-
DTC预后良好,患者的10年生存率>90%[1]。4%~25%的DTC患者发生肺、骨、脑等远处转移后生活质量下降,病死率升高[2-4]。肺是DTC最常见的远处转移部位,行手术、131I治疗和TSH抑制治疗可显著改善其预后[5-6]。但仍有部分肺转移性DTC患者在诊疗过程中出现摄碘功能障碍,导致其无法从131I治疗中获益而进展为碘难治性分化型甲状腺癌(radioiodine refractory differentiated thyroidcancer,RAIR-DTC),这是DTC临床诊疗的重点和难点。本研究对肺转移性DTC患者的临床资料进行回顾性分析,旨在进一步全面探讨影响肺转移性DTC术后131I治疗疗效的独立风险因子,以期为制定精准化的诊疗计划提供循证依据。
-
108例DTC患者中,6例经穿刺或手术组织病理学检查证实发生肺转移,102例根据血清Tg水平和影像学检查结果确诊为肺转移。术后经131I治疗疾病控制的患者86例(79.6%),即为疾病控制组;疾病进展的患者22例(20.4%),即为疾病进展组。单因素分析结果显示,2组患者在年龄、病理学类型、DTC原发灶的长径、首次131I治疗前的血清sTg水平、ΔsTg/TSH、肺转移灶的长径、肺转移灶是否摄碘、肺转移确诊时间之间的差异均有统计学意义(均P<0.05);其余临床病理学特征之间的差异均无统计学意义(均P>0.05),具体数据见表1。由于病历资料缺失,108例患者中有7例患者无法判断是否存在腺外侵犯,疾病控制组83例患者中有45例(54.2%)伴有腺外侵犯,疾病进展组18例患者中有14例(77.8%)伴有腺外侵犯,2组比较,差异无统计学意义(χ2=3.380,P=0.066)。此外,108例患者中有8例患者淋巴结转移情况不详(7例患者病历资料缺失、1例患者术中未清扫淋巴结),疾病控制组83例患者中N0、N1a、N1b分期分别有14例(16.9%)、6例(7.2%)、63例(75.9%) ,疾病进展组17例患者中N0、N1a、N1b分期分别有3例(17.6%)、2例(11.8%)、12例(70.6%) ,2组比较,差异无统计学意义(χ2=0.421,P=0.810)。
影响因素 131I治疗疗效 检验值 P值 疾病控制(n=86) 疾病进展(n=22) 性别[例(%)] χ2=0.581 0.446 男 35(40.7) 7(31.8) 女 51(59.3) 15(68.2) 年龄[M(Q1,Q3),岁] 48.0(17,77) 61.5(23,77) H=−3.194 0.001 病理学类型[例(%)] χ2=19.142 <0.001 甲状腺乳头状癌 80(93.0) 13(59.1) 甲状腺滤泡状癌 6(7.0) 7(31.8) 甲状腺乳头状癌合并甲状腺滤泡状癌 0(0) 2(9.1) DTC原发灶的长径[M(Q1,Q3),cm] 2.0(0.2,7.0) 3.6(0.6,7.0) H=−2.888 0.004 首次131I治疗前的血清sTg水平[M(Q1,Q3),ng/ml] 49.32
(0.04,112 880.00)154.30
(0.69,41 490.00)H=−2.499 0.012 ΔsTg/TSH[M(Q1,Q3),%] −56.19
(−99.92,200.00)19.25
(−88.94,5 350.60)H=−4.140 <0.001 131I治疗次数[M(Q1,Q3),次] 3(2,10) 3(2,12) H=0.849 0.654 131I治疗累积剂量[M(Q1,Q3),×104 MBq] 1.406(0.370,3.700) 1.665(0.555,5.180) H=−1.490 0.136 肺结节的分布特征[例(%)] χ2=0.549 0.464 无结节 17(19.8) 0(0) 散在局灶分布 15(17.4) 6(27.3) 多发弥漫分布 54(62.8) 16(72.7) 肺转移灶的长径[例(%)] χ2=15.380 <0.001 ≤10 mm 73(84.9) 9(40.9) >10 mm 13(15.1) 13(59.1) 肺转移灶是否摄碘[例(%)] χ2=4.069 0.044 是 59(68.6) 10(45.5) 否 27(31.4) 12(54.5) 肺转移确诊时间[例(%)] χ2=10.362 0.016 首次行131I治疗前(术后<6个月) 45(52.3) 8(36.4) 首次行131I治疗后显像时 19(22.1) 1(4.5) 首次行131I治疗前(术后>6个月) 14(16.3) 7(31.8) 131I治疗后随访时 8(9.3) 6(27.3) 注:DTC为分化型甲状腺癌;sTg为刺激性甲状腺球蛋白;TSH为促甲状腺激素;ΔsTg/TSH为第2次131I治疗前较首次131I治疗前sTg与TSH水平比值的变化率 表 1 108例肺转移性DTC患者术后131I治疗疗效影响因素的单因素分析
Table 1. Univariate analysis of influencing factors of therapeutic efficacy of postoperative131I treatment in 108 patients with pulmonary metastatic differentiated thyroid cancer
-
多因素Logistic回归分析结果显示,2组患者在病理学类型、ΔsTg/TSH、肺转移灶的长径间的差异均有统计学意义(均P<0.05),其是预测疾病进展的独立风险因子;2组间其他因素的比较,差异均无统计学意义(均P>0.05),具体数据见表2。
