Published online May 24, 2026. doi: 10.5306/wjco.v17.i5.119615
Revised: March 6, 2026
Accepted: April 1, 2026
Published online: May 24, 2026
Processing time: 108 Days and 3.1 Hours
Treatment options for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) remain severely limited once resistance to first-line multikinase inhibitors, such as sorafenib, develops. Although the novel multikinase inhibitor anlotinib is approved for progressive RAIR-DTC, its combination with cytotoxic chemo
We report the case of a 56-year-old woman who presented with worsening re
Anlotinib combined with albumin-bound paclitaxel, followed by anlotinib maintenance, may represent a promising salvage strategy for sorafenib-refractory RAIR-DTC, which warrants further investigation in larger prospective trials.
Core Tip: Effective salvage treatments for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) following sorafenib failure remain severely limited. This case report presents an innovative combination and maintenance strategy. By employing anlotinib plus albumin-bound paclitaxel as induction therapy to potentially promote vascular normalization and enhance cytotoxic drug delivery, followed by anlotinib maintenance, a patient with metastatic RAIR-DTC achieved a confirmed partial response. With manageable toxicity and progression-free survival exceeding 38 months, this case suggests that the anlotinib-based regimen may provide durable disease control and warrants further prospective evaluation in patients who have exhausted first-line multikinase inhibitors.
- Citation: Zhou CY, Ren XY, Li HH, Pan XM, Lan X, Duan D. Anlotinib plus albumin-bound paclitaxel induction-maintenance for sorafenib-refractory radioiodine-refractory differentiated thyroid cancer: A case report and review of literature. World J Clin Oncol 2026; 17(5): 119615
- URL: https://www.wjgnet.com/2218-4333/full/v17/i5/119615.htm
- DOI: https://dx.doi.org/10.5306/wjco.v17.i5.119615
The global incidence of differentiated thyroid cancer (DTC) has increased markedly over recent decades, with 821214 new cases estimated in 2022, accounting for approximately 4.4% of all newly diagnosed malignancies worldwide[1-3]. Most patients with DTC have an excellent prognosis when treated with standard therapies, including surgery, radioactive iodine (RAI) ablation (131I), and thyroid-stimulating hormone (TSH) suppression, owing to the typically indolent biology of DTC and its unique ability to concentrate radioiodine. However, approximately 5%-15% of patients either present with or subsequently develop disease that loses the ability to adequately concentrate radioiodine or progresses despite appropriate 131I therapy, a condition termed radioiodine-refractory DTC (RAIR-DTC)[4]. Once RAIR status is established, tumors frequently prove resistant to conventional chemotherapy and external-beam radiotherapy, and prognosis deteriorates dramatically. The average survival duration for RAIR-DTC patients is typically 3 years to 5 years, with a 10-year survival rate of approximately 10%[5]. RAIR-DTC, therefore, represents a small but clinically critical subset of DTC and accounts for a disproportionate number of thyroid cancer-related deaths.
For patients with progressive RAIR-DTC, systemic therapy with multi-tyrosine kinase inhibitors (MKIs) has become the mainstay of treatment. Sorafenib and lenvatinib are approved first-line options and have demonstrated significant improvements in progression-free survival compared with placebo[6-8]. Nevertheless, the use of MKIs is hampered by off-target effects and treatmentrelated toxicity, often necessitating dose reduction or discontinuation[6]. In addition, most patients eventually develop acquired resistance within 1-2 years of therapy initiation[8], leaving few effective options in the post-MKI setting.
Anlotinib is an oral, multi-target tyrosine kinase inhibitor that selectively inhibits several receptors implicated in tumor angiogenesis and proliferation, including vascular endothelial growth factor receptors (VEGFR2/3), fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptors (PDGFRα/β), c-KIT, and rearranged during transfection (RET)[9-12]. It has shown sustained antitumor activity in various solid tumors, such as medullary thyroid carcinoma, soft tissue sarcoma, and lung cancer, and has been approved in China for advanced non-small cell lung cancer[9,11,12]. A multicenter, randomized phase II trial in RAIR-DTC demonstrated a significant prolongation of progression-free survival (PFS) and a high objective response rate with anlotinib compared with placebo, leading to its approval by the China National Medical Products Administration (NMPA) for progressive, locally advanced, or metastatic RAIR-DTC[13].
Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel that facilitates drug delivery to the tumor microenvironment via albumin-mediated transport, achieving higher intratumoral concentrations and enhanced antitumor activity compared with conventional solvent-based paclitaxel[14]. It has become an important component of treatment regimens for breast cancer, pancreatic cancer, and non-small cell lung cancer, with a favorable safety profile in clinical practice[14].
