可切除胰腺癌术前评分分级体系的建立与应用

王成方; 王之江; 王伟林

doi:10.3969/j.issn.1001-5256.2022.10.023

可切除胰腺癌术前评分分级体系的建立与应用

DOI: 10.3969/j.issn.1001-5256.2022.10.023

王成方¹,
王之江¹,
王伟林^{1, 2, 3, 4, 5, , ,}

1.
浙江大学医学院附属第二医院肝胆胰外科，杭州 310009
2.
浙江省肝胆胰肿瘤精准诊治研究重点实验室，杭州 310009
3.
浙江省肝癌诊治技术研究中心，杭州 310009
4.
浙江大学肝胆胰疾病精准诊治临床创新中心，杭州 310009
5.
浙江省肝胆胰疾病临床研究中心，杭州 310009

基金项目:

国家自然科学基金 (81773096);

国家自然科学基金 (82072650)

伦理学声明：本研究方案于2021年7月6日经由浙江大学医学院附属第二医院伦理委员会审批，批号：(2021)伦审研第(0677)号，所纳入患者均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：王成方负责课题设计，资料分析，撰写论文；王之江参与收集数据，修改论文；王伟林负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
王伟林，wam@zju.edu.cn

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出版历程
- 收稿日期: 2022-02-23
- 录用日期: 2022-03-29
- 出版日期: 2022-10-20

Establishment and application of a preoperative grading system for resectable pancreatic cancer

Chengfang WANG¹,
Zhijiang WANG¹,
Weilin WANG^{1, 2, 3, 4, 5
, ,
,}

1.
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
2.
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
3.
Zhejiang Provincial Research Center for Diagnosis and Treatment of Liver Cancer, Hangzhou 310009, China
4.
Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Diseases, Zhejiang University, Hangzhou 310009, China
5.
Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310009, China

Research funding:

National Natural Science Foundation of China (81773096);

National Natural Science Foundation of China (82072650)

More Information

Corresponding author: WANG Weilin, wam@zju.edu.cn(ORCID: 0000-0001-9432-2649)

