131I难治性分化型甲状腺癌分子靶向治疗进展

放射性碘难治性分化型甲状腺癌患者因病灶摄碘功能不佳而无法从131I等传统治疗方法中获益。近年来,甲状腺癌分子病理学研究新成果为甲状腺癌的分子诊断和靶向治疗提供了新的契机,相关分子靶向治疗的临床试验和荟萃分析均取得了可喜的结果。本文从临床角度对放射性碘难治性分化型甲状腺癌分子靶向治疗的最新进展进行综述。     

甲状腺癌分子靶向治疗进展

目的：总结近年来国内外甲状腺癌分子靶向治疗方面的进展。方法：应用Medline及CHKD期刊全文数据库，以“甲状腺癌和分子靶向治疗”等为关键词检索2002—01～2007-10相关甲状腺癌分子靶向治疗的文献。对资料进行初选，选择甲状腺癌发病分子机制、分子靶向治疗药物作用机制、治疗效果和毒副反应评价方面的文献。纳入标准：1）甲状腺癌分子病因学研究；2）甲状腺癌分子靶向治疗药物作用机制研究；3）甲状腺癌分子靶向治疗疗效评价的研究；4）甲状腺癌分子靶向治疗发展方向的研究。粗选有近百篇关于甲状腺癌分子靶向治疗方面的文章，根据纳入标准，精选42篇文献，最后纳入分析22篇文献。结果：小分子多靶点酪氨酸激酶抑制剂范得他尼治疗晚期甲状腺髓样癌，索拉非尼治疗晚期甲状腺乳头状癌，羟胺类口服组蛋白去乙酰酶抑制剂SAHA治疗晚期甲状腺癌均取得一定效果，利用选择性COX-2抑制剂塞来昔布治疗晚期分化型甲状腺癌未取得满意疗效。而更多的，1名床实验如AMG706治疗分化型甲状腺癌和甲状腺髓样癌以及利用伊马替尼治疗甲状腺未分化癌的，临床试验正在进行。结论：甲状腺癌分子靶向治疗显示出良好的前景，有望成为治疗的发展方向之一。     

碘难治性甲状腺癌的诊治进展

多数分化型甲状腺癌(differentiated thyroid cancer,DTC)经过规范的手术、选择性131I治疗及促甲状腺激素抑制治疗后预后良好,然而,仍有部分转移性DTC的患者在早期或131I治疗过程中失去了摄碘能力发展为碘难治性DTC(radioiodine-refractory DTC,RAIR-DTC)。RAIR-DTC病情进展快,死亡率高,为这些患者寻找有效的治疗手段一直是甲状腺癌领域研究的热点。该文对碘难治性甲状腺癌的诊断及治疗进展进行综述,为及早识别这些患者,并为其他可能获益的治疗手段如靶向治疗及放疗等的早期干预争取时间。     

131I难治性分化型甲状腺癌的再分化治疗

¹³¹I难治性分化型甲状腺癌(radioiodine-refractory differentiated thyroid cancer,RR-DTC)是目前甲状腺癌临床治疗领域的一大难题。维甲酸类药物、过氧化物酶体增殖物激活受体激动剂、DNA甲基化酶抑制剂及组蛋白脱乙酰化酶抑制剂都曾被用于诱导RR-DTC再分化并与¹³¹I联合治疗,但疗效并不显著。近年来,随着对RR-DTC分子机制认识的不断深入,靶向治疗等新的再分化治疗策略越来越多地被尝试用于治疗RRDTC。相比之下,分子靶向药物用于诱导RR-DTC重摄碘及介导¹³¹I治疗效果较好,可能具有良好的应用前景。     

碘难治性分化型甲状腺癌诱导再分化治疗研究进展

分化型甲状腺癌（DTC）大多进展缓慢,经手术、促甲状腺素抑制治疗和（或）放射性碘（RAI）等规范化治疗后总体预后好,但仍有部分患者治疗后出现复发或远处转移,并可能在自然病程或治疗过程中丧失摄碘能力,不能从后续RAI治疗中获益,成为碘难治性分化型甲状腺癌（RAIRDTC）。RAIR-DTC患者可选择的治疗方法有限,且效果欠佳。近年来,随着对RAIR-DTC分子机制研究的不断深入,诱导再分化联合RAI治疗在RAIR-DTC中展现出一定的应用前景。本文综述了信号通路抑制剂、组蛋白去乙酰化酶抑制剂（HDACi）、DNA甲基化酶抑制剂、维甲酸类药物及过氧化物酶体增殖物激活受体（PPAR）激动剂在RAIR-DTC诱导再分化治疗中的进展。     

Iressa治疗非小细胞肺癌的进展

分子靶向药物，如表皮生长因子受体酪氨酸激酶抑制剂，是近年来在血液和实体肿瘤治疗中涌现出的新治疗手段。现就表皮生长因子受体酪氨酸激酶抑制剂Iressa在非小细胞肺癌治疗中的进展作一综述。     

晚期非小细胞肺癌靶向治疗进展与展望:聚焦小分子酪氨酸激酶抑制剂

目前晚期非小细胞肺癌的治疗已经迈入靶向时代并且发展迅速,药物不断推陈出新.小分子酪氨酸激酶抑制剂占据了其中最大的一块版图,它们往往有明确的分子靶标作为疗效预测因素,在特定分子分型的患者中表现出卓越的疗效,因此成为靶向治疗的典型代表.表皮生长因子酪氨酸激酶抑制剂厄洛替尼、吉非替尼、埃克替尼和间变性淋巴瘤激酶酪氨酸激酶抑制剂克唑替尼带来了里程碑式的进步.而近年来新一代酪氨酸激酶抑制剂在上述两类药物获得性耐药患者中又取得了巨大的成功,同时新的治疗靶点也不断涌现.本文就此对重要的药物和临床研究进行了梳理和总结,并对未来的发展做出展望.     