影响因素 B值 P值 OR值 95%CI 年龄 0.115 0.141 1.122 0.963~1.307 病理学类型 3.059 0.042 21.314 1.112~408.369 ΔsTg/TSH 0.048 0.017 1.050 1.009~1.092 首次131I治疗前的血清sTg水平 0.000 0.377 1.000 1.000~1.000 DTC原发灶的长径 4.963 0.108 143.024 0.335~60 993.78 肺转移灶的长径 4.140 0.029 62.798 1.528~2 581.064 肺转移确诊时间 0.418 0.443 1.520 0.522~4.426 肺转移灶是否摄碘 −0.446 0.770 0.640 0.032~12.727 注:DTC为分化型甲状腺癌;sTg为刺激性甲状腺球蛋白;TSH为促甲状腺激素;ΔsTg/TSH为第2次131I治疗前较首次131I治疗前sTg与TSH水平比值的变化率;OR为比值比;CI为置信区间 表 2 108例肺转移性DTC患者术后131I治疗疗效影响因素的多因素分析
Table 2. Multivariate analysis of influencing factors of therapeutic efficacy of postoperative131I treatment in 108 patients with pulmonary metastatic differentiated thyroid cancer
-
ΔsTg/TSH预测疾病进展的ROC曲线如图1所示,AUC=0.809(95%CI:0.701~0.917,P<0.001),最佳临界值为−0.785%,ΔsTg/TSH预测疾病进展的灵敏度、特异度、阳性预测值、阴性预测值分别为73.68%、77.03%、45.16%、91.94%。
肺转移性分化型甲状腺癌术后131I治疗疗效及其影响因素的分析
Therapeutic efficacy and influencing factors of postoperative 131I treatment for pulmonary metastatic differentiated thyroid cancer
-
摘要:
目的 探讨肺转移性分化型甲状腺癌(DTC)术后131I治疗疗效及其影响因素。 方法 回顾性分析1993年1月至2021年3月青岛大学附属医院收治的108例肺转移性DTC患者的临床资料,其中男性42例、女性66例,中位年龄54.3(17~77)岁,中位随访时间4.19(1.13~23.45)年。对患者行131I治疗,治疗前后进行促甲状腺激素(TSH)、甲状腺球蛋白(Tg)和甲状腺球蛋白抗体(TgAb)水平等血清学检测及胸部CT、131I全身显像、颈部超声等影像学检查,动态评估肺转移灶的进展情况。根据实体肿瘤疗效评价标准(RECIST)1.1及131I治疗前血清刺激性甲状腺球蛋白(sTg)水平变化评估131I治疗疗效,根据疗效将患者分为疾病控制组和疾病进展组。计算第2次131I治疗前较首次131I治疗前sTg与TSH水平比值的变化率(ΔsTg/TSH)。采用χ2检验、Kruskal-Wallis秩和检验对2组患者的临床病理学特征进行单因素分析;采用Logistic回归对上述单因素分析中差异有统计学意义的指标进行多因素分析;通过受试者工作特征(ROC)曲线及最佳临界值评估ΔsTg/TSH对疾病进展的预测价值。 结果 108例患者中,术后经131I治疗达到疾病控制的患者86例(79.6%),即为疾病控制组;疾病进展的患者22例(20.4%),即为疾病进展组。单因素分析结果显示,2组患者在年龄、病理学类型、DTC原发灶的长径、首次131I治疗前的血清sTg水平、ΔsTg/TSH、肺转移灶的长径、肺转移灶是否摄碘、肺转移确诊时间之间的差异均有统计学意义(H=−3.194,χ2=19.142,H=−2.888、−2.499、−4.140,χ2=15.380、4.069、10.362,均P<0.05)。多因素Logistic回归分析结果显示,2组患者在病理学类型、ΔsTg/TSH、肺转移灶的长径之间的差异均有统计学意义(B=3.059、0.048、4.140,OR=21.314、1.050、62.798,95%CI:1.112~408.369、1.009~1.092、1.528~2 581.064,均P<0.05)。ΔsTg/TSH预测疾病进展的最佳临界值为−0.785%,ROC曲线下面积为0.809(95%CI:0.701~0.917,P<0.001)。 结论 病理学类型、ΔsTg/TSH和肺转移灶的长径是影响肺转移性DTC术后 131I治疗疗效及预测进展的独立风险因子。 