基于肝内胆管癌预后模型筛选辅助化疗受益人群

doi:10.16139/j.1007-9610.2024.02.13

摘要/Abstract

摘要：

目的：基于国内多中心数据建立和验证一个预测肝内胆管癌（ICC）术后总体生存（OS）的列线图模型，并基于该预测模型筛选辅助化疗的受益人群。方法：回顾性收集2011年12月至2017年12月我国4家医疗单位278例术后病理学诊断为ICC病人的数据。采用COX回归模型筛选影响OS的独立风险因素并构建列线图模型。使用该模型对所有病人进行OS危险分层，筛选辅助化疗受益人群。结果：共纳入278例，其中23例（8.3%）接受辅助化疗。COX多因素分析显示：饮酒史、ECOG评分、肝切除方式、淋巴结状态、肿瘤数量以及肿瘤分化程度是影响术后OS的独立风险因素。列线图模型在训练集及验证集的一致性指数分别为0.690（95%CI：0.646~0.734）和0.740（95%CI：0.863~0.617）。根据列线图模型的危险分层，在高风险组，辅助化疗组与未辅助化疗组的生存差异有统计学意义（P=0.033），而在低风险组，生存差异无统计学意义（P=0.59）。结论：基于影响OS的独立风险因素建立的列线图模型具有良好的生存预测能力，可用于筛选受益于辅助化疗的ICC病人。

关键词: 肝内胆管癌, 列线图, 辅助化疗, 预后, 多中心

Abstract:

Objective To establish and validate a Nomogram model for predicting the overall survival (OS) of the patients with intrahepatic cholangiocarcinoma (ICC) based on domestic multicenter data, and screen the beneficiaries of adjuvant chemotherapy based on the prediction model. Methods From December 2011 to December 2017, the data of 278 patients with postoperative pathological diagnosis of ICC from 4 medical centers in our country were collected retrospectively COX regression model was used to screen the independent risk factors of OS and constructed a Nomogram model. This model was used to stratify the risk of OS for all patients and to screen the beneficiaries of adjuvant chemotherapy. Results A total of 278 patients were enrolled, and 23 cases(8.3%) received adjuvant chemotherapy. COX multivariate analysis showed that drinking history, ECOG score, method of hepatectomy, lymph node status, number of tumors, and tumor differentiation were independent risk factors for postoperative OS. The Nomogram model had a C-index of 0.690(95% CI: 0.646-0.734) in the training cohort and 0.740(95% CI: 0.863-0.617) in the validation cohort. According to risk stratification by Nomogram model, in the high-risk group there was a statistically significant difference in survival between adjuvant chemotherapy and non-adjuvant chemotherapy (P=0.033), whereas in the low-risk group, there was no significant difference in survival(P=0.59). Conclusion Nomogram model based on independent risk factors of OS demonstrated excellent predictive capability for survival and could be used to screen, and identify the patients with ICC who benefit from adjuvant chemotherapy.

Key words: Intrahepatic cholangiocarcinoma(ICC), Nomogram, Adjuvant chemotherapy, Prognosis, Multicenter

中图分类号:

R735.7

林起柱, 刘红枝, 黄霆峰, 范瑞林, 周伟平, 郑树国, 楼健颖, 曾永毅. 基于肝内胆管癌预后模型筛选辅助化疗受益人群[J]. 外科理论与实践, 2024, 29(02): 170-178.

LIN Qizhu, LIU Hongzhi, HUANG Tingfeng, FAN Ruilin, ZHOU Weiping, ZHENG Shuguo, LOU Jianying, ZENG Yongyi. Screening and identification of the beneficiaries of adjuvant chemotherapy based on the prognostic model of intrahepatic cholangiocarcinoma[J]. Journal of Surgery Concepts & Practice, 2024, 29(02): 170-178.

