文章信息
- 袁维烨, 肖先皓, 宋禾
- YUAN Weiye, XIAO Xianhao, SONG He
- 基于SEER数据库的小肠腺癌患者预后的危险因素分析及预测模型构建
- Prognostic risk factor analysis and prognosis prediction model construction for patients with small bowel adenocarcinoma based on the SEER database
- 中国医科大学学报, 2024, 53(1): 51-59
- Journal of China Medical University, 2024, 53(1): 51-59
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文章历史
- 收稿日期:2023-04-03
- 网络出版时间:2024-01-04 20:52:55
虽然小肠约占消化道总长度(8~9 m)的75%和黏膜表面积的90%,但临床上小肠肿瘤(small bowel tumor,SBT)较为少见,发生率仅占消化系统肿瘤的3.4%[1]。SBT包括小肠腺癌(small intestinal adenocarcinoma,SBA)、间质瘤、神经内分泌肿瘤、淋巴瘤等,其中SBA是最常见的类型之一,约占40%[2-3]。SBA初发症状不明显,确诊时多已进展至晚期,且预后较差。已有研究[4-5]发现,饮食结构、某些肠道炎症性疾病(克罗恩病、乳糜泻)、遗传易感性疾病[家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)、林奇综合征(Lynch syndromes,LS)、波伊茨-耶格综合征(Peutz-Jeghers syndrome,PJS)和青少年息肉病综合征]均可能是SBA的致病因素。研究[5-6]发现微卫星不稳定(microsatellite instability,MSI)在SBA发展过程中起重要作用,主要可能为MMR、hMLH1基因突变所致。
美国国家癌症研究所的监测、流行病学和最终结果(surveillance,epidemiology,and end results,SEER)数据库是临床常用的公共数据库之一,收纳乳腺、消化系统、生殖系统等9类肿瘤患者的人口统计学、原发肿瘤部位、肿瘤形态、分期、诊断阶段以及生存状态随访等临床数据。本研究收集SEER数据库中SBA患者的临床资料,分析影响SBA预后的危险因素,进而构建预后预测模型,旨在为SBA患者提供合理的治疗建议及预后评估提供参考。
1 材料与方法 1.1 临床资料来源从SEER数据库(https://seer.cancer.gov/)中提取2010年至2018年病理诊断为SBA的2 639例患者信息。纳入标准:(1)2010年至2018年诊断为小肠恶性肿瘤并行手术的患者;(2)病理明确为原发SBA(ICD-O-3:8140/3);(3)年龄 > 18岁;(4)临床资料完整。排除标准:(1)其他病理类型的SBT;(2)未明确生存时间及生存状态;(3)合并其他恶性肿瘤。
1.2 资料收集及分组记录纳入患者的各项指标,包括年龄、性别、肿瘤部位、肿瘤大小、T分期、N分期、阳性淋巴结检出率、肿瘤单发灶、继发肝脏转移等,以总生存期(overall survival,OS)和疾病特异性生存期(disease specific survival,DSS)作为预后评估指标。将入选患者按7∶3比例随机分为训练组和验证组。
1.3 统计学分析采用R4.1.1软件进行数据分析,对于不符合正态分布的计量资料采用M(P25~P75)表示。计数资料采用率(%)表示,组间比较采用χ2检验或Fisher确切概率法。从训练组中筛选有统计学意义(P < 0.05)的指标进行单因素和多因素Cox分析来筛选影响SBA患者预后的危险因素,进而构建SBA患者预后预测模型。根据预测模型绘制受试者操作特征(receiver operating characteristic,ROC)曲线,在验证组进行模型验证并绘制临床决策曲线。P < 0.05为差异有统计学意义。
2 结果 2.1 患者临床指标分析共纳入2 639例,其中男1 454例(55.10%),女1 185例(44.90%);年龄20~84岁,中位年龄65岁;生存时间1~107个月,中位生存时间15个月。训练组与验证组患者各项临床指标比较差异均无统计学意义(均P > 0.05),见表 1。
Item | Total | training group(n = 1 847) | validation group(n = 792) | P |
Age(year) | 65(20-84) | 64(20-84) | 66(22-84) | 0.087 |
Survival time(month) | 15(1-107) | 16(1-107) | 15(1-106) | 0.978 |
Sex | 0.501 | |||
Female | 1 185(44.90) | 821(44.45) | 364(45.96) | |
Male | 1 454(55.10) | 1 026(55.55) | 428(54.04) | |
Tumor site | 0.361 | |||
Duodenum | 1 541(58.39) | 1 079(58.42) | 462(58.33) | |
Ileum | 313(11.86) | 230(12.45) | 83(10.48) | |
Jejunum | 451(17.09) | 314(17.00) | 137(17.30) | |
Other | 334(12.66) | 224(12.12) | 110(13.89) | |
Race | 0.810 | |||
Melanoderm | 557(21.11) | 393(21.28) | 164(20.71) | |