Abstract:Objective To investigate the therapeutic efficacy and influencing factors of postoperative 131I treatment for pulmonary metastatic differentiated thyroid cancer (DTC). Methods The clinical data of 108 patients with pulmonary metastatic DTC who were admitted to the Affiliated Hospital of Qingdao University from January 1993 to March 2021 were retrospectively analyzed. There were 42 males and 66 females, with a median age of 54.3(17–77) years old and a median follow-up of 4.19(1.13–23.45) years. Before and after 131I treatment, serum thyroid-stimulating hormone (TSH), thyroglobulin (Tg), and thyroglobulin antibody (TgAb) levels were detected; moreover, chest CT, 131I whole-body scan, neck ultrasound, and other imaging examinations were performed to evaluate the progression of lung metastases. The efficacy of 131I treatment was evaluated following the Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 and the change in serum stimulated thyroglobulin (sTg) level before 131I treatment. On the basis of the efficacy of 131I treatment, the patients were divided into the disease control group and disease progression group. The ratio of sTg level to TSH level before the second 131I treatment compared with the first 131I treatment was calculated (△sTg/TSH). Chi-square test and Kruskal-Wallis rank sum test were used for univariate analysis of the clinical pathological characteristics of the two groups. Logistic regression was used for multivariate analysis of the indicators with statistically significant differences in the above univariate analysis. The predictive value of △sTg/TSH for disease progression was evaluated by receiver operating characteristic (ROC) curve and the optimal cut-off value. Results Among 108 patients, 86 patients (79.6%) were in the disease control group after surgery and 131I therapy. A total of 22 patients (20.4%) were in the disease progression group. The results of univariate analysis showed significant differences between the two groups in age, pathological type, long diameter of the primary DTC lesion, serum sTg level before the first 131I treatment, △sTg/TSH, long diameter of lung metastases, iodine uptake of lung metastases, and diagnosis time (H=−3.194, χ2=19.142, H=−2.888, −2.499, −4.140, χ2=15.380, 4.069, 10.362; all P<0.05). Multivariate logistic regression analysis showed significant differences in the pathological type, △sTg/TSH, and long diameter of lung metastases between the two groups (B=3.059, 0.048, 4.140; OR=21.314, 1.050, 62.798; 95%CI: 1.112–408.369, 1.009–1.092, 1.528–2 581.064; all P<0.05). The optimal cut-off value of △sTg/TSH for predicting disease progression was −0.785%, and the area under the curve of the ROC was 0.809(95%CI: 0.701–0.917, P<0.001). Conclusion Pathological type, △sTg/TSH, and long diameter of lung metastases are independent risk factors affecting the efficacy of postoperative 131I treatment and predicting the progression of pulmonary metastatic DTC. -
