INTRODUCTION

1.5% of all tumors derived from the thyroid gland constitute medullary thyroid carcinoma (MTC). MTC originates from parafollicular C cells of the thyroid gland, and it is the most common thyroid gland tumor after differentiated thyroid cancers^1,2. At diagnosis, the median age is 50 years, and the disease is observed with similar frequency in both genders^3,4. Unlike other thyroid cancers, medullary thyroid cancer has a familial transition at a rate of 25%⁵. The familial forms inherited by autosomal dominant inheritance consist of 3 subtypes: Multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial-MTC. MEN 2A is characterized by pheochromocytoma, primary parathyroid hyperplasia, and, rarely, cutaneous lichen amyloidosis. Although parathyroid hyperplasia and a marfanoid habitus are observed in MEN 2B, pheochromocytoma is not observed. On the other hand, familial-MTC occurs as isolated. In familial cases, MTC is observed at earlier ages and tends to be multifocal. The most common presentation for familial and sporadic cases is a solitary thyroid nodule (90%). Up to 70% of patients with palpable thyroid nodules have cervical lymph node metastases. De novo metastasis to the liver, lung, bone, and brain may be observed in 10% of the patients⁶.

The gain of function mutations in the rearranged during transfection (RET) proto-oncogene observed in the parafollicular C cell has a crucial role in MTC carcinogenesis. Germline mutations are associated with familial forms, while somatic mutations are responsible for sporadic MTC⁷. As a result, mutations triggering autophosphorylation in tyrosine residues of the RET transmembrane protein lead to the initiation of a series of downstream signaling pathways and carcinogenic processes such as cell survival and proliferation⁸.

The most important prognostic factors of the disease are age, tumor diameter, stage, calcitonin, and carcinoembryonic antigen (CEA) levels^3,9-11. In a large-scale analysis performed according to Surveillance, Epidemiology, and End Results data, 10-year survival was reported as 95%, 75%, and 40% in local, regional, and distant metastases, respectively³. Calcitonin and CEA are highly specific MTC markers and have prognostic significance. There is a highly correlated relationship between high calcitonin levels, regional lymph nodes, and distant organ metastasis at diagnosis¹². The assessment of computed tomography should be performed to detect systemic metastases, especially at levels above 400 pg/mL.

The only curative method for the disease is surgery. In addition to total thyroidectomy and central lymph node dissection, surgical intervention can be extended depending on serum calcitonin level and suspected distant cervical lymph node metastasis. The median overall survival (OS) is 8.6 years after diagnosis¹³. There is no effective adjuvant treatment option after surgery. In case of stage 4 disease, systemic treatment is not preferred for asymptomatic patients until symptomatic or radiological progression is observed, according to Response Evaluation Criteria in Solid Tumors (RECIST)^14,15. Studies assessing the efficacy of systemic chemotherapy have limitations, such as a low number of patients and retrospective design, and a minimal effect was observed with systemic chemotherapy in these studies^16,17. Two tyrosine kinase inhibitors have been demonstrated to contribute to progression-free survival (PFS) in metastatic disease in a phase 3 study. In the study of vandetanib compared to placebo, the PFS times were found to be 30.5 months and 19.3 months, respectively. Another agent with proven efficacy, cabozantinib, had a PFS contribution of 60 weeks versus 20 weeks compared to a placebo. Peptide receptor radionuclide therapy (PRRT), an alternative treatment, is another treatment option in MTC due to the development of resistance to both drugs and grade 3-4 side effects. The expression of somatostatin receptors in vivo and in vitro by MTC cells has been the basis for PRRT therapy in MTC patients^18,19. ⁹⁰yttrium and ¹⁷⁷Lu-octreotate have been used commonly in clinical practice, and their contribution to the median OS varies between 8 and 14 months^20,21. Current studies demonstrate that no effective treatment will contribute to OS in postoperative progression. Therefore, we considered it appropriate to share the experiences of our center to contribute to the literature.

