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甲状腺癌是内分泌系统最常见的恶性肿瘤之一,其中DTC占95%以上。尽管甲状腺癌的发病率在逐年上升[1-2],但病死率并没有显著增加。对于DTC患者,关注的重点在于疾病的复发及无疾病生存期。2015年美国甲状腺协会(American Thyroid Association , ATA)指南[3]首次纳入了动态疗效反应评估体系,相关研究结果均表明,即使术后初始复发风险分层为中高危的DTC患者,在经过131I治疗后仍可以达到疗效满意(excellent response, ER),且复发的风险降低[4-5]。因此,了解影响中高危DTC患者的预后因素,在初始治疗时给予个体化治疗可以得到更好的疗效。本研究旨在分析中高危DTC患者术后行131I治疗后ER的影响因素,为其个体化治疗、早期疗效评价及随访策略的制定提供依据。
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参照美国癌症联合委员会甲状腺癌TNM分期(第8版)标准[8]对患者进行分期,其中原发灶Tx期24例、T1期199例、T2期34例、T3期90例、T4期31例;淋巴结转移Nx期17例、N0期18例、N1a期198例、N1b期145例。依据ATA指南(2015版)[3]提出的复发风险分层分为中危321例、高危57例。疗效反应评估结果显示,ER组患者271例,nER组患者107例(包括IDR61例、BIR36例、SIR10例)。其他临床资料和组织病理学资料见表1。
因素 疗效满意组(n=271) 疗效欠佳组(n=107) 检验值 P值 年龄[M(Q1, Q3), 岁] 45(35, 52) 45(34, 51) Z=−0.699 0.484 肿瘤最大径[M(Q1, Q3), cm] 1.2(0.9, 2.0) 1.5(1.0, 2.5) Z=−2.702 0.007 性别[例(%)] χ2=0.224 0.636 男 72(26.6) 31(29.0) 女 199(73.4) 76(71.0) 被膜受累[例(%)] χ2=0.064 0.800 否 191(70.5) 74(69.2) 是 80(29.5) 33(30.8) 肿瘤多灶性[例(%)] χ2=0.358 0.550 单灶 90(33.2) 39(36.4) 多灶 181(66.8) 68(63.6) T分期[例(%)] χ2=5.501 0.240 Tx期 18(6.6) 6(5.6) T1期 151(55.7) 48(44.9) T2期 21(7.8) 13(12.1) T3期 62(22.9) 28(26.2) T4期 19(7.0) 12(11.2) N分期[例(%)] − 0.005 Nx期 14(5.1) 3(2.8) N0期 17(6.3) 1(0.9) N1a期 149(55.0) 49(45.8) N1b期 91(33.6) 54(50.5) 复发风险分层[例(%)] χ2=3.502 0.061 中危 236(87.1) 85(79.4) 高危 35(12.9) 22(20.6) 首次131I治疗剂量[M(Q1, Q3), GBq] 3.7(3.7, 3.7) 3.7(3.7, 3.7) Z=−1.505 0.132 psTg水平[M(Q1, Q3), ng/ml] 1.36(0.22, 4.28) 8.98(1.56, 21.32) Z=−7.127 <0.001 TSH水平[M(Q1, Q3), mIU/L] 126.82(86.23, 150.00) 127.77(91.89, 150.00) Z=−0.664 0.506 尿碘[M(Q1, Q3), μg/L] 109.70(73.10, 181.00) 125.70(81.65, 210.05) Z=−1.005 0.314 甲状腺99TcmO4−显像T/NT
[M(Q1, Q3)]1.47(1.10, 2.49) 1.60(1.20, 2.68) Z=−0.940 0.345 131I Rx-WBS评分[例(%)] − 0.415 0分 2(0.7) 1(0.9) 1分 22(8.1) 7(6.5) 2分 105(38.8) 48(44.9) 3分 89(32.8) 38(35.5) 4分 53(19.6) 13(12.2) 术后与首次131I治疗的间隔时间[例(%)] χ2=6.783 0.009 ≤ 2个月 139(51.3) 39(36.4) > 2个月 132(48.7) 68(63.6) 注:DTC为分化型甲状腺癌;Tx为原发肿瘤无法评估;Nx为淋巴结转移无法评估;psTg为术后刺激性甲状腺球蛋白;TSH 为促甲状腺激素;T/NT为靶/非靶比值;Rx-WBS为治疗性全身显像。−为Fisher确切概率法,无检验值 表 1 378例中高危DTC患者的临床资料和组织病理学资料的比较
Table 1. Comparison of clinical date and histopathological pathological data in 378 patients with intermediate-to-high risk differentiated thyroid cancer
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Spearman秩相关分析结果显示,术后残留甲状腺99TcmO4−显像T/NT值与131I Rx-WBS显像评分呈中度相关(r=0.530,P<0.001)。
