Somatic and Germline Mutations in Atypical Parathyroid Tumors.

This case series examines somatic and germline mutations in atypical parathyroid adenomas using broad next-generation sequencing of tumor samples obtained from patients who underwent surgical resection from 2020 to 2022.

Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.

A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. IMPLICATIONS: Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.

Current Controversies in Low-Risk Differentiated Thyroid Cancer: Reducing Overtreatment in an Era of Overdiagnosis.

CONTEXT: Low-risk differentiated thyroid cancer (DTC) is overdiagnosed, but true incidence has increased as well. Owing to its excellent prognosis with low morbidity and mortality, balancing treatment risks with risks of disease progression can be challenging, leading to several areas of controversy. EVIDENCE ACQUISITION: This mini-review is an overview of controversies and difficult decisions around the management of all stages of low-risk DTC, from diagnosis through treatment and follow-up. In particular, overdiagnosis, active surveillance vs surgery, extent of surgery, radioactive iodine (RAI) treatment, thyrotropin suppression, and postoperative surveillance are discussed. EVIDENCE SYNTHESIS: Recommendations regarding the diagnosis of DTC, the extent of treatment for low-risk DTC patients, and the intensity of posttreatment follow-up have all changed substantially in the past decade. While overdiagnosis remains a problem, there has been a true increase in incidence as well. Treatment options range from active surveillance of small tumors to total thyroidectomy followed by RAI in select cases. Recommendations for long-term surveillance frequency and duration are similarly broad. CONCLUSION: Clinicians and patients must approach each case in a personalized and nuanced fashion to select the appropriate extent of treatment on an individual basis. In areas of evidential equipoise, data regarding patient-centered outcomes may help guide decision-making.

Disparities in Treatment for Differentiated Thyroid Cancer.

Purpose: Disparities in the diagnosis and treatment of patients with differentiated thyroid cancer (DTC) have been described. This review includes the most recent literature on existing diagnostic and treatment disparities in the United States and proposes practical clinical and policy ideas for improving the gap in the treatment of DTC. Methodology: We performed a comprehensive literature review to include key articles related to DTC and disparities of treatment, diagnosis, and outcomes for disadvantaged patient populations. Results: Vulnerable patient populations with DTC have been extensively studied, and the literature shows that clear disparities of diagnosis and treatment exist. Socioeconomically disadvantaged patients, uninsured, rural, elderly, and patients belonging to minoritized racial and ethnic groups are more likely to present with advanced disease at presentation. These same vulnerable patient populations are less likely to have access to high-volume surgeons, less likely to be treated according to guidelines, and receive less aggressive treatment (such as radioactive iodine) compared with white patients. Further, these patients experience financial toxicity more so than their counterparts. Conclusions: Disparities of care exist for certain vulnerable patient populations with DTC. Approaches to rectify these should be multipronged and involve improving access to high-volume specialists with ongoing use of telehealth consults, language concordant care, an emphasis on guideline-directed therapies, ensuring continuity of care and long-term follow-up with better community partnerships, engage diverse patients in national guideline-writing committees of prominent societies and reducing the financial burden of cancer treatments at the state and national policy level.

Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration.

Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.

Endocrine surgeons are performing more thyroid lobectomies for low-risk differentiated thyroid cancer since the 2015 ATA guidelines.

BACKGROUND: The 2015 American Thyroid Association guidelines recommended either total thyroidectomy or lobectomy for surgical treatment of low-risk differentiated thyroid cancer and de-escalated recommendations for central neck dissections. The study aim was to investigate how practice patterns among endocrine surgeons have changed over time. METHODS: All adult patients with low-risk differentiated thyroid cancers (T1-T2, N0/Nx, M0/Mx) in the Collaborative Endocrine Surgery Quality Improvement Program (2014-2021) were identified. The outcomes between patients undergoing lobectomy versus total thyroidectomy were compared using multivariable logistic regression. The annual percent change in the proportion of lobectomies and central neck dissections performed was estimated using joinpoint regression. RESULTS: In total, 5,567 patients with low-risk differentiated thyroid cancers were identified. Of these, 2,261 (40.6%) were very low-risk tumors ≤1 cm, and 2,983 (53.6%) were low-risk tumors >1 and <4 cm. Most patients (67.9%) underwent total thyroidectomy. Compared to total thyroidectomy, lobectomy was associated with outpatient surgery (adjusted odds ratio 5.19, P < .001), a decreased risk of postoperative emergency department visits (adjusted odds ratio 0.63, P = .03), and decreased risk of hypoparathyroidism events (adjusted odds ratio 0.03, P < .001). Compared to before (2014-2015), patients undergoing surgery after publication of the revised guidelines (2016-2021) had higher odds of lobectomy and lower odds of central neck dissection for tumors ≤1 cm (lobectomy adjusted odds ratio 2.70, P < .001; central neck dissections adjusted odds ratio 0.64, P = .03) and tumors between 1 and 4 cm (lobectomy adjusted odds ratio 2.27, P < .001; central neck dissection adjusted odds ratio 0.62, P < .001). CONCLUSION: After publication of the 2015 American Thyroid Association guidelines, there has been an increase in thyroid lobectomies as a proportion of all thyroid operations performed by endocrine surgeons for low-risk differentiated thyroid cancer. This has implications for reduced health care use and costs, with potential population-level benefits.

