Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer—Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.

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Second or none: Many patients treated for refractory differentiated thyroid cancer with small molecular kinase inhibitors do not receive a second line of therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e17589 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e17589-e17589 ◽

Cited By ~ 1

Author(s):

Ronda Copher ◽

Oluwakayode Adejoro ◽

Stacey DaCosta Byfield ◽

Mary DuCharme ◽

Debanjana Chatterjee ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Kinase Inhibitors ◽

The United States ◽

Treatment Patterns ◽

Second Line ◽

Medicare Advantage ◽

First Line ◽

Line Of Therapy

e17589 Background: Describe the treatment patterns of patients initiated on NCCN-recommended small molecular kinase inhibitors (SMKIs) for radioiodine-refractory differentiated thyroid cancer (DTC) approved in the United States. Methods: A large national US claims database was used to identify adult patients diagnosed with thyroid cancer (≥2 non-DX medical claims, ≥ 30 days apart) from 1/1/2006 - 6/30/2016 (study period) with claims for SMKIs from 1/1/2010 - 5/31/2016. Continuous enrollment required participation in a commercial or Medicare Advantage health plan ≥3 months before and ≥1 month following index date (date of first pharmacy claim for SMKI). Line of therapy (LOT) periods were defined by receipt and timing of SMKIs. Patient follow up was earliest disenrollment, death or end of the study period. Patient characteristics and SMKI treatment patterns were described. Results: A total of 217 DTC patients were identified; 63% commercially insured and 37% Medicare Advantage. Almost half were male (48%); mean age was 61.2 years (standard deviation SD 12.5 years) and mean follow-up period was 499 days (SD 414 days). In the study period, 35% (n = 77) of patients had ≥2 LOTs and 18% (n = 39) had ≥3 LOTs. Mean treatment duration was 5.4 months (SD 6.7 mos) for LOT1, 4.9 months (SD 3.8 mos) for LOT2, and 4.2 months (SD 4.9 mo) for LOT3. During the full study period, the most used regimens were Sorafenib for both LOT1 (37%) and LOT2 (25%), pazopanib (18%) and sunitinib (18%) in LOT3. Also, in the study period, 33 patients had sorafenib in LOT1 of which 16 were treated with sorafenib again (48%) in LOT2. Post FDA approval in 2015, Lenvatinib became the predominant first-line regimen (47%, n = 29) during study period. Across all first line therapies, for those patients with ≥12 months of follow-up, 53% (n = 60) initiated LOT2. Conclusions: Sorafenib was the most common first line of therapy for DTC, with Lenvatinib adoption increasing as first-line therapy since the drug’s approval in 2015. Depending on the period evaluated, almost half to 2/3 of patients are not receiving a second line of treatment, efficacious and patient appropriate therapy is of importance in treating this rare cancer.

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Differentiated Thyroid Cancer

10.2310/cgso.16001 ◽

2019 ◽

Author(s):

Rebecca Tuttle ◽

William Cance ◽

James Howe

Keyword(s):

Thyroid Cancer ◽

Thyroid Nodule ◽

Differentiated Thyroid Cancer ◽

Radioactive Iodine ◽

Kinase Inhibitors ◽

Needle Aspiration ◽

Thyroid Stimulating Hormone ◽

Diagnostic Modality ◽

Radioactive Iodine Ablation ◽

Common Malignancy

Differentiated thyroid cancer is a common malignancy with an excellent prognosis. Patients typically present with a thyroid nodule identified on physical exam or imaging. Fine needle aspiration (FNA) is the diagnostic modality of choice; ultrasound of the neck is used preoperatively to evaluate lymphadenopathy. Surgery is the mainstay of treatment, with partial or total thyroidectomy (with or without lymphadenectomy). Intra-operatively, identification of the recurrent laryngeal nerve and preservation of the parathyroid glands is imperative. Postoperatively, patients are considered for adjuvant radioactive iodine ablation. Risk stratification systems are available to assist patient selection for therapy. Surveillance is completed with serial physical exams, laboratory studies, ultrasound, and radioactive iodine scanning. Recurrence can be managed with surgery, thyroid-stimulating hormone suppression, radioactive iodine ablation, radiation, or kinase inhibitors. This review contains 8 figures, 6 tables, and 50 references. Key Words: Bethesda classification, differentiated thyroid cancer, follicular thyroid cancer, papillary thyroid cancer, radioactive iodine, thyroid nodule, thyroidectomy

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Differentiated Thyroid Cancer

10.2310/7800.16001 ◽

2019 ◽

Author(s):

Rebecca Tuttle ◽

William Cance ◽

James Howe

Keyword(s):

Thyroid Cancer ◽

Thyroid Nodule ◽

Differentiated Thyroid Cancer ◽

Radioactive Iodine ◽

Kinase Inhibitors ◽

Needle Aspiration ◽

Thyroid Stimulating Hormone ◽

Diagnostic Modality ◽

Radioactive Iodine Ablation ◽

Common Malignancy

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Prolonged Response to Regorafenib in a Patient with Iodine Refractory Thyroid Cancer

Case Reports in Oncology ◽

10.1159/000503419 ◽

2019 ◽

Vol 12 (3) ◽

pp. 791-795 ◽

Cited By ~ 1

Author(s):

Selina K. Wong ◽

Quincy S.C. Chu ◽

Jennifer L. Spratlin ◽

Randeep Sangha ◽

Alexander J.B. McEwan ◽

...