Caucasian | 1 870(70.86) | 1 309(70.87) | 561(70.83) | |
Asians and Latinos | 198(7.50) | 134(7.26) | 64(8.08) | |
Other | 14(0.53) | 11(0.60) | 3(0.38) | |
Tumor size | 0.250 | |||
≤2 cm | 265(10.04) | 184(10.00) | 81(10.22) | |
> 2-5 cm | 1 125(42.63) | 804(43.53) | 321(40.53) | |
> 5 cm | 578(21.90) | 409(22.14) | 169(21.34) | |
Other | 671(25.43) | 450(24.36) | 221(27.90) | |
T stage | 0.103 | |||
T1/2 | 411(15.58) | 285(15.43) | 126(15.91) | |
T3 | 814(30.85) | 563(30.48) | 251(31.69) | |
T4 | 1 013(38.39) | 734(39.74) | 279(35.23) | |
Other | 401(15.18) | 265(14.35) | 136(17.17) | |
N stage | 0.700 | |||
N0 | 1 328(50.32) | 934(50.57) | 394(49.75) | |
N1 | 726(27.51) | 503(27.23) | 223(28.16) | |
N2 | 390(14.78) | 279(15.10) | 111(14.01) | |
Other | 195(7.39) | 131(7.10) | 64(8.08) | |
Detection rate of positive lymph nodes | 0.165 | |||
≤30% | 1 265(47.93) | 888(48.08) | 377(47.60) | |
> 30% | 351(13.30) | 246(13.32) | 105(13.26) | |
Not detected | 946(35.85) | 668(36.17) | 278(35.10) | |
Other | 77(2.92) | 45(2.43) | 32(4.04) | |
Single tumor focus | 0.199 | |||
No | 230(8.72) | 170(9.20) | 60(7.58) | |
Yes | 2 409(91.28) | 1 677(90.8) | 732(92.42) | |
Secondary liver metastasis | 0.930 | |||
No | 2 197(83.25) | 1 539(83.32) | 658(83.08) | |
Yes | 442(16.75) | 308(16.68) | 134(16.92) |
2.2 患者OS的单因素及多因素分析
单因素分析结果显示,患者年龄、性别、人种、肿瘤位置、肿瘤大小、肿瘤T分期、N分期、淋巴结阳性检出率、肿瘤单发灶、肝脏转移均与OS相关(均P < 0.05),见表 2。
Item | Univariate analysis | Multifactor analysis | |||||
HR | 95%CI | P | HR | 95%CI | P | ||
Age | 1.021 | 1.016-1.026 | < 0.001 | 1.019 | 1.013-1.024 | < 0.001 | |
Sex | 1.159 | 1.026-1.310 | 0.018 | 1.118 | 0.988-1.265 | 0.076 | |
Female | 1 | - | - | 1 | - | - | |
Male | 1.159 | 1.026-1.310 | < 0.001 | 1.094 | 0.966-1.239 | 0.158 | |
Tumor site | 0.856 | 0.807-0.908 | < 0.001 | 0.934 | 0.882-0.988 | 0.018 | |
Duodenum | 1 | - | - | 1 | - | - | |
Ileum | 0.489 | 0.395-0.606 | < 0.001 | 0.752 | 0.602-0.940 | 0.031 | |
Jejunum | 0.553 | 0.462-0.662 | < 0.001 | 0.812 | 0.673-0.982 | 0.031 | |
Other | 0.845 | 0.702-1.018 | 0.076 | 0.960 | 0.795-1.160 | 0.674 | |
Race | 0.930 | 0.866-0.999 | 0.045 | 0.965 | 0.920-1.013 | 0.148 | |
Melanoderm | 1 | - | - | 1 | - | - | |
Caucasian | 0.894 | 0.692-1.155 | 0.391 | 0.918 | 0.707-1.192 | 0.521 | |
Asians and Latinos | 0.877 | 0.759-1.014 | 0.077 | 0.893 | 0.769-1.036 | 0.136 | |
Other | 0.247 | 0.061-0.993 | 0.049 | 0.455 | 0.113-1.837 | 0.268 | |
Tumor size | 1.390 | 1.302-1.485 | < 0.001 | 1.072 | 1.002-1.147 | 0.042 | |
≤2 cm | 1 | - | - | 1 | - | - | |
> 2-5 cm | 1.190 | 0.942-1.503 | 0.144 | 1.118 | 0.880-1.420 | 0.362 | |