Risk factors for venous thromboembolism (VTE) after adrenalectomy for adrenal cortical neoplasms.

BACKGROUND: Incidence of venous thromboembolism (VTE) after adrenalectomy for adrenal cortical carcinoma (ACC) is unknown. Herein, we aim to identify the relative incidence and risk factors of VTE after adrenalectomy for ACC. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients who underwent adrenalectomy for ACC, Cushing syndrome (CS), and benign adrenal cortical syndromes (BACS). Univariable and multivariable analyses were used to determine clinical characteristics, 30-day postoperative VTE occurrences, and associated risk factors. Khorana oncologic risk score (KRS) for VTE was calculated and compared between groups. RESULTS: A total of 5896 patients were analyzed: 576 ACC, 371 CS, and 4949 BACS. Postoperative VTE occurred 0.9%, with the highest rate occurring in ACC (2.6% ACC vs. 1.6% CS vs. 0.7% BACS, p < 0.001). Forty percent of VTEs in the ACC cohort were diagnosed postdischarge. ACC patients with KRS ≥ 2 had a 9.6% incidence of VTE (p = 0.007). Multivariable analysis identified increased age (p = 0.03), presence of adrenal cancer (p = 0.01), and KRS ≥ 2 (p = 0.005) as risk factors for VTE after adrenalectomy. CONCLUSIONS: Postoperative VTE after adrenalectomy occurs most frequently for ACC. ACC patients with increased age and/or Khorana score ≥2 should be considered for extended VTE prophylaxis.

Metagenomic Sequencing of the Gallbladder Microbiome: Bacterial Diversity Does Not Vary by Surgical Pathology.

INTRODUCTION: Alterations in the microbiome contribute to the pathogenesis of many gastrointestinal diseases. However, the composition of the microbiome in gallbladder disease is not well described. METHODS: We aimed to characterize the biliary microbiome in cholecystectomy patients. Bile and biliary stones were collected at cholecystectomy for a variety of surgical indications between 2017 and 2019. DNA was extracted and metagenomic sequencing was performed with subsequent taxonomic classification using Kraken2. The fraction of bacterial to total DNA reads, relative abundance of bacterial species, and overall species diversity were compared between pathologies and demographics. RESULTS: A total of 74 samples were obtained from 49 patients: 46 bile and 28 stones, with matched pairs from 25 patients. The mean age was 48 years, 76% were female, 29% were Hispanic, and 29% of patients had acute cholecystitis. The most abundant species were Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pasteurianus. The bacterial fraction in bile and stone samples was higher in acute cholecystitis compared to other non-infectious pathologies (p < 0.05). Neither the diversity nor differential prevalence of specific bacterial species varied significantly between infectious and other non-infectious gallbladder pathologies. Multivariate analysis of the non-infectious group revealed that patients over 40 years of age had increased bacterial fractions (p < 0.05). CONCLUSIONS: Metagenomic sequencing permits characterization of the gallbladder microbiome in cholecystectomy patients. Although a higher prevalence of bacteria was seen in acute cholecystitis, species and diversity were similar regardless of surgical indication. Additional study is required to determine how the microbiome can contribute to the development of symptomatic gallbladder disease.

Exposure to Polybrominated Diphenyl Ether Flame Retardants Causes Deoxyribonucleic Acid Damage in Human Thyroid Cells In Vitro.

