中国医科大学学报  2019, Vol. 48 Issue (8): 673-677

文章信息

孙翠翠, 张斯萌, 温倜, 曲秀娟, 刘云鹏
SUN Cuicui, ZHANG Simeng, WEN Ti, QU Xiujuan, LIU Yunpeng
晚期非小细胞肺癌肿瘤生长速率与临床病理特征及预后的相关性
Correlation between Tumor Growth Rate and Clinicopathological Features and Prognosis in Advanced Non-Small Cell Lung Cancer
中国医科大学学报, 2019, 48(8): 673-677
Journal of China Medical University, 2019, 48(8): 673-677

文章历史

收稿日期：2019-01-07
网络出版时间：2019-07-15 11:01
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引用本文
孙翠翠, 张斯萌, 温倜, 曲秀娟, 刘云鹏. 晚期非小细胞肺癌肿瘤生长速率与临床病理特征及预后的相关性[J]. 中国医科大学学报, 2019, 48(8): 673-677.
SUN Cuicui, ZHANG Simeng, WEN Ti, QU Xiujuan, LIU Yunpeng. Correlation between Tumor Growth Rate and Clinicopathological Features and Prognosis in Advanced Non-Small Cell Lung Cancer[J]. Journal of China Medical University, 2019, 48(8): 673-677.
晚期非小细胞肺癌肿瘤生长速率与临床病理特征及预后的相关性
孙翠翠 , 张斯萌 , 温倜 , 曲秀娟 , 刘云鹏     
中国医科大学附属第一医院肿瘤内科, 沈阳 110001
收稿日期：2019-01-07；网络出版时间：2019-07-15 11:01
基金项目：国家自然科学基金(31770963);辽宁省中央引导地方科技发展专项资金(2016007010);"重大新药创制"科技重大专项(2017ZX09304025)
作者简介：孙翠翠(1993-), 女, 硕士研究生.
通信作者：刘云鹏, E-mail:ypliu@cmu.edu.cn.
摘要：目的 分析晚期非小细胞肺癌（NSCLC）肿瘤生长速率（TGR）与临床病理特征及预后的相关性。方法 纳入458例诊断时无法行根治性手术切除且经病理学证实的局部晚期或转移性NSCLC患者。回顾性收集相关临床病理参数，测量基线及第1次疗效评价时靶病灶最大直径总和，利用公式计算TGR，分析TGR与临床病理特征的关系，并应用Kaplan-Meier法分析TGR与无进展生存期（PFS）及总生存期（OS）的关系。利用COX风险比例回归模型进行单因素及多因素分析，明确TGR高低对预后的影响。结果 高TGR多见于年龄≥ 60岁（P=0.038）、表皮生长因子受体（EGFR）野生型（P=0.013）、一线首选化疗（P=0.002）的患者。生存分析中，低TGR组中位PFS为8.7个月，高TGR组为4.2个月（P < 0.001）；低TGR组中位OS为24.6个月，高TGR组为16.4个月（P < 0.001）；低TGR组的中位PFS及OS明显优于高TGR组。结论 TGR在晚期NSCLC中与年龄、EGFR基因状态及一线治疗方案相关，且具有良好的预后预测价值，高TGR较低TGR人群生存期短，预后差。高TGR可作为影响PFS及OS的独立危险因素。
关键词：非小细胞肺癌    肿瘤生长速率    临床病理特征    预后    
Correlation between Tumor Growth Rate and Clinicopathological Features and Prognosis in Advanced Non-Small Cell Lung Cancer
SUN Cuicui , ZHANG Simeng , WEN Ti , QU Xiujuan , LIU Yunpeng     
Department of Medical Oncology, The First Hospital, China Medical University, Shenyang 110001, China
Abstract: Objective To analyze the relationship between tumor growth rate (TGR) and clinicopathological features and prognosis in advanced non-small cell lung cancer (NSCLC). Methods A total of 458 patients with advanced NSCLC who never received radiotherapy or underwent surgery were selected. The clinicopathological features were collected retrospectively, and the sum of the maximum diameter of the target lesions at baseline and at first evaluation was measured. TGR was calculated using a formula. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier survival curve. Univariate and multivariate analyses using COX risk proportional regression model were performed to indicate the effects of TGR on the prognosis. Results High TGR occurred frequently in elderly patients (P=0.038), patients with wild-type epidermal growth factor receptor (EGFR) (P=0.013), and patients receiving chemotherapy as the first-line treatment (P=0.002). The median PFS was 8.7 months in the low TGR group and 4.2 months in the high TGR group (P < 0.001). The median OS was 24.6 months in the low TGR group and 16.4 months in the high TGR group (P < 0.001). The PFS and OS in the low TGR group were significantly better than those in the high TGR group. Conclusion TGR correlated with age, EGFR gene, and first-line treatment, and it has a good prognostic value. The survival of patients with a high TGR is shorter than those with a low TGR. High TGR can be used as an independent risk factor for PFS and OS.
Keywords: non-small cell lung cancer    tumor growth rate    clinicopathological feature    prognosis    