图/表 7

表1

图1

图2

图3

图4

图5

表2

ICC根治性切除术后接受和未接受辅助化疗病人临床和病理学资料比较[n(%)]

Characteristics	Group	Non- chemotherapy(n=255)	Chemotherapy(n=23)	P value
Gender	Man	165 (64.71)	15 (65.22)	1
	Woman	90 (35.29)	8 (34.78)
Age (year)	≤60	149 (58.43)	16 (69.57)	0.412 5
	>60	106 (41.57)	7 (30.43)
Smoking history	No	167 (65.49)	16 (69.57)	0.868 8
	Yes	88 (34.51)	7 (30.43)
Drinking history	No	206 (80.78)	22 (95.65)	0.135
	Yes	49 (19.22)	1 (4.35)
HBV	No	97 (38.04)	6 (26.09)	0.362 1
	Yes	158 (61.96)	17 (73.91)
ECOG score	≤2	206 (80.78)	22 (95.65)	0.135
	>2	49 (19.22)	1 (4.35)
CA19-9 (U/mL)	≤37	190 (74.51)	10 (43.48)	0.003 4
	>37	65 (25.49)	13 (56.52)
CEA (μg/L)	≤5	216 (84.71)	13 (56.52)	0.001 9
	>5	39 (15.29)	10 (43.48)
TBIL (μmol/L)	≤20	128 (50.20)	10 (43.48)	0.689 6
	>20	127 (49.80)	13 (56.52)
Blood loss (mL)	≤400	212 (83.14)	13 (56.52)	0.004 6
	>400	43 (16.86)	10 (43.48)
Blood transfusion	No	220 (86.27)	17 (73.91)	0.195 6
	Yes	35 (13.73)	6 (26.09)
Margin (cm)	<1	184 (72.16)	3 (13.04)	<0.000 1
	≥1	71 (27.84)	20 (86.96)
Method of hepatectomy	Anatomical	103 (40.39)	11 (47.83)	0.636 3
	Non-anatomical	152 (59.61)	12 (52.17)
LND	No	201 (78.82)	7 (30.43)	<0.000 1
	Yes	54 (21.18)	16 (69.57)
Lymph node status	Nx	201 (78.82)	7 (30.43)	<0.000 1
	N0	33 (12.94)	6 (26.09)
	N1	21 (8.24)	10 (43.48)
Gross classification	MF	156 (61.18)	20 (86.96)	0.025 7
	Non-MF	99 (38.82)	3 (13.04)
Histological classification	Adenocarcinoma	238 (93.33)	23 (100.00)	0.410 1
	Non-adenocarcinoma	17 (6.67)	0
Tumor differentiation	Well &Moderate	225 (88.24)	12 (52.17)	<0.000 1
	Poor	30 (11.76)	11 (47.83)
Number of tumors	Single	180 (70.59)	22 (95.65)	0.019 3
	Multiple	75 (29.41)	1 (4.35)
Tumor maximum diameter (cm)	≤5	94 (36.86)	8 (34.78)	1
	>5	161 (63.14)	15 (65.22)
MVI	No	218 (85.49)	11 (47.83)	<0.000 1
	Yes	37 (14.51)	12 (52.17)
Complications	No	218 (85.49)	16 (69.57)	0.088 1
	Yes	37 (14.51)	7 (30.43)

