Differentiated thyroid carcinoma (DTC) usually has a good prognosis. Although relatively rare, the prognosis of patients with a distant metastasis, which is present at diagnosis in 1% to 4% of patients and which develops during follow-up in 7% to 23% of patients, is generally poor.1,2 Radioactive iodine (RAI) therapy has been regarded as a standard treatment for such patients. However, a survival benefit can be expected only for patients with RAI-avid lesions.3,4
Until recently, an efficacious treatment modality for RAI-refractory DTC remained to be developed. Molecular-targeted drugs (MTDs) have recently been introduced in a 21st-century clinical setting.5,6 However, an indication for the use of MTDs is limited to the presence of RAI-refractory progressive lesions in accordance with the enrollment criteria of clinical trials for such MTDs. Radioactive iodine–refractory DTC is defined as follows, after appropriate thyroid-stimulating hormone (TSH) stimulation and iodine preparation: (1) malignant/metastatic tissue does not ever concentrate RAI (no uptake outside the thyroid bed at the first diagnostic or therapeutic whole-body scan [WBS]); (2) tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease (in the absence of stable iodine contamination); (3) RAI is concentrated in some lesions but not in others; and (4) metastatic disease progresses despite a significant concentration of RAI.7
Meanwhile, age is considered a prognostic factor for recurrent DTC and has been suggested to be related to the low prevalence of RAI avidity.8,9 The demonstration of refractoriness could be a barrier in terms of time and medical resources for elderly patients. Thus far, a relationship between RAI avidity and age, histological type, and metastatic lesions in a large number of patients has not been reported.
In this study, we evaluated the impact of age on the RAI avidity of recurrent lesions of DTC in a large number of patients. Furthermore, we examined the efficacy of MTDs in terms of the initial RAI avidity of metastatic lesions.
PATIENTS AND METHODS
The study design was a retrospective review of records of 258 patients who underwent a first diagnostic WBS at our institution between 2004 and 2013. The group consisted of 189 patients with classic papillary thyroid carcinoma (cPTC), 8 patients with a follicular variant of PTC (FVPTC), and 61 patients with follicular thyroid carcinoma (FTC). Total thyroidectomy was performed in all patients.
We adopted the age cutoff of the American Joint Committee on Cancer/TNM eighth edition staging system (ie, <55 or ≥55 years) for the initial analysis of RAI avidity of metastatic lesions.
Patients achieved an appropriate TSH stimulation with a serum TSH level greater than 30 μIU/mL. All patients were instructed to follow a low-iodine diet for 2 weeks. For the diagnostic WBS, all patients received from 37 to 185 MBq (1–5 mCi) of an oral dose of 123I or 131I and scanned. The scans were obtained with large-field-of-view gamma cameras (E-COM; Toshiba Medical Systems, Tokyo, Japan) equipped with a high-energy parallel hole collimator. Whole-body scans were acquired in a 256 × 1024 matrix, and the camera's linear tracking speed was 10 cm/min.
All patients except one were RAI naive as ablation has not been a common procedure until recently in Japan. Radioactive iodine uptake into metastatic lesion(s) was retrospectively reviewed using a WBS image interpretation report used by radiologists at our institution. The detailed diagnostic procedure used has been previously described.10
In addition, an MTD (lenvatinib) was subsequently administered to 10 patients of the group who were regarded as RAI refractory. The therapeutic efficacy of RAI was evaluated based on Response Evaluation Criteria in Solid Tumors version 1.1.
Statistical analysis was performed using JMP 13 software (SAS Institute, Cary, SC). A χ2 test was used for any comparative analysis between 2 groups, and a Cochran-Armitage trend test was used for any analysis between multiple groups.
A significant difference in age or the male-to-female ratio was not found among histological types. The distribution of metastatic sites varied among histological types: in cPTC, lung metastases (77.8%) were most frequently found, followed by lymph node (32.8%) and bone metastases (2.6%), whereas in FTC, bone metastases (62.3%) were most frequently found, followed by lung (55.7%) and lymph node metastases (19.7%; Table 1).
In cPTC, the overall prevalence of uptake of RAI into a metastatic lesion was 19.6%. With regard to age, the prevalence of RAI uptake was 41.5% for patients younger than 55 years, but this decreased significantly to 8.1% for those 55 years or older (P < 0.001; Table 2). With regard to metastatic site, unlike for that in bone, the prevalence of RAI uptake to metastatic lesions in the lungs and lymph nodes was significantly different between the 2 patient age groups (P < 0.001, P = 0.002; Table 2).
By contrast, the overall prevalence of uptake was 80.1% in FTC. However, a significant correlation between age and the prevalence of uptake by metastatic lesions, as was observed for cPTC, was not shown. In FVPTC, a similar tendency as for FTC was observed, although the number of patients in this group was too small to statistically evaluate.
For further analysis of the correlation between age and RAI avidity, patients were divided into 4 groups (<44 years, 45–54, 55–64, >65 years). Because of the small number of patients, an analysis for FVPTC was not performed. In cPTC, the overall prevalence of RAI uptake showed a marked inverse and significant correlation with age: 52.8% for patients younger than 44 years and 6.8% for those older than 65 years, respectively (P < 0.001; Fig. 1A). When examining lung and lymph node metastases separately, the same trends were maintained (Figs. 1B, C).
