Initial treatment of patients with thyroid cancer: Outcomes and factors associated with care at academic versus nonacademic cancer centers.

BACKGROUND: Factors associated with receiving initial care for thyroid cancer (TC) at academic centers (ACs) versus nonacademic centers (NACs) and their impact on patient outcomes have not been reported. METHODS: The National Cancer Database with TC cases from 2004 to 2013 was evaluated for association of type of center for initial care with socioeconomic factors and disease and treatment characteristics, as well as overall survival (OS; all-cause mortality). RESULTS: The patients with TC (n = 200,824) included were predominantly women (74%), non-Hispanic Whites (85%), and from metro areas (84%). Sixty percent received initial care at a NAC. There were no significant differences between treatment groups by age or gender. Among those treated at an AC, a higher proportion belonged to racial/ethnic minorities (16.5%) versus at a NAC (11.6%). Hormone therapy was used more in an AC versus a NAC (60% vs 47%). Patients with all TC pathologies combined had a lower likelihood of death when they received initial care at an AC (hazard ratio [HR], 0.948; P = .0006). Among individual pathologic subtypes, a lower likelihood of death was noted when initial care was received at an AC for follicular (HR, 0.828, P = .0010) and Hurthle cell cancers (HR, 792; P = .0008), as well as stage II papillary thyroid cancer (HR, 0.828; P = .0026), but not for other histopathologic subtypes. CONCLUSIONS: Initial care at an AC was associated with lower likelihood of death for patients with TC, especially for those with follicular or Hurthle cell subtypes. Optimal resource use with consideration of patients' socioeconomic and demographic factors is imperative to ensure the most appropriate management of patients with TC in various treatment settings.

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.

ThyroSeq®V2.0 Molecular Testing: A Cost-Effective Approach for the Evaluation of Indeterminate Thyroid Nodules.

OBJECTIVE: Approximately 15 to 30% of thyroid nodules have indeterminate cytology. Many of these nodules are treated surgically, but only 5 to 30% are malignant. Molecular testing can further narrow the risk of malignancy of these nodules. Our objective was to assess the cost effectiveness of ThyroSeq®V2.0 compared to diagnostic thyroidectomy for the evaluation of indeterminate nodules. METHODS: Cytology and histopathology slides of Bethesda category III and IV (suspicious for follicular neoplasia [SFN]) nodules obtained between January 1, 2014 and November 30, 2016 were re-reviewed by 2 endocrine cytopathologists. Costs for a diagnostic approach using ThyroSeq® were calculated and compared to those of diagnostic thyroidectomy. RESULTS: We included 8 Bethesda category III nodules that underwent ThyroSeq® and 8 that underwent diagnostic surgery. Of those submitted for ThyroSeq®, 4 were positive for mutations and underwent thyroid surgery. The average cost per nodule evaluated was $14,669 using ThyroSeq®, compared to $23,338 for diagnostic thyroid surgery. The cost per thyroid cancer case detected was $58,674 using ThyroSeq® compared to $62,233 for diagnostic thyroid surgery. We included 13 nodules Bethesda category IV that underwent ThyroSeq® and 11 that underwent diagnostic surgery. Of those submitted for ThyroSeq®, 6 were positive for mutation and underwent thyroid surgery. The average costs per nodule evaluated were $14,641 using ThyroSeq® and $24,345 using diagnostic thyroidectomy. The cost per thyroid cancer case detected was $31,721 when using ThyroSeq® compared to $53,560 for diagnostic thyroidectomy. CONCLUSION: The use of ThyroSeq® in our institution is cost effective compared to diagnostic thyroid surgery for the evaluation of Bethesda categories III and IV (SFN) nodules. ABBREVIATIONS: FNA = fine-needle aspiration; GEC = gene expression classifier; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid cancer; SFN = suspicious for follicular neoplasia.

Cytokeratin-8 in Anaplastic Thyroid Carcinoma: More Than a Simple Structural Cytoskeletal Protein.

Anaplastic thyroid carcinoma (ATC) is almost universally fatal. Elevated keratin-8 (KRT8) protein expression is an established diagnostic cancer biomarker in several epithelial cancers (but not ATC). Several keratins, including KRT8, have been suggested to have a role in cell biology beyond that of structural cytoskeletal proteins. Here, we provide evidence that KRT8 plays a direct role in the growth of ATCs. Genomic and transcriptomic analysis of >5000 patients demonstrates that KRT8 mutation and copy number amplification are frequently evident in epithelial-derived cancers. Carcinomas arising from diverse tissues exhibit KRT8 mRNA and protein overexpression when compared to normal tissue levels. Similarly, in a panel of patient-derived ATC cell lines and patient tumors, KRT8 expression shows a similar pattern. sh-RNA-mediated KRT8 knockdown in these cell lines increases apoptosis, whereas forced overexpression of KRT8 confers resistance to apoptosis under peroxide-induced cell stress conditions. We further show that KRT8 protein binds to annexin A2, a protein known to mediate apoptosis as well as the redox pathway.

