarest causes of primary hyperparathyroidism (PHPT), and generally presenting more severe symptomatic hypercalcemia than its benign counterparts (hyperplasia and adenoma), with marked skeletal and renal complications, including osteoporosis, fragility fracture, osteitis fibrosa cystica, and nephrolithiasis. This tumor has aggressive behavior and high metastatic potential.

parathyroid carcinoma gene therapy

1. Current Therapies

1.1. Surgery

Surgery is the first-line therapy for parathyroid carcinoma (PC). High pre-operative clinical suspicions of PC and/or the intra-operative identification of malignant features are fundamental in driving surgical management and are key to have a better curative chance. Pre-operative biopsy is contraindicated because of the high risk of tumor capsule rupture and tumor cell dissemination.

The surgical approach to PC consists of the en bloc resection of primary cancer with negative margins, usually associated with the excision of ipsilateral thyroid lobes and adjacent involved structures. Compartmental level VI lymph node dissection is indicated in case of metastatic tumor. The use of an intra-operative measurement of PTH is useful to confirm the removal of all hyperfunctioning parathyroid glands.

However, despite every surgical effort, disease recurrence occurs in over 50% of PC cases, and no specific therapeutic strategy is available to treat such patients.

Prophylactic parathyroidectomy to prevent PC in patients with germline CDC73 mutations is not indicated, since not all carriers develop a malignant tumor. Bilateral exploration of the neck and the identification of all parathyroids glands, with resection of all affected gland(s), are the suggested approaches.

1.2. Adjuvant Therapies

Post-operative external beam radiation therapy is rarely used because PC is generally considered a “radioresistant” tumor. Data on the efficacy of radiation therapy on PC are contrasting and appear to be related to the tumor stage and the presence of local and distant invasion ^[1]^[2]. The treatment is prevalently restricted to palliative therapy of advanced metastatic disease.

Systemic cytotoxic chemotherapy is used even less frequently than radiotherapy and used only in a few extremely restricted cases, since it showed very limited benefits in inoperable PC patients and patients in whom surgery was ineffective, generally resulting in the inability to control tumor progression and functional tumor burden ^[2]^[3].

1.3. Therapies for the Control of Calcium Homeostasis

These pharmacological therapies are aimed to control PC-derived severe hypercalcemia before surgical intervention or in patients with inoperable and recurrent tumors or to mitigate the effect of post-operative permanent hypoparathyroidism after tumor resection.

The first-line treatment of hypercalcemia consists of intravenous hydration, diuretics, and anti-resorption drugs, such as bisphosphonates (typically intravenous administration of pamidronate or zoledronic acid) or denosumab, to inhibit osteoclast activity and reduce serum calcium levels.

In PC patients who do not respond to bisphosphonates or for whom the denosumab effect weakens over time, calcimimetic drugs, selective agonists acting on the calcium-sensing receptor on the membrane of parathyroid cells, can be used. Cinacalcet, a long-acting calcimimetic molecule, showed to be effective in reducing both serum calcium and PTH concentrations in about two-thirds of metastatic and inoperable PCs ^[4]^[5].

Post-operative chronic hypoparathyroidism and hypocalcemia require life-long therapy with calcium and active vitamin D.

2. Emerging Therapies

The administration of some medical therapies targeting molecular pathways showing alterations in a percentage of PC cases, which are currently approved for the treatment of different types of cancer but not PC, showed promising results in some case reports. These therapies need to be further evaluated and confirmed in larger PC case series.

2.1. Inhibitors of the PI3K/AKT/mTOR Pathway

Since somatic gene mutations that constitutively activate the PI3K/AKT/mTOR pathway were found in about up to 20% of PC cases ^[6], the use of PI3K/AKT/mTOR inhibitors could be effective in a subset of PC patients.

Kutahyalioglu et al. ^[7] treated a patient with a somatic mutation of the TSC1 gene, a known regulator of the PI3K/AKT/mTOR pathway, and recurrent PC with liver metastasis by using a combination of everolimus (an mTOR inhibitor) and vandetanib (an antiangiogenic drug). Treatment allowed a stable disease, with better control of serum calcium levels, while on drugs.

Given the extreme rarity of PC, no randomized controlled clinical trial with PI3K/AKT/mTOR inhibitors has been conducted on this parathyroid cancer. “Basket trials”, evaluating treatments in multiple cancer types sharing common alterations of the PI3K/AKT/mTOR genes, may help in overcoming the problem of patient rarity.

2.2. Inhibitors of Angiogenesis

The administration of drugs blocking angiogenesis showed promising results in some case reports in patients with PC.

Mutations in the KDR gene, encoding vascular endothelial growth factor receptor 2 (VEGFR2), were found in 13% of PCs ^[8]. After the identification of an activating somatic missense mutation (p.Thr688Lys) of the KDR gene in a patient with PC, Kang et al. ^[8] treated, sequentially, this patient with three inhibitors of VEGFR2, cabozantinib (a potent inhibitor of multiple receptor tyrosine kinases, including MET, RET, AXL, KIT, TIE2, and FLT3), ramucirumab (a monoclonal antibody against VEGFR2), and regorafenib (pleiotropic inhibitor of VEGFR1, VEGFR2, and TIE2). Cabozantinib treatment showed to reduce intact PTH (iPTH) and the size of the paratracheal lymph node over 3 months of treatment but induced various side effects, such as fatigue, hypertension, diarrhea, and epistaxis. After cabozantinib discontinuation, iPTH rose again. Treatment with ramucirumab failed to reduce iPTH levels. Treatment with regorafenib was well tolerated and effective in dropping the iPTH levels. Data from this case report indicate the benefit of performing genetic profiling of PC tumor samples to allow the choice of targeted therapy.

