Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives

Abstract

Notwithstanding 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.

Current Understanding of Nonsurgical Interventions for Refractory Differentiated Thyroid Cancer: a Systematic Review

“…The frequent progression of DTC to treatment refractory disease and the poor outcomes associated promote the need for effective novel treatment modalities. Although there have been some successes demonstrated with TKI treatment, their efficacy is short lived and treatment-associated adverse outcomes are common [ 18 , 19 ]. While Dadu et al [ 62 ] and Cabanillas et al [ 30 ] have demonstrated optimistic treatment options with second- and third-line alternatives for a proportion of patients who developed treatment failure with first-line TKI therapy, both studies had low participant numbers (60 and 25, respectively) and further larger-scale Phase III trials are needed.…”

“…Although the development of TKIs has increased treatment options for recurrent/refractory disease, they have a limited duration of efficacy, meaning that disease progression is delayed, but ultimately not stopped [ 18 ]. TKIs are also associated with a significant side effect profile, necessitating discontinuation in a significant number of patients [ 19 ].…”

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

“…The specific mechanisms regarding both treatment efficiency and the development of TEAEs needs further investigation to offer patients the best treatment regime and prognosis possible. So far, in the clinical context, lenvatinib is the widely preferred first-line drug, based on its superior PFS benefit, improved OS in patients over 65 years, higher objective response rate, and an overall more tolerable and manageable spectrum of side effects compared to sorafenib [127]. The much higher incidence and the severity of TE-HTN induced by lenvatinib play only minor roles in these considerations, as they are outweighed by other, less well-manageable AEs.…”

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

“…MKI-related toxicities (listed in Table 5 ) are very common and likely reflect target-binding affinities specific to each drug [ 62 , 166 , 167 , 168 , 169 ]. Among the AEs observed during treatment, HT appears to be the most frequent and is managed using standard antihypertensive drugs.…”

“…The majority of severe side effects occur early in the course of treatment, and if managed, patients may experience persistent long-term disease control [ 172 ]. Side effects occur more frequently in older patients and may differ according to the patient’s ethnicity [ 169 ].…”