In FTC, the overall prevalence of RAI uptake was approximately 80%, regardless of age (Fig. 2A). With respect to bone metastases, more than 90% of patients had RAI-avid lesions, irrespective of age (Fig. 2B). By contrast, lung metastases showed a moderate prevalence of RAI avidity, irrespective of age (Fig. 2C).
We evaluated the therapeutic effects of MTD (lenvatinib) on patients who were regarded as RAI refractory. Three patients had primary RAI-avid metastatic lesions that subsequently became RAI refractory, whereas the remaining 7 patients had primary non–RAI-avid metastatic lesions for whom RAI therapy was not applied. Considerable clinical responses were observed irrespective of initial RAI uptake or histological type (Table 3).
In the present study, a low prevalence of RAI uptake by metastatic lesions of cPTC was demonstrated, especially for patients older than 55 years; the prevalence of RAI uptake by lung metastases was almost negligible. By contrast, the prevalence of RAI uptake by metastatic lesions of FTC was equally high among all age groups. These results suggested that only a small fraction of elderly patients with metastatic cPTC is amenable to RAI therapy.
In previous reports, old age, a larger tumor diameter, and high FDG uptake have been suggested as predictive factors for low RAI uptake; however, a small number of patients and a lack of histological information may obscure such findings. Furthermore, poor RAI uptake into metastatic lesions, which does not suggest an indication for RAI therapy, has been shown to be a factor for a poor prognosis.10 The numbers of patients studied by us were large enough to show the importance of age in predicting the RAI avidity of metastatic lesions, especially in specific histological types, that is, cPTC.
The sodium iodide symporter (NIS) is a transmembrane glycoprotein involved in the uptake of iodine into follicular cells in the thyroid gland.11,12 The function of the NIS is closely related to the efficacy of RAI therapy, with patients who show reduced NIS expression having a poor prognosis.13 Reduced expression of NIS is also observed in tumors of the elderly or in tumors with a large diameter.14 Such reports are in agreement with our findings of the low prevalence of RAI avidity in elderly patients with cPTC.
In Western countries, RAI ablation after total thyroidectomy has been the standard of care for most cases with DTC. By contrast, in Japan, subtotal thyroidectomy and extensive lymph node dissection have been performed for DTC in most institutions. Radioactive iodine ablation has also not been a common procedure in Japan until recently because of a shortage of facilities appropriate for RAI therapy and a sense of aversion to radioactivity.15 In addition, according to the latest Japanese guidelines for thyroid tumors, lobectomy is acceptable for T1 N0 M0 patients.16 This therapeutic strategy is incorporated in recent guidelines in Western countries.17 This means that indications for lobectomy have expanded, even in Western countries. However, the likelihood of recurrence in the future remains, even in such cases, that is, lobectomized patients.
If a distant metastasis develops in a patient who did not undergo a total thyroidectomy, a completion thyroidectomy in order to perform an RAI-WBS for the evaluation of RAI avidity of metastases is mandatory, regardless of age, according to current guidelines. However, a completion thyroidectomy is accompanied with a considerable risk of persistent recurrent nerve paralysis and hypoparathyroidism that may seriously compromise the quality of life of patients.18 The finding that the prevalence of RAI avidity in patients older than 55 years with lung metastases from cPTC is only 3% minimizes the clinical significance of a completion thyroidectomy followed by RAI-WBS in such patients.
Molecular-targeted drugs have recently been introduced to treat RAI-refractory DTC. Lenvatinib is one of such MTDs. A phase 3 clinical trial that evaluated the therapeutic effect of lenvatinib on DTC showed potent tumor reduction, with prolonged progression-free survival compared with placebo. Additional analyses confirmed that this therapeutic effect was maintained irrespective of age.19 Because the prevalence of RAI avidity was found to be low in patients older than 55 years with cPTC in this study, MTDs may become an effective treatment option for such patients.
The limitations of this study are that it is a retrospective study, with nonuniform WBS procedures used, although consecutive patients with metastatic lesions of DTC were included. This reflects real-world clinical practice. Ablation is not undertaken in almost all cases that may obscure the RAI avidity of metastatic lesions. However, according to a previous report from our institution, the RAI nonavidity of lung metastases can predict the ineffectiveness of RAI therapy in nonablated patients.10 Although the patient cohort of this previous report differed from ours with a slight overlap, WBS procedures and the background of patients were almost identical during the study period. This supports the notion that non–RAI-avid lesions are refractory to RAI therapy, even if the patients did not undergo an ablation.
Although it is premature to recommend the administration of MTDs to elderly patients with metastatic cPTC for which RAI refractoriness has not been confirmed, we should reconsider therapeutic strategies incorporating MTDs without RAI-WBS because the RAI avidity of metastatic lesions of cPTC in elderly patients is significantly low. This strategy may obviate possibly unnecessary surgical procedures and reduce the risk of complications. Further studies will provide us a rationalized therapeutic strategy for metastatic DTC.
The RAI avidity of metastatic lesions of cPTC in elderly patients, especially in those older than 55 years, was seldom demonstrated. Adherence to the strategy that the administration of MTDs is restricted after the confirmation of RAI refractoriness should be revisited for elderly patients. A strategy of omitting RAI therapy should be taken into account when considering the age of the patients and the histological type of their DTC.
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