lenvatinib and Thyroid-Neoplasms

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Skin Ulcer; Thyroid Neoplasms

Topics: Humans; Iodine Radioisotopes; Phenylurea Compounds; Thyroid Neoplasms; Treatment Outcome

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy.. This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy.. Lenvatinib has been established as standard-of-care either as a monotherapy or in combination with other anticancer agents for the treatment of radioiodine-refractory differentiated thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and is being investigated further across several other tumor types. The dosing and adverse-event management strategies for lenvatinib have been developed through extensive clinical trial experience. Collectively, the data provide the rationale to start lenvatinib at the recommended doses and then interrupt or dose reduce as necessary to achieve required dose intensity for maximized patient benefit. The adverse-event profile of lenvatinib is consistent with that of other tyrosine kinase inhibitors, and clinicians are encouraged to review and adopt relevant symptom-management strategies.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Iodine Radioisotopes; Kidney Neoplasms; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Thyroid carcinoma is the most common endocrine neoplasm. Multimodal therapy including surgery, radioactive iodine (RAI) therapy, and indefinite suppression of thyroid-stimulating hormone has led to an 85% cure rate in differentiated thyroid tumors (DTT). Approximately 5-10% of patients will have recurrence or metastases that have the potential to become resistant to RAI treatment.. We are reporting a very rare case of late renal toxicity in a 68-year-old woman with a history of type 2 diabetes and metastatic RAI-resistant follicular thyroid carcinoma (Hurthle cell variant) who developed thrombotic microangiopathy 21 months after initiation of treatment.. It was determined that LEN should be held, due to worsening renal function secondary to TKI-induced kidney injury. Although the patient's renal function eventually improved and returned to her baseline after discontinuation of LEN, there was marked disease progression after drug cessation.. Renal toxicity is a rare adverse event (AE) that tends to occur typically within three weeks of initiation of treatment. The utilization of TKIs can lead to glomerulosclerosis, and careful considerations and precautions should be taken by clinicians who intend to initiate TKI therapy in patients with pre-existing diabetes to prevent renal toxicity.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Diabetes Mellitus, Type 2; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib.. Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment.. Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

This meta-analysis was performed to assess the relationship between Lenvatinib use for malignancy and hypertension (HTN). A total of 2483 patients met inclusion criteria. The relative risk (RR) for all-grade and high-grade (≧3) HTN were 2.61 (p ≦ .001) and 3.35 (p≦ .001), respectively, for Lenvatinib compared with other multitarget tyrosine kinase inhibitors or placebo. The cumulative incidence of all-grade and high-grade HTN was 70% and 34%, respectively. The studies with median treatment duration (TD) longer than 7.4 months demonstrated a higher incidence of high-grade HTN than studies with shorter TD (34% vs 28%). The incidence of all levels of HTN increased with TD (68% vs 49%). Trials with median progression-free survival (PFS) longer than nine months had a higher incidence of both all-grade (37% vs 28%) and high-grade (71% vs 48%) HTN. Lenvatinib, a drug commonly used in cancer treatment, is a risk factor for the development of HTN. A longer duration of Lenvatinib treatment was associated with higher frequency of HTN. Further investigation for Lenvatinib of the association between the occurrence of HTN and prognosis will be warranted.

Topics: Antineoplastic Agents; Humans; Hypertension; Incidence; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far.. A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration.. This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Topics: Adult; Child; Disease Progression; Humans; Iodine Radioisotopes; Male; Orbital Neoplasms; Thyroid Neoplasms

Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy.. An 87-year-old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive-iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post-initiation of treatment.. Lenvatinib may be effective in RAI-naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible.

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quality of Life; Quinolines; Thyroid Neoplasms

Bone is the second most common distant metastasis site in differentiated thyroid cancer (DTC) and is normally associated with the presence of other metastases, which are usually radioiodine-resistant. The presence of bone metastasis (BM) determines low survival and greater morbidity due to the frequency of skeletal-related events (SREs), which can be a serious complication of BM. There is evidence that antiresorptive therapy (AT) reduces SREs in other solid tumors, but not yet in DTC BM, for which data are scant. The same is true for systemic therapy with multikinase inhibitors (MKIs). In general, the results for MKI use are well known, although the effect on BM has rarely been evaluated. While MKIs are indicated in current clinical practice guidelines, studies evaluating the benefits and risks of concomitant treatment with MKIs and AT are lacking, and the available data come from small samples in retrospective studies. The objective of this article is to review the latest evidence for concomitant MKIs and AT.

Topics: Adenocarcinoma; Antineoplastic Agents; Bone Neoplasms; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Lenvatinib has shown promising efficacy in targeted therapies that have been tested to treat anaplastic thyroid carcinoma (ATC) in both preclinical and clinical studies. The aim of this study was to evaluate the efficacy and safety of lenvatinib in the treatment of patients with ATC.. PubMed, the Cochrane Library, Embase, and ClinicalTrials.gov were searched for potential eligible studies from inception to February 1, 2022. The outcomes included partial response (PR), stable disease (SD), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS). Effect sizes for all pooled results were presented with 95% CIs with upper and lower limit.. Ten studies met the inclusion criteria. The aggregated results showed that the pooled PR, SD, and DCR were 15.0%, 42.0%, and 63.0%, respectively. The pooled mPFS and mOS were 3.16 (2.18-5.60) months and 3.16 (2.17-5.64) months, respectively. Furthermore, PFS rate at 3 months (PFSR-3m), PFSR-6m, PFSR-9m, PFSR-12m, and PFSR-15m were 52.0%, 22.5%, 13.9%, 8.4%, and 2.5%, respectively. Meanwhile, the 3-month OS rate (OSR-3m), OSR-6m, OSR-9m, OSR-12m, and OSR-15m were 64.0%, 39.3%, 29.7%, 18.9%, and 14.2%, respectively. The most common adverse events (AEs) of lenvatinib were hypertension (56.6%), proteinuria (32.6%), and fatigue (32%).. This meta-analysis showed that lenvatinib has meaningful antitumor activity, but limited clinical efficacy in ATC.. PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022308624].

Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Lenvatinib is one the most active drugs in radioiodine-refractory differentiated thyroid cancer (RR-DTC) such that it has become an important therapeutic tool in tumor control and survival. Renal and hepatic impairments are common comorbidities in cancer patients. Treating these patients is a challenge that requires careful consideration. As a first approach to patients with RR-DTC and renal or hepatic impairment, Summary of Product Characteristics recommendations for lenvatinib use and dose adjustments should be strictly followed. Close clinical and blood monitoring is the gold standard approach to optimizing lenvatinib's use during the whole course of treatment.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Thyroid cancer is the most frequent endocrine tumor. In locally advanced or metastatic disease there are only two types of treatment available: radioactive iodine (RAI) while the disease is RAI-sensitive and multikinase inhibitors, lenvatinib and sorafenib, when the disease becomes RAI-refractory. The objective of this publication is to review the current knowledge on the use of targeted therapy and the specific practical considerations concerning lenvatinib in the treatment of patients with differentiated thyroid cancer under special circumstances.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

Antiangiogenic tyrosine kinase inhibitors are the treatment of choice in radioiodine refractory-differentiated thyroid cancer (RR-DTC). Nevertheless, these therapies present class toxicities that may impact their feasibility and patient's quality of life. Their mechanism of action explains the high prevalence of hypertension associated with their use, which reaches 68% with lenvatinib. Moreover, up to 85% of patients treated in the SELECT clinical trial were receiving baseline antihypertensive treatment. These data support the need for prevention, detection, and early management of hypertension. Prevention can be accomplished by controlling cardiovascular risk factors (hypertension, diabetes, obesity, and dyslipidemia) and those associated with lifestyle (smoking, harmful alcohol consumption, and physical inactivity) and electrolyte disorders. It is necessary to achieve stabilization of cardiovascular diseases. Detection involves baseline measurement and monitoring of blood pressure and cardiac function. Treatment requires optimization of baseline blood pressure and early initiation of antihypertensive agents.

Topics: Adenocarcinoma; Antihypertensive Agents; Antineoplastic Agents; Cardiovascular Diseases; Electrolytes; Heart Disease Risk Factors; Humans; Hypertension; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quality of Life; Quinolines; Risk Factors; Thyroid Neoplasms

Thyroid cancer is the most frequent endocrine tumor. However, in locally advanced or metastatic disease we have only two types of treatment at our disposal: radioactive iodine (RAI) when the disease is RAI-sensitive and multikinase inhibitors (MKIs), lenvatinib and sorafenib, when the disease becomes RAI-refractory (RR). This review revisits the published data on the potential combination of MKIs/lenvatinib with RAI in RR-differentiated thyroid cancer and evaluates some special situations where this combination may be of particular interest. The combination of MKIs/lenvatinib with RAI could, at least hypothetically, improve the efficacy seen in both treatments alone via a synergistic effect and with a lower rate of toxicity rates. Early preclinical data support this notion, while its generalized use awaits the results of ongoing clinical trials.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

This review focuses on patients with differentiated thyroid carcinoma (DTC) associated with multiple primary malignant neoplasm (MPMN) treated by multikinase inhibitors (MKIs) as systemic treatment for advanced disease. Despite the increasing frequency of MPMNs (many at an advanced stage) and the usefulness of MKIs for multiple metastatic cancers, published data on the management of MPMN and MKI therapies in this scenario are scarce. There are infrequent descriptions of patients with advanced MPMN treated with MKIs, but only a few have described advanced DTC. The management of MPMNs, including DTC and its particular circumstances, is reviewed, focusing on the evidence for MKI therapies. Some considerations for MPMN patients with advanced DTC are discussed, with the intention of helping physicians make decisions in these challenging situations and improving treatment and patient outcomes.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Locoregional recurrence of differentiated thyroid cancer (DTC) occurs in 20% of thyroid cancer patients. Currently, there are many strategies for management of locoregional recurrence of DTC that lead to local control of the disease. The introduction of lenvatinib into the therapeutic armamentarium provides a new option for the treatment of radioiodine-refractory DTC (RR-DTC). However, results for simultaneous treatment with lenvatinib and locoregional therapies are unknown in patients with RR-DTC. This paper reviews the current status of this approach and gives recommendations on the management of lenvatinib during concomitant locoregional procedures.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Multi-receptor tyrosine kinase inhibitors with anti-angiogenic activity, particularly lenvatinib, have become the standard treatment for radioiodine-refractory metastatic differentiated thyroid cancer but are associated with a high incidence of toxicity. Although patients treated with lenvatinib have been shown to have a significant improvement in progression-free survival, lenvatinib-associated toxicity may result in dose reductions, dose interruptions or even complete lenvatinib withdrawal, compromising anti-tumor efficacy.. The article covers the main cardiological and renal toxicities of lenvatinib, including hypertension, prolonged QT interval, heart failure, arterial and venous thromboembolic events, proteinuria and renal failure, and proposes appropriate management of these events during lenvatinib therapy. We performed a literature review of cardiovascular and renal toxicities of Lenvatinib in radioiodine-refractory differentiated thyroid cancer. We discussed prophylactic and therapeutic management for each toxicity based on literature and clinical expertise.. Specific pre-therapeutic evaluation and close monitoring of patients treated with lenvatinib is necessary to prevent and detect cardiovascular and/or renal toxicities early, and to propose appropriate management. Oncologists who treat patients with lenvatinib should know how to monitor and treat these adverse events, and when to ask for the advice of a specialist (cardiologist or nephrologist).

Topics: Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Renal Insufficiency; Thyroid Neoplasms

Poorly differentiated thyroid cancer (PDTC) is now classified as a separate thyroid tumor entity. It has male predominance and poor prognosis compared to differentiated TC.. We report a case of a patient with PDTC who was previously deemed inoperable. A trial of neoadjuvant lenvatinib therapy was given to the patient after that the tumor become operable and the surgery went successfully.. Lenvatinib is a feasible option in patients with inoperable TC and can stabilize the lesion size or even reduce it, leading to a more favorable surgical outcome.

Topics: Female; Humans; Middle Aged; Neoadjuvant Therapy; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Thyroidectomy

Several molecularly targeted drugs for treating radioiodine resistant differentiated thyroid carcinomas (RAIR-DTC) have been identified. Among these, sorafenib and lenvatinib have been approved for clinical use in many countries. The present review will analyze efficacy and safety 'real-world' data (RWD) emerging after their commercialization.. RWDs confirmed sorafenib and lenvatinib efficacy in terms of progression-free survival and, perhaps, overall survival improvement in patients with RAIR-DTC. Lenvatinib performance in RWDs appeared somehow lower than in randomized clinical trials (RCT), probably because the decision to start treatment in 'real life' was made when patients were in worse clinical conditions than in RCTs. Concerning safety, RWD studies corroborated RCT evidence of elevated overall and serious adverse event incidence. Notably, adverse events were manageable in most cases with appropriate treatment or dose reduction/interruption, so that the need for definitive withdrawal was limited. The suitability of multikinase inhibitors (MKI) as salvage therapy in RAIR-DTCs was also confirmed by RWD experience, at least for lenvatinib in the second-line setting.. RWD analysis has corroborated RCT results in terms of MKI efficacy for both first-line and salvage treatment in patients with RAIR-DTC. The safety profiles emerging from RWDs seem to justify the caution recommended by most scientific guidelines.

Topics: Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Randomized Controlled Trials as Topic; Sorafenib; Thyroid Neoplasms

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinolines; Sorafenib; Thyroid Neoplasms

To evaluate the efficacy of lenvatinib in the treatment of radioiodine-refractory thyroid carcinoma.. Thyroid carcinoma is one of the top ten carcinomas worldwide. Clinically, thyroid cancers are managed with resections and adjuvant therapy with radioiodine. However, radioiodine is not effective for radioiodine-refractory (RR) thyroid carcinoma in some patients. Lenvatinib is a multi-kinase inhibitor for the treatment of RR thyroid carcinoma. Several clinical trials showed its efficacy in prolonging progression-free survival (PFS) and overall survival (OS).. A systematic search was done on databases (PubMed, Embase, MEDLINE, Cochrane) on 8 June 2020. Search keywords were lenvatinib, thyroid carcinoma and randomized controlled trials. Clinical trials fulfilling the SELECT protocol were selected to evaluate the efficacy of lenvatinib in terms of prolongation of PFS, OS and objective response rate (ORR). The risk ratio and distribution of grade 3 or above adverse events were documented.. Of the 3997 patients of mean age 62.5 years in fifteen selected studies, lenvatinib is associated with prolonged PFS (hazard ratio 0.24, 95% CI, 0.19-0.31, p < .001) and OS (hazard ratio 0.65, 95% CI, 0.52-0.81, p < .001). Compared with placebo, the risk ratio of ORR and incidence of grade 3 or above adverse events are 35.41 (95% CI, 19.42-64.58, p < .001) and 8.25 (95% CI, 6.50-10.46, p < .001), respectively. Subgroup analysis shows that lenvatinib is effective for all patients with RR thyroid carcinoma, regardless of age, histological subtypes, radiological subtypes and mutation status.. Lenvatinib is effective in the treatment of RR thyroid carcinoma. Close monitoring of serious adverse events is recommended.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Middle Aged; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Treatment Outcome

Lenvatinib is a non-selective tyrosine kinase inhibitor (TKI) with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight <60 kg or severe hepatic failure. No significant change in lenvatinib pharmacokinetics has been observed with other patient-related factors and very few data are available on lenvatinib pharmacogenetics. Lenvatinib can be administered orally regardless of food and no clinically relevant drug-drug interactions have been reported.

Topics: Drug Interactions; Humans; Pharmaceutical Preparations; Pharmacology, Clinical; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain.. We provide an overview from the literature of. According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.

Topics: Antineoplastic Agents; Combined Modality Therapy; Disease Progression; Drugs, Investigational; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Thyroidectomy

Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03-0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62-2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06-1.24); PFS_HR: 0.99 (95% CI: 0.82-1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05-1.33); PFS_HR: 0.99 (95% CI: 0.81-1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68-16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16-2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22-1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82-5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0-2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians' decisions.

Topics: Anilides; Antineoplastic Agents; Humans; Network Meta-Analysis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine.. A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'.. Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes.. Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

Topics: Antineoplastic Agents; Consensus; Disease Management; Drug-Related Side Effects and Adverse Reactions; Expert Testimony; Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC).. We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima. EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined.. We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC.. Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained.. We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib.. Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway.. This study is registered as PROSPERO CRD42017055516.. The National Institute for Health Research Health Technology Assessment programme.. Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima. We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment.. Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects.. At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

Topics: Antineoplastic Agents; Cost-Benefit Analysis; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quality-Adjusted Life Years; Quinolines; Sorafenib; Technology Assessment, Biomedical; Thyroid Neoplasms; United Kingdom

Lenvatinib is a type I tyrosine kinase inhibitor exhibiting powerful antiangiogenic activity in cancer therapy. Displaying activity in multiple solid tumors, it has been approved in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma as single agent or in combination. In addition, lenvatinib has shown promise in several other tumor types including medullary, anaplastic thyroid, adenoid cystic, and endometrial cancer. Exploring synergy between angiogenic and immune checkpoint inhibitors, the lenvatinib/pembrolizumab combination is poised to become the next pair of active drugs in endometrial, lung, and gastrointestinal malignancies. Despite robust activity, the drug can be difficult to tolerate. Optimization of dose and biomarkers for prediction of efficacy and toxicities will be of great help. IMPLICATIONS FOR PRACTICE: Readers will be presented with an update on U.S. Food and Drug Administration approval of lenvatinib and suggestions for off-label use in thyroid cancer and adenoid cystic carcinomas. They will become familiarized with the common side effects, frequency, and predicators of response. In addition, they will learn that different strengths of lenvatinib are prescribed and why. Finally, readers are pointed to the latest efforts to combine lenvatinib and pembrolizumab, as well as to unresolved issues such as long-term side effects/toxicities of this drug.

Topics: Humans; Kidney Neoplasms; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Iodine Radioisotopes; Liver Neoplasms; Male; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Treatment Outcome

Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC).. We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments.. Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited.. Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Progression; Humans; Iodine Radioisotopes; Meta-Analysis as Topic; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Quinolines; Randomized Controlled Trials as Topic; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.

Topics: Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Drug-Related Side Effects and Adverse Reactions; Everolimus; Humans; Iodine Radioisotopes; Liver Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored.. Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well.. Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.

Topics: Aged; Chemoradiotherapy; Humans; Iodine Radioisotopes; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC) represent a challenging subgroup of DTC because they are at higher risk of cancer-related death. Multidisciplinary discussions can assess the role and the nature of local treatments, but also determine the optimal timing for first-line antiangiogenic therapy as some of these patients can be followed for several months or years without any treatment. In this review, we will examine the definition of RAIR-DTC, the different treatment options and finally some of the most recent cancer research breakthroughs for RAIR-DTC.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Humans; Immunotherapy; Iodine Radioisotopes; Middle Aged; Network Meta-Analysis; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Sorafenib; Thyroid Neoplasms

Lenvatinib is an oral, multitargeted Tyrosine Kinase Inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR1-VEGFR3), fibroblast growth factor receptors (FGFR1-FGFR4), Platelet-Derived Growth Factor Receptor (PDGFR)α, rearranged during transfection (RET), and v-kit (KIT) signaling networks implicated in tumor angiogenesis.. Here, we review the scientific literature about lenvatinib in the treatment of thyroid cancer.. In vitro studies have shown antineoplastic activity of lenvatinib in Differentiated Thyroid Cancer (DTC), mainly because of its antiangiogenetic effects, but a slight effect on thyroid cancer cell proliferation has been shown. In vivo Phase II, and Phase III studies in patients with aggressive DTC not responsive to radioiodine, have shown that lenvatinib administration was associated with an amelioration in Progression-Free Survival (PFS) with respect to placebo (median PFS 18.2 vs. 3.6 months). However, overall survival was not significantly changed. Lenvatinib is also effective in patients resistant to sorafenib as salvage therapy. Adverse effects of any grade occur in more than 40% of lenvatinib-treated patients, mainly hypertension, diarrhea, asthenia or fatigue, nausea, decreased appetite, and decreased weight. Discontinuations of the therapy because of adverse effects occur in about 14% of patients. Moreover, deaths considered to be drug-related can occur.. On the basis of the above-mentioned considerations, it is necessary to prove the effectiveness of lenvatinib in the context of associated moderate to severe toxicities requiring frequent dose reduction and delays, and for this reason, many interesting patents have been recently applied.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Humans; Patents as Topic; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To obtain further insights into this "orphan disease," we have established the ATC Research Consortium of Japan (ATCCJ) in 2009. It represents a multicenter registry for ATC that have been treated in Japan. To date, 67 institutions have taken part in the collaborative research system and over 1,200 cases have been accumulated in its database. Using this big data, several retrospective studies were carried out to evaluate 1) prognostic factors to determine initial treatment policy, 2) significance of extended radical surgery for Stage IVB cases, 3) characteristics of ATC incidentally found on pathological examination and 4) pathological features of ATC with long-term survival. Moreover, the ATCCJ has conducted an investigator-initiated, nationwide, prospective clinical trial since 2012; namely, the feasibility, safety and efficacy study of weekly paclitaxel administration for patients with ATC (UMIN: 000008574). Revised Japanese guidelines for treatment of thyroid tumors are going to adopt the recommendations from the results of this research. Since 2016, the ATCCJ has started the phase II study assessing the efficacy and safety of lenvatinib, a newly developed tyrosine kinase inhibitor for ATC (UMIN: 000020773). Our nationwide clinical trial network will strengthen the activity to recruit orphan disease patients and may discover new strategies to conquer this dismal malignancy in the near future.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Databases as Topic; Humans; Japan; Neoplasm Staging; Paclitaxel; Phenylurea Compounds; Practice Guidelines as Topic; Prognosis; Protein Kinase Inhibitors; Quinolines; Registries; Research; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Lenvatinib (LEN) is a multi-kinase anti-angiogenic drug recently approved in several cancers. LEN is not easily manageable due to its complex safety profile. Proteinuria and renal failure (RF) were reported among the most frequent LEN-induced adverse events (AEs), often leading to discontinuations or dose modifications. Understanding the pathogenesis of these AEs could ameliorate the management of LEN-induced renal toxicity. Areas covered: We present two cases of LEN-induced renal failure (LIRF) with different pathogenesis. 1) LIRF with severe proteinuria in a man treated for a metastatic papillary thyroid carcinoma. Kidney biopsy showed a glomerular damage secondary to LEN, having excluded other causes of RF. 2) LIRF without proteinuria in a woman with metastatic adenoid cystic carcinoma of minor salivary gland. A tubulointerstitial nephropathy was supposed by clinical evaluation and laboratory tests. Effective management was obtained by oral steroids without interrupting LEN. Expert opinion: The case 1 presented for the first time the histological picture of LIRF with a classical glomerular damage leading to secondary proteinuria and tubular failure. Case 2 showed an alternative LIRF pattern of likely tubulointerstitial injury without proteinuria. These reports reflect two sides of the same coin, both to be considered in case of LIRF.

