Search

Background: The overall survival of patients with advanced thyroid cancers that have progressed following targeted therapies is limited, indicating a strong need for salvage treatments., Methods: We retrospectively analyzed patients with refractory advanced thyroid cancer treated with pemetrexed-carboplatin (PC) at Mayo Clinic since 2019., Results: Eleven patients, three with anaplastic thyroid cancer (ATC), seven with differentiated or poorly differentiated thyroid cancer (DTC), and one with oncocytic carcinoma of the thyroid, were treated with novel salvage PC. Patients with DTC (n = 7) had durable responses with a median progression-free survival of 29 months. One responder included a patient with ATC whose disease progressed following pembrolizumab/axitinib, lenvatinib, and dabrafenib/trametinib. On this fourth line treatment, the patient remains on therapy to date, over 12 months after initial response., Conclusions: This case series reinforces prior published phase I clinical trial data and shows that pemetrexed can have potent efficacy in the treatment of the most advanced thyroid cancers., (© 2024 Wiley Periodicals LLC.)

Background: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population., Methods: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m 2 ) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m 2 ), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete., Findings: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group)., Interpretation: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated., Funding: National Cancer Institute and Novartis., Competing Interests: Declaration of interests KCB declares in the past 36 months an unpaid chair of the Americans Thyroid Association Anaplastic Thyroid Cancer Guidelines Task Force, now published. CHC declares in the past 36 months participation on a Data Safety Monitoring Board or Advisory Board for Bristol-Myers Squibb, Cue Biopharma, Sanofi, Mirati, Merck, Brooklyn ImmunoTherapuetics, and Exelixis. MFD declares in the past 36 months support for attending Radiation Oncologists (PA, USA), American Society for Radiation Oncology (ASTRO) Head and Neck Meeting (Scottsdaye, AZ, USA), 2020 ASTRO Annual Meeting (San Antonio, TX, USA); and reimbursement for travel, registration and food, Health Policy Committee Payer Relations for ASTRO. RLF declares in the past 36 months royalties from Bionix TruGuard oral stent, paid to the Mayo Clinic and to himself, honoria for lecture ITCCIR 2021, Elsevier royalties for providing content for sale textbook as Editor, and Hitachi-unrestricted use of research funds paid to the Mayo Clinic for named professorship (Hitachi Professor of Radiation Oncology Research). RAG declares in the past 36 months receipt of National Institutes of Health grant P30CA008748 to the Memorial Sloan Kettering Cancer Center. SAK declares in the past 36 months research support from Merck, Bristol Myers Squibb, and Castle BioSciences; consulting fees from Regeneron; Merck-paid advisory board; an unpaid advisory board role at Castle BioSciences; author for UpToDate; and a data safety monitoring board role at AlphaTau. NYL declares in the past 36 months advisory board roles at Pfizer, Merck, Merck EMD, Elsie, and Mirati. Q-TL declares in the past 36 months consultant roles for Nanobiotix, Roche, and Coherus; honoraria from Johns Hopkins Lecture and 2021 China International Exchange, and Promotive Association for Medical and Health Care Nasopharyngeal Cancer Branch Inaugural Conference and Minimally Invasive Surgery Training Course of Nasopharyngeal Cancer, paid flights or hotels Radiation Therapy Oncology Group (RTOG) foundation meetings or retreats, RTOG group chair (NRG Oncology), and stock or stock options exceeding US$1000 from Aldea. NR reports since the initial planning of the work research support from Pfizer, Repertoire, REPARE Therapuetics, and BMS, and in the past 36 months consulting fees from Illumina Paige.AI. MHS declares in the past 36 months grants from Merck and Eli-Lilly for clinical trials with payment made to his institution. EJS reports since the initial planning of the work support from GSK/Novartis (no payment) and in the past 36 months consulting fees from Eli Lilly, Roche, Regeneron, Eisai, and Elixis, advisory board roles (no compensation) with Eli Lilly, Novartis, and DSMB, and a Protocol Chair (unpaid) role with Eli Lilly and Novartis. PAT-S reports since the initial planning of the work NRG Oncology Statistics and Data Management Center grant from the National Cancer Institute (NCI). PX declares in past 36 months payment to his institution, research grants from AVO and Philips, and support from Philips to present at a Sun Nuclear QA meeting in 2019. SSY declares in past 36 months research support paid to his institution from Merck, Bristol-Myers Squibb, EMD Serono, Genentech, and BioMimetix; book chapter royalties from Springer and UpToDate; and service positions at ASTRO, Elsevier, and NRG Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence-based statement on the definition of advanced thyroid cancer and its targeted systemic treatment., Methods: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel., Results: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided., Conclusions: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted., (© 2022 Wiley Periodicals LLC.)

