The pathogenesis and treatment differences between differentiated thyroid carcinoma and medullary thyroid carcinoma

Dear editor,

We read with great interest the paper by Liu et al. entitled “Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials”¹.

It is worth noting that distinguishing differentiated thyroid carcinoma (DTC) from medullary thyroid carcinoma (MTC) is necessary. Although these two forms of thyroid cancer share certain similarity in the selection of multi-target tyrosine kinase inhibitors (TKIs), the pathogenesis followed by treatment varies. Thyroid cancer can be divided into three main histological types: DTC, MTC as well as anaplastic thyroid carcinoma (ATC); the last type is not included in the discussion here. DTC accounts for approximately 90% of all thyroid cancers, the pathogenesis of which is related to targets like vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), involving rearranged during transfection (RET)-RAS-RAF-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-Akt -mammalian target of rapamycin (mTOR) signalling pathways. RET/PTC translocations along with BRAF^V600E mutation in papillary thyroid carcinoma², and RAS mutation in follicular and poorly DTC are the most common genetic variant. MTC is a neuroendocrine tumour originating from parafollicular thyroid cells, which can be classified into sporadic and hereditary types. Hereditary MTC is primarily associated with RET mutation, where transmitting an abnormal signal by an encoded protein affects growth, survival, invasion, metastasis of tumour cells. Therefore, MTC has a poorer prognosis than DTC.

According to several recent clinical studies, anti-angiogenesis therapy is regarded as a most frequent selection in DTC treatment^2–7, both lenvatinib and apatinib are highly selective VEGFR inhibitors⁸. In the two lenvatinib and one apatinib phase III randomized controlled trial, patients in the treatment group had a longer median progression-free survival (PFS) of 14.4⁴, 20.2⁶, and 17.7 months⁷, respectively, than those in the control group. The similar drug, vandetanib, only prolonged median PFS by 5.2 months in advanced DTC trials, while it significantly prolonged PFS in advanced MTC patients⁹, suggesting that vandetanib is more suitable for MTC studies with a focus on inhibiting RET. The poor performance of vandetanib showed in phase III clinical trial (NCT01876784) of RAI-rDTC in 2017¹⁰, was primarily due to selection differences, that is, strong inhibition of RET and poor inhibition of VEGFR. In patients treated with cabozantinib¹¹, who had progressive MTC, all RET mutation status subgroups showed prolonged PFS (RET mutation status: negative, HR = 0.47, CI > 1.0; positive, HR = 0.24), the CI for the RET mutation-negative subgroup crossed 1.0, indicating that there was no statistical significance of cabozantinib on PFS in RET mutation-negative patients, further proving that RET inhibitors are a better option for MTC treatment. So far, both pralsetinib and selpercatinib¹² have been approved by Food and Drug Administration (FDA) for the treatment of MTC with RET mutation. TKIs possess broader targets than RET inhibitors, so it is inappropriate to discuss MTC and DTC together with no specific elaboration of using RET inhibitors in treating MTC. Additionally, so as to achieve a convincing outcome, importance should be attached to treatment comparison among different TC.

Furthermore, Liu et al. presented several research methodological issues. The authors mentioned in line 10–11 on page 6 that both the Kiyota et al.¹³ and Schlumberger et al.⁴ studies came from the same source; what Kiyota conducted is actually a subgroup analysis, so there should be only five literature citations included instead of six. Figure 1 shows a p>.10 and I²<50% indicating low heterogeneity. Therefore, a fixed-effect model should be adopted here, rather than a random one. The authors only showed overall survival (OS) and adverse events (AEs) in the paper, offering no plausible explanation for its heterogeneity. Besides, when it comes to AEs analysis, there would be results exaggeration with the absence of subgroup analysis among different TC. Liu et al.¹ identified the five most common AEs of TKIs in RAI-rDTC patients were hypertension, alopecia, rash, diarrhoea, and nausea. However, while counting the number of patients suffering AEs during TKIs treatment, we found 986 patients here in five studies, and the five most common AEs should be diarrhoea (n = 616), hypertension (n = 429), fatigue or asthenia (n = 418), decreased appetite (n = 363), and hand-foot skin reaction (n = 348). This difference may reflect some selection bias, which needs to be noted; otherwise, the bias here will influence the reliability of the adverse reaction results.

We greatly appreciate authors’ contributions in reporting the efficacy of various TKIs in patients with advanced or metastatic thyroid cancer, but vague description of pathogenesis and treatment among disparate TC as well as not well-defined details may lead to confusion.

Transparency

Declaration of funding

This letter was written independently; No funding or sponsorship was received for this study and for publication of this letter article.

Declaration of financial/other relationships

The authors on this letter have no relevant financial or other relationships to disclose.

Acknowledgements

None.