In parallel with advances in targeted therapy, combination strategies have gained increasing attention in oncology. Recent studies have highlighted the underlying mechanisms of tumor angiogenesis and the significance of targeted vascular interventions[15-17]. Preclinical and clinical studies have shown that anti-angiogenic agents can normalize aberrant tumor vasculature, reduce interstitial fluid pressure, and improve oxygenation, thereby enhancing the delivery and efficacy of concomitant chemotherapy[18,19]. Anlotinib-based combinations with chemotherapy have already demonstrated enhanced antitumor efficacy and acceptable toxicity in advanced ovarian cancer, triple-negative breast cancer, and non-small cell lung cancer[15,20,21].
To date, however, the efficacy and safety of combining anlotinib with chemotherapy followed by anlotinib maintenance have not been reported in RAIR-DTC, particularly after the failure of first-line MKI therapy. Here, we describe, to our knowledge, one of the first reported cases of metastatic RAIR-DTC that progressed on sorafenib and was subsequently treated with anlotinib plus albumin-bound paclitaxel followed by anlotinib maintenance, achieving durable disease control with acceptable toxicity. We also review the relevant literature to place this case in the context of current evidence.
A 56-year-old woman who presented with worsening respiratory symptoms due to progressive pulmonary metastases and recurrent pleural effusion. Worsening chest tightness, wheezing, and dyspnea over the past few months, 26 years after thyroid cancer surgery.
The patient was initially diagnosed with papillary thyroid carcinoma 26 years prior to the current admission. At that time, she underwent a subtotal thyroidectomy with central neck lymph node dissection. Postoperatively, she did not adhere to the recommended TSH suppression therapy and was lost to regular follow-up. In April 2017, she presented to our hospital with a persistent cough. A chest computed tomography scan revealed multiple nodular lesions in both lungs, and a bronchoscopic biopsy confirmed metastatic papillary thyroid carcinoma. A comprehensive timeline illustrating the subsequent clinical milestones, therapeutic interventions, and biochemical responses over the prolonged disease course is provided in Figure 1. A diagnostic RAI whole-body scan demonstrated residual thyroid tissue in the neck alongside metastatic lesions in the upper mediastinum, lungs, and pleura. Subsequently, she received three courses of RAI therapy with a cumulative dose of 510 mCi. Despite these sequential treatments, serial chest computed tomography scans revealed progressive enlargement of the pulmonary metastases, accompanied by diminishing radioiodine uptake and rising thyroglobulin (Tg) levels, which confirmed the diagnosis of RAIR-DTC (Figure 2). In May 2021, she was initiated on first-line targeted therapy with sorafenib. Although this provided temporary disease stabilization and a transient reduction in both the pleural effusion and Tg levels, she developed biochemical progression by December 2021. Clinically, she began experiencing worsening chest tightness, wheezing, and dyspnea. A follow-up computed to
The patient had a previous diagnosis of hypertension, with a maximum recorded blood pressure of 170 mmHg to 180 mmHg over 90 mmHg. Her blood pressure was well controlled with an oral regimen of levamlodipine 2.5 mg once daily and sacubitril/valsartan 100 mg twice daily. She was also on long-term levothyroxine replacement therapy at a dose of 125 mcg once daily. She explicitly denied any history of diabetes mellitus, chronic kidney disease, coronary heart disease, chronic liver diseases, or infectious diseases such as hepatitis and tuberculosis. Furthermore, she denied any history of significant physical trauma, blood transfusions, substance poisoning, recent relevant vaccinations, or any known food and drug allergies.
The patient had resided in her native hometown long-term and denied traveling to any pasturelands or known epidemic areas. She had absolutely no history of smoking, alcohol consumption, high-risk behaviors, or illicit drug use. Her family medical history was unremarkable, with no known familial genetic disorders or history of similar malignancies among her relatives.
Vital signs upon admission were completely stable. Examination of the neck, cardiovascular system, and abdomen was unremarkable, with no enlarged cervical lymph nodes detected. However, respiratory examination revealed diminished breath sounds over the right lower lung field, which was consistent with the subsequent imaging findings of a right pleural effusion. No other significant positive signs were observed.
Upon admission, relevant baseline laboratory evaluations were performed. Routine blood tests and routine urine tests were all within normal limits. Furthermore, comprehensive panels assessing blood biochemistry, immune indexes, and infection indexes revealed no clinically significant abnormalities. Specific tumor marker profiles confirmed the previously documented elevated Tg, while all other general laboratory parameters remained stable.
