Abstract
Background/Aim: Refractory differentiated thyroid carcinoma (DTC) and anaplastic thyroid carcinoma (ATC) are associated with poor prognoses. Molecularly targeted agents such as lenvatinib are expected to significantly improve outcomes. However, data from real-world settings remain limited.
Patients and Methods: A retrospective analysis was conducted in 48 patients with thyroid carcinoma treated with lenvatinib at Kyushu University Hospital between April 2015 and October 2024. We compared overall survival (from time of treatment initiation to death, censoring, or data cutoff) and progression-free survival (from time of treatment initiation to tumor progression as confirmed by image examination) using Kaplan-Meier analysis. A subgroup analysis was also conducted for patients who had and had not received prior radioactive iodine (RAI) therapy.
Results: The analysis included 29 female and 19 male cases. The histologic types were papillary thyroid carcinoma in 26 patients, follicular thyroid carcinoma in seven patients, and ATC in 15 patients. Of 33 DTC cases, RAI was not administered in nine cases. The median progression-free survival was 30 months for papillary thyroid carcinoma, 18 months for follicular thyroid carcinoma, and four months for ATC. The median progression-free survival for patients with DTC who received RAI therapy was 19 months, whereas that for patients with DTC without RAI therapy was 46 months. No significant difference was found between the two groups (p=0.243).
Conclusion: Lenvatinib may be effective in patients with DTC in whom RAI treatment is not feasible in real-world settings.
- Differentiated thyroid carcinoma
- anaplastic thyroid carcinoma
- without RAI therapy
- lenvatinib
- real-world data
Introduction
Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) account for 90%-95% of all thyroid cancers (1-4). The 10-year survival rate is approximately 95% (5). The majority of patients with differentiated thyroid carcinoma (DTC) can be cured through thyroidectomy; in those with advanced disease, postoperative adjuvant therapy with thyroid-stimulating hormone suppression and radioactive iodine I-131 (RAI) is typically administered (2, 3, 6). DTC cells, which comprise the majority of thyroid carcinomas (TCs), typically express sodium iodide symporter (NIS) and respond favorably to RAI therapy. However, when differentiation is lost, NIS expression is reduced, leading to resistance to RAI therapy (1). This condition is known as RAI-refractory differentiated thyroid cancer (RR-DTC). Approximately 10%-20% of patients with DTC have RR-DTC (7). The prognosis for RR-DTC remains poor, with a 10-year survival rate of less than 20% (8). Anaplastic thyroid carcinoma (ATC) is rare, accounting for 1%-2% of TCs (3). It is characterized by an aggressive tumor and an extremely poor prognosis, with a 1-year survival rate of less than 20% (9). Owing to its rapid progression, surgical intervention is only feasible in approximately 25% of patients, and palliative care remains the primary treatment modality for the majority of patients (9, 10). Lenvatinib is recognized as one of the agents that have contributed to advancements in the treatment of TCs. It is a multi-kinase inhibitor (mTKI) that exerts its anticancer effects through the inhibition of vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor-α, c-kit, and REarranged during Transfection (RET) (11). In the SELECT trial focusing on RR-DTC, the median progression-free survival (PFS) in the lenvatinib group was 18.3 months, compared with only 3.6 months in the observation group, demonstrating a significant improvement in PFS (11). Furthermore, subsequent analyses demonstrated that in lenvatinib responders, the median PFS was 33.1 months, indicating sustained efficacy over the long term (12). Since the SELECT trial, meta-analyses have consistently reported the high efficacy of lenvatinib in RR-DTC (11, 13, 14), and it has now become one of the standard treatment options for refractory DTC (10). Lenvatinib has also shown limited efficacy in ATC (15). The study showed that the partial response rate was 15.0%, and the median PFS was 3.16 (2.18-5.60) months.
In real-world clinical settings, patients who are ineligible for the SELECT trial are frequently encountered. The reasons reported for ineligibility include cases in which general anesthesia was not applicable and surgery could not be performed, or cases in which RAI could not be performed. For the latter cases, the efficacy of lenvatinib has rarely been reported and remains unknown (13). In the present study, a retrospective evaluation was conducted to assess the therapeutic value of lenvatinib in patients with PTC, FTC, and ATC at a single institution. Particular attention was given to the efficacy of lenvatinib in patients who had not undergone RAI and were not enrolled in the SELECT trial.
Patients and Methods
Patients. A retrospective analysis was conducted in patients with TC treated with lenvatinib at Kyushu University Hospital between April 2015 and October 2024. The study participants were selected by listing patients with a history of lenvatinib administration at our institution, and relevant data were collected from medical records. The drugs were administered to patients with rapidly growing RR-DTC, DTC that could not be treated with RAI and was progressing rapidly, and ATC that could not be treated with surgery.