Context: Metastatic pheochromocytomas and paragangliomas (mPPGL) are rare vascular neuroendocrine tumors that highly express vascular growth factors. Systemic treatment options in cases of unresectable multisite disease are limited. Multikinase inhibitors that inhibit angiogenesis, such as lenvatinib, have proven effective in several other malignancies, and may be a viable option for mPPGL., Objective: We aimed to evaluate the efficacy of lenvatinib as salvage therapy in mPPGLs., Methods: This was a retrospective analysis of mPPGL patients ≥ 18 years of age who received lenvatinib from 2015 to 2020 at a tertiary referral center. Patients were started on lenvatinib 20 mg daily and dose was adjusted according to tolerance or disease progression., Results: Eleven patients were included. Median treatment duration was 14.7 months (95% CI, 2.3-NE). Treatment was discontinued due to disease progression, adverse events, or death. Overall survival at 12 months was 80.8% (95% CI, 42.3-94.9%) but its median was not reached. Median progression-free survival was 14.7 months (95% CI, 1.7-NE). Among the 8 patients with measurable disease, overall response rate was 63%, as 5/8 experienced a partial response and 3/8 had stable disease. Worsening hypertension and anemia were the most common adverse events., Conclusion: Lenvatinib may be a viable treatment option for mPPGL, although at the potential risk of worsening hypertension. Larger, multicenter studies are needed to better characterize treatment efficacy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Radiation therapy (RT) plays an important role in locoregional tumor control for anaplastic thyroid cancer (ATC). Due to its rarity, RT guidelines for ATC are lacking. We describe ATC patterns of nodal disease at presentation and progression and propose corresponding RT target volumes., Methods and Materials: We identified all patients with ATC treated at our institution with definitive or adjuvant intensity modulated radiation therapy and concomitant chemotherapy from 2006 to 2020. We identified in-field, marginal, and out-of-field sites of locoregional recurrence and progression (LRR)., Results: Forty-seven patients met inclusion. Median follow-up was 6.6 months (interquartile range, 1.9-19.6). Nodal levels involved at presentation included: IB (2.1%), II (23.4%), III (21.3%), IV (21.3%), V (12.8%), VI (34%), and mediastinal (6.4%). All patients received elective nodal RT to levels II-IV and VI. RT volumes also included: IA (23.4%), IB (44.7%), V (87.2%), retropharyngeal/retrostyloid (RP/RS) (27.7%), and mediastinal 1 to 6 (53.2%). Cumulative incidence of LRR at 3- and 12-months was 26.1% (95% confidence interval, 15.9-42.8) and 35.7% (23.9-53.4). Isolated LRR risk at 3- and 12-months was 6.5% (2.2-19.8) and 8.9% (3.4-22.9). Fourteen (29.8%) patients experienced in-field LRR in the thyroid gland or postoperative tumor bed, II-IV, VI, and mediastinal 1 and 3A. Four (8.5%) patients had marginal LRRs, 3 of whom progressed in the mediastinum at 2, 3P, 4, and 6. Two (4.3%) patients experienced out-of-field LRRs. Throughout the pretreatment and follow-up period, no patients had disease at IA, and 1 (2.1%) patient each had disease at IB and