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PD-1抑制剂治疗消化系统恶性肿瘤后超进展发生率及影响因素分析

陈诗韵 千年松 闫欢 苟苗苗 戴广海

陈诗韵, 千年松, 闫欢, 苟苗苗, 戴广海. PD-1抑制剂治疗消化系统恶性肿瘤后超进展发生率及影响因素分析[J]. 解放军医学院学报, 2021, 42(1): 1-6. doi: 10.3969/j.issn.2095-5227.2021.01.001
引用本文: 陈诗韵, 千年松, 闫欢, 苟苗苗, 戴广海. PD-1抑制剂治疗消化系统恶性肿瘤后超进展发生率及影响因素分析[J]. 解放军医学院学报, 2021, 42(1): 1-6. doi: 10.3969/j.issn.2095-5227.2021.01.001
CHEN Shiyun, QIAN Niansong, YAN Huan, GOU Miaomiao, DAI Guanghai. Incidence and risk factors of hyperprogressive disease caused by PD-1 inhibitors for treatment of digestive system malignancies[J]. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL, 2021, 42(1): 1-6. doi: 10.3969/j.issn.2095-5227.2021.01.001
Citation: CHEN Shiyun, QIAN Niansong, YAN Huan, GOU Miaomiao, DAI Guanghai. Incidence and risk factors of hyperprogressive disease caused by PD-1 inhibitors for treatment of digestive system malignancies[J]. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL, 2021, 42(1): 1-6. doi: 10.3969/j.issn.2095-5227.2021.01.001

PD-1抑制剂治疗消化系统恶性肿瘤后超进展发生率及影响因素分析

doi: 10.3969/j.issn.2095-5227.2021.01.001
基金项目: 国家自然科学基金面上项目(31671298)
详细信息
    作者简介:

    陈诗韵,女,硕士,医师。研究方向:消化系统恶性肿瘤。Email: 279439732@qq.com

    通讯作者:

    戴广海,男,主任医师,教授,博士生导师。Email: daigh301@vip.sina.com

  • 中图分类号: R 730.51

Incidence and risk factors of hyperprogressive disease caused by PD-1 inhibitors for treatment of digestive system malignancies

Funds: Supported by the National Natural Science Foundation of China (31671298)
More Information
  • 摘要:   背景  免疫检查点抑制剂(immunocheckpoint inhibitors,ICIs)已经被批准用于多种类型的肿瘤治疗,并显示出了良好的抗肿瘤活性。但在临床实践中,一些患者似乎并没有从ICI中受益,而是出现了疾病的加速进展,称为超进展(hyper progressive disease,HPD)。  目的  分析消化系统恶性肿瘤患者应用PD-1抑制剂时超进展的发生率并探究其相关因素。  方法  收集解放军总医院第一医学中心2015年4月- 2019年4月行PD-1抑制剂(纳武利尤单抗/帕博利珠单抗)治疗的消化系统恶性肿瘤患者病历,计算治疗前和治疗过程中的肿瘤生长速率(tumor growth rate,TGR)。超进展定义为在应用免疫治疗后6 ~ 8周内首次评估时的TGR与先前治疗时的TGR增加值超过50%。计算超进展发生率并分析其影响因素。  结果  从135例可评估的消化系统恶性肿瘤患者中鉴定出22例超进展患者(16.3%),其中胰腺癌7例、食管癌2例、结直肠癌5例、胆管癌3例、肝癌2例、壶腹癌1例、胃癌2例。超进展组行免疫治疗前转移器官数目超过2个的患者比例更高(54.5% vs 18.6%,P<0.01),肝转移(77.3% vs 52.2%,P<0.01)及乳酸脱氢酶超出正常上限者(45.5% vs 18.6%,P<0.01)比例更高。与未发生HPD的进展(progressive disease,PD)患者相比,HPD组患者的总生存期(overall survival,OS)较低(中位OS:3.6个月vs 6.2个月,P<0.01)。ROC分析显示,胰腺癌患者使用PD-1单抗治疗后1个月内特征性肿瘤标志物CA199较影像学检查前升高166.84%,对HPD的发生有预示作用(敏感度85.70%,特异性94.10%)。  结论  接受PD-1抑制剂治疗的消化系统恶性肿瘤患者中,超进展可能与转移器官数目、肝转移、乳酸脱氢酶水平升高相关,其中胰腺癌患者在接受免疫治疗后CA199在1个月内上升幅度达到166.84%或以上提示可能发生HPD。

     

  • 图  1  135例消化系统恶性肿瘤患者TGRPOST与TGRPRE的成对比较散点图。红点为HPD,蓝点为非HPD

    Figure  1.  Pairwise comparison of TGRPOST and TGR PRE in 135 patients with malignant tumors of digestive system. Blue spots indicate patients with non-HPD, and red spots indicate patients with HPD

    图  2  CA199预测HPD的ROC曲线(最佳阈值为166.84%)