近年来肺癌发病率和死亡率显著增长, 现我国每年肺癌发病约78.1万人, 肺癌死亡率居我国恶性肿瘤之首[1-2]。非小细胞肺癌(non-small cell lung cancer, NSCLC)在肺癌中占比最高且预后差, 晚期患者主要的治疗手段包括放化疗、靶向治疗以及免疫治疗等[3-4]。临床上一直应用实体肿瘤的疗效评价标准(Response Evaluation Criteria in Solid Tumors, RECIST)对药物疗效进行评价, 但仍有局限性[5]。随着靶向治疗时代的到来及个体化医疗的发展, 如何找到简便、实时并精准的评价疗效和预测预后的指标, 从而量化NSCLC患者治疗后的肿瘤反应, 以预测疾病进展的生存差异, 仍是临床工作中急需解决的问题。

肿瘤生长速率(tumor growth rate, TGR)定义为1个月内肿瘤体积增加的百分比[6]。TGR的计算包含了靶病灶最大直径总和以及2次评估间隔的时间, 可对肿瘤进行动态、定量评估, 有助于临床医生确认给定药物能否控制肿瘤生长。因此, TGR可能成为评价抗肿瘤治疗是否改变疾病进程的有用工具[7]。在最新的免疫治疗中, TGR增加≥2倍为超进展的定义之一[8-9]。本研究主要探讨晚期NSCLC中TGR与临床病理特征及预后的相关性。

1 材料与方法 1.1 研究对象

选取2014年1月至2018年3月于中国医科大学附属第一医院肿瘤内科就诊的NSCLC患者458例。纳入标准:(1)初治的局部晚期或转移性NSCLC; (2)有完整的病历资料及影像学图像; (3)预计生存期 > 3个月。排除标准:(1)行手术、放疗等局部治疗后; (2)无法明确病理类型; (3)多原发恶性肿瘤; (4)有严重基础疾病。

1.2 研究方法

回顾性收集性别、年龄、吸烟史、肿瘤家族史、东部肿瘤协作组(Eastern Cooperative Group, ECOG)评分、病理类型、组织学分级、Ki-67指数、表皮生长因子受体(epidermal growth factor receptor, EGFR)基因状态、肿瘤大小(T)、淋巴结转移(N)、临床分期、一线治疗方案等资料, 其中部分参数不详, 未予分析。假设肿瘤生长遵循指数定律, 通过以下公式计算TGR:TGR=100 [exp (TG)-1], 其中TG=3log (Dt/D0) /t, D0、Dt分别为基线及第1次疗效评价时靶病灶最大直径总和, t为2次肿瘤评估间隔的时间[6]。本文遵循RECIST标准测量靶病灶, 排除基线时仅存在非靶病灶(如仅有胸腔积液或骨转移)及第1次疗效评价时出现新发病灶的患者。

1.3 统计学分析

数据处理使用SPSS 20.0软件, 计数资料以百分率(%)表示; TGR与临床病理特征的相关性采用Pearson χ2检验及Fisher精确概率法。采用Kaplan-Meier法绘制生存曲线, 应用log-rank比较各组生存曲线的分布差异; 利用Cox风险比例回归模型分析TGR对预后的影响。P < 0.05为差异有统计学意义。

2 结果 2.1 TGR与NSCLC临床病理特征的关系

本研究共纳入458例晚期NSCLC患者, 其中男214例, 女244例; < 60岁235例, ≥60岁223例; 腺癌357例, 非腺癌101例; EGFR野生型154例, 突变型160例; Ⅲ期142例, Ⅳ期316例; 化疗组295例, 靶向治疗组163例。在治疗后进行第1次疗效评价时, 判定为部分缓解142例, 疾病稳定255例, 疾病进展61例; 至随访截止时间, 458例患者中共有375例疾病进展, 83例未进展, 进展发生率为81.9%;共有203例死亡, 255例存活, 死亡率为44.3%。利用受试者操作特征曲线找到TGR最佳截断点为-16.128 (-99.127, 283.759), 以此为界分为高TGR组和低TGR组。结果显示, TGR高低与年龄、EGFR基因状态、一线治疗方案相关, 且高TGR多见于年龄≥60岁(P = 0.038)、EGFR野生型(P = 0.013)、一线首选化疗(P = 0.002)的患者。见表 1。