Topics: Adult; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Carcinoma, Papillary; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Renal Insufficiency; Salivary Gland Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

Lenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required. This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice. For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit.

Topics: Adenocarcinoma; Cell Differentiation; Humans; Iodine Radioisotopes; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Thyroid Neoplasms

Lenvatinib, an oral multikinase inhibitor, was approved by the US Food and Drug Administration in February 2015. In a pivotal phase III study of 392 patients with progressive radioiodine-refractory thyroid cancer, the overall response rate of patients receiving lenvatinib was 64.8%, with complete response in four patients. The median progression-free survival was 18.3 months in the lenvatinib arm versus 3.6 months in patients receiving placebo. Median overall survival was not reached in either arm. Lenvatinib is a promising new treatment for patients with radioiodine (iodine-131)-refractory differentiated thyroid cancer.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Distant metastases from differentiated thyroid cancer (DTC) are a rare event, occurring in less than 10% of patients with persistent or recurrent clinical disease. About 50% of these patients do respond to radioiodine (RAI) therapy, either with complete remission or stabilization of the disease on a long term period. Unfortunately, another 50% of these patients are refractory to the treatment with RAI, either from the first appearance of distant metastases or during follow-up. Overall, these patients represent 4-5 new cases/year/million. After the discovery of RAI-refractory disease, the 10-year survival rate is usually less than 10% and the mean life expectancy is 3-5 years (Durante et al., 2006). Tyrosine hinase inhibitors (TKI) have been introduced in the clinical practice based on the results of several phase III clinical trial, which brought to the approval from competent authorities in USA and Europe of two specific drugs: sorafenib and lenvatinib. Both of them, have shown objective response rates improving the progression-free survival rates, although no overall survival benefit has been demonstrated yet (Schlumberger et al., 2015; Brose et al., 2014) [2,3]. The most challenging issue in RAI-refractory thyroid cancer is when a patient should be considered RAI-refractory and when to initiate treatment with TKI.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Niacinamide; Patient Selection; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Survival Analysis; Thyroid Neoplasms; Treatment Failure

The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided.

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Niacinamide; Phenylurea Compounds; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms; Treatment Failure

In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response. Areas covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach. Expert commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.

Topics: Adult; Antineoplastic Agents; Disease Progression; Female; Humans; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms; Tomography, X-Ray Computed

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR-1-4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Clinical Trials as Topic; Combined Modality Therapy; Everolimus; Humans; Infant; Iodine Radioisotopes; Mice; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasms; Paclitaxel; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Growth Factor; Signal Transduction; Thyroid Neoplasms; Thyroidectomy; Xenograft Model Antitumor Assays

Lenvatinib (Lenvima®) is an oral, multi-targeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor alpha, and RET and KIT signalling networks, which are implicated in tumour growth and maintenance. In the EU and USA, lenvatinib is indicated for the treatment of locally recurrent or metastatic progressive, radioiodine-refractory differentiated thyroid cancer (RR-DTC). This approval was based on the results of the randomized, double-blind, multinational, phase 3 SELECT study, in which lenvatinib significantly improved median progression-free survival (PFS) and overall response rate compared with placebo in patients with RR-DTC. The PFS benefit with lenvatinib was seen in all pre-specified subgroups, including patients who had received either one or no prior VEGF-targeted therapy. Moreover, the PFS benefit with lenvatinib was maintained regardless of BRAF or RAS mutation status. The safety and tolerability profile of lenvatinib in SELECT was consistent with that of other VEGF/VEGF receptor-targeted therapies and was mostly manageable. Hypertension was the most common treatment-related adverse event in lenvatinib-treated patients, but only infrequently led to discontinuation of the drug. Although not collected in SELECT, information on quality of life would be useful in assessing the overall impact of therapy on the patient. This notwithstanding, the data which are available indicate that lenvatinib is an effective and generally well-tolerated treatment option for patients with RR-DTC. Lenvatinib, therefore, offers an acceptable alternative to sorafenib--currently, the only other TKI approved for this indication.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Neoplasms

Thyroid cancer is the most common endocrine malignancy, with over 60,000 cases reported per year in the US alone. The incidence of thyroid cancer has increased in the last several years. Patients with metastatic differentiated thyroid cancer (DTC) generally have a good prognosis. Metastatic DTC can often be treated in a targeted manner with radioactive iodine, but the ability to accumulate iodine is lost with decreasing differentiation. Until recently, chemotherapy was the only treatment in patients with advanced thyroid cancer, which is no longer amenable to therapy with radioactive iodine. The modest efficacy and significant toxicity of chemotherapy necessitated the need for urgent advances in the medical field. New insights in thyroid cancer biology propelled the development of targeted therapies for this disease, including the tyrosine kinase inhibitor sorafenib as salvage treatment for DTC. In 2015, the US Food and Drug Administration approved a second tyrosine kinase inhibitor, lenvatinib, for the treatment of radioiodine-refractory thyroid cancer. Although associated with a significant progression-free survival improvement as compared to placebo in a large Phase III study (median progression-free survival 18.2 vs 3.6 months; hazard ratio 0.21; 99% confidence interval 0.14-0.31; P<0.001), the benefit of lenvatinib needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays. This article reviews the evidence supporting the use of lenvatinib as salvage therapy for radioactive iodine-refractory thyroid cancer, with a focus on the toxicity profile of this new therapy.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Patient Selection; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinolines; Thyroid Neoplasms

Metastatic differentiated thyroid cancer (DTC) is a rare disease that is in the first line treated with iodine-131 radioisotope therapy. Until recently, options were very limited in the case of progressive radioactive-iodine (RAI)-refractory disease. Based on new study results, tyrosine kinase inhibitors (TKIs) have attracted attention. The TKI sorafenib demonstrated significantly improved progression-free survival (PFS) in a phase III trial. Recent data from another phase III trial showed that the TKI lenvatinib achieved high response rates and a large improvement in PFS in metastatic RAI-refractory DTC patients in the first-line setting and after 1 prior line of TKI. However, little is known about the response to lenvatinib in patients pretreated with multiple lines of TKIs.. We present the case of a 45-year-old man with metastatic RAI-refractory DTC progressing after multiple prior treatments with TKIs and chemotherapy. A very good and long-lasting response to lenvatinib was observed. Careful and prospective monitoring as well as management of side effects including dose adaptation were necessary to ensure success of treatment.. Here, we review different novel treatment options for patients with metastatic RAI-refractory DTC.

Topics: Antineoplastic Agents; Dose-Response Relationship, Radiation; Humans; Iodine Radioisotopes; Male; Middle Aged; Molecular Targeted Therapy; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiopharmaceuticals; Rare Diseases; Thyroid Neoplasms; Treatment Failure; Treatment Outcome

Thyroid carcinoma is the most prevalent endocrine malignancy, with an increasing incidence over the past decades. Treatment of differentiated thyroid cancer consists of surgery followed by radioactive iodine (RAI) ablation of the thyroid remnant, and TSH suppression. Among new therapeutic solutions for patients with advanced RR-DTC stage, the most promising seem to be sorafenib and lenvatinib, up to now considered to be orphan drugs. Areas covered: We performed a systematic review of medical databases to collect all eligible clinical trials referring to the topic of our analysis. Due to the lack of direct clinical trials comparing the drugs we used an adjusted indirect comparison of efficacy and safety of tyrosine kinase inhibitors (TKIs) by Bucher method. Expert commentary: Lenvatinib and sorafenib are drugs with strong evidence on efficacy in treatment of RR-DTC. Based on the currently available clinical data lenvatinib occurred more efficacious then sorafenib in RR-DTC therapy. Safety profile of the drugs was acceptable and comparative. Kinase inhibitors constitute a substantial progress in treatment of advanced thyroid cancer, have achieved long-lasting response and have improved survival without progress of the disease. In the near future we will deal with a range of therapeutic options for patients.

Topics: Antineoplastic Agents; Humans; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Survival Rate; Thyroid Neoplasms; Treatment Outcome

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Doxorubicin; Humans; Indazoles; Japan; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Quinolines; Slovenia; Sorafenib; Sulfonamides; Thyroid Neoplasms; Treatment Outcome

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC).

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Humans; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

Lenvatinib (Lenvima™) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor α, RET and KIT. In addition to their role in normal cellular function, these kinases have been implicated in pathogenic angiogenesis, tumour growth and cancer progression. Lenvatinib is being developed by Eisai Co. Ltd for the treatment of solid tumours, primarily for differentiated thyroid cancer, and other malignancies. A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Lenvatinib is in pre-registration for this indication in the EU, Australia, Brazil, Canada, Japan, South Korea, Russia, Singapore and Switzerland, and is in phase 3 development in Argentina, Chile and Thailand. Lenvatinib has orphan designation in the EU and Japan for use in differentiated thyroid cancer. In addition, an ongoing global, phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma. This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Interactions; Drugs, Investigational; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; United States; United States Food and Drug Administration

During the past two decades, several key somatic mutations associated with development and progression of differentiated thyroid cancer (DTC) have been revealed. Historically, the treatment for advanced DTC is challenging after patients become refractory to radioactive iodine. The response to doxorubicin, the only chemotherapy agent approved by the US Food and Drug Administration, is disappointing either as monotherapy or combination therapy. Because of the lack of effective systemic treatment coupled with increased understanding of molecular and cellular pathogenesis, multiple kinase inhibitors (MKIs) as an alternative therapy for the treatment of advanced DTC has generated much interest, enthusiasm, and, most excitingly, promising results. After the encouraging results of these agents in earlier trials, the Food and Drug Administration approved sorafenib for the treatment of locally recurrent, progressive, or metastatic DTC refractory to radioactive iodine treatment based on the results of a multicenter DECISION trial. Sorafenib therefore became the first MKI approved for this indication in more than 20 years. However, even more impressive responses and progression-free survival benefits were seen in the phase III SELECT trial with lenvatinib, giving even higher hopes for the future management of what was considered just a decade ago an orphan disease. Given the role of MKIs, a new era in the treatment of advanced DTC has begun. We review the key therapeutic targets, oncogenic pathways, and promising clinical results of these agents in refractory disease, as well as their roles after failure of first line kinase inhibitors.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Humans; Iodine Radioisotopes; Mutation; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Signal Transduction; Sorafenib; Thyroid Neoplasms; Treatment Failure

Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Until recently, there was no effective therapy for these patients. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed for this group of patients. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer.

Topics: Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasm Staging; Niacinamide; Outcome Assessment, Health Care; Phenylurea Compounds; Quinolines; raf Kinases; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Thyroid Neoplasms

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Drug Approval; Humans; Imidazoles; Indazoles; Indoles; MAP Kinase Signaling System; Molecular Targeted Therapy; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Thyroid Neoplasms; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of VEGFR1,2,3,4, FGFR1,2,3,4, PDGFR-α as well as RET and KIT signaling network. Its activity against radioiodine-resistant differentiated thyroid cancer (DTC) has been recently demonstrated. Patients, who were given lenvatinib, showed significantly longer median progression free survival than placebo group, 18.3 vs 3.6 months, respectively. This review is focused on lenvatinib safety profile in patients treated due to DTC and medullary thyroid carcinoma. Among the most frequent lenvatinib-related adverse events (AEs) were hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea and stomatitis. Although a lot of them were manageable, in 35-68% of patients dose reduction was required. Nevertheless, only 15% of subjects withdrew the drug due to its toxicity.. published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer.. Lenvatinib shows acceptable safety profile in patients with thyroid carcinoma. Treatment-related side effects are usually manageable by dose modifications or by concomitant non-pharmacological and pharmacological treatment. However, the early recognition of any potential drug toxicity is crucial to avoid serious complications as well as to keep a patient on drug as long as the treatment is beneficial.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease-Free Survival; Dose-Response Relationship, Drug; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Management options are limited for patients with radioactive iodine refractory, locally advanced, or metastatic differentiated thyroid carcinoma. Prior to 2015, sorafenib, a multitargeted tyrosine kinase inhibitor, was the only approved treatment and was associated with a median progression-free survival (PFS) of 11 months and overall response rate (ORR) of 12% in a phase III trial. Lenvatinib, a multikinase inhibitor with high potency against VEGFR and FGFR demonstrated encouraging results in phase II trials. Recently, the pivotal SELECT trial provided the basis for the FDA approval of lenvatinib as a second targeted therapy for these patients. Median PFS of 18.3 months in the lenvatinib group was significantly improved from 3.6 months in the placebo group, with an HR of 0.21 (95% confidence interval, 0.4-0.31; P < 0.0001). ORR was also significantly increased in the lenvatinib arm (64.7%) compared with placebo (1.5%). In this article, we will review the molecular mechanisms of lenvatinib, the data from preclinical studies to the recent phase III clinical trial, and the biomarkers being studied to further guide patient selection and predict treatment response.

Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Humans; Iodine Radioisotopes; Molecular Targeted Therapy; Neoplasm Grading; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Retreatment; Signal Transduction; Thyroid Neoplasms; Treatment Outcome

The aim of this meta-analysis was to analyze the relationship of toxicities and clinical benefits of newly approved lenvatinib and sorafenib to thyroid cancer (TC) in patients.. Three major medical databases, PubMed, EMBASE, and ISI web of science were systematically searched to identify all studies on lenvatinib and sorafenib in TC. A meta-analysis was performed to clarify the toxicities and clinical benefits of newly Food and Drug Administration (FDA) approved lenvatinib and sorafenib to thyroid cancer.. Ten studies (n = 749) were included which evaluated the toxicities and clinical benefits of newly FDA approved lenvatinib and sorafenib to thyroid cancer. 537 (71.7%) of the 749 patients bearing TC (radioiodine-refractory, differentiated thyroid cancer) clinical benefits from lenvatinib or sorafenib, and serious adverse events occurred in 430 (57.4%) of the 749 patients ([risk ratio (RR) = 1.27, 95% confidence interval (CI) = (1.05-1.53), P = 0.01]). While 31 (4.1%) of the 749 patients died due to various reasons, that mainly accounts for severe bleeding events and cardiac arrest. The clinical benefit is obvious compared to deaths ([RR = 17.06, 95% CI = (12.08-24.11), P < 0.001]). Subgroup analyses were then conducted according to cancer type (radioiodine-refractory thyroid cancer [RR-TC] and TC). We found that in treating RR-TC, the clinical benefits are close to toxicities. While in treating TC, the clinical benefits are better than toxicities. And we found that sorafenib and lenvatinib might be proper to deal with TC (benefits rate 79.7%) compared to RR-TC (benefits rate 69.5%), taking consider of toxicities.. Lenvatinib and sorafenib are useful in the treatment of TC. Although, their toxicities remain high (57.4%) in the patients, the death rate is controlled (4.1%). Take consider of toxicities, lenvatinib, and sorafenib are more useful for TC compared to RR-TC.

Topics: Antineoplastic Agents; Female; Humans; Male; Neoplasm Recurrence, Local; Niacinamide; Odds Ratio; Phenylurea Compounds; Protein Kinase Inhibitors; Publication Bias; Quinolines; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Quinolines; Thyroid Neoplasms

After the pathogenesis of thyroid carcinomas was better understood and the role of molecular alterations in RET, BRAF and RET/PTC rearrangement was revealed, several trials using multikinase inhibitors were developed during the last decade for the treatment of recurrent radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), achieving a remarkable success. Sorafenib became the first drug approved for this indication in more than two decades after a significant improvement in the progression-free survival was demonstrated. Lenvatinib (E-7080), an orally active inhibitor of multiple receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR) 1, 2 and 3, proto-oncogene tyrosine-protein kinase receptor Ret and mast/stem cell growth factor receptor Kit, yielded highly promising early clinical data, even when given after progression on first-line therapy. The phase III SELECT trial recently demonstrated the impressive clinical activity of the drug in RAI-refractory thyroid cancer, leading to the drug's approval by the regulatory agencies and potentially making lenvatinib the most effective drug available to date for the treatment of the disease.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Mas; Quinolines; Thyroid Neoplasms

Radio-iodine refractory metastatic thyroid cancers are rare and their management was until recently relatively complex. New therapeutic agents, kinase inhibitors, joined since the early 2000s the fight against these cancers with very promising results. These targeted agents showed for two of them (sorafenib; lenvatinib), in randomized phase III trials, a significant improvement in response rate and progressionfree survival when compared to placebo, leading to the first approval for radio-iodine refractory metastatic thyroid cancers. In parallel, patients also benefited from the development of interventional radiology techniques and organization of cares in oncology, with multidisciplinary management strengthened by the creation of a national network (TUTHYREF).

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Randomized Controlled Trials as Topic; Sorafenib; Thyroid Neoplasms; Treatment Failure

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Humans; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Niacinamide; Nivolumab; Phenylurea Compounds; Quinolines; Skin Neoplasms; Sorafenib; Sulfonamides; Thyroid Neoplasms; Vemurafenib

Up until now there have been no promising drugs for the treatment of advanced thyroid cancer, but the development of novel therapeutic agents is now anticipated as a result of the advent of molecular targeted drugs that inhibit tumor growth signals or angiogenesis. Against a background in which the development of numerous molecular targeted drugs for advanced thyroid cancer is being pursued worldwide, the development of sorafenib, vandetanib, and lenvatinib is currently also under way in Japan. All three of these compounds are undergoing phase 3 trials or have been approved abroad, and because they are in the final stage of development in Japan, they are expected to be introduced in clinical settings in the near future. After they have been introduced, it will be necessary to understand the differences between these compounds and to administer them to patients appropriately.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Japan; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Piperidines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival.. Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary.. So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Diarrhea; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Benzoquinones; Bibenzyls; Boronic Acids; Bortezomib; Depsipeptides; ErbB Receptors; Gefitinib; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Lactams, Macrocyclic; Lenalidomide; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Receptor Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thalidomide; Thyroid Neoplasms; Valproic Acid; Vorinostat

In the phase 2 double-blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met; safety was similar in both arms. Impact of lenvatinib treatment on health-related quality-of-life (HRQoL) was a secondary endpoint of Study 211.. Patients with RR-DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off-treatment visit, using the EQ-5D-3L and FACT-G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated.. Baseline EQ-5D and FACT-G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day (n = 77) and 24 mg/day arms (n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were -0.42 (95% CI -4.88, 4.03) for EQ-5D-VAS and 0.47 (95% CI -3.45, 4.39) for FACT-G total. Time to first deterioration did not significantly favor either arm; EQ-5D-VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61-1.40), EQ-5D-HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44-1.05), FACT-G total HR [18 mg/24 mg] 0.73 (95% CI 0.48-1.12). Time to definitive deterioration did not significantly favor either arm, though EQ-5D-VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72; 95% CI 0.99-3.01); EQ-5D-HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57-1.63), FACT-G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43-1.21).. In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR-DTC.. NCT02702388.

Topics: Adenocarcinoma; Double-Blind Method; Humans; Iodine Radioisotopes; Quality of Life; Thyroid Neoplasms

Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity.. Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded.. The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4).. A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary.

