Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Introduction: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options.

Areas covered: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers.

Expert opinion: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA gene-edited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.     

The mTOR protein as a target in thyroid cancer

Introduction: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents.

Areas covered: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer.

Expert opinion: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

不同剂量131I对分化型甲状腺癌患者血清中TH水平及生活质量的影响

目的：探讨不同剂量131I对分化型甲状腺癌患者血清中甲状腺激素水平及生活质量的影响。方法：回顾性分析2012年1月—2015年3月我院收治的85例分化型甲状腺癌患者,所有患者均进行甲状腺癌切除手术,术后给予131I治疗,根据剂量不同分为3组,A组为1次应用131I治疗的患者,共27例,累计剂量为2.96～3.70 GBq,B组为2次应用131I治疗的患者,共23例,累计剂量为8.14～10.36 GBq,C组3次应用131I治疗的患者,共20例,累计剂量为12.95～17.02 GBq,比较3组患者治疗前后的临床疗效,生活质量评分,另15例同期未接受131I治疗的患者作为对照。结果：131I治疗组的有效率均显著高于对照组,B、C组有效率最高,A组次之（P<0.05）;3组患者治疗后躯体功能、角色功能、认知功能、情绪功能以及社会功能等方面的评分均显著高于治疗前, B组治疗后的生存质量评分最高,C组次之,A组最低,组间差异有统计学意义。结论：131I治疗分化型甲状腺癌疗效显著,可提高患者的生活质量,其中以B组的治疗方案效果最佳。     

手术治疗分化型甲状腺癌合并淋巴细胞性甲状腺炎的临床疗效分析

目的:讨论手术治疗分化型甲状腺癌合并淋巴细胞性甲状腺炎的临床疗效。方法:选取2014年1月~2016年10月于某院收治的80例分化型甲状腺癌合并淋巴细胞性甲状腺炎患者,所有患者均实施甲状腺切除术联合区域性颈部淋巴结廓清术,观察患者的手术治疗效果、甲状旁腺功能情况。结果:80例患者经手术治疗后,平均手术操作时间为(126.3±30.7)min、平均术中出血量(22.2±10.2)ml、平均术后住院时间(3.4±1.1)d,治疗总有效率为96.25%(77/100);3例声音嘶哑,2例手足抽搐,2例呼吸困难,1例甲状腺危象现象,所有不良并发症经及时干预处理后均得以纠正。随访3年后,80例患者均未出现死亡以及病情复发现象,仅有1例患者出现颈部淋巴结转移情况,经再次手术治疗后已恢复。80例患者术后的血清PTH水平及血钙水平均明显低于对照组,P<0.05。结论:手术治疗分化型甲状腺癌合并淋巴细胞性甲状腺炎的临床疗效显著,可有效降低该病症复发率,值得推广。     

放射性^131I治疗分化型甲状腺癌术后转移临床分析

目的：分析放射性^131I治疗分化型甲状腺癌术后转移灶的临床观察和远期随访结果。方法：根据患者残留甲状腺组织大小和摄碘率,合理应用^131I投放剂量,每位患者治疗1～4个疗程,每个疗程间隔3～8个月,并对22例患者的治疗结果作一疗效分析。结果：22例患者共经49次治疗,有效22例（100％）,清除12例（57％）,无效0例。结论：放射性^131I甲状腺手术彻底、单发软组织转移且转移灶肿块较小者治疗效果较好,反之较差。“手术＋ⅢI治疗＋甲状腺素抑制”是最佳分化型甲状腺癌综合治疗方案,这一方案可有效降低复发率和转移率。     

分化型甲癌术后首次大剂量131I 治疗的护理探讨

目的探讨分化型甲癌术后首次大剂量131I治疗的有效护理措施。方法回顾性分析334例分化型甲癌术后首次行大剂量131I治疗患者的临床资料。采取护理措施包括重点加强131I治疗健康教育及心理护理,加强治疗反应护理和放射防护护理。结果本组患者均顺利完成首次大剂量131I治疗,其中颈部残留甲状腺组织首次完全清除率为55.69%（186/334）。对战胜疾病有信心的患者由治疗前的10.78%上升至治疗后的86.53%。治疗后次日2例出现呕吐,半年内63（18.86%）例出现唾液腺功能受损症状,无一例因颈部肿胀导致呼吸困难。医护人员个人放射线剂量检测,测得季度个人剂量当量Hp（10）均〈0.3mSv。结论加强系统全面的健康教育、心理护理、治疗反应的护理及放射防护护理,可提高分化型甲癌术后首次大剂量131I治疗的疗效,增强患者战胜疾病的信心,减轻不良反应,提高工作人员辐射防护水平。     

Drug safety evaluation of lenvatinib for thyroid cancer

Introduction: 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.Areas covered: published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer.Expert opinion: 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.     