表 1 108例肺转移性DTC患者术后131I治疗疗效影响因素的单因素分析
Table 1. Univariate analysis of influencing factors of therapeutic efficacy of postoperative131I treatment in 108 patients with pulmonary metastatic differentiated thyroid cancer
影响因素 131I治疗疗效 检验值 P值 疾病控制(n=86) 疾病进展(n=22) 性别[例(%)] χ2=0.581 0.446 男 35(40.7) 7(31.8) 女 51(59.3) 15(68.2) 年龄[M(Q1,Q3),岁] 48.0(17,77) 61.5(23,77) H=−3.194 0.001 病理学类型[例(%)] χ2=19.142 <0.001 甲状腺乳头状癌 80(93.0) 13(59.1) 甲状腺滤泡状癌 6(7.0) 7(31.8) 甲状腺乳头状癌合并甲状腺滤泡状癌 0(0) 2(9.1) DTC原发灶的长径[M(Q1,Q3),cm] 2.0(0.2,7.0) 3.6(0.6,7.0) H=−2.888 0.004 首次131I治疗前的血清sTg水平[M(Q1,Q3),ng/ml] 49.32
(0.04,112 880.00)154.30
(0.69,41 490.00)H=−2.499 0.012 ΔsTg/TSH[M(Q1,Q3),%] −56.19
(−99.92,200.00)19.25
(−88.94,5 350.60)H=−4.140 <0.001 131I治疗次数[M(Q1,Q3),次] 3(2,10) 3(2,12) H=0.849 0.654 131I治疗累积剂量[M(Q1,Q3),×104 MBq] 1.406(0.370,3.700) 1.665(0.555,5.180) H=−1.490 0.136 肺结节的分布特征[例(%)] χ2=0.549 0.464 无结节 17(19.8) 0(0) 散在局灶分布 15(17.4) 6(27.3) 多发弥漫分布 54(62.8) 16(72.7) 肺转移灶的长径[例(%)] χ2=15.380 <0.001 ≤10 mm 73(84.9) 9(40.9) >10 mm 13(15.1) 13(59.1) 肺转移灶是否摄碘[例(%)] χ2=4.069 0.044 是 59(68.6) 10(45.5) 否 27(31.4) 12(54.5) 肺转移确诊时间[例(%)] χ2=10.362 0.016 首次行131I治疗前(术后<6个月) 45(52.3) 8(36.4) 首次行131I治疗后显像时 19(22.1) 1(4.5) 首次行131I治疗前(术后>6个月) 14(16.3) 7(31.8) 131I治疗后随访时 8(9.3) 6(27.3) 注:DTC为分化型甲状腺癌;sTg为刺激性甲状腺球蛋白;TSH为促甲状腺激素;ΔsTg/TSH为第2次131I治疗前较首次131I治疗前sTg与TSH水平比值的变化率 表 2 108例肺转移性DTC患者术后131I治疗疗效影响因素的多因素分析
Table 2. Multivariate analysis of influencing factors of therapeutic efficacy of postoperative131I treatment in 108 patients with pulmonary metastatic differentiated thyroid cancer
影响因素 B值 P值 OR值 95%CI 年龄 0.115 0.141 1.122 0.963~1.307 病理学类型 3.059 0.042 21.314 1.112~408.369 ΔsTg/TSH 0.048 0.017 1.050 1.009~1.092 首次131I治疗前的血清sTg水平 0.000 0.377 1.000 1.000~1.000 DTC原发灶的长径 4.963 0.108 143.024 0.335~60 993.78 肺转移灶的长径 4.140 0.029 62.798 1.528~2 581.064 肺转移确诊时间 0.418 0.443 1.520 0.522~4.426 肺转移灶是否摄碘 −0.446 0.770 0.640 0.032~12.727 注:DTC为分化型甲状腺癌;sTg为刺激性甲状腺球蛋白;TSH为促甲状腺激素;ΔsTg/TSH为第2次131I治疗前较首次131I治疗前sTg与TSH水平比值的变化率;OR为比值比;CI为置信区间 -
[1] 中华医学会核医学分会. 131I治疗分化型甲状腺癌指南(2021版)[J]. 中华核医学与分子影像杂志, 2021, 41(4): 218−241. DOI: 10.3760/cma.j.cn321828-20201113-00412.