Topics: Adult; Aged; Aged, 80 and over; Chemoradiotherapy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Response Evaluation Criteria in Solid Tumors; Thyroid Neoplasms; Young Adult

Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) is an aggressive form of thyroid cancer. Lenvatinib is a multikinase inhibitor approved for treatment of RAI-R DTC. The impact of tumor response and tumor burden on overall survival (OS) after lenvatinib treatment in patients with RAI-R DTC was assessed.. Data from patients treated with lenvatinib (N = 261) in SELECT were retrospectively analyzed. Patients were divided into lenvatinib responder or nonresponder subgroups and into low (≤40 mm) or high (>40 mm) tumor burden subgroups based on baseline sums of diameters of target lesions using Response Evaluation Criteria in Solid Tumors, version 1.1 (cutoff values were determined by receiver-operating characteristic analyses). Associations of tumor response and tumor burden with OS were assessed.. Median OS was prolonged in lenvatinib responders versus nonresponders (52.2 vs 19.0 months; hazard ratio [HR], 0.32; 95% CI, 0.23-0.46). Patients with a lower tumor burden who received lenvatinib had prolonged OS versus those with a higher tumor burden (median OS, not reached vs 29.1 months, respectively; HR, 0.42; 95% CI, 0.28-0.63). Baseline tumor burden was associated with OS by multivariate analysis (HR, 0.56; 95% CI, 0.35-0.89; P = .0138).. Patients with a lower tumor burden receiving lenvatinib had prolonged OS compared with those with a higher tumor burden receiving lenvatinib. Baseline tumor burden may be a prognostic factor for OS in patients with RAI-R DTC treated with lenvatinib.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms; Tumor Burden

Anaplastic thyroid cancer (ATC) is a rare and highly aggressive cancer for which effective systemic therapy has long been sought. Here, we assessed the efficacy and safety of lenvatinib in patients with unresectable ATC.. The study was investigator-initiated and conducted under a multicenter, open-label, nonrandomized, phase II design. Eligibility criteria included pathologically proven ATC; unresectable measurable lesion as defined by RECIST 1.1; age 20 years or older; ECOG PS 0-2; and adequate organ function. The primary end-point was overall survival. Secondary end-points were progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety.. Of 52 patients enrolled from 17 institutions, 42 patients who were confirmed to have ATC were included for efficacy analysis, and 50 patients were included for safety analysis. The estimated 1-year overall survival rate was 11.9% (95% CI, 4.4%-23.6%). One patient (2.4%) achieved complete response, four patients (9.5%) partial response, and 26 patients (61.9%) stable disease, including nine patients (21.4%) who demonstrated durable stable disease, giving an objective response rate of 11.9%, disease control rate of 73.8%, and clinical benefit rate of 33.3%. Adverse events of any grade were observed in 45 patients (90.0%), the most common of which of any grade included loss of appetite (48.0%), fatigue (48.0%), hypertension (44.0%), and palmar-plantar erythrodysesthesia syndrome (26.0%).. Lenvatinib treatment resulted in disappointing survival for unresectable ATC patients. Although the number of responders was small, responses were durable, indicating that lenvatinib may be beneficial for selected patients. Further investigation to identify suitable candidates for lenvatinib monotherapy is needed.

Topics: Adult; Antineoplastic Agents; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Young Adult

Topics: Adenocarcinoma; Antineoplastic Agents; Cohort Studies; Humans; Iodine Radioisotopes; Phenylurea Compounds; Prospective Studies; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroid Neoplasms

Lung metastases may worsen overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). We investigated (post hoc) the impact of lung metastases on survival in SELECT (a phase 3 study).. 392 patients with RR-DTC were randomised 2:1 to lenvatinib 24 mg daily (n = 261) or placebo (n = 131). Placebo-treated patients could crossover to open-label lenvatinib following progression. Patients were grouped by size of baseline lung metastases. Safety/efficacy outcomes, collated by these lung-metastases subgroups, were generated.. Lenvatinib-treated population distributions per baseline lung metastases subgroup were any lung metastases (target/nontarget lesions; n = 226), and by maximum size of target lung lesions ≥1.0 cm (n = 199), ≥1.5 cm (n = 150), ≥2.0 cm (n = 94) and <2.0 cm (n = 105). In patients with any lung metastases, no statistically significant difference in OS was observed between treatment arms (HR: 0.76; 95% CI: 0.57-1.01; P = 0.0549). Median OS for lung metastases of ≥1.0 cm was 44.7 months (lenvatinib) versus 33.1 months (placebo) (HR: 0.63; 95% CI: 0.47-0.85; P = 0.0025). OS was significantly prolonged with lenvatinib versus placebo among patients with lung metastases of ≥1.0 cm, ≥1.5 cm, ≥2.0 cm and <2.0 cm; median OS was shorter in the ≥2.0 cm subgroup (lenvatinib: 34.7 months) versus other subgroups (lenvatinib: 44.1-49.2 months). Multivariate analysis demonstrated lenvatinib significantly prolonged OS in patients with lung metastases of ≥1.0 cm after adjustment for baseline characteristics.. Lenvatinib treatment resulted in longer OS in patients with lung metastases of ≥1.0 cm versus placebo (even with the 89% crossover rate). Early initiation of lenvatinib may improve outcomes in patients with RR-DTC and lung metastases of ≥1.0 cm.. ClinicalTrials.Gov Identifier: NCT01321554.

Topics: Aged; Antineoplastic Agents; Cell Differentiation; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Lung Neoplasms; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Radiopharmaceuticals; Thyroid Neoplasms; Time Factors; Tumor Burden

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Neutrophils; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Retrospective Studies; Survival Analysis; Thyroid Neoplasms; Treatment Outcome

Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC.. Progression-free survival was significantly longer with lenvatinib treatment [. Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; China; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Quinolines; Radiation Tolerance; Thyroid Neoplasms; Young Adult

In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly improved efficacy outcomes versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Lenvatinib-treated patients had more adverse events (AEs), which were generally managed with dose modifications, including dose interruption. This exploratory post hoc analysis investigated the impact of dose interruption on lenvatinib efficacy.. Dose modifications were required for grade 3 or intolerable grade 2 AEs in SELECT. Lenvatinib-treated patients were dichotomised based on the duration of dose interruption relative to total treatment duration: shorter dose interruption (<10% of total treatment duration) and longer dose interruption (≥10%).. At the time of primary data cut-off (November 15, 2013; median follow-up, 17.1 months), the median progression-free survival (PFS) for the shorter dose-interruption group had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% confidence interval [CI], 9.3-16.5). Compared with placebo, the hazard ratios for PFS in the shorter and longer dose-interruption groups were 0.14 (95% CI, 0.09-0.20) and 0.31 (95% CI, 0.22-0.43), respectively. In a multivariate model, dose interruption was significantly associated with lenvatinib efficacy, even after adjustment for patient characteristics.. Lenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions. This analysis highlights the importance of timely management of lenvatinib toxicities to minimise dose interruptions and maximise lenvatinib efficacy in patients with RR-DTC. CLINICALTRIALS.. NCT01321554.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Differentiation; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Risk Assessment; Risk Factors; Thyroid Neoplasms; Time Factors

To investigate the safety and efficacy of lenvatinib in advanced thyroid cancer.. In this Phase II study, 51 Japanese patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC) received once-daily lenvatinib 24 mg. The primary end point was safety.. All patients experienced ≥1 adverse event (AE); only one patient experienced an AE leading to discontinuation. The most common any-grade AEs were hypertension, decreased appetite, palmar-plantar erythrodysesthesia, fatigue and proteinuria. Response rates for RR-DTC: 68%; MTC: 22%; ATC: 24%. Median progression-free survival for RR-DTC: 25.8 months; MTC: 9.2 months; ATC: 7.4 months.. Lenvatinib demonstrated a manageable safety profile, proven antitumor activity in RR-DTC and promising efficacy in MTC and ATC.. clinicaltrials.gov NCT01728623.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Neuroendocrine; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome; Young Adult

Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial.. SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data.. The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field.. SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.

Topics: Antineoplastic Agents; Benzimidazoles; Clinical Trials, Phase II as Topic; Humans; Iodine Radioisotopes; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Metastasis; Phenylurea Compounds; Quinolines; Sorafenib; Thyroid Neoplasms; United Kingdom

Hypertension (HTN) is an established class effect of vascular endothelial growth factor receptor (VEGFR) inhibition. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, HTN was the most frequent adverse event of lenvatinib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and stem cell factor receptor (KIT). This exploratory analysis examined treatment-emergent hypertension (TE-HTN) and its relation with lenvatinib efficacy and safety in SELECT.. In the multicenter, double-blind SELECT trial, 392 patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to lenvatinib (24 mg/d on a 28-day cycle) or placebo. Survival endpoints were assessed with Kaplan-Meier estimates and log-rank tests. The influence of TE-HTN on progression-free survival (PFS) and overall survival (OS) was analyzed with univariate and multivariate Cox proportional hazards models.. Overall, 73% of lenvatinib-treated patients and 15% of placebo-treated patients experienced TE-HTN. The median PFS for lenvatinib-treated patients with (n = 190) and without TE-HTN (n = 71) was 18.8 and 12.9 months, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39-0.88; P = .0085). For lenvatinib-treated patients, the objective response rate was 69% with TE-HTN and 56% without TE-HTN (odds ratio, 1.72; 95% CI, 0.98-3.01). The median change in tumor size for patients with and without TE-HTN was -45% and -40%, respectively (P = .2). The median OS was not reached for patients with TE-HTN; for those without TE-HTN, it was 21.7 months (HR, 0.43; 95% CI, 0.27-0.69; P = .0003).. Although HTN is a clinically significant adverse event that warrants monitoring and management, TE-HTN was significantly correlated with improved outcomes in patients with RR-DTC, indicating that HTN may be predictive for lenvatinib efficacy in this population. Cancer 2018;124:2365-72. © 2018 American Cancer Society.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure Determination; Chemotherapy, Adjuvant; Double-Blind Method; Female; Humans; Hypertension; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Placebos; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Mas; Quinolines; Radiation Tolerance; Response Evaluation Criteria in Solid Tumors; Survival Rate; Thyroid Gland; Thyroid Neoplasms; Young Adult

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2%; 95% confidence interval (CI) 54.2-66.1) was 30.0 months (95% CI 18.4-36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99% CI 0.17-0.35; nominal

Topics: Aged; Antineoplastic Agents; Disease-Free Survival; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiopharmaceuticals; Thyroid Neoplasms; Treatment Outcome

Lenvatinib (Lenvima. Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000. All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function.. We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Determination; Disease Progression; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Japan; Male; Middle Aged; Nitric Oxide; Phenylurea Compounds; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Quinolines; Risk Factors; Thyroid Neoplasms; Vascular Endothelial Growth Factor A; Vascular Resistance

Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Double-Blind Method; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Quinolines; Radiation Tolerance; Survival Rate; Thyroid Neoplasms

While there is a clear consensus for defining radioiodine-refractory differentiated thyroid cancer (RR-DTC), it is unknown whether these criteria are equally valid for determining when radioiodine (RAI) therapy is no longer beneficial and systemic treatment should be considered. Lenvatinib, a multikinase inhibitor, significantly prolonged progression-free survival (PFS) compared to placebo in a Phase 3 trial in RR-DTC (SELECT; hazard ratio [HR]: 0.21 [99% confidence interval (CI) 0.14-0.31]; p < 0.001). This sub-analysis compared clinical outcomes of lenvatinib-treated patients in SELECT stratified by RR-DTC inclusion criteria.. In SELECT, patients with measurable RR-DTC and radiologic evidence of disease progression ≤13 months prior to study entry were randomized 2:1 to lenvatinib (24 mg/day; 28-day cycle) or placebo. In this analysis, patients were stratified based on the following RR-DTC inclusion criteria: no RAI uptake, disease progression within 12 months of RAI therapy despite RAI avidity at the time of treatment, and extensive (>600 mCi) cumulative RAI exposure. All had disease progression as an inclusion criterion for SELECT.. Of 392 patients (261 lenvatinib; 131 placebo) enrolled, 275, 235, and 73 patients met the inclusion criteria for no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. There was significant overlap between the patient groups, with 167 (42.6%) patients meeting more than one inclusion criterion. Lenvatinib improved median PFS compared to placebo in all groups ("no RAI uptake": lenvatinib not quantifiable [NQ; CI 14.8-NQ] vs. placebo, 3.7 months [CI 2.5-5.3]; "disease progression despite RAI avidity": lenvatinib 16.5 months [CI 12.8-NQ] vs. placebo, 3.7 months [CI 1.9-5.4]; "extensive RAI exposure": lenvatinib 18.7 months [CI 10.7-NQ] vs. placebo, 3.6 months [CI 1.9-5.5]). Objective response rates were 71.8%, 60.0%, and 56.0% for patients with no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. Lenvatinib-related adverse events were similar across groups.. Comparable efficacy and safety profiles were observed in lenvatinib-treated patients regardless of RR-DTC criteria, possibly because of a large overlap among patients fulfilling each criterion. However, differing definitions for RR-DTC may be equally valid because both lenvatinib and placebo arms exhibited similar PFS outcomes across groups.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cross-Over Studies; Dose-Response Relationship, Radiation; Double-Blind Method; Female; Follow-Up Studies; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiopharmaceuticals; Survival Analysis; Terminology as Topic; Thyroid Neoplasms; Tissue Distribution; Treatment Failure; Tumor Burden

In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study.. Adverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables.. The most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months).. In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.

Topics: Antineoplastic Agents; Diarrhea; Disease-Free Survival; Double-Blind Method; Exanthema; Fatigue; Female; Humans; Incidence; Male; Phenylurea Compounds; Proteinuria; Quinolines; Thyroid Neoplasms; Treatment Outcome

Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).. Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.. Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.. Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers; Carcinoma, Neuroendocrine; Disease Progression; Female; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Mas; Quinolines; Retreatment; Thyroid Neoplasms; Treatment Outcome; Young Adult

Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans.. This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC.. The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function.. The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biological Availability; Female; Healthy Volunteers; Humans; Individuality; Male; Meta-Analysis as Topic; Middle Aged; Models, Biological; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Young Adult

Lenvatinib improved the progression-free survival (PFS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).. The objective of the study was to characterize tumor size changes with lenvatinib treatment.. SELECT was a phase 3, randomized, double-blind, multicenter study.. In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals.. Patients with complete or partial response were defined as responders to lenvatinib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis.. Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death.. This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction.. The median maximum percentage change in tumor size was -42.9% for patients receiving lenvatinib (responders, -51.9%; nonresponders, -20.2%). Tumor size reduction was most pronounced at first assessment (median, -24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (-1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PFS (P = .06).. The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Young Adult

Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).. In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.. The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.. Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Topics: Adult; Aged; Disease-Free Survival; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC).. Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed.. After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%).. In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Mas; Quinolines; Thyroid Neoplasms; Treatment Outcome

Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10-1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade ≥3: Japanese, 80%; overall, 42%), palmar-plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade ≥3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade ≥3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Carcinoma; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

RET kinase inhibitors have significant activity in patients with medullary thyroid carcinoma (MTC).. We retrospectively reviewed the electronic medical record for patterns of calcitonin, carcinoembryonic antigen (CEA) and tumor measurement responses in consecutive patients with MTC who received treatment with a RET inhibitor for at least 6 months.. Twenty-six patients who received RET kinase inhibitors for at least 6 months were included. All patients experienced an initial decline in calcitonin; 20 (77%) demonstrated later fluctuations in calcitonin, which spiked above baseline levels in 9 individuals (35%). Twenty of the 22 patients (91%) with elevated CEA experienced a decline with treatment, with 11 individuals (50%) later demonstrating transient fluctuations in CEA, including spikes above baseline in 7 patients (32%). Ten of the 26 patients (38%) also demonstrated short-lived fluctuations in RECIST measurements, including changes of over 20% from nadir values. Vacillations in calcitonin, CEA and measurements often occurred repeatedly in individual patients and did not regularly correlate with each other.. Repeated transient fluctuations in tumor markers and measurements are a characteristic of patients with MTC receiving treatment with RET inhibitors, and such short-term vacillations may not reflect responsiveness over the long term.. NCT00215605; NCT00244972; NCT00121680; NCT00495872.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Female; Humans; Indoles; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-ret; Pyridines; Pyrroles; Quinolines; Quinolones; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Neoplasms; Treatment Outcome; Valproic Acid

Few available data indicate that a mutation-based "neoadjuvant" therapy in advanced anaplastic thyroid carcinoma (ATC) might convert an initially unresectable primary tumor to resectable and optimize local tumor control. We evaluated a preoperative short-term "neoadjuvant" therapy with a BRAF-directed therapy or, in case of BRAF non-mutated tumors, an mKI/checkpoint inhibitor combination in three patients with ATC stage IVB and C.. In the context of preoperative diagnostics, immunohistochemistry (IHC) assessment and genetic analysis was started as soon as possible. The antiangiogenetic therapy with lenvatinib was immediately after diagnosis of ATC started as bridging therapy. In case of a BRAF-mutated ATC, a combination therapy of dabrafenib and trametinib, in case of BRAF-wildtype ATC a combination of pembrolizumab and lenvatinib was given for 4 weeks. If re-staging has shown a significant therapy response due to a decrease in size of > 50%, surgical resection was reconsidered. A primary tumor resection was performed first. As a second step, limited distant metastasis have been resected approximately 4 weeks after thyroid surgery. After postoperative recovery, the targeted systemic therapy was continued.. Two patients presented with BRAF-wildtype ATC stage IVC, one with BRAF-mutated ATC stage IVB. All patients were evaluated by surgery, nuclear medicine and oncology upon diagnosis of ATC.. In all three cases, the "neoadjuvant" therapy induced a dramatic response and led to local resectability in primarily non-resectable ATC stage IVB or C. We have chosen for the first time a short-term "neoadjuvant" treatment period to reduce the risk of bleeding and/or fistula due to potential rapid tumor shrinkage. The results of surgery after only short-term "neoadjuvant" therapy showed two R0 und one R1 resections. Postoperative histopathological findings confirmed an extent of tumor necrosis or regressive fibrotic tissue between 60 and > 95% in our patients.. A short-term mutation-based "neoadjuvant" therapy can achieve local resectability in initially unresectable ATC stage IVB or C. A neoadjuvant treatment period of about 4 weeks seems to show similar response as a treatment duration of at least 3 months.

Topics: Humans; Mutation; Neoadjuvant Therapy; Proto-Oncogene Proteins B-raf; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Lenvatinib showed promising results in a subgroup of patients with poorly differentiated thyroid carcinoma (PDTC) in the SELECT trial. Our aim was to report the effectiveness and tolerability of lenvatinib in our series of PDTC patients.. Medical records of eight consecutive patients with PDTC treated with lenvatinib in a single center between January 2019 and October 2022 were retrospectively reviewed. Inclusion criteria were PDTC diagnosis based on Turin criteria and evidence of disease progression in the previous 6 months.. Eight PDTC patients received an average dose of lenvatinib of 18.1 mg for a median duration of treatment of 10.3 months. The baseline Eastern Cooperative Oncology Group performance status was ≥2 in 50% of patients. Two patients had unresectable primary tumor. Seven patients showed extrathyroidal disease, particularly mediastinal lymph nodes (85.7%), lung (71.4%), and bone (71.4%). The disease control rate was 100%, with partial response and stable disease in 12.5 and 87.5%, respectively. The median time to best overall response was 3 months, and the median duration of response was 7.5 months. Median progression-free survival was 12 months and median overall survival was not reached. At 6, 12, and 18 months, overall survival was 87.5, 71.4, and 57.1%, respectively. All patients experienced drug-related adverse effects (AEs). Four (50%) had dose reductions and two (25%) had temporary treatment interruptions. Lenvatinib was stopped in two patients due to grade ≥3 AEs.. Lenvatinib is an effective treatment for real-world PDTC patients. Adequate management of comorbidities and AEs increases treatment tolerability and minimizes dose reductions.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Retrospective Studies; Thyroid Neoplasms

Recently, selpercatinib, a highly selective inhibitor of

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Republic of Korea; Thyroid Neoplasms

Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (

Topics: Antineoplastic Agents; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Hypertension; Iatrogenic Disease; Pilot Projects; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Thyroid Neoplasms

Topics: Adenocarcinoma; Humans; Oxyphil Cells; Phenylurea Compounds; Thyroid Neoplasms

We describe the use of the tyrosine kinase inhibitor lenvatinib in a patient with brain tumor metastases from anaplastic thyroid carcinoma (ATC). A 52-year-old Japanese male presented with consciousness loss. Imaging revealed a thyroid tumor and multiple brain lesions. After the brain tumor's resection, pathology results provided the diagnosis of ATC. Total thyroidectomy was performed, followed by whole-brain irradiation. Additional brain lesions later developed, and lenvatinib therapy was initiated with no remarkable complications. However, the treatment effects were limited, and the patient died 2 months after starting lenvatinib, 202 days after the initial brain surgery. Relevant literature is discussed.

