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。     

未分化及失分化甲状腺癌治疗进展

未分化及失分化甲状腺癌是死亡率较高的内分泌恶性肿瘤,目前尚缺乏有效的治疗手段,寻找新的治疗手段显得尤为迫切.一系列新的治疗方法的出现为未分化及失分化甲状腺癌患者的治疗提供了可能:基因治疗,如通过恢复抑癌基因功能的基因治疗(恢复P53基因功能)或自杀基因导入治疗,抗肿瘤血管形成的基因治疗,钠/碘转运蛋白(NIS)基因介导的放射性碘治疗;诱导分化治疗如:通过维甲酸及组蛋白乙酰化酶抑制剂诱导分化治疗可促进肿瘤细胞的分化,有助于控制肿瘤的发展,而金属蛋白酶抑制剂的应用可控制肿瘤细胞的转移.而手术方式、放化疗方案的改进及综合应用亦可延长甲状腺未分化及失分化癌患者的生存时间.本文就上述新的甲状腺癌的治疗方案做一综述.     

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。     

颈部超声联合血清甲状腺球蛋白评估阿帕替尼治疗进展性碘难治性分化型甲状腺癌的短期疗效

背景与目的：放射性碘难治性分化型甲状腺癌患者（radioactive iodine-refractory differentiated thyroid cancer，RAIR-DTC）的治疗方案有限。结合甲状腺癌血清标志物甲状腺球蛋白（thyroglobulin，Tg），评估阿帕替尼对RAIR-DTC颈部淋巴结转移的治疗效果。方法：2016年1月—2017年12月前瞻性纳入9例成人RAIR-DTC患者，口服阿帕替尼（750mg，每天1次）。持续给药直至病情进展或不能耐受药物引起的不良事件。超声定期监测颈部可疑转移淋巴结的变化，并每2周观察血清Tg的水平变化。结果：该研究9例患者中，男性5例，女性4例，平均年龄52.6（33.0~65.0）岁。颈部可疑淋巴结的最大者的最大径基线均值为29.1 mm，经阿帕替尼治疗8~12周后最大径均值为20.0 mm，平均同比下降31.3%。8例Tg可评价的患者中，全部（100%）经阿帕替尼治疗后Tg水平下降，较基线平均同比下降96.3%。结论：从超声检测颈部转移淋巴结及血清学Tg的变化，证实阿帕替尼可用于RAIR-DTC的治疗。     

维甲酸诱导分化在分化型甲状腺癌治疗中的初步应用

目的探讨分化型甲状腺癌（DTC）放射性碘治疗过程中应用维甲酸（RA）治疗的作用。方法20例患者在^131I治疗期间由于全身^131I扫描显示肺或骨转移灶不摄取碘或摄碘能力不够不足以达到治疗目的，在下一次治疗前1．5个月服用RA。将RA治疗后^131I摄取较前增加的病例归为治疗有效组，而RA治疗后无^131I摄取或同前相比^131I摄取无变化的病例归为治疗无效组。应用配对t检验来比较RA治疗前后血清甲状腺球蛋白（Tg）的变化。结果20例患者共计25例次在^131I治疗期间服用RA，其中11例次（44％）治疗有效。治疗有效组的中位Tg值（382-1000ng／ml）较治疗无效组（176．35～616．25ng／ml）增高明显，但治疗前后Tg值进行统计学比较没有显著性意义（P〉0．05）。结论RA治疗能恢复DTC细胞的摄碘功能。     

碘难治性分化型甲状腺癌靶向治疗新进展

近年来，靶向治疗为碘难治性分化型甲状腺癌带来了革命性的突破。新型靶向药物的研发，让更多晚期分化型甲状腺癌患者获得了更好的生存。以索拉非尼和仑伐替尼为代表的多靶点小分子酪氨酸激酶抑制剂显著提升了患者的无进展生存期。与此同时，靶向BRAF及靶向RET的新型酪氨酸激酶抑制剂同样也取得了瞩目的疗效，丰富了甲状腺癌的治疗手段。本文就靶向治疗在碘难治性分化型甲状腺癌中的最新研究进展进行综述。     

全反式维甲酸诱导再分化在16例甲状腺癌治疗中的应用

目的：探讨全反式维甲酸（ATRA）在分化型甲状腺癌（DTC）放射性碘治疗过程中的临床应用。方法：16例分化型甲状腺癌转移患者,131I治疗中转移灶不摄取或轻度摄取131I,服ATRA2个月后再行131I治疗,7天后SPECT显像,对转移灶部位进行感兴趣区（ROI）计数,并和ATRA治疗前SPECT显像进行比较,评价ATRA治疗前后131I摄取变化情况。结果：16例患者服用ATRA后,其中7例131I摄取增加,治疗有效率43.7%。结论：ATRA治疗能促进部分失分化DTC细胞的再分化。     

分化型甲状腺癌碘拮抗相关基因研究进展

甲状腺癌是最常见的内分泌系统恶性肿瘤,其中分化型甲状腺癌占多数,后者的主要治疗手段有手术治疗、术后碘放射性同位素(131I)治疗和促甲状腺激素抑制治疗等.131I在分化型甲状腺癌的诊断与治疗中有较为广泛的应用,然而,一部分分化型甲状腺癌患者因钠-碘转运体基因、BRAF基因、双链复合蛋白8、微小RNA、细胞角蛋白19等基因的改变而降低或丧失对131I的摄取能力.这些基因在分化型甲状腺癌的治疗中尤为重要,可作为肿瘤治疗疗效评估的重要指标.     