Nuclear Medicine Association of the Chinese Medical Association. Guidelines for radioiodine therapy of differentiated thyroid cancer (2021 edition)[J]. Chin J Nucl Med Mol Imaging, 2021, 41(4): 218−241. DOI: 10.3760/cma.j.cn321828-20201113-00412.[2] Albano D, Bertagna F, Bonacina M, et al. Possible delayed diagnosis and treatment of metastatic differentiated thyroid cancer by adopting the 2015 ATA guidelines[J]. Eur J Endocrinol, 2018, 179(3): 143−151. DOI: 10.1530/EJE-18-0253. [3] Chopra S, Garg A, Ballal S, et al. Lung metastases from differentiated thyroid carcinoma: prognostic factors related to remission and disease-free survival[J]. Clin Endocrinol (Oxf), 2015, 82(3): 445−452. DOI: 10.1111/cen.12558. [4] Lang BHH, Wong KP, Cheung CY, et al. Evaluating the prognostic factors associated with cancer-specific survival of differentiated thyroid carcinoma presenting with distant metastasis[J]. Ann Surg Oncol, 2013, 20(4): 1329−1335. DOI: 10.1245/s10434-012-2711-x. [5] Long B, Yang MD, Yang ZW, et al. Assessment of radioiodine therapy efficacy for treatment of differentiated thyroid cancer patients with pulmonary metastasis undetected by chest computed tomography[J]. Oncol Lett, 2016, 11(2): 965−968. DOI: 10.3892/ol.2015.4034. [6] Wang RF, Zhang YQ, Tan J, et al. Analysis of radioiodine therapy and prognostic factors of differentiated thyroid cancer patients with pulmonary metastasis: an 8-year retrospective study[J]. Medicine (Baltimore), 2017, 96(19): e6809. DOI: 10.1097/MD.0000000000006809. [7] Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2016, 26(1): 1−133. DOI: 10.1089/thy.2015.0020. [8] Yang K, Wang H, Liang ZY, et al. BRAFV600E mutation associated with non-radioiodine-avid status in distant metastatic papillary thyroid carcinoma[J]. Clin Nucl Med, 2014, 39(8): 675−679. DOI: 10.1097/RLU.0000000000000498. [9] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada[J]. J Natl Cancer Inst, 2000, 92(3): 205−216. DOI: 10.1093/jnci/92.3.205. [10] Li CY, Wu Q, Sun SG. Radioactive iodine therapy in patients with thyroid carcinoma with distant metastases: a SEER-based study[J]. Cancer Control, 2020, 27(1): 1073274820914661. DOI: 10.1177/1073274820914661. [11] Matsuzu K, Sugino K, Masudo K, et al. Clinical outcomes and risk stratification for papillary thyroid carcinoma presenting with distant metastasis before the era of tyrosine kinase inhibitors[J]. Endocr J, 2020, 67(8): 869−876. DOI: 10.1507/endocrj.EJ20-0081. [12] Kim M, Kim WG, Park S, et al. Initial size of metastatic lesions is best prognostic factor in patients with metastatic differentiated thyroid carcinoma confined to the lung[J]. Thyroid, 2017, 27(1): 49−58. DOI: 10.1089/thy.2016.0347. [13] 陈立波, 丁勇, 关海霞, 等. 中国临床肿瘤学会(CSCO)持续/复发及转移性分化型甲状腺癌诊疗指南-2019[J]. 肿瘤预防与治疗, 2019, 32(12): 1051−1080.
