Abstract
Medullary thyroid carcinoma (MTC) is a rare cancer of the thyroid’s calcitonin-producing C cells. This review covers recent advances in MTC treatment, emphasizing surgical and systemic therapies. For localized MTC, surgery remains the primary and most effective treatment, with total thyroidectomy and lymph node dissection providing the highest potential for cure. However, prognosis worsens significantly with local and distant metastases, underscoring the importance of early diagnosis and intervention. MTC can be sporadic or hereditary, with the latter associated with germline RET proto-oncogene mutations linked to multiple endocrine neoplasia types 2A and 2B. Genetic discoveries have enabled preventive measures such as prophylactic thyroidectomy, increasing the cure rate of hereditary cases. Since 2011, systemic treatment options have expanded with multikinase inhibitors (MKIs), such as vandetanib and cabozantinib, and selective RET inhibitors such as selpercatinib and pralsetinib. MKIs extend progression-free survival in advanced cases by targeting tumor growth and angiogenesis but can cause off-target effects. RET inhibitors offer precision treatment for RET-mutated tumors, showing high efficacy and fewer side effects, though resistance to these inhibitors has emerged, and current research focuses on developing next-generation inhibitors to overcome these barriers. Effective MTC management, particularly given its rarity, benefits from specialized high-volume centers. Precision medicine, standardized therapy selection and ongoing research are essential for improving outcomes in both RET-positive and RET-negative MTC patients.
Overview of medullary thyroid carcinoma treatment
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the parafollicular cells (C cells) of the thyroid, which secrete calcitonin (Ctn) and carcinoembryonic antigen (CEA), both valuable tumor markers for diagnosing and managing MTC (Wells et al. 2015). Surgical resection remains the primary and most effective treatment, offering the highest chance of cure when the tumor is localized to the thyroid. However, prognosis worsens significantly once the disease metastasizes to the cervical lymph nodes, reducing the cure rate to around 30%. Lymph node involvement at diagnosis is a key prognostic factor (Weber et al. 2001, Machens et al. 2005).
Before 2011, no effective systemic treatments were available for advanced MTC. However, the past 14 years have witnessed remarkable advancements, notably with the introduction of multikinase inhibitors (MKIs) that target metastatic disease (Wells et al. 2012, Schlumberger et al. 2017, Kreissl et al. 2020). In the last 5 years, even more promising therapeutic developments have been made, including the approval of selective RET inhibitors, offering renewed hope for patients with advanced or metastatic MTC (Subbiah et al. 2018a , b , 2021b , 2024, Wirth et al. 2020, Hadoux et al. 2023).
Although MTC is a rare malignancy, accounting for only 5% of thyroid cancers, it is associated with considerable morbidity and mortality, corresponding to 13.4% of deaths from thyroid cancer (Kebebew et al. 2000). When treated according to current guidelines, patient survival and quality of life can improve significantly. This highlights the importance of adhering to current treatment guidelines, as 25% of MTC cases are still not being managed in accordance with best practices, which can negatively affect patient outcomes (McMullin et al. 2023, Szabo Yamashita & Grubbs 2024). This review will focus on the current therapeutic approaches for MTC.
Epidemiology and prevalence in adults and young patients: hereditary and sporadic forms
MTC can occur in two forms: sporadic and hereditary. The hereditary form is associated with pathogenic gain-of-function germline variants in the RET proto-oncogene and is linked to an autosomal dominant genetic syndrome known as multiple endocrine neoplasia type 2 (MEN2) (Wells et al. 2015). MTC is the predominant clinical manifestation of MEN2, occurring in over 95% of individuals carrying pathogenic RET variants, generally in the first two decades of life. MEN2 syndromes are characterized by a combination of endocrine tumors and non-endocrine manifestations and are classified into two subtypes: MEN type 2A (MEN 2A) and MEN type 2B (MEN 2B). MEN 2A is characterized by the development of MTC, pheochromocytoma and primary hyperparathyroidism. MEN 2B is associated with a distinctive phenotype that includes a marfanoid habitus, mucosal and gastrointestinal ganglioneuromas and ocular abnormalities, along with MTC and pheochromocytoma (Wells et al. 2015).
In adults, approximately 75% of MTC cases are sporadic, while the remaining 25% or more are hereditary. The increasing detection of hereditary cases is largely attributed to the widespread implementation of routine genetic screening within families (Wells et al. 2015). This rare cancer is even more uncommon in individuals under the age of 20, accounting for only 5% of all MTC cases (Zhao et al. 2020). Among this younger population, hereditary cases make up 86%, while sporadic cases represent just 14%.
In young patients with sporadic MTC, the RET gene is the primary driver, found in 80–93% of cases (Vanden Borre et al. 2017, Castroneves et al. 2024). Two recent studies of young patients with sporadic MTC demonstrated similarly aggressive disease profiles to those observed in MEN 2B patients, with a high prevalence of somatic RET variants, particularly the p.Met918Thr variant (Castroneves et al. 2024, Hensley et al. 2024).
Genetic and molecular basis of hereditary and sporadic forms
The RET proto-oncogene, located on the long arm of chromosome 10 (10q11.2), encodes a receptor tyrosine kinase critical for cell proliferation, differentiation and survival (Wells et al. 2015, Romei et al. 2016b , Salvatore et al. 2021). Germline RET variants account for over 95% of MEN2 cases, and the identification of these variants in 1993 revolutionized the diagnosis and management of affected individuals (Donis-Keller et al. 1993, Mulligan et al. 1993).
