lenvatinib and Adenocarcinoma--Follicular

Lenvatinib is a multikinase inhibitor used for treating unresectable or metastatic cancers, including thyroid cancer. As total thyroidectomy followed by radioactive iodine therapy is a commonly recommended initial treatment for thyroid cancer, histological findings of the thyroid after lenvatinib therapy remain unclear. Therefore, the aim of this study was to analyse in-vivo changes in patients who underwent thyroidectomy after lenvatinib therapy.. We screened 167 patients with thyroid cancer [papillary thyroid cancer (PTC), n = 102; follicular thyroid cancer (FTC), n = 26; anaplastic thyroid cancer (ATC), n = 39] who underwent lenvatinib therapy. Among these patients, six underwent thyroidectomy (lenvatinib-treated group: PTC, n = 3; FTC, n = 1; ATC, n = 2), and the specimens were examined. Five patients with PTC who did not receive lenvatinib therapy were included for comparison (untreated group). Microvessel density (MVD) was evaluated in both groups. The PTC and FTC specimens showed relatively more ischaemic changes than ATC specimens. Coagulative necrosis and ischaemic changes in cancer cells were frequently observed. ATC specimens showed fibrosis and mild cell damage. As hypothyroidism is a common side effect of lenvatinib therapy, non-cancerous thyroid tissues were also examined. Histological findings included mild lymphocytic infiltration, lymphoid follicular formation, histiocytic reaction and follicular epithelial destruction. The MVD in lenvatinib-treated tissues was significantly lower than that in untreated tissues.. Lenvatinib therapy probably induces relatively specific ischaemic changes in thyroid cancer cells. Moreover, inflammatory cell infiltration and decreased MVD occur to varying degrees in non-cancerous thyroid tissue and may be related to hypothyroidism, a side effect of lenvatinib.

Topics: Adenocarcinoma, Follicular; Humans; Iodine Radioisotopes; Phenylurea Compounds; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Patients with advanced differentiated thyroid cancer develop resistance to lenvatinib treatment from metabolic dysregulation. Heat shock protein 90 is a molecular chaperone that plays an important role in glycolysis and metabolic pathway regulation. We hypothesize that lenvatinib-resistant differentiated thyroid cancer cells will have an increased dependency on glycolysis and that a novel C-terminal heat shock protein 90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis.. Inhibitory concentration 50 values of thyroid cancer cells were determined by CellTiter-Glo assay (Promega Corp, Madison, WI). Glycolysis was measured through Seahorse experiments. Reverse transcription-polymerase chain reaction and Western blot evaluated glycolytic pathway genes/proteins. Exosomes were isolated/validated by nanoparticle tracking analysis and Western blot. Differentially expressed long non-coding ribonucleic acids in exosomes and cells were evaluated using quantitative polymerase chain reaction.. Extracellular acidification rate demonstrated >2-fold upregulation of glycolysis in lenvatinib-resistant cells versus parent cells and was downregulated after KU757 treatment. Lenvatinib-resistant cells showed increased expression of the glycolytic genes lactic acid dehydrogenase, pyruvate kinase M1/2, and hexokinase 2. KU757 treatment resulted in downregulation of these genes and proteins. Several long non-coding ribonucleic acids associated with glycolysis were significantly upregulated in WRO-lenvatinib-resistant cells and exosomes and downregulated after KU757 treatment.. Lenvatinib resistance leads to increased glycolysis, and KU757 effectively treats lenvatinib-resistant cells and overcomes this increased glycolysis by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids.

Topics: Adenocarcinoma, Follicular; Aminocoumarins; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Glycolysis; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Phenylurea Compounds; Quinolines; Thyroid Epithelial Cells; Thyroid Neoplasms

