Metastatic differentiated thyroid cancer: worst prognosis in patients with metachronous metastases

Between January 1, 2010 and December 31, 2015, a total of 2620 new cases of CDT were treated in our institution, and 53 patients of them had metastatic involvement at diagnosis or during follow-up, and met the inclusion criteria. Additionally, 48 patients diagnosed between 2005 and 2009 with metastatic disease were included, because they received some treatment for metastases during the study period. For the total population, 81 patients (80.2%) were women and the mean age at diagnosis was 49 years (12–80). The mean follow-up time from the time of diagnosis was 122 months (48–375).

The main characteristics of the patients included in the analysis are shown in Table 1. The mean dominant primary tumor diameter in the thyroid gland was 3.1 cm (0.3–7.9) and the most common histologic subtype of DTC was papillary carcinoma, found in 90 patients (89.1%), followed by follicular carcinoma in 10 patients (9.9%) and 1 patient with Hürtle cell carcinoma. The most frequently found variants of papillary thyroid carcinoma were classical (67.3%) and follicular (12.8%). Cervical lymph node compromise at diagnosis was evident in 86 patients (85%) of which 52 had involvement in both central and lateral compartments, and extra nodal extension was found in 21 patients. All patients were treated with total thyroidectomy and 75 patients (74.2%) received an initial dose of radioiodine between the 2- and 12-month post-thyroidectomy period.

Table 1 Demographic and histologic characteristics of patients with DTC

Synchronous metastatic disease, defined as the finding of distant metastases in perioperative staging studies up to 6 months after surgery or in the first radioiodine body scan, was evident in 55 patients. Out of these, 52 patients had exclusive pulmonary metastatic compromise, 2 patients had an exclusive bone metastasis, and 1 patient had both pulmonary and bone metastatic compromise.

On the other hand, metachronous metastasis was diagnosed in 46 patients, all with pulmonary compromise and only 8 patients with additional metastases in other sites (four to the central nervous system and four to the liver). The mean time between initial diagnosis and the finding of distant metastases was 5 years (0.7–21). Both groups of patients had elevated mean pre-ablative thyroglobulin levels (Synchronous: 1148 ng/ml and Metachronous: 1021 ng/mL) without statistical differences (P = 0.68).

Overall, distant 131I-avid metastases accounted for 42 patients (41.5%). The rate of patients with 131I avidity was 58.1% (32/55) in those with synchronous metastases, and 21.7% (10/46) in those with metachronous metastases, with a non-significant difference (P = 0.36). Table 2 summarizes the comparison between both groups of patients.

Table 2 Comparison between patients with synchronous and metachronous metastases

The mean time to progression, estimated between the date of metastasis diagnosis and the finding of progression (determined by the growth of 20% or more in the sum of the diameters of the target lesions, or by new lesions) using computed tomography imaging, was 103 months as shown in Fig. 1. In patients with 131I-refractory metastases, the mean time to progression was 96 months while in patients with 131I-avid metastases it was not reached (P = 0.057) (Fig. 2). The median time to progression was significantly longer in patients with synchronous metastases compared to those with metachronous metastases (Not reached versus 95 months, P = 0.017) (Fig. 3).

Fig. 1figure 1

Progression-free survival of patients. Median: 103 months Events: 33 Censored: 66

Fig. 2figure 2

Progression-free survival stratified by 131 I uptake. Median time to progression in patients with 131 I-avid metastates: not reached; events: 10,censored: 40. Median time to progression in patients with 131 I-refractory metastatis: 96 months; events: 23, censored: 35. Log-rank test, P = 0.057

Fig. 3figure 3

Progression-free survival stratified by the time of metastasis diagnosis (synchronous vs metachronous). Median time to progressionin patients with synchronous metastates: not reached; events: 11, censored: 43. Median time to progression in patients with metachronousmetastates: 95 months; events: 22, censored: 23. Log-rank test, P = 0.017

A total of 15 patients received Sorafenib after being considered as iodine refractory, 8 with synchronous metastases and 7 with metachronous metastases. The average time of use of Sorafenib was 13.2 months (range 1–28) Three patients reached partial response, and 11 patients had stable disease for 6 or more months; One patient discontinued treatment due to toxicity.

The disease status at the time of last visit is summarized in Table 2. There were more partial responses in patients with synchronous metastases (p 0.005). We did not find complete responses (structural excellent response).

The bivariate analysis of qualitative variables showed that patients with synchronous metastases had a lower risk of progression, with a RR value of 0.496 (95% CI: 0.294–0.825; P < 0.05). There were 11 deaths during the follow-up time, 8 of 55 patients with synchronous metastases (14.5%) and 3 of 46 patients with metachronous metastases (6.5%) died in the follow-up period. Among the 11 patients who died, 6 received Sorafenib, with an average duration of treatment of 7.4 months. In the entire cohort, the median overall survival was not reached (Fig. 4). The 5-year overall survival rate was 95%.

Fig. 4figure 4

Overall survival. Median survival: not reached; events: 11, censored: 90

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