MATERIALS AND METHODS

We retrospectively obtained clinical data of 47 patients diagnosed with progressive MTC between June 2000 and June 2019 in our oncology department. Patients aged 18 years and older, who were diagnosed with MTC pathologically and who progressed after the thyroidectomy +/- regional lymph node dissection, were included in the study. Data regarding age, gender, family history of MTC, symptoms at first admission, and Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) were extracted from the patients’ medical records. Primary tumor diameter and metastatic sites of the tumor were recorded based on the preoperative images. Clinical staging was performed according to the 8^th edition American Joint Committee on Cancer stage classification for MTC. Treatment responses of all patients were evaluated radiologically by computerized tomography. The RECIST 1.1 was used to evaluate radiological progression²². In progressive MTC patients, systemic therapy was initiated in case of symptomatic progression in vital organs. Another indication for systemic therapy was rapid progression (within one year).

OS and PFS were primarily targeted in the survival analysis. OS was considered as the time from the start of systemic therapy to death or the last visit. PFS was considered as the time from the onset of systemic treatment to tumor progression. 

Statistical Analysis

All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows, version 21.0 (SPSS Inc, Chicago, Ill). For descriptive statistics, categorical variables were presented as count and percent. Numerical variables were presented as mean, standard deviation, and minimum and maximum values. OS and PFS were assessed using the Kaplan-Meier methods. The multivariate Cox regression models were used for each subgroup’s potential prognostic risk factors on OS. The log-rank test was performed for all prognostic variables. Survival and regression analyses were performed only in progressive MTC patients receiving systemic therapy. The statistical significance level of alpha was accepted as p<0.05

RESULTS

Demographic and Clinicopathologic Features

Detailed demographic and clinical features of patients were summarized in Table 1. The median age was 46 (17-72) years in metastatic MTC patients. The number of males (32; 68.1%) was considerably higher than female patients (15; 31.9%). The most common clinical presentation at first admission was solitary thyroid nodule (89.4%), followed by constitutional symptoms (46.8%) and dysphagia (12.8%). At the time of diagnosis, 28 patients had T3-T4 disease, while 11 patients had T1-T2 disease. There were 31 (73.8%) patients with lymph node metastases and 8 (20.5%) patients with distant organ metastases. When we evaluated the first progression after thyroidectomy, local recurrence was found to be the most common progression type (80.9%), which was followed by bone (68.1%) and lymph node metastasis (66.0%). In our cohort, we observed visceral metastasis in 3 organs, including the lung (23.4%), liver (12.8%), and pancreas (2.1%). Thirty-four of the 47 progressive MTC patients received systemic therapy due to symptomatic or rapid progression. Vandetanib (18; 52.9%), ¹⁷⁷Lu-octreotate (9; 26.5%), and capecitabine + temozolomide (7; 20.6%) treatments were administered as the systemic therapy (Table 2). Of our cohort, eight patients did not develop symptomatic or rapid progression after thyroidectomy. Four patients died within three months of progression, and one patient did not come to follow-up after progression. Therefore, 13 patients in the study did not receive any systemic therapy.

Survival and Risk Factors

The median time from diagnosis to death was 194.2±21.8 months (151.4-236.9 mos). After thyroidectomy, the median time to the first recurrence was 31.3±5.2 months (21.0-41.6 mos). The median time from the first recurrence to initiation of the systemic therapy was 17.6±26.8 (0.0-118.54 mos) months.

OS and PFS analyses were performed on 34 patients who received systemic therapy. Four patients died within three months of progression during the follow-up period without any systemic treatment. The mortality and progression rates were 58.8% (14 patients) and 44.1% (15 patients) in patients receiving systemic therapy, respectively. From the start of systemic therapy, the median PFS and the median OS were 51.7±11.9 months (28.2-75.1 mos) and 55.6±20.9 months (14.6-96.7 mos), respectively (Figure 1). 

When systemic therapies were divided into two groups as vandetanib and other treatments, the Kaplan-Meier survival analysis showed that the patients receiving vandetanib had a better OS compared to those receiving other treatments (84.7 months vs. 37.1 months, respectively; p=0.047; Figure 2). ECOG-PS was another significant parameter for OS; patients with ECOG-PS 0 had higher median OS compared to those with ECOG-PS 1 (77.2 months vs. 34.4 months, respectively; P=0.002; Figure 3). The presence of liver or bone metastases did not affect survival (p>0.05, for both). Also, there was no difference between familial and sporadic MTC subgroups for OS (p=0.131). The univariate survival analysis (Kaplan-Meier analysis) and log-rank test results are shown in Table 3.

Multivariate analysis of the factors related to OS demonstrated that ECOG-PS 1 was an independent prognostic factor and associated with poor outcomes (HR: 14.7; 95% CI: 1.7-124.7; p=0.013; Table 4).