Topics: Antineoplastic Agents; Brain Neoplasms; Humans; Male; Middle Aged; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Hypertension (HTN) is the most frequent adverse event during treatment with lenvatinib (LEN), but data on its best management are limited.. The objective of this study was to assess incidence, features and best management of LEN-related HTN in a consecutive single tertiary-care centre cohort.. Twenty-nine patients were followed up for a mean time of 29.8 months (6-77 months).. After a mean follow-up of 6.8 months, HTN was recorded in 76% of cases, as a de novo occurrence in half of them. HTN significantly correlated with LEN dose and was of grade 1, grade 2 and grade 3 in 5%, 50% and 45% of patients, respectively. The majority (77%) of patients with HTN developed proteinuria. There was no correlation between HTN and proteinuria or clinical features or best morphological response or any other adverse event (AE), with the exception of diarrhoea. Patients with or without pre-existing HTN or any other cardiovascular disease had a similar incidence of HTN during LEN, thus excluding the impact of this potential predisposing factor. After evaluation by a dedicated cardiologist, medical treatment was introduced in 21/22 patients (polytherapy in 20 of them). The most frequently used drugs were calcium channel blockers (CCBs) due to their effect on vasodilation. In case of poor control, CCBs were associated with one or more anti-hypertensive drug.. HTN is a frequent and early AE in patients on LEN treatment. We suggest a diagnostic and therapeutic algorithm to be applied in clinical practice to allow efficient HTN control and improve patient compliance, reducing LEN discontinuation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Retrospective Studies; Thyroid Neoplasms

Topics: Animals; Disease Models, Animal; Humans; Iodine Radioisotopes; Mice; Pericytes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Thrombospondin 1; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment; Tyrosine Kinase Inhibitors

Most thyroid cancers of follicular origin have a favorable outcome. Only a small percentage of patients will develop metastatic disease, some of which will become radioiodine refractory (RAI-R). Important challenges to ensure the best therapeutic outcomes include proper, timely, and appropriate diagnosis; decisions on local, systemic treatments; management of side effects of therapies; and a good relationship between the specialist, patients, and caregivers.. With the aim of providing suggestions that can be useful in everyday practice, a multidisciplinary group of experts organized the following document, based on their shared clinical experience with patients with RAI-R differentiated thyroid cancer (DTC) undergoing treatment with lenvatinib. The main areas covered are patient selection, initiation of therapy, follow-up, and management of adverse events.. It is essential to provide guidance for the management of RAI-R DTC patients with systemic therapies, and especially lenvatinib, since compliance and adherence to treatment are fundamental to achieve the best outcomes. While the therapeutic landscape in RAI-R DTC is evolving, with new targeted therapies, immunotherapy, etc., lenvatinib is expected to remain a first-line treatment and mainstay of therapy for several years in the vast majority of patients and settings. The guidance herein covers baseline work-up and initiation of systemic therapy, relevance of symptoms, multidisciplinary assessment, and patient education. Practical information based on expert experience is also given for the starting dose of lenvatinib, follow-up and monitoring, as well as the management of adverse events and discontinuation and reinitiating of therapy. The importance of patient engagement is also stressed.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Thyroid Neoplasms

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

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2-3 months intervals 2-4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Topics: Aged; Antineoplastic Agents; Humans; Leukocytes, Mononuclear; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

In the last decade, new systemic treatment options have been made available for patients with advanced thyroid cancer. However, little is known about the real-world utilization of these systemic therapies.. We used Optum's de-identified Clinformatics® Data Mart Database to characterize trends in the use of 15 systemic therapies that are available for the treatment of advanced thyroid cancer between 2013 and 2021. Joinpoint regression was used to calculate annual percentage changes in the use of systemic therapy by patients' race/ethnicity. The sequence of therapies was determined by the date of prescription claims.. Between 2013 and 2021, the annual number of patients treated for advanced thyroid cancer with systemic therapy increased from 45 patients in 2013 to 114 patients in 2021 (N of total cohort = 885). Most patients were female (54.7%) and non-Hispanic White (62.1%). Between 2013 and 2021, there was a significant decrease in the proportion of non-Hispanic White patients treated for advanced thyroid cancer with systemic therapy (annual percentage change -3.9%, 95% confidence intervals, -6.0% to -1.8%). Since its approval by the US Food and Drug Administration (FDA) in 2015, lenvatinib remains the most frequently prescribed first-line therapy for the treatment of radioiodine-refractory thyroid cancer (48.8% of patients between 2017 and 2021). Between 2017 and 2021, most patients (79.7%) were initiated on 1 of the 10 FDA-approved agents and 81.7% received only a first-line therapy.. Between 2013 and 2021, the use of systemic treatment options for advanced thyroid cancer increased significantly, largely driven by the prescription of lenvatinib following its approval by the FDA in 2015, with an increasing trend for use in non-White patients.

Topics: Female; Humans; Iodine Radioisotopes; Male; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Ataxia telangiectasia and Rad3-related protein (ATR) is a critical component of the DNA damage response and a potential target in the treatment of cancers. An ATR inhibitor, BAY 1895344, was evaluated for its use in differentiated thyroid cancer (DTC) therapy. BAY 1895344 inhibited cell viability in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238) in a dose-dependent manner. BAY 1895344 treatment arrested DTC cells in the G2/M phase, increased caspase-3 activity, and caused apoptosis. BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines. The combination of BAY 1895344 with dabrafenib plus trametinib revealed synergistic effects in K1 cells that harbor BRAFV600E. BAY 1895344 monotherapy retarded the growth of K1 and FTC-133 tumors in xenograft models. The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.

Topics: Adenocarcinoma; Animals; Ataxia Telangiectasia Mutated Proteins; Humans; Phenylurea Compounds; Sorafenib; Thyroid Neoplasms

Lenvatinib is an oral anticancer medication used to treat radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma. The purpose of this study is to evaluate lenvatinib adherence by patients and to identify factors associated with decreased lenvatinib adherence.. Among 153 patients who started treatment with lenvatinib for unresectable thyroid cancer or unresectable hepatocellular carcinoma between May 1, 2015 and August 31 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 102 were eligible for this study (55 thyroid cancer, 47 hepatocellular carcinoma). The lenvatinib adherence rate in a treatment cycle was defined as the number of times a patient took lenvatinib in a 28-day cycle divided by the prescribed 28 doses. The rate was determined by pill counting and self-reporting at the pharmaceutical outpatient clinic. Reasons for non-adherence were established by interview and analyzed.. The median adherence rate of lenvatinib in the first cycle was 90.1% (n = 55) in thyroid cancer and 94.9% (n = 47) in hepatocellular carcinoma. In thyroid cancer, there were 255 incidents of lenvatinib non-adherence. Non-adherence was mainly associated with bleeding events (18.6%), followed by hand-foot skin reactions (10.6%). In hepatocellular carcinoma, there were 97 incidents of non-adherence. Hypertension accounted for 20.6%, followed by hoarseness (18.6%) and diarrhea (17.5%).. The adherence rate for lenvatinib in Japanese patients with thyroid and hepatocellular carcinoma in real-world clinical practice was more than 90% in this study. Hypertension was a major reason for non-adherence, followed by hand-foot skin reactions and diarrhea.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Diarrhea; Humans; Hypertension; Iodine Radioisotopes; Liver Neoplasms; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors.. Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration.. The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration.. These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.

Topics: Animals; Cell Line, Tumor; Cetuximab; Drug Carriers; ErbB Receptors; Glycols; Humans; Iodine Radioisotopes; Lactic Acid; Mice; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Quality of Life; Thyroid Neoplasms; Tissue Distribution

Tyrosine kinase inhibitors have become the mainstay of treatment for many malignancies, but their use can be accompanied by unusual and often puzzling side effects.. We describe herein a 64-year-old patient who developed a robust and sustained erythrocytosis shortly after starting treatment with lenvatinib. Our patient also experienced elevated blood pressure, mucositis, and hand-foot syndrome that are not uncommonly seen with this agent. The clinico-laboratory work-up suggested that lenvatinib was the likely culprit in this case.. Lenvatinib had to be discontinued due to suboptimal tolerance and a short-lived response. With the discontinuation of lenvatinib, hemoglobin trended downwards and subsequently resolved. A score of 6 on the Naranjo nomogram supported a probable causality relationship between lenvatinib and the observed erythrocytosis.. Erythrocytosis has previously been described with sunitinub, sorafenib and pazopanib. The exact mechanism of this phenomenon is not known. It might increase the risk of venous and arterial thromboses in cancer patients that are already in a hypercoagulable state due to cancer itself. In addition, laboratory work-up for polycythemia may prove extensive and costly. Therefore, clinicians need to be aware of this important side effect of tyrosine kinase inhibitors.

Topics: Humans; Middle Aged; Phenylurea Compounds; Polycythemia; Quinolines; Thyroid Neoplasms

Lenvatinib, a multi-tyrosine kinase inhibitor, is used for the treatment of thyroid carcinoma. However, it can cause pneumonia and pulmonary cavitation leading to pneumothorax. The mechanism underlying the occurrence of cavitation and pneumothorax is not well understood. Coronavirus disease 2019 (COVID-19), which is an infectious condition characterized primarily by pneumonia, is sometimes accompanied by pulmonary cavitation. Patients with COVID-19 who present with pulmonary cavitation may have a poor prognosis. In the present case, a patient with papillary thyroid carcinoma presented with multiple pulmonary metastatic tumors that were treated with lenvatinib. After 9 weeks from treatment initiation, he experienced fever and presented with pulmonary consolidation and ground-glass opacity (GGO). Pneumonia improved after the withdrawal of lenvatinib. After 21 weeks from treatment initiation, he developed fever again and the clinical tests led to the diagnosis of COVID-19. Computed tomography (CT) showed new GGO in both sides of the lung. Therefore, the patient was diagnosed with moderate COVID-19. He was treated with dexamethasone plus remdesivir, and GGO due to COVID-19 disappeared. However, the previous pulmonary shadow associated with lenvatinib became a cavitary lesion. The initial CT findings of COVID-19 and pneumonia associated with lenvatinib are similar. Thus, both conditions must be considered for a differential diagnosis in patients presenting with GGO during lenvatinib treatment.

Topics: COVID-19; Humans; Male; Phenylurea Compounds; Pneumonia; Pneumothorax; Quinolines; SARS-CoV-2; Thyroid Neoplasms

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients.. We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups.. A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib.. Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible subcortical vasogenic brain oedema in patients with acute neurological symptoms. Drug-induced PRES has been described with the usage of drugs that target receptors regulating vascular permeability or altering immune response. Lenvatinib is a receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor receptors implicated in cancer progression in addition to their normal cellular functions. The oedema associated with PRES is a consequence of disruption of cerebral blood flow autoregulation. Herein, we present a case of a 77-year-old lady who was on treatment with Lenvatinib for metastatic thyroid cancer who subsequently developed PRES. Her clinical and radiological findings improved after discontinuing Lenvatinib and the patient was switched to a different drug and remains asymptomatic on the same. This is the first such report of atypical findings of PRES in a patient on Lenvatinib therapy. Recognition of this entity is crucial for timely withdrawal of the drug and prevent further morbidity and mortality.

Topics: Aged; Female; Humans; Phenylurea Compounds; Posterior Leukoencephalopathy Syndrome; Quinolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Tyrosine kinase inhibitors (TKIs) have provided excellent clinical benefits to patients with advanced differentiated thyroid cancer (DTC): however, the tumor status for which maximum efficacy can be obtained remains controversial. We conducted this study to identify effective clinical predictors, focusing on disease progression.. Using the data of 42 DTC patients treated with lenvatinib, we investigated the clinical factors related to overall survival (OS) and progression-free survival (PFS), and conducted analyses by the scoring of the factors.. The 3 year OS and median PFS were 51% and 13.8 months, respectively. Univariate analysis identified performance status (PS), tumor-related symptoms, and tumor diameter as the only factors affecting both these outcomes. Giving 1-point for each of these three factors, a higher score was significantly related to shorter OS and PFS. Patients with two or fewer points (n = 34) had better median OS (NR vs 3.9 months, p < 0.001) and PFS (15.7 vs 2.1 months, p < 0.001) than patients with three points (n = 8). Patients with all three factors had a significantly worse prognosis than patients with two or fewer factors.. DTC patients with all three indicators are unlikely to have longer survival. Therefore, it is important to commence TKIs before disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Disease Progression; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Thyroid Neoplasms

Thyroid cancer is the most common endocrine malignancy. A multitargeted tyrosine kinase inhibitor, lenvatinib, has been used for the treatment of advanced thyroid cancer. To elucidate the mechanism of resistance to lenvatinib in thyroid cancer cells, we established lenvatinib-resistant sublines and analyzed the molecular mechanisms of resistance. Two thyroid cancer cell lines (TPC-1 and FRO) were used, and resistant sublines for lenvatinib (TPC-1/LR, FRO/LR) were established. In TPC-1/LR, the phosphorylation of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), and Akt was enhanced whereas in FRO/LR, the phosphorylation of EGFR and downstream signal transduction molecules was not enhanced. The addition of epidermal growth factor decreased sensitivity to lenvatinib in TPC-1 and FRO. The combination of EGFR inhibitors lapatinib and lenvatinib significantly inhibited the growth of TPC-1/LR in both in vitro and mouse xenograft models. Short-term exposure to lenvatinib enhanced the phosphorylation of EGFR in six thyroid cancer cell lines regardless of their histological origin or driver gene mutations; however, phosphorylation of ERK was enhanced in all cells except TPC-1. A synergistic growth-inhibitory effect was observed in three thyroid cancer cell lines, including intrinsically lenvatinib-resistant cells. The results indicate that signal transduction via the EGFR pathway may be involved in the development of lenvatinib resistance in thyroid cancer cells. The inhibition of the EGFR pathway simultaneously by an EGFR inhibitor may have therapeutic potential for overcoming lenvatinib resistance in thyroid cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Mice; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Hyperthyroidism after total thyroidectomy is extremely rare. No studies have investigated hyperthyroidism during multiple kinase inhibitor treatment for advanced thyroid carcinoma.. A 57-year-old man with a history of radioactive iodine refracted thyroid follicular carcinoma presented to our hospital with back pain. Computed tomography (CT) showed a huge tumor at the left ilium and multiple metastases in the lung, liver, and bone. His serum thyroglobulin was 322,000 ng/mL and bone biopsy revealed thyroid carcinoma metastasis. After left iliac tumor decompression surgery, lenvatinib and denosumab treatment were initiated. Serum thyroglobulin decreased to 88,600 ng/mL, and no progression was observed on CT. Although thyrotropin (TSH) was suppressed at 125 µg of levothyroxine sodium, serum free T3 started to increase at 70 weeks after lenvatinib initiation. Levothyroxine sodium was gradually reduced to 25 µg. At 83 weeks after initiation, the patient was hospitalized due to nausea, diarrhea, and anorexia. Serum free T3 increased to 13.98 pg/mL, whereas CT showed progression of lung and liver metastasis. Given the patient's positivity for anti-thyrotropin receptor antibody (TRAb), levothyroxine sodium and lenvatinib were discontinued and methimazole was administered at the dose of 15 mg/day. Lenvatinib was restarted after 2 weeks withdrawal. Methimazole was gradually reduced to 5 mg/day as thyroid function normalized. However, CT showed pleural effusion and enlargement of the lung, liver, and adrenal metastases. The patient died at 100 weeks after lenvatinib initiation due to disease progression.. The patient developed Graves' disease after lenvatinib treatment for radioactive iodine refracted thyroid follicular carcinoma. Persistent TSH stimulation caused by TRAb can be involved in tumor growth and thyroid hormone secretion from metastases.

Topics: Carcinoma; Humans; Hyperthyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Thyroglobulin; Thyroid Neoplasms; Thyrotropin; Thyroxine

Lenvatinib is started at a standard dose, continuing with dose reduction and interruption, balancing between efficacy and adverse events (AEs). Because few drugs are available for thyroid cancer, efforts for continuing treatment with one agent, such as "dose escalation (DE)", are made. The dose is increased, aiming to regain the anti-tumor effect after dose reduction. The effects of lenvatinib DE in differentiated thyroid carcinoma (DTC) patients are reported.. The efficacy of lenvatinib DE in DTC patients using the serum thyroglobulin (Tg) level and management of AEs was investigated.. A total of 70 DE episodes in 33 patients were investigated. The median increased dose was 2.0 (1.0-14.0) mg, increased from 8.6 (2-16) mg to 10.1 (6-24) mg. The serum Tg level decreased in 53 DE episodes. Though the serum Tg level in 17 DE episodes was not decreased, the Tg rate of increase was decreased in 7 of these DE episodes using the Tg-doubling rate. Overall, clinical benefit was seen in 60 (86%) DE episodes. AEs that could not be controlled after DEs were seen in only 16% of cases. No intolerable AEs were observed in patients who received more drug holidays at the time of DEs compared to two times before the DEs.. DE may become one of the standard treatment strategies after disease progression if AEs are well managed. Drug holidays may be a key for successfully controlling AEs with DE. DE can be useful for controlling progressive disease with increasing Tg levels.

Topics: Adenocarcinoma; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

This study aimed to analyze the clinical course of patients with differentiated thyroid cancer (DTC) who were treated by lenvatinib and investigate the specific criteria for the initiation of lenvatinib in lung metastasis.. A total of 111 patients with DTC treated by lenvatinib were included in the study. Patients were divided into two groups based on the target lesion for the initiation of lenvatinib: lung metastasis group and other metastases group.. In the univariate analysis, the tumor size for the lung metastasis (p = 0.002) and the factor of lung metastasis group (p < 0.001) were significantly associated with overall survival (OS). Multivariate analysis revealed that the factor of lung metastasis group [hazard ratio, 0.408; 95% confidence interval (CI), 0.206-0.810; p = 0.010] was the only independent prognostic factor of OS. Of the 53 patients in the lung metastasis group, 12 (23%) had lung metastasis-related finding such as pleural effusion (n = 12), hemoptysis (n = 2), and dyspnea (n = 1) at the initiation of lenvatinib treatment. The median OS in patients with or without lung metastasis-related findings were 41.0 [95% CI, 10.4-not available (NA)] months and 62.9 (95% CI, 53.0-NA) months, respectively (p = 0.022).. Patients with lung metastasis-related finding at the initiation of lenvatinib treatment had a poorer prognosis among the lung metastasis group. It is important to consider not only the tumor size but also the presence of lung metastasis-related findings when initiating lenvatinib treatment for DTC patients with lung metastasis.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Iodine Radioisotopes; Lung Neoplasms; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Neoplasms

Patients with differentiated thyroid cancer (DTC) usually have good prognosis, while those with advanced disease have poor clinical outcomes. This study aimed to investigate the antitumor effects of combination therapy with lenvatinib and

Topics: Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Symporters; Thyroid Neoplasms

Anaplastic thyroid carcinoma (ATC) accounts for 1-2% of all malignant thyroid tumors. There are only a small number of patients with ATC and most of them die within 6 months after diagnosis, making it difficult to establish a standard treatment strategy. Although multimodal therapy, including radical surgery, radiotherapy, and chemotherapy, has been introduced, the survival rate remains poor. The use of molecular-targeted drugs for cancer therapy has become widely popular. Lenvatinib, a new molecular-targeted anticancer drug, is a multi-targeted receptor tyrosine kinase inhibitor (TKI). We report a rare case of a patient with ATC (T4N0M0) who responded extremely well to the administration of lenvatinib after radical surgery. Although ATC is one of the most fatal neoplasms, lenvatinib is a promising drug.

Topics: Humans; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.. Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope. PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.. High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; B7-H1 Antigen; Drug Evaluation, Preclinical; Female; Germany; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Receptors, Fibroblast Growth Factor; RNA, Messenger; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Topics: Anilides; Antineoplastic Agents; Carcinoma, Medullary; Drug Approval; Humans; Mutation; Phenylurea Compounds; Piperidines; Precision Medicine; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Pneumatosis intestinalis is a rare disease characterized by gas-filled cysts within the submucosa or serosa of the intestinal tract. In recent years, pneumatosis intestinalis was reported in patients undergoing cancer treatment, and some case reports exist that report that pneumatosis intestinalis occurs during administration of vascular endothelial growth factor inhibitors, such as bevacizumab and sunitinib. Here, we report the first case of pneumatosis intestinalis during lenvatinib treatment.. A 77-year-old Japanese man presented to our hospital with a chief complaint of numbness in the right leg and weakness of the lower limbs 9 years after right thyroid lobectomy. Computed tomography showed a tumor 90 mm in size from the lumbar spine to the sacrum, causing spinal cord compression. Blood tests showed that the patient's thyroglobulin level was increased to 11,600 ng/ml. We diagnosed him with thyroid cancer with bone metastases. External beam radiotherapy (39 Gy/13 Fr) was performed on the bone metastases, followed by total thyroidectomy and radioactive iodine therapy. Four months after radioactive iodine therapy, lenvatinib was introduced because the symptoms of numbness and weakness recurred. Lenvatinib was introduced at dose of 24 mg, and then it was reduced to 14 mg owing to Common Terminology Criteria for Adverse Event grade 3 paronychia of the right foot. Although no further significant adverse events occurred, a scheduled computed tomography image showed pneumatosis intestinalis of the ascending colon 14 weeks after the introduction of lenvatinib. No abdominal or digestive symptoms were observed; therefore, we selected conservative treatment. We discontinued lenvatinib for a week, but we were required to restart lenvatinib as the numbness in the right leg worsened after withdrawal. Since the introduction of lenvatinib, 3 years and 5 months passed; we continued lenvatinib treatment, and the therapeutic effect remains partial response. There has been no recurrence of pneumatosis intestinalis.. Although rare, it is important to recognize that pneumatosis intestinalis can occur in association with lenvatinib and should be differentiated from intestinal perforation. Pneumatosis intestinalis association with lenvatinib can be improved by withdrawal.