RP/RS. No baseline or treatment characteristics, including RT dose (stratified by < or ≥66 Gy), were significant predictors of LRR on univariate analysis., Conclusions: Isolated LRR risk in patients with ATC treated with comprehensive RT and chemotherapy is low. Aggressive multimodality therapy should be reserved for willing, fit patients with no or limited distant disease burden. When treating comprehensively, complete inclusion of mediastinal levels 1 to 6 may be warranted to avoid marginal disease progression. Omission of levels I and RP/RS can be considered., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without BRAF mutations or NTRK or RET fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC., Methods: This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS)., Results: The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred., Conclusion: The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted., Competing Interests: Lori J. WirthConsulting or Advisory Role: Merck, Loxo, Blueprint Medicines, Eisai, Lilly, Bayer, ExelixisResearch Funding: Checkmate Pharmaceuticals, Lilly, Ayala Pharmaceuticals, EisaiExpert Testimony: Eisai Marcia S. BroseHonoraria: BayerConsulting or Advisory Role: Bayer, Eisai, Blueprint Medicines, Loxo, ExelixisResearch Funding: Bayer, Eisai, Exelixis, Blueprint Medicines, Loxo, Lilly Eric J. ShermanConsulting or Advisory Role: Cota Healthcare, Goldilocks, Eisai, Regeneron, UpToDate, Lilly, Blueprint MedicinesResearch Funding: Plexxikon, Regeneron Lisa LicitraConsulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, SOBI, Novartis, Bayer, MSD, Merck Serono, Roche, Bristol Myers Squibb, Incyte, Doxapharma, GlaxoSmithKline, Nanobiotix, Debiopharm Group, Amgen, IpsenResearch Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck Serono, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm GroupTravel, Accommodations, Expenses: Merck Serono, Bristol Myers Squibb, MSD, Eisai, AstraZeneca Martin SchlumbergerConsulting or Advisory Role: Eisai, Genzyme, Bayer, Exelixis/Ipsen Steven I. ShermanHonoraria: EisaiConsulting or Advisory Role: Exelixis, Loxo, LillyResearch Funding: Exelixis Bruce RobinsonLeadership: Cochlear, Mayne PharmaStock and Other Ownership Interests: Cochlear, Mayne PharmaConsulting or Advisory Role: Loxo, EisaiSpeakers' Bureau: EisaiTravel, Accommodations, Expenses: Eisai Patrice RodienConsulting or Advisory Role: Eisai EuropeResearch Funding: Pfizer Yann GodbertHonoraria: Eisai Europe, Bayer, LillyTravel, Accommodations, Expenses: Eisai Europe Christelle De La FouchardiereHonoraria: Merck Serono, RocheConsulting or Advisory Role: Lilly, Bayer, Amgen, Bristol Myers Squibb, Servier, Roche, Pierre FabreResearch Funding: RocheTravel, Accommodations, Expenses: Roche, Celgene, Amgen, Bristol Myers Squibb, ServierOther Relationship: Incyte, MSD Oncology Kate NewboldSpeakers' Bureau: Eisai Europe Christopher NuttingEmployment: Advanced Oncotherapy Soamnauth MisirEmployment: Eisai, Urogen Pharma Ana AlmonteEmployment: Eisai Maria E. CabanillasHonoraria: Loxo/LillyConsulting or Advisory Role: Loxo, IgnytaResearch Funding: Kura Oncology, Eisai, Roche/Genentech, Exelixis, MerckNo other potential conflicts of interest were reported.