    Figure  2.  ROC curve of change in serum levels of CA199 to predictHPD (the optimal cut-off value is 166.84%)

    图  3  HPD组与非HPD的PD组OS曲线比较

    Figure  3.  Overall survival for hyperprogressive disease (HPD) compared with progressive disease without hyperprogression

    表  1  PD-1抑制剂治疗的消化系统恶性肿瘤患者HPD与非HPD相关指标比较(n, %)

    Table  1.   Comparisons of demographic and clinical characteristics between the HPD and the non-HPD patients with digestive system malignant tumors treated with PD-1 inhibitors (n, %)

    CharacteristicNon-HPD (n=113)HPD (n=22) χ2PCharacteristicNon-HPD (n=113)HPD
    (n=22)
    χ2P
    Age/yrs1.3320.248 Surgical history0.5470.460
     ≥ 60 51(45.1)7(31.8)  Yes76(67.3)13(59.1)
     < 60 62(54.9)15(68.2)  No37(32.7)9(40.9)
    Gender0.1330.715 PD-L1 positivity1.8970.168
     Male62(54.9)13(59.1)  Positive63(66.3)10(50.0)
     Female51(45.1)9(40.9) Negative32(33.7)10(50.0)
    Smoking history0.7860.375  Missing182
     Ever-smoker45(39.8)11(50.0)Response to line before
     immunotherapy
    2.2650.322
     Never-smoker68(60.2)11(50.0) PR3(2.7)0(0.0)
    Smoking exposure0.9590.407 SD35(31.0)4(18.2)
     > 30 packs per year26(23.0)3(13.6)  PD75(66.4)18(81.8)
     ≤ 30 packs per year87(77.0)19(86.4) Number of metastatic sites12.8940.000
    Tumor type6.1830.403 0-192(81.4)10(45.5)
     Pancreatic cancer18(15.9)7(31.8) ≥ 221(18.6)12(54.5)
     Esophageal cancer8(7.1)2(9.1) ECOG performance status3.8180.085
     Colorectal cancer17(15.0)5(22.7) ≥ 24(3.5)3(13.6)
     Cholangiocarcinoma19(16.8)3(13.6) 0-1109(96.5)19(86.4)
     Liver cancer15(13.3)2(9.1) Neutrophil-to-lymphocyte ratio0.7330.392
     Ampullary carcinoma5(4.4)1(4.5) > 347(41.6)7(31.8)
     Gastric carcinoma31(27.4)2(9.1) ≤ 366(58.4)15(68.2)
    Pathology8.4790.132Lactate dehydrogenase level7.5160.006
     Adenocarcinoma91(80.5)16(72.7)  ≤ Upper limit of normal92(81.4)12(54.5)
     Squamous carcinoma5(4.4)4(18.2)  > Upper limit of normal21(18.6)10(45.5)
     Hepatocellular carcinoma5(4.4)2(9.1) Liver metastasis4.7000.030
     Cholangiocarcinoma9(8.0)0(0.0) Present59(52.2)17(77.3)
     Neuroendocrine carcinoma2(1.8)0(0.0) Absent54(47.8)5(22.7)
     Small cell carcinoma1(0.9)0(0.0)
    下载: 导出CSV

    表  2  接受PD-1抑制剂治疗的胰腺癌及结直肠癌患者基因状态与超进展的关系(n, %)

    Table  2.   Association between genetic status and HPD for immunotherapy-treated patients with pancreatic cancer and colorectal cancer (n, %)

    CharacteristicNon-HPD (n=35)HPD (n=12)χ2P
    KRAS mutation1.1540.283
     Mutated type14(48.3)8(66.7)
     Wild type15(51.7)4(33.3)
     Missing60
    No. of molecular alterations0.2560.613
     0-112(41.4)6(50.0)
     ≥ 217(58.6)6(50.0)
     Missing60
    下载: 导出CSV

    表  3  胰腺癌患者免疫抑制剂治疗前后两组肿瘤标志物CA199水平比较(Md , IQR)

    Table  3.   Comparison of levels of CA199 before and after immunotherapy in patients with pancreatic cancer (Md , IQR)

    CA199HPDNon-HPDZP
    Baseline/(U·ml-1)163.00
    (156.50, 3524.00)
    181.20
    (21.03, 1 185.75)
    −0.8480.397
    Increase/%214.50
    (194.64,425.18)
    30.37
    (−7.48,93.42)
    −2.7240.006
    下载: 导出CSV

    表  4  CA199对接受免疫疗法的胰腺癌患者HPD发生的预测价值(%)

    Table  4.   Value of CA199 in predicting HPD in patients with pancreatic cancer undergoing immunotherapy (%)

    Diagnosis performance parameterData
       Sensitivity85.70
       Specificity94.10
       Positive predictive value85.71(6/7)
       Negative predictive value94.44(17/18)
    下载: 导出CSV
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  • 收稿日期:  2020-10-13
  • 网络出版日期:  2021-03-01
  • 刊出日期:  2021-01-28

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