Parathyroid cancer is one of the very rare malignancies and is estimated to account for 0.005% of all malignancies. Parathyroid cancer is one of the rare causes of primary hyperparathyroidism (PHPT), accounting for less than 1% of patients with PHPT. Parathyroid cancer usually has an onset age of 45 to 59 years old, and there is no significant difference in the incidence of male and female. However, the age of onset of benign parathyroid tumors is generally about 10 years older than parathyroid carcinoma, and the male-to-female ratio is 1:3. The cause of parathyroid cancer is still unclear, and it can be either sporadic or part of the genetic syndrome. Genetic syndromes associated with parathyroid carcinoma have been reported to include hyperparathyroidism-mandibular tumor syndrome (HPT-JT), multiple endocrine neoplasia syndrome (MEN1), MEN2A, and isolated familial hyperparathyroidism. There is a parathyroid carcinoma in 15% of HPT-JT. In addition, some parathyroid carcinoma occurs after radiation therapy in the neck, or secondary hyperparathyroidism caused by renal failure. A recent Swedish retrospective study reported that the occurrence of parathyroid carcinoma is associated with the history of thyroid cancer and parathyroid adenoma. And other studies have reported that parathyroid carcinoma can occur simultaneously or sequentially with parathyroid adenoma and parathyroid hyperplasia. However, there is no direct evidence showed that parathyroid carcinoma is transformed from these benign lesions.
Case Study
Management of inoperable parathyroid carcinoma presents a challenge because until recently, effective medical therapy was not available. In addition, morbidity and mortality result primarily from severe hypercalcemia. According to the existing research, the allosteric regulator of calcium sensitive receptor, directly reduce parathyroid cell hormone secretion by binding to the calcium-sensitively receptor on parathyroid cells, increasing the sensitively of parathyroid cell to extracellular calcium. A first-generation calcimimetic, R-568, controlled hypercalcemia for nearly 2 years in a patient with widely metastatic parathyroid cancer. R-568 has been replaced by cinacalcet HCI (hereafter called cinacalcet), a more potent second-generation agent with a longer half-life. In benign primary hyperparathyroidism, cinacalcet normalized serum calcium and reduced PTH (parathyroid hormone) concentrations for up to 3 years. Next, we will report the results of the first multicenter investigation of cinacalcet in patients with inoperable parathyroid carcinoma.
A Jonckheere-Terpstra test was used to assess the significance of the observed trend of larger calcium reduction associated with increasing baseline calcium. Two-tailed t tests were used to assess the percent changes from baseline for key laboratory parameters; a two-tailed paired t test was used to assess changes in health-related quality of life.
Design:
Twenty-nine patients with parathyroid carcinoma were enrolled in this open-label, single-arm study consisting of titration and maintenance phases.
Participants:
The study was conducted at 15 centers in the United States and Europe. Twenty-nine patients (15 men, 14 women; 24-79 years old) with parathyroid cancer documented by histopathological examination of surgical specimens were enrolled. Exclusion criteria were any other malignancy (excluding non-melanomatous skin cancer or in situ cervical cancer), concurrent cancer chemotherapy, non-parathyroid malignancy-associated hypercalcemia, and use of drugs metabolized by cytochrome P450-2D6 (inhibited by cinacalcet) with a narrow therapeutic index (flecanide, thioridazine, and tricyclic antidepressants).
Table 1. Baseline biochemical data of parathyroid carcinoma patients (n=29)
BCE, Bone collagen equivalents.
a Two patients had normal serum calcium at study initiation, one after treatment with iv bisphosphonates for severe hypercalcemia.
Length of Enrollment period:
16 weeks
Interventions:
Cinacalcet were titrated (30 mg twice daily to 90 mg four times daily) for 16 weeks or until serum calcium was no more than 10.0 mg/dl reduction in calcium at the end of the titration phase (responders). Study visits occurred weekly during the titration phase and every 8 weeks during the maintenance phase.
Results:
By the end of the titration phase, serum calcium fell by at least 1 mg/dl in 62% of patients. In the group as a whole, mean calcium concentrations declined from 14.1± 0.4 mg/dl at baseline to 12.4 ± 0.5 mg/dl (P= 0.049; Fig 1A). In the 18 patients who responded to cinacalcet with more than 1 mg/dl decline, serum calcium fell from 15.0 ± 0.5 mg/dl to 11.2 ± 0.3 mg/dl (P< 0.001; Fig 2B). In addition, there were 10 subjects who had sustained declines in serum calcium concentration. In these patients, the last serum calcium measured in the maintenance phase (on drug for 80 ± 12 weeks; range, 33-151 weeks) showed a decline from a baseline value of 15.4 ± 0.6 to 10.9 ± 0.3 mg/dl. In some patients, the treatment target was achieved before the end of the titration period. The average reduction in all patients across the cinacalcet dose range was 1.7 mg/dl. Mean (SE) serum calcium concentrations by titration phase and maintenance phase study week are shown in Fig. 1A. The greatest reductions in serum calcium were observed in patients with the highest baseline levels. From the Fig. 1B we can see, decline in serum calcium concentration during titration phase in parathyroid cancer patients treated with cinacalcet. Data (mean ± SE) are presented for all patients and for drug responders (who experienced a decline of ≥ 1 mg/dl in serum calcium levels). Decline in serum calcium was significant by paired t test: *, p < 0.05, ** p < 0.001.
Figure 1. Changes in serum calcium
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References:
1. Enomoto Keisuke, Uchino Shinya, Ito Akiko et al. (2010) ‘The surgical strategy and the molecular analysis of patients with parathyroid cancer’, World J Surg, 34(11): 2604-10.
2. Takeuchi Yasuhiro, Takahashi Shunsuke, Miura Daishu et al. (2017) ‘Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism’, J. Bone Miner. Metab, 35(6): 616-622.
3. Duan Kai, Mete Özgür. (2015) ‘Parathyroid Carcinoma: Diagnosis and Clinical Implications’, Turk Patoloji Derg, 31 Suppl 1: 80-97.