Tyrosine kinase inhibitors in differentiated thyroid carcinoma: a review of the clinical evidence

AbstractNotwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Download Full-text

Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review]

Endocrine Journal ◽

10.1507/endocrj.ej16-0064 ◽

2016 ◽

Vol 63 (7) ◽

pp. 597-602 ◽

Cited By ~ 19

Author(s):

Yasuhiro Ito ◽

Shinichi Suzuki ◽

Ken-ichi Ito ◽

Tsuneo Imai ◽

Takahiro Okamoto ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Differentiated Thyroid Carcinoma

Download Full-text

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2

Hormone and Metabolic Research ◽

10.1055/a-1145-8479 ◽

2020 ◽

Vol 52 (08) ◽

pp. 588-597 ◽

Cited By ~ 2

Author(s):

Maran Ilanchezhian ◽

Sophia Khan ◽

Christian Okafor ◽

John Glod ◽

Jaydira Del Rivero

Keyword(s):

Thyroid Carcinoma ◽

Tyrosine Kinase ◽

Medullary Thyroid Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Multiple Endocrine Neoplasia ◽

Kinase Inhibitors ◽

Multiple Endocrine Neoplasia Type ◽

Medullary Thyroid ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

AbstractMedullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1–2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.

Download Full-text

Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.758010 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mengfei Cheng ◽

Fang Yang ◽

Jiahui Liu ◽

Dan Yang ◽

Shuo Zhang ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Qt Interval ◽

Clinical Evidence ◽

Kinase Inhibitors ◽

Qt Prolongation ◽

Small Sample ◽

Interval Prolongation ◽

Preclinical Trial ◽

Qt Interval Prolongation

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

Download Full-text

Adverse effects of tyrosine kinase inhibitors in advanced thyroid carcinoma – a summary of 10-year experience

Endocrine Abstracts ◽

10.1530/endoabs.70.aep923 ◽

2020 ◽

Author(s):

Jolanta Krajewska ◽

Aleksandra Kukulska ◽

Ewa Paliczka-Cieslik ◽

Tomasz Gawlik ◽

Tomasz Olczyk ◽

...

Keyword(s):

Adverse Effects ◽

Thyroid Carcinoma ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors

Download Full-text

Use of Tyrosine Kinase Inhibitors for Treatment of Medullary Thyroid Carcinoma

Medullary Thyroid Carcinoma - Recent Results in Cancer Research ◽

10.1007/978-3-319-22542-5_11 ◽

2015 ◽

pp. 227-249 ◽

Cited By ~ 10

Author(s):

Ramona Dadu ◽

Mimi N. Hu ◽

Elizabeth G. Grubbs ◽

Robert F. Gagel

Keyword(s):

Thyroid Carcinoma ◽

Tyrosine Kinase ◽

Medullary Thyroid Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Medullary Thyroid

Download Full-text

Sorafenib therapy decreases the clearance of thyrotropin

Acta Endocrinologica ◽

10.1530/eje-12-0828 ◽

2013 ◽

Vol 168 (2) ◽

pp. 163-167 ◽

Cited By ~ 12

Author(s):

Herman Verloop ◽

Johannes W A Smit ◽

Olaf M Dekkers

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Standard Dose ◽

Thyroid Tissue ◽

Area Under The Curve ◽

Differentiated Thyroid Carcinoma ◽

Sorafenib Treatment ◽

Sorafenib Therapy ◽

Before And After

ObjectiveThyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied.DesignIn a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy.MethodsBefore and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH48 h) and 96 h (TSH96 h) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated.ResultsTSH48 h levels (120.5 mU/l before vs 146.3 mU/l after; P=0.029), TSH96 h levels (22.0 mU/l before vs 35.5 mU/l after; P=0.001), and TSH-AUC (142.7 vs 186.8 mU/l; P=0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l.ConclusionsSorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

Download Full-text

THERAPY OF ENDOCRINE DISEASE: Response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis

Acta Endocrinologica ◽

10.1530/eje-14-0788 ◽

2015 ◽

Vol 172 (5) ◽

pp. R215-R225 ◽

Cited By ~ 38

Author(s):

E N Klein Hesselink ◽

D Steenvoorden ◽

E Kapiteijn ◽

E P Corssmit ◽

A N A van der Horst-Schrivers ◽

...

Keyword(s):

Systematic Review ◽

Thyroid Carcinoma ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Clinical Benefit ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Disease Response ◽

Hand Foot Syndrome

ContextMany tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.MethodsAll major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand–foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.ResultsIn total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33–64)%, and was 17 (95% CI 12–24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14–77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34–46)% and 27 (95% CI 22–32)% respectively. Clinical benefit was found in 53 (95% CI 48–59)% of DTC patients on sorafenib, and in 84 (95% CI 79–88)% and 55 (95% CI 49–61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.ConclusionThe currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Download Full-text