Papillary thyroid carcinoma (PTC) metastasizes not only to lymph nodes but also to distant sites such as the lung and bone, for which RAI therapy is the first-line treatment. However, no therapy was available for the patient’s RAI-refractory metastases except for TSH suppression. Some molecular-targeted agents were recently reported to be effective for differentiated thyroid carcinomas (DTCs), including PTCs, with RAI-refractory metastases [3, 4]. However, in clinical practice, it remains unclear whether and when molecular-targeted agents should be administered, since not all RAI-refractory cancers are rapidly progressive and life threatening.

It was reported that sorafenib and lenvatinib significantly prolonged the progression-free survival (PFS) of DTC patients in randomized phase III studies [3, 4]. However, these agents displayed a high frequency of various adverse events, e.g., hand-foot syndrome (76 %), diarrhea (69 %), alopecia (67 %), rash (50 %), and hypertension (41 %), for sorafenib [3] and hypertension (68 %), diarrhea (60 %), fatigue/asthenia (59 %), decreased appetite (50 %), and nausea/vomiting (46 %) for lenvatinib [4]. The median PFS and hazard ratio (HR) with 95 % confidence intervals (CI) of the DECISION (sorafenib) and SELECT (lenvatinib) trials were 10.8 months (vs. 5.8 months for placebo), 0.59 (0.45–0.76) and 18.3 months (vs. 3.6 months for placebo), 0.21 (0.14–0.31), respectively [3, 4]. These agents are very costly, and since these trials were crossover studies, it was not proved that they prolong overall survival of patients. Clinicians must therefore carefully weigh the advantages and disadvantages of using these agents for individual patients.

Not all RAI-refractory metastases are progressive or immediately life threatening. In our prior series, the 5- and 10-year carcinoma-related death rates of 74 DTC patients with RAI-refractory metastases (metastases without RAI uptake from the time of the initial treatment) were 5 % and 30 %, respectively [5]. Therefore, these data suggest that not all patients with RAI-refractory thyroid cancer require treatment with molecular-targeted agents. Without appropriate selection, many of these patients would likely suffer various adverse events without clear improvement in quality of life or survival.

We also demonstrated by a multivariate analysis that older age (≥60 years) was an independent prognostic factor for cause-specific survival (CSS) [6], indicating that RAI-refractory metastases are more progressive in elderly patients. Therefore, molecular-targeted agents are more likely to be administered to elderly patients. We have to be careful in this clinical context, because elderly patients more often have comorbidities such as hypertension, liver and renal dysfunctions, and diabetes mellitus, and they have lower immune resistance than younger patients.

The change in serum Tg levels is the most important prognostic factor for thyroglobulin antibody (TgAb)-negative patients who have undergone a total thyroidectomy for PTC. We reported that a short Tg-DT (<1 year) after total thyroidectomy strongly predicted a poor disease-free survival (DFS) and CSS (Table 15.1) and that the Tg-DT shorter than 1 year was a very strong predictor of disease recurrence and carcinoma-related death: HR with 95 % CIs for locoregional recurrence, distant recurrence, and carcinoma-related death were 2.38 (1.20–4.71), 4.20 (1.73–10.21), and 47.06 (5.47–405.13), respectively (superior to other conventional prognostic factors in a multivariate analysis) [7]. We also found that the incidence of persistent disease was significantly higher in young (<40 years) and old (≥60 years) patients than in middle-aged patients (40–59 years), whereas short Tg-DT was more frequently observed in old patients than others [8].