Topics: Aged; Humans; Iodine Radioisotopes; Male; Neoplasm Recurrence, Local; Phenylurea Compounds; Pneumatosis Cystoides Intestinalis; Quinolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.

Topics: Antibodies, Monoclonal, Humanized; Female; Humans; Middle Aged; Phenylurea Compounds; Quinolines; Salvage Therapy; 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

Topics: Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

We aimed to evaluate the clinical efficacy and safety of lenvatinib in patients with advanced anaplastic thyroid cancer (ATC) in real-world practice.. This multicenter, retrospective cohort study included 14 patients with advanced ATC who received lenvatinib. We evaluated the response rate according to RECIST.. Ten patients had de novo ATC, and lenvatinib was used as a neoadjuvant treatment in eight patients. During a median follow-up of 6.7 months, patients received lenvatinib at a median dose of 13 mg daily. Overall, four patients (29%) showed partial response, nine (64%) had stable disease, and one (7%) had progressive disease. Tumor burden was reduced in 13 patients (93%), and the median best percent change from the baseline was -15.8%. The median progression-free survival and overall survival were 5.7 months (95% confidence interval [CI], 2.2-8.3) and 6.7 months (95% CI, 3.0-8.4), respectively. All patients experienced adverse events (AEs). Most AEs were manageable but two AEs-tracheal perforation, and pneumothorax and pneumomediastinum-were life-threatening. One patient underwent flap surgery for reconstruction of their tracheal perforation, and another died of pneumothorax and pneumomediastinum, which seemed to be related to lenvatinib.. In this multicenter real-world study, lenvatinib demonstrated limited clinical activity in advanced ATC. It effectively reduced the tumor burden but showed doubtful survival benefit. Although most AEs were manageable, one fatal AE was related to rapid tumor shrinkage. Further studies are needed to clarify the efficacy and optimal dose of lenvatinib in patients with advanced ATC.

Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Lenvatinib (LEN) has been approved for the treatment of patients with progressive radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Real-life studies reported a lower progression-free survival (PFS) than the registration study, likely due to the more advanced stage of tumors, the more frequent pretreatment with other TKIs, the limited follow-up, and the worse clinical condition of the patients included.. We evaluated the clinical data of our cohort of 13 consecutive patients, all receiving LEN as a first-line TKI treatment, and followed-up in a single tertiary Center.. All patients had an ECOG of 0-1 and regional or distant metastases were documented in 61.5% and 77% of patients, respectively. Median PFS was 22 months (95% CI 14-35) with partial response in 69% and stable disease in 31% of patients. All patients experienced at least one adverse event (AE), the most frequent being fatigue, anorexia, diarrhea, and hypertension. The daily dose was reduced in 70% of patients and only one patient (7.7%) discontinued the drug for AEs.. In this series of RAI-R DTC patients, with the unique features to have an ECOG 0 or 1 and to be naive for TKI treatments, PFS was the longest among all real-life published so far, with the highest rate of patients with partial response and one of the lowest drug discontinuation rate for AEs. The correct timing of treatment start, the tailoring of the dose, and a proper management of the AEs may have a significant impact on the treatment response to LEN.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Combined Modality Therapy; Female; Gamma Rays; Humans; Mice; Mice, Congenic; Mice, Nude; Neoplasms, Experimental; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Tumor Cells, Cultured

Papillary thyroid cancer is the most common thyroid tumor in childhood. In advanced stages, it can present with respiratory failure. The treatment of choice is total thyroidectomy and radioactive iodine. In cases of unresectable tumors, therapy with multikinase inhibitors should be considered. A 10-year-old girl was referred for progressive respiratory failure. A diagnosis of papillary thyroid cancer with pulmonary metastases was made. Due to the presence of an unresectable tumor not subject to surgery, the compassionate use of lenvatinib was indicated, showing a rapid and favorable clinical response with resolution of respiratory failure on the ninth day. Early diagnosis of papillary thyroid cancer prevents severe respiratory morbidity caused by late diagnoses. The use of lenvatinib should be considered as a previous step towards first-line therapies (surgery and radioactive iodine) in cases with great local and distant involvement.. El cáncer papilar de tiroides es el tumor tiroideo más común en la infancia. En estadios avanzados, puede presentarse con cuadro de insuficiencia respiratoria. El tratamiento de elección es la tiroidectomía total y iodo radiactivo. En tumores irresecables, se debería considerar terapia con inhibidores multicinasa. Niña de 10 años de edad derivada por insuficiencia respiratoria progresiva. Se realizó el diagnóstico de cáncer papilar de tiroides con metástasis pulmonares. Por presentar un tumor irresecable no pasible de cirugía, se indicó el uso compasivo de lenvatinib, que mostró una rápida y favorable respuesta clínica con resolución de la insuficiencia respiratoria al noveno día del tratamiento. El diagnóstico temprano de cáncer papilar de tiroides previene la grave morbilidad respiratoria ocasionada por diagnósticos tardíos. Podría considerarse el uso de lenvatinib como alternativa previa a las terapias de primera línea (cirugía e iodo radiactivo) en casos de enfermedad con gran compromiso local y a distancia.

Topics: Child; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Respiratory Insufficiency; Thyroid Cancer, Papillary; Thyroid Neoplasms

An 82-year-old woman who underwent total thyroidectomy and left cervical lymph node dissection 21 years ago admitted our hospital because of left cervical pain. Neck CT scan showed a 6 cm tumor on the left clavicle. Pathological diagnosis by needle biopsy revealed poorly differentiated to undifferentiated carcinoma, positive for TTF-1, and diagnosed as thyroid cancer lymph node metastasis anaplastic transformation. Administration of lenvatinib was started after radiation therapy. Since thrombocytopenia was observed, lenvatinib was gradually reduced from 14 mg and the dose was continued at 4 mg. The tumor shrinked and the effect of chemotherapy was partial response. She survived for 3 years while continuing lenvatinib. We reported long-term survival due to radiation therapy and lenvatinib of anaplastic transformation of thyroid cancer in lymph node metastasis due to radiation therapy and lenvatinib.

Topics: Aged, 80 and over; Female; Humans; Lymphatic Metastasis; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Thyroidectomy

Lenvatinib is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor used against nonoperative thyroid cancer; however, hypertension is a major dose-limiting side effect. In this study, hypertension caused by lenvatinib was described through a novel population pharmacodynamic model using postmarketing surveillance data obtained in Japan. The model consists of two maximum effect model components based on the (1) concentration of lenvatinib in plasma and (2) cumulative area under the curve of lenvatinib. In addition, antihypertensive drug of either an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or calcium channel blocker accounted for by lowering effect on diastolic blood pressure. Based on virtual simulations, the combination of antihypertensive drug and dose adjustment of lenvatinib showed a reduction in the probability of grade greater than or equal to 3 hypertension. The present model provides useful guidance in managing hypertension during treatment with lenvatinib in the real-world setting.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Area Under Curve; Blood Pressure; Calcium Channel Blockers; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypertension; Japan; Male; Middle Aged; Phenylurea Compounds; Product Surveillance, Postmarketing; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Neoplasms; Young Adult

The efficacy of lenvatinib for advanced and progressive radioactive iodine refractory differentiated thyroid cancer is well established. Herein, we retrospectively evaluated the long-term safety and efficacy of lenvatinib in 23 patients treated at a single Institution.. Clinical data of all patients treated for a differentiated thyroid cancer with lenvatinib from April 2015 to September 2020 were retrospectively analyzed.. A total of 23 patients were included. In all, 21 patients received lenvatinib as first-line systemic therapy. Median age at initiation of lenvatinib treatment was 68 (44-90) years. Median duration of the study from initiation of lenvatinib to study end was 23 (2-65) months. The indication for lenvatinib treatment was documented progression of distant metastases in 20 patients and of locally advanced disease in the other 3 and median duration of lenvatinib therapy was 15 (2-64) months. Best treatment responses were: partial response in 6 patients, stable disease in 14, progressive disease in 1, and not evaluable in 2. Median progression-free survival was 25 months (95% CI: 12-40) and median overall survival was 46 months (95% CI: 28-65). Three patients had to discontinue lenvatinib treatment due to serious adverse events and no drug-related death was observed. Ten patients continued lenvatinib for more than 24 months and the only newly registered adverse event after this period of time was one case of G2 proteinuria. Six patients continued lenvatinib treatment beyond documented tumor progression due to oligoprogression or slowly progressive disease (median time 18.5 months, 8-42 months). A total of 14 patients were alive at the end of the study: 11 showed partial response/stable disease on lenvatinib, including 3 who had a stable disease after local ablative therapy for oligoprogressive metastases; 3 had to change treatment, including 2 for lenvatinib-related serious adverse events and 1 for progressive disease.. Long-term lenvatinib treatment is safe and some patients may experience persistent long-term control of the disease. Late treatment-related AEs rarely occurred. Oligoprogressive and slowly progressive disease can be managed without treatment withdrawal as long as there are some clinical benefits.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy.. Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment.. At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib.. In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Case-Control Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Salvage Therapy; Survival Rate; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) is characterized by a rapid and aggressive course of progression. Despite significant advances in surgery, radiotherapy and chemotherapy, the disease‑specific mortality due to ATC is approximately 100%. New strategies, such as molecular targeted therapies, are imperative for improving survival. Livin, a member of the human inhibitor of apoptosis protein family, has been found to be associated with tumor progression and poor prognosis in various human cancers. The aim of the present study was to evaluate the role of Livin in cancer progression and chemoradioresistance of ATC and to investigate its potential as a therapeutic target. Endogenous Livin expression in the human BHT101 ATC cell line was silenced by Livin‑specific small interfering RNA. To assess the impact of Livin on cancer cell behavior in human ATC cells, various methods such as cell invasion, cell viability and cell apoptosis assays were applied. To assess the expression of Livin and the change of apoptosis‑related proteins associated with Livin expression, reverse transcription‑quantitative PCR and western blotting were performed. Immunohistochemistry was performed to detect Livin protein expression in human ATC tissues. The association between Livin expression and apoptotic/proliferation index was analyzed in human ATC cells. Livin‑knockdown suppressed tumor cell invasion; and conversely, it enhanced cell apoptosis, with elevated expression levels of cleaved caspase‑3 and ‑7 and cleaved PARP. Livin‑knockdown enhanced radiation‑induced apoptosis, while reducing cell viability following radiotherapy, as well as lenvatinib treatment. In addition, human ATC tissues with high Livin‑expression exhibited a high Ki‑67 labeling index and low apoptotic index. In summary, these findings indicate the contribution of Livin to tumor progression and chemoradioresistance in ATC.

Topics: Adaptor Proteins, Signal Transducing; Aged; Apoptosis; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Humans; Inhibitor of Apoptosis Proteins; Male; Neoplasm Invasiveness; Neoplasm Proteins; Phenylurea Compounds; Quinolines; Radiation Tolerance; RNA, Small Interfering; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib.. Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions.. Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (<42 mm) group. This result was more significant in patients with fast-growing tumours. BTS was an independent prognostic factor for both PFS and OS.. Starting lenvatinib at BTS <42 mm should be recommended to achieve good treatment outcomes in patients with RR-DTC.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Iodine Radioisotopes; Lung Neoplasms; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Retrospective Studies; Thyroid Neoplasms

Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described.. From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test.. Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62).. Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

Topics: Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments.. This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center.. A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems.. Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.

Topics: Age Factors; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Imidazoles; Male; Middle Aged; Oximes; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

There are many histological morphological types of papillary thyroid carcinoma (PTC), but the most frequently seen types are conventional. A single PTC commonly has a conventional and/or a variant morphological pattern. PTC with multiple (more than two) well-differentiated morphological patterns are extremely rare. We herein report the rare case of a 48-year-old male with initial diaphragmatic, pancreatic, and liver tumors from PTC. Then, the PTC was discovered following resection of these tumors, an ultrasound-guided fine-needle aspiration (US-FNA) cytology of a huge mass in the thyroid's left lobe revealed a PTC. After postoperative recovery, physical and ultrasound examinations identified an irregular large nodule in the thyroid's isthmus and left lobe, several swollen lymph nodes in the left neck, a mass in the left gluteus maximus, and several masses in both the bilateral parotid and salivary regions. The US-FNA's pathological examination confirmed metastatic PTCs in the left gluteus maximus and bilaterally in the parotid and salivary glands. An 18-fluorodeoxyglucose positron-emission tomography and computed tomography scan revealed abnormal uptakes in numerous locations (e.g., thyroid's isthmus and left lobe, bilateral parotid gland, and subcutaneous tissues). The patient underwent palliative therapy-including total thyroidectomy, bilateral central neck dissection, left lateral neck dissection, and excision of the bilateral parotid and salivary glands. A whole-body scan post-therapeutic radioactive iodine ablation revealed exclusive thyroid bed uptake. The patient subsequently underwent thyroid stimulating hormone (TSH) repression therapy and chemotherapy with lenvatinib, and thereafter achieved stable clinical conditions. Further histopathological analysis of the PTC revealed multiple differentiated morphological patterns in the single tumor located in the isthmus and left lobe of the thyroid, and in some metastatic lesions. Different metastatic lesions also presented different morphological patterns of PTC. In conclusions, we identified a new entity of PTC as a multiple differentiated variant of PTC (MDV-PTC) with an aggressive clinical nature.

Topics: Biopsy, Fine-Needle; Carcinoma, Papillary; Fluorodeoxyglucose F18; Humans; Iodine Radioisotopes; Liver Neoplasms; Lymphatic Metastasis; Male; Medical Oncology; Middle Aged; Neck Dissection; Pancreatic Neoplasms; Phenylurea Compounds; Positron-Emission Tomography; Quinolines; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Thyroidectomy; Thyrotropin; Whole Body Imaging

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

During the coronavirus disease 2019 (COVID-19) pandemic, clinicians are required to manage patient care for pre-existing conditions. Currently, there are no clear indications regarding the management of lenvatinib-treated patients for radioiodine-refractory thyroid cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 74-year-old male patient was treated with lenvatinib since March 2019, with disease recurrence in the thyroid bed and bilateral multiple lung metastases. The patient partially responded to treatment, with reduction in lung metastases. In September 2019, the patient tested positive for SARS-CoV-2 and isolated at home. Initially asymptomatic, the patient developed mild symptoms. Lenvatinib treatment continued with daily monitoring of vital signs. After telemedicine consultation of patient's clinical condition, severity of symptoms was low. He tested negative for SARS-CoV-2 21 days after testing positive. The patient received the full course of lenvatinib treatment. This is the first reported case of a lenvatinib-treated patient who developed COVID-19 and could continue treatment. Despite concerns over COVID-19, clinicians should not overlook treatment of pre-existing diseases or discontinue treatment, particularly for cancer. Clinicians should evaluate a patient's history and clinical presentation, monitoring the patient to reduce the development of complications in high-risk settings, avoiding treatment discontinuation.

Topics: Aged; COVID-19; Humans; Lung Neoplasms; Male; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-β [PDGFR-β]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-β. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression.. Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells.. Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRAFWT/V600E-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response.. Pericyte abundance is significantly higher in BRAFV600E-PTC with hTERT mutations and copy number alterations compared with NT or BRAFWT-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-β, pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-β. Critically, lenvatinib significantly induces higher BRAFWT/V600E-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-β.. This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib.

Topics: Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Humans; Mutation; Pericytes; Phenylurea Compounds; Prognosis; Proto-Oncogene Proteins B-raf; Quinolines; Receptor, Platelet-Derived Growth Factor beta; Thyroid Cancer, Papillary; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor associated with poor prognosis due to a lack of efficient therapies. In Japan, lenvatinib is the only drug approved for patients with ATC; however, its efficacy is limited. Therefore, novel therapeutic strategies are urgently required for patients with ATC. The present study aimed to identify compounds that enhance the antiproliferative effects of lenvatinib in ATC cells using a compound library. IRAK1/4 Inhibitor I was identified as a candidate compound. Combined treatment with lenvatinib and IRAK1/4 Inhibitor I showed synergistic antiproliferative effects via the induction of cell cycle arrest at G2/M phase in the ATC cell lines 8305C, HTC/C3, ACT-1, and 8505C. Furthermore, IRAK1/4 Inhibitor I enhanced the inhibition of ERK phosphorylation by lenvatinib in 8305C, HTC/C3, and 8505C cells. In an HTC/C3 xenograft mouse model, tumor volume was lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the vehicle control, IRAK1/4 Inhibitor I, and lenvatinib groups. IRAK1/4 Inhibitor I was identified as a promising compound that enhances the antiproliferative and antitumor effects of lenvatinib in ATC.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Synergism; Female; G2 Phase Cell Cycle Checkpoints; Gene Knockout Techniques; Humans; Interleukin-1 Receptor-Associated Kinases; M Phase Cell Cycle Checkpoints; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Drug Development; Drug Discovery; Drug Evaluation, Preclinical; Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial.. From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies.. A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04).. PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Thyroid Neoplasms

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: Aged; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Republic of Korea; Retreatment; Survival Rate; Thyroid Neoplasms; Treatment Outcome

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

Some thyroid cancer patients experience a rapid disease progression after the discontinuation of tyrosine kinase inhibitors (TKIs), which is called flare phenomenon. The incidence of the flare phenomenon of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) ranged from 4% to 11.1% and the median time to occurrence of the flare phenomenon ranged from 7 to 12 days in previous reports. In this study, we investigate the timing and incidence of the flare phenomenon in thyroid cancer patients treated with lenvatinib.The records of patients treated with lenvatinib were retrospectively reviewed. The primary outcomes were the incidence rate and timing of the flare phenomenon after the discontinuation of lenvatinib. The flare phenomenon was defined as death, hospitalization attributable to tumor progression, or unexpected event (e.g., pleural drainage) within 1 month of lenvatinib cessation. We excluded patients with progression of underlying diseases other than thyroid cancer or infection, those in whom the disease progressed, or those who died without achieving a clinical response (stable disease, partial response, or complete response).In total, 8 (14.3%) of the 56 patients experienced the flare phenomenon. The median time from lenvatinib cessation to the flare phenomenon was 9 (range, 4-30) days. Three patients in the flare group died within 1 month of lenvatinib cessation without an imaging evaluation. The remaining 5 patients had dyspnea and pleural effusion, and pleural drainage was performed in 3 of the 5 patients. Lenvatinib was resumed in 4 of the 8 patients in the flare group. Median overall survival (OS) was 15.1 months in the flare group and 41.9 months in the non-flare group. The OS tended to be poor in the flare group than in the non-flare group; however, this difference was not statistically significant (P = .051).In lenvatinib treatment for thyroid cancer, the incidence and timing of the flare phenomenon were similar to those observed with other TKIs. OS tended to be poor in the flare group than in the non-flare group. Further studies are needed to determine the mechanism of the flare phenomenon and establish measures and treatment policies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cross-Sectional Studies; Disease Progression; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Thyroid Neoplasms

A 61-year-old female was diagnosed with multiple endocrine neoplasia type 2A (MEN2A), caused by a heterozygous point mutation in the RET gene (TGC to TAC at codon 634) resulting in the substitution of cytosine with leucine (C634Y). The patient had pheochromocytoma (PCC) in the left adrenal gland and medullary thyroid carcinoma (MTC) with liver metastasis. Primary hyperparathyroidism (PHP) was not evident. Family history data suggested that the RET gene mutation was inherited from the father. The PCC was removed laparoscopically, but the MTC was observed conservatively for 7 years because the status of the MTC was compatible with T1N1M1 and stage IVC; therefore, it was not curable with surgery. The MTC liver metastasis increased in size. Lenvatinib, an oral multi-tyrosine kinase inhibitor, was administered until the patient had received a total dose of 1336mg, and then administration was stopped because of nausea. The reduction rate of the MTC liver metastasis was 31%, which was considered partial response. At this point, the patient was doing well, suggesting that lenvatinib was effective in treating the MTC liver metastasis and may be one of the treatment for advanced MTC caused by C634Y mutation in the RET gene.

