促甲状腺激素抑制疗法的应用
国际上有多种关于分化型甲状腺癌术后复发和转移的危险度评估方法。2009年ATA [37]首次将手术及131I治疗后DTC患者复发、转移和死亡的风险分为低、中、高危3组，这也是目前被广泛接受的DTC患者危险度评估方法。指南建议高危组且肿瘤持续存在的患者，TSH抑制到＜0.1mIU/L；高危组的无瘤生存者，建议将TSH维持在0.1～0.5mU/L之间，并维持5～10年；初治低危组和无瘤生存低危组患者，建议将TSH控制在正常低限（0.1～0.5mIU/L）。但是该指南未提及THST的潜在风险。2010年Biondi和Cooper[22]首次提出，对DTC患者进行THST时，应综合考虑肿瘤的复发风险和L-T4治疗风险，制定个体化TSH抑制目标。根据TSH抑制程度对心血管系统、骨代谢以及生活质量的影响，将其风险分为高、中、低危3组。如果复发风险低而L-T4治疗风险较高，则可放宽TSH控制目标（术后1年内0.5～1.0 mIU/L，1年后1.0～2.0mIU/L），即明确提出了双风险评估策略。2012年美国国立综合癌症网络发表的第二版《甲状腺癌治疗指南》[38]中对THST描述得更加详细，指南建议如有明确残余病灶或有复发高危因素的患者TSH需被抑制在0.1mIU/L以下，无瘤生存且复发低风险的患者TSH只需抑制在正常值低限即可。但对于生化检查阳性但无形态学肿瘤证据的低危患者（如血清Tg阳性但影像检查阴性），TSH需抑制在0.1～0.5mIU/L之间，同时明确提出THST应兼顾治疗的获益和风险。但是该指南并仍然没有给出具体的评估内容。2012年中国《甲状腺结节和分化型甲状腺癌诊治指南》[39]充分借鉴了这些循证证据，对THST的控制目标提出了“基于DTC患者的肿瘤复发危险度和TSH抑制治疗的副作用风险，设立DTC患者术后TSH抑制治疗的个体化目标”的推荐，分别设立初治期（术后1年内）和随访期的TSH控制目标（表49-1），充分体现了对DTC患者治疗的个体化和精细化管理。
2015年10月，ATA通过对近年来最新循证医学证据的总结，对指南再次做出更新，在线发布了新版《甲状腺结节与分化型甲状腺癌诊治指南》[40]。新版指南放宽了初始治疗期中危及部分低危患者TSH控制目标，并推荐随访期结合治疗反应及副作用来制定并调整TSH控制目标，提出了动态风险评估的理念。建议对于复发风险，除在初始时进行评估以外，还应在随访中动态修正。治疗过程中应使用ATA复发风险分层系统，根据患者对治疗的反应情况，动态评估复发风险，再相应地调整治疗方案，使治疗更加个性化和精细化。基于双风险评估和大规模前瞻性临床研究结果，指南将TSH控制目标重新做了界定：①DTC复发与进展危险度高的患者TSH可抑制在＜0.1mIU/L；如果伴有L-T4治疗的不良反应时，推荐TSH抑制到0.1～0.5mIU/L。②DTC复发与进展危险度低的患者，均推荐TSH 0.5～2mIU/L（表49-2）。关于THST的时限，指南建议高危组推荐终身服用L-T4；低危组可在术后5年内服用L-T4，并严密随访，5年后若无复发，可将L-T4调整为生理需要量，使血清TSH水平维持在正常范围内即可。
表49-1 基于双风险评估的DTC患者术后TSH控制治疗目标（mIU/L）
注：TSH：促甲状腺激素；DTC：分化型甲状腺癌；a：TSH抑制治疗的副作用风险为高中危层次者，应个体化抑制TSH至接近达标的最大可耐受程度，予以动态评估，同时预防和治疗心血管和骨骼系统相应病变；b：对DTC的复发危险度为高危层次、同时TSH抑制治疗副作用危险度为低危层次的DTC患者，应定期评价心血管和骨骼系统情况；c：表格中的0.5mIU/L因各实验室的TSH正常参考范围下限不同而异；d：5～10年后如无病生存，可仅进行甲状腺激素替代治疗。
表49-2 《ATA甲状腺结节与分化型甲状腺癌诊治指南2015》TSH控制治疗目标
总之，内科治疗即TSH抑制治疗是DTC术后管理中不可或缺的重要环节。由于每个个体对L-T4治疗效应及治疗导致的不良反应耐受性不同，迄今仍没有一个最适宜的L-T4使用剂量推荐，剂量调整应坚持个体化原则即“基于DTC患者的肿瘤复发危险度和TSH抑制治疗的副作用风险，设立DTC患者术后TSH抑制治疗的个体化目标”。期望未来能通过更好的生物标志物或基因分析来指导个体化治疗，确保高风险患者得到充分且有效的治疗，同时又可避免低风险患者面临过度治疗带来的风险，真正达到对DTC患者进行个体化和精细化管理的目标。
参考文献
[1] Siegel R,Ward E,Brawley O,et al.Cancer statistics，2011：the impact of eliminating socioeconomic and racial disparities on premature cancer death[J].CA Cancer J Clin,2011,61(4):212-236.