Evaluation. Computed tomography scans of the neck, thorax, and/or abdomen were performed before and after lenvatinib therapy. The extent of disease progression was confirmed via imaging approximately every three months. Disease progression was determined based on the RECIST criteria (version 1.1), defined as progressive disease, i.e., an increase of 20% or more in the sum of tumor diameters.
Follow-up. The observation period was defined as either the date of death or the cutoff date (April 2025). The median follow-up was 19 months (range=1-99 months).
Ethical considerations. The study was approved by the institutional review board of Kyushu University (approval number: 22027). Informed consent was obtained from all patients, with most providing written consent. In certain cases, participation was declined by responding to an official opt-out announcement posted on the institution’s website. This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki.
Statistical analyses. All calculations were performed using SPSS Statistics software version 22.0 (IBM Japan, Ltd., Tokyo, Japan). The overall survival (OS) was defined as the time from the initiation of lenvatinib treatment to death or data cutoff. PFS was defined as the time from the initiation of lenvatinib treatment to tumor progression. The OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method and compared using the log-rank test. A p-value of <0.05 was considered significant.
Results
Patient characteristics. The current study included 48 patients (29 women and 19 men). The median age at the initiation of lenvatinib was 72 years (range=34-88 years). The Eastern Cooperative Oncology Group performance status (PS) scores at treatment initiation were 0-1 in 27 patients and 2-3 in 21 patients. The histologic types were PTC in 26 patients, FTC in seven patients, and ATC in 15 patients (Table I). Table I summarizes the pathology-specific characteristics of 48 patients. Among those with PTC, the most common initial treatment was total thyroidectomy and RAI therapy (61.5%, 16/26). Prior to lenvatinib therapy, 71.3% (19/26) of patients underwent total thyroidectomy and RAI therapy, whereas 26.9% (7/26) did not undergo RAI therapy. Partial thyroidectomy was the most common initial treatment for FTC. Total thyroidectomy and RAI therapy were performed in 71.4% (5/7) of patients prior to lenvatinib therapy, but RAI therapy was omitted in 28.6% (2/7). Among the 33 patients with DTC treated with lenvatinib, 27.3% (9/33) did not receive RAI therapy. In the ATC group, 60% (9/15) of patients underwent either total thyroidectomy alone or in combination with adjuvant RT prior to lenvatinib therapy.
Pathology-specific characteristics of 48 patients.
Of the 48 patients, 41 (85.4%) received an initial dose of 24 mg, whereas 14.6% (7/48) started with a reduced dose. The median durations of treatment were six months (range=0.5-99 months) for PTC, four months (range=2-27 months) for FTC, and three months (range=0.5-32 months) for ATC.
Patients who have not undergone RAI. RAI was not performed in nine patients with DTC (seven PTCs and two FTCs). The reasons for not performing RAI were as follows: rapid disease progression that made the typical RAI waiting period (~3 months) unacceptable (four patients), poor cardiopulmonary function precluding general anesthesia and total thyroidectomy (two patients), lack of iodine uptake on scintigraphy (one patient), patient refusal of surgery and RAI (one patient), and an initial diagnosis of ATC that was later revised to PTC after the initiation of lenvatinib (one patient) (Table II).
List of patients who did not receive radioactive iodine (RAI) therapy.
Clinical outcomes. The median OS periods for PTC, FTC, and ATC were 41 months [95% confidence interval (CI)=22.4-59.5], 32 months (95%CI=0.0-71.5), and eight months (95%CI=2.2-13.8), respectively (Figure 1A). The median PFS periods for PTC, FTC, and ATC were 30 months (95%CI=13.9-46.1), 18 months (95%CI=2.6-33.4), and four months (95%CI=0.4-7.6), respectively (Figure 1B). Among patients with DTC, the median OS periods were 36 months (95%CI=13.4-58.6) for those who received RAI therapy and 54 months (95%CI=36.6-71.4) who did not receive RAI therapy (Figure 2A). No significant difference was found between the two groups (p=0.243). The median PFS periods were 19 months (95%CI=8.7-29.3) for patients who received RAI therapy and 46 months (95%CI=20.0-72.0) for those who did not (Figure 2B). No significant difference was found between the two groups (p=0.243).
Kaplan-Meier analysis of A) overall survival B) progression-free survival. PTC: Papillary carcinoma; FTC: follicular carcinoma; ATC, anaplastic carcinoma; mOS: median overall survival; mPFS: median progression-free survival.
Kaplan-Meier analysis of differentiated thyroid carcinoma (DTC) stratified by radioactive iodine (RAI) therapy status: A) Overall survival (OS) among patients with and without prior RAI therapy. B) Progression-free survival (PFS) among patients with and without prior RAI therapy. No statistically significant differences were observed between the two groups in either OS or PFS (p=0.243 for both comparisons). mOS: Median overall survival; mPFS: median progression-free survival.