摘要

摘要: 目的探讨分析可切除胰腺癌早期复发的危险因素及评分分级体系的建立与应用。方法采用回顾性病例对照研究方法，纳入浙江大学医学院附属第二医院肝胆胰外科2015年3月—2021年6月行根治性切除手术的可切除胰腺癌患者303例，其中283例直接手术患者分为早期复发组(术后6个月内)(n=95)和非早期复发组(n=188)；术前行新辅助治疗患者20例为新辅助治疗组。观察指标包括患者的一般资料及术前影像资料；患者术前实验室检验资料，血常规、血生化及衍生指标，肿瘤标志物及凝血指标；随访获得无复发生存情况。正态分布的计量资料两组间比较采用t检验；非正态分布的计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ²检验。通过受试者工作特征曲线确定各指标的最佳临界值。采用多因素Logistic回归分析胰腺癌患者早期复发的危险因素。绘制Kaplan-Meier曲线并采用Log-rank检验比较各组患者的无复发生存期。结果单因素分析结果显示，与非早期复发组相比，早期复发组患者BMI、甘油三酯较低，CA19-9、CA242、CA125、血浆纤维蛋白原较高(P值均＜0.05)。多因素Logistic回归分析结果显示，BMI(OR=1.150，95%CI：1.038~1.273，P=0.007)、血浆纤维蛋白原(OR=2.513，95%CI：1.355~4.663，P=0.003)和CA242(OR=2.482，95%CI：1.067~5.774，P=0.035)是可切除胰腺癌患者早期复发的独立危险因素。将BMI、CA242、血浆纤维蛋白原3项指标纳入评分分级体系，临界值分别为23.00 kg/m²、30.00 U/mL和4.00 g/L。BMI＜23.00 kg/m²计为1分，否则计为0分；CA242≥30.0 U/mL计为1分，否则0分；血浆纤维蛋白原≥4.00 g/L计为1分，否则0分，总分为0~3分。对早期复发与非早期复发患者进行评分，结果显示早期复发组评分更高[2(0~3)分vs 1(0~3)分，Z=-5.339，P＜0.001]。Kaplan-Meier曲线分析结果显示，不同评分组别的患者无复发生存时间比较差异有统计学意义(χ²=28.116，P＜0.001)，分值越高预期无复发生存时间越短。将3分定义为高危组，0~2分定义为低危组。高危组早期复发率为84.6%，低危组早期复发率为31.2%。结论基于BMI、血浆纤维蛋白原和CA242这3项指标建立的评分系统能够在一定程度上预测患者术后复发情况。
- 胰腺肿瘤 /
- 肿瘤复发, 局部 /
- 危险因素
Abstract: Objective To investigate the risk factors for early recurrence of resectable pancreatic cancer and the establishment and application of a grading system. Methods A retrospective case-control study was conducted among 303 patients with resectable pancreatic cancer who underwent radical resection in Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, from March 2015 to June 2021, and according to the presence or absence of early recurrence (within 6 months after surgery), the 283 patients directly operated on were divided into early recurrence group with 95 patients and non-early recurrence group with 188 patients; 20 patients who received neoadjuvant therapy before surgery were enrolled as neoadjuvant therapy group. Observation indicators included general information, preoperative imaging data, preoperative laboratory data, routine blood test/blood biochemistry and derived indicators, tumor markers, and coagulation markers, and follow-up was conducted to observe recurrence-free survival. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. A multivariate Logistic regression analysis was used to investigate the risk factors for early recurrence in patients with pancreatic cancer, and the receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of each indicator. The Kaplan-Meier curve was plotted, and the Log-rank test was used for comparison of recurrence-free survival time between groups. Results The univariate analysis showed that compared with the non-early recurrence group, the early recurrence group had significantly lower body mass index (BMI) and triglyceride and significantly higher CA19-9, CA242, CA125, and plasma fibrinogen (all P < 0.05). The multivariate logistic regression analysis showed that BMI (odds ratio [OR]=1.150, 95% confidence interval [CI]: 1.038-1.273, P=0.007), plasma fibrinogen (OR=2.513, 95%CI: 1.355-4.663, P=0.003), and CA242 (OR=2.482, 95%CI: 1.067-5.774, P=0.035) were independent risk factors for early recurrence in patients with resectable pancreatic cancer. BMI, CA242, and plasma fibrinogen were included in the grading system, with a cut-off value of 23.00 kg/m², 30.0 U/mL, and 4.00 g/L, respectively. BMI < 23.00 kg/m² was counted as 1 point, otherwise it was counted as 0 point; CA242≥30.00 U/mL was counted as 1 point, otherwise it was counted as 0 point; plasma fibrinogen ≥4.00 g/L was counted as 1 point, otherwise it was counted as 0 point; the total score was 0-3 points. The patients in both the early recurrence group and the non-early recurrence group were scored, and the results showed that the early recurrence group had a significantly higher score than the non-early recurrence group [2(0-3) points vs 1(0-3) point, Z=-5.339, P < 0.001]. The Kaplan-Meier curve analysis showed that there was a significant difference in time to recurrence between groups (χ²=28.116, P < 0.001), and the higher the score, the shorter the expected time to recurrence. The patients with 3 points were defined as high-risk group and those with 0-2 points were defined as low-risk group, and the early recurrence rate was 84.6% in the high-risk group and 31.2% in the low-risk group. Conclusion The grading system based on BMI, plasma fibrinogen, and CA242 can reliably predict postoperative recurrence.
- Pancreatic Neoplasms /
- Neoplasm Recurrence, Local /
- Risk Factors

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图 1 不同评分患者的无复发生存曲线

Figure 1. Recurrence free survival curve of patients with different scores

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表 1 患者基线资料

Table 1. Baseline data of patients

指标	早期复发组(n=95)	非早期复发组(n=188)	统计值	P值
男/女(例)	52/43	114/74	χ²=0.906	0.372
年龄(岁)	64.67±9.60	63.31±8.90	t=-1.186	0.236
BMI(kg/m²)	22.04±3.03	23.00±2.99	t=2.522	0.012
糖尿病史[例(%)]	22(23.16)	56(29.79)	χ²=1.389	0.262
烟酒史[例(%)]	39(41.05)	92(48.94)	χ²=1.578	0.256
肝炎病史[例(%)]	9(9.47)	17(9.04)	χ²=0.014	＞0.05
术前疼痛[例(%)]	50(52.63)	80(42.55)	χ²=2.581	0.130
影像肿瘤直径(mm)	28.50(13.20~102.00)	26.00(3.00~83.00)	Z=-1.580	0.114
肿瘤位置[胰头，例(%)]	60(63.16)	99(52.66)	χ²=3.186	0.203
肿大淋巴结[例(%)]	44(46.32)	67(35.64)	χ²=3.018	0.094
周围血管侵犯¹⁾[例(%)]	39(41.05)	60(31.91)	χ²=2.317	0.147
临近器官侵犯²⁾[例(%)]	11(11.58)	21(11.17)	χ²=0.011	＞0.05
胰管扩张[例(%)]	74(77.89)	132(70.21)	χ²=1.880	0.203
胰腺萎缩[例(%)]	26(27.37)	39(20.74)	χ²=1.565	0.233
黄疸[例(%)]	28(29.47)	56(29.79)	χ²=0.003	＞0.05
术前行胆道引流³⁾[例(%)]	15(15.79)	33(17.55)	χ²=0.139	0.741
注：1)，周围血管侵犯均符合可切除胰腺癌标准，包括侵犯门静脉但未超过180°，且静脉轮廓规则；侵犯脾动脉和/或脾静脉；4例胰头癌侵犯胃十二指肠动脉。2)，临近器官侵犯主要指十二指肠或胆管下段侵犯。3)，术前行胆道引流应用内镜下支架植入术和/或经皮肝穿刺胆道引流术。