[2] WHO．GLOBOCAN2012：Estimated cancer incidence，mortality and prevalence in 2012．[2013-12-31]．http://globocan.iarc.fr/Pages/fact_Sheets_population.aspx．
[3] DeSantis C E, Lin C C, Mariotto A B, et al.Cancer treatment and survivorship statistics[J].CA Cancer J Clin,2014,64:252-271.
[4] 刘玉琴，张书全，陈万青.中国2003—2007年甲状腺癌发病死亡现状及流行趋势分析[J].中华流行病学杂志， 2012， 33（10）： 1044-1048.
[5] Enewold L，Zhu K，Ron E，et al.Rising thyroid cancer incidence in the United States by demographic and tumor characteristic,1980—2005[J].Cancer Epidemiol Biomarkersn Prev，2009,18(3):784-791.
[6] Mazzaferri EL.Approach to the pregnant patient with thyroid cancer[J].J clin Endocrinol metab,2011,96(2):265-272.
[7] Brabant G.Thyrotropin suppressive therapy in thyroid carcinoma: what are the targets[J].J Clin Endocrinol Metab, 2008, 93: 1167-1169.
[8] Greer M A, Astwood E B.Treatment of simple goiter with thyroid[J].Clin Endocrinol Metab, 1953,13:1312-1331.
[9] Dunhill T P.Surgery of the thyroid gland[J].BMJ,1937,1:460-461.
[10] Balme H W.Metastatic carcinoma of the thyroid successfully treated with thyroxine[J].Lancet,1954,1:812-813.
[11] Crile G Jr.Treatment of cancer of the thyroid with desiccated thyroid[J].Cleve Clin Q,1955,22:161-163.
[12] Thomas C G Jr.Hormonal treatment of thyroid cancer[J].Clin Endocrinol Metab,1957,17:232-237.
[13] Thomas C G Jr.Role of thyroid stimulating hormone suppression in the management of thyroid cancer[J].Semin Surg Oncol,1991,7:115-119.
[14] Mazzaferfi E L,Jhiang S M.Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer[J].Am J Med, 1994,97:418-428．
[15] Pujol P, Daures J P, Nsakala N,et al.Degree of thyrotropin suppression as a prognostic determinan in differentiated thyroid cancer[J].J Clin Endocrinol Metab,1996,81:4318-4322.
[16] Uzzan B, Campos J, Cucherat M, et al.Effects on bone mass of long term treatment with thyroid hormone: A meta-analysis[J].J Clin Endocrinol Metab,1996,81:4278-4289.(https://www.daowen.com)
[17] Sawin C T, Geller A, Wolf P A, et al.Low serum TSH concentrations as a risk factor for atrial fibrillation in older persons[J].N Engl J Med,1994,331:1249-1252.
[18] Larsen P R.Thyroid neoplasia.In: De Groot L J, Larsen P R, Hennemann G (ed) The Thyroid and its Diseases.Sixth edition[M].New York:Churchill Livingstone, 1996.
[19] Greenspan F S.The thyroid gland.In: Greenspan F S,Strewler G J (ed) Basic and Clinical Endocrinology[M].Fifth edition.Appleton and Lange, Stamford, CT, 1997.