ER组与nER组间的肿瘤最大径、psTg水平、N分期、术后与首次131I治疗的间隔时间的差异均有统计学意义(均P<0.05);年龄、性别、被膜受累、肿瘤多灶性、T分期、复发风险分层、首次131I治疗剂量、TSH水平、尿碘水平、甲状腺99TcmO4−显像T/NT、131I Rx-WBS评分指标的差异均无统计学意义(均P>0.05)。
多因素Logistic回归分析结果显示,psTg为ER的独立危险因素(OR=0.981,95%CI=0.849~0.923,P<0.001,表2)。ROC曲线分析结果显示,psTg水平预测ER的最佳诊断临界值为5.90 ng/ml、灵敏度为83.76%、特异度为59.81%、AUC为0.735(图1)。
预后因素 β值 OR值 95%CI P值 术后与首次131I治疗时间间隔 0.960 2.611 0.856~7.966 0.092 肿瘤最大径 −0.020 0.981 0.765~1.258 0.878 psTg水平 −1.222 0.885 0.849~0.923 <0.001 N分期 − − − 0.310 注:DTC为分化型甲状腺癌;CI为置信区间;psTg为术后刺激性甲状腺球蛋白;−表示无此项数据 表 2 影响中高危DTC患者131I治疗预后的多因素Logistic回归分析
Table 2. The multivariate Logistic regression analysis of prognostic factors in patients with intermediate-to-high risk DTC after 131I treatment
中高危DTC患者术后较高剂量131I治疗后疗效反应的影响因素分析
Therapeutic response outcomes and influencing factors after surgery and a higher does of 131I in patients with intermediate-to-high risk differentiated thyroid cancer
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摘要:
目的 探讨无转移的中高危分化型甲状腺癌(DTC)患者术后给予较高剂量131I治疗的疗效及其影响因素。 方法 回顾性分析2018年1月至2020年12月于山西医科大学第一医院行DTC全切术后的378例中高危DTC患者的临床资料,其中男性103例、女性275例,中位年龄45(13~85)岁。所有患者均在术后给予首次131I清甲和(或)辅助治疗,剂量3.70~5.55 GBq。同时131I治疗前行术后残留甲状腺99TcmO4−显像,治疗后2~7 d行131I治疗后全身显像(Rx-WBS)。所有患者在131I治疗后至少6个月进行随访,中位随访时间16.3个月。依据2015年美国甲状腺协会(ATA)指南的疗效反应评估体系进行术后131I治疗疗效反应评估并分析影响因素。采用Spearman秩相关分析评估术后残留甲状腺99TcmO4−显像靶/非靶比值(T/NT)与Rx-WBS评分的相关性;采用Mann-Whitney U检验、χ2检验或Fisher确切概率法分析所有观察指标在疗效满意(ER)组与疗效欠佳(nER)组间的差异是否有统计学意义;采用Logistic回归分析影响预后ER的独立危险因素,并绘制ROC曲线,获得最佳诊断临界值。 结果 ER组与nER组间在肿瘤最大径、术后刺激性甲状腺球蛋白(psTg)水平、N分期、术后与首次131I治疗间隔时间的差异均有统计学意义(Z=−7.127、−2.702,Fisher确切概率法, χ2=6.783,均P<0.05);年龄、性别、被膜受累、肿瘤多灶性、T分期、复发风险分层、首次131I治疗剂量、TSH水平、尿碘水平、甲状腺99TcmO4−显像半定量指标T/NT、131I Rx-WBS评分的差异均无统计学意义(Z=−1.505~−0.664, χ2=0.064~5.501,Fisher确切概率法,均P >0.05)。Spearman 秩相关检验分析结果显示,99TcmO4−显像T/NT与Rx-WBS显像评分呈中度相关(r=0.530,P<0.001)。多因素Logistic回归分析结果显示,psTg水平是预后ER的独立危险因素。ROC曲线分析结果显示,psTg水平预测ER的最佳临界值为5.90 ng/ml、灵敏度为83.76%、特异度为59.81%。 结论 给予较高剂量131I治疗的中高危DTC患者,不论甲状腺99TcmO4−显像提示残留甲状腺多少均可以得到同样的ER比率;且术后2个月内行首次131I治疗,可能获得更好的治疗疗效。另外,psTg是预测无转移中高危DTC患者临床ER的独立危险因素。 