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

Abstract

Context: Many 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. Methods: All 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. Results: In 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. Conclusion: The 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.

Clinical factors related to the efficacy of tyrosine kinase inhibitor therapy in radioactive iodine refractory recurrent differentiated thyroid cancer patients

“…Antiangiogenic drugs targeting the VEGF pathway have been assessed in RR-DTC patients in phase II studies [13][14][15]. Previous TKI agents have been very disappointing in terms of objective responses in RR-DTC patients [16]; however, both the recently developed TKI sorafenib and lenvatinib have shown promise. Both sorafenib and lenvatinib have been demonstrated to exhibit significant efficacy against RR-DTC in the international phase III study [5,6] and, both have become available as new lines of therapy.…”

Novel Therapies Against Aggressive Differentiated Thyroid Carcinomas

“…Sorafenib was the most studied TKI showing a clinical benefit in 53% of DTC patients. Lenvatinib studies were not available in this meta-analysis [35].…”

“…In the meta-analysis of Klein Hesselink et al [35], AEs and dose reductions or discontinuations due to treatmentrelated AEs were also very common. Sorafenib and cabozantinib were associated with the highest percentage of dose reductions or discontinuation (70 and 77%, respectively) due to AEs.…”

“…Sorafenib and cabozantinib were associated with the highest percentage of dose reductions or discontinuation (70 and 77%, respectively) due to AEs. The most frequent AEs were hand-foot skin reaction, diarrhea and nausea/vomiting, which could be quite disabling [35]. TKIs can induce multiple AEs that require close monitoring and frequently dosage reductions or therapy suspension, depending on severity.…”

ENDOCRINE TUMOURS: Progressive metastatic medullary thyroid carcinoma: first- and second-line strategies

“…Moreover, currently studied TKIs, including those directed against the RET protein, were found to have a considerable dose-dependent toxicity in the majority of patients. For patients with metastasised MTC who still have a considerable life expectancy, the benefits of progression-free survival often do not outweigh the side effects caused by these drugs (42).…”