A significant genotype–phenotype correlation exists within MEN2, particularly regarding the aggressiveness of MTC based on the earliest reported age of onset and the risk of developing other endocrine tumors (Machens et al. 2003). This correlation has enabled the classification of RET variants into highest-, high- and moderate-risk categories, which are essential for determining the appropriate timing of prophylactic thyroidectomy, initiating surveillance for pheochromocytoma and primary hyperparathyroidism, and identifying non-carriers who do not require follow-up (Table 1) (Wells et al. 2015, Elisei et al. 2019a , Machens et al. 2003).
Recommended age for prophylactic thyroidectomy, indications for central neck dissection, and initiation of pheochromocytoma and hyperparathyroidism screening based on the consensus classification of RET variant risk (modified from Wells et al. (2015)).
| Risk category | RET codon | Recommended age for prophylactic thyroidectomy | Central neck dissection | Initial age for pheochromocytoma screening | Initial age for hyperparathyroidism screening |
|---|---|---|---|---|---|
| Highest | 918 | <1 year | If suspicion of metastases Prophylactic only if the parathyroids are visible |
11 years | --------- |
| High | 634 | <5 years | Calcitonin > 40 pg/mL or suspicion of lymph node metastases | 11 years | 11 years |
| 883 | |||||
| Moderate | 533 609 611 618 620 630 631 666 786 790 804 891 912 |
Before or after 5 years # Elevated calcitonin (basal or after stimulus) # Consider aggressiveness of MTC in the family # No consensus / no extensive experience to define most appropriate age |
Calcitonin > 40 pg/mL or suspicion of lymph node metastases | 16 years | 16 years |
Multiple endocrine neoplasia type 2B (MEN 2B) represents the most aggressive form of MTC. In 95% of MEN 2B cases, a pathogenic variant in exon 16 of the RET gene (p.Met918Thr) is identified. Tumor development in MEN 2B patients typically occurs early, with prophylactic thyroidectomy recommended within the first year of life. However, many cases arise from de novo pathogenic variants, with no family history, leading to delayed diagnosis. As a result, these cases are often detected at more advanced or metastatic stages (Wells et al. 2015, Elisei et al. 2019b ).
Sporadic MTC generally occurs later in life compared to most hereditary forms, typically between the fourth and sixth decades of life. Approximately 7–10% of patients with apparently sporadic MTC, who have no family history of the disease, are found to carry germline RET variants (Wiench et al. 2001, Romei et al. 2011). Consequently, it is recommended that all MTC patients undergo RET germline testing, regardless of family history or age at diagnosis (Wells et al. 2015).
The RET gene also plays a pivotal role in the somatic development of sporadic MTC. Studies show that somatic RET variants are present in 40–50% of sporadic MTC cases, with a prevalence of up to 90% in patients with more aggressive disease forms. The presence of a pathogenic RET variant in the tumor is associated with a more aggressive disease course, characterized by a higher incidence of distant metastases and a poorer prognosis (Elisei et al. 2008, Moura et al. 2009, Romei et al. 2012, 2016a ).
In addition to RET, variants in the H-RAS and K-RAS genes have been identified in 6–28% of sporadic RET-negative MTC tumors (Moura et al. 2011, Boichard et al. 2012, Agrawal et al. 2013, Ciampi et al. 2013, 2019, Oczko-Wojciechowska et al. 2015, Heilmann et al. 2016, Chang et al. 2018, Shirali et al. 2024). These RAS variants are mutually exclusive with RET variants. Recent somatic analyses of four sporadic MTC patients negative for RET and RAS variants revealed biallelic inactivation of NF1, a tumor suppressor gene associated with neurofibromatosis type 1 (Shi et al. 2022, Ciampi et al. 2023, Castroneves et al. 2024). In these cases, NF1 loss of heterozygosity leads to the loss of functional neurofibromin, a negative regulator of the RAS signaling pathway. This results in the constitutive activation of the pathway, promoting cell proliferation and survival, which is critical for tumor development. This discovery highlights NF1 as a novel driver gene for MTC (Elisei et al. 2008, Steinmann et al. 2009, Laycock-Van Spyk et al. 2011).
Rearrangements of the anaplastic lymphoma kinase (ALK) gene have also been detected in sporadic MTC, with ALK fusions identified in two adult patients from a cohort of 98 individuals, as well as in one pediatric patient (Ji et al. 2015, Hillier et al. 2019).
Other genetic alterations, whose roles in tumor progression remain uncertain, have been identified in genes such as MET, MDC1, ATM, BRAF, TSHR, ITGA10 and PDE4DIP. However, these alterations have not yet been observed in a significant number of MTC patients (Agrawal et al. 2013, Simbolo et al. 2014, Ji et al. 2015, Heilmann et al. 2016, Chang et al. 2018, Ciampi et al. 2019, Shi et al. 2022). In addition, variants in the FAT1 or FAT4 genes were found in 18 Chinese patients with MTC, with somatic variants present in 22.2% of cases and germline variants in 38.8% (Qu et al. 2020). A substantial proportion of sporadic MTC cases lack a clear, identifiable driver gene, with recent research suggesting this proportion may be around 18–20% (Ciampi et al. 2023).
Identifying somatic drivers in sporadic MTC, particularly RET variants, is crucial for guiding targeted treatments. Both non-selective MKIs and selective RET inhibitors have shown significant potential in improving progression-free and overall survival (OS) in patients with metastatic MTC (Wells et al. 2012, Elisei et al. 2013, Wirth et al. 2020, Hadoux et al. 2023, Subbiah et al. 2024).