ACTIVE SURVEILLANCE FOR PAPILLARY THYROID MICROCARCINOMA: NEW CHALLENGES AND OPPORTUNITIES FOR THE HEALTH CARE SYSTEM.

OBJECTIVE: The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. METHODS: We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. RESULTS: Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. CONCLUSION: With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies.

The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth through transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at serine473 in ATC cell lines and tissues of ATC patients, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to downregulation of CCNA1 mRNA and protein. These combined data suggest an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth through transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in tumor tissues of ATC patients. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution in relation to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.

New therapeutic options for advanced forms of thyroid cancer.

INTRODUCTION: While the vast majority of patients with thyroid cancer have an excellent prognosis, those with more aggressive courses experience significant morbidity and mortality. Advanced forms of thyroid cancer are typically refractory to standard therapy. Numerous agents with potential usefulness in the treatment of advanced thyroid cancer have recently come under study. AREAS COVERED: This article reviews agents identified through a systematic review of the scientific literature as being under investigation for treatment of advanced thyroid cancer. A search of both PubMed and the NCI Clinical Trials website was performed to identify such agents having reached Phase II or III testing. Improved understanding of cancer cell signaling pathways has led to the identification of > 500 kinases as potential therapeutic targets. Additional agents of interest include those that inhibit neoangiogenesis, alter epigenetic factors or stimulate antitumor immune reactions. While presently available agents have shown promise in improving progression-free survival (PFS), complete responses are not seen and significant adverse side effects are encountered. EXPERT OPINION: The development of numerous new anticancer agents holds the promise of treatment regimens that will extend PFS and ultimately overall survival in patients with advanced thyroid cancer. Anticipated future developments include individualized, multimodal treatment regimens based on specific tumor cell biology and driver mutations.

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Anaplastic thyroid cancer: An update.

Anaplastic thyroid cancer (ATC) is one of the most lethal of all cancers. It is more common in women and occurs primarily in older patients. ATC has a median overall survival of 3-5 months and a nearly 100% disease-specific mortality. It is known to spread rapidly to locoregional structures as well as outside the neck to distant sites, hence ATC is always considered stage IV. With better understanding of the disease at a molecular level, the introduction of newer treatment strategies has been possible and is part of the multimodal (surgery, radiation, and systemic therapy) therapeutic approach. However, there is extensive work needed to achieve better survival outcomes.

Evaluating new treatments for anaplastic thyroid cancer.

INTRODUCTION: Anaplastic thyroid cancer (ATC) is one of the most lethal diseases known to humans with a median survival of 5 months. The American Thyroid Association (ATA) recently published guidelines for the treatment of this dreadful thyroid malignancy. AREAS COVERED: This review presents the current therapeutic landscape of this challenging disease. We also present the results from trials published over the last five years and summarize currently active clinical trials. EXPERT OPINION: Recent attempts to improve the prognosis of these tumors are moving toward personalized medicine, basing the treatment decision on the specific genetic profile of the individual tumor. The positive results of dabrafenib and trametinib for ATC harboring the BRAF V600E mutation have provided a useful treatment option. For the other genetic profiles, different drugs are available and can be used to individualize the treatment, likely using drug combinations. Combinations of drugs act on different molecular pathways and achieve inhibition at separate areas. With new targeted therapies, average survival has improved considerably and death from local disease progression or airway compromise is less likely with improvement in quality of life. Unfortunately, the results remain poor in terms of survival.

Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study.

BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Cardiovascular outcomes and rates of fractures and falls among patients with brand-name versus generic L-thyroxine use.

PURPOSE: To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use. METHODS: Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control. RESULTS: 195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58-1.60), myocardial infarction (HR 0.66, 0.39-1.14), congestive heart failure (HR 1.30, 0.78-2.16), stroke (0.72, 0.49-1.06), spine (HR 0.87, 0.38-1.99) and hip fractures (HR 0.86, 0.26-2.82), or fall outcomes (HR 1.02, 0.14-7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61-1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups. CONCLUSIONS: We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine.

2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC. Methods: The specific clinical questions and topics addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of the Task Force members (authors of the guideline). Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues, including end of life. The guidelines include 31 recommendations and 16 good practice statements. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of ATC. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with ATC.

Case of aggressive metastatic follicular variant papillary thyroid carcinoma with BRAF K601E and BCORL1 mutations.

BCL6 corepressor like-1 (BCORL1) mutation has rarely been described in thyroid cancer or in association with BRAF mutations in any malignancy. However, we report a 49-year-old woman who had aggressive follicular variant papillary thyroid carcinoma (FV-PTC) with both the BRAF K601E and BCORL1 mutations. The patient underwent a total thyroidectomy for a 3.6 cm right thyroid nodule and a smaller lesion in the left lobe in 2007; both were FV-PTCs with no lymphovascular invasion or metastases. In 2015, a positron emission tomography-CT scan showed a small defect in the left posterior lateral fifth rib with mild increased hypermetabolic activity with standardised uptake value of 3.9 and another lesion in the right hip at the junction of the femoral neck and trochanter. Tumour biopsy and genetic analysis revealed an uncommon BRAF K601E and a rare BCORL1 mutation. While rare, we report a case of aggressive FV-PTC with both the BRAF K601E and BCORL1 mutations.

Comparative Effectiveness of Generic vs Brand-Name Levothyroxine in Achieving Normal Thyrotropin Levels.

Importance: Whether the use of generic vs brand levothyroxine affects thyrotropin levels remains unclear. Objective: To compare the effectiveness of generic vs brand levothyroxine in achieving and maintaining normal thyrotropin levels among new users. Design, Setting, and Participants: This retrospective, 1:1 propensity score-matched longitudinal cohort study used the OptumLabs Data Warehouse administrative claims database linked to laboratory results from commercially insured and Medicare Advantage enrollees throughout the United States. Eligible patients were adults (aged ≥18 years) with thyrotropin levels ranging from 4.5 to 19.9 mIU/L who initiated use of generic or brand-name levothyroxine from January 1, 2008, to October 1, 2017. Data were analyzed from August 13, 2018, to October 25, 2019. Exposure: Patients received generic or brand-name levothyroxine. Main Outcomes and Measures: Proportion of patients with normal vs markedly abnormal thyrotropin levels (<0.1 or >10 mIU/L) within 3 months and with stable thyrotropin levels within 3 months after the thyrotropin value fell into the normal range. Results: A total of 17 598 patients were included (69.0% female; 74.0% White; mean [SD] age, 55.1 [16.0] years), of whom 15 299 filled generic and 2299 filled brand-name levothyroxine prescriptions during the study period. Among 4570 propensity score-matched patients (mean [SD] age, 50.3 [13.8] years; 3457 [75.6%] female; 3510 [76.8%] White), the proportion with normal thyrotropin levels within 3 months of filling levothyroxine prescriptions was similar for patients who received generic vs brand-name levothyroxine (1722 [75.4%; 95% CI, 71.9%-79.0%] vs 1757 [76.9%; 95% CI, 73.4%-80.6%]; P = .23), as was the proportion with markedly abnormal levels (94 [4.1%; 95% CI, 3.4%-5.0%] vs 88 [3.9%; 95% CI, 3.1%-4.7%]; P = .65). Among 1034 propensity score-matched patients who achieved a normal thyrotropin value within 3 months of initiation of levothyroxine, the proportion maintaining subsequent normal thyrotropin levels during the next 3 months was similar for patients receiving generic vs brand-name levothyroxine (427 [82.6%] vs 433 [83.8%]; P = .62). Conclusions and Relevance: Initiation of generic vs brand-name levothyroxine formulations was associated with similar rates of normal and stable thyrotropin levels. These results suggest that generic levothyroxine as initial therapy for mild thyroid dysfunction is as effective as brand-name levothyroxine.

Foundation One Genomic Interrogation of Thyroid Cancers in Patients With Metastatic Disease Requiring Systemic Therapy.

CONTEXT: Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. OBJECTIVES, DESIGN, AND SETTING: We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. PATIENT CONTEXT: Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. INTERVENTION: The intervention was Foundation One tumor interrogation. MAIN OUTCOME MEASURES: Main outcome measures included genomic alterations, patient characteristics, and overall survival. RESULTS: Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine-refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)-but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. CONCLUSIONS: Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies.

Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of approximately 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.

Ethanol Ablation of Neck Metastases from Differentiated Thyroid Carcinoma.

Differentiated thyroid cancer often metastasizes to cervical lymph nodes, characteristically with slow growth rate and low-level aggressiveness. Cervical lymph node resection is the treatment of choice, but ethanol ablation offers a therapeutic option for patients with few nodes unresponsive to radioiodine therapy and who are poor surgical candidates. The ethanol ablation procedure is minimally invasive, guided sonographically, easily and safely repeated, and easily implemented with minimal technology and cost. Transient nerve injury is infrequent and virtually the only important complication. Current experience indicates that ethanol ablation has the safest therapeutic profile compared to surgery and thermal ablation, and the effectiveness is comparable to thermal ablation and approaches that of surgery. Well-designed clinical trials are lacking.