Abstract:Objective To investigate the efficacy response and influencing factors of higher dose 131I in patients with metastasis-free intermediate-to-high risk differentiated thyroid cancer (DTC). Methods The clinical date of 378 patients with intermediate-to-high risk DTC who attended in the First Hospital of Shanxi Medical University from January 2018 to December 2020 were retrospectively analyzed. The patients included 103 male and 275 female with a median age of 45(13–85) years. All patients were given the first 131I remnant ablation and/or adjuvant therapy at a dose range of 3.70–5.55 GBq. Postoperative residual thyroid 99TcmO4− image was performed before 131I treatment, and 131I post-treatment whole body scan (Rx-WBS) was performed 2–7 days after treatment. All patients were followed up at least 6 months with a median follow-up time of 16.3 months. The efficacy response evaluation system was evaluated according to the 2015 American Thyroid Association assessment system, and its influencing factors were analyzed. Spearman rank correlation analysis was used to evaluate the correlation between 99TcmO4− image target/non-target (T/NT) ratio and Rx-WBS score.The Mann-Whitney U test, χ2 test or Fisher's exact probability method was utilized to analyze whether the difference between the excellent response (ER) and non-excellent response (nER) groups was statistically significant for all observed indicators. Binary multivariate Logistic regression was used to analyze the independent influencing factors of prognostic ER, receiver operator characteristic (ROC) curves were utilized to obtain optimal diagnostic thresholds. Results Stistically significant differences were observed in maximum tumor diameter, postoperative stimulated thyroglobulin (psTg) level, N stage, and interval time between the two groups of ER and nER (Z=−7.127, −2.702, Fisher's exact probability method, χ2=6.783; all P<0.05). The differences were statistically insignificant for age, sex, capsule involvement, tumor multifocality, T-staging, risk of recurrence stratification, first dose of 131I treatment, thyroid-stimulating hormone (TSH) level, urinary iodine level, 99TcmO4− image T/NT values, and Rx-WBS score (Z=−1.505 to −0.664, χ2=0.064–5.501, Fisher's exact probability method; all P>0.05). Spearman rank correlation analysis showed a moderate correlation between 99TcmO4− image T/NT values and Rx-WBS imaging scores (r=0.530, P<0.001). A multivariate Logistic regression analysis showed that psTg level was the independent risk factor of ER. The ROC curve analysis showed that the optimal cut-off value of ER was 5.90 ng/ml, the sensitivity was 83.76%, and the specificity was 59.81%. Conclusions Patients with intermediate-to-high risk DTC