甲状腺癌靶向化疗进展

由于传统治疗方法疗效所限,晚期甲状腺癌患者的死亡风险居高不下.近年来,靶向化疗在抑制甲状腺癌生长及延长患者无进展生存期上显示出良好的疗效,但也带来了一些临床困惑.该文综述了激酶抑制剂在甲状腺癌靶向化疗中的应用现状及面临的临床问题,更新甲状腺癌的治疗策略并提出未来的研究方向.     

Iressa治疗非小细胞肺癌的进展

分子靶向药物,如表皮生长因子受体酪氨酸激酶抑制剂,是近年来在血液和实体肿瘤治疗中涌现出的新治疗手段。现就表皮生长因子受体酪氨酸激酶抑制剂Iressa在非小细胞肺癌治疗中的进展作一综述。     

晚期分化型甲状腺癌的分子靶向治疗

随着针对分化型甲状腺癌研究的深入,其特征性的分子分型和信号转导通路得以揭示,从而促进了分子靶向治疗的发展。对于放射性碘治疗失败的分化型甲状腺癌,索拉非尼和乐伐替尼等针对血管内皮生长因子通路的多靶点抑制剂被证明具有明显的抗肿瘤活性。此外,其他选择性的单靶点抑制剂以及促放射性碘摄取药物均显示出一定的治疗效果,而个体化的基因检测将为未来个体化的分子靶向治疗奠定基础。     

Thyroid cancer: emerging role for targeted therapies

The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies.     

Differentiated Thyroid Cancer: Focus on Emerging Treatments for Radioactive Iodine‐Refractory Patients

Background.

The treatment of differentiated thyroid cancer refractory to radioactive iodine (RAI) had been hampered by few effective therapies. Recently, tyrosine kinase inhibitors (TKIs) have shown activity in this disease. Clinical guidance on the use of these agents in RAI-refractory thyroid cancer is warranted.

Materials and Methods.

Molecular mutations found in RAI-refractory thyroid cancer are summarized. Recent phase II and III clinical trial data for TKIs axitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetinib are reviewed including efficacy and side effect profiles. Molecular targets and potencies of these agents are compared. Inhibitors of BRAF, mammalian target of rapamycin, and MEK are considered.

Results.

Routine testing for molecular alterations prior to therapy is not yet recommended. TKIs produce progression-free survival of approximately 1 year (range: 7.7–19.6 months) and partial response rates of up to 50% by Response Evaluation Criteria in Solid Tumors. Pazopanib and lenvatinib are the most active agents. The majority of patients experienced tumor shrinkage with TKIs. Common adverse toxicities affect dermatologic, gastrointestinal, and cardiovascular systems.

Conclusion.

Multiple TKIs have activity in RAI-refractory differentiated thyroid cancer. Selection of a targeted agent should depend on disease trajectory, side effect profile, and goals of therapy.     

Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: where do we stand?

The median survival for patients with malignant pleural mesothelioma remains extremely poor and there is a need for the development of more effective treatment modalities. The epidermal growth factor receptor is frequently over-expressed in malignant pleural mesothelioma samples and therefore may be a potential therapeutic target. Targeted EGFR therapy has been successful in non-small cell lung cancer using small molecule tyrosine kinase inhibitors and in colorectal cancer using monoclonal anti-EGFR antibodies. However, phase II clinical trials based on EGFR tyrosine kinase inhibitor therapy have so far not shown promise in mesothelioma. This review includes a background to targeted EGFR treatment strategies, explores putative therapy resistance mechanisms, including the role of predictive biomarkers, and describes the current status of targeted EGFR therapeutic strategies for mesothelioma patients.     

Clinical Efficacy of Targeted Biologic Agents as Second‐Line Therapy of Advanced Thyroid Cancer

Introduction.

Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established.

Methods.

We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant.

Results.

We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6–8.2), and median PFS (4.6 months; 95% confidence interval: 3.2–8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months).

Conclusion.

Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.     

Epidermal Growth Factor Mutation as a Diagnostic and Therapeutic Target in Metastatic Poorly Differentiated Thyroid Carcinoma: A Case Report and Review of the Literature

Poorly differentiated cancers are a diagnostic and therapeutic challenge in oncology. New therapies are needed for patients with poorly differentiated thyroid carcinoma (PDTC) or anaplastic thyroid cancer, as these patients often present with advanced disease and effective systemic treatment options are currently limited. Epidermal growth factor (EGFR) mutations may occur in PDTC more often than previously thought. However, there are fewer than 6 cases reported in the literature where EGFR tyrosine kinase inhibitors (TKIs) (such as erlotinib or gefitinib) were used to target EGFR mutations in PDTC. Here, we present the case of a 79-year-old male with metastatic PDTC with an EGFR mutation who responded to treatment with the selective EGFR TKI erlotinib, with a progression-free survival of more than 11 months. A lung primary rather than a thyroid primary was initially detected. We suggest that the EGFR status should be analysed at diagnosis in any patient with a poorly differentiated tumour. The presence of an EGFR mutation may provide an effective therapeutic pathway for these patients. This pathway requires further investigation and consideration in the future.Key words: Metastatic thyroid carcinoma, Poorly differentiated thyroid carcinoma, Targeted therapy, Epidermal growth factor mutation, Tyrosine kinase inhibitors, Erlotinib, Intratumoural heterogeneity, Poorly differentiated carcinoma     

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.