碘-125粒子植入治疗碘难治性分化型甲状腺癌淋巴结转移灶的临床研究

背景与目的：随着甲状腺癌发病率不断攀升，碘难治性分化型甲状腺癌（radioactive iodine-refractory differentiated thyroid cancer，RAIR-DTC）成为目前临床诊疗的难点。探索碘-125（ ¹²⁵ I）粒子植入治疗RAIR-DTC的疗效及安全性。方法：对中南大学湘雅医学院附属肿瘤医院自2013年—2017年收治的39例RAIR-DTC患者颈部淋巴结转移灶行 125 I粒子植入治疗，每3个月监测血清甲状腺球蛋白（thyroglobulin，Tg）水平及病灶变化情况。采用实体瘤疗效评价标准1.1（response evaluation criteria in solid tumors，RECIST 1.1）评估疗效，采用常见不良事件评价标准5.0（common terminology criteria for adverse events，CTCAE 5.0）评估安全性。结果：治疗后39例患者的客观缓解率为43.6%，疾病控制率为92.3%。治疗3个月血清Tg水平较治疗前有显著降低（t=2.2，P<0.05）；治疗后6个月较治疗后3个月、治疗后9个月较治疗后6个月、治疗后12个月较治疗后9个月差异无统计学意义（P均>0.05）。治疗后3、6、9和12个月的淋巴结最大截面短径分别为（15.1±1.1）、（13.8±1.0）、（12.9±1.0）和（12.9±1.0）mm，与治疗前的（18.3±1.2）mm相比，差异均有统计学意义（P<0.001）。粒子植入数量与可测量病灶短径缩小量弱相关（P<0.05），与Tg水平减少量不相关（P>0.05）。未观察到与该治疗相关的严重不良事件。结论： ¹²⁵ I粒子植入治疗RAIR-DTC颈部淋巴结转移灶疗效及安全性良好。     

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。     

Well‐differentiated thyroid carcinoma: The role of post‐operative radioactive iodine administration

Post‐operative management of differentiated thyroid cancer (DTC) often involves administration of radioactive iodine (RAI) for remnant ablation or adjuvant therapy. However, given the favorable prognosis associated with DTC, the risk versus benefit ratio of RAI remains unclear. RAI is associated with substantial, albeit rare side effects, including a possible increased risk of secondary malignancy and altered fertility, which must be balanced against the magnitude of benefit for decreasing recurrence and improving survival. J. Surg. Oncol. 2013;107:665–672. © 2012 Wiley Periodicals, Inc.     

New approaches for patients with advanced radioiodine-refractory thyroid cancer

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/ oncologists on the basis of patient’s features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.     

Birth rates after radioactive iodine treatment for differentiated thyroid cancer

Treatment with radioactive iodine (RAI) for differentiated thyroid cancer has been associated with alterations in gonadal function in women, including changes in menstrual function and an earlier age at menopause. Our objective was to evaluate associations between RAI and postdiagnosis live birth rates among thyroid cancer survivors diagnosed at ages 15–39 years. We identified women diagnosed with differentiated thyroid cancer between January 2000 and December 2013 in the North Carolina Central Cancer Registry (CCR). CCR records were linked to state birth certificate files to identify livebirths to thyroid cancer survivors through December 2014. Person‐years of follow‐up were accrued from 6 months after diagnosis to first birth, 46th birthday, death, or December 31, 2014, whichever came first. Cox proportional hazards regression was used to estimate hazards ratios (HR) and 95% confidence intervals (CI) for first livebirth. Among 2,360 women with a differentiated thyroid cancer diagnosis, 53% received RAI. The cumulative incidence of birth at the end of follow‐up (maximum 14.5 years) was 30.0 and 29.3% among those who were and were not treated with RAI, respectively. Overall, first birth rates did not significantly differ between groups (HR = 1.00; 95% CI: 0.82, 1.23). In our observational cohort, treatment with RAI was not associated with a reduced birth rate. Our findings add to the evidence available for counseling thyroid cancer patients with concerns about future fertility.     

The role of radioactive iodine in the management of patients with differentiated thyroid cancer – An oncologic surgical perspective

With improved understanding of the biology of differentiated thyroid carcinoma its management is evolving. The approach to surgery for the primary tumour and elective nodal surgery is moving from a “one-size-fits-all” recommendation to a more personalised approach based on risk group stratification. With this selective approach to initial surgery, the indications for adjuvant radioactive iodine (RAI) therapy are also changing. This selective approach to adjuvant therapy requires understanding by the entire treatment team of the rationale for RAI, the potential for benefit, the limitations of the evidence, and the potential for side-effects.This review considers the evidence base for the benefits of using RAI in the primary and recurrent setting as well as the side-effects and risks from RAI treatment. By considering the pros and cons of adjuvant therapy we present an oncologic surgical perspective on selection of treatment for patients, both following pre-operative diagnostic biopsy and in the setting of a post-operative diagnosis of malignancy.     