INTRODUCTION: The incidence of papillary thyroid cancer (PTC) in the United States has tripled in the past 30 y. Polybrominated diphenyl ethers (PBDEs) are flame retardants that were ubiquitously used over that time period, and exposure to PBDEs has been associated with PTC prevalence. They are potential carcinogens via their induction of reactive oxygen species (ROS) formation and resultant deoxyribonucleic acid (DNA) damage. We sought to determine the effects of PBDE and tris(2-chloroethyl) phosphate (TCEP), another flame retardant implicated in PTC incidence, on thyrocytes in vitro and measure PBDE levels in human thyroid tissue to determine their carcinogenic potential. METHODS: Nthy-Ori, an immortalized benign human thyroid follicular cell line was used as a model of normal human thyroid. MTT assays were used to measure cell viability after exposure to PBDEs and TCEP. ROS levels and double-stranded and single-stranded DNA breaks were measured to determine genotoxicity. DNA damage response protein levels were measured with immunoblotting. RESULTS: Exposure to 20µM PBDE or TCEP for 48 h had minimal effects on thyrocyte viability. There was no significant increase in intracellular ROS up to 6 h following PBDE or TCEP exposure in thyrocytes; however, cells exposed to PBDE 47 showed evidence of DNA single-stranded and double-stranded breaks. There was a dose-dependent increase in γH2AX levels following exposure to PBDEs 47 and 209 in Nthy-Ori cells but not with TCEP treatment. CONCLUSIONS: PBDE 47 and 209 demonstrated genotoxicity but not cytotoxicity in follicular thyrocytes in vitro. Therefore, PBDE 47 and 209 may be carcinogenic in human thyroid cells.

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.

RET Fusion-Positive Papillary Thyroid Cancers are Associated with a More Aggressive Phenotype.

BACKGROUND: It is unclear if different genetic drivers in papillary thyroid cancer (PTC) confer different phenotypic tumor behavior leading to more aggressive disease. We hypothesized that RET-driven cancers are more aggressive. PATIENTS AND METHODS: We reviewed records of consecutive patients treated for newly diagnosed PTC at this single institution from 2015 to 2016. Tumor samples from these patients were genotyped to identify RET-translocated, BRAFV600E mutant, and HRAS, KRAS, and NRAS mutant tumors. Patient demographic, clinicopathologic, and outcomes data were compared to identify genotype-specific patterns of disease. RESULTS: Of the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAFV600E mutant tumors (BRAF), 14 (4.3%) had RET-rearranged tumors (RET), 46 (14.1%) had RAS mutant tumors (RAS), and 75 (22.9%) had BRAF, RET, and RAS wildtype tumors. RET-driven tumors were more likely to have extrathyroidal extension (50.0% versus 27.0% for BRAF and 2.2% for RAS, P < 0.001), multifocal disease (85.7% versus 60.3%, and 44.4%, respectively, P = 0.017), and distant metastases (14.3% versus 1.1%, and 0%, respectively, P = 0.019). RET and BRAF patients also had worse disease-free survival than RAS patients (Kaplan-Meier log rank, P = 0.027). CONCLUSIONS: Patients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAFV600E or RAS mutations. Patients with RET-rearranged tumors had similar disease-free survival to patients with BRAFV600E mutant tumors. RET rearrangement may confer an aggressive phenotype in PTC.

Insurance type is associated with appropriate use of surgical and adjuvant care for differentiated thyroid carcinoma.

BACKGROUND: We aimed to characterize the association between differentiated thyroid cancer (DTC) patient insurance status and appropriateness of therapy (AOT) regarding extent of thyroidectomy and radioactive iodine (RAI) treatment. METHODS: The National Cancer Database was queried for DTC patients diagnosed between 2010 and 2016. Adjusted odds ratios (AOR) for AOT, as defined by the American Thyroid Association guidelines, and hazard ratios (HR) for overall survival (OS) were calculated. A difference-in-differences (DD) analysis examined the association of Medicaid expansion with outcomes for low-income patients aged <65. RESULTS: A total of 224,500 patients were included. Medicaid and uninsured patients were at increased risk of undergoing inappropriate therapy, including inappropriate lobectomy (Medicaid 1.36, 95% confidence interval [CI]: 1.21-1.54; uninsured 1.30, 95% CI: 1.05-1.60), and under-treatment with RAI (Medicaid 1.20, 95% CI: 1.14-1.26; uninsured 1.44, 95% CI: 1.33-1.55). Inappropriate lobectomy (HR 2.0, 95% CI: 1.7-2.3, P < .001) and under-treatment with RAI (HR 2.3, 95% CI: 2.2-2.5, P < .001) were independently associated with decreased survival, while appropriate surgical resection (HR 0.3, 95% CI: 0.3-0.3, P < .001) was associated with improved odds of survival; the model controlled for all relevant clinico-pathologic variables. No difference in AOT was observed in Medicaid expansion versus non-expansion states with respect to surgery or adjuvant RAI therapy. CONCLUSION: Medicaid and uninsured patients are at significantly increased odds of receiving inappropriate treatment for DTC; both groups are at a survival disadvantage compared with Medicare and those privately insured.