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.

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.

Background: There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC., Methods: A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC., Results: Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21-49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2-9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8-not reached) and median duration of therapy was 8.5 months (range 2-22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events., Conclusions: In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response., Competing Interests: Competing interests: KDE has received research funding from Mirati Therapeutics. MAH has received research funding from Exelixis. AVC received funding from Eisai Inc and Merck Inc for clinical trial unrelated to this work (both institutional grants)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed., Methods: Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches., Results: Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8-not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7)., Conclusions: Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response., (© Endocrine Society 2020.)

Whereas preemptive screening for the presence of lymph node and lung metastases is standard-of-care in thyroid cancer patients, bone metastases are less well studied and are often neglected in thyroid cancer patient surveillance. Bone metastases in thyroid cancer are, however, independently associated with poor/worse prognosis with a median overall survival from detection of only 4 years despite an otherwise excellent prognosis for the vast majority of thyroid cancer patients. In this review we summarize the state of current knowledge as pertinent to bony metastatic disease in thyroid cancer, including clinical implications, impacts on patient function and quality of life, pathogenesis, and therapeutic opportunities, proposing approaches to patient care accordingly. In particular, bone metastasis pathogenesis appears to reflect cooperatively between cancer and the bone microenvironment creating a "vicious cycle" of bone destruction rather than due exclusively to tumor invasion into bone. Additionally, bone metastases are more frequent in follicular and medullary thyroid cancers, requiring closer bone surveillance in patients with these histologies. Emerging data also suggest that treatments such as multikinase inhibitors (MKIs) can be less effective in controlling bone, as opposed to other (e.g. lung), metastases in thyroid cancers, making special attention to bone critical even in the setting of active MKI therapy. Although locoregional therapies including surgery, radiotherapy and ablation play important roles in palliation, antiresorptive agents including bisphosphonates and denosumab appear individually to delay and/or lessen skeletal morbidity and complications, with dosing frequency of every 3 months appearing optimal; their early application should therefore be strongly considered., Competing Interests: All authors state that they have no conflicts of interest., (© 2020 The Authors.)

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation-one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion-prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.

Anaplastic thyroid cancer (ATC) is a devastating and usually incurable diagnosis. Clinical and pathologic diagnosis is best assessed at a tertiary center with concentrated ATC expertise. Expeditious multidisciplinary management is recommended for optimal patient outcomes. Based on multiinstitutional and population-based studies, multimodal therapy that includes chemoradiotherapy with surgery (when feasible) is the preferred initial treatment because it is associated with incrementally improved overall survival. In ATC that carries a BRAF V600E somatic mutation, combination therapy with BRAF and MEK inhibitors has shown promise but needs further study. Immunotherapeutic agents in neoadjuvant and metastatic settings are being investigated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions., Summary: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions., Conclusions: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.

Progress in the treatment of advanced medullary thyroid cancer (MTC) has resulted from the approval of 2 drugs within the past 5 years, vandetanib and cabozantinib. These multikinase inhibitors (MKIs) possess overlapping specificities for multiple kinase targets implicated in the progression of MTC. Both drugs are associated with toxicities, including hypertension, hemorrhage/perforation, diarrhea and other gastrointestinal events, several dermatologic events, and hypothyroidism. In addition, vandetanib is uniquely associated with QTc prolongation through interaction with myocardial potassium channels, and cabozantinib is uniquely associated with hand-foot skin reaction. Treatment-related toxicities occur frequently and can be severe or life-threatening, and patients undergoing long-term treatment will likely experience adverse events (AEs). Here we offer specific practical recommendations for managing AEs commonly occurring with vandetanib and cabozantinib. The recommended approach relies on early recognition and palliation of symptoms, dose interruption, and dose reduction as necessary in order for the patient to maintain the highest tolerable dose for as long as possible and optimal quality of life. Treatment guidelines do not specify a recommended sequence for treating with vandetanib and cabozantinib; however, most patients will receive both drugs during their lifetime. The choice for first-line therapy is individualized after a risk-benefit assessment and depends on physician preference and patient-related factors, such as comorbid conditions. Because most generalist practices may not be familiar with the intricacies of agents such as vandetanib and cabozantinib, we commend that patients with advanced MTC be managed and treated by a thyroid cancer specialist with coordination of care within a multidisciplinary team., (Copyright © 2018. Published by Elsevier Ltd.)