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表 2 血常规相关指标

Table 2. Blood routine related indexes

指标	早期复发组(n=95)	非早期复发组(n=188)	统计值	P值
白细胞(×10⁹/L)	5.90(3.10~11.70)	5.40(2.20~10.50)	Z=-1.512	0.131
血红蛋白(g/L)	126.85±16.54	128.49±15.28	t=0.830	0.407
红细胞(×10¹²/L)	4.14±0.52	4.20±0.53	t=0.778	0.437
血小板计数(×10⁹/L)	207.68±69.40	196.18±66.01	t=-1.361	0.175
中性粒细胞计数(×10⁹/L)	3.98±1.59	3.71±1.28	t=-1.546	0.123
中性粒细胞百分比	64.06±9.19	63.58±9.23	t=-0.412	0.680
淋巴细胞计数(×10⁹/L)	1.45±0.47	1.45±0.54	t=-0.028	0.978
中性粒细胞/淋巴细胞比值	2.56(1.05~20.80)	2.49(0.69~9.30)	Z=-0.456	0.648
单核细胞计数(×10⁹/L)	0.40(0.20~1.80)	0.39(0.13~1.08)	Z=-0.876	0.381
嗜酸性粒细胞计数(×10⁹/L)	0.12(0.02~0.66)	0.10(0~1.38)	Z=-1.832	0.067
嗜碱性粒细胞计数(×10⁹/L)	0.03(0~0.10)	0.02(0~0.08)	Z=-1.091	0.275
血小板/淋巴细胞比值	154.15±62.20	149.99±64.94	t=-0.516	0.607

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表 3 生化指标比较

Table 3. Comparison of biochemical indexes

指标	早期复发组(n=95)	非早期复发组(n=188)	统计值	P值
PNI	46.82±5.21	47.38±5.62	t=0.805	0.421
GPS评分¹⁾(0/1/2，例)	39/12/8	79/34/10	χ²=2.051	0.359
CRP/白蛋白比值	0.18(0~2.00)	0.13(0~4.27)	Z=-1.102	0.271
总蛋白(g/L)	67.07±6.29	68.14±7.11	t=1.238	0.217
白蛋白(g/L)	39.56±4.05	40.13±4.46	t=1.037	0.301
谷草转氨酶(U/L)	24.0(13.0~588.0)	24.5(9.0~480.0)	Z=-0.412	0.681
谷丙转氨酶(U/L)	23.0(5.0~846.0)	25.0(7.0~828.0)	Z=-0.799	0.425
脂肪酶(U/L)	61.5(3.0~3 138.0)	51.0(8.0~923.0)	Z=-0.757	0.449
淀粉酶(U/L)	78.0(16.0~1 053.0)	69.0(26.0~572.0)	Z=-0.286	0.775
葡萄糖(mmol/L)	5.85(3.35~17.28)	6.20(3.62~18.57)	Z=-0.713	0.476
糖化白蛋白(%)	16.40(8.40~47.60)	16.70(10.60~45.60)	Z=-0.202	0.840
糖化白蛋白1(g/L)	6.00(3.60~36.90)	5.70(3.10~12.70)	Z=-1.018	0.309
糖化白蛋白2(g/L)	39.34±7.26	39.12±6.12	t=-0.185	0.854
尿素氮(mmol/L)	4.60(1.84~9.65)	4.63(2.64~13.67)	Z=-1.064	0.287
肌酐(μmol/L)	56.00(32.00~126.00)	59.00(13.00~160.00)	Z=-1.716	0.086
总胆固醇(mmol/L)	4.98(2.14~14.46)	4.69(1.97~16.69)	Z=-1.016	0.310
甘油三酯(mmol/L)	1.16(0.42~4.34)	1.40(0.46~7.36)	Z=-2.501	0.012
CRP(mg/L)	7.50(0.10~76.40)	5.10(0.10~141.40)	Z=-1.082	0.279
碱性磷酸酶(U/L)	106.0(53.0~1 220.0)	103.0(53.0~1 558.0)	Z=-0.273	0.785
γ-谷氨酰转肽酶(U/L)	32.0(10.0~2 230.0)	38.0(9.0~2 634.0)	Z=-0.406	0.684
α-L-岩藻糖苷酶(U/L)	27.00(12.00~75.00)	27.00(9.00~93.00)	Z=-0.282	0.778
注：1)，部分患者观察指标数据缺失。

