重组人促甲状腺激素用于低中危分化型甲状腺癌患者的术后评估:Ⅰ期临床研究报告

Recombinant human thyroid-stimulating hormone for post-operative assessment in patients with low-to intermediate-risk differentiated thyroid cancer:results of phaseⅠstudy

目的:评价我国自主研发的重组人促甲状腺激素(rhTSH)在辅助分化型甲状腺癌(DTC)患者^(131)I治疗前后动态评估中的作用。方法:该Ⅰ期研究采用剂量递增设计,纳入2019年5月至2020年11月就诊于北京协和医院及郑州大学附属肿瘤医院的24例DTC患者(男5例、女19例,中位年龄41岁),根据国产rhTSH(简称rhTSH)使用方法分为4个剂量组[0.9 mg×1 d(A组),0.9 mg×2 d(B组),1.8 mg×1 d(C组),1.8 mg×2 d(D组)],每组6例。每例患者接受2个阶段自身对照研究,依次为rhTSH阶段及停用甲状腺激素(THW)阶段。评估rhTSH的安全性、耐受性、患者生活质量[甲状腺功能减退症(简称甲减)症状体征积分、简式心境状态量表(POMS)]、药效学[促甲状腺激素(TSH)及甲状腺球蛋白(Tg)水平、诊断性全身显像(Dx-WBS)]及药代动力学(达峰时间、峰浓度)特征。采用配对t检验或Wilcoxon符号秩检验进行统计分析。结果:4个剂量组均未观察到剂量限制性毒性事件、严重不良事件或≥3级的不良事件。rhTSH阶段的生活质量相关评分明显优于THW阶段:甲减症状体征积分[-53.00(-53.00,-53.00)与-39.50(-47.00,-23.00)分;S=119.50,P<0.001];简式POMS评分[(91.92±12.06)与(99.67±19.13)分;t=0.95,P=0.025]。rhTSH末次给药后24 h血清TSH水平从基线的0.04(0.02,0.11)mU/L升至150.00(105.20,173.31)mU/L;随着rhTSH剂量增加,各组TSH呈增高趋势。在THW阶段,患者需经中位时间23 d的THW方达TSH≥30 mU/L水平,THW阶段TSH水平为73.51(57.22,106.22)mU/L;Tg在rhTSH给药后从基线[0.10(0.10,0.41)μg/L]逐渐升高,48 h达峰值[0.85(0.12,3.01)μg/L],THW阶段Tg水平为0.88(0.15,8.04)μg/L;2个阶段诊断性全身显像结果一致率为95.8%(23/24)。结论:在辅助DTC术后评估中,国产rhTSH对患者显示出较好的安全性,患者生活质量较好;其可有效升高患者TSH水平,并快速刺激Tg分泌及残余甲状腺摄碘。

Objective To evaluate the efficacy by using domestic recombinant human thyroid-stimulating hormone(rhTSH)in patients with differentiated thyroid cancer(DTC)before or after^(131)I therapy.Methods From May 2019 to November 2020,a total of 24 patients with DTC(5 males,19 females,median age 41 years)in Peking Union Medical College Hospital and Affiliated Tumor Hospital of Zhengzhou University were enrolled into the open-label,dose escalation phaseⅠstudy.All patients were divided into 4 domestic rhTSH dose groups:0.9 mg×1 d(group A),0.9 mg×2 d(group B),1.8 mg×1 d(group C),1.8 mg×2 d(group D)in succession,with 6 patients in each group.Each patient underwent rhTSH phase and thyroid hormone withdrawal(THW)phase.The end point included safety,tolerability,the quality of life(hypothyroidism symptom and sign score(Billewicz score),profile of mood states(POMS)),effectiveness(thyroid-stimulating hormone(TSH)and thyroglobulin(Tg)levels,diagnostic whole-body scan(Dx-WBS))and pharmacokinetic characteristics(peak time,peak concentration)of rhTSH.Paired t test and Wilcoxon signed rank test were used for statistical analysis.Results There were no dose-limiting toxicities,serious adverse events,or no grade≥3 adverse events reported.The quality of life in rhTSH phase was significantly better than those in THW phase,including the lower Billewicz score(-53.00(-53.00,-53.00)vs-39.50(-47.00,-23.00);S=119.50,P<0.001)and the lower POMS score(91.92±12.06 vs 99.67±19.13;t=0.95,P=0.025).Serum TSH level was increased from 0.04(0.02,0.11)mU/L(baseline)to 150.00(105.20,173.31)mU/L 24 h after the last rhTSH administration,which was increased along with the elevation of rhTSH doses.In the THW phase,patients′TSH levels were≥30 mU/L after 23 d(median)of THW,with the median of 73.51(57.22,106.22)mU/L.Median Tg level of baseline was 0.10(0.10,0.41)μg/L,which reached a peak of 0.85(0.12,3.01)μg/L at 48 h after rhTSH administration.The peak Tg level in the THW phase was 0.88(0.15,8.04)μg/L.The Dx-WBS consistency rate between rhTSH and THW phase was 95.8%(23/24).Conclusion rhTSH is a safe and effective method to stimulate the serum Tg level and radioiodine uptake in patients undergoing post-operation or post-^(131)I assessment for DTC,as well as maintain a higher quality of life in comparison to THW phase.