Association of the Affordable Care Act with access to highest-volume centers for patients with thyroid cancer.

BACKGROUND: Disparities exist in access to high-volume surgeons, who have better outcomes after thyroidectomy. The association of the Affordable Care Act's Medicaid expansion with access to high-volume thyroid cancer surgery centers remains unclear. METHODS: The National Cancer Database was queried for all adult thyroid cancer patients diagnosed from 2010 to 2016. Hospital quartiles (Q1-4) defined by operative volume were generated. Clinicodemographics and adjusted odds ratios for treatment per quartile were analyzed by insurance status. An adjusted difference-in-differences analysis examined the association between implementation of the Affordable Care Act and changes in payer mix by hospital quartile. RESULTS: In total, 241,448 patients were included. Medicaid patients were most commonly treated at Q3-Q4 hospitals (Q3 odds ratios 1.05, P = .020, Q4 1.11, P < .001), whereas uninsured patients were most often treated at Q2-Q4 hospitals (Q2 odds ratios 2.82, Q3 2.34, Q4 2.07, P < .001). After expansion, Medicaid patients had lower odds of surgery at Q3-Q4 compared with Q1 hospitals (odds ratios Q3 0.82, P < .001 Q4 0.85, P = .002) in expansion states, but higher odds of treatment at Q3-Q4 hospitals in nonexpansion states (odds ratios Q3 2.23, Q4 1.86, P < .001). Affordable Care Act implementation was associated with increased proportions of Medicaid patients within each quartile in expansion compared with nonexpansion states (Q1 adjusted difference-in-differences 5.36%, Q2 5.29%, Q3 3.68%, Q4 3.26%, P < .001), and a decrease in uninsured patients treated at Q4 hospitals (adjusted difference-in-differences -1.06%, P = .001). CONCLUSIONS: Medicaid expansion was associated with an increased proportion of Medicaid patients undergoing thyroidectomy for thyroid cancer in all quartiles, with increased Medicaid access to high-volume centers in expansion compared with nonexpansion states.

Association of medicaid expansion of the Affordable Care Act with the stage at diagnosis and treatment of papillary thyroid cancer: A difference-in-differences analysis.

BACKGROUND: The Affordable Care Act's (ACA) Medicaid expansion has increased insurance coverage and improved various cancer outcomes. Its impact in papillary thyroid cancer (PTC) remains unclear. METHODS: Non-elderly patients (40-64 years-old) with PTC living in low-income areas either in a 2014 expansion, or a non-expansion state were identified from the National Cancer Database between 2010 and 2016. Insurance coverage, stage at diagnosis, and RAI administration were analyzed using a difference-in-differences analysis. RESULTS: 10,644 patients were included. Compared with non-expansion states, the percentage of uninsured patients (adjusted-DD -2.6% [95%-CI -4.3to-0.8%],p = 0.004) and patients with private insurance decreased, and those with Medicaid coverage increased (adjusted-DD 9.7% [95%-CI 6.9-12.5%],p < 0.001) in expansion states after ACA implementation. The percentage of patients with pT1 did not differ between expansion and non-expansion states; neither did the use of RAI. CONCLUSIONS: Medicaid expansion has resulted in a smaller uninsured population in PTC patients, but without earlier disease presentation nor change in RAI treatment.

The Use and Benefit of Adjuvant Radiotherapy in Parathyroid Carcinoma: A National Cancer Database Analysis.