> 5 cm | 0.981 | 0.758-1.269 | 0.882 | 0.995 | 0.763-1.297 | 0.972 | |
Other | 2.632 | 2.073-3.340 | < 0.001 | 1.562 | 1.212-2.014 | 0.001 | |
T stage | 1.535 | 1.428-1.651 | < 0.001 | 1.223 | 1.142-1.308 | < 0.001 | |
T1/2 | 1 | - | - | 1 | - | - | |
T3 | 0.775 | 0.630-0.952 | 0.015 | 1.171 | 0.935-1.467 | 0.169 | |
T4 | 1.506 | 1.248-1.816 | < 0.001 | 1.956 | 1.594-2.400 | < 0.001 | |
Other | 2.783 | 2.239-3.459 | < 0.001 | 1.418 | 1.125-1.787 | 0.003 | |
N stage | 1.231 | 1.156-1.311 | < 0.001 | 1.031 | 0.970-1.096 | 0.320 | |
N0 | 1 | - | - | 1 | - | - | |
N1 | 1.280 | 1.110-1.476 | < 0.001 | 1.270 | 1.086-1.485 | 0.003 | |
N2 | 1.284 | 1.079-1.527 | 0.005 | 1.142 | 0.904-1.441 | 0.264 | |
Other | 2.261 | 1.807-2.828 | < 0.001 | 0.910 | 0.718-1.151 | 0.431 | |
Detection rate of positive lymph nodes | 1.805 | 1.698-1.918 | < 0.001 | 1.494 | 1.391-1.604 | < 0.001 | |
≤30% | 1 | - | - | 1 | - | - | |
> 30% | 2.388 | 1.986-2.872 | < 0.001 | 1.983 | 1.585-2.483 | < 0.001 | |
Not detected | 3.942 | 3.429-4.532 | < 0.001 | 2.728 | 2.287-3.253 | < 0.001 | |
Other | 2.812 | 1.934-4.087 | < 0.001 | 1.788 | 1.207-2.649 | 0.004 | |
Single tumor focus | 0.282 | 0.244-0.326 | < 0.001 | 2.046 | 1.749-2.393 | < 0.001 | |
No | 1 | - | - | 1 | - | - | |
Yes | 3.547 | 3.068-4.101 | < 0.001 | 2.039 | 1.740-2.389 | < 0.001 | |
Secondary liver metastasis | 0.602 | 0.482-0.751 | < 0.001 | 0.663 | 0.530-0.829 | < 0.001 | |
No | 1 | - | - | 1 | - | - | |
Yes | 1.660 | 1.330-2.075 | < 0.001 | 1.497 | 1.196-1.874 | < 0.001 |
将单因素分析有统计学意义(P < 0.05)指标纳入多因素分析。结果显示,年龄(P < 0.01)、肿瘤部位(P = 0.018)、肿瘤大小(P = 0.042)、T分期(P < 0.01)、阳性淋巴结检出率(P < 0.01)、肿瘤单发灶(P < 0.01)和肝脏转移(P < 0.01)是SBA患者OS的独立影响因素,见表 2。
2.3 患者DSS的单因素及多因素分析单因素分析结果显示,年龄、性别、肿瘤位置、肿瘤大小、肿瘤T分期、N分期、淋巴结阳性检出率、肿瘤单发灶、肝脏转移均与DSS相关(均P < 0.05),见表 3。
Item | Univariate analysis | Multifactor analysis | |||||
HR | 95%CI | P | HR | 95%CI | P | ||
Age | 1.018 | 1.012-1.023 | < 0.001 | 1.015 | 1.010-1.021 | < 0.001 | |
Sex | 1.156 | 1.017-1.315 | 0.027 | 1.101 | 0.967-1.254 | 0.145 | |
Female | 1 | - | - | 1 | - | - | |
Male | 1.156 | 1.017-1.315 | 0.027 | 1.069 | 0.939-1.220 | 0.315 | |
Tumor site | 0.874 | 0.822-0.929 | < 0.001 | 0.950 | 0.895-1.008 | 0.088 | |
Duodenum | 1 | - | - | 1 | - | - | |
Ileum | 0.503 | 0.402-0.630 | < 0.001 | 0.795 | 0.629-1.005 | 0.055 | |
Jejunum | 0.588 | 0.488-0.708 | < 0.001 | 0.872 | 0.717-1.060 | 0.170 | |
Other | 0.876 | 0.722-1.065 | 0.184 | 1.008 | 0.827-1.227 | 0.941 | |
Race | 0.979 | 0.932-1.030 | 0.417 | ||||
Melanoderm | 1 | - | - | ||||