甲状腺癌65例手术治疗分析

目的 对65例甲状腺癌患者手术治疗方法和治疗效果进行分析,总结经验为今后患者提供临床指导.方法 收集本院2010年至2015年进行手术治疗的65例甲状腺癌患者资料,对临床表现、治疗方案、疗效进行分析,探讨甲状腺癌的治疗方案.结果 统计显示65例患者,男18例,女47例,发病比例1∶2.6,平均发病年龄42岁,其中分化型乳头状癌为主50例(76.92％),患侧甲状腺叶加峡部切除术21例,患侧甲状腺叶加峡部大部分切除术18例,甲状腺近全切除术11例,甲状腺全切除术13例,姑息切除术2例.结论 临床甲状腺癌以分化型为主,预后较好,手术方式应根据病变性质、肿瘤分期及患者情况而采取个体化方案,选择合理的术式,可取得满意的临床治疗效果.     

The discovery and development of vandetanib for the treatment of thyroid cancer

Introduction: Thyroid cancer represents over 90% of all endocrine malignancies, with medullary thyroid carcinoma (MTC) accounting for 5 – 9% of them. Patients with early-stage disease have a favorable prognosis, but once distant metastasis develops, survival drops to 50% or less. Although surgery remains effective for early-stage disease, patients with advanced disease pose a challenge as traditional therapies have not provided long-term benefits. Vandetanib, initially developed to target other receptors, demonstrated anti-rearranged during transfection (anti-RET) kinase activity. This led to preclinical studies followed by recent human clinical trials, culminating in its FDA approval in April 2011 for application in the treatment of symptomatic or progressive MTC in patients with surgically unresectable, locally advanced or metastatic disease.

Areas covered: The authors provide a review of the discovery strategy and preclinical development of vandetanib. The authors also provide some insight into the clinical development and the drug's post-launch situation.

Expert opinion: Vandetanib has been shown to improve progression-free survival in MTC patients, but its impact on overall survival is still inconclusive. Further data analysis will be needed to answer the question of whether it impacts overall survival in MTC. Despite its advancements, vandetanib still lacks durable efficacy, carries moderate toxicity and has issues with drug resistance over time, not to mention issues of cost. There is a significant need for additional research to discover and develop improved therapeutic strategies for this difficult disease.     

甲状腺结节与甲状腺癌的临床评估和处理

成人甲状腺结节的发病率相当高,其中大多数为良性病变,无需特殊处理,而恶性病变占5%~15%,需要及时处理。鉴于良恶性甲状腺结节对患者生存质量的影响有显著差异,且临床处理方法不同,所以鉴别结节的良、恶性非常重要。一般可通过病史、体格检查、影像学、核素扫描、细针穿刺、实验室检查等几方面评估甲状腺结节性质。对于分化型甲状腺癌需采取手术、同位素、甲状腺激素抑制治疗等综合手段,预后良好。     

Novel therapies for thyroid cancer

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

Efficacy of lenvatinib in treating thyroid cancer

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

The safety of vandetanib for the treatment of thyroid cancer

ABSTRACT

Introduction: The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.

Areas covered: The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.

Expert opinion: Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.     

