Treatment Compliance and Severe Adverse Events Limit the Use of Tyrosine Kinase Inhibitors in Refractory Thyroid Cancer

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the ONA take:

Tyrosine kinase inhibitors (TKIs) for the treatment of refractory thyroid cancer should be used with caution because of their adverse events, a recent study published in the journal OncoTargets and Therapy has suggested.

Although novel TKIs, such as sorafenib, sunitinib, cabozantinib, and vandetanib, have been utilized for the treatment of refractory and progressive differentiated thyroid cancer (DTC) and c-cell-derived medullary thyroid cancer (MTC), they are associated with numerous adverse events that can negatively impact patients’ quality of life and treatment compliance. Therefore, researchers sought to evaluate compliance-, efficacy-, and safety-associated TKI therapy in patients with refractory or progressive thyroid cancer.

For the study, researchers retrospectively analyzed data from 24 patients with metastatic DTC or MTC unresponsive to conventional treatment, such as radioactive iodine (RAI) ablation, who received TKIs. Results showed that dose reduction was required in 8 patients and 5 patients discontinued TKI therapy due to its effect on performing daily activities.

The most frequent adverse events associated with TKI use were fatigue, nausea, diarrhea, hypertension, and stomatitis; and the most common serious side effects were epistaxis, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue.

In regard to efficacy, 2 patients achieved a partial response and 3 had stable disease.

OncoTargets and Therapy
OncoTargets and Therapy

Objective: The aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents.
Methods: We retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment.
Results: Twenty-four patients received TKIs. The median duration of treatment was four (range: 1–19) cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment.
Conclusion: Patient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary.

Keywords: medullary thyroid carcinoma, differentiated thyroid cancer, TKIs, sorafenib, sunitinib, vandetanib 


Differentiated thyroid cancer (DTC) is the most frequent type of thyroid cancer,1 comprising more than 90% of all cases. Thyroidectomy and radioactive iodine (RAI) ablation remain the cornerstones of treatment. Although the disease course is indolent in the majority of patients, aggressive cases with metastases (refractory to conventional treatment) exist, and remain challenging for clinicians. Over recent decades, the trend of an increasing incidence of thyroid cancer has inevitably given rise to a number of patients who present with aggressive disease and eventually succumb to it.2 The survival rate in patients with RAI-refractory metastatic DTC has been estimated to be 10% at 10 years.3 Until recently, the therapeutic options available for patients with progressive, metastatic, RAI-refractory DTC have been limited.

C-cell-derived medullary thyroid carcinoma (MTC), although uncommon, has a much worse prognosis than iodine-positive DTC, which is approximately the same with RAI-refractory DTC.4 In most cases, MTC is already metastatic at initial presentation, with no available effective therapeutic options other than surgery, when possible.

Novel tyrosine kinase inhibitors (TKIs), such as sorafenib, sunitinib, cabozantinib, and vandetanib, have been used recently for the treatment of refractory cases of thyroid cancer5–7 where all conventional treatment options (surgery, RAI, chemotherapy) have been proven ineffective. These molecules inhibit cellular signaling by targeting multiple tyrosine kinase receptors as well as platelet-derived growth factor receptors and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and proliferation of tumor cells. Simultaneous inhibition of these targets leads to reduced tumor vascularization, apoptosis of cancer cells, and ultimately tumor shrinkage. Some Phase II and III trials8,9 have reported promising results regarding favorable response rates in metastatic thyroid cancer that has been non-responsive to conventional treatment. Recently, vandetanib and cabozantinib were approved for patients with MTC and sorafenib was approved for those with DTC.9,10 However, because both agents target many different receptors, they have numerous side effects, including hematological, skin, and cardiac toxicities that may have a negative impact on patients' quality of life.

The aim of the present study was to assess the effects of TKI inhibitors in a cohort of patients with refractory and progressive thyroid cancer (DTC or MTC), in particular severe adverse events during TKI therapy, ability and willingness of patients to remain on long-term treatment, and response rates.  

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