Camrelizumab combined with transcatheter arterial chemoembolization and sorafenib or lenvatinib for unresectable hepatocellular carcinoma: A multicenter, retrospective study.

INTRODUCTION AND OBJECTIVES: We initiated this study to explore the efficacy of camrelizumab combined with transcatheter arterial chemoembolization (TACE) plus sorafenib or lenvatinib versus TACE plus sorafenib or Lenvatinib for unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From June 2019 to November 2022, 127 advanced HCC patients were retrospectively analyzed in this study. This consisted of 44 patients that received camrelizumab plus TACE plus sorafenib or lenvatinib (triple therapy group) and 83 patients that received TACE plus sorafenib or lenvatinib (double treatment group). The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were compared between the two patient groups. RESULTS: Our findings demonstrated that patients received the triple therapy exhibited superior median OS (15.8 vs. 10.3 months, P=0.0011) and median PFS (7.2 vs. 5.2 months, P=0.019) compared to the double treatment group. In addition, the triple therapy group exhibited better 6-month (93.5% vs. 66.3%), 12-month (67.2% vs. 36.3%), and 24-month (17.2% vs. 7.6%) survival rates than the double treatment group. However, the ORR (43.2% vs. 28.9%, P = 0.106) and DCR (93.2% vs. 81.9%, P = 0.084) of the two groups were similar. Subgroup analysis showed that compared with the double treatment group, the triple therapy group had a better mOS for HCC with HBV (15.8 vs. 9.6 months, P = 0.0015) and tumor diameter ≥ 5cm (15.3 vs. 9.6 months, P = 0.00055). CONCLUSIONS: Camrelizumab plus TACE and sorafenib or lenvatinib may be a promising treatment approach for the clinical management of unresectable HCC patients.

Challenges in treating radioiodine-refractory thyroid cancer: a global perspective with a focus on developing nations in Latin America.

PURPOSE: This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels. METHODS: To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences. RESULTS: Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes. CONCLUSION: Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries.

Ten years' real-life experience on the use of multikinase inhibitors in patients with advanced differentiated thyroid cancer.

PURPOSE: To evaluate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) associated with tyrosine kinase inhibitors (TKIs) in patients with radioiodine refractory differentiated thyroid cancer (RR-DTC). Additionally, to compare: (i) ORR and PFS among patients treated with lenvatinib and sorafenib; (ii) ORR and PFS among patients receiving lenvatinib as first-line vs. second-line and; (iii) adverse effects (AEs) observed in patients treated with these medications. METHODS: Retrospective analysis of RR-DTC adult patients treated with TKIs at the Division of Endocrinology, Hospital de Clinicas, University of Buenos Aires (March 2011-November 2023). RESULTS: Among 43 patients included in the study, 32 received sorafenib (30 as first-line and 2 as second-line), while 29 received lenvatinib (12 as first-line and 17 as second-line). The median PFS and OS for the entire cohort were 32.7 and 39.0 months, respectively. Lenvatinib demonstrated a significantly higher ORR compared to sorafenib (37.9% vs. 9.4%, p = 0.008). However, both drugs exhibited similar median PFS (23.2 vs. 16.0 months, p = 0.419). No significant difference was observed in ORR and PFS between patients receiving first-line vs. second-line lenvatinib. Sorafenib-treated patients experienced higher rates of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018), whereas lenvatinib-treated patients had higher rates of proteinuria (31% vs. 0%, p < 0.001) and grade 3 hypertension (31% vs. 9%, p = 0.034). CONCLUSION: TKIs demonstrated efficacy and tolerability comparable to real-world data in RR-DTC. PFS was not statistically different between sorafenib and lenvatinib. Our study will help guide physicians in making informed decisions regarding treatment sequencing with TKIs in these patients.

