Excellent Objective Response to Lenvatinib in a Patient of Recurrent Radioiodine Refractory Poorly Differentiated Thyroid Carcinoma

Abstract

We herein present a patient of recurrent radioiodine refractory poorly differentiated thyroid carcinoma (PDTC) with excellent response to lenvatinib in recurrent setting. The patient was a known case of PDTC, operated for primary followed by local radiotherapy to the neck. The patient presented with recurrence at 8 years' follow-up with left-sided supraclavicular neck swelling and elevated serum thyroglobulin levels. Biopsy from the supraclavicular nodal mass demonstrated metastasis in known case of PDTC. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) done for disease extent evaluation, demonstrated two hypermetabolic large volume soft tissue density nodal masses in the left supraclavicular region and anterior mediastinum. The patient was administered lenvatinib with possible surgical intent as the disease was unresectable due to encasement of critical vessels (left common carotid artery). Four months into the therapy with lenvatinib, response evaluation ¹⁸F-FDG PET/CT showed excellent partial response, which lasted for a year, and the disease eventually progressed.

Keywords

[18F]FDG-PET/CT - lenvatinib - objective response - poorly differentiated thyroid carcinoma - radioiodine refractory

Introduction

Poorly differentiated thyroid carcinoma (PDTC) is a rare type of thyroid carcinoma with reported incidence ranging between 2 and 15%.[1] In 2004, the World Health Organization recognized it as a separate entity, intermediate between differentiated thyroid cancers (DTC) and undifferentiated anaplastic thyroid cancer.[2] Following the SELECT trial, lenvatinib was Food and Drug Administration (FDA)-approved in 2015 for the treatment of locally recurrent or metastatic DTC that has progressed despite radioiodine (RAI) therapy. We report one such case, in a 61-year-old man, of recurrent radioiodine-refractory PDTC showing excellent partial response to lenvatinib.

Case Report

A 61-year-old male, known case of PDTC with nodal metastasis, who underwent total thyroidectomy with nodal resection followed by local radiotherapy to the neck presented with left supraclavicular swelling and elevated stimulated serum thyroglobulin levels of 1038 ng/mL. Ultrasonography revealed ill-defined heterogeneous lesion with central calcifications measuring 3.3 × 2.6 cm in the left supraclavicular fossa closely abutting the left internal jugular vein and common carotid artery. Biopsy from the nodal mass was reported as metastatic carcinoma consistent with metastatic PDTC. Tissue next-generation sequencing report of the supraclavicular nodal mass revealed tier-1 pathogenic missense mutation in EXON 11 of BRAF gene.¹⁸F-fluorodeoxyglucose (FDG)- positron emission tomography (PET)/computed tomography (CT) as a part of evaluation of disease extent revealed two large hypermetabolic soft tissue density nodal masses in the left supraclavicular fossa (maximum standardized uptake value [SUVmax]: 14.82) and anterior mediastinum (SUVmax: 15.43) ([Fig. 1]).

Fig. 1 Maximum intensity projection (MIP) of [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan (A) done for disease extent evaluation showing intense uptake in the left supraclavicular and anterior mediastinal region (blue arrows). Second and 3rd column of images (B and C) represent the fused axial and coronal views (top to bottom) of the same demonstrating large left supraclavicular and anterior mediastinal nodal masses, respectively (yellow arrows). Fourth column represents MIP of [¹⁸F]-FDG PET/CT (D) done post-4 months of initiation of lenvatinib showing significant reduction in extent and intensity of metabolism in the left supraclavicular and anterior mediastinal region (green arrows). Fifth and 6th column of images (E and F) represent the fused axial and coronal sections (top to bottom) of the same, additionally showing significant reduction in size (white arrows).

In view of morphologically large volume disease, surgical resection was contemplated but as nodal mass in the supraclavicular region was encasing the left common carotid artery by more than 270 degrees, it was deemed unresectable. Thus, tyrosine kinase inhibitors (TKIs) were considered with neoadjuvant intent. After appropriate workup, patient was started on daily oral lenvatinib with a starting dose of 24 mg/day. He tolerated the dose of lenvatinib well with no adverse effects and continued therapy for 4 months. ¹⁸F-FDG-PET/CT scan done at the end of 4th month of initiation of TKI revealed significant interval reduction in size, extent, and metabolism of the nodal masses (SUVmax: 3.79 in supraclavicular and SUVmax: 4.96 in mediastinal mass) illustrating an excellent partial response to lenvatinib ([Fig. 1]). The patient was reassessed for surgery, but he opted out and decided to continue the TKI therapy. ¹⁸F-FDG PET/CT done at 4 monthly intervals showed stable disease with development of adverse effects (grade II mucositis, hand-foot skin syndrome [HFS], and sternocutaneous suture site dehiscence). Subsequently, dose was reduced to 18 mg/day and 4 months postreduction in dose, progression occurred with increase in number of mediastinal nodes and new-onset bilateral hilar nodes (SUVmax: 6.28) ([Fig. 2]).

Fig. 2 Maximum intensity projection (MIP) of [¹⁸F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in sequential order (left to right), pre-lenvatinib (A), 4 months after initiation (B) showing excellent partial response, 8 months after initiation (C) showing stable disease, and 12 months after initiation of lenvatinib (D) showing progression.

In view of RAI therapy naive status, he was additionally referred for RAI therapy. However, ¹³¹I-NaI scintigraphy showed no concentration of iodine in the lesions ([Fig. 3]), while serum-stimulated thyroglobulin was elevated, thus qualifying as radioiodine refractory (RAIR) disease. He was then started on cabozantinib, in view of progression on lenvatinib, on which he is presently symptom free and serum thyroglobulin is 0.45 ng/mL.