Chen LB, Ding Y, Guan HX, et al. Guidelines of Chinese Society of Clinical Oncology (CSCO): persistent/recurrent and metastatic differentiated thyroid cancer-2019[J]. J Canc Control Treat, 2019, 32(12): 1051−1080.[14] Yang X, Liang J, Li TJ, et al. Postoperative stimulated thyroglobulin level and recurrence risk stratification in differentiated thyroid cancer[J]. Chin Med J (Engl), 2015, 128(8): 1058−1064. DOI: 10.4103/0366-6999.155086. [15] 王宸, 赵腾, 李娇, 等. 分化型甲状腺癌肺转移131I治疗后早期Tg变化与远期临床转归的关系[J]. 中华核医学与分子影像杂志, 2017, 37(9): 555−558. DOI: 10.3760/cma.j.issn.2095-2848.2017.09.007.
Wang C, Zhao T, Li J, et al. Relationship between the initial change of Tg and outcome in differentiated thyroid carcinoma patients with pulmonary metastases after 131I treatment[J]. Chin J Nucl Med Mol Imaging, 2017, 37(9): 555−558. DOI: 10.3760/cma.j.issn.2095-2848.2017.09.007.[16] 赵腾, 梁军, 李田军, 等. 分化型甲状腺癌131I治疗前刺激性Tg动态变化与远处转移的关系[J]. 中国医学科学院学报, 2015, 37(3): 315−319. DOI: 10.3881/j.issn.1000-503X.2015.03.013.
Zhao T, Liang J, Li TJ, et al. Relationship between variation of pre-ablation stimulated thyroglobulin and distant metastasis in patients with differentiated thyroid cancer[J]. Acta Acad Med Sin, 2015, 37(3): 315−319. DOI: 10.3881/j.issn.1000-503X.2015.03.013.[17] Wang C, Zhang X, Li H, et al. Quantitative thyroglobulin response to radioactive iodine treatment in predicting radioactive iodine-refractory thyroid cancer with pulmonary metastasis[J/OL]. PLoS One, 2017, 12(7): e0179664[2022-03-23]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179664. DOI: 10.1371/journal.pone.0179664. [18] 慕转转, 刘杰蕊, 鲁涛, 等. 血清Tg用于远处转移性分化型甲状腺癌131I治疗的疗效评估[J]. 中华核医学与分子影像杂志, 2020, 40(6): 329−333. DOI: 10.3760/cma.j.cn321828-20200220-00055.
Mu ZZ, Liu JR, Lu T, et al. Serum thyroglobulin in evaluating the response to 131I treatment in patients with distant metastatic differentiated thyroid cancer[J]. Chin J Nucl Med Mol Imaging, 2020, 40(6): 329−333. DOI: 10.3760/cma.j.cn321828-20200220-00055.[19] Miyauchi A, Kudo T, Miya A, et al. Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy[J]. Thyroid, 2011, 21(7): 707−716. DOI: 10.1089/thy.2010.0355. [20] Kim HJ, Lee JI, Kim NK, et al. Prognostic implications of radioiodine avidity and serum thyroglobulin in differentiated thyroid carcinoma with distant metastasis[J]. World J Surg, 2013, 37(12): 2845−2852. DOI: 10.1007/s00268-013-2213-4.