Context: Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal., Objective: To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival., Design: MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999., Patients: Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT., Main Outcome Measure: Overall survival (OS) and progression-free survival determined by Kaplan-Meier method., Results: Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy., Conclusion: MMT appears to convey longer survival in ATC among patients with stage IVA/B disease., (Copyright © 2017 Endocrine Society)

Purpose/objectives: To evaluate the role of external beam radiation therapy (EBRT) for treatment of malignant paraganglioma (PGL) and pheochromocytoma (PCC)., Methods and Materials: A retrospective review was performed of all patients with malignant PGL/PCC treated with EBRT at our institution between 1973 and 2015. Local control (LC) per treated lesion and overall survival were estimated using the Kaplan-Meier method. Toxicities were scored using the Common Toxicity Criteria for Adverse Events (AE), version 4., Results: The cohort included 41 patients with 107 sites treated. Median (range) age at EBRT was 33 (11-80) years. Treatment intention was curative in 20 patients (30 lesions) and palliative in 21 patients (77 lesions). The primary tumor was PGL (63%) and PCC (37%). Previous local therapies were surgical resection (90%) and percutaneous ablation (19%). Indications for EBRT were local control (66%), pain (22%), or spinal cord compression (12%). Treatment site included bone (69%), soft tissue (30%), and liver (1%). Median (range) EBRT dose was 40 (6.5-70) Gy. Median biologic effective dose using α/β = 10 (BED 10 ) was 53 (9-132). Median follow-up was 3.8 years (0.04-41.5), and mean follow-up was 9.7 years. Overall survival at 5 years was 65%: 79% for curative- and 50% for palliative-intention patients ( P  = .028). LC at 5 years was 81% for all lesions; 91% for lesions receiving BED 10 ≥53, and 62% for lesions receiving BED 10 <53 ( P  = .001). All 11 lesions treated with stereotactic body RT or radiosurgery had LC at a median of 3.0 (0.2-5.4) years. For the symptomatic lesions, symptoms improved in 94%. There were no acute grade ≥3 treatment-related AEs, including no hypertensive crises. Two patients developed a late grade ≥3 AE., Conclusions: EBRT is a useful treatment modality for malignant PGL and PCC. Higher RT dose was associated with improved LC.

Objective: Lenvatinib is approved for use in advanced radioactive iodine-resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience., Methods: Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed., Results: The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0-10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response., Conclusion: Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy., Abbreviations: DTC = differentiated thyroid cancer; LASA = linear analog self-assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor.

Introduction: Pheochromocytomas and paragangliomas (Pheo/PGL) are rare, vascular, sometimes malignant endocrine tumors. Case reports indicate the activity of vascular endothelium growth factor receptor-targeted kinase inhibitors in these cancers., Objectives: To assess the antitumor activity and tolerability of pazopanib in progressive malignant Pheo/PGL., Patients and Methods: This multicenter Phase II trial (MC107C) enrolled individuals  ≥18 years old with disease progression ≤ 6 months prior to registration, Eastern Cooperative Oncology Group PS 0-2, and measurable disease (response evaluation criteria in solid tumors 1.0). Pazopanib was administered in 28-day cycles, with the regimen ultimately being as follows: cycle 1: 400 mg daily on days 1-14, cycle 2: 800 mg daily on days 1-14, and then cycle 2 + : 800 mg daily on all days., Results: The study was halted due to poor accrual. Seven patients were enrolled (05/2011-11/2014). One patient withdrew consent prior to treatment, leaving six evaluable patients. Treatment was discontinued, due to the following reasons: disease progression (4); withdrawal (1); and grade 4 (Takotsubo) cardiomyopathy (1). The median number of cycles administered was 4 (range: 2-29, total: 49). Four patients had >1 dose reduction due to the following reasons: fatigue (1), abnormal liver tests (2), hypertension and (Takotsubo) cardiomyopathy (1), and headaches (1). Common severe (Common Terminology Criteria for Adverse Events v3.0 grades 3-5) toxicities were as follows: hypertension (3/6), (Takotsubo) cardiomyopathy (2/6), diarrhea (1/6), fatigue (1/6), headache (1/6), and hematuria (1/6). One confirmed partial response was observed in PGL (17%, duration 2.4 years); median progression-free survival and overall survival were 6.5 and 14.8 months, respectively., Conclusion: Pazopanib has activity in Pheo/PGL requiring more study; optimal alpha- and beta-blockade are imperative pre-therapy in patients with secretory tumors, as risk of hypertension and cardiomyopathy are potentially life threatening.