表 1 TGR与NSCLC患者临床病理特征的关系 Tab.1 Relationship between TGR and the clinicopathological features in NSCLC
Clinicopathological feature NSCLC (n = 458) P
Low TGR [n (%)] High TGR [n (%)] Sum [n (%)]
Gender 0.166
  Male 126(44.2) 88(50.9) 214(46.7)
  Female 159(55.8) 85(49.1) 244(53.3)
Age (year) 0.038
   < 60 157(55.1) 78(45.1) 235(51.3)
  ≥60 128(44.9) 95(54.9) 223(48.7)
Smoking history 0.497
  No 151(53.0) 86(49.7) 237(51.7)
  Yes 134(47.0) 87(50.3) 221(48.3)
Family history 0.856
  No 207(72.6) 127(73.4) 334(72.9)
  Yes 78(27.4) 46(26.6) 124(27.1)
ECOG 0.421
  0-1 276(96.8) 165(95.4) 441(96.3)
  2-3 9(3.2) 8(4.6) 17(3.7)
Pathological type 0.789
  Adenocarcinoma 221(77.5) 136(78.6) 357(77.9)
  Other 64(22.5) 37(21.4) 101(22.1)
Histological grade 0.692
  Low 25(38.5) 19(42.2) 44(40.0)
  High 40(61.5) 26(57.8) 66(60.0)
Ki-67 index 0.611
   < 25% 91(46.0) 49(43.0) 140(44.9)
  ≥25% 107(54.0) 65(57.0) 172(55.1)
EGFR 0.013
  Wild type 84(43.5) 70(57.9) 154(49.0)
  Mutant type 109(56.5) 51(42.1) 160(51.0)
T stage 0.522
  T1-T3 153(59.3) 103(62.4) 256(60.5)
  T4 105(40.7) 62(37.6) 167(39.5)
N stage 0.262
  N0 55(19.3) 41(23.7) 96(21.0)
  N1-N3 230(80.7) 132(76.3) 362(79.0)
TNM stage 0.733
  Ⅲ 90(31.6) 52(30.1) 142(31.0)
  Ⅳ 195(68.4) 121(69.9) 316(69.0)
Treatment 0.002
  Chemotherapy 168(58.9) 127(73.4) 295(64.4)
  Targeted therapy 117(41.1) 46(26.6) 163(35.6)
表选项

2.2 TGR与NSCLC的生存曲线

采用Kaplan-Meier法进行无进展生存期(progression-free survival, PFS)及总生存期(overall survival, OS)生存分析。整体中位PFS为7.1个月, 低TGR组中位PFS为8.7个月, 高TGR组中位PFS为4.2个月(P < 0.001);整体中位OS为21.3个月, 低TGR组中位OS为24.6个月, 高TGR组中位OS为16.4个月(P < 0.001);低TGR组的PFS及OS时间均明显优于高TGR组。见图 1。

图 1 TGR与NSCLC患者预后的关系 Fig.1 Relationship between TGR and the prognosis of NSCLC patients
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2.3 Cox回归分析TGR对NSCLC预后的影响

将各个临床病理参数和TGR纳入Cox回归模型进行单因素分析, 将P < 0.200的影响因素进行多因素分析。结果提示:有吸烟史(HR=3.463;95% CI:1.272, 9.428;P = 0.015)、组织学为低未分化(HR= 4.586;95% CI:1.795, 11.721;P = 0.001)、临床分期为Ⅳ期(HR=4.613;95% CI:1.870, 11.384;P = 0.001)、高TGR (HR=2.991;95% CI:1.330, 6.732;P = 0.002)为PFS的独立危险因素; 病理类型为非腺癌(HR=5.198; 95% CI:1.148, 23.524;P = 0.032)、高Ki-67指数(HR=5.057;95% CI:1.283, 19.932;P = 0.021)、临床分期为Ⅳ期(HR=9.932;95% CI:2.940, 33.549;P < 0.001)、高TGR (HR= 10.103;95% CI:3.044, 33.528;P < 0.001)为OS的独立危险因素。见表 2、3。