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表 4 肿瘤标志物及凝血指标

Table 4. Coagulation and tumor markers

指标	早期复发组(n=95)	非早期复发组(n=188)	统计值	P值
CA19-9(U/mL)	426.90(2.00~12 000.00)	197.70(2.00~12 000.00)	Z=-3.433	＜0.001
CA242(U/mL)	40.90(1.00~530.00)	19.50(0.50~1 000.00)	Z=-3.804	＜0.001
CA125(U/mL)	17.65(4.20~114.20)	14.40(2.10~893.90)	Z=-2.383	0.017
CEA(ng/mL)	3.40(0.70~125.90)	3.25(0.80~258.50)	Z=-0.198	0.843
AFP(ng/mL)	2.50(0.90~8.30)	2.70(0.70~90.90)	Z=-1.740	0.082
凝血酶原时间(s)	13.1(11.5~18.5)	13.0(11.0~32.6)	Z=-0.613	0.540
D-二聚体(μg/L)	480(180~7140)	440(40~11 340)	Z=-0.524	0.600
血浆纤维蛋白原(g/L)	3.76(2.16~7.94)	3.52(2.16~7.33)	Z=-2.266	0.023
国际标准化比值	1.01(0.85~1.55)	0.99(0.82~3.33)	Z=-0.580	0.562
FPR	21.09±8.54	20.76±7.82	t=-0.321	0.748

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表 5 术后病理指标与辅助治疗

Table 5. Post-operative clinicopathologic characteristics and adjuvant therapy

指标	早期复发组(n=95)	非早期复发组(n=188)	统计值	P值
肿瘤直径(cm)	3.17±1.22	3.06±1.25	t=-0.741	0.459
T分期(1/2/3/4，例)	21/54/16/1	56/98/29/1	χ²=2.223	0.695
N分期(0/1/2，例)	42/42/8	120/37/23	χ²=18.880	＜0.001
R0切除[例(%)]	90(94.7)	176(93.6)	χ²=0.140	0.797
神经侵犯[例(%)]	78(82.1)	158(84.0)	χ²=0.171	0.736
脉管侵犯[例(%)]	37(38.9)	67(35.6)	χ²=0.297	0.603
肿瘤分化情况(0/1/2/3/4，例)	12/32/44/4/3	9/39/100/19/20	χ²=17.581	0.004
术后辅助治疗[例(%)]	62(65.3)	143(76.1)	χ²=3.687	0.067
注：T分期、N分期、肿瘤分化情况中部分患者观察指标数据缺失。肿瘤分化情况，0/1/2/3/4依次为低分化/中低分化/中分化/中高分化/高分化。

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表 6 多因素Logistic回归分析

Table 6. Multivariate Logistic regression analysis

项目	B值	SE	Wald	P值	OR	95%CI
截距	-4.506	1.230	13.414	0.000
BMI	0.139	0.052	7.191	0.007	1.150	1.038~1.273
甘油三酯	0.243	0.160	2.305	0.129	1.275	0.932~1.746
淋巴结肿大	0.309	0.289	1.139	0.286	1.362	0.772~2.402
CA19-9	0.400	0.418	0.914	0.339	1.492	0.657~3.386
CA242	0.909	0.431	4.450	0.035	2.482	1.067~5.774
CA125	0.479	0.294	2.655	0.103	1.614	0.907~2.870
血浆纤维蛋白原	0.922	0.315	8.540	0.003	2.513	1.355~4.663

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