Caucasian | 0.932 | 0.710-1.224 | 0.612 | ||||
Asians and Latinos | 0.931 | 0.797-1.087 | 0.365 | ||||
Other | 0.288 | 0.072-1.158 | 0.080 | ||||
Tumor size | 1.431 | 1.335-1.533 | < 0.001 | 1.087 | 1.012-1.167 | 0.022 | |
≤2 cm | 1 | - | - | 1 | - | - | |
> 2-5 cm | 1.382 | 1.064-1.797 | 0.016 | 1.255 | 0.960-1.640 | 0.097 | |
> 5 cm | 1.179 | 0.887-1.568 | 0.257 | 1.160 | 0.866-1.553 | 0.319 | |
Other | 3.081 | 2.358-4.026 | < 0.001 | 1.786 | 1.346-2.368 | < 0.001 | |
T stage | 1.630 | 1.509-1.761 | < 0.001 | 1.262 | 1.174-1.357 | < 0.001 | |
T1/2 | 1 | - | - | 1 | - | - | |
T3 | 0.850 | 0.676-1.067 | 0.161 | 1.242 | 0.970-1.590 | 0.086 | |
T4 | 1.781 | 1.448-2.191 | < 0.001 | 2.228 | 1.780-2.788 | < 0.001 | |
Other | 3.200 | 2.524-4.057 | < 0.001 | 1.533 | 1.194-1.969 | < 0.001 | |
N stage | 1.266 | 1.185-1.352 | < 0.001 | 1.044 | 0.980-1.113 | 0.186 | |
N0 | 1 | - | - | 1 | - | - | |
N1 | 1.326 | 1.140-1.542 | < 0.001 | 1.283 | 1.088-1.512 | 0.003 | |
N2 | 1.402 | 1.171-1.678 | < 0.001 | 1.203 | 0.945-1.532 | 0.134 | |
Other | 2.361 | 1.867-2.987 | < 0.001 | 0.910 | 0.711-1.164 | 0.451 | |
Detection rate of positive lymph nodes | 1.836 | 1.721-1.958 | < 0.001 | 1.499 | 1.389-1.616 | < 0.001 | |
≤30% | 1 | - | - | 1 | - | - | |
> 30% | 2.596 | 2.140-3.149 | < 0.001 | 2.064 | 1.632-2.610 | < 0.001 | |
Not detected | 4.113 | 3.545-4.772 | < 0.001 | 2.934 | 2.436-3.535 | < 0.001 | |
Other | 3.044 | 2.064-4.489 | < 0.001 | 1.932 | 1.285-2.904 | 0.002 | |
Single tumor focus | 3.737 | 3.213-4.347 | < 0.001 | 2.096 | 1.781-2.467 | < 0.001 | |
No | 1 | - | - | 1 | - | - | |
Yes | 3.737 | 3.213-4.347 | < 0.001 | 2.100 | 1.781-2.475 | < 0.001 | |
Secondary liver metastasis | 0.456 | 0.350-0.594 | < 0.001 | 0.508 | 0.390-0.663 | < 0.001 | |
No | 1 | - | - | 1 | - | - | |
Yes | 2.192 | 1.684-2.854 | < 0.001 | 1.943 | 1.489-2.534 | < 0.001 |
将单因素分析有统计学意义(P < 0.05)的指标纳入多因素分析。结果显示,年龄(P < 0.01)、肿瘤大小(P = 0.022)、T分期(P < 0.01)、阳性淋巴结检出率(P < 0.01)、肿瘤单发灶(P < 0.01)和肝脏转移(P < 0.01)是SBA患者DSS的独立影响因素,见表 3。
2.4 SBA患者预后预测模型建立及验证基于年龄、肿瘤位置、肿瘤大小、T分期、阳性淋巴结检出率、肿瘤单发灶、肝脏转移等OS预后的独立危险因素建立关于OS的列线图(图 1A)。基于年龄、肿瘤大小、T分期、阳性淋巴结检出率、肿瘤单发灶、继发肝脏转移等DSS预后的独立危险因素建立了关于DSS的列线图(图 1B)。验证组对模型进行验证的结果显示,校准曲线检验结果显示拟合良好(图 2、3),3年、5年ROC曲线显示模型可信度良好(图 4、5),可见模型预测值与实测值基本一致,预测能力较好。临床预测决策曲线分析(decision curve analysis,DCA)显示模型具有良好应用价值,见图 6。
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A, OS;B, DSS. 图 1 SBA患者OS、DSS的列线图 Fig.1 The nomograms of OS and DSS of SBA patients |