Keyword(s):

Thyroid Cancer ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Phase 1 ◽

Progression Free Survival ◽

Standard Of Care ◽

Thyroid Stimulating Hormone ◽

Chemical Structures ◽

Standard Of Care Treatment ◽

Cancer Network

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline.

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MON-LB76 Impact of Age on Survival and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Cancer Patients

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1996 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Camille Buffet

Keyword(s):

Thyroid Cancer ◽

Prognostic Factors ◽

Differentiated Thyroid Cancer ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Therapeutic Management ◽

Duration Of Treatment ◽

Free Survival ◽

Secondary Endpoints ◽

Systemic Therapies

Abstract BACKGROUND Age has been identified as a major prognostic factor in differentiated thyroid cancer (DTC). Prognostic factors of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) are poorly described. The objectives of our study were to analyze the influence of age on the survival of patients with RAIR-DTC and to determine their prognostic factors according to age. PATIENTS AND METHOD This single centre, retrospective study enrolled 155 patients diagnosed with a RAIR-DTC between 1991 and 2017. The primary end point was overall survival (OS). Secondary endpoints were progression free survival (PFS) and prognostic factors. RESULTS Median OS was 8.2 years (95% IC: 5.3-9.6). There was no difference according to age (P = 0.47) with median OS at 8.3 years in patients < 65 (95% IC: 4.9-10), and 7.5 years in patients > 65 (IC: 4,9-11,3). PFS after RAIR-diagnosis was 2.1 years (95% IC: 0.8-3) in patients < 65, and 1 year in patients > 65 (95% IC: 0.34-0.68). In both groups, progressive disease despite 131I reduced OS, in comparison with other RAIR criteria. In patients < 65, an interval between the initial diagnosis of DTC and the diagnosis of RAIR metastatic disease more than 3 years was protective from poor OS (HR: 2.12; 95% CI: 1.05-4.27). In patients > 65, presence of a mediastinum metastasis at RAIR-diagnosis was a significant factor for decreased OS (HR: 0.22; 95% CI: 0.11-0.44). No difference was found between groups regarding therapeutic management. One third of patients received tyrosine kinase inhibitors in both groups (< 65 years: 20 patients (28%), ≥ 65 years: 28 (33%), P = 0.49). They were also similar regarding the number of lines received or the median duration of treatment (< 65 years: 19.5 months (2-59), ≥ 65 years: 19 months (1-64), p= 0.35). At least one line of TKI was transitorily or definitively withdrawn due to toxicity in 40% of patients (< 65 years: 8/20 patients (40%), ≥ 65 years: 13/28 (46%), p= 0,037). CONCLUSION In RAIR-DTC patients, age was not predictive of the outcome. In our study, older patients seem to have benefited from intensive therapeutic management. Continual progress made in the management of RAIR-DTC, especially with the implementation of systemic therapies should probably make reconsider the natural history and conventional prognostic factors of RAIR-DTC.

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EFFICACY AND SAFETY OF MULTI-TARGETED KINASE INHIBITORS IN PROGRESSIVE, RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCERS: A META-ANALYSIS

Journal of Cancer & Allied Specialties ◽

10.37029/jcas.v2i1.50 ◽

2016 ◽

Vol 2 (1) ◽

Author(s):

Mutahir A Tunio ◽

Mushabbab AlAsiri ◽

Yasser Bayoumi

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Radioactive Iodine ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Locally Advanced ◽