Fig. 3 Image set (left: anterior acquisition; right: posterior acquisition) of [¹³¹I]-NaI whole body planar scintigraphy showing no abnormal concentration of radioactive iodine (RAI).

Discussion

Oral TKIs have become an important line of treatment in RAIR-DTC and advanced thyroid cancers, which progress despite of RAI therapy and suppression therapy.[3] To date, seven drugs have been approved by the FDA for RAIR-DTC.[4] These include sorafenib, lenvatinib, and cabozantinib, which are not mutation specific, selpercatinib and pralsetinib for RET-fusion RAIR-DTC, and larotrectinib and entrectinib for NTRK fusion positive cancers. Lenvatinib is an oral multikinase inhibitor targeting vascular endothelial growth factor receptors 1–3 (VEGFR1–3), fibroblast growth factor receptors 1–4 (FGFR-1–4), RET, and platelet-derived growth factor receptor α (PDGFR-α). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effect.[5] Of the nonmutation-specific approved TKIs approved by the FDA in RAIR-DTC, lenvatinib is the most promising due to its broad-spectrum antitumor activity and requiring only a minimal inhibitory dose to arrest tumor growth. It also exhibits shorter time to response and high objective response rates (ORRs).[6]

It showed promising results in (SELECT) phase-3 randomized, double-blind, multicenter study involving 392 patients with progressive thyroid cancer refractory to iodine-131 showing a progression-free survival (PFS) of 18.3 months versus 3.6 months and response rate of 64.8% versus 1.5% with lenvatinib and placebo, respectively.[6] PDTC patients were also the part of the study (47 patients, 28 in the lenvatinib group and 19 in the placebo group). Subgroup analysis of those patients revealed a median PFS of 14.8 months with lenvatinib versus 2.1 months with placebo. The usual starting dose of 24 mg/day was used in our patient owing to his good performance status. Brose et al, in a phase 2 multicenter, randomized, double-blind study comparing lenvatinib starting dose of 24 mg versus 18 mg in RAIR-DTC, reported inferior ORR at 24 weeks in the 18 mg/day arm (40.3%) versus 24 mg/day arm (57.3%) with no significant difference in safety and adverse effect profile.[7]

Timely assessment of response is also a requirement for effective therapy with TKIs, thereby differentiating between responders versus nonresponders.¹⁸F- FDG PET/CT remains a standard tool for evaluation of disease extent and assessing response to TKIs in RAIR-DTC. Rendl et al demonstrated metabolic response assessed at 4 months after treatment initiation provides valid and distinctive long-term prognostic information.[8] Common adverse effects following lenvatinib include hypertension, diarrhea, fatigue or asthenia, decreased appetite, decreased weight, skin changes, proteinuria, and fistula formation, etc.[6] [9] In our case, the patient was doing well with no significant side effects for first 6 months, later developed grade II HFS, mucositis, and sternocutaneous fistula formation at the surgical suture site. Prompt reduction of dose to 18 mg/day was done and patient did well and response lasted for 4 months postreduction. Appropriate supportive care and identifying adverse effects and managing them avoid longer dose interruptions and increase the efficacy.[9]

A substudy from the SELECT trial assessing the duration of response (DOR) and PFS in responders versus nonresponders revealed a DOR of 30.0 months and prolonged PFS of 33.1 months in responders.[10] However, contrary to that in our patient PFS lasted for a period of approximately 12 months even after an excellent partial response. This might be due to the poorly differentiated status of thyroid carcinoma. Roque et al, in their case series of 8 PDTC patients treated with lenvatinib, showed a disease control rate of 100% with partial response and stable disease in 12.5% and 87.5%, respectively, and a median PFS of 12 months agreeing with our case.[11] In our case, the progression might be due to PDTC running its natural course and resistance to lenvatinib.[12] Gay et al reported a case of PDTC with tracheal invasion, judged eligible for total thyroidectomy but delayed due to pulmonary thromboembolism being treated with lenvatinib with a neoadjuvant intent showed slight reduction in lesion size.[13] Similarly, Katoh et al reported a case in which use of lenvatinib allowed surgical resection of a papillary thyroid cancer lesion initially judged inoperable due to common carotid artery (CCA) involvement.[14] To the best of our knowledge, very few data are available on the role of TKI in patients with PDTC/DTC in neoadjuvant setting with few phase II trials currently undergoing.[15] In our literature review on the use of lenvatinib in PDTC or in neoadjuvant setting, no complete responses were seen, instead reduction of summed maximum diameters of target lesion were seen ranging from 40 to 84%.[11] [13] [14] [16] Contrary to this, four patients (1.5%) in the SELECT trial have showed complete response lasting until follow-up period ranging from 84 to 124 weeks.[6] In our case, though primary intent was neoadjuvant lenvatinib followed by surgery for resection of nodal masses, the patient opted out from surgery and continued TKI therapy.

In our case, as progression ensued, in view of RAI-naive status, the option of RAI was explored which showed noniodine concentrating nature of the disease (RAIR). Given the poorly differentiated status, progression on lenvatinib and RAIR status, cabozantinib was chosen as second-line TKI based on the evidence from COSMIC 311 trial, which in previously treated RAIR-DTC patients (lenvatinib/sorafenib) demonstrated a PFS of 11 months versus 1.9 months and ORR of 11% versus 0% in the cabozantinib arm and placebo, respectively.[17]

Conclusion

In this study, we reported a case of recurrent RAIR-PDTC with large volume unresectable nodal disease showing excellent partial response to oral lenvatinib. Appropriate time of starting, optimal starting dose, risk assessment, early adverse effect identification, and appropriate management remain the corner stone of TKI therapy that helps to improve efficacy of treatment and the prognosis of patients.

Conflict of Interest

None declared.

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Publication History

Article published online:
09 June 2025