Discussion
Our study showed that the efficacy of lenvatinib in a real-world setting was comparable to or exceeded that reported in several previous studies. These results support the effectiveness of lenvatinib for RR-DTC in routine clinical practice. Real-world data on the use of lenvatinib for RR-DTC are gradually accumulating. Worden et al. reported a median PFS of 49.0 months for 308 patients with RR-DTC treated with lenvatinib (16). Jerkovich et al. observed a median PFS of 22.2 months in 29 patients with RR-DTC treated with lenvatinib (17). Masaki et al. reported a 3-year survival rate of 51% in 42 patients with RR-DTC treated with lenvatinib (18). Koehler et al. noted a median PFS of 12 months in 53 RR-DTC patients treated with lenvatinib (19). Our median PFS data of 30 months in PTC and 18 months in FTC were similar to those reported by some studies, but inferior to those reported by Worden et al. We hypothesize that this may be due to the inclusion of cases immediately following FDA approval of lenvatinib in this study. Cases immediately following approval inevitably include patients with advanced disease who had no other treatment options – i.e., cases in which drug administration likely should have been started earlier. Currently, as treatment can be introduced at an early stage, we believe that PFS will improve further as the number of treated cases accumulates in the future and the proportion of cases immediately after approval decreases.
Not all patients with RR-DTC are immediate candidates for systemic anticancer therapy (10, 20) due to the slow progression of DTC. Only approximately one-third of patients with recurrent RR-DTC in a high-risk DTC group treated with RAI were ultimately transitioned to anticancer drug therapy (20). On the other hand, waiting until the tumor becomes too large before administering drugs has been reported to result in poor prognosis (21). In addition, in clinical practice, certain patients present with either contraindications to RAI or insufficient time to confirm RAIR-DTC due to rapid tumor progression. Masaki et al. reported a similar efficacy of lenvatinib in 19 patients with RR-DTC who did not meet the eligibility criteria for the SELECT trial (18). Additionally, Yan et al. found that patients without prior RAI exposure had a better prognosis following lenvatinib treatment compared to those who had received RAI (13). These findings, along with the results of our study, suggest that lenvatinib may be effective even in patients who are not candidates for RAI, underscoring its potential utility in real-world clinical settings.
Lenvatinib has also been one of the few treatment options for ATC with aggressive disease progression. Huang et al. reported a median PFS and OS of 3.16 months in 349 patients with ATC treated with lenvatinib (15). Although this meta-analysis demonstrated significant antitumor activity of lenvatinib, its clinical efficacy in ATC remains limited (15). Similarly, our study observed modest outcomes, with a median PFS of four months and a median OS of eight months. Fukuda et al. reported that the neutrophil-to-lymphocyte ratio may serve as a reference when introducing lenvatinib for ATC (22), suggesting that lenvatinib may only be effective in a limited subset of ATC cases. We therefore speculate that appropriate patient selection may ensure the efficacy of lenvatinib for ATC. Recently, BRAF/MEK inhibitors have shown promising efficacy in patients with ATC harboring BRAF mutations (23) and are recommended as the first-line treatment in current guidelines (10). Further accumulation of clinical data on patients with ATC treated with BRAF/MEK inhibitors is warranted to better define their role.
Current treatment options for TC include, in addition to mTKI such as lenvatinib and sorafenib, targeted therapies against BRAF, RET, and NTRK alterations (10, 24, 25). In the future, the number of patients in which lenvatinib salvage therapy is administered following the introduction of these agents–or conversely, cases in which patients switch from lenvatinib to other targeted therapies–is expected to increase. As such, the sequencing of anticancer therapies for TC will become an important area of clinical interest and research.
The limitations of this study include the small number of cases, short median observation period, and possibility that the evaluation of lenvatinib for DTC with a long prognosis may be insufficient. In the future, we plan to accumulate more cases, extend the observation period, and add additional considerations such as the transition to second-line drugs such as BRAF inhibitors.
Conclusion
RAI treatment after total resection is the optimal treatment for advanced DTC. However, there are cases in which this is not possible. Lenvatinib appears to be effective in real-world clinical settings for patients with DTC who are not candidates for RAI therapy. This study is one of the few to demonstrate lenvatinib’s potential efficacy in this specific population and contributes valuable insights into current real-world treatment practices.
Footnotes
Authors’ Contributions
Mioko Matsuo: Writing - original draft, Conceptualization. Mamoru Ito, Shogo Masuda, Kenji Tsuchihashi, Hirofumi Ohmura, Masanobu Sato: Data collection. Kazuki Hashimoto: Validation. Ryunosuke Kogo: Investigation. Takashi Nakagawa: Supervision.
Conflicts of Interest
The Authors declare no relevant conflicts of interest in relation to this study.
Funding
The publication costs of this study were supported by GlaxoSmithKline K.K. and the Ascent Development Services Foundation.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received June 16, 2025.
- Revision received July 8, 2025.
- Accepted July 11, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
