-
甲状腺癌是内分泌系统最常见的肿瘤,其中90%为分化型甲状腺癌(differentiated thyroid cancer,DTC),DTC包括乳头状甲状腺癌(papillary thyroid carcinoma,PTC)和滤泡状甲状腺癌(follicular thyroid carcinoma,FTC)[1]。2010年中国甲状腺癌发病率为4.12/10万,占全部恶性肿瘤的1.75%[2]。近年来,甲状腺癌发病率在迅速增长,美国癌症学会(ACS)发布的数据显示:2001年至2013年间,甲状腺癌发病率上升了209%,其中59%的发病率增长出现在近6年[3-4]。虽然绝大多数DTC患者可以通过手术、放射性碘(radioactive iodine,RAI)治疗、TSH抑制三步曲的治疗获得长达30年的无疾病生存期,但是仍有一部分DTC患者在治疗过程中肿瘤细胞形态和功能出现退行性变化,出现失分化[5],摄碘能力下降或者丧失,无法从放射性碘治疗中获益,称为放射性碘难治性DTC(RAI-refractory DTC,RAIR-DTC)。此类患者生存时间大大缩短,平均生存期仅为2.5~3.5年,10年生存率仅为10%[6]。目前对于RAIR-DTC的发生机制、诊断以及治疗方法有大量的文献报道,现对其进行一系列详细综述。
碘难治性分化型甲状腺癌靶向药物治疗进展
Radioactive iodine refractory differentiated thyroid cancer targeted therapy
-
摘要: 甲状腺癌是内分泌系统最常见的恶性肿瘤, 其中90%为分化型甲状腺癌。外科手术、放射性碘治疗、TSH抑制是目前分化型甲状腺癌治疗的三步曲。虽然目前对分化型甲状腺癌的诊断和治疗手段非常成熟, 但是仍有少量患者因病灶出现失分化摄碘能力下降, 而无法获益于传统的131I治疗, 称为碘难治性分化型甲状腺癌, 对于这类患者使用分子靶向药物治疗是甲状腺癌治疗上的进步。甲状腺癌分子病理学的研究, 为分子诊断和靶向治疗提供了可靠的理论基础。笔者就目前对于碘难治性分化型甲状腺癌的分子靶向治疗进展进行综述。Abstract: Thyroid cancer is the most common endocrine malignancy, and ninety percent is differentiated thyroid cancer. Surgery, radioactive iodine treatment, TSH suppressive therapy is one of the trilogies of differentiated thyroid cancer treatment. Although the diagnosis and treatment of differentiated thyroid cancer is very mature, there are some patients cannot benefit from the radioactive iodine treatment naming RAI-refractory DTC. For these patients showing dedifferentiated and a lower level of iodine uptake now use targeted drugs achieving curative effect. The studies of molecular pathology of thyroid provide a theoretical basis for the diagnosis and treatment of thyroid cancer. This review comprehensively discussing the progress of molecular targeted therapy about refractory thyroid cancer.
-
Key words:
- Thyroid neoplasms /
- Protein-tyrosine kinase /
- Molecular targeted therapy
-
[1] Hundahl SA, Fleming ID, Fremgen AM, et al.A National cancer data base report on 53, 856 cases of thyroid carcinoma treated in the U.S., 1985-1995[J].J Cancer, 1998, 83(12):2638-2648. doi: 10.1002/(SICI)1097-0142(19981215)83:12<2638::AID-CNCR31>3.0.CO;2-1 [2] 杨雷, 郑荣寿, 王宁, 等.2010年中国甲状腺癌发病和死亡情况[J].中华预防医学杂志, 2014, 48(8):663-668.DOI:10.3760/cma.j.issn.0253-9624.2014.08.003.YangL,
Yang L, Zheng RS, Wang N, et al.Analysis of incidence and mortality of thyroid cancer in China[J].Chin J Prev Med, 2014, 48(8):663-668. doi: 10.3760/cma.j.issn.0253-9624.2014.08.003.YangL,[3] Sosa JA, Hanna JW, Robinson KA, et al.Increases in thyroid nodule fine-needle aspirations, operations, and diagnoses of thyroid cancer in the United States[J].Surgery, 2013, 154(6):1420-1427.DOI:10.1016/j.surg.2013.07.006. [4] Li N, Du XL, Reitzel LR, et al.Impact of enhanced detection on the increase in thyroid cancer incidence in the United States:review of incidence trends by socioeconomic status within the surveillance, epidemiology, and end results registry, 1980-2008[J].Thyroid, 2013, 23(1):103-110.DOI:10.1089/thy.2012.0392. [5] Rivera M, Ghossein RA, Schoder H, et al.Histopathologic characterization of radioactive iodine-refractory fluorodeoxyglucose-positron emission tomography-positive thyroid carcinoma[J].Cancer, 2008, 113(1):48-56.DOI:10.1002/cncr.23515. [6] Durante C, Haddy N, Baudin E, et al.Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma:Benefits and limits of radioiodine therapy[J].J Clin Endocrinol Metab, 2006, 91(8):2892-2899.DOI:10.1210/jc.2005-2838. [7] Xing MZ.Molecular pathogenesis and mechanisms of thyroid cancer[J].Nat Rev Cancer, 2013, 13(3):184-199.DOI:10.1038/nrc3431. [8] Cancer Genome Atlas Research Network.Integrated genomic characterization of papillary thyroid carcinoma[J].Cell, 2014, 159(3):676-690.DOI:10.1016/j.cell.2014.09.050. [9] Elisei R, Ugolini C, Viola D, et al.BRAFV600E mutation and outcome of patients with papillary thyroid carcinoma:a 15-year median follow-up study[J].J Clin Endocrinol Metab, 2008, 93(10):3943-3949.DOI:10.1210/jc.2008-0607. [10] Hou P, Liu D, Xing M.Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer[J].Cell Cycle, 2007, 6(3):377-379. [11] O'neill CJ, Bullock M, Chou A, et al.BRAFV600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer[J].Surgery, 2010, 148(6):1139-1146.DOI:10.1016/j.surg.2010.09.005. [12] Kebebew E, Weng J, Bauer J, et al.The prevalence and prognostic value of BRAF mutation in thyroid cancer[J].Ann Surg, 2007, 246(3):466-471.DOI:10.1097/SLA.0b013e318148563d. [13] Durante C, Puxeddu E, Ferretti E, et al.BRAF mutations in papillary thyroid carcinomas inhibit genes involved in Iodine metabolism[J].J Clin Endocrinol Metab, 2007, 92(7):2840-2843.DOI:10.1210/jc.2006-2707. [14] Xing M.BRAF mutation in papillary thyroid cancer:pathogenic role, molecular bases, and clinical implications[J].Endocr Rev, 2007, 28(7):742-762.DOI:10.1210/er.2007-0007. [15] Zhu Z, Ciampi R, Nikiforova MN, et al.Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas:effects of the detection methods and genetic heterogeneity[J].J Clin Endocrinol Metab, 2006, 91(9):3603-3610.DOI:10.1210/jc.2006-1006. [16] Santoro M, Carlomagno F, Hay ID, et al.Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype[J].J Clin Invest, 1992, 89(5):1517-1522.DOI:10.1172/JCI115743. [17] Trapasso F, Iuliano R, Chiefari E, et al.Iodide symporter gene expression in normal and transformed rat thyroid cells[J].Eur J Endocrinol, 1999, 140(5):447-451. [18] Schlumberger M, Brose M, Elisei R, et al.Definition and management of radioactive iodine-refractory differentiated thyroid cancer[J].Lancet Diabetes Endocrinol, 2014, 2(5):356-358.DOI:10.1016/S2213-8587(13)70215-8. [19] Wilhelm SM, Carter C, Tang L, et al.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J].Cancer Res, 2004, 64(19):7099-7109.DOI:10.1158/0008-5472.CAN-04-1443. [20] Thomas L, Lai SY, Dong W, et al.Sorafenib in metastatic thyroid cancer:a systematic review[J].Oncologist, 2014, 19(3):251-258.DOI:10.1634/theoncologist.2013-0362. [21] Brose MS, Nutting CM, Jarzab BA, et al.Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer:a randomised, double-blind, phase 3 trial[J].Lancet, 2014, 384(9940):319-328.DOI:10.1016/S0140-6736(14)60421-9. [22] White PT, Cohen MS.The discovery and development of sorafenib for the treatment of thyroid cancer[J].Expert Opin Drug Discov, 2015, 10(4):427-439.DOI:10.1517/17460441.2015.1006194. [23] Walko CM, Grande C.Management of common adverse events in patients treated with sorafenib:nurse and pharmacist perspective[J].Semin Oncol, 2014, 41(Suppl 2):S17-28.DOI:10.1053/j.seminoncol.2014.01.002. [24] Dadu R, Devine C, Hernandez M, et al.Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib[J].J Clin Endocrinol Metab, 2014, 99(6):2086-2094.DOI:10.1210/jc.2013-3588. [25] Wells SA Jr, Robinson BG, Gagel RF, et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized, Double-Blind phase Ⅲ trial[J].J Clin Oncol, 2012, 30(2):134-141.DOI:10.1200/JCO.2011.35.5040. [26] Cabanillas ME, Schlumberger M, Jarzab B, et al.A phase 2 trial of lenvatinib(E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer:A clinical outcomes and biomarker assessment[J].Cancer, 2015, 121(16):2749-2756.DOI:10.1002/cncr.29395. [27] Schlumberger M, Tahara M, Wirth LJ, et al.Lenvatinib versus placebo in radioiodine-refractory thyroid cancer[J].N Engl J Med, 2015, 372(7):621-630.DOI:10.1056/NEJMoa1406470. [28] Carr LL, Mankoff DA, Goulart BH, et al.Phase Ⅱ study of daily sunitinib in FDG-PET-Positive, Iodine-Refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation[J].Clin Cancer Res, 2010, 16(21):5260-5268.DOI:10.1158/1078-0432.CCR-10-0994. [29] Cohen EE, Rosen LS, Vokes EE, et al.Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer:Results from a phase Ⅱ study[J].J Clin Oncol, 2008, 26(29):4708-4713.DOI:10.1200/JCO.2007.15.9566. [30] Bible KC, Suman VJ, Molina JR, et al.Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers:results of a phase 2 consortium study[J].Lancet Oncol, 2010, 11(10):962-972.DOI:10.1016/S1470-2045(10)70203-5. [31] Sherman SI, Wirth LJ, Droz JP, et al.Motesanib diphosphate in progressive differentiated thyroid cancer[J].N Engl J Med, 2008, 359(1):31-42.DOI:10.1056/NEJMoa075853. [32] Cabanillas ME, Brose MS, Holland J, et al.A phase I study of cabozantinib(XL184) in patients with differentiated thyroid cancer[J].Thyroid, 2014, 24(10):1508-1514.DOI:10.1089/thy.2014.0125. [33] Sherman SI.Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers[J].J Clin Endocrinol Metab, 2009, 94(5):1493-1499.DOI:10.1210/jc.2008-0923. [34] Kim KB, Cabanillas ME, Lazar AJ, et al.Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAFV600E mutation[J].Thyroid, 2013, 23(10):1277-1283.DOI:10.1089/thy.2013.0057. [35] Brose MS, Cabanillas ME, Cohen E, et al.An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer(PTC) positive for the BRAFV600 mutation and resistant to radioactive Iodine(NCT01286753, NO25530)[J].Eur J Cancer, 2013, 49(3):S13. [36] Dadu R, Shah K, Busaidy NL, et al.Efficacy and tolerability of vemurafenib in patients with BRAFV600E-positive papillary thyroid cancer:M.D.Anderson Cancer Center off label experience[J].J Clin Endocrinol Metab, 2015, 100(1):E77-E81.DOI:10.1210/jc.2014-2246. [37] Falchook GS, Millward M, Hong D, et al.BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer[J].Thyroid, 2015, 25(1):71-77.DOI:10.1089/thy.2014.0123. [38] Lorch JH, Busaidy N, Ruan DT, et al.A phase Ⅱ study of everolimus in patients with aggressive RAI refractory(RAIR)thyroid cancer(TC)[J/OL].J Clin Oncol, 2013, 31(15): 6023[2015-11-18].http://meeting.ascopubs.org/cgi/content/abstract/31/15_suppl/6023. [39] Lim SM, Chang H, Yoon MJ, et al.A multicenter, phase Ⅱ trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes[J].Ann Oncol, 2013, 24(12):3089-3094.DOI:10.1093/annonc/mdt379.
计量
- 文章访问数: 3571
- HTML全文浏览量: 2310
- PDF下载量: 9