表2

参考文献 28

[1]	中国抗癌协会肝癌专业委员会胆管癌协作组. 原发性肝癌诊疗指南之肝内胆管癌诊疗中国专家共识(2022版)[J]. 中华消化外科杂志, 2022, 21(10):1269-1301.
	Chinese Society of Liver Cancer Cholangiocarcinoma Cooperative Group. Chinese expert consensus on management of intrahepatic cholangiocarcinoma(2022 edition)[J]. Chin J Dig Surg, 2022, 21(10):1269-1301.
[2]	BRIDGEWATER J, GALLE P R, KHAN S A, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma[J]. J Hepatol, 2014, 60(6):1268-1289. doi: 10.1016/j.jhep.2014.01.021 pmid: 24681130
[3]	SINGAL A K, VAUTHEY J N, GRADY J J, et al. Intra-hepatic cholangiocarcinoma—frequency and demographic patterns: thirty-year data from the M.D. Anderson Cancer Center[J]. J Cancer Res Clin Oncol, 2011, 137(7):1071-1078.
[4]	MASSARWEH N N, EL-SERAG H B. Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma[J]. Cancer Control, 2017, 24(3):1073274817729245.
[5]	GRAVELY A K, VIBERT E, SAPISOCHIN G. Surgical treatment of intrahepatic cholangiocarcinoma[J]. J Hepatol, 2022, 77(3):865-867. doi: 10.1016/j.jhep.2022.01.004 pmid: 35676107
[6]	CHUN Y S, JAVLE M. Systemic and adjuvant therapies for intrahepatic cholangiocarcinoma[J]. Cancer Control, 2017, 24(3):1073274817729241.
[7]	ALTMAN A M, KIZY S, MARMOR S, et al. Adjuvant chemotherapy for intrahepatic cholangiocarcinoma:approaching clinical practice consensus?[J]. Hepatobiliary Surg Nutr, 2020, 9(5):577-586.
[8]	QU W F, LIU W R, SHI Y H. Adjuvant chemotherapy for intrahepatic cholangiocarcinoma: far from a clinical consensus[J]. Hepatobiliary Surg Nutr, 2021, 10(6):887-889.
[9]	MA K W, CHEUNG T T, LEUNG B, et al. Adjuvant chemotherapy improves oncological outcomes of resectable intrahepatic cholangiocarcinoma:a meta-analysis[J]. Medicine (Baltimore), 2019, 98(5):e14013.
[10]	WANG M L, KE Z Y, YIN S, et al. The effect of adjuvant chemotherapy in resectable cholangiocarcinoma:a meta-analysis and systematic review[J]. Hepatobiliary Pancreat Dis Int, 2019, 18(2):110-116.
[11]	BÜTTNER S, GALJART B, BEUMER B R, et al. Quality and performance of validated prognostic models for survival after resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis[J]. HPB (Oxford), 2021, 23(1):25-36.
[12]	ESNAOLA N F, MEYER J E, KARACHRISTOS A, et al. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma[J]. Cancer, 2016, 122(9):1349-1369. doi: 10.1002/cncr.29692 pmid: 26799932
[13]	KUBO S, SHINKAWA H, ASAOKA Y, et al. Liver cancer study group of Japan clinical practice guidelines for intrahepatic cholangiocarcinoma[J]. Liver Cancer, 2022, 11(4):290-314. doi: 10.1159/000522403 pmid: 35978598
[14]	VOGEL A, BRIDGEWATER J, EDELINE J, et al. Bi-liary tract cancer:ESMO clinical practice guideline for diagnosis,treatment and follow-up[J]. Ann Oncol, 2023, 34(2):127-140.
[15]	PRIMROSE J N, FOX R P, PALMER D H, et al. Capecitabine compared with observation in resected bi-liary tract cancer(BILCAP):a randomised,controlled,multicentre,phase 3 study[J]. Lancet Oncol, 2019, 20(5):663-673.
[16]	EDELINE J, BENABDELGHANI M, BERTAUT A, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase Ⅲ study[J]. J Clin Oncol, 2019, 37(8):658-667.
[17]	林起柱, 刘红枝, 周伟平, 等. 术后辅助化疗对肝内胆管癌预后影响的多中心回顾性研究[J]. 中华外科杂志, 2023, 61(4):305-312.
	LIN Q Z, LIU H Z, ZHOU W P, et al. Effect of postoperative adjuvant chemotherapy on prognosis of patients with intrahepatic cholangiocarcinoma:a multicenter retrospective study[J]. Chin J Surg, 2023, 61(4):305-312.
[18]	WIRASORN K, NGAMPRASERTCHAI T, KHUNTIKEO N, et al. Adjuvant chemotherapy in resectable cholangiocarcinoma patients[J]. J Gastroenterol Hepatol, 2013, 28(12):1885-1891.
[19]	MIURA J T, JOHNSTON F M, TSAI S, et al. Chemotherapy for surgically resected intrahepatic cholangiocarcinoma[J]. Ann Surg Oncol, 2015, 22(11):3716-3723. doi: 10.1245/s10434-015-4501-8 pmid: 25777092
[20]	SUR M D, IN H, SHARPE S M, et al. Defining the be-nefit of adjuvant therapy following resection for intrahepatic cholangiocarcinoma[J]. Ann Surg Oncol, 2015, 22(7):2209-2217.
[21]	REAMES B N, BAGANTE F, EJAZ A, et al. Impact of adjuvant chemotherapy on survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis[J]. HPB (Oxford), 2017, 19(10):901-909.
[22]	TSILIMIGRAS D I, HYER J M, PAREDES A Z, et al. Tumor burden dictates prognosis among patients undergoing resection of intrahepatic cholangiocarcinoma: a tool to guide post-resection adjuvant chemotherapy?[J]. Ann Surg Oncol, 2021, 28(4):1970-1978. doi: 10.1245/s10434-020-09393-7 pmid: 33259043
[23]	SCHWEITZER N, WEBER T, KIRSTEIN M M, et al. The effect of adjuvant chemotherapy in patients with intrahepatic cholangiocarcinoma:a matched pair analysis[J]. J Cancer Res Clin Oncol, 2017, 143(7):1347-1355.
[24]	LI X H, ZHAO C Y, ZHOU E L, et al. Efficacy and safety of adjuvant chemotherapy in T1N0M0 intrahepatic cho-langiocarcinoma after radical resection[J]. BMC Cancer, 2022, 22(1):1159.
[25]	苏敬博, 张景玮, 陈晨, 等. 辅助化疗对肝内胆管癌根治性切除术后患者预后的影响[J]. 中华外科杂志, 2022,(4):356-362.
	SU J B, ZHANG J W, CHEN C, et al. Impact of adjuvant chemotherapy on prognosis in intrahepatic cholangiocarcinoma patients underwent radical resection[J]. Chin J Surg, 2022, 60(4):356-362. doi: 10.3760/cma.j.cn112139-20220110-00021 pmid: 35272427
[26]	IZQUIERDO-SANCHEZ L, LAMARCA A, LA CASTA A, et al. Cholangiocarcinoma landscape in Europe: diagnostic,prognostic and therapeutic insights from the ENSCCA registry[J]. J Hepatol, 2022, 76(5):1109-1121.
[27]	ENDO Y, MOAZZAM Z, ALAIMO L, et al. Predictive risk-score model to select patients with intrahepatic cho-langiocarcinoma for adjuvant chemotherapy[J]. HPB (Oxford), 2023, 25(2):229-238.
[28]	LI Q, ZHANG J, CHEN C, et al. A nomogram model to predict early recurrence of patients with intrahepatic cholangiocarcinoma for adjuvant chemotherapy guidance: a multi-institutional analysis[J]. Front Oncol, 2022,12:896764.