BACKGROUND: The routine use of external beam radiotherapy (EBRT) is not recommended for parathyroid carcinoma (PC). However, case series have demonstrated a potential benefit in preventing local recurrence with EBRT. We aimed to characterize the patient population treated with EBRT and identify any impact of EBRT on overall survival (OS) in parathyroid carcinoma. METHODS: Patients who underwent surgery for PC from 2004 to 2016 were identified from the National Cancer Database. Clinicopathologic variables and OS were compared between patients based on treatment with EBRT. Multivariable logistic and Cox regression models were performed with propensity scores and inverse-probability-weighting (IPW) adjustment to reduce treatment-selection bias in the OS analysis. RESULTS: A total of 885 patients met the inclusion criteria, with 126 (14.2%) undergoing EBRT. Demographics were similar between the two cohorts (EBRT vs. no EBRT). However, patients treated with EBRT had a higher frequency of regionally extensive disease, nodal metastases, and residual microscopic disease (all p < 0.05). On multivariable analysis, Black race, regional tumor extension, nodal metastasis, and treatment at an urban facility were independently associated with EBRT. The 5-year OS was 85.3% with a median follow-up of 60.8 months. EBRT was not associated with a difference in OS in crude, multivariable, or IPW models. More importantly, 10.5% of patients with completely resected localized disease (M0, N0 or Nx) underwent EBRT without a benefit in OS (p = 0.183). CONCLUSIONS: EBRT is not associated with any survival benefit in the treatment of PC. Therefore, it may be overutilized, particularly in patients with localized disease and complete surgical resection.

Hypertension resolution after adrenalectomy for primary hyperaldosteronism: Which is the best predictive model?

BACKGROUND: We aimed to compare the predictive performance of three distinct clinical models purported to predict the resolution of aldosteronoma-associated hypertension after adrenalectomy. METHODS: A tri-institutional database of aldosteronoma patients who underwent adrenalectomy between 2004 and 2019 was retrospectively reviewed. The three models of interest incorporate various preoperative clinical factors, such as age and sex. The predictive accuracy, as measured by area under the curve of receiver operator characteristic, was estimated. Receiver operator characteristic was evaluated across the whole cohort, then stratified by treatment location. RESULTS: A total of 200 patients were included (91 American, 109 French). The clinicodemographic variables between groups were similar; the French cohort had a lower mean body mass index (P = .02). The overall complete clinical resolution of hypertension after adrenalectomy for the entire data set was 45.5% (n = 91). The regression coefficients in the Utsumi et al (2014) Japanese model produced a superior overall area under the curve (0.78, 95% confidence interval [CI] [0.71-0.84]). This model also performed best when the cohort was stratified by treatment location (French area under the curve = 0.74, 95% CI [0.64-0.83], US area under the curve = 0.82, 95% CI [0.72-0.91]). CONCLUSION: When comparing three predictive models of aldosteronoma-associated hypertension resolution after adrenalectomy, the Utsumi et al model demonstrated the highest predictive validity across all cohorts. Counseling based on this model regarding probability of cure is recommended.

Impact of multikinase inhibitor approval on survival and physician practice patterns in advanced or metastatic medullary thyroid carcinoma.

BACKGROUND: This study aimed to identify whether multikinase inhibitor approval for medullary thyroid carcinoma was associated with changes in systemic therapy administration or overall survival. METHODS: The National Cancer Database was queried for advanced medullary thyroid carcinoma patients. Clinicopathologic comparisons were performed between premultikinase inhibitor (2005-2010) and postmultikinase inhibitor (2011-2016) approval groups. Multivariable logistic and Cox regressions were applied to assess predictors of systemic therapy and overall survival. RESULTS: A total of 2,891 patients met the criteria. Postmultikinase inhibitor patients were less likely to undergo radiation (P = .02) and more likely to receive systemic therapy (P = .01). The rate of systemic therapy nearly doubled from 2010 to 2011 (8.1% to 13.8%, P = .04); it subsequently declined back toward preapproval rates. Before multikinase inhibitor approval, only metastases and radiation were associated with systemic therapy (P < .05). After multikinase inhibitor approval, patients with small tumors, extrathyroidal extension, positive lymph nodes, or metastases were more likely to receive systemic therapy (P < .05). The 5-year overall survival between pre and postmultikinase inhibitor groups, for those who received systemic therapy (n = 288), was similar (P = .58), even when restricted to patients with distant metastases (P = .55). CONCLUSION: After approval of multikinase inhibitors, physicians broadened the criteria for systemic therapy. Prescription rates have since declined. Given the toxicities of these drugs and no improvement in overall survival since introduction, selective utilization may be warranted.