Progression Free Survival ◽

Cochrane Library ◽

Differentiated Thyroid Cancers ◽

The Impact

Purpose: A meta-analysis was conducted to evaluate the impact of oral multitargeted kinase inhibitors (MTKIs) in radioactive-iodine refractory locally advanced, recurrent/metastatic differentiated thyroid cancer (DTC) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) rates. Materials and Methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database and other search engines were searched to identify randomised controlled trials (RCTs) comparing MTKIs with placebo in locally advanced, recurrent/metastatic DTC. Pooled data were expressed as odds ratio (OR), with 95% con dence intervals (CIs, Mantel–Haenszel xed-effect model). Results: Three RCTs with a total patient population of 954 patients were identi ed. The use of MTKIs was associated with improved PFS (OR: 0.262, 95% CI: 0.19–0.35; heterogeneity (I2) = 22.4%; P < 0.0001), improved DCR (complete and partial responses + stable disease, P < 0.0001) and improved OS 0.66, 95% CI: 0.46–0.96 (I2 = 43%, P = 0.034). Lenvatinib (compliance = 87%) was associated with more grade ≥3 hypertension. However, its other adverse effects were much lower than sorafenib (compliance = 56%) and vandetanib. Conclusion: In radioactive iodine-refractory recurrent, metastatic DTC patients, lenvatinib and sorafenib were associated with improved PFS, DRC and OS rates, while the compliance was better with lenvatinib. Key words: Meta-analysis, multitargeted kinase inhibitors, progressive differentiated thyroid cancer, radioactive iodine- refractory

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Neoadjuvant Therapy in Differentiated Thyroid Cancer

International Journal of Surgical Oncology ◽

10.1155/2016/3743420 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Rajan P. Dang ◽

Daniel McFarland ◽

Valerie H. Le ◽

Nadia Camille ◽

Brett A. Miles ◽

...

Keyword(s):

Thyroid Cancer ◽

Neoadjuvant Chemotherapy ◽

Neoadjuvant Therapy ◽

Differentiated Thyroid Cancer ◽

Potential Role ◽

Kinase Inhibitors ◽

Tracheal Resection ◽

Complete Surgical Resection ◽

Select Trial ◽

Short Time

Objectives. Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy.Methods. We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan.Results. These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC. Additionally, the SELECT trial shows that the targeted therapy lenvatinib is effective in the treatment of DTC and could be useful as neoadjuvant therapy for this disease due to its short time to response. Pazopanib has also demonstrated promise in phase II data.Conclusions. Thus, chemotherapy in the neoadjuvant setting could possibly be useful for managing advanced DTC. Additionally, some of the new tyrosine kinase inhibitors (TKIs) hold promise for use in the neoadjuvant setting in DTC.

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Utility of recombinant human TSH stimulation test in the follow-up of patients with differentiated thyroid cancer depending on basal thyroglobulin results

Advances in Laboratory Medicine / Avances en Medicina de Laboratorio ◽

10.1515/almed-2019-0017 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Amaia Sandúa ◽

Monica Macias ◽

Carolina Perdomo ◽

Juan Carlos Galofre ◽

Roser Ferrer ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Characteristic Curve ◽

Area Under The Curve ◽

High Sensitivity ◽

Thyroid Stimulating Hormone ◽

Stimulation Test ◽

Human Thyroid ◽

Antithyroglobulin Antibodies ◽

Structural Disease

AbstractBackgroundThyroglobulin (Tg) is fundamental for differentiated thyroid cancer (DTC) monitoring. Tg detection can be enhanced using recombinant human thyroid-stimulating hormone (TSH) (rhTSH). This study is aimed to evaluate the use of the rhTSH stimulation test when using a high-sensitivity Tg assay.MethodsWe retrospectively studied 181 rhTSH tests from 114 patients with DTC and negative for antithyroglobulin antibodies (anti-TgAb). Image studies were performed in all cases. Serum Tg and anti-TgAb were measured using specific immunoassays.ResultsrhTSH stimulation in patients with basal serum Tg (b-Tg) concentrations lower than 0.2 ng/mL always resulted in rhTSH-stimulated serum Tg (s-Tg) concentrations lower than 1.0 ng/mL and negative structural disease. In patients with b-Tg concentration between 0.2 and 1.0 ng/mL, s-Tg detected one patient (1/30) who showed biochemical incomplete response. Patients with negative images had lower s-Tg than those with nonspecific or abnormal findings (p<0.05). Receiver operating characteristic curve analysis of the s-Tg to detect altered images showed an area under the curve of 0.763 (p<0.05). With an s-Tg cutoff of 0.85 ng/mL, the sensitivity was 100%, decreasing to 96.15% with an s-Tg cutoff of 2 ng/mL.ConclusionsPatients with DTC with b-Tg concentrations equal or higher than 0.2 ng/mL can benefit from the rhTSH stimulation test.

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Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

International Journal of Molecular Sciences ◽

10.3390/ijms22063117 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3117

Author(s):

Loredana Lorusso ◽

Virginia Cappagli ◽

Laura Valerio ◽

Carlotta Giani ◽

David Viola ◽

...

Keyword(s):

Thyroid Cancer ◽

Kinase Inhibitors ◽

Therapeutic Option ◽

Progression Free Survival ◽

Thyroid Cancers ◽

Poorly Differentiated ◽

Differentiated Thyroid Cancers ◽

Approved Drugs ◽

New Generation ◽

Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

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