Diagnostic approaches
Thyroid nodule evaluation is primarily performed using ultrasound (US), with fine-needle aspiration cytology (FNAC) conducted when US features suggest malignancy (Haugen et al. 2016). Most studies on US features predicting malignancy focus on papillary thyroid cancer due to its higher prevalence. MTC nodules are typically solid, hypoechoic and have regular margins, with approximately half showing calcifications, although microcalcifications are less frequent. Few MTC nodules exhibit a ‘taller-than-wide’ shape, and only 7.9% of MTC nodules demonstrate at least four simultaneous US features suggestive of malignancy. Studies highlight the limited performance of neck US in identifying MTC, often leading to its underdiagnosis and missed FNAC evaluations (Trimboli et al. 2012, Matrone et al. 2021b ).
Classic cytological features of MTC on FNAC include plasmacytoid and polygonal cells, multinucleation, dispersed cell arrangement, salt-and-pepper chromatin and the presence of amyloid (Geddie et al. 1984, Pusztaszeri et al. 2014). However, these findings are uncommon, and FNAC sensitivity is variable. A systematic review reported a sensitivity of 56.4% (95% confidence interval (CI): 52.6–60.1), with FNAC often yielding benign, indeterminate or nondiagnostic results. MTC is frequently misinterpreted as other tumors, such as oncocytic or follicular neoplasms, corresponding to Bethesda categories II to V (Essig et al. 2013, Trimboli et al. 2015, Suzuki et al. 2017, Workman et al. 2021).
In cases with a high suspicion of MTC, diagnostic accuracy can be enhanced by measuring Ctn levels in the fine-needle aspiration (FNA) washout fluid and/or by using immunocytochemical staining for markers such as Ctn, chromogranin and CEA (Wells et al. 2015, Trimboli et al. 2016, Liu et al. 2021).
Routine serum Ctn measurement for all patients with thyroid nodules or before thyroid surgery remains controversial, as only 1 in 200 screened individuals is likely to have MTC (Wells et al. 2015, Durante et al. 2023). While early diagnosis via Ctn screening can potentially improve prognosis (Elisei et al. 2004, Elisei 2008), limitations include the lack of randomized trials, variability in Ctn assay accuracy, limited availability of pentagastrin stimulation tests and cost-effectiveness concerns.
Nevertheless, studies suggest that universal Ctn screening in patients with non-highly suspicious thyroid nodules can be cost-effective, particularly when using a Ctn threshold of >50 pg/mL to define a positive test (Cheung et al. 2008, Al-Qurayshi et al. 2020). Although not without limitations, Ctn screening is a cost-effective tool for identifying MTC before thyroid lobectomy or during the follow-up of benign nodules. It is particularly recommended for patients with suspicious nodules, those scheduled for surgery, or with indeterminate FNAC results (Bethesda III–V), as it enhances preoperative detection of MTC (Sencar et al. 2022, Durante et al. 2023).
In addition, calcitonin testing should be prioritized in individuals with a personal or family history of MTC or MEN2 (Wells et al. 2015, Durante et al. 2023).
For patients with confirmed MTC, preoperative evaluation should include imaging to assess the extent of the disease. Basal Ctn levels can guide the selection of appropriate imaging tests. In patients with Ctn levels below 500 pg/mL, the disease is typically localized (Machens & Dralle 2010, Wells et al. 2015), and US and/or computed tomography (CT) of the neck are recommended to evaluate the cervical lymph nodes. For patients with basal Ctn levels exceeding 500 pg/mL, the risk of distant metastasis significantly increases. Therefore, additional imaging is recommended, such as contrast-enhanced chest CT, magnetic resonance imaging (MRI) of the abdomen and pelvis, triphasic abdominal CT, bone scintigraphy and spinal MRI (Machens & Dralle 2010, Wells et al. 2015).
Currently, no positron emission tomography (PET) imaging modality offers optimal whole-body diagnostic assessment for patients with biochemical or metastatic MTC. However, 18F-DOPA PET has shown the highest accuracy in detecting recurrent MTC (Lee et al. 2020). In addition, 68Ga-DOTATATE PET/CT is particularly effective in identifying bone lesions, offering detection rates superior to those of bone scintigraphy and comparable to a combination of bone scans and spine MRI (Castroneves et al. 2018).
Testing for the germline RET proto-oncogene is recommended in the following situations: i) genetic testing should be performed for all cases of MTC, even in the absence of a family history (Wells et al. 2015, Elisei et al. 2019a ); ii) testing is also recommended for first-degree relatives of individuals confirmed to carry MTC and pathogenic RET variants (Wells et al. 2015, Elisei et al. 2019a ).
Since the results of germline RET testing may take several weeks, it is important to perform preoperative screening for pheochromocytoma and hyperparathyroidism. This applies to both cases without a confirmed genetic diagnosis and known hereditary cases. Proper screening helps prevent hypertensive crises during surgery and avoids the need for a second neck surgery to treat primary hyperparathyroidism (Wells et al. 2015, Viola & Elisei 2019).
Annual screening for pheochromocytoma, including plasma metanephrines and normetanephrines or 24-h urinary metanephrines and normetanephrines, is recommended for patients with MEN 2A, along with screening for hyperparathyroidism through serum calcium and parathyroid hormone (PTH) levels. For patients with MEN 2B, annual screening for pheochromocytoma is advised. The appropriate age to begin screening depends on the risk classification associated with specific RET gene variants (Table 1) (Wells et al. 2015).
Surgical management of MTC
Surgery is the only definitive treatment for MTC, and optimal outcomes are more likely when performed by experienced high-volume neck surgeons (Machens & Dralle 2010, McMullin et al. 2023, Szabo Yamashita & Grubbs 2024). A thorough preoperative evaluation is essential, with neck ultrasound and/or CT scans being important to identify nodal disease before surgery. Proper imaging ensures precise surgical planning and execution. The chance of a cure significantly drops if there are lymph node metastases at the time of diagnosis, which makes early detection critical (Wells et al. 2015).