Based on the previously reported good response to the antiangiogenic sunitinib treatment in renal cell carcinoma patients with KDM5C mutations, Kutahyalioglu et al. ^[7] treated with sorafenib (an antiangiogenic multi-targeted tyrosine kinase inhibitor with a target profile similar to sunitinib) a patient with a somatic mutation of the KDM5C gene and persistent PC with lung metastases, which was not responsive to cinacalcet and intermittent doses of bisphosphonates. The treatment allowed good control of calcemia, even after the discontinuation of cinacalcet, for three years. Then, both PTH and calcium levels started to rise again with the progression of pulmonary metastases. The switch to a more potent antiangiogenic molecule, lenvatinib, granted a radiographically stable disease and good control of calcemia, without any calcimimetic administration, during the 20 months of therapy follow-up reported in the study.

Rozhinskaya et al. ^[9] positively treated, off-label, a CDC73-mutated woman with PC and multiple lung metastases by using sorafenib, an antiangiogenic multi-kinase inhibitor that blocks the activity of VEGFRs, resulting in the normalization of PTH and calcemia, the prevention of tumor progression, and a significant reduction in the size of lung metastases.

Very recently, Makino et al. ^[10] showed the effectiveness of combined therapy with sorafenib, denosumab, and evocalcet (a calcium-sensing receptor agonist) to treat refractory hypercalcemia in a CDC73-mutated patient with recurrent PC due to multiple lung metastases.

References

Harari, A.; Waring, A.; Fernandez-Ranvier, G.; Hwang, J.; Suh, I.; Mitmaker, E.; Shen, W.; Gosnell, J.; Duh, Q.Y.; Clark, O. Parathyroid carcinoma: A 43-year outcome and survival analysis. J. Clin. Endocrinol. Metab. 2011, 96, 3679–3686.
Christakis, I.; Silva, A.M.; Williams, M.D.; Garden, A.; Grubbs, E.G.; Busaidy, N.L.; Lee, J.E.; Perrier, N.D.; Zafereo, M. Postoperative local-regional radiation therapy in the treatment of parathyroid carcinoma: The MD Anderson experience of 35 years. Pract. Radiat. Oncol. 2017, 7, e463–e470.
Cetani, F.; Pardi, E.; Marcocci, C. Update on parathyroid carcinoma. J. Endocrinol. Investig. 2016, 39, 595–606.
Silverberg, S.J.; Rubin, M.R.; Faiman, C.; Peacock, M.; Shoback, D.M.; Smallridge, R.C.; Schwanauer, L.E.; Olson, K.A.; Klassen, P.; Bilezikian, J.P. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J. Clin. Endocrinol. Metab. 2007, 92, 3803–3808.
Takeuchi, Y.; Takahashi, S.; Miura, D.; Katagiri, M.; Nakashima, N.; Ohishi, H.; Shimazaki, R.; Tominaga, Y. Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism. J. Bone Miner. Metab. 2017, 35, 616–622.
Kong, S.H. Updates of Genomics and Proteomics of Parathyroid Carcinoma. Endocrines 2022, 3, 745–752.
Kutahyalioglu, M.; Nguyen, H.T.; Kwatampora, L.; Clarke, C.; Silva, A.; Ibrahim, E.; Waguespack, S.G.; Cabanillas, M.E.; Jimenez, C.; Hu, M.I.; et al. Genetic profiling as a clinical tool in advanced parathyroid carcinoma. J. Cancer Res. Clin. Oncol. 2019, 145, 1977–1986.
Kang, H.; Pettinga, D.; Schubert, A.D.; Ladenson, P.W.; Ball, D.W.; Chung, J.H.; Schrock, A.B.; Madison, R.; Frampton, G.M.; Stephens, P.J.; et al. Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. Oncologist 2019, 24, 791–797.
Rozhinskaya, L.; Pigarova, E.; Sabanova, E.; Mamedova, E.; Voronkova, I.; Krupinova, J.; Dzeranova, L.; Tiulpakov, A.; Gorbunova, V.; Orel, N.; et al. Diagnosis and treatment challenges of parathyroid carcinoma in a 27-year-old woman with multiple lung metastases. Endocrinol. Diabetes Metab. Case Rep. 2017, 2017, 16-0113.
Makino, H.; Notsu, M.; Asayama, I.; Otani, H.; Morita, M.; Yamamoto, M.; Yamauchi, M.; Nakao, M.; Miyake, H.; Araki, A.; et al. Successful Control of Hypercalcemia with Sorafenib, Evocalcet, and Denosumab Combination Therapy for Recurrent Parathyroid Carcinoma. Intern. Med. 2022, 61, 3383–3390.

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