甲磺酸阿帕替尼治疗进展性碘难治性甲状腺癌的短期疗效及安全性初步报告

背景与目的：碘难治性甲状腺癌(radioactive iodine-refractory differentiated thyroid cancer,RAIR-DTC)是目前临床诊疗的难点与热点,目前国际指南中推荐的靶向治疗药物仅有索拉非尼及乐伐替尼。该研究报告具有我国自主知识产权的靶向药物甲磺酸阿帕替尼治疗进展性碘RAIR-DTC 8周后的短期疗效及安全性。方法：纳入10例进展性RAIR-DTC患者予阿帕替尼治疗(750 mg,每天1次,口服)。每2周复查甲状腺球蛋白(thyroglobulin,Tg),每4周CT监测靶病灶(target lesions,TL)。观察甲状腺癌血清标志物Tg水平变化,采用实体瘤疗效评价标准1.1(response evaluation criteria in solid tumors,RECIST 1.1)评估疗效。初步评估患者经药物治疗的短期不良事件(adverse event,AE)以评估安全性。结果：8例Tg可评价的患者,在治疗2周后Tg即出现下降,在治疗8周后较基线平均降幅达68%,达到“生化部分缓解”。10例患者共18个TL,治疗4周后即出现缩小,在8周后较基线平均缩小达40％,9例患者(9/10,90%)达到部分缓解,1例(1/10,10%)呈疾病稳定,客观缓解率及疾病控制率分别达90%和100%。最常见的3级以上AE主要包括手足皮肤反应、高血压和低钙血症,分别占50%、30%和20%,未观察到与药物相关的严重AE。结论：甲磺酸阿帕替尼可安全用于RAIR-DTC治疗,且在8周治疗中从血清学及结构影像学角度证实快速有效,客观缓解率高。     

Complications of radioactive iodine treatment of thyroid carcinoma

Radioactive iodine (RAI) in the form of (131)I has been used to treat thyroid cancer since 1946. RAI is used after thyroidectomy to ablate the residual normal thyroid remnant, as adjuvant therapy, and to treat thyroid cancer metastases. Although the benefits of using RAI in low-risk patients with thyroid cancer are debated, it is frequently used in most patients with thyroid cancer and is clearly associated with acute and long-term risks and side effects. Acute risks associated with RAI therapy include nausea and vomiting, ageusia (loss of taste), salivary gland swelling, and pain. Longer-term complications include recurrent sialoadenitis associated with xerostomia, mouth pain, dental caries, pulmonary fibrosis, nasolacrimal outflow obstruction, and second primary malignancies. This article summarizes the common complications of RAI and methods to prevent and manage these complications.     

Initial management and follow-up of differentiated thyroid cancer in children

Children with differentiated thyroid cancer (DTC) often present with metastatic disease and have a high risk for recurrence, but rarely die of the disease. This article reviews DTC in children and discusses current approaches to their initial care and follow-up. These recommendations take into account the greater risk for recurrence and lower disease-specific mortality in these patients. Total thyroidectomy and central compartment lymph node dissection are appropriate for most children, but should be performed by a high-volume thyroid surgeon. Radioactive iodine (RAI) should generally be prescribed for those at very high risk for recurrence or known to have microscopic residual disease, and those with iodine-avid distant metastases. RAI should be considered in other patients only after carefully weighing the relative risks and benefits and the aggressiveness of the clinical presentation, because RAI may be associated with an increased risk for second malignancies and an increase in overall morbidity and mortality. All patients should be treated with thyroid hormone suppression, and follow-up should be lifelong. However, the degree of thyroid hormone suppression and frequency of disease surveillance usually decrease over time as patients are determined to be disease-free.     

The current role of targeted therapies to induce radioiodine uptake in thyroid cancer

Targeted therapy pinpointing specific alteration in cancer cells has gained an important role in the treatment of cancer. Compounds that re-induce thyroid-specific functions could be particularly useful in differentiated thyroid cancers by rendering them susceptible to radioiodine treatment, which is relatively specific and has few adverse effects. This review describes the rationale for radioiodine treatment, considering the targets of compounds with differentiation-inducing effects, and the impact of these drugs on the expression of thyroid-specific proteins and on iodine-uptake. We survey the results from the clinical trials thus far performed. We conclude that although retinoids, thiazolidinediones, histone deacetylase inhibitors and DNA methyltransferase inhibitors do increase the expression of thyroid-specific proteins, their clinical efficacy is limited. The relatively low rate of remissions in clinical trials with re-differentiating compounds could be due to low levels of the target, heterogeneity of iodine uptake into the tumor, poor correlation of radioiodine uptake and clinical remission, and/or the slow onset of the therapeutic effect. Although the mode of action is not clear, the combination of tyrosine kinase inhibitors and RAI treatment could improve clinical responses in non-radioiodine avid metastatic thyroid carcinoma.