A Prospective Study of Publicly Funded Molecular Testing of Indeterminate Thyroid Nodules: Canada's Experience.

CONTEXT: Indeterminate thyroid nodules (ITNs) lead to diagnostic surgeries in many countries. Use of molecular testing (MT) is endorsed by several guidelines, but costs are limitative, especially in public healthcare systems like in Canada. OBJECTIVES: Primary objective: evaluate the clinical value of Thyroseq® v3 (TSv3) using benign call rate (BCR) in a real-world practice. Secondary objective: assess cost-effectiveness of MT. DESIGN: This is a multicentric prospective study. SETTING: This study was conducted in 5 academic centers in Quebec, Canada. PATIENTS OR OTHER PARTICIPANTS: 500 consecutive patients with Bethesda III (on 2 consecutive cytopathologies) or IV and TIRADS 3 or 4 nodules measuring 1 to 4 cm were included. INTERVENTION: MT was performed between November 2021 and November 2022. Patients with a positive TSv3 were referred to surgery. Patients with a negative TSv3 were planned for follow-up by ultrasonography for a minimum of 2 years. MAIN OUTCOME MEASURE: The BCR, corresponding to the proportion of ITNs with negative TSv3 results, was assessed. RESULTS: 500 patients underwent TSv3 testing, with a BCR of 72.6% (95% CI: 68.5-76.5; p<0.001). 99.7% of patients with a negative result avoided surgery. The positive predictive value of TSv3 was 68.2% (95% CI: 58.5-76.9). The cost-benefit analysis identified that the implementation of MT would yield cost savings of $6.1 million over the next 10 years. CONCLUSIONS: Use of MT (TSv3) in a well-selected population with ITNs led to a BCR of 72.6%. It is cost-effective and prevents unnecessary surgeries in a public healthcare setting.

Canadian consensus statement on the management of radioactive iodine-resistant differentiated thyroid cancer.

Radioactive iodine-resistant differentiated thyroid cancer (RAIRTC) is an aggressive form of thyroid cancer that is uncommon and heterogeneous in its clinical behavior. With the emergence of more effective systemic therapy, the need for guidance in decision-making was recognized and a consensus committee of national experts was assembled. The consensus committee consisted of 13 clinicians involved in treating RAIRTC from across Canada and included endocrinologists, nuclear medicine physicians, surgeons, and radiation and medical oncologists. Domains of interest were identified by consensus, and evidence gathered using systematic reviews. Consensus recommendations for the diagnosis and management of RAIRTC were developed. It was recognized that the rarity of RAIRTC in practice and heterogeneous patterns of thyroid cancer care could limit access to effective therapy for some RAIRTC patients. This document offers guidance to manage RAIRTC patients in a multidisciplinary manner.

Acute hypercalcemia and excessive bone resorption following anti-RANKL withdrawal: Case report and brief literature review.

Denosumab is an anti-RANKL antibody that is commonly used for the treatment of osteoporosis; in oncology, bisphosphonates and denosumab have become the standard therapies for the treatment and prevention of skeletal complications in patients with myeloma and solid tumors. In recent years, excessive bone remodeling following the discontinuation of denosumab has raised concerns. Several cases of hypercalcemia have been reported after the discontinuation of high-dose denosumab (120 mg every 4 weeks), mainly in children. In this study, we report a new case of severe refractory hypercalcemia in a 54-year-old woman who received high-dose denosumab for 5 years as an adjuvant therapy for breast cancer. She is currently in remission and undergoing treatment with anastrazole, an aromatase inhibitor. The peculiarities of this case are the presence of associated bone pain with subperiosteal bone resorption on hand X-rays, and diffuse, long bone diaphyseal uptake on a bone scan. Hyperparathyroidism has been ruled out, and existing evidence suggests that this high-level of bone remodeling could be due to a rebound hyperactivation of the RANKL pathway. In addition to rehydration, repeated use of i.v. bisphosphonates was required to control recurrent hypercalcemia. As hypercalcemia is a serious metabolic complication, a gradual dose reduction should be considered when interruption of high dose denosumab therapy is planned.

Tyrosine kinase inhibitor treatments in patients with metastatic thyroid carcinomas: a retrospective study of the TUTHYREF network.

OBJECTIVE: Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers. DESIGN AND METHODS: THERE WERE 62 PATIENTS (37 MEN, MEAN AGE: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints. RESULTS: Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment. CONCLUSIONS: This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Body composition variation and impact of low skeletal muscle mass in patients with advanced medullary thyroid carcinoma treated with vandetanib: results from a placebo-controlled study.

OBJECTIVES: Vandetanib was approved by the U.S. Food and Drug Association for the treatment of advanced medullary thyroid cancer (MTC). Because body weight (BW) loss is observed in MTC and because low skeletal muscle mass (SM) is associated with drug toxicity, this study assessed effects of vandetanib on SM and adipose tissue (AT) and explored the association between SM, toxicity, and serum concentration of vandetanib. METHODS: Thirty-three patients with MTC received vandetanib (n = 23) or placebo (n = 10) in the ZETA study. Visceral AT (VAT), sc AT (SAT), and SM were assessed with computed tomography imaging by measuring tissue cross-sectional areas (square centimers per square meter). Dose-limiting toxicities (DLTs) were prospectively recorded. RESULTS: Early at 3 months, compared with placebo group who lost BW, muscle, and SAT, patients treated with vandetanib gained 1.5 kg BW (P = 0.02), 1.3 cm(2)/m(2) (∼0.7 kg) of SM (P = 0.009), and 4.5 cm(2)/m(2) (∼0.5 kg) of SAT (P = 0.004) and gained more VAT, 5.1 cm(2)/m(2) (∼0.7 kg) (P = 0.02). Patients with DLT had lower SM index (37.2 vs 44.3 cm(2)/m(2), P = 0.003) and a higher vandetanib serum concentration (1091 vs 739 ng/mL, P = 0.03). Patients with SM index <43.1 cm(2)/m(2) had a higher probability of DLT (73% vs 14%, P = 0.004) and a higher vandetanib serum concentration (1037 vs 745 ng/mL, P = 0.04). Patients with the highest compared with the intermediate and lower levels of vandetanib serum concentration experienced more DLT, respectively, 78% vs 40% vs 20% (P = 0.04). CONCLUSIONS: Muscle and adipose tissues are restored after only 3 months of vandetanib treatment. Patients with low muscle mass had high vandetanib serum concentration and high incidence of toxicities.

Kinase inhibitors for advanced medullary thyroid carcinoma.

The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

Kinase inhibitors for advanced medullary thyroid carcinoma

The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.