		Univariate analysis			Multivariate analysis
		HR	95%CI	P value	HR	95%CI	P value
Gender	Woman vs. Man	0.82	0.57-1.19	0.3
Age(years)	>60 vs. ≤60	0.98	0.7-1.37	0.897
Smoking history	Yes vs. No	1.13	0.8-1.59	0.48
Drinking history	Yes vs. No	2.26	1.51-3.38	<0.001	2.49	1.65-3.77	<0.001
HBV	Yes vs. No	1.19	0.85-1.67	0.304
ECOG score	>2 vs. ≤2	1.7	1.16-2.49	0.007	1.46	0.98-2.16	0.048 7
CA19-9（U/mL）	>37 vs. ≤37	1.79	1.22-2.63	0.003	1.42	0.95-2.13	0.091 1
CEA(μg/L)	>5 vs. ≤5	1.46	0.9-2.37	0.128
TBIL(μmol/L)	>20 vs. ≤20	0.94	0.68-1.31	0.725
Blood loss	>400 vs. ≤400	1.05	0.66-1.69	0.828
Blood transfusion	Yes vs. No	1.4	0.8-2.43	0.234
Margin(cm)	≥1 vs. <1	0.71	0.41-1.21	0.205
Method of hepatectomy	Non-anatomical vs. Anatomical	0.64	0.45-0.89	0.009	0.7	0.49-0.99	0.042
LND	Yes vs. No	1.41	0.9-2.19	0.132
Lymph node status	N0 vs. Nx	0.9	0.5-1.63	0.728
	N1 vs. Nx	3.3	1.8-6.03	<0.001	2.6	1.36-4.98	0.003 9
Gross classification	Non-MF(mass forming) vs. MF	1.31	0.94-1.82	0.111
Histological classification	Non-adenocarcinoma vs. Adenocarcinoma	0.47	0.21-1.05	0.067
Tumor differentiation	Poor vs. Well &moderate	1.88	1.12-3.17	0.017	2.28	1.31-3.95	0.003 5
Number of tumors	Multiple vs. Single	1.72	1.22-2.42	0.002	1.48	1.02-2.14	0.038 2
Tumor maximum diameter (cm)	>5 vs. ≤5	1.53	1.07-2.21	0.021	1.37	0.94-2	0.096 7
MVI	Yes vs. No	1.2	0.75-1.93	0.444
Complications	Yes vs. No	1.5	0.93-2.41	0.093