Topics: Carcinoma; Female; Humans; Liver Neoplasms; Middle Aged; Multiple Endocrine Neoplasia Type 2a; Phenylurea Compounds; Point Mutation; Proto-Oncogene Proteins c-ret; Quinolines; Thyroid Neoplasms

To describe the experience with radioiodine-resistant differentiated thyroid cancer (RR-DTC) patients treated with lenvatinib in two university hospitals from Argentina.. Adult patients with a diagnosis of RR-DTC treated with lenvatinib from April 2017 to February 2020 were registered into a retrospective database. Primary objectives were assessment of progression-free survival (PFS) and tumor response evaluated according to RECIST v 1.1. Adverse events (AEs) were evaluated by using Common Terminology Criteria for Adverse Events v5.0.. Twenty-two patients were treated with lenvatinib, 13 of whom had previously received one or more multikinase inhibitors. Median duration of treatment was 7.1 months (2.2-24). Best overall response was complete response in one patient (4.5%), partial response in seven (31.8%), stable disease in seven (31.8%), and progressive disease in six (27.3%). Median PFS was 13.7 months (95% CI 3.2-24.2). All patients experienced at least one AE. Grade ≥3 AEs were observed in eight (36.4%) patients. Hypertension was the most frequent AE (63.6%) and the most common grade ≥3 AE (22.7%). Definitive withdrawal was necessary in two patients due to recurrent proteinuria (9%).. Tumor responses and PFS in our study were in line with other real-life clinical data and they seem to be inferior to the reported in the SELECT trial, probably related to the higher number of patients with prior MKI therapy, comorbidities, and poor performance status. Although virtually all patients experienced AEs, most of them were manageable and rarely a definitive withdrawal was necessary.

Topics: Adult; Antineoplastic Agents; Argentina; Humans; Iodine Radioisotopes; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Thyroid Neoplasms

Topics: Aneurysm; Antineoplastic Agents; Bronchial Arteries; Humans; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test.. Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated.. Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR.. Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Creatinine; Female; Humans; Kidney Function Tests; Male; Middle Aged; Phenylurea Compounds; Proteinuria; Quinolines; Thyroid Neoplasms; Urinalysis

Lenvatinib has become the most commonly prescribed first-line (1L) agent for the treatment of radioactive iodine-refractory differentiated thyroid cancer (RAI-r DTC) since its approval in 2015. With no real-world studies describing clinical outcomes of 1L lenvatinib and subsequent therapy, the current study aimed to assess treatment sequencing and related clinical outcomes in patients treated with 1L lenvatinib in the USA METHODS: We conducted a multisite, retrospective chart review of US patients with a diagnosis of RAI-r DTC who had initiated 1L therapy with lenvatinib from January 1, 2016 through May 31, 2017 with follow-up through October 17, 2018. Physicians completed electronic case report forms for two patient cohorts: patients still receiving 1L lenvatinib (cohort 1) and those who had initiated second-line (2L) therapy prior to data cutoff (cohort 2). Real-world objective response rate (ORR) was assessed for both cohorts. Progression-free survival (PFS) and overall survival (OS) were assessed for cohort 2.. A total of 252 patients met the study criteria with 71 in cohort 1 and 181 in cohort 2. Patients were predominantly female, had papillary DTC, and had lung metastases. The ORR was 64.8% for cohort 1 and 53.6% for cohort 2. In cohort 2, median PFS from 1L lenvatinib initiation was 14.0 months (95% CI 12.7-15.0). Second-line treatments included sorafenib (49.7%), cabozantinib (19.3%), and other targeted/chemotherapy/immuno-oncology agents. The ORR in 2L therapy was 15.5%. For cohort 2, the 12-, 18-, and 24-month OS from initiation of 1L lenvatinib was 92.8%, 81.5%, and 66.9%, respectively.. In this first real-world examination of clinical effectiveness of 1L lenvatinib and subsequent therapy among patients in the US, the results demonstrated that treatment with 1L lenvatinib followed by another 2L therapy may deliver a clinical benefit, thus allowing a number of potential 2L options following 1L lenvatinib for patients with RAI-r DTC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Retrospective Studies; Thyroid Neoplasms; Treatment Outcome; United States

Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to vinorelbine, lenvatinib, as well as to concomitant combinations. ABCB1, ABCG2 and CSF-1 mRNA expression was evaluated by real time PCR. The relative levels of pospho Akt were investigated as part of a human phospho-kinase array analysis, and CSF-1 and VEGFR-2 protein levels were measured by ELISA. The intracellular concentration of lenvatinib in ATC cells was measured by combined reversed-phase liquid chromatography-tandem mass spectrometry. An ATC subcutaneous xenograft tumor model in nude mice was treated with vinorelbine, lenvatinib, or vinorelbine plus lenvatinib. After treatment with vinorelbine, lenvatinib, a significant antiproliferative effect in ATC cell lines was observed. The concomitant treatment of vinorelbine and lenvatinib revealed synergism for all the fractions of affected cells. A decrease in ABCB1 expression was reported in both ATC cell lines treated with the lenvatinib plus vinorelbine combination, as was an increase in the intracellular concentration of lenvatinib. The combination caused a decrease in Akt, GSK3α/β, PRAS40 and Src phosphorylation, and in both CSF-1 mRNA and protein levels. In the subcutaneous tumor model, the combination reduced the tumor volume during the treatment period. Our results establish the synergistic ATC antitumor activity of a vinorelbine and lenvatinib combination.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Mice, Transgenic; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Vinorelbine

Lenvatinib is approved in Japan for treating patients with all histological subtypes of unresectable thyroid cancer, including differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC). However, safety and effectiveness data are limited in Japanese patients. Therefore, this prospective, post-marketing observational study evaluated, in daily clinical practice, the safety and effectiveness of lenvatinib in Japanese patients with unresectable thyroid cancer.. All patients with unresectable thyroid cancer first treated with lenvatinib between May and November 2015 were registered. Patients were orally administered lenvatinib and followed up for 12 months. The endpoints included adverse drug reactions (ADRs), overall survival (OS), overall response rate (ORR), and time-to-treatment failure. Post hoc Cox multivariate analyses were performed to assess prognostic factors associated with the 12-month OS rate.. Of 629 registered patients, 594 were included in the analysis. A total of 442 patients (74.4%) had DTC, 28 (4.7%) had MTC, and 124 (20.9%) had ATC. Hypertension, proteinuria, and palmar-plantar erythrodysesthesia syndrome were the most frequently reported ADRs across all histological subtypes. The median OS was 101.0 days in patients with ATC which was not reached in patients with DTC and patients with MTC, with 12-month OS rates of 15.6%, 75.7%, and 83.0%, respectively. The ORRs were 59.2%, 45.0%, and 43.8% among 368 patients with DTC, 20 with MTC, and 105 with ATC, respectively. Multivariate analyses revealed that Eastern Cooperative Oncology Group performance status (ECOG PS), tumor size, the presence of tumor invasion, and body weight were baseline prognostic factors affecting OS in patients with DTC, while ECOG PS and the presence of liver metastasis were prognostic factors in patients with ATC.. Lenvatinib demonstrated an acceptable safety profile for patients with thyroid cancer in a real-world setting in Japan. The safety profile and effectiveness findings for lenvatinib in this study were consistent with those from previous clinical trials, irrespective of histological subtype.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Neuroendocrine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Japan; Male; Middle Aged; Phenylurea Compounds; Prospective Studies; Quinolines; Survival Rate; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Young Adult

Although infrequent, distant metastasis from differentiated thyroid cancer is the main cause of mortality in patients and mostly involves the lung, bone, and brain. Distant metastases to other sites in differentiated thyroid cancer patients are rare, thus, the clinical course of unusual metastases has not been adequately researched. In the present study, the clinico-pathological findings and treatment outcomes of unusual metastases in differentiated thyroid cancer patients in Korea were evaluated.. We retrospectively reviewed the medical records of differentiated thyroid cancer patients with unusual metastases in four Korean tertiary hospitals (Chonnam National University Hwasun Hospital, Asan Medical Center, Busan National University Hospital, Severance Hospital). Unusual metastases were diagnosed using (1) cytology or histology and/or (2) imaging studies including fluorodeoxyglucose F 18 positron emission tomography/computed tomography and/or iodine 131 whole body scans with simultaneously elevated serum levels of thyroglobulin. The pathological findings of primary thyroid cancer, diagnostic method for unusual metastases, and treatment responses of unusual metastases were examined.. In all, 25 unusual metastatic foci of 19 patients were analyzed; 13 patients (68.4%) had papillary thyroid carcinoma including 4 follicular variant papillary thyroid carcinomas. The median time interval between the first diagnosis of primary thyroid cancer and unusual metastases diagnosis was 110 months (11.0-138.0 months). Only 4 patients (21.1%) had synchronous unusual metastases and 6 patients (31.6%) were symptomatic. Unusual metastases included 19 metastases to solid organs (6 to kidney, 5 to liver, 4 to pancreas, 3 to adrenal gland, and 1 to ovary) and 6 to the skin and muscles. Unusual metastases were pathologically proven in 10 patients (52.6%) and 11 of 16 patients (68.8%) who received iodine 131 whole body scans had radioiodine-refractory differentiated thyroid cancer. Among 5 patients treated with tyrosine kinase inhibitors, 4 treated with lenvatinib showed stable disease or a partial response at the first treatment response. Six patients (31.6%) died due to disease progression during the median 20.0-month follow-up period (11.0-55.0 months).. Unusual metastases from differentiated thyroid cancer are thought to be underestimated due to disease rarity and their metachronous nature with other distant metastases. The most of unusual metastases in differentiated thyroid cancer patients are existed with usual distant metastasis and clinical outcomes of those could not be significantly different from the prognosis of usual distant metastasis.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Papillary; Combined Modality Therapy; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Organ Specificity; Phenylurea Compounds; Positron Emission Tomography Computed Tomography; Prognosis; Protein Kinase Inhibitors; Quinolines; Republic of Korea; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms; Time Factors; Whole Body Imaging

Topics: Aged; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Survival Rate; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.

Topics: Aged; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Humans; Male; Phenylurea Compounds; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Gland; Thyroid Neoplasms; Thyroidectomy; Treatment Outcome

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

Topics: Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Recent thyroid cancer guidelines found it reasonable to use local therapies during treatment with tyrosine kinase inhibitors (TKIs) in selected patients with oligoprogressive disease, namely, in the presence of a single progressing lesion in an otherwise TKI-responsive metastatic cancer. However, there is a lack of experience in the management of oligoprogressive thyroid cancers. This report illustrates the case of one patient with oligoprogressive thyroid cancer during therapy with lenvatinib. We found that the application of local ablative therapy in oligoprogressive disease prolonged the progression-free survival and thus extended the time to therapy interruption. However, the optimal care for TKI-treated oligoprogressive cancers remains unclear and needs to be investigated in prospective trials.

Topics: Combined Modality Therapy; Disease Progression; Female; Humans; Lung Neoplasms; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

As for other tyrosine kinase inhibitors, a prolongation of ECG-recorded QTc intervals may be observed during lenvatinib treatment; a warning on this phenomenon has been stated. However, methods and frequency of ECG recordings have seldom been reported in this context. We present two cases of patients treated with lenvatinib for radioiodine-refractory differentiated thyroid cancer in whom the QTc interval was long monitored through a weekly 12-lead ECG registration. Overall, the maximum QTc increase above baseline was 3 and 31 ms in the first and second patient, respectively. QTc interval did not reach the toxicity value for drug withdrawal in either of the patients. These data may provide further information on cardiac safety profile of lenvatinib in a real-life practice.

Topics: Combined Modality Therapy; Electrocardiography; Heart Ventricles; Humans; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Recurrence, Local; Phenylurea Compounds; Progression-Free Survival; Quinolines; Thyroid Neoplasms

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Predictive Value of Tests; Progression-Free Survival; Quinolines; Radiotherapy; Republic of Korea; Retrospective Studies; Thyroid Neoplasms; Thyroidectomy; Tomography, X-Ray Computed; Treatment Failure; Treatment Outcome; Young Adult

Topics: Aged; Antineoplastic Agents; Cohort Studies; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Republic of Korea; Retrospective Studies; Salvage Therapy; Sorafenib; Survival Analysis; Thyroid Neoplasms; Treatment Outcome

In 2014/2015, tyrosine kinase inhibitors (TKIs) were introduced as a secondary treatment for refractory differentiated thyroid cancer (DTC) in Japan. While renal dysfunction is an adverse event of TKI, data on this adverse event in TKI-treated DTC remains insufficient. Here, we investigated renal function in patients undergoing TKI treatment for DTC and evaluated the efficacy of dose reduction/withdrawal for cases of renal dysfunction.A total of 73 cases of radioactive iodine-refractory DTC treated with sorafenib (n = 22) or lenvatinib (n = 51) were included. Patient data evaluated were TKI treatment period, estimated glomerular filtration rate (eGFR) before and after TKI therapy, incidence and degree (maximum value at time of TKI treatment) of proteinuria, and albumin levels before and after TKI therapy were compared.The mean ΔeGFR was -6.75% with lenvatinib and +5.90% with sorafenib. It was not significant (P = .15). The mean Δalbumin was -8.90% and -5.85% with lenvatinib and sorafenib, respectively; there was no significant difference between the lenvatinib and sorafenib groups (P = .77). According to our program of TKI dose reduction and withdrawal, all patients except 2 with diabetes were successfully continuing treatment.Overall, the present results demonstrated that renal function is negatively affected by long-term TKI treatment for RAI-refractory DTC. However, heightened proteinuria, decreased eGFR and albumin levels, and significant but apparently reversible renal dysfunction were more frequent with lenvatinib than sorafenib.

Topics: Aged; Drug Substitution; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Iodine Radioisotopes; Kidney Diseases; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinolines; Radiation Tolerance; Retrospective Studies; Sorafenib; Thyroid Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

Topics: Aged; Biopsy; Eosinophils; Exanthema; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Neutrophils; Phenylurea Compounds; Quinolines; Skin; Thyroid Carcinoma, Anaplastic; Thyroid Gland; Thyroid Neoplasms

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Therapy, Combination; Exportin 1 Protein; GTPase-Activating Proteins; Humans; Karyopherins; Mice, Inbred ICR; Mice, SCID; p21-Activated Kinases; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcriptome; Xenograft Model Antitumor Assays

Two tyrosine kinase inhibitors (TKIs), lenvatinib and vandetanib, are often used to treat advanced radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) and medullary thyroid cancer (MTC), respectively. Fatigue is a common adverse event during treatment with these and other TKIs and a common cause of drug discontinuation or dosage reduction.. We evaluated the basal and stimulated adrenal function in 12 patients with advanced RAI-R DTC and MTC treated with lenvatinib or vandetanib, respectively. Ten patients complaining of fatigue showed a progressive ACTH increase with normal cortisol levels. Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI). The causal relationship between TKIs and PAI onset was also demonstrated by the repeated testing of adrenal function before and during treatment. Patients with PAI received cortisone acetate replacement therapy, with a substantial and prompt improvement in the degree of fatigue, as assessed by the Common Terminology Criteria for Adverse Events version 4.03, thus supporting the major impact of impaired adrenal function in the genesis of this adverse event.. We show that the occurrence of PAI may be a common cause of fatigue during lenvatinib and vandetanib treatment, and we therefore recommend testing adrenal function for a prompt start of replacement therapy to avoid treatment discontinuation, dosage reduction, and potentially severe PAI complications.

Topics: Addison Disease; Adult; Aged; Carcinoma, Neuroendocrine; Child; Cortisone; Dose-Response Relationship, Drug; Fatigue; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Thyroid Neoplasms; Treatment Outcome; Young Adult

Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8

Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Myeloid-Derived Suppressor Cells; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Quinolines; T-Lymphocytes, Regulatory; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment

To describe the experience of our Division of Endocrinology with multikinase inhibitor (MKI) treatment in radioiodine-resistant differentiated thyroid cancer (DTC) patients.. Adults patients with a diagnosis of DTC treated with an MKI drug from March 2011 to October 2018 were registered into a retrospective database. Primary objectives were: the assessment of progression-free survival (PFS) and radiographic response evaluated according to RECIST v. 1.1. Adverse events (AEs) were evaluated by using Common Terminology Criteria for Adverse Events v. 5.0.. Twenty-two patients were treated with MKIs (21 with sorafenib, one with lenvatinib as first-line treatment). Seven patients required a second-line therapy with lenvatinib and one patient required a third-line treatment with pazopanib. Median duration of treatment was 11.2 (4.8-79.6) months. Best responses with sorafenib were partial response (PR) in two patients (11%), stable disease (SD) >6 months in 13 patients (72%), and progressive disease (PD) in three patients (17%). Best responses with second-line lenvatinib were PR in one patient (33%) and SD in two patients (66%). Median PFS was 31.5 months. AEs were present in 19 (90%) patients under sorafenib. The most common AEs were hand-foot syndrome (HFS) (67%), diarrhea (52%), and hypertension (52%). Definitive withdrawal was necessary in only one patient (4.7%).. Our study reflects the real-world clinical experience of an Endocrinology Division on the management of radioiodine-resistant DTC patients with sorafenib and lenvatinib, showing a beneficial therapeutic effect with acceptable tolerability.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Sorafenib; Thyroid Neoplasms

Little is known about real-world use of small molecule kinase inhibitors (SMKI) for advanced thyroid cancer in the United States. This study examined prescribing patterns of SMKI agents recommended by the National Comprehensive Cancer Center (NCCN).. This retrospective study used a national health insurance database to identify patients diagnosed with thyroid cancer during 1/1/2006-6/30/2016 and with prescription claims for NCCN-recommended SMKI during 1/1/2010-5/31/2016 whose first claim date was the index date. Inclusion also required continuous enrollment in a health plan for 3 months pre-index (baseline) and ≥ 1 month post-index (follow-up) with no claims for SMKI during baseline. Lines of therapy (LOT) were defined by the date of SMKI claims and days of drug supply. Median time to SMKI discontinuation in each LOT was estimated by Kaplan-Meier method.. The study included 217 patients. During follow-up (mean duration 499.0 days), 35.5% of patients (n = 77) received a second or later LOT; among patients with ≥ 12 months follow-up after first LOT (LOT1) initiation, 53.1% (n = 60) received a second or later LOT. Median treatment duration was 5.0 months for LOT1 and 5.1 months for LOT2. Over the entire follow-up period (2010-2016), sorafenib was the most common regimen in LOT1 (36.9% of patients) and LOT2 (24.7%) followed by sunitinib and levantinib (13.4% each) in LOT1 and sunitinib (19.5%) in LOT2. Starting in 2015, the year lenvatinib was approved for differentiated thyroid cancer, lenvatinib was the most common first-line regimen among patients initiating LOT1 in 2015 (43.4%) and 2016 (66.7%).. Sorafenib was the most common first-line agent during 2010-2014 but was supplanted by lenvatinib starting in 2015. Approximately 36-53% of patients received a second-line treatment. Median treatment duration results suggested potential benefit of SMKI in second-line therapy. SMKI treatment after first-line failure may be considered for appropriately selected patients.. Eisai, Inc. (Woodcliff Lake, NJ).

Topics: Databases, Factual; Drug Utilization Review; Female; Humans; Male; Middle Aged; Molecular Targeted Therapy; Phenylurea Compounds; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Quinolines; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Neoplasms; United States

Some patients with differentiated thyroid cancer (DTC) may require an initial low dose (LD) of lenvatinib. However, few studies have investigated the efficacy of LD lenvatinib. We compared the efficacy and tolerability of lenvatinib at an initial LD to those of the standard initial dose of 24 mg in patients with DTC.In this cross-sectional study, records of patients with DTC treated with lenvatinib were retrospectively reviewed. Patients were divided into 2 groups based on the initial dose of lenvatinib: a full-dose (FD) group that received an initial dose of 24 mg/d and a LD group that received an initial dose of less than 24 mg/d. Categorical variables were compared with the Fisher exact test and continuous variables with Student t test. A progression-free survival (PFS) curve was constructed with the Kaplan-Meier method. A probability (P) value of < .05 was considered statistically significant.Thirty-six patients with DTC were treated with lenvatinib (30 in the FD group and 6 in the LD group). The response rates were 43% and 33% in the FD and LD groups, respectively. The median PFS duration was 696 [95% confidence interval (CI): 318-not available (NA)] days in the FD group. The median PFS of the LD group was not reached (95% CI: 124-NA) (P = .293). Treatment interruptions were required in 25 (83%) patients in the FD group and 4 (67%) in the LD group (P = .573). Dose reductions were required in 28 (93%) patients in the FD group and 4 (67%) in the LD group (P = .121). There were no significant differences in the incidences of common adverse events between the 2 groups.The LD group also required dose reduction and interruption frequently. Since these findings are only the short-term results of a limited number of cases, a large number of cases and long-term observations are needed to determine whether an initial LD is effective for patients with DTC in poor general condition.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Survival Analysis; Thyroid Neoplasms; Treatment Outcome

We present a rare case of a patient with anaplastic thyroid carcinoma (ATC) who survived for 87 months after surgery. The patient was a 71-year-old man who presented with a painful enlarged mass in the right side of his neck that rapidly enlarged over 2 months. He was diagnosed with T4a, stage IVA ATC with no distant metastasis and underwent total thyroidectomy with modified neck dissection. Although only radiation and radioactive iodine therapy were administered after surgery, he remained disease-free for 84 months. Bone metastasis occurred after 84 months, and he was treated with Lenvatinib, but he died from a decline in his general condition 3 months later. We suggest that surgery is effective for stage IVA ATC, but adjuvant therapy is necessary for long-term disease-free survival in this patient population.

