Publications by authors named "Keith C Bible"

58 Publications

Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma.

J Immunother Cancer 2020 07;8(2)

Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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.
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http://dx.doi.org/10.1136/jitc-2020-001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394183PMC
July 2020

Salvage Therapy With Multikinase Inhibitors and Immunotherapy in Advanced Adrenal Cortical Carcinoma.

J Endocr Soc 2020 Jul 9;4(7):bvaa069. Epub 2020 Jun 9.

Division of Medical Oncology, Mayo Clinic, Rochester, MN, US.

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.
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http://dx.doi.org/10.1210/jendso/bvaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326479PMC
July 2020

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

Thyroid 2020 09 29;30(9):1254-1262. Epub 2020 Jul 29.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

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. 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  = 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. 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:  = 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 -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. 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.
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http://dx.doi.org/10.1089/thy.2019.0269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482116PMC
September 2020

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

J Clin Endocrinol Metab 2020 07;105(7)

Division of Endocrinology, Metabolism and Lipid Research, Washington University, School of Medicine, St Louis, Missouri.

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.
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http://dx.doi.org/10.1210/clinem/dgaa246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263749PMC
July 2020

Bone metastases in thyroid cancer.

J Bone Oncol 2020 Apr 19;21:100282. Epub 2020 Feb 19.

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First Street SW Rochester, MN, 55905, USA.

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.
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http://dx.doi.org/10.1016/j.jbo.2020.100282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058902PMC
April 2020

A Phase 2 Study of Pembrolizumab Combined with Chemoradiotherapy as Initial Treatment for Anaplastic Thyroid Cancer.

Thyroid 2019 11;29(11):1615-1622

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.

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. An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 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%. 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. 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.
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http://dx.doi.org/10.1089/thy.2019.0086DOI Listing
November 2019

A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma.

Invest New Drugs 2019 08 6;37(4):755-762. Epub 2019 Jun 6.

Mayo Clinic Cancer Center, 200 First St. SW, Rochester, MN, 55905, USA.

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.
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http://dx.doi.org/10.1007/s10637-019-00797-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515770PMC
August 2019

Diagnosis and Management of Anaplastic Thyroid Cancer.

Endocrinol Metab Clin North Am 2019 03;48(1):269-284

Division of Medical Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ecl.2018.10.010DOI Listing
March 2019

European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium.

Thyroid 2019 01 7;29(1):7-26. Epub 2019 Jan 7.

18 Department of Endocrinology and Metabolism, Endocrine Tumor Center at WTZ, Essen University Hospital, Essen, Germany.

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.
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http://dx.doi.org/10.1089/thy.2017.0129DOI Listing
January 2019

Management of treatment-related toxicities in advanced medullary thyroid cancer.

Cancer Treat Rev 2018 May 22;66:64-73. Epub 2018 Apr 22.

Dana-Farber Cancer Institute, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ctrv.2018.04.007DOI Listing
May 2018

External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma.

Adv Radiat Oncol 2018 Jan-Mar;3(1):25-29. Epub 2017 Nov 22.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

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) 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 ( = .028). LC at 5 years was 81% for all lesions; 91% for lesions receiving BED ≥53, and 62% for lesions receiving BED <53 ( = .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.
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http://dx.doi.org/10.1016/j.adro.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856976PMC
November 2017

Effect of thyroid hormone suppression on control of advanced well-differentiated thyroid cancer.

Endocrine 2018 01 1;59(1):228-229. Epub 2017 Nov 1.

Mayo Clinic Division of Medical Oncology, Rochester, MN, USA.

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http://dx.doi.org/10.1007/s12020-017-1464-5DOI Listing
January 2018

Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer.

J Clin Endocrinol Metab 2017 12;102(12):4506-4514

Division of Medical Oncology, Mayo Clinic.

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.
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http://dx.doi.org/10.1210/jc.2017-01180DOI Listing
December 2017

OPTIMIZING LENVATINIB THERAPY IN PATIENTS WITH METASTATIC RADIOACTIVE IODINE-RESISTANT DIFFERENTIATED THYROID CANCERS.

Endocr Pract 2017 Oct 17;23(10):1254-1261. Epub 2017 Aug 17.

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.
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http://dx.doi.org/10.4158/EP171822.ORDOI Listing
October 2017

Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma.

Endocrine 2017 Aug 6;57(2):220-225. Epub 2017 Jul 6.

Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

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.
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http://dx.doi.org/10.1007/s12020-017-1359-5DOI Listing
August 2017

Toward predictive biomarkers of response to kinase inhibitor therapies in differentiated thyroid cancer.

Endocrine 2017 09 22;57(3):364-365. Epub 2017 Jun 22.

Divisions of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1007/s12020-017-1342-1DOI Listing
September 2017

"Pseudo-progression" in advanced thyroid cancer in response to kinase inhibitor therapy.

Endocrine 2017 07 16;57(1):187-188. Epub 2017 May 16.

Mayo Clinic Minnesota, Rochester, MN, USA.

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http://dx.doi.org/10.1007/s12020-017-1321-6DOI Listing
July 2017

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

Thyroid 2017 07 31;27(7):923-927. Epub 2017 May 31.

2 Division of Medical Oncology, Mayo Clinic Rochester , Minnesota.

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.
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http://dx.doi.org/10.1089/thy.2016.0627DOI Listing
July 2017

Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study.

J Clin Endocrinol Metab 2017 06;102(6):1943-1950

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905.

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.
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http://dx.doi.org/10.1210/jc.2016-3756DOI Listing
June 2017

American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Thyroid 2017 04 21;27(4):481-483. Epub 2017 Feb 21.

12 University of Texas M.D. Anderson Cancer Center , Houston, Texas.

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.
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http://dx.doi.org/10.1089/thy.2016.0628DOI Listing
April 2017

Surgical Treatment of Malignant Pheochromocytoma and Paraganglioma: Retrospective Case Series.

Ann Surg Oncol 2017 Jun 5;24(6):1546-1550. Epub 2017 Jan 5.

Department of Surgery, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1245/s10434-016-5739-5DOI Listing
June 2017

Mutated BRAF and personalised medicine in differentiated thyroid cancer.

Lancet Oncol 2016 09 23;17(9):1181-3. Epub 2016 Jul 23.

Mayo Clinic, Rochester, MN 55905, USA.

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http://dx.doi.org/10.1016/S1470-2045(16)30230-3DOI Listing
September 2016

New drugs for medullary thyroid cancer: new promises?

Endocr Relat Cancer 2016 06 16;23(6):R287-97. Epub 2016 May 16.

Division of Medical OncologyMayo Clinic, Rochester, Minnesota, USA.

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.
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http://dx.doi.org/10.1530/ERC-16-0104DOI Listing
June 2016

Evolving molecularly targeted therapies for advanced-stage thyroid cancers.

Nat Rev Clin Oncol 2016 07 1;13(7):403-16. Epub 2016 Mar 1.

Division of Medical Oncology, Department of Oncology, and Endocrine Malignancies Disease Oriented Group, Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

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.
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http://dx.doi.org/10.1038/nrclinonc.2016.19DOI Listing
July 2016

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

Thyroid 2016 Jan;26(1):1-133

16 MedStar Washington Hospital Center , Washington, DC.

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.
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http://dx.doi.org/10.1089/thy.2015.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739132PMC
January 2016

Correlative Studies in Clinical Trials: A Position Statement From the International Thyroid Oncology Group.

J Clin Endocrinol Metab 2015 Dec 29;100(12):4387-95. Epub 2015 Sep 29.

Mayo Clinic (K.C.B.), Rochester, Minnesota, Minnesota 55905; MD Anderson Cancer Center (G.J.C.), Houston, Texas 77030; Translational Genomics Research Institute (M.J.D.), Phoenix, Arizona 85004; University of Pisa (R.E.), 56126 Pisa, Italy; and The Ohio State University and Arthur G. James Comprehensive Cancer Center (S.J., M.D.R.), Columbus Ohio 43210.

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.
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http://dx.doi.org/10.1210/jc.2015-2818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399506PMC
December 2015

Surgical resection of synchronously metastatic adrenocortical cancer.

Ann Surg Oncol 2015 Jan 5;22(1):146-51. Epub 2014 Aug 5.

Department of Surgery, Mayo Clinic, Rochester, MN, USA,

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.
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http://dx.doi.org/10.1245/s10434-014-3944-7DOI Listing
January 2015

Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets.

Lancet Diabetes Endocrinol 2014 Oct 2;2(10):830-42. Epub 2014 Jun 2.

Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1016/S2213-8587(14)70051-8DOI Listing
October 2014