Phase II study of the efficacy and safety of lenvatinib for anaplastic thyroid cancer (HOPE).

PURPOSE: Anaplastic thyroid cancer (ATC) is a rare and highly aggressive cancer for which effective systemic therapy has long been sought. Here, we assessed the efficacy and safety of lenvatinib in patients with unresectable ATC. PATIENTS AND METHODS: The study was investigator-initiated and conducted under a multicenter, open-label, nonrandomized, phase II design. Eligibility criteria included pathologically proven ATC; unresectable measurable lesion as defined by RECIST 1.1; age 20 years or older; ECOG PS 0-2; and adequate organ function. The primary end-point was overall survival. Secondary end-points were progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety. RESULTS: Of 52 patients enrolled from 17 institutions, 42 patients who were confirmed to have ATC were included for efficacy analysis, and 50 patients were included for safety analysis. The estimated 1-year overall survival rate was 11.9% (95% CI, 4.4%-23.6%). One patient (2.4%) achieved complete response, four patients (9.5%) partial response, and 26 patients (61.9%) stable disease, including nine patients (21.4%) who demonstrated durable stable disease, giving an objective response rate of 11.9%, disease control rate of 73.8%, and clinical benefit rate of 33.3%. Adverse events of any grade were observed in 45 patients (90.0%), the most common of which of any grade included loss of appetite (48.0%), fatigue (48.0%), hypertension (44.0%), and palmar-plantar erythrodysesthesia syndrome (26.0%). CONCLUSION: Lenvatinib treatment resulted in disappointing survival for unresectable ATC patients. Although the number of responders was small, responses were durable, indicating that lenvatinib may be beneficial for selected patients. Further investigation to identify suitable candidates for lenvatinib monotherapy is needed.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

The Safety and Efficacy of Weekly Paclitaxel Administration for Anaplastic Thyroid Cancer Patients: A Nationwide Prospective Study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel. METHODS: An investigator-initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization. RESULTS: Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (>84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post-treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0-7.8], p = 0.018). SUMMARY: The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients. CONCLUSIONS: Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo-adjuvant setting.

A Calcitonin Non-producing Neuroendocrine Tumor of the Thyroid Gland.

Neuroendocrine tumors of the thyroid gland are generally considered to derive from parafollicular endocrine cells (C cells) and are generally referred to as medullary thyroid carcinomas (MTC). Calcitonin secretion is almost always detected in MTC and a prerequisite for both clinical and pathological diagnosis. Thyroid neuroendocrine tumors without any apparent calcitonin secretion reflect a diagnostic dilemma because non-calcitonin-producing MTCs have virtually not been characterized. Here, we report a case of primary thyroid neuroendocrine tumors lacking calcitonin secretion or expression. The tumor cells expressed cytokeratins, chromogranin A, and synaptophysin, all of which were consistent with epithelial and neuroendocrine differentiation. Thyroid transcription factor-1 paired box gene 8, and carcinoembryonic antigen were also immunohistochemically detected, consistent with its thyroid origin. However, the tumor was negative for calcitonin both by immunohistochemistry and in situ hybridization, hence, not meeting the definition of MTC. Despite the loss of calcitonin expression, immunoreactivity for the calcitonin-gene-related peptide was detected in the tumor. Somatic gene mutations of RET, H-RAS, K-RAS, or BRAF were not detected in this case. A limited number of calcitonin non-producing thyroid neuroendocrine tumors are available in the scientific literature available in English, and its etiology and clinical manifestations remain largely unknown. Our case, along with the rare, previously reported cases, suggests that calcitonin non-producing neuroendocrine tumors of the thyroid gland are most likely derived from C cells, but should be differentiated from ordinary MTCs.

Induction of adrenomedullin 2/intermedin expression by thyroid stimulating hormone in thyroid.

TSH is the important regulator of thyroid function but detailed molecular mechanisms have not been clarified. We first generated the iodine deficient (ID) rat in which goiter is induced by accelerated endogenous TSH secretion. The result of microarray analysis demonstrated markedly increased levels of adrenomedullin 2/intermedin (AM2/IMD) expression in the ID rat thyroid. AM2/IMD is a potent vasodilator. AM2/IMD mRNA expression was induced by TSH in a rat thyroid follicular cell line FRTL-5. Immunohistochemical analysis in human normal and Graves' disease thyroid revealed that AM2/IMD immunoreactivity was detected in follicular cells and more pronounced in Graves' disease. These results indicated that TSH induced AM2/IMD expression in the rat thyroid gland and it could locally work as a potent vasodilator, resulting in the expansion of thyroid inter-follicular capillaries. AM2/IMD could also contribute to facilitate thyroid hormone synthesis possibly via vasodilation effects and/or cAMP stimulating effects in the human thyroid gland.

Water-clear cell adenoma associated with primary hyperparathyroidism: report of a case.

We report a case of water-clear cell adenoma associated with primary hyperparathyroidism. A 59-year-old woman with a history of renal stones and bone fracture was referred for investigation of hypercalcemia and an elevated serum parathyroid hormone level. Skeletal X-rays showed osteopenia and ultrasound showed enlarged tumors in both sides of the inferior thyroid region. Computed tomography demonstrated a tumor in the posterior aspect of the left thyroid lobe but no lesion in the right aspect of the neck. Grossly, we found a 500 mg left lower parathyroid gland (PTG) and a 100 mg right lower PTG. Histologically, the left lower PTG comprised mainly water-clear cells (WCCs) containing numerous vacuoles. Chief cells were dispersed among the WCCs, but the right lower PTG showed normal parathyroid tissue. Several investigators have speculated that WCCs are derived from chief cells, and we diagnosed WCC adenoma. Following this case report, we review the relevant literature.

The relationship of thyroid cancer with radiation exposure from nuclear weapon testing in the Marshall Islands.

The US nuclear weapons testing program in the Pacific conducted between 1946 and 1958 resulted in radiation exposure in the Marshall Islands. The potentially widespread radiation exposure from radio-iodines of fallout has raised concerns about the risk of thyroid cancer in the Marshallese population. The most serious exposures and its health hazards resulted from the hydrogen-thermonuclear bomb test, the Castle BRAVO, on March 1, 1954. Between 1993 and 1997, we screened 3,709 Marshallese for thyroid disease who were born before the BRAVO test. It was 60% of the entire population at risk and who were still alive at the time of our examinations. We diagnosed 30 thyroid cancers and found 27 other study participants who had been operated for thyroid cancer before our screening in this group. Fifty-seven Marshallese born before 1954 (1.5%) had thyroid cancer or had been operated for thyroid cancer. Nearly all (92%) of these cancers were papillary carcinoma. We derived estimates of individual thyroid dose proxy from the BRAVO test in 1954 on the basis of published age-specific doses estimated on Utirik atoll and 137Cs deposition levels on the atolls where the participants came from. There was suggestive evidence that the prevalence of thyroid cancer increased with category of estimated dose to the thyroid.