The standard surgical treatment for both hereditary and sporadic MTC is total thyroidectomy with central neck compartment dissection for all patients (Wells et al. 2015). However, in hereditary cases identified through family screening, central neck dissection can be avoided if specific criteria are met: serum Ctn level is below 40 pg/mL, the thyroid nodule is smaller than 5 mm, and there is no evidence of lymph node metastases. In such cases, only a prophylactic thyroidectomy is performed (Machens & Dralle 2010, Wells et al. 2015, Viola & Elisei 2019). The recommended age for this procedure, according to the risk category of the RET variant, is detailed in Table 1 (Wells et al. 2015).
If preoperative imaging indicates nodal disease in the neck or mediastinum, a compartmental dissection of the affected region is required. Confirmation of metastasis should be achieved through FNA, with cytology and/or Ctn measurements in the needle wash. This protocol applies to both central and lateral neck compartments (Wells et al. 2015).
For patients with serum Ctn levels between 50 and 200 pg/mL, which typically correlate with ipsilateral N1b disease (Machens & Dralle 2010), elective neck dissection may only be considered if metastatic disease is confirmed through FNAC. In cases where serum Ctn levels exceed 200 pg/mL, contralateral N1b disease or mediastinal involvement becomes more likely (Machens & Dralle 2010), necessitating preoperative confirmation of metastatic disease before undertaking dissection (Wells et al. 2015).
If MTC is unexpectedly diagnosed following a thyroid lobectomy, the decision to proceed with a completion thyroidectomy should be guided by the presence of a germline RET variant. If a pathogenic RET variant is identified, a total thyroidectomy with central neck dissection is recommended. However, if no RET variant is detected and postoperative Ctn levels are undetectable, a more conservative approach may be taken, involving regular follow-ups with tumor marker assessments and cervical ultrasounds (Wells et al. 2015).
In cases where primary hyperparathyroidism is diagnosed, thyroid surgery should be accompanied by parathyroidectomy after accurate localization of the parathyroid disease. For patients with pheochromocytoma, an adrenalectomy must always precede thyroidectomy to prevent adrenal crises during surgery (Wells et al. 2015).
Follow-up and management after primary surgery
Post-surgical follow-up is crucial for evaluating the response to initial treatment. While patients with MTC require thyroid hormone replacement, TSH suppression is not necessary. The postoperative normalization of Ctn levels is the most significant predictor of prognosis. Ctn and CEA levels should be measured no earlier than 3 months after surgery to assess for any persistent disease (Wells et al. 2015, Viola & Elisei 2019).
Patients with undetectable tumor markers and a normal neck US after surgery are considered to have an excellent response to the initial treatment. These patients should undergo follow-up monitoring with neck US and tumor marker tests every 6 months for the first 2 years and then annually thereafter.
Residual disease is common in MTC, with retrospective studies showing that 24–90% of patients have detectable Ctn levels after initial surgery, indicating either biochemical or structural residual disease (Hoff & Hoff 2007, Prete et al. 2023). Ctn levels up to 150 pg/mL are often associated with metastatic disease localized to the neck or with biochemical disease and should be evaluated alongside tumor markers (Ctn and CEA) and neck US (Machens & Dralle 2010).
Data from a large cohort of patients with sporadic MTC showed that individuals with a biochemical incomplete response after initial treatment have a 50% risk of developing structural disease within 10 years, most commonly in cervical lymph nodes. Predictive factors for the development of structural disease include elevated Ctn levels (≥50 pg/mL and advanced tumor stage (IVA or IVB). During follow-up, a shorter Ctn doubling time (≤24 months) was also identified as a significant predictor. Patients with these risk factors require closer monitoring and stricter follow-up protocols. In contrast, patients with Ctn levels below 50 pg/mL and earlier tumor stages (I–III) can be safely monitored every 9–12 months using cervical US and tumor markers, without requiring additional imaging unless tumor markers show a significant increase (Prete et al. 2023).
Locally recurrent disease may be managed through either observation or surgical intervention, depending on the risk of tumor involvement with vital structures and other patient-specific factors (Wells et al. 2015). For patients whose initial surgical intervention was incomplete, reoperation with central (level VI) and bilateral neck compartment (levels II–V) dissection may be considered if metastatic disease is confirmed by FNAC.
Calcitonin levels exceeding 150 pg/mL can be associated with distant metastases (Machens & Dralle 2010). Staging of the primary metastatic sites – including the neck, mediastinum, lungs, liver and bones – is recommended through neck US, chest CT, MRI of the abdomen and pelvis, or triple-phase abdominal CT, along with bone scintigraphy and spinal MRI. The frequency of follow-up depends on the stability or rise in tumor markers, with intervals ranging from every 3–12 months (Wells et al. 2015).
Although CEA is not a specific marker for MTC, it remains valuable for monitoring disease progression. Significant increases in CEA, particularly when Ctn levels remain stable or decrease, may suggest poorly differentiated MTC, which is associated with a worse prognosis. Calculating the doubling times of Ctn and CEA is a useful prognostic tool, correlating with 5- and 10-year survival rates. For accurate results, at least four measurements over a 2-year period are recommended. Doubling times can be determined using the American Thyroid Association’s online calculator (https://www.thyroid.org/professionals/calculators/thyroid-cancer-carcinoma/) (Miyauchi et al. 1984, Barbet et al. 2005, Wells et al. 2015). This information helps determine the frequency of imaging exams and follow-up evaluations.
Management of advanced and metastatic disease
Distant metastatic disease is present at diagnosis in approximately 15–20% of patients. Retrospective studies report a 10-year survival rate of 20–40% from the time of initial metastasis, highlighting the challenges associated with this advanced stage of the disease (Roman et al. 2006). While surgical resection remains the primary treatment for localized MTC, advanced or metastatic disease poses significant therapeutic challenges.