[20] Cooper D S，Specker,Ho M,et a1.Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer：results from the National Thyroid Cancer Treatment Cooperative Registry[J].Thyroid,1998,8:737-744.
[21] Jonklaas J,Sarlis N J,Litofsky D，et a1.Outcomes of patients with differentiated thyroid carcinoma following initial therapy[J].Thyroid, 2006, 16: 1229-1242．
[22] Biondi B,Cooper D S.Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer[J].Thyroid,2010,20(2):135-146.
[23] Sugitani I, Fujimoto Y.Does postoperative thyrotropin suppression therapy truly decrease recurrence in papillary thyroid carcinoma?A randomized controlled trial[J].J Clin Endocrinol Metab, 2010, 95: 4576-4583.
[24] Aubrey A.Carhill, Danielle R.Litofsky, Douglas S.Ross, et al.Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987—2012[J].Clin Endocrinol Metab,2015,100(9)：3270-3279.
[25] Wang L Y, Smith A W, Palmer F L, et al.Thyrotropin suppression increases the risk of osteoporosis without decreasing recurrence in ATA low- and intermediaterisk patients with differentiated thyroid carcinoma[J].Thyroid,2015, 25(3):300-307.
[26] Bassett J H, Williams G R.Critical role of the hypothalamic-pituitary-thyroid axis in bone[J].Bone,2008,43: 418-426.
[27] Abe E,Marians R C,Yu W,et al．TSH is a negative regulator of skeletal remodeling[J].Cell,2003,115:151-162．
[28] Bauer D C, Ettinger B, Nevitt M C,et al.Risk for fracture in women with low serum levels of thyroid-stimulating hormone[J].Ann Intern Med,2001,134:561-568.
[29] Heemstra K A, Hamdy N A T, Romijn J A, et al.The effects of thyrotropin suppressive therapy on bone metabolism in patients with well differentiated thyroid carcinoma[J].Thyroid, 2006, 16(6):583-591.
[30] Lee M Y, Park J H, Bae K S, et al.Bone mineral density and bone turnover markers in patients on long-term suppressive levothyroxine therapy for differentiated thyroid cancer[J].Ann Surg Treat Res,2014, 86(2):55-60.
[31] Klein I, Ojamaa K.Thyroid hormone and the cardiovascular system[J].N Engl J Med, 2001,344:501-509.
[32] Abonowara A, Quraishi A, Sapp J L, et al.Prevalence of atrial fibrillation in patients taking TSH suppression therapy for management of thyroid cancer[J].Clin Invest Med, 2012, 5:E152-E156.
[33] Tan Z S, Vasan R S.Thyroid function and Alzheimer’s disease[J].Alzheimers Dis,2009,16: 503 -507.
[34] Gan E H, Pearce S H.Clinical review: The thyroid in mind:cognitive function and low thyrotropin in older people[J].Clin Endocrinol Metab,2012,97:3438-3449.
[35] Moon J H, Park Y J, Kim T H, et al.Lower-But-Normal Serum TSH level Is Associated With the Development or Progression of Cognitive Impairment in Elderly: Korean Longitudinal Study on Health and Aging(KLOSHA)[J].Clin Endocrinol Metab,2014,99:424-432.
[36] Moon J H, Soyeon Ahn, Jiyeong Seo,et al.The effect of long-term thyroid stimulating hormone suppressive therapy on the cognitive function of elderly patients with differentiated thyroid carcinoma[J].Clinical Endocrine,2014,99(10):3782-3789.
[37] Cooper D S, Doherty G M, Haugen B R, et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association(ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer[J].Thyroid, 2009,19(11):1167-1214.
[38] NCCN Clinical Practice Guidelines in Oncology.Thyroid carcinoma[S/OL].Version.2012.http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf.
[39] 中华医学会内分泌学分会，中华医学会外科学分会内分泌学组，中国抗癌协会头颈肿瘤专业委员会，等．甲状腺结节和分化型甲状腺癌诊治指南[J]．中华内分泌代谢杂志， 2012， 28：779-797．
[40] Bryan R.Haugen, Erik K.AlexanderKeith, C.Bible, et al.2015American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer [J].Thyroid, 2015.[Epub ahead of print].）