treated with higher dose of 131I had the same good ER proportion regardless of the amount of residual thyroid indicated by thyroid 99TcmO4− imaging. Patients receiving 131I treatment within 2 months after surgery may obtain better ER proportion. Meanwhile, psTg was an independent risk factor for predicting ER proportion in patients with metastasis-free intermediate-to-high risk DTC. -
表 1 378例中高危DTC患者的临床资料和组织病理学资料的比较
Table 1. Comparison of clinical date and histopathological pathological data in 378 patients with intermediate-to-high risk differentiated thyroid cancer
因素 疗效满意组(n=271) 疗效欠佳组(n=107) 检验值 P值 年龄[M(Q1, Q3), 岁] 45(35, 52) 45(34, 51) Z=−0.699 0.484 肿瘤最大径[M(Q1, Q3), cm] 1.2(0.9, 2.0) 1.5(1.0, 2.5) Z=−2.702 0.007 性别[例(%)] χ2=0.224 0.636 男 72(26.6) 31(29.0) 女 199(73.4) 76(71.0) 被膜受累[例(%)] χ2=0.064 0.800 否 191(70.5) 74(69.2) 是 80(29.5) 33(30.8) 肿瘤多灶性[例(%)] χ2=0.358 0.550 单灶 90(33.2) 39(36.4) 多灶 181(66.8) 68(63.6) T分期[例(%)] χ2=5.501 0.240 Tx期 18(6.6) 6(5.6) T1期 151(55.7) 48(44.9) T2期 21(7.8) 13(12.1) T3期 62(22.9) 28(26.2) T4期 19(7.0) 12(11.2) N分期[例(%)] − 0.005 Nx期 14(5.1) 3(2.8) N0期 17(6.3) 1(0.9) N1a期 149(55.0) 49(45.8) N1b期 91(33.6) 54(50.5) 复发风险分层[例(%)] χ2=3.502 0.061 中危 236(87.1) 85(79.4) 高危 35(12.9) 22(20.6) 首次131I治疗剂量[M(Q1, Q3), GBq] 3.7(3.7, 3.7) 3.7(3.7, 3.7) Z=−1.505 0.132 psTg水平[M(Q1, Q3), ng/ml] 1.36(0.22, 4.28) 8.98(1.56, 21.32) Z=−7.127 <0.001 TSH水平[M(Q1, Q3), mIU/L] 126.82(86.23, 150.00) 127.77(91.89, 150.00) Z=−0.664 0.506 尿碘[M(Q1, Q3), μg/L] 109.70(73.10, 181.00) 125.70(81.65, 210.05) Z=−1.005 0.314 甲状腺99TcmO4−显像T/NT
[M(Q1, Q3)]1.47(1.10, 2.49) 1.60(1.20, 2.68) Z=−0.940 0.345 131I Rx-WBS评分[例(%)] − 0.415 0分 2(0.7) 1(0.9) 1分 22(8.1) 7(6.5) 2分 105(38.8) 48(44.9) 3分 89(32.8) 38(35.5) 4分 53(19.6) 13(12.2) 术后与首次131I治疗的间隔时间[例(%)] χ2=6.783 0.009 ≤ 2个月 139(51.3) 39(36.4) > 2个月 132(48.7) 68(63.6) 注:DTC为分化型甲状腺癌;Tx为原发肿瘤无法评估;Nx为淋巴结转移无法评估;psTg为术后刺激性甲状腺球蛋白;TSH 为促甲状腺激素;T/NT为靶/非靶比值;Rx-WBS为治疗性全身显像。−为Fisher确切概率法,无检验值 表 2 影响中高危DTC患者131I治疗预后的多因素Logistic回归分析
Table 2. The multivariate Logistic regression analysis of prognostic factors in patients with intermediate-to-high risk DTC after 131I treatment
预后因素 β值 OR值 95%CI P值 术后与首次131I治疗时间间隔 0.960 2.611 0.856~7.966 0.092 肿瘤最大径 −0.020 0.981 0.765~1.258 0.878 psTg水平 −1.222 0.885 0.849~0.923 <0.001 N分期 − − − 0.310 注:DTC为分化型甲状腺癌;CI为置信区间;psTg为术后刺激性甲状腺球蛋白;−表示无此项数据 -
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