Given the complexity of managing patients with metastatic MTC, a multidisciplinary team approach is highly beneficial. Such a team typically includes endocrinologists, oncologists, surgeons, radiotherapists, interventional radiologists, dermatologists, cardiologists, psychologists and nutritionists.
The primary goal of treating advanced MTC is to manage life-threatening or symptomatic tumors. This is often achieved through surgical resection or localized therapies such as ablation or radiotherapy, particularly for isolated metastatic lesions that are growing or located in problematic areas. For solitary or localized disease, particularly in the bone or in the liver, local treatment options include surgery, cryoablation, chemoembolization or radiation therapy.
Metastatic MTC is often associated with the secretion of peptides such as serotonin, vasoactive intestinal peptide, histamine and kinins. These substances can cause clinical symptoms such as flushing and diarrhea, which may significantly impact the patient’s quality of life. The decision to initiate systemic therapy is primarily guided by the presence of symptomatic disease, high-volume metastases or progressive disease. This is particularly important when the disease involves vital structures, presents with a high tumor burden, or shows rapid progression on radiologic imaging. For patients with high-volume, progressive or symptomatic metastatic disease, systemic therapy is recommended (Wells et al. 2015).
Conventional chemotherapy, including dacarbazine, 5-fluorouracil and anthracyclines, has shown poor efficacy in metastatic MTC, with response rates (RR) ranging between 10 and 20% (Nocera et al. 2000). As a result, chemotherapy is no longer recommended for metastatic MTC due to its limited effectiveness.
Advances in understanding the molecular biology of MTC have paved the way for targeted therapies, particularly with anti-angiogenic MKIs and RET inhibitors, which will be discussed in detail in this review.
Recent studies have identified a subset of MTC patients who lack RET and RAS variants but instead display biallelic NF1 inactivation (Shi et al. 2022, Ciampi et al. 2023, Castroneves et al. 2024). However, treatment options for these metastatic cases are still limited, with current therapeutic choices including vandetanib and cabozantinib. Notably, patients with neurofibromatosis type 1 (NF1) who develop unresectable plexiform neurofibromas – benign peripheral nerve sheath tumors – often face significant symptoms such as pain, disfigurement and motor dysfunction. Recent advancements in targeted therapies, particularly with the MEK inhibitor selumetinib, have shown promising efficacy, leading to its approval for treating symptomatic, inoperable plexiform neurofibromas in pediatric patients in both the US and Europe. Ongoing research is evaluating the effectiveness of MEK inhibitors in other NF1-associated tumors, including cutaneous neurofibromas and low-grade gliomas. However, clinical experience with the treatment of metastatic MTC cases harboring NF1 variants remains absent (Fangusaro et al. 2019, Armstrong et al. 2023, Church et al. 2024).
Figure 1 outlines a standardized approach for selecting the most effective systemic therapy for each patient, tailored to their unique molecular biology. In addition, the following sections will provide a detailed discussion of approved drugs and emerging therapies for MTC.
Nonselective multi-kinase inhibitors (MKIs)
In thyroid cancers, there are several signaling pathways that are upregulated, promoting disease growth and progression. These include RET, the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) (Trovato et al. 1998, Capp et al. 2010). The primary therapeutic target of MKIs is VEGFR2 to inhibit angiogenesis. Inhibition of VEGFR2 is associated with adverse events (AEs), including hypertension, an increased risk of bleeding and impaired wound healing, leading to dose reductions, treatment interruptions and, in some cases, drug discontinuation, which limit their efficacy (Fig. 2) (Liu et al. 2016, Zhang et al. 2016).
Key targets of multikinase and RET inhibitors in thyroid cancer tumorigenesis.
Citation: Endocrine Oncology 5, 1; 10.1530/EO-24-0077
Sorafenib
The MKIs approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive, radioactive-refractory, differentiated metastatic thyroid carcinoma are the broad-spectrum kinase inhibitors sorafenib and lenvatinib. These were approved based on phase III clinical trials (Brose et al. 2014, Schlumberger et al. 2015).
Sorafenib demonstrates potent activity by inhibiting downstream Raf serine/threonine kinase activity and blocking several tyrosine kinase receptors, including VEGFR2, VEGFR3, PDGFR, RET and c-Kit. In a phase II clinical trial for patients with metastatic MTC, sorafenib showed a median PFS of 17.9 months in the sporadic MTC group, with most patients achieving stable disease (Lam et al. 2010). In addition, a retrospective study by Castroneves et al. on patients with metastatic MTC reported that it is well tolerated and provides a durable clinical response, with 75% of patients experiencing stable disease for at least 6 months and a PFS of 9 months among those treated with sorafenib (Fig. 2) (De Castroneves et al. 2016).
Lenvatinib
Lenvatinib is an inhibitor of multiple tyrosine kinases, including VEGFR1-3, FGFR1-4, PDGFRα, RET and Kit. In a phase II clinical trial involving 59 patients with unresectable, progressive metastatic MTC, lenvatinib demonstrated an overall response rate of 36% (95% CI: 24–49%). The response rate was similar between patients with or without prior exposure to anti-vascular endothelial growth factor (VEGF) therapy. All responses were partial, and no correlation was observed between RET tumor status and clinical outcomes. Lenvatinib exhibited a manageable safety profile, with a disease control rate of 80% (95% CI: 67–89%). Among responders, the median time to response was 3.5 months (95% CI: 1.9–3.7 months), and the median PFS was 9.0 months (95% CI: 7.0 months–not evaluable) (Schlumberger et al. 2016).
In real-world clinical practice, ten patients with advanced, progressive metastatic MTC and a large tumor burden – each previously treated with a TKI – achieved disease stabilization and control with lenvatinib, with a median time to response of 3 months. Although AEs were notable, they remained manageable. These findings suggest that lenvatinib could be a viable treatment option, especially for patients who are RET-negative and lack access to newer targeted therapies (Matrone et al. 2021a ).
Vandetanib
Vandetanib and cabozantinib are MKIs approved by the FDA for the treatment of metastatic MTC. They are the first-line systemic treatments for progressive MTC in patients with negative RET mutational status.
Vandetanib is a multi-targeted TKI that inhibits RET, VEGFR and EGFR (Valerio et al. 2017). It was FDA-approved based on the results of the phase III ZETA trial (NCT00410761) (Wells et al. 2012). This trial showed an increase in PFS of 11.2 months compared to placebo, with an objective response rate (ORR) of 45% (Wells et al. 2012). Subgroup analysis of PFS by RET M918T mutation status suggested that patients with a positive mutation exhibited a higher response rate to vandetanib compared to those with a negative mutation status (Wells et al. 2012). In Europe, since the activity of vandetanib, based on available data, is considered insufficient in patients with no identified RET mutation, treatment with vandetanib is strongly recommended only in patients harboring a RET (germline or somatic) positive mutation, and the presence of a RET mutation should be determined by a validated test before initiation of the treatment (https://www.ema.europa.eu/en/documents/product-information/caprelsa-epar-product-information_en.pdf).
The rate of treatment discontinuation because of toxicity was 12%. The most prevalent AEs included diarrhea, rash, nausea and hypertension, affecting more than 30% of patients (Table 2). Clinically significant QTc prolongation occurred in 8% of patients, and nearly half of those on vandetanib required an increase in their thyroid hormone replacement dose (Wells et al. 2012). The IC50 against RET kinase domain mutations is 1.83 (1.57–2.08) (Fig. 2) (Liu et al. 2018).
AEs related to MKIs (Wells et al. 2012, Elisei et al. 2013, Brose et al. 2014, Schlumberger et al. 2015).
| Vandetanib | Cabozantinib | Sorafenib | Lenvatinib |
|---|---|---|---|
| Diarrhea (57%) | Diarrhea (63.1) | Hand foot skin (76%) | Hypertension (67.8%) |
| Rash (45%) | Palmar-plantar erythrodysesthesia (50%) | Diarrhea (69%) | Diarrhea (59.4%) |
| Nausea (33%) | Decreased weight (47.7%) | Alopecia (67%) | Fatigue (59%) |
| Hypertension (32%) | Decreased appetite (45.8) | Rash/desquamation (50%) | Anorexia (50.2%) |
| Fatigue (24%) | Nausea (43%) | Fatigue (50%) | Weight loss (50%) |
| Headache (26%) | Fatigue (40.7%) | Weight loss (47%) | Nausea (41%) |
| Decrease appetite (21%) | Dysgeusia (34.1%) | Hypertension (41%) | Stomatitis (35.6%) |
| Acne (20%) | Hair color changes (33.6%) | Anorexia (32%) | Palmar plantar erythrodysesthesia (31.8%) |
AEs, adverse events; MKIs, multikinase inhibitors.
Cabozantinib
Cabozantinib is a potent inhibitor of VEGFR2 that also inhibits RET and, unlike vandetanib, targets mesenchymal epithelial transition factor (MET). It was FDA-approved for the treatment of unresectable, progressive metastatic MTC, regardless of tumor mutational status, based on the results of the EXAM trial (NCT00704730). This trial showed a median PFS of 7.2 months for cabozantinib versus 4.0 months for placebo, an ORR of 28%, and a median estimated duration of response (DoR) of 14.6 months (Elisei et al. 2013). Responses were independent of mutational status, with prolonged PFS observed across all subgroups, including by age and prior TKI treatment (Elisei et al. 2013). The IC50 against RET kinase domain mutations is 1.57 (1.41–1.74) (Liu et al. 2018). The most frequently reported AEs were diarrhea, palmar-plantar erythrodysesthesia, weight loss, nausea, fatigue and hypertension (Table 2) (Elisei et al. 2013).
It is important to note that the ZETA and EXAM trials are not directly comparable, given their differences in inclusion criteria and trial design. Notably, the EXAM trial required participants to meet RECIST criteria for radiologic progression before enrollment, which likely resulted in a cohort with more advanced disease, whereas the ZETA trial did not have this requirement (Fig. 2) (Wells et al. 2012, Elisei et al. 2013).
Mechanism of resistance to MKIs
In addition to off-target side effects, secondary RET mutations that confer resistance to MKIs during therapy have been described. Examples include the V804L and V804M gatekeeper mutations, which reduce the ability of drugs such as cabozantinib and vandetanib to effectively bind to the RET kinase’s ATP-binding site, potentially allowing the RET kinase to bind more tightly to ATP, reducing the effectiveness of these drugs (Drilon et al. 2018). Here, we can consider the RET kinase as a two-compartment lock, with one compartment devoted to the action of the gate (the V804 residue). MKIs act such as keys that fit on either side of the gate and bind to both compartments, locking the molecular machine in a nonfunctional state. However, these mutations switch the amino acid in the gate from valine (V) to leucine (L) or methionine (M) – two much bulkier amino acids – making it much harder for the MKIs ‘key’ to fit through and reach the compartments on either side of the gate, rendering the key less effective at binding to the gate and reducing the drug’s effectiveness. RET gatekeeper mutations, such as V804M and V804L, have been reported in non-small cell lung carcinoma and MTC (Carlomagno et al. 2004, Wirth et al. 2019, Liu et al. 2018).
Selective RET inhibitors
With the advent of comprehensive next-generation sequencing of tumors, the identification of molecular drivers of tumorigenesis has led to the development of targeted therapies with greater efficacy and reduced potential for off-target AEs. Two specific RET inhibitors have been approved for the management of MTC.
Selpercatinib
This highly selective, ATP-competitive small-molecule RET inhibitor effectively targets RET with minimal effects on other proteins and can cross the blood–brain barrier (Subbiah et al. 2018a ). The drug was approved by the FDA in May 2020 for the treatment of RET fusion-positive non-small-cell lung cancer (NSCLC) and RET fusion-positive thyroid cancers, as well as RET-mutant MTC in patients ≥12 years of age. Approval was based on the phase I/II LIBRETTO-001 trial, which included 55 RET-mutant MTC previously treated with vandetanib or cabozantinib, 88 treatment-naïve RET-mutant MTC patients, and 19 previously treated RET fusion-positive thyroid cancer patients (Wirth et al. 2020, Subbiah et al. 2022). Among patients with MTC previously treated with vandetanib or cabozantinib, the ORR was 69%, regardless of the number of prior therapies or specific RET mutations. Treatment-naïve patients showed a 73% ORR (Table 3), with biochemical response rates of 91% for Ctn and 66% for CEA. Selpercatinib demonstrated efficacy regardless of the number of previous MKI therapies or specific RET mutations, including the resistance-associated mutation RET V804M (Table 3) (Wirth et al. 2020).
Efficacy of selective RET inhibitors in clinical trials (Hadoux et al. 2023, Subbiah et al. 2024).
| Agent | Cancer type | ORR (%) | CR (%) |
|---|---|---|---|
| Selpercatinib | RET + MTC (previously treated) | 69% | 9% |
| RET + MTC (treatment naive) | 73% | 11% | |
| RET fusion + thyroid cancer | 79% | 5% | |
| Pralsetinib | RET + MTC (previously treated) | 60% | 2% |
| RET + MTC (treatment naive) | 71% | 5% | |
| RET fusion + thyroid cancer | 89% | 0% |
In the post-hoc analysis of LIBRETTO-001, with a median treatment duration of 30.1 months (range: 0.1–66.8), the most common treatment-related AEs occurring in over 20% of patients included diarrhea, dry mouth, hypertension, fatigue, elevated AST/ALT, peripheral edema, constipation, nausea, headache, abdominal pain, increased blood creatinine, vomiting, cough, rash, arthralgia, dyspnea, back pain, decreased appetite and QT prolongation. Severe grade 3–4 AEs included hypertension (19.4%), ALT elevation (11.8%), hyponatremia (9.2%), lymphopenia (5.9%) and diarrhea (5.9%) (Table 4). Only 4.3% of patients discontinued due to treatment-related AEs (Raez et al. 2024).
Common AEs related to selective RET inhibitors (Subbiah et al. 2021b , Raez et al. 2024).
| Selpercatinib | Pralsetinib |
|---|---|
| Diarrhea ++++ | Leukopenia ++++ |
| Dry mouth ++++ | Increased AST ++++ |
| Hypertension ++++ | Neutropenia ++++ |
| Increased AST +++ | Hypertension ++++ |
| Increased ALT +++ | Anemia +++ |
| Increased ALT +++ | Constipation +++ |
| Peripheral edema +++ | Increased ALT +++ |
Interpretation: ++++: >40% +++: 20–30%. AEs, adverse events.
Although generally well tolerated compared to other MKIs, after wider use, selpercatinib has been associated with specific AEs. Gastrointestinal symptoms, small-bowel edema and ascites have been reported, presenting with abdominal pain and bloating that typically resolve with dose interruption or reduction (Tsang et al. 2022). Effusions, often chylous, developed in 80% of patients in one study, with dose reduction significantly improving symptoms (Prete et al. 2022). Weight gain was more frequent in patients with prior TKI treatment compared to TKI-naïve patients (Gouda et al. 2023).
Erectile dysfunction (ED) was reported in 90% of male patients with normal sexual function before treatment, with higher prevalence when actively assessed. Improvement was observed in 90% of cases treated with phosphodiesterase-5 inhibitors (Matrone et al. 2024).
Rare events included fluctuating obliterative bronchiolitis, managed with active surveillance due to mild clinical features (Gambale et al. 2024), and Langerhans cell histiocytosis (LCH) driven by a somatic BRAF mutation, which improved with inhaled corticosteroids. RET blockade may have activated a downstream BRAF mutation in this case (Wu et al. 2024).
Long-term outcomes and rare complications of selpercatinib remain under investigation. Understanding its full AE profile is essential for optimizing prevention and management strategies to prolong treatment duration.
LIBRETTO-531 (NCT04211337) is a large, multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib with physicians’ choice of cabozantinib or vandetanib in patients with advanced metastatic RET-mutant MTC who had not previously received MKIs (Wirth et al. 2022). The primary endpoint was PFS, with treatment failure-free survival also evaluated as a secondary endpoint. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Patients were randomly assigned in a 2:1 ratio to receive either selpercatinib (160 mg twice daily) or the physician’s choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily) (Hadoux et al. 2023). The study enrolled 291 patients with progressive RET-mutant MTC, with RET M918T as the most common mutation in both groups. At 12 months, PFS was 86.8% in the selpercatinib group compared to 65.7% in the control. Median PFS was not reached in the selpercatinib group and was 16.8 months in the control group (vandetanib or cabozantinib), which indicates a significant better PFS in the selpercatinib group. The median treatment failure–free survival was not reached in the selpercatinib group but was 13.9 months in the control group (Hadoux et al. 2023).
The recommended starting dose of selpercatinib is 160 mg twice daily for patients weighing over 50 kg and 120 mg twice daily for those weighing under 50 kg.
Pralsetinib
This highly selective RET inhibitor targets RET-altered kinases, including V804L/M gatekeeper mutations. FDA approval was based on the ARROW trial (NCT03037385), a phase 1/2 open-label study of RET-altered, locally advanced or metastatic RET-mutant MTC with disease progression within 14 months before enrollment and RET fusion-positive thyroid cancers (Subbiah et al. 2021b ). The phase I study evaluated pralsetinib dose escalation, establishing a recommended dose of 400 mg daily for the phase II study (Subbiah et al. 2021b ). The phase II primary endpoints were ORR per RECIST version 1.1 and safety, enrolling patients with RET-mutant MTC and RET fusion-positive thyroid cancer.
The study included 84 individuals with RET-mutant MTC, mostly with sporadic disease. Among them, 55 were evaluated for response, with most having prior treatment with vandetanib or cabozantinib, while 21 were treatment-naïve (Subbiah et al. 2021b ). In previously treated patients, the ORR was 60% (33/55), with a complete response (CR) rate of 2% (1/55). The median time to first response was 3.7 months, and the median DoR was not reached after a median follow-up of 11.2 months. At a median follow-up of 14.9 months, the estimated 1-year PFS was 75%, and the estimated 1-year OS was 89%. In treatment-naïve patients, the ORR was 71% (15/21), with a CR rate of 5% (1/21) (Table 2) and an estimated 1-year PFS of 81% at a median follow-up of 15.1 months. Responses were observed irrespective of the RET mutation, including V804L/M gatekeeper mutations (Subbiah et al. 2021b ).
The most common side effects were anemia, muscle and bone pain, constipation, elevated liver enzymes and hypertension. More serious side effects (Grade 3) were hypertension and reduced white cell counts (neutropenia and lymphopenia) (Table 4) (Subbiah et al. 2021b ).
Pralsetinib was FDA-approved in December 2020 for adults and pediatric patients ≥12 years old with advanced or metastatic RET-mutant MTC requiring systemic therapy. However, its accelerated approval was voluntarily withdrawn for the treatment of advanced or metastatic RET-mutant MTC in the United States on July 20, 2023 (Fig. 2).
Mechanisms of resistance to RET inhibitors
Selective RET inhibitors were designed to overcome gatekeeper mutations. Both selpercatinib and pralsetinib bind to the RET kinase in a distinctive manner, different from MKIs. They fill both the front and back pockets, avoiding the usual gate formed by the amino acids V804 and K758. In this way, gatekeeper mutations do not disrupt their binding mode. However, these inhibitors remain susceptible to several known non-gatekeeper mutations. These include mutations in RET located at the solvent front (RET G810C/S/R), the hinge region (RET Y806C/N) and the β2 strand (RET V738A), which confer resistance to both selpercatinib and pralsetinib (Subbiah et al. 2018b , 2021a ). The solvent front mutations (SFMs) were first described by Solomon et al. in five patients with RET fusion-positive NSCLC and RET-mutant MTC, with progressing tumors and measurable levels of circulating tumor DNA for G810R/S/C mutations (Solomon et al. 2020).
Emergent therapies are currently under investigation to develop drugs capable to overcome this mechanism of resistance.
Emerging therapies
TPX-0046
TPX-0046 is a potent RET and SRC inhibitor that spares VEGFR2. Its rigid, macrocyclic structure enhances its potency against RET mutations, including those associated with resistance, such as RET G810. TPX-0046 demonstrated antitumor properties in both cell line and patient-derived xenograft models of RET-driven tumors. While effective against SFMs, it does not target V804 gatekeeper mutations (Drilon et al. 2019). The drug was evaluated in a phase 1/2 clinical trial involving adults with advanced solid tumors harboring RET fusions or mutations. However, this study was terminated due to side effects that altered the risk-benefit profile (http://clinicaltrials.gov/show/NCT04161391, accessed 01.05.2025).
Vepafestinib
Vepafestinib (TAS0953/HM0) is a novel, highly selective, ATP-competitive RET inhibitor designed to overcome SFMs. It shows strong selectivity for RET and efficacy against common on-target resistance mutations (RETL730, RETV804 and RETG810). Moreover, vepafestinib improved blood-brain barrier penetration and distribution compared to approved RET inhibitors (Miyazaki et al. 2023). The phase 1/2 margaRET trial will assess its safety and efficacy in solid tumors with Ret alterations (https://clinicaltrials.gov/study/NCT04683250, accessed 01.05.2025).
BOS172738
BOS172738 is a highly potent and selective RET inhibitor. Preclinically, it has exhibited potency against several oncogenic RET mutations, including wild-type RET, M918T, V804L, V804M and RET fusions. BOS172738 is evaluated in patients with advanced NSCLC and MTC (NCT03780517) (Keegan et al. 2019, Schoffski et al. 2019).
Conclusion
Due to the rarity and complexity of MTC, it is highly recommended that patients receive care at specialized high-volume centers with expertise in the management of this disease. The development of more selective RET inhibitors has marked a new era in the treatment of RET-positive tumors, providing targeted and highly effective therapeutic options. For RET-negative cases, MKIs such as cabozantinib remain valuable treatment options, while vandetanib may exhibit lower efficacy.
The increasing emphasis on precision medicine underscores the importance of identifying additional actionable genetic alterations to further refine and personalize treatment strategies. Furthermore, disparities in the availability of therapeutic agents globally remain a significant concern. In many countries, certain therapies are either unavailable, not approved as first-line options or not covered by national health systems. These limitations present challenges for patients and highlight the importance of improving global access to effective therapies for MTC.
Declaration of interest
The authors declare no conflicts of interest that could affect the impartiality of this work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
MAJ and LAC contributed equally to the writing of this paper.
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