辅助化疗对胃神经内分泌癌患者预后的意义

doi:10.19401/j.cnki.1007-3639.2022.09.008

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (9): 807-817.doi: 10.19401/j.cnki.1007-3639.2022.09.008

辅助化疗对胃神经内分泌癌患者预后的意义

张日虹¹(), 郭宇², 梁贇³, 陈洛海², 陈洁³(), 王玮¹()

1.中山大学肿瘤防治中心胃外科,华南肿瘤学国家重点实验室,肿瘤医学协同创新中心,广东广州 510060
2.中山大学附属第一医院消化内科,广东广州 510080
3.复旦大学附属肿瘤医院神经内分泌肿瘤中心,头颈及神经内分泌肿瘤内科,复旦大学上海医学院肿瘤学系,上海 200032

收稿日期:2022-08-02 修回日期:2022-09-07 出版日期:2022-09-30 发布日期:2022-10-24
通信作者: 陈洁,王玮
作者简介:张日虹（ORCID: 0000-0002-5667-1597）,硕士。
王玮,中山大学肿瘤防治中心胃外科副主任医师。中国抗癌协会胰腺癌专业委员会神经内分泌肿瘤学组委员,中国医疗保健国际交流促进会神经内分泌肿瘤专业委员会委员,广东省抗癌协会胃癌专业委员会青委会委员兼秘书,广东省中西医结合协会胃肠外科分会委员。主持国家自然科学基金青年项目、广州市产学研协同创新重大专项、广东省自然科学基金面上项目、广东省卫健委面上项目及教育部博士点专项基金青年基金等多项课题。近5年以第一作者在SCI收录期刊上发表论文20余篇。
基金资助:
国家自然科学基金青年项目(81802451);国家自然科学基金“罕见肿瘤研究专项”项目(82141104);广东省自然科学基金面上项目(2018A030313827);广东省自然科学基金面上项目(2021A1515011327)

Prognostic significance of adjuvant chemotherapy in patients with gastric neuroendocrine carcinoma

ZHANG Rihong¹(), GUO Yu², LIANG Yun³, CHEN Luohai², CHEN Jie³(), WANG Wei¹()

1. Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
2. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
3. Center for Neuroendocrine Tumors, Department of Head, Neck and Neuroendocrine Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Received:2022-08-02 Revised:2022-09-07 Published:2022-09-30 Online:2022-10-24
Contact: CHEN Jie, WANG Wei

摘要/Abstract

摘要：

背景与目的： 胃神经内分泌肿瘤（neuroendocrine neoplasm,NEN）是胃恶性肿瘤中一种较为罕见的类别,根据2019年世界卫生组织（World Health Organization,WHO）消化系统NEN的分类标准,分为分化好的神经内分泌瘤（neuroendocrine tumor,NET）和分化差的神经内分泌癌（neuroendocrine carcinoma,NEC）。目前,关于胃NEC（gastric NEC,GNEC）辅助化疗预后的研究匮乏,本研究旨在探讨辅助化疗能否使GNEC患者获益,以期为临床决策提供参考依据。方法： 回顾性分析中山大学肿瘤防治中心、中山大学附属第一医院和复旦大学附属肿瘤医院2008年7月—2019年6月收治的184例GNEC患者的临床病理学资料,随访截至2022年5月31日。利用Kaplan-Meier法绘制生存曲线,根据单因素COX回归分析和多因素COX回归分析筛选出影响GNEC患者生存的独立预后因素,并进一步分析化疗、手术等因素对患者预后的影响。检验水准为α = 0.05,所有统计学分析均使用SPSS 25.0软件。结果： 单因素分析显示,手术（P<0.001）、化疗（P <0.001）、综合治疗模式（P<0.001）、N分期（P = 0.029）、M分期（P<0.001）及TNM综合分期（P<0.001）是影响GNEC患者预后的变量。多因素COX回归分析显示,手术（P<0.001）、化疗（P<0.001）及M分期（P<0.001）是影响GNEC患者生存的独立预后因素。在所有患者中,TNM Ⅰ、Ⅱ、Ⅲ和Ⅳ期的3年累积生存率分别为51.9%、55.8%、40.7%和23.6%。在行根治性切除的患者中,辅助化疗可以改善GNEC患者的预后,辅助化疗和非辅助化疗的3年累积生存率分别为58.8%和33.3%（P = 0.008）。分层分析结果显示,辅助化疗能够改善TNM Ⅱ（P = 0.018）和Ⅲ期（P = 0.023）患者的预后。此外,NEC化疗方案[依托泊苷+顺铂（etoposide plus cisplatin,EP）、伊立替康+顺铂（irinotecan plus cisplatin,IP）]与胃腺癌方案[奥沙利铂+卡培他滨（oxaliplatin plus capecitabine,XELOX）、奥沙利铂+替吉奥（oxaliplatin plus tegafur,SOX）、奥沙利铂+5-氟尿嘧啶（oxaliplatin plus 5-fluorouracil,FOLFOX）]在改善预后方面差异无统计学意义（P = 0.668）。结论： 辅助化疗可改善GNEC患者预后,为临床决策提供参考。

