Efficacy and safety of anlotinib combined with chemotherapy plus anlotinib maintenance in Radioiodine-refractory differentiated thyroid cancer: a case report and literature review

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Case Report

Efficacy and safety of anlotinib combined with chemotherapy plus anlotinib maintenance in Radioiodine-refractory differentiated thyroid cancer: a case report and literature review

https://doi.org/10.21203/rs.3.rs-5232411/v1

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Background: Radioiodine-refractory differentiated thyroid cancer is one of the leading causes of mortality among patients with thyroid cancer, presenting significant clinical challenges in both diagnosis and management. In addition to sorafenib and levatinib, China's self-developed tyrosine kinase inhibitor, anlotinib, has been approved by the national medical products administration for the treatment of progressive, locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer. Despite the potential of single-agent therapy to improve treatment efficacy, the management of patients with advanced radioiodine-refractory differentiated thyroid cancer who have exhausted first- and second-line treatments remains a considerable challenge, with limited chances of achieving satisfactory outcomes. Recent research has shown that anlotinib combined with chemotherapy has an enhanced antitumor efficacy and a tolerable safety profile in patients with triple-negative breast cancer and advanced ovarian cancer. However, the efficacy and safety of anlotinib with chemotherapy for radioiodine-refractory differentiated thyroid cancer have not been reported in the literature.

Case presentation: Here, we present a case of metastatic radioiodine-refractory differentiated thyroid cancer that was treated with a combination of anlotinib and chemotherapy, along with anlotinib maintenance therapy after the failure of sorafenib treatment, resulting in favorable outcomes.

Conclusions: The combination of anlotinib and chemotherapy, followed by anlotinib maintenance, showed promising efficacy and manageable toxicity in the treatment of advanced radioiodine-refractory differentiated thyroid cancer.

radioiodine-refractory differentiated thyroid cancer

anlotinib

chemotherapy

The incidence of differentiated thyroid cancer (DTC) has exhibited an exponential growth in recent decades^[1,2]. In 2020, 586,202 new cases were reported globally, accounting for 3.0% of all malignancies^[3]. Most patients with DTC have a favorable prognosis after undergoing standard treatments including surgery, radioactive iodine therapy, and thyroid-stimulating hormone suppression therapy^[4]. This favorable outlook is due to the low invasiveness of DTC and its unique ability to accumulate significant doses of radioactive iodine. However, a subset of patients, approximately 5% to 23%, might show or gradually develop non-iodine uptake or insensitivity to radioactive iodine in the natural progression of the disease or during treatment, a condition known as radioiodine-refractory differentiated thyroid cancer(RAIR-DTC)^[5]. RAIR-DTC exhibits insensitivity to conventional radiotherapy and chemotherapy, thereby resulting in a significantly shorter survival when compared to iodine-responsive DTC patients. The average survival duration for RAIR-DTC patients is typically 3 to 5 years, with a 10-year survival rate of approximately 10%. It represents a primary cause of mortality among thyroid cancer and presents significant clinical challenges in terms of both diagnosis and treatment. This condition is a major cause of death in thyroid cancer and poses significant clinical difficulties in diagnosis and treatment.

Currently, two multi-tyrosine kinase inhibitors (MKIs), sorafenib and lenvatinib, have received approval from the China national medical products administration for first-line systemic treatment of patients with progressive RAIR-DTC^[6]. While sorafenib has shown efficacy in improving progression-free survival in RAIR-DTC, drug-induced adverse reactions are prevalent at standard doses of MKIs, potentially diminishing the quality of life for patients and even leading to the termination of MKI therapy^[7]. Furthermore, a significant proportion of RAIR-DTC patients may develop resistance to MKIs within 1 to 2 years after initiating treatment^[8].

Anlotinib is an oral multi-target tyrosine kinase inhibitor (TKI). It selectively targets multiple receptor kinases associated with tumor proliferation and the tumor microenvironment, such as vascular endothelial growth factor receptors 2 and 3, fibroblast growth factor receptors 1 to 4, platelet-derived growth factor receptors α and β, c-Kit, and Ret. It has shown persistent anti-tumor activity in various solid tumors, like medullary thyroid cancer, soft tissue sarcoma, and lung cancer ^[9-12]. Based on outcomes from a multicenter, randomized, phase II clinical trial^[13], anlotinib has achieved landmark success in treating RAIR-DTC, leading to its approval by the China national medical products administration for progressive, locally advanced, or metastatic RAIR-DTC. Albumin-bound paclitaxel is a novel taxane chemotherapeutic agent. Compared to solvent-based paclitaxel, it effectively reaches the tumor microenvironment and shows a higher affinity for cancer cells, thereby significantly improving therapeutic efficacy. It is commonly utilized in the treatment of breast cancer, pancreatic cancer and non-small cell lung cancer, and has demonstrated good safety and fewer adverse reactions in clinical applications^[14]. Despite the potential of single-agent therapy in enhancing treatment efficacy, the management of advanced RAIR-DTC patients who have exhausted first-and second-line treatments remains a significant challenge, with limited prospects of achieving satisfactory results. In the ever-changing realm of biomedical science, combination therapy has attracted increasing attention in clinical oncology. Recent research has indicated that the combination of anlotinib and chemotherapy demonstrates enhanced antitumor efficacy and a manageable safety profile in patients with advanced ovarian cancer and triple-negative breast cancer ^[15-16]. However, the effectiveness and safety of anlotinib in combined with chemotherapy for RAIR-DTC are still unknown.

Here, we report a case of metastatic RAIR-DTC. After the failure of sorafenib treatment, this case received combination therapy consisting of anlotinib and chemotherapy, followed by maintenance treatment with anlotinib, and achieved satisfactory outcomes. To our knowledge, this case is the first report of the successful application of anlotinib combined with chemotherapy and subsequent anlotinib maintenance therapy post-sorafenib failure in metastatic RAIR-DTC.

Treatment before anlotinib

A 56-year-old woman was initially diagnosed with a malignant thyroid tumor at our institution twenty-seven years ago. She underwent subtotal thyroidectomy and central neck lymph node dissection, with pathological examination confirming papillary thyroid carcinoma. Following surgery, the patient did not adhere to the recommended TSH suppression therapy and failed to attend regular follow-up appointments.

In April 2017, the patient was readmitted due to a persistent cough. CT revealed multiple metastatic lesions in both lungs. Fibrobronchoscopy confirmed these pulmonary nodules as metastatic thyroid papillary carcinoma. Iodine-131 whole-body imaging demonstrated residual thyroid tissue in the neck and metastatic thyroid carcinoma in the superior mediastinum, lungs, and subpleura. The patient underwent three courses of radioiodine therapy in May 2017, November 2017, and August 2018, respectively. Subsequent whole-body imaging indicated no residual thyroid tissue in the neck but persistent metastases in the left subclavian lymph nodes and lungs (refer to Figures 1A, 1B, and 1C).

Even after three course of radioiodine treatments, the metastases in the patient's lungs continued to grow and spread further (refer to Figures 2). Thirty three months after the third course of radioiodine therapy, the patient was readmitted to our facility due to complaints of chest and back pain accompanied by coughing. CT scans indicated widespread tumor metastasis throughout the lungs, complicated by obstructive pneumonia in the right upper lobe and right-sided pleural effusion (refer to Figures 3). As a result, she was diagnosed with RAIR-DTC and initiated targeted therapy with sorafenib starting in May 2021.

Following treatment initiation, there was a gradual reduction in the patient's right pleural effusion and lung metastases, concomitant with a decline in thyroglobulin levels from 65.27 to 43.23 ng/mL. However, Tg levels in December 2021 indicated disease progression(from 43.23 to 52.50 ng/mL). Throughout treatment, the patient increasingly experienced symptoms such as chest tightness, wheezing, and dyspnea. Subsequent CT imaging in February 2022 showed an escalation in both the number and size of metastatic lung lesions compared to previous assessments, with a notable increase in right-sided pleural effusion (refer to Figures 4), at which point the patient's Tg level increased significantly (106.28ng/mL). Despite initially demonstrating disease stabilization upon initiation of the first-line MKI therapy, the patient experienced progressive disease (PD) and discontinued the first-line MKI treatment in February 2022.

Anlotinib combined with chemotherapy plus anlotinib maintenance therapy

Considering the obvious hand-foot reaction and poor efficacy of sorafenib, combined with the patient's economic situation, after a multidisciplinary team consultation, it was decided to replace the targeted drug with domestic anlotinib and give albumin-paclitaxel chemotherapy at the same time. TThis protocol includes anlotinib (12 mg daily, administered for two weeks followed by a one-week interval) in conjunction with chemotherapy utilizing albumin-bound paclitaxel (100 mg on days 1, 8, and 15 of a 21-day cycle), augmented by maintenance therapy with anlotinib. The patient commenced this new treatment regimen on February 23, 2022.

Efficacy

After 6 weeks of treatment, CT scans showed that the patient's lungs had significantly less inflammation and pleural effusion than before treatment (refer to Figure 5A).After 41 weeks of treatment, CT scans showed that the patient's lung inflammation and pleural effusion were further reduced, and the lung metastases were also reduced. The maximum cross-sectional area decreased from 1.5×1.3 cm to 1.3×1.2 cm, with the Tg level dropped to 36.26ng/mL. According to the response evaluation criteria in solid tumors (RECIST) version 1.1, it indicated a partial response (PR). As of the manuscript preparation, the patient has received 30 months of anlotinib combined with chemotherapy plus anlotinib maintenance therapy. Currently, the patient exhibits favorable outcomes across all monitored parameters, with a thyroglobulin level of 31.89ng/mL at the most recent review.

Adverse effect

A review approximately 30 months after treatment showed that the patient had a good quality of life with no significant adverse effects. The only adverse event observed during anlotinib treatment was hypertension, which was controlled smoothly with regular oral antihypertensive medication. Interestingly, the patient had been diagnosed with high blood pressure 20 years earlier. Therefore, we strongly believe that anlotinib is a safe treatment option for this patient.

Angiogenesis is a vital process in the formation and progression of thyroid cancer, where overexpression of vascular endothelial growth (VEGF) and vascular endothelial growth factor (VEGFR) is commonly observed in cancerous thyroid cells. Consequently, mTKIs are utilized for clinically targeted therapy of thyroid cancer. The China NMPA has approved sorafenib and lenvatinib for use as first-line systemic treatments in patients with progressive RAIR-DTC. However, adverse drug reactions and drug resistance restrict their clinical utility to some extent. In our case, we presented a woman with RAIR-DTC who initially received sorafenib treatment upon diagnosis. The initial course of sorafenib therapy led to disease stabilization, however, the patient experienced progressive lung metastases several months post-treatment initiation. Previous studies have indicated that anlotinib exhibits stronger anti-angiogenic activity compared to sorafenib^[17]. After a multidisciplinary team discussion, the patient was enrolled in an anlotinib treatment regimen on February 23, 2022.

Anlotinib can inhibit tumor angiogenesis, growth, invasion, lymphangiogenesis, and spread of lymphatic metastasis^[18-20], and has been shown to be effective against a variety of solid tumors^[21-26]. In 2018, it was approved by the China NMPA as a new third-line treatment option for advanced non-small cell lung cancer ^[27]. In addition, the selectivity of anlotinib for inhibiting the VEGF receptor-2 is over twenty times that of other anti-VEGF medications^[27], making it more effective in anti-tumor activity at the same concentration compared to other anti-VEGF receptor TKIs. In April 2022, the Chinese NMPA officially approved anlotinib for the treatment of inoperable, iodine-refractory, locally advanced or metastatic DTC.

Preclinical research indicates that anlotinib significantly suppresses the viability of PTC and anaplastic thyroid cancer (ATC) cells, primarily by inducing G2/M cell cycle arrest and upregulating TP53 expression. It suppresses thyroid cancer cell migration in vitro and restrains the growth of xenograft thyroid tumors in mice, thus exerting an anti-tumor effect^[28]. Clinical studies have indicated that anlotinib can induce objective responses and prolong PFS of advanced thyroid cancer. A Phase II trialhas confirmed anlotinib's sustained anti-tumor effect in patients with locally advanced or metastatic medullary thyroid cancer, with a PFS rate of 85.5% at 48-week ^[12]. In a multicenter Phase IIB trial ^[29], anlotinib demonstrated efficacy and safety in 91 Asian patients with unresectable medullary thyroid carcinoma, achieving an objective response rate (ORR) of 48.4% and significantly extending PFS (20.7 vs. 11.1 months, P = 0.029). Additionally, anlotinib in combination with the PD-1 inhibitor sintilimab has shown promising results in ATC patients, with significant tumor reduction and a sustained remission period of 18.3 months^[30]. In RAIR-DTC, a Phase II trial ^[13] revealed a substantial PFS extension for the anlotinib group (40.5 vs. 8.4 months, p < 0.001) and an ORR of 59.21%. Notably, a patient with recurrent and metastatic RAIR-DTC exhibited over 37 months of PFS, carrying both TERT promoter C228T and BRAF V600E mutations^[31]. Anlotinib's potential in neoadjuvant settings was also explored, with a Phase II trial ^[32]reporting an ORR of 76.9% in the neoadjuvant treatment of locally advanced thyroid cancer.

Targeted therapies have significantly enhanced the treatment outcomes for thyroid cancer, yet challenges such as "off-target effects", intolerance to toxic side effects, and resistance remain. Research indicates that anti-angiogenic agents can induce normalization of tumor vasculature, thereby enhancing blood perfusion and drug delivery, and subsequently augmenting the efficacy of chemotherapy^[33-35]. In the treatment of other tumor types, the addition of chemotherapy drugs has been shown to enhance the effects of targeted therapies. Specifically, in the treatment of Her-2-positive advanced breast cancer, the combination of paclitaxel with anti-Her-2 targeted drugs has emerged as a standard therapeutic approach. Thyroid cancer, traditionally insensitive to chemotherapy alone, has shown improved outcomes with the concurrent use of chemotherapy and targeted therapy, which also allows for reduced chemotherapy dosages and diminished toxic side effects. Anlotinib-based chemotherapy regimens have exhibited promising efficacy and tolerability in locally advanced or metastatic ATC^[36]. Adopting a 'targeted therapy plus chemotherapy' approach for the case. The initial six months of combination therapy with anlotinib and albumin-bound paclitaxel effectively controlled the disease, stabilizing structural lesions and biochemical thyroglobulin levels. At the 12-month evaluation, a partial response was achieved per RECIST 1.1 criteria. Ongoing treatment indicates lesion size reduction, suggesting anlotinib's efficacy in stabilizing RAIR-DTC, particularly in patients with suboptimal responses to sorafenib.

For combination treatment regimens, safety and therapeutic tolerance are paramount. A comprehensive systematic review of clinical studies evaluating the safety and adverse event management of anlotinib in oncology treatment concluded that anlotinib's toxicity is acceptable or manageable, both in clinical trials and in real-world cases involving advanced cancer patients^[37]. Furthermore, research indicates that maintenance therapy with anlotinib following chemotherapy and anlotinib combination treatment yields favorable outcomes for patients with advanced or metastatic soft tissue sarcoma, extending survival and demonstrating good tolerability^[38]. In the present case, the primary adverse reactions observed were mild myelosuppression associated with chemotherapy and hypertension related to anti-angiogenic therapy. However, through appropriate management, the patient's myelosuppression was mitigated, and hypertension was effectively controlled. This indicate that the combination of anlotinib with albumin-bound paclitaxel does not elevate the risk of serious toxicity, and the treatment's safety profile is manageable. Nevertheless, there is a dearth of randomized, prospective clinical trials exploring the combination of anlotinib with chemotherapy for RAIR-DTC. The findings of this case report require further validation in a larger cohort of patients, with particular emphasis on the safety of the combined treatment approach.

We report a case of a metastatic RAIR-DTC patient who, after developing resistance to sorafenib, underwent combination therapy with anlotinib and albumin-bound paclitaxel. This treatment led to an extended PFS and significant tumor control. The safety profile of this regimen was favorable, with manageable adverse drug reactions and good patient compliance noted during treatment. As far as we know, this is the first case report employing this combination treatment approach for RAIR-DTC patients resistant to sorafenib. While the sample size is limited, combining anlotinib with chemotherapy might provide an additional therapeutic option for patients. Future clinical trials are expected to verify the efficacy of this novel treatment approach in RAIR-DTC patients.

DTC Differentiated thyroid cancer

RAIR-DTC Radioiodine-refractory differentiated thyroid cancer

ATC Anaplastic thyroid cancer

MKIs Multi-tyrosine kinase inhibitors

TKI Tyrosine kinase inhibitor

RECIST Response evaluation criteria in solid tumors

VEGF Vascular endothelial growth

VEGFR Vascular endothelial growth factor

Acknowledgements

Not applicable.

Authors’ contributions

CZ participate in the manuscript writing. HL, XL, XP and FS participate in the data collection. DD participate in the final editing of the approval. All authors read and approved the fnal manuscript.

Funding

Natural Science Foundation of Chongqing, China (CSTB2023NSCQ-MSX0678) provided the fnancial support for language editing and publication.

Availability of data and materials

All data supporting our findings are contained within the manuscript.

Ethics approval and consent to participate

Not applicable.

Clinical trial number

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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Efficacy and safety of anlotinib combined with chemotherapy plus anlotinib maintenance in Radioiodine-refractory differentiated thyroid cancer: a case report and literature review

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