New treatment modalities in advanced thyroid cancer

BackgroundThyroid cancer is a heterogeneous disease that is classified into differentiated thyroid carcinoma (DTC), undifferentiated/anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma. Results of conventional treatment modalities in advanced thyroid cancer have been disappointing and therefore, new therapies are needed.MethodsWe searched PubMed, The Cochrane Library, Medline and EMBASE databases and abstracts published in annual proceedings for new treatment modalities in advanced thyroid cancer. We also searched for ongoing trials in www.clinicaltrials.govResultsSix phase I, 17 phase II and 1 phase III trials with tyrosine kinase inhibitors were carried out. We found 2 pilot studies and 11 phase II trials with redifferentiation therapies, mainly in DTC. For antiproliferative approaches, three phase I and four phase II trials were found. Immunomodulatory gene therapy was tested in a pilot study in ATC patients. Two phase II trials were carried out with immunotherapy. One phase I and nine phase II trials were found with radionucleotide therapy in patients with DTC.ConclusionsThe developments in the treatment of advanced thyroid cancer are intriguing. Future trials should aim at combinations of targeted agents with or without other treatment modalities, and will hopefully contribute to further improvement of outcomes.     

Medullary thyroid carcinoma: Management of lymph node metastases

Opinion statement Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells. Spread of MTC commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine, and are not sensitive to hormonal manipulation. Because of these features, the treatment of metastatic or recurrent MTC is different from the treatment of differentiated thyroid cancer. Surgery is the only effective therapy at present that can result in cure, or reduction in tumor burden, or effective palliation. Systematic surgical removal of at-risk or involved lymph node basins should be done in patients with palpable primary tumors and recurrence. A “berry-picking” approach is discouraged. Although data are limited, standard chemotherapy and radiation therapy have not been effective in the treatment of MTC. Newer targeted drug therapies are being examined in therapeutic clinical trials.     

Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options

Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14%-39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer.     

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Hereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of-function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, and will summarize the therapies designed to strategically interfere with the pathologic activation of the RET oncogene.     

甲状腺未分化癌的研究进展

甲状腺未分化癌（anaplastic thyroid cancer,ATC）是一种罕见的甲状腺肿瘤,约占甲状腺恶性肿瘤的1%~2%,是最具侵袭性的甲状腺癌,可导致显著的发病率和死亡率。高龄、男性、双侧肿瘤、局部浸润和（或）远处转移等是多数ATC患者预后欠佳因素。ATC最佳治疗方案尚未明确,目前虽以手术、放疗、化疗、靶向治疗、免疫治疗等综合治疗为主,然而治疗现状不容乐观。本文通过整理国内外ATC的相关研究,就目前的诊断、治疗方案、近期临床试验结果,以及今后的研究方向等进行综述,为ATC的诊疗决策提供参考。      

Medullary thyroid cancer: therapeutic targets and molecular markers

PURPOSE OF REVIEW: The present review will provide an update of important studies in medullary thyroid cancer (MTC) with an emphasis on targeted preclinical and translational research studies published over the past 2 years. RECENT FINDINGS: Recent advances in the biology of MTC, particularly in RET proto-oncogene signaling, are now being translated into promising new therapies and biomarkers. Multifunction tyrosine kinase inhibitors that target RET, plus vascular endothelial growth factor receptors and additional kinases, are now being evaluated in Phase II clinical trials in MTC. Important unanswered questions include the optimal means for selecting high-risk patients, appropriate biomarkers for monitoring kinase inhibitor trials, and trial endpoints. Similar to ABL, epidermal growth factor receptors and other kinases, individual mutant RET forms have differential sensitivity to different inhibitors. In addition to RET, an old marker, calcitonin, has assumed increasing importance, but may not adequately reflect changes in tumor burden in RET inhibitor trials. A number of new therapeutic strategies are being developed that could be appropriate for the approximately 50% of patients who lack RET mutations in their tumors. SUMMARY: Progress is being made toward effective targeted MTC therapy. Patients with advanced, progressive MTC should be considered for enrollment in clinical trials.     

Lenvatinib: Role in thyroid cancer and other solid tumors

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.     