Topics: Aged; Bone Neoplasms; Disease-Free Survival; Fatal Outcome; Humans; Iodine Radioisotopes; Lymph Node Excision; Male; Neck; Neoplasm Staging; Phenylurea Compounds; Quinolines; Radiopharmaceuticals; Radiotherapy, Adjuvant; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy; Time Factors

Tyrosine kinase inhibitors (TKIs) aid in prolonging life in patients with advanced locoregional thyroid malignancy. Such patients may undergo total laryngectomy for local disease control and tracheoesophageal puncture (TEP) for speech rehabilitation. Enlargement of TEP fistulas is usually attributed to wound healing issues and leads to major complications. Four laryngectomies with TEP were performed between 2015 and 2016 and subsequently placed on a TKI. Three patients developed a complication after TKI treatment, and 2 patients had a tracheoesophageal fistula. Patients should be counseled about possible wound healing risks associated with TKIs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Esophagus; Female; Humans; Laryngectomy; Male; Middle Aged; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Punctures; Quinazolines; Quinolines; Speech Disorders; Surgical Wound; Thyroid Neoplasms; Trachea; Wound Healing

Multitarget kinase inhibitors (m-TKI), including lenvatinib, are now available as treatment options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, the optimal timing of treatment initiation with m-TKI in these patients remains to be defined.. We retrospectively reviewed the clinical records of 30 consecutive patients with RR-DTC. The relationship between clinical characteristics was evaluated, including tumor growth parameters at pretreatment/post-treatment and efficacy of lenvatinib.. A total of 26 patients with RR-DTC treated with lenvatinib were evaluable for response and eligible for analysis. From the results of multivariate analysis, baseline tumor size and tumor-related symptoms were independent negative prognostic factors for overall survival (OS) and progression-free survival (PFS). Pretreatment tumor growth parameters were not prognostic for either PFS or OS.. Patients with RR-DTC with a high tumor burden and tumor-related symptoms had significantly worse prognosis. Greater tumor reduction after starting lenvatinib may lead to better prognosis, irrespective of pretreatment high tumor growth rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Phenylurea Compounds; Prognosis; Quinolines; Radiopharmaceuticals; Retrospective Studies; ROC Curve; Survival Rate; Thyroid Neoplasms

Lenvatinib has become an important treatment option for advanced thyroid cancer. Fistula and tumor-related bleeding are life-threatening adverse effects that are triggered by tumor shrinkage. The aim of this study was to evaluate basic parameters, such as time and tumor shrinkage level, and analyze patient characteristics that might be related to onset of complications.. A retrospective study of 16 patients who received lenvatinib for thyroid cancer treatment was performed.. Fistula was observed in two patients (12.5%), while tumor-related bleeding was observed in one (6.3%). Complications were found to appear at 10.4 weeks from initiation and with tumor decrease of 19.2%. Risk factors for complications were identified as anaplastic histological type, tumor invasion, and leukocytopenia induced by lenvatinib.. Individual dose adjustment is needed with respect to these features in order to manage severe adverse effects induced by lenvatinib.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Female; Fistula; Hemorrhage; Humans; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy.. The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data.. From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively.. Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Differentiation; Compassionate Use Trials; Disease Progression; Female; Humans; Iodine Radioisotopes; Italy; Male; Middle Aged; Patient Safety; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Radiopharmaceuticals; Retrospective Studies; Risk Factors; Thyroid Neoplasms; Time Factors; Young Adult

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Colonoscopy; Female; Genes, APC; Humans; Lung Neoplasms; Neck Dissection; Phenylurea Compounds; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Young Adult

We report a case of a 37-year-old man with metastatic differentiated thyroid carcinoma, previously submitted to total thyroidectomy, radio-iodine therapy and lung metastasectomy, who underwent systemic treatment with lenvatinib for tumor recurrence in the lung, mediastinal lymph nodes, left gluteus and left orbit. Lenvatinib induced rapid and durable disease regression; the drug effect has continued after >1 year, as well as a very considerable clinical benefit. The results achieved by lenvatinib in treatment of metastatic differentiated thyroid carcinoma are clear and irrefutable. Real-life data, obtained by case reports and retrospective studies, are equally important to increase the knowledge about this drug and improve the clinical management.

Topics: Adult; Combined Modality Therapy; Humans; Iodine Radioisotopes; Lung Neoplasms; Male; Metastasectomy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Thyroidectomy

Topics: Antineoplastic Agents; Carcinoma; Humans; Italy; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications.

Topics: Adenoma, Oxyphilic; Angiogenesis Inhibitors; Combined Modality Therapy; Embolization, Therapeutic; Humans; Ilium; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

We report a case of an elderly woman presenting with a huge cervical mass invading the tracheal lumen. Diagnosed as invasive poorly differentiated thyroid cancer, after an endotracheal biopsy, stenting and radiotherapy, it was judged eligible for total thyroidectomy, but surgery was delayed due to pulmonary thromboembolism. The patient was therefore treated with lenvatinib with a neoadjuvant intent until hemodynamic stability was obtained. Thyroidectomy and radioiodine therapy were then performed and the postdose scan revealed an area of modest uptake in the anterior part of the neck. The patient is now in a good clinical status and she continues her follow-up program without any adjuvant therapy.

Topics: Aged, 80 and over; Carcinoma, Papillary; Female; Humans; Iodine Radioisotopes; Neoadjuvant Therapy; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Thyroidectomy

Primary squamous cell carcinoma (SCC) of the thyroid is a rare disease. It usually presents with locally advanced disease and has an overall poor prognosis. In this study, we investigated the characteristics and outcomes of patients with SCC of the thyroid, and reported our experience with chemotherapy with lenvatinib in the treatment of SCC of the thyroid.. The management outcome of 10 patients who had SCC of the thyroid between January 2000 and 2015 at Kyushu University Hospital or associated facilities was reviewed.. There were 3 males and 7 females, ranging in age from 53 to 77 years. Extent of disease was staged as follows: stage IVA, 3 cases; stage IVB, 3 cases; stage IVC, 4 cases. Only tracheostomy was applied for 2 cases, surgical resection, such as total thyroidectomy and neck dissection, for the other 8 cases. Radiotherapy following surgical treatment was applied for 9 cases. Four patients started on oral lenvatinib due to recurrent or progressive SCC of the thyroid. The one year actuarial survival rate of patients was 22.7%. There was no 2-year survivor of all patients.. Treatment should primarily be targeted at surgical resection with negative margins in patients with resectable disease. Lenvatinib may show promise to potentially extend survival.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neck Dissection; Phenylurea Compounds; Quinolines; Radiotherapy, Adjuvant; Squamous Cell Carcinoma of Head and Neck; Survival Rate; Thyroid Neoplasms; Thyroidectomy; Tracheostomy; Treatment Outcome

Lenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for <2% of all thyroid cancers. Current treatments for ATC have limited efficacy. We report the case of a woman with recurrent well-differentiated papillary carcinoma of the thyroid that had transformed into ATC who developed a perforation of the small intestine secondary to a marked effect of lenvatinib. She received lenvatinib (24 mg once a day) at only two doses during two weeks due to pleurodesis with talc for malignant pleural effusion. Eventually, she developed peritonitis due to the perforation and died of sepsis. However, an autopsy revealed marked efficacy of lenvatinib for ATC at a metastatic site in the small intestine despite limited exposure to the drug. Here, we report on our experience with lenvatinib treatment and gastrointestinal perforation concerning anti-angiogenic therapy.

Topics: Aged; Angiogenesis Inhibitors; Female; Humans; Intestinal Perforation; Neoplasm Metastasis; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial.. This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAF. The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable.. Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Oximes; Phenylurea Compounds; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Posterior reversible encephalopathy syndrome (PRES) is a rare reversible neurological syndrome that causes subcortical vasogenic brain edema and which is associated with the use of target-specific agents. Lenvatinib is a target-specific agent that was recently approved for inoperable thyroid cancer. We herein describe the case of a 66-year-old woman with anaplastic thyroid cancer (ATC) who was treated with lenvatinib and who subsequently developed PRES. The clinical and radiological findings improved after suspending therapy for 1 week, and there was no recurrence with intermittent lower-dose lenvatinib treatment. Lenvatinib may prolong survival in patients with ATC and can be administered intermittently, even after PRES onset.

Topics: Aged; Antineoplastic Agents; Fatal Outcome; Female; Humans; Neoplasm Recurrence, Local; Phenylurea Compounds; Posterior Leukoencephalopathy Syndrome; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

New insights in thyroid cancer biology propelled the development of targeted therapies as salvage treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC), and the tyrosine kinase inhibitor (TKI) lenvatinib has recently become available as a new line of therapy for RR-DTC. The aim of this study is to investigate clinical factors related to the efficacy of TKI therapy in recurrent RR-DTC patients and identify the optimal timing for the start of TKI therapy. The subjects consisted of 29 patients with progressive RR-DTC, 9 males and 20 females, median age 66 years. A univariate analysis was conducted in relation to progression free survival (PFS) and overall survival (OS) by the Kaplan-Meier method for the following variables: age, sex, histology of the primary tumor, thyroglobulin doubling time before the start of lenvatinib therapy, site of the target lesions, presence of a tumor-mediated symptom at the start of lenvatinib therapy, and baseline tumor size of the target lesions. Median duration of lenvatinib therapy was 14.7 months and median drug intensity was 9.5 mg. At the time of the data cut-off for the analysis, 9 patients (31.0%) have died of their disease (DOD), and a PR (partial response), SD (stable disease), and PD (progressive disease) were observed in 20 patients (69%), 6 patients (20.7%), 3 patients (10.3%), respectively. Univariate analyses showed that the presence of a symptom was the only factor significantly related to poorer PFS and OS. Clinical benefit of TKI therapy will be possibly limited when the therapy starts after tumor-mediated symptoms appear.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Thyroglobulin; Thyroid Neoplasms; Tumor Burden

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

Anaplastic thyroid cancer (ATC) constitutes less than 2% of total thyroid cancers but accounts for 20-40% of thyroid cancer-related deaths. Cancer stem cell drug resistance represents a primary factor hindering treatment. This study aimed to develop targeted agents against thyroid malignancy, focusing on individual and synergistic effects of HNHA (histone deacetylase), lenvatinib (FGFR), and sorafenib (tyrosine kinase) inhibitors. Patients with biochemically and histologically proven papillary thyroid cancer (PTC) and ATC were included. Cell samples were obtained from patients at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. PTC and ATC cells were treated with lenvatinib or sorafenib, alone or in combination with HNHA. Tumor-bearing mice (10/group) were administered 10 mg/kg lenvatinib (p.o.) or 40 mg/kg sorafenib (p.o.), alone or in combination with 25 mg/kg HNHA (i.p.) once every three days. Gene expression in patient-derived PTC and ATC cells was compared using a microarray approach. Cellular apoptosis and proliferation were examined by immunohistochemistry and MTT assays. Tumor volume and cell properties were examined in the mouse xenograft model. HNHA-lenvatinib combined treatment induced markers of cell cycle arrest and apoptosis and suppressed anti-apoptosis markers, epithelial-mesenchymal transition (EMT), and the FGFR signaling pathway. Combined treatment induced significant tumor shrinkage in the xenograft model. HNHA-lenvatinib combination treatment thus blocked the FGFR signaling pathway, which is important for EMT. Treatment with HNHA-lenvatinib combination was more effective than either agent alone or sorafenib-HNHA combination. These findings have implications for ATC treatment by preventing drug resistance in cancer stem cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Papillary; Cell Cycle; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Drug Therapy, Combination; Epithelial-Mesenchymal Transition; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mice; Mice, Inbred BALB C; Mice, Nude; Naphthalenes; Neoplastic Stem Cells; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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

We retrospectively analyzed the efficacy and safety of lenvatinib in 12 patients with advanced radioiodine-refractory thyroid cancer in the setting of daily clinical practice.. The starting daily dose of lenvatinib was 24 mg, tapered in the case of adverse events. Disease status was periodically evaluated by a single radiologist and safety assessment was regularly performed.. After a median follow-up of 13.3 months, 6- and 12-month progression-free survival rates were 63.6% and 54.6%, respectively. Overall survival at 6 and 12 months was 83.3% and 75.0%. Partial response was observed in five patients, while two showed stable disease as their best response. Conversely, progressive disease at first radiological assessment was detected in four patients. All patients experienced at least one adverse event, including systemic and gastrointestinal toxicity, high blood pressure and hand-foot syndrome. In order to manage toxicity, transient drug interruption and dose reduction were required in 10 and 9 cases, respectively.. Our data confirm lenvatinib efficacy in patients with advanced thyroid cancer, despite an important toxic profile.

Topics: Aged; Antineoplastic Agents; Disease Progression; Drug Resistance, Neoplasm; Female; Gastrointestinal Diseases; Humans; Hypertension; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies; Thyroid Neoplasms; Treatment Outcome

For dichotomous outcomes, odds ratio (OR) is one of the usual summary measures of indirect treatment comparison. A corresponding number needed to treat (NNT) estimate may facilitate understanding of the treatment effect.. We show how to estimate NNT based on OR results of a matching adjusted indirect comparison. We also have derived the explicit formula of its 95% CIs by applying the delta method, and as an alternative, a simulation-based method.. The method was applied in a case study example in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients, comparing lenvatinib to sorafenib. For every two RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have progressed and for every eight RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have died.. Using NNT to summarize the results of a matching adjusted indirect comparison can help the clinicians to better understand the results in addition to OR.

Topics: Antineoplastic Agents; Humans; Iodine Radioisotopes; Numbers Needed To Treat; Phenylurea Compounds; Quinolines; Sorafenib; Statistics as Topic; Thyroid Neoplasms

Treatment of patients with liver metastasis of differentiated thyroid carcinoma (DTC) has not been sufficiently defined, because liver metastasis of DTC has been described mostly as case reports. Additionally, such patients are considered end-of-treatment responders. A relatively new approach using tyrosine kinase inhibitors (TKIs) may provide opportunities to manage systemic metastasis. This study aims to define the clinical features of DTC patients with liver metastasis and evaluate the benefits of TKIs.. We retrospectively analyzed clinical features of 29 patients (mean age 67.8 years) diagnosed with liver metastasis of DTC at our institution between January 1981 and May 2017.. All patients had distant metastasis at other organ sites upon diagnosis of liver metastasis; 41% of them developed new metastasis afterward. Management after diagnosis of liver metastasis comprised palliative care (48%), radioactive iodine therapy (28%), and TKI therapy (24%). The median survival after diagnosis of liver metastasis was only 4.8 months. Survival rates were significantly better in patients with performance statuses between 0 and 2 on the Eastern Cooperative Oncology Group scale at diagnosis of liver metastasis (n = 22, 76%) treated with TKI compared to those who were not (P = 0.017; log-rank test; hazard ratio 0.19). One-year survival rates were 71.4 and 26.7% for patients treated with or without TKI, respectively.. Patients with liver metastasis had poor clinical prognosis. When other distant metastases existed at diagnosis of liver metastasis, TKI therapy was considered an effective therapeutic option for patients with liver metastasis of DTC.

Topics: Aged; Aged, 80 and over; Carcinoma, Papillary, Follicular; Female; Humans; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Protein-Tyrosine Kinases; Quinolines; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms

Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib.

Topics: Aged; Antineoplastic Agents; Drug Substitution; Female; Humans; Iodine Radioisotopes; Lung Neoplasms; Phenylurea Compounds; Proteinuria; Quinolines; Radiation Tolerance; Sorafenib; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tomography, X-Ray Computed; 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

The advent of tyrosine kinase inhibitors (TKIs) has changed the treatment of RAI refractory, unresectable recurrent differentiated thyroid cancer (DTC), which was formerly treated with multidisciplinary remedies.. Here we describe the case of a 64-year-old woman who underwent total thyroidectomy with tracheal resection and suffered from a recurrent tumor in the neck and multiple lung and bone metastases 3 and 11 months, respectively, after the operation. Multimodal therapies, RI (I-131), EBRT, and taxane-based chemotherapy were ineffective, and sorafenib was started as a TKI. However, because of disease progression, sorafenib was replaced by lenvatinib after 9 months. The effect of lenvatinib has continued for more than 1 year and 9 months, and the patient has well survived. During the treatment period, a tracheal pin-hole fistula suddenly emerged, which was naturally cured by the temporary cessation of lenvatinib. Adverse events such as hypertension, proteinuria, and diabetes as innate complications have been successfully managed until the present according to our institute regulations.. Even where multimodal treatment was ineffective, lenvatinib was suggested to be an alternative treatment option for RAI refractory recurrent DTC and patient could have a chance to be controlled successfully.

Topics: Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Angiogenesis plays a crucial role in the development, growth, and metastasis of carcinomas, and studies have reported conflicting evidence regarding the VEGFR expression in anaplastic thyroid cancer. We investigated the expression of VEGFR2 in patients with anaplastic thyroid cancer (ATC) and analyzed the clinical response to the VEGFR inhibitor lenvatinib.. This cross-sectional study included primary tumor samples obtained from 12 patients with ATC, including 5 males and 7 females (age range 63-89 years) who underwent surgery or core needle biopsy for a thyroid tumor in the Department of Breast and Endocrine Surgery at Kanagawa Cancer Center in Kanagawa, Japan. VEGFR2 protein expression in the ATC samples was analyzed by immunohistochemistry in all patients, and the therapeutic effect of lenvatinib was evaluated in seven patients who underwent tissue biopsy and lesion evaluation.. VEGFR expression was not detected in any of the samples from the 12 patients. Four of the 12 patients treated with lenvatinib had partial response, the three patients achieved stable disease, and the five patients were not examined.. There was no correlation between the expression of VEGFR2 in tumor tissue and the clinical response to lenvatinib among patients with ATC. Further studies are necessary to elucidate the mechanism underlying the response to lenvatinib.

Topics: Aged; Antineoplastic Agents; Biopsy, Large-Core Needle; Cell Proliferation; Cross-Sectional Studies; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Japan; Male; Neovascularization, Pathologic; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Gland; Thyroid Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

This study is planned as a non-randomised single-arm multicentre study; patients with pathologically confirmed differentiated thyroid carcinoma (DTC) with lesions that are refractory to radioiodine treatment are eligible. The main exclusion criteria are medullary or anaplastic carcinoma, prior treatment with chemotherapy, poor general condition and thromboembolism-requiring treatment. Patients to be included in the study will be treated with lenvatinib and undergo FDG-PET/CT examination twice: before and 1 week after the initiation of treatment. Contrast-enhanced CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum standard uptake value for FDG PET/CT performed 1 week after the initiation of treatment to predict outcomes compared with the response evaluation obtained via contrast-enhanced CT performed at least 4 weeks after the initiation of treatment.. This study is conducted in accordance with the Declaration of Helsinki and has received ethical approval from the institutional review board of the Hokkaido University Hospital (approval number: 015-402). The results of this study will be disseminated through a presentation at a conference and the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the SPIRIT statement.. UMIN000022592.

Topics: Adult; Antineoplastic Agents; Clinical Protocols; Fluorodeoxyglucose F18; Humans; Iodine Radioisotopes; Phenylurea Compounds; Positron-Emission Tomography; Quinolines; Thyroid Gland; Thyroid Neoplasms; Treatment Failure; Treatment Outcome

Once-daily lenvatinib 24 mg is the approved dose for radioiodine-refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure-response model to investigate the risk-benefit of different dosing regimens for lenvatinib.. A population pharmacokinetics/pharmacodynamics modeling analysis was used to simulate the potential benefit of lower starting doses to retain efficacy with improved safety. The seven lenvatinib regimens tested were: 24 mg; and 20 mg, 18 mg, and 14 mg, all with or without up-titration to 24 mg. Exposure-response models for efficacy and safety were created using a 24-week time course.. The approved dose of lenvatinib at 24 mg, predicted the best efficacy. However, the lenvatinib dosing regimens of 14 mg with up-titration or 18 mg without up-titration potentially provides comparable efficacy (objective response rate at 24 weeks) and a better safety profile.. Treatment with lenvatinib at starting doses lower than the approved once-daily 24 mg dose could provide comparable antitumor efficacy and a similar or better safety profile. Based on the results from this modeling and simulation study, a comparator dose of lenvatinib 18 mg without up-titration was selected for evaluation in a clinical trial.