Upon admission, radiologic and ancillary evaluations were conducted to assess the extent of the disease. A plain chest computed tomography scan revealed a massive right pleural effusion alongside extensive tumor metastases involving both lungs and the right pleura. These metastatic lesions were also complicated by the presence of obstructive pneumonia in the right upper lung lobe. Furthermore, the scan demonstrated significant mediastinal lymphadenopathy. Conversely, additional baseline assessments, including an electrocardiogram and an abdominal ultrasound, were unremarkable and showed no clinically significant abnormalities.
Based on these findings that structurally progressive disease despite appropriate cumulative 131I therapy and diminishing radioiodine uptake, this patient met the criteria for radioiodinerefractory DTC as defined by contemporary international and national guidelines[22,23]. The final diagnosis for this patient was structurally progressive RAIR-DTC with pulmonary metastases.
In May 2021, systemic therapy with the multikinase inhibitor sorafenib was initiated as first-line targeted treatment for progressive RAIR-DTC. Following the initiation of sorafenib, the right pleural effusion and pulmonary metastases initially regressed, and serum Tg dropped to 43.23 ng/mL from a baseline of 65.27 ng/mL. However, by December 2021, Tg had risen to 52.50 ng/mL, indicating biochemical progression. Clinically, the patient developed worsening chest tightness, wheezing, and shortness of breath. A follow-up computed tomography (CT) scan in February 2022 revealed marked progression of bilateral pulmonary metastases and a substantial increase in the right pleural effusion compared to previous imaging (Figure 4). At that time, Tg had sharply increased to 106.28 ng/mL. Although sorafenib initially achieved temporary disease stabilization, the patient ultimately experienced progressive disease characterized by increasing tumor burden, pleural effusion, and rising Tg levels. Consequently, sorafenib was discontinued in February 2022. Given the clear radiologic and biochemical progression on sorafenib, the presence of symptomatic pleural effusion, and clinically significant hand-foot skin reaction, the overall clinical management strategy was adjusted. Considering the patient’s economic situation and the availability of domestic targeted agents, anlotinib was selected as the next-line multi-target tyrosine kinase inhibitor. To enhance antitumor efficacy and capitalize on potential vascular normalization, combination therapy with albumin-bound paclitaxel was also proposed. In February 2022, a new treatment cycle began, consisting of oral anlotinib (12 mg daily, 2 weeks on/1 week off) and intravenous albumin-bound paclitaxel (100 mg on days 1, 8, and 15 within the same 3-week schedule). The combination therapy was continued for an extended period due to sustained clinical benefit and acceptable tolerability. In September 2024, the nab-paclitaxel component of the combination regimen was discontinued after a total of six cycles, whereas the overall combination treatment had lasted for approximately 31 months. The discontinuation was primarily driven by the achievement of a deep and confirmed radiographic response, as well as the patient's preference to stop intravenous chemotherapy to improve quality of life and reduce the burden of hospital visits. Thereafter, anlotinib was continued as monotherapy for maintenance.
After approximately six weeks of treatment with anlotinib combined with albumin-bound paclitaxel, chest CT revealed a significant reduction in pulmonary inflammation and a notable decrease in the volume of the right pleural effusion compared to the pre-treatment scan (Figure 5A). The patient’s respiratory symptoms, including chest tightness and dyspnea, improved correspondingly.
At 41 weeks after treatment initiation, chest CT scans demonstrated a further reduction in bilateral pulmonary metastases and near-complete resolution of the pleural effusion (Figure 5B). According to RECIST v1.1 criteria, the patient was classified as having stable disease at this early assessment. With continued anlotinib-based therapy, the radiographic response progressively deepened over time. As summarized in Table 1, the sum of the diameters of the pulmonary target lesions surpassed the 30% reduction threshold at Week 112 (April 2024), meeting the criteria for a confirmed partial response (PR) per RECIST v1.1. The maximal tumor shrinkage reached 49.3% at the most recent follow-up in April 2025 (week 164), and the PR remained sustained following de-escalation to anlotinib monotherapy maintenance.
| Timepoint (date) | Lesion 1 (right lobe) (mm) | Lesion 2 (right lobe) (mm) | Sum of diameters (mm) | % change from baseline | Response evaluation |
| Baseline (February 2022) | 15.0 | 35.5 | 50.5 | 0 | - |
| Week 6 (April 2022) | 14.2 | 33.0 | 47.2 | -6.50 | SD |
| Week 17 (June 2022) | 13.5 | 32.0 | 45.5 | -9.90 | SD |
| Week 41 (December 2022) | 13.0 | 29.4 | 42.4 | -16.00 | SD |
| Week 56 (March 2023) | 12.4 | 27.2 | 39.6 | -21.60 | SD |
| Week 82 (September 2023) | 11.0 | 25.5 | 36.5 | -27.70 | SD |
| Week 112 (April 2024) | 10.2 | 22.6 | 32.8 | -35.00 | PR |
| Week 138 (October 2024) | 9.1 | 19.9 | 29.0 | -42.60 | PR |
| Week 164 (April 2025) | 8.0 | 17.6 | 25.6 | -49.30 | PR |
Radiographic assessments were conducted according to a clinically driven schedule. During the induction and early maintenance phases, chest CT scans were obtained at approximately 6-week to 12-week intervals. As disease control was sustained and the response deepened, the follow-up interval was extended to approximately every 6 months. At the most recent follow-up, the patient remained free of radiographic progression, and serum Tg levels had decreased to 31.89 ng/mL. Consequently, the patient has achieved a PFS of at least 38 months with the anlotinib-based regimen, with ongoing clinical benefit.
Adverse events were monitored through regular clinical and laboratory assessments throughout the treatment course. All toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Hypertension presented as a grade 3 event, necessitating the addition of a second antihypertensive agent in a patient with pre-existing, conventionally controlled hypertension. Blood pressure was successfully normalized with this optimized dual-antihypertensive regimen, allowing for the uninterrupted administration of full-dose anticancer treatment. Regarding hematologic toxicities, primarily observed during the nab-paclitaxel induction phase, the patient developed grade 2 leukopenia, grade 2 neutropenia, and grade 1 lymphopenia. These hematologic adverse events were transient and effectively managed with standard supportive care. Importantly, no severe (grade ≥ 3) adverse events occurred other than the aforementioned clinically managed hypertension, and there were no dose reductions, treatment interruptions, or delayed cycles for either agent during the induction or maintenance phases.
RAIR-DTC remains a therapeutic challenge because once refractoriness is established, additional RAI treatments rarely provide durable benefits, and progressive disease often necessitates systemic therapy. In progressive RAIR-DTC, systemic treatment with MKIs such as sorafenib and lenvatinib has improved PFS in randomized trials. However, clinical benefits are frequently limited by treatment-related toxicity and acquired resistance[6-8]. Consequently, management after progression on first-line MKI therapy represents a common and clinically significant unmet need.
RAIR-DTC is defined by either the absence of RAI avidity in all known lesions or structural/biochemical progression within one year after RAI therapy despite persistent RAI avidity, after excluding inadequate TSH stimulation and other confounding factors[22]. In the present case, progressive enlargement of pulmonary metastases on serial CT scans, rising serum Tg levels, and diminishing RAI uptake on post-therapy scans collectively fulfilled the criteria for RAIR-DTC and justified transitioning from RAI-based management to systemic therapy. Based on this diagnosis, sorafenib was initiated as first-line systemic therapy.
Sorafenib initially achieved clinical and radiologic stabilization, including transient regression of pleural effusion and a short-lived decline in Tg, consistent with its known ability to slow disease progression in RAIR-DTC. However, the patient subsequently experienced clinically significant progression characterized by diffuse pulmonary metastases, recurrent symptomatic pleural effusion, rising Tg levels, and worsening respiratory symptoms, accompanied by a treatment-limiting hand-foot skin reaction. According to current guideline recommendations, systemic therapy is indicated for patients with RAIR-DTC who present with symptomatic, rapidly progressive, or high-burden metastatic disease. Therefore, an urgent change in therapy was necessary to achieve rapid disease control and symptom relief.
While lenvatinib is often considered for high-burden progressive disease due to its high objective response rate, real-world drug accessibility and patient-specific factors can influence treatment selection. In April 2022, the Chinese NMPA officially approved anlotinib for the treatment of inoperable, iodine-refractory, locally advanced, or metastatic DTC. After a multidisciplinary discussion, anlotinib was selected as an evidence-supported and locally accessible multi-target antiangiogenic tyrosine kinase inhibitor. It was combined with albumin-bound paclitaxel as an induction and cytoreductive agent in the context of high-burden symptomatic pulmonary disease. In this case, the combination phase was extended due to sustained benefit and acceptable tolerability, followed by de-escalation to anlotinib monotherapy maintenance.
Anlotinib is an oral multi-target tyrosine kinase inhibitor that potently inhibits VEGFR2/3, FGFR1-4, PDGFRα/β,
Beyond switching targeted therapies, we combined anlotinib with albumin-bound paclitaxel because the patient had a high pulmonary tumor burden and symptomatic pleural effusion that required prompt disease control. It is important to acknowledge that DTC is generally considered relatively insensitive to cytotoxic chemotherapy, and guidelines typically reserve chemotherapy for palliative scenarios when other systemic options are not applicable[22]. Nevertheless, in this patient, the combination strategy produced rapid clinical improvement, including regression of pleural effusion and relief of dyspnea. Importantly, serial target-lesion measurements documented a deepening radiographic response over long-term follow-up. As detailed in Table 1, the patient achieved a confirmed PR by RECIST v1.1 starting at week 112, which further deepened and remained sustained through the latest follow-up at week 164. Concurrently, serum Tg levels measured under TSH suppression declined from 106.28 ng/mL at sorafenib progression to 31.89 ng/mL during anlotinib-based therapy, supporting a consistent biochemical response accompanying durable radiographic benefit.
The vascular normalization hypothesis offers a biologically plausible framework for this combined therapeutic approach. Beyond its direct antiproliferative effects, anlotinib can remodel aberrant tumor vasculature, resulting in “vascular normalization” characterized by decreased vessel density, improved perfusion, and reduced vascular permeability[16,17,21]. Preclinical studies indicate that such vascular normalization enhances the intratumoral delivery of concurrently administered chemotherapeutic agents, increases intratumoral drug concentrations, improves antitumor efficacy, and may delay or overcome drug resistance[18,33]. Consistent with this concept, early clinical studies have demonstrated that combining anlotinib with cytotoxic agents such as docetaxel or platinum-based regimens yields higher response rates and longer PFS than chemotherapy alone in advanced non-small cell lung cancer and other solid tumors, without unexpected safety signals[15,19,20,34]. Although the individual contributions of albumin-bound paclitaxel vs anlotinib alone cannot be definitively separated in a single case, the rapid early response and subsequent durable control during maintenance suggest a synergistic interaction between anti-angiogenic therapy and chemotherapy in this context.
Long-term tolerability is essential for maintenance therapy. In our patient, the primary adverse event was hypertension, which was anticipated given her baseline history and was effectively controlled by adjusting antihypertensive medications without interrupting anlotinib. Mild myelosuppression occurred during the chemotherapy phase and was managed with supportive care. No adverse events required hospitalization or permanent discontinuation. Overall, the tolerability observed in this case aligns with previous trials and real-world studies reporting a favorable safety profile for anlotinib in advanced cancers, with common toxicities being manageable through close monitoring and timely intervention[13,30].
Several limitations should be acknowledged. First, due to the complexity of individual cases, we were unable to quantify the respective contributions of combination chemotherapy and anlotinib maintenance therapy to the overall efficacy. Additionally, key parameters such as optimal dosing regimens and cycle durations for both the combination phase and subsequent maintenance therapy remain to be further defined through prospective studies. Second, the patient, constrained by financial limitations, was unable to undergo systematic molecular testing (including key genes such as BRAF, TERT, RET, and NTRK) and fluorodeoxyglucose positron emission tomography/CT metabolic assessment. This resulted in a lack of molecular profiling and tumor metabolic dynamic data to guide precision therapy, thereby limiting in-depth analysis of underlying therapeutic mechanisms and predictive factors of efficacy. Larger prospective studies are needed to clarify patient selection, optimize induction and maintenance schedules, and validate integrated structural, biochemical, and molecular imaging endpoints. These limitations indicate that the observed clinical benefits in this case require validation in prospective studies with greater sample sizes.
Despite these limitations, this case contributes to the growing evidence that anlotinib is an effective and tolerable agent in RAIR-DTC. It also suggests that rational combinations with chemotherapy, followed by maintenance therapy, may provide a viable option for patients after first-line MKI failure, especially when other approved options are inaccessible or unsuitable.
In summary, this case suggests that an anlotinib-based combination regimen with albumin-bound paclitaxel, followed by anlotinib monotherapy maintenance, may represent a potential and feasible salvage strategy with manageable toxicity for sorafenib-refractory metastatic RAIR-DTC. Given the single-patient nature of this evidence, the durable radiographic and biochemical responses observed in this case warrant further investigation in larger prospective clinical trials to validate efficacy and optimize treatment protocols.
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