DISCUSSION

Our study aimed to determine the prognostic risk factors affecting survival in MTC patients who received systemic therapy after surgery. When we reviewed the demographic data, we observed that the median age was 46 years, and the male gender was dominant (68.1%). In a phase 3 study, in which Wells et al.²³ assessed the efficacy of vandetanib in metastatic MTC, the median age was 50.7 years, and the male ratio was 53.4%. In the study of Elisei et al.²⁴, who assessed the efficacy of cabozantinib in progressive MTC patients, the median age was 55 years, and the male ratio was 68.9%. Both studies show male gender dominance, consistent with our study. However, in our study, the median age of patients with progressive MTC was younger. The median time to the first recurrence after thyroidectomy in our cohort was 31.3±5.2 months (21.0-41.6 mos). It seems that our patients had a faster progression after thyroidectomy compared to the literature^25,26. Most of our patients had advanced T and N stages at first diagnosis (Table 1). In addition, reasons such as residual disease after thyroidectomy and persistence of calcitonin may be responsible for rapid progression. Due to the retrospective nature of our study, we lacked sufficient data to assess these factors.

Local recurrence was the most common one among the progression patterns, followed by bone and lymph node metastases, respectively. The most frequent visceral metastatic organ was the lung. In prospective studies assessing the efficacy of vandetanib and cabozantinib, the liver was observed to be the most common visceral metastasis site^23,24. In a phase 2 study assessing the efficacy of pazopanib in 35 MTC patients, the liver was reported to be the most common visceral metastasis site²⁷. Our results seem to contradict other studies in the literature. The fact that our study was conducted with a sample from a single center may be the reason for this discordance. Our results need to be confirmed by multicenter studies.

Although vandetanib and cabozantinib are Food and Drug Administration-approved treatments for progressive disease (PD), not every patient can access the drug due to its cost and reimbursement conditions. Approximately half of the patients in our study received vandetanib treatment. There were also patients treated with ¹⁷⁷Lu-octreotate or a combination of capecitabine-temozolomide chemotherapy. In retrospective studies on ¹⁷⁷Lu-octreotate, PD was observed in 37.6% of MTC patients^21,28. PD with ¹⁷⁷Lu-octreotate was observed in 11.1% of our patients. In the study of Nocera et al.¹⁶, in which they assessed the effectiveness of chemotherapy in progressive MTC patients, the PD rate was 45%. In our patients receiving vandetanib, compared to the patients in the study of Wells et al.²³, the PD rate was 38.8% to 13%, respectively. Although vandetanib and cabozantinib have PFS advantages in MTC, ¹⁷⁷Lu-octreotate and chemotherapy may provide significant benefits in selected patients.

The median OS was 55.6 months after the first systemic therapy (Figure 1). Factors affecting survival within the subgroups were vandetanib use and ECOG-PS. Also, ECOG-PS was the only prognostic factor on OS in multivariate analysis. Classical risk factors known to affect survival in MTC patients are age, disease stage, and biomarker elevation at diagnosis. In our study, ECOG-PS was an independent prognostic risk factor, unlike these factors. In a retrospective study, Valerio et al.²⁹ evaluated 79 MTC patients treated with vandetanib and found that ECOG-PS was an important factor in predicting the longer and durable response. Current findings show that ECOG-PS is an important prognostic marker in progressive MTC patients receiving systemic therapy.

Study Limitations

The important limitations of our study are that it was a single-center study and it included a limited patient group. In addition, as a retrospective-based analysis, it is not possible to generalize the study results.

CONCLUSION

MTC is a rare endocrine malignancy and has limited systemic treatment options in PDs. Apart from tyrosine kinase inhibitors with evidence-based efficacy, chemotherapy and ¹⁷⁷Lu-octreotate treatments may provide additional contributions to selected patients. Multicenter studies involving more patients are required to understand the efficacy of alternative treatments. 

Ethics

Ethics Committee Approval: The Academic Committee approved retrospective analyses of clinical data of İstanbul University (protocol no: 2021/2103, date: 04.03.2021).

Informed Consent: Retrospective study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Pratices: F.F., N.P., M.B., Concept: N.P., M.B., Design: F.F., Data Collection or Processing: N.P., M.B., Analysis or Interpretation: F.F., M.B., Literature Search: F.F., N.P., Writing: F.F., N.P., M.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.