甲状腺未分化癌的综合治疗

甲状腺未分化癌（ATC）是一种罕见的肿瘤,占甲状腺癌的1%~2%,其死亡病例占甲状腺癌致死病例的大多数。目前,主要采用的治疗方式包括手术、放疗、化疗、靶向治疗和免疫治疗。本文根据最新的美国甲状腺学会（ATA）指南和近年相关文献,阐述ATC的综合治疗方式以提高ATC患者的生存率和生活质量     

Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the malignant tumors with the poor prognosis that is thought to arise from well-differentiated thyroid cancer (DTC). To investigate the molecular mechanism of ATC, we studied genomic alterations of eight ATC cell lines and three DTC cell lines by means of the comparative genomic hybridization (CGH) method. Loss of 16p was observed in five of eight ATC cell lines (62. 5%), but none of the three DTC cell lines showed loss of this chromosome arm. It is notable that loss of 18q [7/8 of ATC (87.5%), 2/3 of DTC (67%)] and gain of 20q [5/8 of ATC (62.5%), 3/3 of DTC (100%)] were frequently seen in both histologic types. Our results suggest that there is a gene in 16p that is closely associated with transformation from well-differentiated thyroid cancer to anaplastic cancer.     

Systemic therapies for recurrent and/or metastatic salivary gland cancers

Salivary gland carcinomas are rare cancers, comprising 1-5% of head and neck cancers. They represent a morphologically and clinically diverse group of tumors. The most commonly histopathologic types are mucoepidermoid cancer, adenoid cystic cancer and adenocarcinomas. Malignant salivary gland tumors generally present as painless, slow-growing tumors that are indistinguishable from benign tumors. Surgery is the principal treatment and is curative in early stage. Radiation therapy should be considered in most patients after surgical resection. Chemotherapy is reserved for palliative treatment of metastatic disease but results are disappointing. Recent studies have investigated the role of targeted therapies in a palliative setting. Multicentre cooperative group clinical trials are required to assess novel therapies to maximize patient resources in this uncommon tumor.     

Sorafenib in Metastatic Thyroid Cancer: A Systematic Review

Background.

Sorafenib was recently approved by the U.S. Food and Drug Administration for radioiodine-resistant metastatic differentiated thyroid cancer (DTC). In addition, two drugs (vandetanib and cabozantinib) have received U.S. Food and Drug Administration approval for use in medullary thyroid cancer (MTC). Several published phase II trials have investigated the efficacy of sorafenib in thyroid cancers, but to date, results from those studies have not been compared.

Methods.

A systematic review of the literature was performed to assess response rate, median progression-free survival, and adverse events associated with sorafenib therapy for metastatic thyroid cancers.

Results.

This review included seven trials involving 219 patients: 159 with DTC (papillary, follicular, and poorly differentiated), 52 with MTC, and 8 with anaplastic thyroid cancer. No study reported complete responses to treatment. Overall partial response, stable disease, and progressive disease rates were 21%, 60%, and 20%, respectively. The median progression-free survival was 18 months for patients with all subtypes of thyroid cancer. Drug was discontinued in 16% of patients because of toxicities or intolerance, and the dose was reduced in a further 56%. Side effects with an incidence ≥50% were hand-foot syndrome (74%), diarrhea (70%), skin rash (67%), fatigue (61%), and weight loss (57%). Deaths not related to progressive disease occurred in nearly 4% of patients.

Conclusion.

Treatment with sorafenib in patients with progressive DTC and MTC is a promising strategy, but the adverse event rate is high, leading to a high rate of dose reduction or discontinuation. Consequently, sorafenib use in patients with metastatic thyroid cancer requires careful selection of patients and careful management of side effects.     

A conditionally replicative, Wnt/beta-catenin pathway-based adenovirus therapy for anaplastic thyroid cancer

Thyroid cancer affects between 10,000 and 15,000 people per year in the US. Typically, this disease can be controlled with surgical resection and radioiodide treatment. However, resistance to these conventional therapies is observed in some patients, who develop intractable anaplastic thyroid cancer (ATC), for which no effective therapies exist. Recently, a sizable fraction of undifferentiated or poorly differentiated thyroid cancers were shown to contain mutations in beta-catenin, an oncogenic protein involved in the etiology of cancers of many tissues. We developed a conditionally replicative adenovirus (named 'HILMI') which, by virtue of TCF response elements drives E1A and E1B expression, replicates specifically in cells with an active Wnt/beta-catenin pathway. We show that several thyroid cancer cell lines, derived from undifferentiated or anaplastic tissues and possessing an active Wnt/beta-catenin pathway, are susceptible to cell killing by HILMI. Furthermore, viral replication in ATC cells as xenograft tumors in nude mice was observed, and prolonged survival of mice with ATC tumors was observed following administration of the HILMI therapeutic vector. The results warrant further development of this therapeutic approach for ATC patients.     