Clinical efficacy of lenvatinib, trans-arterial chemoembolization, and PD-1/L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Currently, the effectiveness of TACE, Lenvatinib, and PD-1/L1 inhibitors used alone or in combination has been thoroughly reported. However, the differences in effectiveness between these treatment protocols require further verification. To this end, this study employs a Bayesian network meta-analysis to compare the efficacy and safety of TACE, Lenvatinib, and PD-1/L1 inhibitors, whether administered by monotherapy or in combination, providing evidence-based medicine for the treatment of unresectable HCC. PURPOSE: This study employed a network meta-analysis to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE), Programmed Cell Death Protein/Ligand 1 (PD-1/L1) inhibitors, and Lenvatinib in the treatment of advanced HCC. METHODS: Literature on the treatment of advanced HCC with TACE, PD-1/L1 inhibitors, and Lenvatinib was searched for in both Chinese and English databases, including PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library, CNKI, and Wanfang. Two researchers conducted independent screening and data extraction, and the meta-analysis was performed using R language with the gemtc package. RESULTS: After retrieval and screening, a total of 21 articles were included, involving 2052 participants and six treatment modalities: Lenvatinib (L), TACE (T), TACE + Lenvatinib (TL), Lenvatinib + PD-1/L1 inhibitors (LP), TACE + Lenvatinib + PD-1/L1 inhibitors (TLP), and TACE + PD-1/L1 inhibitors (TP). In terms of objective response rate (ORR), the TLP regimen provided the optimal effect. In predicting the best ORR, TLP had the highest (75.5%) probability. In terms of disease control rate (DCR), the TLP regimen showed the best effect. In predicting the best DCR, the TLP again offered the highest (76.1%) probability. In terms of overall survival (OS), the best outcome was observed in the TLP protocol. In predicting the best OS, the TLP holds the highest (86.00%) probability. Furthermore, the best outcome in progression-free survival (PFS) was found in the TLP regimen. In predicting the best PFS, the TLP still holds the highest (97.0%) result. CONCLUSION: The combination of TACE, Lenvatinib, and PD-1/L1 inhibitors appears to provide the maximum benefit for inoperable HCC patients.

Differentiated thyroid carcinoma: what the nonspecialists needs to know.

Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

Differentiated thyroid carcinoma: what the nonspecialists needs to know

ABSTRACT Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

Posterior Reversible Encephalopathy Syndrome as an Adverse Effect of Lenvatinib in a Patient with Papillary Thyroid Carcinoma: A Case Report.

Posterior reversible encephalopathy syndrome (PRES) is an uncommon transient neuroradiological phenomenon that develops vasogenic cerebral edema and could be caused by some pharmacological agents, such as molecular-specific target agents. Lenvatinib belongs to the tyrosine kinase inhibitors and was approved in 2015 for progressive locally advanced or metastatic thyroid cancer refractory to radioactive iodine (I-131) treatment. Herein, we present the case of a 65-year-old woman who, while receiving treatment with lenvatinib for radioiodine-refractory metastatic papillary thyroid carcinoma, developed PRES without hypertension at the initial evaluation. Her clinical and radiological findings improved after withdrawing from the mentioned therapy, and later it was possible to re-incorporate lower doses of the medication, as described in the other three case reports found in the worldwide medical literature. The recognition of this entity is essential to timely suspend the drug and avoid greater comorbidity. This is the first paper reporting this kind of adverse event using lenvatinib in a Hispanic population.

SEOM-GECP-GETTHI Clinical Guidelines for the treatment of patients with thymic epithelial tumours (2021).

Thymic epithelial tumours (TET) represent a heterogeneous group of rare malignancies that include thymomas and thymic carcinoma. Treatment of TET is based on the resectability of the tumour. If this is considered achievable upfront, surgical resection is the cornerstone of treatment. Platinum-based chemotherapy is the standard regimen for advanced TET. Due to the rarity of this disease, treatment decisions should be discussed in specific multidisciplinary tumour boards, and there are few prospective clinical studies with new strategies. However, several pathways involved in TET have been explored as potential targets for new therapies in previously treated patients, such as multi-tyrosine kinase inhibitors with antiangiogenic properties and immune checkpoint inhibitors (ICI). One third of patient with thymoma present an autoimmune disorders, increasing the risk of immune-related adverse events and autoimmune flares under ICIs. In these guidelines, we summarize the current evidence for the therapeutic approach in patients with TET and define levels of evidence for these decisions.

Ubiquitin-specific protease 1 acts as an oncogene and promotes lenvatinib efficacy in hepatocellular carcinoma by stabilizing c-kit.