Background: Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy., Methods: A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015., Results: Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib., Conclusion: This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.

Introduction: Pheochromocytoma and paraganglioma (PPGL) are rare neoplasms; about 10% are malignant. Literature regarding possible benefit from resection is extremely limited., Methods: A 20 year review of all patients undergoing surgery for malignant PPGL at the Mayo Clinic Rochester Campus between 1994 and June 2014 was performed., Results: We identified 34 patients undergoing surgery for malignant PPGL. Median follow up was 6 and 5 years survival was 90% (median 11 years). Complete resection (R0) was achieved in 14 patients (41%). Median disease-free survival was 4.6 years for patients with R0 resection (up to 12 years). Only eight patients (23%) were disease-free on last follow up. Elevated preoperative fractionated metanephrines or catecholamines were documented in 23 patients (68%); these normalized in 13 of 23 patients (56%) postoperatively-with symptom relief in 15 of 18 preoperatively symptomatic patients (79%). Among 23 patients with hormone-producing tumors, significant reduction in number of antihypertensive medications was also noted postoperatively; 11 patients have remained off all antihypertensives, 6 required 1 medication, 1 required 2, while 5 required full blockade with phenoxybenzamine and a beta-adrenergic blocker., Conclusion: Surgery plays a significant role in the management of selected malignant PPGL. Resection can be effective in normalizing or significantly reducing levels of catecholamines and metanephrines, and can improve hormone-related symptoms and hypertension. Surgical resection, either complete or incomplete, is associated with durable survival despite a high rate of tumor recurrence.

Context: Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown., Objective: Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC., Design: Retrospective study of a uniformly treated cohort., Setting: Single institution retrospective cohort study., Patients or Other Participants: Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied., Main Outcome Measure: Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS)., Results: All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS., Conclusion: PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients., (Copyright © 2017 Endocrine Society)

American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Task Force to review, comment on, and make recommendations related to the suggested new classification of encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists of members from the 2015 guidelines task force with the recusal of three members who were authors on the paper under review. Four pathologists and one endocrinologist were added for this specific review. The manuscript proposing the new classification and related literature were assessed. It is recommended that the histopathologic nomenclature for eFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of this neoplastic variant. This is a weak recommendation based on moderate-quality evidence. It is also noted that prospective studies are needed to validate the observed patient outcomes (and test performance in predicting thyroid cancer outcomes), as well as implications on patients' psychosocial health and economics.

Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research.

Medullary thyroid cancer (MTC) is a rare tumor arising from the calcitonin-producing parafollicular C cells of the thyroid gland, occurring either sporadically or alternatively in a hereditary form based on germline RET mutations in approximately one-third of cases. Historically, patients with advanced, metastasized MTC have had a poor prognosis, partly due to limited response to conventional chemotherapy and radiation therapy. In the past decade, however, considerable progress has been made in identifying key genetic alterations and dysregulated signaling pathways paving the way for the evaluation of a series of multitargeted kinase inhibitors that have started to meaningfully impact clinical practice. Two drugs, vandetanib and cabozantinib, are now approved in the US and EU for use in advanced, progressive MTC, with additional targeted agents also showing promise or awaiting results from clinical trials. However, the potential for toxicities with significant reduction in quality of life and lack of curative outcomes has to be carefully weighed against potential for benefit. Despite significant PFS prolongation observed in randomized clinical trials, most patients even with metastatic disease enjoy indolent courses with slow progression observed over years, wherein watchful waiting is still the preferred strategy. As advanced, progressive MTC is a rare and complex disease, a multidisciplinary approach centered in specialized centers providing interdisciplinary expertise in the individualization of available therapeutic options is preferred. In this review, we summarize current concepts of the molecular pathogenesis of advanced MTC and discuss results from clinical trials of targeted agents and also cytotoxic chemotherapy in the context of clinical implications and future perspectives., (© 2016 Society for Endocrinology.)