18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ([18F]-FDG-PET/CT)-positive metastatic lesions in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have a poor prognosis and lenvatinib represents the best therapy.. We investigated the role of [18F]-FDG-PET/CT in the evaluation of metabolic response and prediction of the outcome of RAI-R DTC patients treated with lenvatinib.. Patients (n = 33) with progressive metastatic RAI-R DTC who were treated with lenvatinib were investigated at baseline and during follow-up with biochemical (thyroglobulin and thyroglobulin antibodies), morphological (whole-body CT scan) and metabolic ([18F]-FDG-PET/CT) evaluation.. Nineteen (57.6%) patients showed the greatest metabolic response at the first [18F]-FDG-PET/CT scan, performed after 4 weeks of lenvatinib, while 5/33 (15.1%) patients had this response later. Moreover, 66.7% of patients had both a metabolic response at the first [18F]-FDG-PET/CT scan and a morphological response at the first CT scan. We observed a correlation between the metabolic response at [18F]-FDG-PET/CT scan performed after 4 weeks of treatment and the biochemical response at the same time in 60.6% of patients. The median overall survival (OS) was significantly longer in patients with either a metabolic response at last [18F]-FDG-PET/CT (40.00 vs 8.98 months) or a morphological response at last CT scan (37.22 vs 9.53 months) than in those without response. Moreover, the OS was longer in patients with a metabolic response at [18F]-FDG-PET/CT performed after 4 weeks of treatment (36.53 vs 11.28 months).. Our data show that [18F]-FDG-PET/CT can early predict the response to lenvatinib and correlates with the OS of RAI-R DTC patients treated with this drug.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Antineoplastic Agents; Female; Fluorodeoxyglucose F18; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Positron Emission Tomography Computed Tomography; Quinolines; Survival Rate; Thyroid Neoplasms; Tomography, X-Ray Computed; Treatment Outcome; Whole Body Imaging

Topics: Adenocarcinoma, Follicular; Antibodies, Monoclonal; Antineoplastic Agents; Autoantibodies; Female; Graves Disease; Graves Ophthalmopathy; Humans; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Middle Aged; Phenylurea Compounds; Quinolines; Radiopharmaceuticals; Receptors, Thyrotropin; Thyroid Neoplasms; Treatment Outcome

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Retreatment; Retrospective Studies; Survival Rate; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Topics: Adenocarcinoma, Follicular; Aged; Calcium; Female; Humans; Hypocalcemia; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

This case report describes an elderly patient with radioiodine-resistant differentiated thyroid cancer and additional multiple metastases living in a rural setting, remote from the specialist oncology service. This case is of interest because effective systemic therapies for treatment-resistant cancers, such as lenvatinib, are now available but can potentially cause significant toxicities that require extensive medical management. Here, we discuss how patient care was provided collaboratively by the local community teams integrated with remote specialist oncology services. A 77-year-old patient presented with symptoms of cauda equina secondary to a large metastatic sacral deposit. The deposit was biopsied, and histology revealed a diagnosis of differentiated follicular thyroid cancer that was treated with external beam radiotherapy and thyroidectomy, followed by radioiodine. However, the disease was found to be resistant to radioiodine therapy, and the patient subsequently developed back pain due to new bone metastases. After further palliative external beam radiotherapy, the patient was started on systemic treatment with lenvatinib. Treatment has continued for more than 2.5 years with a slow but steady improvement in symptoms and quality of life. Monitoring and assessment of lenvatinib therapy and management of associated toxicities was coordinated remotely from a specialist cancer center over 200 miles away, using the skills of the local medical and nursing teams. This case report demonstrates how a cooperative effort using local teams and video-conferencing links to a specialist cancer center can be applied to safely treat a patient with a medication that may result in significant potential toxicities that require attentive and dynamic management.

Topics: Adenocarcinoma, Follicular; Aged; Antineoplastic Agents; Bone Neoplasms; Disease Management; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Prognosis; Quinolines; Radiation Tolerance; Remote Consultation; Thyroid Neoplasms

The aim of this study is to describe our clinical experience with tyrosine kinase inhibitors (TKIs) and to evaluate their efficacy and tolerability in patients with iodine-refractory differentiated thyroid cancer (DTC).. There were 17 patients (47.1% women, mean age: 65.7) with DTC iodine-refractory (9 papillary, 2 follicular and 3 Hürthle cell), treated with TKIs: 16 with sorafenib and 1 with lenvatinib as first-line treatment; 7 required second-line treatment (4 lenvatinib and 3 axitinib). Primary endpoints were progression-free survival (PFS) and radiographic response (determinate at 3, 6, 12, 18, and 24 months after the initiation of treatment) and second endpoints were determining differences in baseline characteristics depending on clinical course and describing toxicities and tolerability.. Median PFS was 18 months. During the first 24 months of treatment with TKIs PR rate was 35.3% (only 5.8% ≥ 6 months) and SD ≥ 6 months was observed in 58.8%. There were no significant differences in baseline characteristics between patients with good and poor evolution. Adverse events (AEs) were present in 100% of patients, but most of them were grade 1 and 2.. In our population of patients with iodine-refractory DTC, treatment with sorafenib, lenvatinib, and axitinib allows the stabilization of the disease in a high percentage of cases, with acceptable tolerability.

Topics: Adenocarcinoma, Follicular; Adenoma, Oxyphilic; Adult; Aged; Antineoplastic Agents; Axitinib; Carcinoma, Papillary; Disease-Free Survival; Female; Humans; Imidazoles; Indazoles; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Survival Rate; Thyroid Neoplasms; Treatment Outcome

Lenvatinib, a multi-tyrosine kinase inhibitor, has been proven to be an effective treatment option for patients with iodine-131-refractory thyroid cancer. Many adverse effects of lenvatinib have been reported; thus, dose reduction is common. However, a few studies have analyzed the causes of lenvatinib dose reduction in daily clinical practice. Here, we investigate the factors involved in early lenvatinib dose reduction to analyze lenvatinib dose modification. We analyzed 20 thyroid cancer patients who began receiving lenvatinib at the Kumamoto University Hospital Cancer Center from July 2015 to November 2016. Patients were classified into the following groups based on the time until first withdrawal or dose reduction in lenvatinib: group A (early, ≤ 10 days) and group B (other, > 10 days). Patients' clinical features and reasons for withdrawal or dose reduction were analyzed. The age range of patients was 54-91 years, and the median observation period was 293 days. There were no significant differences in the administered line of lenvatinib; the presence/absence of primary residual tumors; or the history of hypertension, proteinuria, and diarrhea between the two groups (A, n = 7; B, n = 13). The cause for initial withdrawal or dose reduction was grade 3 hypertension in all group A patients, which was significantly higher than that in group B (p = 0.0001). Our results suggest that early blood pressure control may be effective as a method to maintain the lenvatinib dose intensity.

Topics: Adenocarcinoma, Follicular; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Papillary; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Risk Factors; Thyroid Neoplasms; Treatment Outcome

Topics: Acute Disease; Adenocarcinoma, Follicular; Aged; Aneurysm, False; Blood Vessels; Female; Humans; Pancreatic Pseudocyst; Pancreatitis; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Spleen; Thyroid Neoplasms; Withholding Treatment

Although advanced thyroid carcinoma patients who cannot be cured by conventional therapy have lacked effective treatment, multitargeted tyrosine kinase inhibitors have recently become available. Phase 3 trials of lenvatinib showed a median time to objective response of 2 (95 % confidence interval (CI) 1.9-3.5) months, demonstrating that shrinks tumors rapidly. The phenomenon of immediate tumor shrink is known as early tumor shrinkage (ETS) which is related to clinical outcome in other malignancies. However, precisely when within 8 weeks lenvatinib starts to affect tumors remains unclear. In tumors near the carotid arteries, trachea, or esophagus, a rapid therapeutic effect can induce fistula formation or arterial bleeding. To prevent such treatment-emergent serious adverse events (SAE), early imaging evaluation seems to be very important. In this study, the point in time when lenvatinib started to shrink tumors was retrospectively investigated. The subjects were 16 patients who started lenvatinib administration between May and August 2015. Tumor size was evaluated by computed tomography (CT) scans frequently within the first 8 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline. Initial tumor response was defined as ≥ 10% tumor reduction. Serum thyroglobulin (Tg) level was monitored in 8 differentiated thyroid carcinoma (DTC) without TgAb patients. At the first evaluation, 13 patients (83.3 %) showed tumor reduction and that decreased with time. Thirteen patients (83.3 %) showed >10 % tumor reduction within 8 weeks. In all DTC patients, serum Tg level was markedly decreased. In conclusion, lenvatinib immediately shrinks tumors, the so-called ETS phenomenon. Therefore, careful attention should be paid to fistula formation from the early phase.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Medullary; Carcinoma, Papillary; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Thyroid Gland; Thyroid Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2-3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.

Topics: Adenocarcinoma, Follicular; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Papillary; Cell Differentiation; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Quinolines; Radiation Tolerance; Thyroglobulin; Thyroid Neoplasms; Treatment Outcome

Differentiated thyroid cancers are usually cured by an appropriate surgery and a radioiodine remnant ablation. If metastases occur, successive radioiodine administrations and/or local treatments can be provided. Nevertheless, some patients will be, or become refractory to radioiodine. In case of significant and rapid progression of metastatic lesions, they will be candidate to kinase inhibitor treatments. Two agents are now approved in this situation: sorafenib and lenvatinib. Lenvatinib (Lenvima

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Clinical Trials as Topic; Compassionate Use Trials; Humans; Iodine Radioisotopes; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

Topics: Adenocarcinoma, Follicular; Aged; Antineoplastic Agents; Female; Humans; Middle Aged; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Thyrotoxicosis; Treatment Outcome