临床药师应用慢病管理系统管理分化型甲状腺癌术后患者的效果及影响

探索临床药师参与分化型甲状腺癌的术后管理方式。选取我院甲状腺乳腺外科行甲状腺切除术的分化型甲状腺癌患者107例,随机分为实验组和对照组,其中实验组55人,对照组52人。临床药师应用慢病管理系统对实验组进行管理;对照组仅接受常规的药学服务。随访1年后,实验组患者甲状腺功能达标情况、达标时间、依从性与对照组均有显著的统计学差异,但两组患者药物不良反应发生情况并无显著性差异。临床药师应用慢病管理系统为实验组患者制定个体化随访方案和药学监护,显著缩短了术后甲状腺功能达标时间,提高了达标率和依从性。     

腔镜手术序贯131I消融治疗甲状腺癌的可行性研究

目的探讨腔镜手术序贯131I消融治疗甲状腺癌的可行性。方法回顾性分析2008年2月至2011年10月我院收治39例低危甲状腺癌患者临床资料,其中行腔镜手术序贯131I消融治疗19例(腔镜组),行传统开放手术治疗20例(传统组),统计学分析两组间手术时间、术中出血量、术后引流量、术后肿瘤种植及复发转移率、患者切口满意度和并发症发生率等指标的差异。结果腔镜组19例患者均成功完成手术。腔镜组术后患者满意度高于传统组,有显著性统计学差异(P<0.01);而手术时间、术中出血量、术后引流量、术后并发症、术后肿瘤种植及复发转移,两组间无统计学差异(P>0.05)。结论腔镜手术序贯131I消融治疗低危的分化型甲状腺癌安全、可行。     

Clinical uses of recombinant human thyrotropin

Recombinant human thyroid-stimulating hormone (rhTSH), used to enhance diagnostic radioiodine whole body scanning and thyroglobulin testing, has dramatically altered the management of patients with thyroid cancer. Withdrawal from thyroid hormone suppression therapy and subsequent hypothyroidism is no longer the only safe and effective method for thyroid cancer surveillance. Currently, rhTSH is only approved for the monitoring of low-risk patients with well-differentiated thyroid cancer and radioactive iodine administration, in selected cases. Additional applications of rhTSH include enhancing the sensitivity of positron emission tomography in thyroid cancer, the management of multinodular goiter, and dynamic testing of thyroid reserve. The diagnostic and therapeutic role of rhTSH in these areas is discussed in this review.     

miR-155联合超声对分化型甲状腺癌淋巴结转移的诊断价值分析

目的　探讨微小RNA-155（miR-155）联合超声对分化型甲状腺癌淋巴结转移的诊断价值。方法　选取接受治疗的分化型甲状腺癌患者112例作为甲状腺癌组,另选取同期收治的结节性甲状腺肿患者30例作为良性对照组。采用实时荧光定量PCR（qPCR）检测2组患者血清及组织中miR-155的相对表达量,分析分化型甲状腺癌患者血清及组织中miR-155的表达与临床病理参数的关系。采用受试者工作特征（ROC）曲线分析术前超声以及血清miR-155对分化型甲状腺癌淋巴结转移的诊断价值。结果　甲状腺癌组的血清及组织中miR-155的相对表达量均明显高于良性对照组（P＜0.01）,有淋巴结转移、肿瘤直径＞2 cm、TNM分期Ⅲ+Ⅳ期的患者血清及组织中miR-155的相对表达量分别高于无淋巴结转移、肿瘤直径≤2 cm、TNM分期Ⅰ+Ⅱ期的患者（均P＜0.05）。ROC结果显示,超声以及血清miR-155对分化型甲状腺癌淋巴结转移均有一定的诊断价值,曲线下面积分别为：0.839（95%CI：0.760～0.919）、0.837（95%CI：0.763～0.912）,但漏诊率和误诊率均超过10%。两者联合应用后对分化型甲状腺癌淋巴结转移的诊断价值可得到进一步的提升,曲线下面积为0.912（95%CI：0.851～0.973）,漏诊率和误诊率也降至10%以下。结论　血清miR-155联合超声对分化型甲状腺癌淋巴结转移的诊断价值较高,具有一定的临床应用价值。     

血清甲状腺球蛋白水平对术后分化型甲状腺癌患者预后的临床价值分析

目的:探讨血清甲状腺球蛋白水平对术后分化型甲状腺癌患者预后的临床价值.方法:选择2012年5月～2015年5月期间某院接收的分化型甲状腺癌患者62例作为研究对象,均行甲状腺全切除治疗,术后12个月复诊测定血清甲状腺球蛋白水平,评估不同临床病理特征甲状腺球蛋白水平及不同甲状腺球蛋白水平的无进展生存期.结果:淋巴结转移及远...