Monoclonal antibodies-based treatment in gastric cancer: current status and future perspectives

Gastric cancer (GC) is the second leading cause of cancer-related death, and despite having improved treatment modalities over the last decade, for most patients, only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and the related signaling pathways offers, from the clinical point of view, promising advances for selected groups of patients. In the past, targeted therapies have significantly impacted the treatment strategy of several common solid tumors such as breast, colorectal, and lung cancers. Unfortunately, translational and clinical research shows fewer encouraging targeted treatments with regards to the GC. To date, only two monoclonal antibodies (mAb), named trastuzumab and ramucirumab, are approved for the treatment of advanced GC, suggesting that in GC, maybe more than in other cancers, effective targeted therapy requires patient selection based on precise predictive molecular biomarkers. The aim of this review is to summarize the available data on the clinical advantages offered by the use of mAbs in the treatment of advanced/metastatic GC. Future perspective is also discussed.     

Current status of gene therapy for cancers

Gene therapy with viral/unviral vectors is thought to be one of the most promising treatments for malignant diseases including cancers. The potential targeted genes researched are categorized into 2 groups: 1) those comprising oncogenes and oncosuppressor genes such as p 53 and E 1 A to directly kill tumors, and 2) others comprising immunoregulatory molecules such as TAA, cytokines, and T-cell costimulatory molecules to enhance anti-tumor immunity. These modalities have been intensively investigated for cancer treatment, and the anti-tumor efficacies are being shown in many preclinical studies using animal tumor models. To date, nevertheless, the clinical trials have not been successful overall. It is sometimes doubted whether this strategy with gene therapeutics is more beneficial than existing therapeutic modalities such as standard therapy with radiation and chemotherapeutics or immunotherapy with cytokines and immune cells to treat cancers. In fact,however,clinical responses of some targeted genes are now being revealed at higher levels of clinical trials, Phase II/III. Here, the genes targeted for cancer therapy and the current clinical trials are reviewed for a better understanding of cancer gene therapy.     

Systemic treatment and management approaches for medullary thyroid cancer

Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.     

Differentiated thyroid cancers: a comprehensive review of novel targeted therapies

Differentiated thyroid carcinoma (DTC) accounts for more than 90% of new thyroid cancer diagnoses, and includes papillary, follicular and Hürthle cell carcinoma. The prognosis for the vast majority of individuals diagnosed with DTC is excellent, with current treatment that includes surgery, radioactive iodine ablation and postoperative thyroid-stimulating hormone suppression. Unfortunately, the small proportion of individuals who develop radioactive iodine-resistant recurrent disease have few treatment options, and the vast majority will eventually die from their disease. Recently, several novel targets for anticancer agents have been identified and offer new hope for thyroid cancer patients diagnosed with progressive disease. In addition to targeting genes commonly altered in thyroid cancer, which include mutations in BRAF, RAS and RET, proangiogenic growth factor receptors and the sodium-iodide symporter have also been targeted. Several clinical trials evaluating tyrosine kinase and angiogenesis inhibitors for treatment of individuals diagnosed with metastatic or treatment-refractory DTC are currently underway. The objective of this review is to evaluate recent clinical trials that have studied novel targeted drugs for treatment of DTC.     