Topics: Antineoplastic Agents; Area Under Curve; Clinical Trials, Phase III as Topic; Computer Simulation; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Iodine Radioisotopes; Models, Biological; Phenylurea Compounds; Predictive Value of Tests; Probability; Quinolines; Thyroid Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Glioblastoma; Humans; Magnetic Resonance Imaging; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Lenvatinib is a molecular-targeting agent that was recently approved in Japan for treatment of curatively unresectable, radioactive iodine-refractory, progressive differentiated thyroid cancer (DTC). Because only a few Japanese patients have received lenvatinib in clinical trials, there are limited domestic data on its safety and efficacy or prognostic factors. Therefore, a prospective observational study has been designed to collect safety and efficacy data in at least 300 patients with curatively unresectable DTC receiving lenvatinib therapy (24 mg/day), in order to find predictors of antitumor activity and survival. Patients with progressive curatively unresectable DTC refractory to radioiodine therapy will be enrolled and the primary endpoint will be overall survival. This study is designed to estimate the 95% confidence intervals of the 1-year and 2-year survival rates with a two-sided width of less than 10%. Secondary endpoints will be the time to treatment failure, time to strategy failure, progression-free survival time with clinical progressive disease, response rate, quality of life, safety, and patient reports. The ultimate goal is to obtain information for developing evidence-based guidelines for treatment of DTC, including recommendations on patient selection, dosages, and duration of treatment. This study has been registered with the UMIN Clinical Trials Registry (UMIN000022243).

Topics: Antineoplastic Agents; Cohort Studies; Disease-Free Survival; Humans; Japan; Phenylurea Compounds; Prospective Studies; Quality of Life; Quinolines; Research Design; Survival Rate; Thyroid Neoplasms

Topics: Abdomen; Aged; Carcinoma; Carcinoma, Hepatocellular; Folliculitis; Hand-Foot Syndrome; Humans; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Skin Diseases; Sorafenib; Thigh; Thyroid Neoplasms

The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital.. Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment.. During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment.. About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma; Carcinoma, Medullary; Female; Follow-Up Studies; Heart Failure; Humans; Intestinal Perforation; Kaplan-Meier Estimate; Male; Middle Aged; Oophoritis; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Retrospective Studies; Risk Factors; Sorafenib; Thrombocytopenia; Thyroid Neoplasms; Time Factors; Young Adult

The objective of the study was to reveal through pragmatic MCDA (EVIDEM) the contribution of a broad range of criteria to the value of the orphan drug lenvatinib for radioiodine refractory differentiated thyroid cancer (RR-DTC) in country-specific contexts.. The study was designed to enable comprehensive appraisal (12 quantitative, 7 qualitative criteria) in the current disease context (watchful waiting, sorafenib) of France, Italy and Spain. Data on the value of lenvatinib was collected from diverse stakeholders during country-specific panels and included: criteria weights (individual and social values); performance scores (judgments on evidence-collected through MCDA systematic review); qualitative impacts of contextual criteria; and verbal and written insights structured by criteria. The value contribution of each criterion was calculated and uncertainty explored.. Comparative effectiveness, Quality of evidence (Spain and Italy) and Disease severity (France) received the greatest weights. Four criteria contributed most to the value of lenvatinib, reflecting its superior Comparative effectiveness (16-22% of value), the severity of RR-DTC (16-22%), significant unmet needs (14-21%) and robust evidence (14-20%). Contributions varied by comparator, country and individuals, highlighting the importance of context and consultation. Results were reproducible at the group level. Impacts of contextual criteria varied across countries reflecting different health systems and cultural backgrounds. The MCDA process promoted sharing stakeholders' knowledge on lenvatinib and insights on context.. The value of lenvatinib was consistently positive across diverse therapeutic contexts. MCDA identified the aspects contributing most to value, revealed rich contextual insights, and helped participants express and explicitly tackle ethical trade-offs inherent to balanced appraisal and decisionmaking.

Topics: Advisory Committees; Antineoplastic Agents; Decision Support Techniques; Evidence-Based Medicine; France; Humans; Italy; Outcome and Process Assessment, Health Care; Phenylurea Compounds; Quinolines; Spain; Thyroid Neoplasms

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy.. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015.. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib.. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Fatigue; Female; Humans; Hypertension; Male; Middle Aged; Phenylurea Compounds; Pulmonary Embolism; Quinolines; Retrospective Studies; Salvage Therapy; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Lenvatinib (Lenvima. A Markov model was developed to estimate the costs and health benefits for treatment of RR-DTC. The probabilities and survival rates were obtained from two Phase III trials: the SELECT trial comparing lenvatinib to placebo, and the DECISION trial comparing sorafenib to placebo. A bimonthly cycle length and half-cycle correction were used for a lifetime time horizon. Medical costs and utility data were obtained from RedBook, Healthcare Cost and Utilization Project, and the published literature. All costs were adjusted to US$2015, discounted at 3% annually. Then second-order Monte Carlo simulation with distributions was conducted to obtain the acceptability curve to address the uncertainty around model inputs.. In the base case, lenvatinib was the most cost-effective treatment compared to sorafenib (incremental cost-effectiveness ratio [ICER] = $25,275/quality-adjusted life year [QALY]) and placebo (ICER = $40,869). Sorafenib is also cost-effective compared to placebo (ICER = $64,067/QALY). The treatment decisions were found to be sensitive to the treatment costs and the health utility associated with lenvatinib and its side effects. The acceptability curve showed lenvatinib optimal 80% of time at WTP of $100,000/QALY.. This study suggests that lenvatinib is the optimally cost-effective treatment for RR-DTC, although both lenvatinib and sorafenib are cost-effective compared to placebo.

Topics: Aged; Antineoplastic Agents; Cell Differentiation; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Cost-Benefit Analysis; Drug Costs; Female; Health Care Costs; Humans; Male; Middle Aged; Models, Economic; Monte Carlo Method; Neoplasm Grading; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quality of Life; Quinolines; Sorafenib; Survival Analysis; Thyroid Neoplasms; Tumor Burden; United States

Topics: Antineoplastic Agents; Carcinoma, Papillary; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Middle Aged; Neoplasm Metastasis; Phenylurea Compounds; Positron-Emission Tomography; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Thyroidectomy; Thyrotropin

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

Topics: Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

In municipal hospitals, there are few cases of thyroid cancer for which the multi-kinase inhibitor lenvatinib is used. Moreover, there are very few reports of lenvatinib use. We examined interventions related to the use of lenvatinib made at the pharmaceutical outpatient clinic in our facility. Seven patients received lenvatinib. The prescription proposals from the pharmacist( 45 cases)provided advice on dosage(15.6%), discontinuation of medication(11.1%), supportive care(64.4%), and other advice(9.0%). The prescription acceptance rate was 84.4%. Among the prescription proposals of supportive care, there were suggestions regarding blood pressure(26.7%), diarrhea(8.9%), nausea(8.9%), and oral hemorrhage(6.7%). Some patients also experienced side effects, such as abnormalities in equilibrioception and visual field defects; however, the relationship between such abnormalities and lenvatinib is unclear. In addition, we asked physicians to confirm if the outpatient pharmacists contributed to the examination process. We believe that lenvatinib administration can be continued safely with pharmaceutical outpatient clinic support for patients, even in municipal hospitals.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Outpatients; Phenylurea Compounds; Physicians; Quinolines; Surveys and Questionnaires; Thyroid Neoplasms

Topics: Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

Glioblastoma (GBM) is a lesion radiologically characterized by magnetic resonance imaging findings, such as ring enhancement with extensive perifocal edema and a butterfly appearance extending into the bilateral lobes. However, these characteristic findings could be changed by antiangiogenic therapy, with decreased contrast enhancement and improved perifocal edema. Herein, we report a case of GBM that arose during treatment with a tyrosine kinase inhibitor for another cancer.. A 57-year-old man presented with seizures. Until the seizure onset, he had been treated with the multireceptor tyrosine kinase inhibitor lenvatinib for 4 years for thyroid cancer and its metastasis to the thoracic vertebral body. Magnetic resonance imaging revealed a slightly high intensity lesion in the left frontal base area on T. Lenvatinib, which is antiangiogenic, might have affected the radiologic characteristics, as well as the pathology of the tumor. Brain tumors arising during treatment with receptor tyrosine kinases for other cancers could show atypical imaging findings.

Topics: Antineoplastic Agents; Brain Neoplasms; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Treatment Outcome

Lenvatinib is approved for use in advanced radioactive iodine-resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience.. Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed.. The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0-10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response.. Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy.. DTC = differentiated thyroid cancer; LASA = linear analog self-assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Calibration; Carcinoma, Papillary, Follicular; Dose-Response Relationship, Drug; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Metastasis; Phenylurea Compounds; Quality of Life; Quinolines; Retrospective Studies; Thyroid Neoplasms; Treatment Failure

The 208 trial showed that lenvatinib has a significant antitumor effect on unresectable anaplastic thyroid cancer(ATC). Herein, we present a retrospective review of data from 7 patients with unresectable ATC who received lenvatinib in our hospital between May 2015 and October 2016. Two patients were men and 5 were women. The median age was 78(range, 72-85)years, and 1 patient had Stage IV A disease, 1 had Stage IV B, and 5 had Stage IV C at diagnosis, respectively. Three patients experienced a partial response and 1 patient experienced stable disease. The response rate was 43%, and the disease control rate was 57%. The median progression-free survival(PFS)was 4.1(range, 1.1-12.2)months. Grade 3 and Grade 4 gastrointestinal hemorrhage were observed in 2patients and Grade 3 anorexia was observed in 1 patient. Further clinical research seems to be needed to establish a treatment strategy involving lenvatinib for ATC.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Cell Differentiation; Dose-Response Relationship, Drug; Hemorrhage; Humans; Male; Phenylurea Compounds; Precision Medicine; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Topics: Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Thyroid Neoplasms

We report a case of a rupture of the common carotid artery caused by the medication of lenvatinib. The patient, 70-yearold female, was referred to our hospital by unresectable papillary thyroid cancer infiltrated the left common carotid artery. Externalbeam radiotherapy and radioiodine therapy were undergone after totalthyroidectomy. After 1 year 7 months from operation, she admitted our hospital due to left shoulder pain and dysphagia caused by the growing left cervical tumor. The medication of lenvatinib was decided after the careful informed consent. Computed tomography on the eighth day of lenvatinib medication showed the existence of air infiltration into the tumor surrounded left common carotid artery. So, a discontinuance of lenvatinib medication was decided immediately. But, on the ninth day, a rupture of the left common carotid artery occurred and on the tenth day, she died. Lenvatinib medication for the patient with the tumor surrounded artery should be decided carefully.

Topics: Aged; Antineoplastic Agents; Carcinoma, Papillary; Carotid Artery Diseases; Fatal Outcome; Female; Humans; Phenylurea Compounds; Quinolines; Rupture; Thyroid Cancer, Papillary; Thyroid Neoplasms

There are currently no effective therapeutic methods for locally recurrent, metastatic, or progressive radioactive iodine (RAI)-refractory differentiated thyroid cancer. However, multitargeted tyrosine kinase inhibitors (TKIs) such as lenvatinib or sorafenib have been approved for patients with RAI-refractory differentiated thyroid cancer as a second targeted therapy, and these agents can prolong patient survival. However, several cases have been reported that TKIs have caused fatal complications such as fistula formation or bleeding.. We report a case of a 53-year-old woman, who underwent repeated neck dissections and RAI therapy after total thyroidectomy in an outside hospital. Pathology revealed a papillary carcinoma of the tall cell variant. Locoregional recurrence was not under control; therefore, she visited our hospital. Although surgery was performed for locoregional recurrences three times in our hospital, they were not under control and distant metastases were found in the lung and bone a year later. Therefore, although sorafenib was initiated, the locoregional recurrence progressed 6 months later and computed tomography (CT) showed a 7-cm mass in the right subclavicular lesion. Lenvatinib was started at a dose of 24 mg daily. However, although tumor was rapidly reduced, an ulcer occurred in the right subclavicular lesion and was gradually increasing in size. The pulsation of subclavicular artery was found in the deep portion of the ulcer. Therefore, a pectoralis major myocutaneous flap was transplanted to cover the ulcer. Lenvatinib was an antiangiogetic TKI; therefore, it was preoperatively discontinued for 8 days and postoperatively for 12 days. The postoperative course was uneventful.. Fistula formation or bleeding is known to be a severe side effect of antiangiogenic TKIs such as lenvatinib or sorafenib. There is a possibility that severe complications can occur when initiating TKIs in patients whose tumor has invaded into the skin, vessels, trachea, esophagus, and other areas. Therefore, it is necessary to use antiangiogenic TKIs very carefully. It is important to determine the appropriate time to start TKIs; however, there is no established protocol for this, and it is a problem that needs urgent attention.

Topics: Carcinoma, Papillary; Clavicle; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Middle Aged; Myocutaneous Flap; Neoplasm Recurrence, Local; Pectoralis Muscles; Phenylurea Compounds; Plastic Surgery Procedures; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; Thyroidectomy; Ulcer

There are limited treatment options for patients with radioactive iodine refractory, progressive differentiated thyroid cancer. Although there is consensus that multikinase inhibitor therapy should be considered in patients with progressive disease with considerable tumor load or symptomatic disease, uncertainty exists on the optimal timing to treat with a multikinase inhibitor, especially for asymptomatic patients. RIFTOS MKI is an international, prospective, open-label, multicenter, noninterventional study with the primary objective to compare the time to symptomatic progression from study entry in asymptomatic patients with radioactive iodine refractory, progressive differentiated thyroid cancer for whom there is a decision to initiate multikinase inhibitors at study entry (cohort 1) with those for whom there is a decision to not initiate multikinase inhibitors at study entry (cohort 2). Secondary endpoints are overall survival and progression-free survival, which will be compared between cohorts 1 and 2. Additional secondary endpoints are postprogression survival from time of symptomatic progression, duration of and response to each systemic treatment regimen and dosing of sorafenib throughout the treatment period. Asymptomatic, multikinase inhibitor-naive patients aged ≥18 years with histologically/cytologically documented differentiated thyroid cancer that is radioactive iodine refractory are eligible. Patients may receive any therapy for differentiated thyroid cancer, including sorafenib or other multikinase inhibitors if indicated and decided on by the treating physician. In total, 700 patients are estimated to be enrolled from >20 countries. Final analysis will be performed once the last enrolled patient has been followed up with for 24 months (ClinicalTrials.gov identifier: Nbib2303444).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma; Drug Administration Schedule; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Salvage Therapy; Sorafenib; Thyroid Neoplasms; Time Factors; Treatment Failure

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

Radioiodine [RAI]-resistant advanced and progressive differentiated thyroid cancer [DTC], although rare, constitutes a real challenge as its prognosis is poor and available therapeutic options, until now, have been limited. Discovery of a crucial role of distinct tyrosine kinases in DTC pathogenesis opened up new options in systemic treatment. Lenvatinib is an oral potent multi kinase inhibitor [MKI] of different growth factor receptors including VEGFR1/Flt-1, VEGFR2/KDR, VEGFR3, FGFR1,2,3,4, PDGFR-β as well as RET and KIT signaling networks. Its activity against RAI-refractory DTC was demonstrated in clinical studies fulfilling evidence-based medicine [EBM] criteria. The drug showed acceptable tolerance and manageable toxicity.. published results of phase II and III studies and other reports evaluated the efficacy and safety of lenvatinib in DTC and in medullary thyroid carcinoma.. Currently there are two different MKIs, lenvatinib and sorafenib, which have demonstrated effectiveness against RAI-refractory DTC. However, to date, the question of which drug should be chosen for first line treatment remains open. The other question: when to start the treatment seems to be no less important. Whether disease progression, even by RECIST, is enough to initiate a therapy or tumor burden also plays an important role? EBM study, to resolve these issues, is our task for the nearest future.

Topics: Biomarkers; Calcitonin; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Half-Life; Humans; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thyroglobulin; Thyroid Neoplasms

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

A 73-year-old woman visited our hospital 1 year 4 months ago because of multiple lung masses that were incidentally detected on CT. We subsequently conducted a whole body examination. Ultrasonography revealed multiple masses in her thyroid. We performed fine needle aspiration biopsy cytology(ABC), and the cytological diagnosis was papillary carcinoma. Total thyroidectomy and modified radical neck dissection were performed. Two months after the operation, cervical lymph nodes were enlarged, and she received I -131 radioisotope therapy. However, the lung masses became enlarged. Five months after operation, she was stared on lenvatinib therapy. The lung lesions did not progress during the 10 months after starting this therapy. In this case, lenvatinib was effective against metastatic thyroid cancer.

Topics: Aged; Antineoplastic Agents; Biopsy, Fine-Needle; Carcinoma, Papillary; Female; Humans; Lung Neoplasms; Lymphatic Metastasis; Neck; Phenylurea Compounds; Quinolines; Thyroid Neoplasms; Thyroidectomy; Treatment Outcome

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Molecular Targeted Therapy; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms; Time Factors; Treatment Outcome

The FDA approved lenvatinib to treat progressive, differentiated thyroid cancer, potentially offering the most effective treatment to date for a subset of thyroid cancer patients who do not respond to standard therapy.

Topics: Antineoplastic Agents; Drug Approval; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms; United States; United States Food and Drug Administration

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thyroid Neoplasms

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Drug Approval; Humans; Iodine Radioisotopes; Multicenter Studies as Topic; Phenylurea Compounds; Quinolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms; Treatment Outcome; United States; United States Food and Drug Administration

Lenvatinib mesylate (E7080; 4-[3-chloro-4-(N'-cyclopropylureido) phenoxy] 7-methoxyquinoline-6-carboxamide mesylate) is an oral molecule that inhibits multiple tyrosine kinase receptors such as VEGF-R-1-3, FGF-R-1-4, RET, c-KIT and PDGF-R-β. Phase I studies identified the maximum tolerated dose to be 25 mg daily that, in fasting treated patients, is rapidly absorbed with maximum concentrations achieved within 3 h of administration. In these studies, lenvatinib showed activity in solid tumors. Subsequently, Phase II studies in thyroid cancer, in particular differentiated thyroid cancer (DTC), confirmed good clinically significant activity and the recently published Phase III SELECT trial reported median progression-free survival was 18.3 months with lenvatinib versus 3.6 months with placebo (hazard ratio for progression or death: 0.21; 99% CI: 0.14-0.31; p < 0.001). Treatment-related adverse effects occurred in more than 40% of patients on lenvatinib. These were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%) and nausea (in 41.0%). Discontinuations of lenvatinib because of adverse effects occurred in 37 patients (14.2%) compared with three patients who received placebo (2.3%). Six of 20 deaths in patients on lenvatinib were considered to be drug-related. Lenvatinib has been licensed by the US FDA and EMA based on these data and provides an option for the treatment of radioiodine refractory DTC.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Phenylurea Compounds; Quinolines; Radiation Tolerance; Radiopharmaceuticals; Signal Transduction; Thyroid Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Quinolines; Sorafenib; Thyroid Neoplasms

The FDA approved lenvatinib (Lenvima, Eisai Inc.) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory (RAI-refractory) differentiated thyroid cancer (DTC). In an international, multicenter, double-blinded, placebo-controlled trial (E7080-G000-303), 392 patients with locally recurrent or metastatic RAI-refractory DTC and radiographic evidence of disease progression within 12 months prior to randomization were randomly allocated (2:1) to receive either lenvatinib 24 mg orally per day (n = 261) or matching placebo (n = 131) with the option for patients on the placebo arm to receive lenvatinib following independent radiologic confirmation of disease progression. A statistically significant prolongation of progression-free survival (PFS) as determined by independent radiology review was demonstrated [HR, 0.21; 95% confidence interval (CI), 0.16-0.28; P < 0.001, stratified log-rank test], with an estimated median PFS of 18.3 months (95% CI, 15.1, NR) in the lenvatinib arm and 3.6 months (95% CI, 2.2-3.7) in the placebo arm. The most common adverse reactions, in order of decreasing frequency, observed in the lenvatinib-treated patients were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib at the 24 mg dose and 18% of patients discontinued lenvatinib for adverse reactions leading to residual uncertainty regarding the optimal dose of lenvatinib.

Topics: Adult; Aged; Antineoplastic Agents; Disease Progression; Drug Approval; Female; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Radiation Tolerance; Randomized Controlled Trials as Topic; Retreatment; Thyroid Neoplasms; Treatment Outcome; United States; United States Food and Drug Administration

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

In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening.. Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall.. Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Topics: Academic Medical Centers; Angiogenesis Inhibitors; Anilides; Combined Modality Therapy; Drugs, Investigational; Esophageal Fistula; Fatal Outcome; Humans; Indoles; Male; Middle Aged; Neck Dissection; Phenylurea Compounds; Postoperative Complications; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinolines; Receptor Protein-Tyrosine Kinases; Respiratory Tract Fistula; Risk Factors; Sunitinib; Texas; Thyroid Neoplasms; Thyroidectomy; Tracheoesophageal Fistula

Topics: Disease Progression; Disease-Free Survival; Humans; Phenylurea Compounds; Quinolines; Thyroid Neoplasms