表 2 Cox回归分析临床病理参数及TGR对PFS的影响 Tab.2 Cox regression analysis of the effects of the clinicopathological features and TGR on PFS
Clinicopathological feature Univariate Analysis Multivariate Analysis
HR 95%CI P HR 95%CI P
Gender (male vs female) 1.761 1.429-2.169 < 0.001 0.380 0.142-1.020 0.055
Age (≥60 vs＜60 years) 0.972 0.794-1.191 0.787
Smoking (yes vs no) 1.574 1.285-1.929 < 0.001 3.463 1.272-9.428 0.015
Family history (yes vs no) 1.055 0.838-1.329 0.648
ECOG (2-3 vs 0-1) 1.060 0.641-1.750 0.821
Pathology (other vs adenocarcinoma) 1.949 1.530-2.484 < 0.001 2.187 0.763-6.265 0.145
Histological grade (low vs high) 1.707 1.113-2.618 0.014 4.586 1.795-11.721 0.001
Ki-67 index (≥25% vs＜25%) 1.717 1.340-2.201 < 0.001 0.799 0.343-1.863 0.604
EGFR (wild vs mutant) 2.121 1.648-2.731 < 0.001 3.152 0.869-11.436 0.081
T stage (T4 vs T1- T3) 0.964 0.778-1.195 0.738
N stage (N1-N3 vs N0) 1.065 0.834-1.359 0.614
TNM stage (Ⅳ vs Ⅲ) 0.725 0.582-0.902 0.004 4.613 1.870-11.384 0.001
Treatment (chemotherapy vs targeted therapy) 2.623 2.082-3.304 < 0.001 0.300 0.083-1.088 0.067
TGR (high vs low) 1.934 1.575-2.375 < 0.001 2.991 1.330-6.723 0.002
表选项

表 3 Cox回归分析临床病理参数及TGR对OS的影响 Tab.3 Cox regression analysis of the effects of the clinicopathological features and TGR on OS
Clinicopathological feature Univariate Analysis Multivariate Analysis
HR 95%CI P HR 95%CI P
Gender (male vs female) 1.761 1.334-2.325 < 0.001 1.192 0.290-4.902 0.808
Age (≥60 vs＜60 years) 1.285 0.974-1.694 0.076 2.514 0.636-9.930 0.188
Smoking (yes vs no) 1.817 1.373-2.405 < 0.001 1.979 0.404-9.690 0.400
Family history (yes vs no) 1.114 0.821-1.512 0.487
ECOG (2-3 vs 0-1) 1.857 1.035-3.333 0.038 0.473 0.028-7.946 0.603
Pathology (other vs adenocarcinoma) 2.042 1.505-2.770 < 0.001 5.198 1.148-23.524 0.032
Histological grade (low vs high) 1.633 0.938-2.844 0.083 1.311 0.373-4.609 0.672
Ki-67 index (≥25% vs＜25%) 2.112 1.483-3.007 < 0.001 5.057 1.283-19.932 0.021
EGFR (wild vs mutant) 2.928 2.016-4.253 < 0.001 5.241 0.520-52.848 0.160
T stage (T4 vs T1- T3) 1.004 0.750-1.345 0.979
N stage (N1-N3 vs N0) 1.292 0.916-1.822 0.144 1.781 0.408-7.770 0.443
TNM stage (Ⅳ vs Ⅲ) 0.749 0.561-0.999 0.049 9.932 2.940-33.549 < 0.001
Treatment (chemotherapy vs targeted therapy) 2.171 1.570-3.003 < 0.001 0.390 0.066-2.325 0.302
TGR (high vs low) 2.239 1.696-2.957 < 0.001 10.103 3.044-33.528 < 0.001
表选项

3 讨论

全球范围内肺癌的发病率及死亡率逐年升高。随着基因检测及靶向治疗时代的到来, 肺癌基因型的异同对其治疗选择及预后有着显著影响, 更加需要新的指标对肿瘤的动态变化进行评估。传统的影像学仅提供主观、半定量的信息, 辅助临床决策的判定有限, 通过更加精准的影像学信息发掘肿瘤生长、药物疗效及生存预后的信息, 将是研究的重点。

TGR在肾癌、乳腺癌、结直肠癌、肝癌、鼻咽部鳞癌等多种肿瘤中与PFS和OS显著相关[10-14], 尤其在肾癌领域, TGR已经进入临床决策层面, 直接影响治疗方案的选择及预后的评估[15]。本研究回顾性收集458例NSCLC患者的临床资料并计算TGR, 分析TGR与临床病理参数及预后的关系。结果表明, TGR与NSCLC患者预后相关, 高TGR患者生存期较短, 且为影响预后的独立危险因素。NISHINO等[16]的研究发现, 一线厄洛替尼或吉非替尼治疗的EGFR突变型晚期NSCLC患者的8周肿瘤体积减少与生存率有关, 从侧面验证了本研究方向的正确性。

本研究是一项在单中心进行的回顾性研究, 研究时间和样本数量有限。本研究排除了接受手术、放疗后出现复发转移的患者, 纳入的晚期人群不够全面; 排除了基线时仅包含不可测量病灶(如仅有胸腔积液或骨转移)、第1次疗效评价时出现新发病灶的患者, 因此未能评估这类具有侵袭性的肿瘤。最后, 考虑到肿瘤生长千变万化、人为测量的主观性及可变性, TGR的计算可能存在误差。

综上所述, 本研究表明TGR与NSCLC预后密切相关, 高TGR人群生存期短, 预后差。高TGR可作为影响NSCLC预后的独立危险因素。

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