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer., Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members., Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research., Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Objective: Patients with progressive thyroid cancer in distant metastatic sites represent a population with a need for new therapeutic options. Aspiring to improve the treatment of such patients, the objective of this position statement from the International Thyroid Oncology Group (ITOG) is to clarify the importance of incorporating high-quality correlative studies into clinical trials., Participants: ITOG was formed to develop and support high-quality multicenter and multidisciplinary clinical trials for patients with aggressive forms of thyroid cancer. The Correlative Sciences Committee of the ITOG focuses on the quality and types of correlative studies included in ITOG-associated clinical trials., Evidence: This document represents expert consensus from ITOG regarding this issue based on extensive collective experience in clinical and translational trials informed by basic science., Consensus Process: The Correlative Studies Committee identified an international writing group representative of diverse specialties, including basic sciences. Drafts were reviewed by all members of the writing group, the larger committee, and the ITOG board. After consideration of all comments by the writing group and modification of the document, the final document was then approved by the authors and the ITOG board., Conclusions: High-quality correlative studies, which include variety in the types of correlates, should be intrinsic to the design of thyroid cancer clinical trials to offer the best opportunity for each study to advance treatment for patients with advanced and progressive thyroid cancer.

Introduction: Metastatic adrenocortical carcinoma (ACC) is rapidly fatal, with few options for treatment. Patients with metachronous recurrence may benefit from surgical resection. The survival benefit in patients with hematogenous metastasis at initial presentation is unknown., Methods: A review of all patients undergoing surgery (European Network for the Study of Adrenal Tumors) stage IV ACC between January 2000 and December 2012 from two referral centers was performed. Kaplan-Meier estimates were analyzed for disease-free and overall survival (OS)., Results: We identified 27 patients undergoing surgery for stage IV ACC. Metastases were present in the lung (19), liver (11), and brain (1). A complete resection (R0) was achieved in 11 patients. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02). The 1- and 2-year OS was also improved in patients undergoing R0 versus R2 resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02). Patients undergoing neoadjuvant therapy (eight patients) had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) [83.3 %, 62.5 %, 41.7 % vs. 56.8 %, 26.6 %, 8.9 %; p = 0.1]. Adjuvant therapy was associated with improved recurrence-free survival at 6 months and 1 year (67 %, 33 % vs. 40 %, 20 %; p = 0.04) but not improved OS (p = 0.63). Sex (p = 0.13), age (p = 0.95), and location of metastasis (lung, p = 0.51; liver, p = 0.67) did not correlate with OS after operative intervention. Symptoms of hormonal excess improved in 86 % of patients., Conclusion: Operative intervention, especially when an R0 resection can be achieved, following systemic therapy may improve outcomes, including OS, in select patients with stage IV ACC. Response to neoadjuvant chemotherapy may be of use in defining which patients may benefit from surgical intervention. Adjuvant therapy was associated with decreased recurrence but did not improve OS.

Approximately 30% of patients with advanced, metastatic differentiated thyroid cancer have radioiodine-refractory disease, based on decreased expression of the sodium iodide symporter SLC5A5 (NIS), diminished membrane targeting of NIS, or both. Patients with radioiodine-refractory disease, therefore, are not amenable to (131)I therapy, which is the initial systemic treatment of choice for non-refractory metastatic thyroid cancer. Patients with radioiodine-refractory cancer have historically had poor outcomes, partly because these cancers often respond poorly to cytotoxic chemotherapy. In the past decade, however, considerable progress has been made in delineating the molecular pathogenesis of radioiodine-refractory thyroid cancer. As a result of the identification of key genetic and epigenetic alterations and dysregulated signalling pathways, multiple biologically targeted drugs, in particular tyrosine-kinase inhibitors, have been evaluated in clinical trials with promising results and have begun to meaningfully impact clinical practice. In this Review, we summarise the current knowledge of the molecular pathogenesis of advanced differentiated thyroid cancer and discuss findings from clinical trials of targeted drugs in patients with radioiodine-refractory disease. Additionally, we focus on the molecular basis of loss of NIS expression, function, or both in refractory disease, and discuss preclinical and clinical data on restoration of radioiodine uptake., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem., Approach and Methods: To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2-7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 μM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance., Results: Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition., Conclusions: Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem.

