Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma

Beukhof, Carolien; Doorn, Leni van; Visser, Theo J.; Bins, Sander; Visser, W. Edward; Heerebeek, Ramona van; Kemenade, Folkert J. van; Rijke, Yolanda B. de; Herder, Wouter W. de; Chaker, Layal; Mathijssen, Ron H.J.; Peeters, Robin P.

doi:10.1210/jc.2016-4025

Cited by 15 publications

(10 citation statements)

References 37 publications

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“…Supportive drugs to control AEs such as hypertension will expand the use of lenvatinib. With respect to fatigue, several reports recommend the use of thyroid hormone preparations or steroids [24,29]. In addition, in our study, 20 patients required administration of thyroid hormone preparations to combat fatigue caused by lenvatinib treatment.…”

Section: Discussionmentioning

confidence: 79%

“…The incidence rate of any grade and grade ≥ 3 fatigue was 53.1% and 16.0%, respectively (Figure 2A). Based on previous reports that hypothyroidism and hypoadrenocorticism are correlated with fatigue related to anti-angiogenic drugs (AAD) [17,[22][23][24], we assessed the patients' levels of free T4, thyroid-stimulating hormone (TSH), cortisol, and acetylthiocholine iodide (ACTH). Among the 135 patients, thyroid function was evaluated before and after treatment in 118 patients.…”

Section: Mechanisms For the Occurrence Of Fatigue In Lenvatinib Treatmentioning

confidence: 99%

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Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Iwamoto

Suzuki

Shimose

et al. 2020

Cancers

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Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

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Section: Discussionmentioning

confidence: 79%

Section: Mechanisms For the Occurrence Of Fatigue In Lenvatinib Treatmentioning

confidence: 99%

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Iwamoto

Suzuki

Shimose

et al. 2020

Cancers

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“…One of the reasons may be that the onset of hypothyroidism is delayed and long-term and may even persist when VEGFR-TKIs treatment is paused. 22 However, signals for hyperthyroidism were detected with the use of all the VEGFR-TKIs, except for vandetanib. This revealed that the use of VEGFR-TKIs may be associated with hyperthyroidism.…”

Section: Discussionmentioning

confidence: 99%

Thyroid dysfunction related to vascular endothelial growth factor receptor tyrosine kinase inhibitors: A real‐world study based on FAERS

Liao

Liu²,

Hong-tao

2021

J Clin Pharm Ther

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Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis; it binds to a particular VEGF receptor (VEGFR) to activate the growth, survival and proliferation of vascular endothelial cells. 1,2 Therefore, VEGFR-tyrosine kinase inhibitors (TKIs) are widely used in the treatment of cancers, particularly solid tumours. To date, a total of nine VEGFR-TKIs have been approved for clinical use by the US Food and Drug Administration (FDA) (Table 1). 3 VEGFR-TKIs are used in the treatment of thyroid cancer, because VEGF plays an essential role in the development and progression of thyroid malignancies. 4,5 However, clinical studies have shown that VEGFR-TKIs can induce adverse drug events (ADE), including thyroid dysfunction. [6][7][8] Thyroid dysfunction includes hyperthyroidism and hypothyroidism, both of which could have serious outcomes, and may warrant discontinuation of VEGFR-TKIs treatment. Notably, VEGFR-TKI-induced thyroid dysfunction may be associated with the prognosis of cancer. [9][10][11] The onset of hypothyroidism is usually

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“…The tricyclic antidepressant desipramine inhibits both MCT8 and MCT10 (194), whereas the flavonolignan silychristin appears to be a specific inhibitor of MCT8 (79). Moreover, several tyrosine kinase inhibitors have been found to interfere with MCT8 and MCT10 function through noncompetitive Review inhibition (195)(196)(197)(198). Although not as extensively studied as short MCT8, the long isoform of human MCT8 also efficiently transports iodothyronines (80,199).…”

Section: Substrate Specificity and Transport Directionmentioning

confidence: 99%

Thyroid Hormone Transporters

et al. 2019

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Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.

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Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma

Abstract: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.

Cited by 15 publications

References 37 publications

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Thyroid dysfunction related to vascular endothelial growth factor receptor tyrosine kinase inhibitors: A real‐world study based on FAERS

Thyroid Hormone Transporters

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