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A, B, 3-year calibration curve of OS in the training group and validation group; C, D, 5-year calibration curve of OS in the training group and validation group. 图 2 SBA患者OS的3年及5年校准曲线验证 Fig.2 Calibration curve validation curve of SBA patients' OS in 3 and 5 years |
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A, B, 3-year calibration curve of DSS in the training group and validation group; C, D, 5-year calibration curve of DSS in the training group and validation group. 图 3 SBA患者DSS的3年及5年校准曲线验证 Fig.3 Calibration curve validation curve of SBA patients' DSS in 3 and 5 years |
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A, B, the ROC curves of the training group; C, D, the ROC curves of the validation group. TP, true positive rate; FP, false positive rate. 图 4 SBA患者OS的3年、5年ROC曲线 Fig.4 3-year and 5-year ROC curves of OS for patients with SBA |
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A, B, the ROC curves of the training group; C, D, the ROC curves of the validation group. TP, true positive rate; FP, false positive rate. 图 5 SBA患者DSS的3年、5年ROC曲线 Fig.5 3-year and 5-year ROC curves of DSS for patients with SBA |
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A, B, the 3-year and 5-year DCA curves for OS in SBA patients; C, D, the 3-year and 5-year DCA curves for DSS in SBA patients. 图 6 SBA患者OS与DSS的临床预测DCA Fig.6 Decision curve analysis of OS and DSS in patients with SBA |
3 讨论
SBA临床上较少见,初始症状多不明显,慢性病程常有隐匿性消化道出血及贫血症状[7]。手术切除为SBA唯一根治性治疗方式。对于Ⅰ~Ⅲ期患者,优先选择根治性手术切除+区域性淋巴结清扫;对于Ⅳ期及不可根治性切除患者,可采用姑息性手术和化疗,目前使用的化疗方案有5-FU+亚叶酸+奥沙利铂(FOLFOX方案)、奥沙利铂联合卡培他滨方案(CAPEOX方案,又称XELOX方案)以及5-Fu联合伊立替康方案等。已有研究[8-9]显示,采用辅助化疗的晚期SBA患者的OS明显延长。
BILIMORIA等[3]研究发现SBA患者平均年龄为66岁,且男女比例约为1.3∶1;本研究患者平均年龄为65岁,男女比例为1.2∶1,与之相近。本研究结果显示,年龄、T分期、阳性淋巴结检出率与继发肝脏转移为影响SBA预后的危险因素,与HUFFMAN等[10-12]的研究结论一致。但GU等[11]研究发现N分期同样是影响预后危险因素,本研究中N分期未被纳入,其原因可能是样本量较小所致。
本研究结果显示,SBA原发位置位于十二指肠占58.39%,位于空肠、回肠分别占17.09%和11.86%,与已有研究[13-17]指出的SBA最常见于十二指肠(50%~55%),其次为空肠(16%~30%)及回肠(13%~20%)的结论一致。HOWE等[18]研究表明,与空、回肠腺癌患者相比,十二指肠腺癌患者预后更差。与本研究结论一致。另外,本研究发现SBA伴远处转移者预后更差,与国外相关研究[19-20]结果相似。有研究[21]推荐检测 > 9个淋巴结对SBA患者预后具有预测效果。肝脏是SBA最易远处转移的器官,伴肝脏转移的SBA患者较无远处转移患者预后差,与焦若男等[22]研究结论一致。
本研究中,患者3年、5年OS和DSS的验证曲线在训练组及验证组中表现出显著相关性,表明建立的预后预测模型具有良好的预测价值。3年与5年生存的DCA曲线分析显示训练组及验证组在死亡风险方面具有显著的正净收益,表明列线图在预测3年、5年的OS和DSS方面具有良好的临床价值,与以往研究[14, 23]结果一致。
本研究不足之处:(1)构建的列线图中,TNM分期对患者的预后影响未能得到完整体现;(2)N分期未被纳入到多因素分析中;(3)肿瘤直径 > 5 cm评分小于肿瘤直径为 > 2~5 cm评分;(4)阳性淋巴结未检者在列线图中评分高于其他项,考虑可能是纳入样本量相对较少所致。
综上所述,年龄、肿瘤大小、T分期、阳性淋巴结检出率、肿瘤单发灶、继发肝脏转移是影响SBA患者OS和DSS的独立危险因素;肿瘤部位也是影响SBA患者OS的独立危险因素。本研究建立的列线图具有良好的预测价值,可对患者预后进行准确评估,同时也可以为SBA患者提供合理的治疗建议。
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