Medullary thyroid carcinoma: multivariate analysis of prognostic factors influencing survival

Background Medullary thyroid carcinoma (MTC) is a rare development of thyroid cancer with a no negligible mortality rate. Our aim was to determine factors that predict outcome in patients with MTC. Methods We reviewed the records of all patients with MTC (n=56) who underwent treatment at our institution between January 1990 and December 2000. Univariate and multivariate analysis of clinicopathologic predictors of MTC outcome were performed to identify subsets of patients with different probabilities in terms of overall survival, local recurrence, and distant metastases. Results Multivariate analysis demonstrated that a statistically significant decrease in overall survival is associated with T4b tumours (p=0.06), the presence of distant metastases at the time of presentation (p=0.033), lymphatic invasion (p=0.099), and postoperative treatment (p=0.045). Conclusions The analysis of survival curves of patients with MTC shows that the occurrence of locoregional and distant metastases occurs preferentially within the first 5 years, which identifies this as a crucial period for follow-up. In this series of patients with MTC, the tumours classified as T4b, metastases at presentation, the presence of lymphovascular invasion, and postoperative treatment were the most important prognostic features. At present, there is no available beneficial adjuvant therapy. However, as the development of molecular therapy progresses, it should be tested in clinical trials with the purpose of achievement of novel targeted therapies for selected MTC patients with risk factors.     

ONYX-411, a conditionally replicative oncolytic adenovirus, induces cell death in anaplastic thyroid carcinoma cell lines and suppresses the growth of xenograft tumors in nude mice

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer variant, accounting for 1-2% of all cases, but 33% of deaths, and exhibiting an average life expectancy of 5 months. ATC is largely unresponsive to radioactive iodine, chemotherapy, external beam radiation or surgery, underscoring the need for new and effective therapies. We evaluated the therapeutic potential of an oncolytic adenovirus, ONYX-411, that replicates selectively in and kills cells with dysfunction of the retinoblastoma (RB) pathway. In the present study, we report that ONYX-411 is able to induce cell death in eight human anaplastic carcinoma cell lines in vitro. The cytopathic effect of the virus is specific to cells with RB dysfunction, which appears to be frequent in ATC. We confirmed the expression of the coxsackie adenovirus receptor, CAR, in all ATC cell lines, demonstrating the potentially universal application of this oncolytic viral therapy to ATC. In addition, the growth of xenograft tumors induced in athymic mice with the ARO and DRO cell lines was significantly reduced by ONYX-411 treatment. These results indicate that ONYX-411 can be a potential therapeutic agent for the treatment of ATC, rendering this class of conditionally replicating adenoviruses an attractive candidate for clinical trials.     

Can mouse models for brain tumors inform treatment in pediatric patients?

Brain tumors represent the most common solid tumor of childhood. Although the histology of many pediatric brain tumors is similar to that of their adult counterparts, significant differences exist with regard to tumor location and response to therapy. The biological and genetic basis for this difference is poorly understood, as tumor tissue is generally unavailable for such studies. While targeted therapies directed against specific molecules active in cancer represents a new arsenal of agents for treating these tumors, such agents are generally not being developed for pediatric cancer in particular. Therefore, new agents for treatment of pediatric glioma must be obtained from compounds being tested against tumors of comparable histology in adult patients. Compounding this problem, although brain tumors are among the most lethal tumors of childhood, their absolute number is relatively small. As a consequence, trials with new agents must be prioritized based on the likelihood that a particular agent or combination of agents will have efficacy in pediatric cancer. Mouse models for brain tumors may help to identify targeted agents, and combinations of agents, effective against these tumors. Such data can be used to prioritize therapies for clinical trials in children with these tumors.     

中国抗癌协会甲状腺癌整合诊治指南（2022精简版）

甲状腺癌（thyroid cancer,TC）是内分泌系统和头颈部最常见的恶性肿瘤。既往的30年中,全球范围内TC发病率大幅增加,成为十大恶性肿瘤之一。如何对TC进行筛查、诊断、规范化治疗,如何对持续/复发/转移性TC基于多学科会诊（multi-disciplinary team,MDT）客观评估地系统性整合治疗,以及规范、有效的治疗后动态评估及系统随访,将是提高中国TC患者生存率、改善生存质量的重要保证,也是甲状腺领域专家肩负的重要责任。为了更好地推动中国TC的临床管理,中国抗癌协会甲状腺癌专业委员会组织相关专家结合中国经验,撰写了《中国肿瘤整合诊治指南》。本指南涵盖不同病理类型TC的疾病管理,包括甲状腺乳头状癌、滤泡癌、髓样癌、未分化癌,旨在为中国TC的规范化诊治提供指导与参考。