Thyroid cancer illustration
Credit: Getty Images

The only curative treatment for medullary thyroid carcinoma (MTC) is total thyroidectomy and lymph node dissection. However, even with patients in whom a radical surgical approach has been taken, serum calcitonin levels can be persistently high in macroscopic MTC. In a 10-year period, 50% of patients undergo relapse despite surgery. Distant metastases in the lungs, bone, and liver are usually detected upon diagnosis or at a later follow-up. 

In other words, the prognosis for MTC patients remains poor. As for nonsurgical treatment options, chemotherapy was once considered first-line therapy; however, studies have shown that it demonstrates poor efficacy and is no longer considered first-line treatment for patients with advanced MTC.

Read more about MTC epidemiology

Continue Reading

One of the more promising therapeutic developments in MTC is the use of tyrosine kinase inhibitors (TKIs), which studies have shown play a crucial role in MTC pathogenesis. Several studies investigating the uses of TKIs on MTC have demonstrated clear clinical benefits to the patient. Hence, TKIs such as vandetanib and cabozantinib have gained regulatory approval in several jurisdictions globally. 

Prolonged Progression-Free Survival

Let us take a closer look at these two TKIs, beginning with vandetanib. A phase 3 study trial involved 331 patients with MTC. Patients were randomly assigned to the vandetanib group or the placebo group; however, upon disease progression, patients in the placebo group were allowed to receive vandetanib during the post-progression open-label phase of the trial. Vandetanib was prescribed at the dose of 300 mg per day. 

Read more about MTC prognosis

In the study, vandetanib was observed to significantly prolong progression-free survival (PFS). Patients who received vandetanib had a median PFS of 30.5 months, compared with 19.3 months in the control group. 

In addition, success was observed in 4 other areas:

  • Objective response: 45% of treated patients vs 13% in the placebo group
  • Disease control: 87% of treated patients vs 21% in the placebo group
  • Calcitonin biochemical response: 69% of treated patients vs 3% in the placebo group
  • Carcinoembryonic antigen (CEA) response: 52% of treated patients vs 2% in the placebo group. 

Another study investigating the merits of vandetanib divided the patients into 4 subcategories. A total of 164 patients were in the “progression and symptoms” group, 88 patients were in the “progression only” group, 38 patients were in the “symptoms only” group, and 21 patients were in the “no symptoms” group. 

The study found that patients in the “progression and symptoms” group demonstrated a statistically significant decrease in the risk of disease progression when they received vandetanib, compared with placebo. Other key findings included:

  • The median PFS of patients in the “progression and symptoms” group who received vandetanib was 21.4 months vs 8.40 months in the placebo group. 
  • In the “symptoms only” group, the difference between vandetanib and placebo was borderline significant. 
  • The median PFS was 22.4 months in patients from the “symptoms only” group who received vandetanib, compared to 9.7 months in the placebo group. 
  • Similar trends were observed in the other 2 groups, “progression only” and “no progression,” but they did not reach statistical significance. 

Decreased Serum Calcitonin and CEA Concentration

A landmark phase 3 clinical trial involving cabozantinib included 300 patients who had advanced MTC—either unresectable locally advanced disease or the presence of metastasis. Cabozantinib treatment was observed to result in a statistically significant improvement in PFS compared to placebo: 11.2 months vs 4.0 months.

In addition, cabozantinib was observed to decrease serum calcitonin and CEA concentration in patients across subgroups, including patients with hereditary and sporadic MTC, metastases at baseline, and in patients treated previously with or without a TKI. However, no statistically significant difference in overall survival (OS) was observed between the treatment group and the placebo. 

Further genetic analysis revealed that cabozantinib performed best in patients with RET M918T-positive tumors. In the group of patients with this mutation: 

  • PFS in the cabozantinib group was 13.9 months, compared with 4.0 months in the placebo group 
  • OS in the cabozantinib group was 44.3 months compared with 18.9 months in the placebo group
  • Overall response rate in the cabozantinib group was 34% compared with 0% in the placebo group. 

The authors of the study elaborated, “Cabozantinib was favored over placebo regarding PFS and OS in patients with unknown RET mutation status and without RET mutation.” In addition, in a RAS-positive group of patients, PRS was significantly longer at 47 weeks in the treated group compared to 8 weeks in the placebo group.

Future Developments 

In our rapidly changing medical landscape, vandetanib and cabozantinib are now considered fairly established TKIs prescribed for MTC. Despite their flaws (for example, common adverse reactions), the main clinical benefit they provide is that they slow disease progression and thus buy physicians crucial time.

Looking to the future, scientists are already testing selective RET inhibitors for MTC patients with the RET mutation. “Importantly, selective RET inhibitors demonstrated antitumor activity” for patients “who showed primary resistance to vandetanib and cabozantinib,” the authors of a literature review wrote. Among the new RET-targeting drugs are selpercatinib and pralsetinib. Interestingly, studies have shown that they are also effective in patients with brain metastases.

According to Priya et al, “Targeted therapy should be considered where other better tolerated and more accessible local treatments have been exhausted.” Scientists are increasingly looking towards developing new somatic drugs that bypass or minimize the need for radical surgery. Although that remains a distant goal, we should never doubt our ability to make progress when we work together.


Jolanta K, Aleksandra K, Malgorzata O-W, Barbara J. Recent advances in precision medicine for the treatment of
medullary thyroid cancer
. Expert Rev Precis Med Drug Dev. 2021;6:5, 307-315. doi:10.1080/23808993.2021.1964952

Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted therapy for medullary thyroid cancer: a reviewFront Oncol. Published Online October 6, 2017. doi:10.3389/fonc.2017.00238