Context: Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptors-α and -β; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). OBJECTIVE, DESIGN, SETTING, PATIENTS, INTERVENTION, AND OUTCOME MEASURES: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multiinstitutional phase II clinical trial to assess tumor response rate (by Response Evaluation Criteria In Solid Tumors criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability., Results: From September 22, 2008, to December 11, 2011, 35 individuals (80% males, median age 60 y) were enrolled. All patients have been followed up until treatment discontinuation or for a minimum of four cycles. Eight patients (23%) are still on the study treatment. The median number of therapy cycles was eight. Five patients attained partial Response Evaluation Criteria In Solid Tumors responses (14.3%; 90% confidence interval 5.8%-27.7%), with a median progression-free survival and overall survival of 9.4 and 19.9 months, respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%), and abnormal liver tests (6%); 3 of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment related., Conclusions: Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

Introduction: Adrenocortical cancer (ACC) recurs despite apparent complete resection. We examined the survival and palliative benefit of resection for recurrent ACC., Methods: A review of all patients undergoing operation for ACC between 1980 and 2010 at our institution was performed in which we compared resection with nonoperative therapy., Results: Overall, 164 patients underwent operation for ACC, 125 of whom underwent a complete resection (R0). Recurrence occurred in 93 R0 patients (median, 15 months; range, 1.5-150 months). Symptoms at recurrence were present in 71% (66/93), including pain (34%) and hormone excess (43%). There were 67 patients who underwent reoperation for recurrence. Forty-eight of 67 patients underwent R0 resection for recurrence. Operative patients had a greater overall operative versus nonoperative management or no therapy (65 months vs 6 months, P < .01). Median survival for nonoperatively managed patients (226 days) and those undergoing no therapy (179 days) was less than for debulking (1,272 days, P = .002). R0 for recurrence (P = .005) and a disease-free interval >6 months (P < .001) were associated with survival after operation, whereas original tumor size (P = .47), grade (P = .8), and stage (P = .23) were not. Pain and hormonal symptoms improved in 84% of operative patients versus 29% of nonoperatively managed patients (P = .005). Debulking had similar symptomatic improvement to R0 resection (P = .52)., Conclusion: Patients with recurrent ACC can benefit from operative intervention with improvement in survival and symptoms. Patients with a disease-free interval >6 months and complete resection are likely to benefit from resection of the recurrence, but the near universal improvement in symptoms may expand the criteria for operation in recurrent ACC., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models., Methods: This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles., Results: Fourteen patients (7 males, median age 65, range 24-74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m(2), establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease., Conclusions: The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m(2) on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.

Purpose: A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer., Experimental Design: Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics., Results: Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients., Conclusions: Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.

Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.

Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Rapid evaluation and establishment of treatment goals are imperative for optimum patient management and require a multidisciplinary team approach. Here we present guidelines for the management of ATC. The development of these guidelines was supported by the American Thyroid Association (ATA), which requested the authors, members the ATA Taskforce for ATC, to independently develop guidelines for ATC., Methods: Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The quality and strength of recommendations were adapted from the Clinical Guidelines Committee of the American College of Physicians, which in turn was developed by the Grading of Recommendations Assessment, Development and Evaluation workshop., Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, 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 65 recommendations., Conclusions: These are the first comprehensive guidelines for ATC and provide recommendations for management of this extremely aggressive malignancy. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach (surgery, radiation, systemic therapy) is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for a clinical trial or hospice/palliative care, depending upon their preference.

Purpose: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers., Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance≤2 were required., Results: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual., Conclusions: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study., (Copyright © 2012 Elsevier Inc. All rights reserved.)