INTRODUCTION AND OBJECTIVES: Ubiquitin-specific proteases (USPs) act as proto-oncogenes or tumor suppressors in a wide variety of cancers. In this study, we intended to explore the role of USP1 in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The clinical significance of USP1 in HCC was analyzed based on The Cancer Genome Atlas (TCGA) data and immunohistochemical staining. siRNAs and lentivirus were used to knock down and overexpress indicated genes, respectively. qRT-PCR and immunoblotting were performed to examine mRNA and protein expression, respectively. CCK8, colony formation and PI/Annexin V-APC staining were performed to examine cellular function. Immunoprecipitation, coomassie blue staining, mass spectrum and immunoblotting were conducted to evaluate the interaction between USP1 and c-kit. RESULTS: USP1 was over-expressed in HCC patients. Patients with high expression of USP1 had shorter overall and disease free survival than those with low expression of USP1. Functional results showed that USP1 was critical for HCC cell growth and proliferation. Immunoprecipitation and immunoblotting results suggested that USP1 interacted with c-kit and promoted the stability of c-kit, which is an important target of lenvatinib in HCC. Knockdown of c-kit reversed the oncogenic function of USP1 on HCC cell growth. Lastly, USP1 upregulation conferred higher sensitivity of HCC cells to lenvatinib treatment. CONCLUSIONS: Our study demonstrated that USP1 acted as an oncogene in HCC. It also promoted lenvatinib efficacy by stabilizing c-kit.

Respuesta al lenvatinib en una paciente pediátrica con insuficiencia respiratoria secundaria a carcinoma papilar de tiroides / Response to lenvatinib in a pediatric patient with respiratory failure associated with papillary thyroid carcinoma

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.

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.

[Response to lenvatinib in a pediatric patient with respiratory failure associated with papillary thyroid carcinoma]. / Respuesta al lenvatinib en una paciente pediátrica con insuficiencia respiratoria secundaria a carcinoma papilar de tiroides.

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.

Tyrosine Kinase Inhibitors and Hepatocellular Carcinoma.

Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.

Real-life use of lenvatinib in patients with differentiated thyroid cancer: experience from Argentina.

PURPOSE: To describe the experience with radioiodine-resistant differentiated thyroid cancer (RR-DTC) patients treated with lenvatinib in two university hospitals from Argentina. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

The experience of an Endocrinology Division on the use of tyrosine multikinase inhibitor therapy in patients with radioiodine-resistant differentiated thyroid cancer.

PURPOSE: To describe the experience of our Division of Endocrinology with multikinase inhibitor (MKI) treatment in radioiodine-resistant differentiated thyroid cancer (DTC) patients. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Respuesta parcial a lenvatinib como segunda línea de tratamiento en cáncer diferenciado avanzado de tiroides / Partial response to lenvatinib as a second line of treatment in advanced differentiated cancer of thyroid

RESUMEN Las metástasis a distancia ocurren en alrededor del 10% de los pacientes con cáncer diferenciado de tiroides (CDT), y cerca de la mitad de estos casos serán refractarios al radioyodo (RAIR). Sorafenib fue el primer inhibidor multicinasa (IMK) aprobado por la FDA para su uso en cáncer diferenciado de tiroides RAIR avanzado y progresivo, y hasta el momento es el único aprobado por la ANMAT en nuestro país para esta indicación. Lenvatinib es el segundo IMK aprobado por la FDA para este grupo de pacientes, y es una alternativa terapéutica que debe ser considerada, debido a su disponibilidad como fármaco de uso compasivo en nuestro país. Presentamos nuestra experiencia con el uso de lenvatinib como segunda línea de tratamiento en una paciente con CDT progresivo previamente tratado con sorafenib.

ABSTRACT Distant metastases occur in around 10% of patients with differentiated thyroid cancer (DTC), and half of these cases will become refractory to radioiodine therapy (RAIR). Sorafenib was the first multikinase inhibitor (MKI) approved by the FDA for patients with differentiated advanced and progressive RAIR thyroid cancer, and it is the only one approved by ANMAT in our country for this indication. Lenvatinib is the second MKI approved by the FDA for this group of patients, and is a therapeutic alternative that should be considered, due to its availability as a compassive use drug in our country. We present our experience with the use of lenvatinib as a second line of treatment in a patient with DTC with advanced and progressive disease under treatment with sorafenib.

Consensus on the management of advanced radioactive iodine-refractory differentiated thyroid cancer on behalf of the Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and Spanish Rare Cancer Working Group (GETHI).

Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC.