lenvatinib and Carcinoma--Papillary

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

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

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

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

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

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

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

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

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