关键词: 胃神经内分泌癌, 辅助化疗, 预后

Abstract:

Background and purpose: Gastric neuroendocrine neoplasm (NEN) is a rare type of gastric malignant tumors. According to the 2019 World Health Organization (WHO) classification criteria for gastrointestinal NEN, gastric NEN can be divided into well-differentiated neuroendocrine tumor (NET) and poorly-differentiated neuroendocrine carcinoma (NEC). At present, there is a lack of research on the prognosis of adjuvant chemotherapy for gastric NEC (GNEC). The aim of the research was to investigate whether adjuvant chemotherapy can benefit patients with GNEC and provide a basis for clinical decision-making. Methods: A retrospective analysis was performed on the clinical data of about 184 patients with GNEC from July 2008 to June 2019 in Sun Yat-sen University Cancer Center, The First Affiliated Hospital of Sun Yat-sen University and Fudan University Shanghai Cancer Center. The follow-up deadline was May 31, 2022. Kaplan-Meier method was used to draw the survival curve, and prognostic relevant factors affecting the survival of patients with GNEC and the independent prognostic factors were screened out according to univariate and multivariate COX regression analyses. Finally, the effects of chemotherapy and surgery on the prognosis of patients were further analyzed. The test level was α = 0.05, and SPSS 25.0 was used for all statistical analyses. Results: By univariate COX regression analysis, it was found that surgery, chemotherapy, treatment method, N stage, M stage and TNM stage were the variables affecting the prognosis of patients with GNEC (P<0.05). Multivariable COX regression analysis results showed that surgery, chemotherapy and M stage were independent prognostic factors for survival in patients with GNEC (P<0.001). The 3-year cumulative survival rates of TNM stage Ⅰ, Ⅱ, Ⅲ and Ⅳ were 51.9%, 55.8%, 40.7% and 23.6%, respectively. In the radical resection group, adjuvant chemotherapy could improve the prognosis of patients with GNEC (P=0.008). The 3-year cumulative survival rates of adjuvant chemotherapy group and non-adjuvant chemotherapy group were 58.8% and 33.3%, respectively. Stratified analysis showed that adjuvant chemotherapy could benefit the prognosis of patients with TNM stage Ⅱ (P = 0.018) and TNM stage Ⅲ (P = 0.023). In addition, there was no significant difference in prognosis between the first-line chemotherapy regimen [etoposide plus cisplatin (EP), irinotecan plus cisplatin (IP)] and the gastric adenocarcinoma regimen [oxaliplatin plus capecitabine (XELOX), oxaliplatin plus tegafur (SOX), oxaliplatin plus 5-fluorouracil (FOLFOX)] (P = 0.668). Conclusion: Adjuvant chemotherapy can significantly improve the prognosis of patients with GNEC, providing a reference for clinical decision-making.

Key words: Gastric neuroendocrine carcinoma, Adjuvant chemotherapy, Prognosis

中图分类号:

R735.2

张日虹, 郭宇, 梁贇, 陈洛海, 陈洁, 王玮. 辅助化疗对胃神经内分泌癌患者预后的意义[J]. 中国癌症杂志, 2022, 32(9): 807-817.

ZHANG Rihong, GUO Yu, LIANG Yun, CHEN Luohai, CHEN Jie, WANG Wei. Prognostic significance of adjuvant chemotherapy in patients with gastric neuroendocrine carcinoma[J]. China Oncology, 2022, 32(9): 807-817.

图/表 6

表1

表2

单因素和多因素分析结果"

Variable	Univariate analysis		Multivariate analysis
Variable	HR (95% CI)	P value	HR (95% CI)	P value
Age/year		0.154
<60	1.000
≥60	1.365 (0.890-2.094)
Gender		0.784
Male	1.000
Female	1.067 (0.672-1.694)
Tumor site		0.774
Upper stomach	1.000
Middle stomach	0.861 (0.560-1.324)	0.496
Lower stomach	1.000 (0.607-1.648)	0.998
Tumor size/cm		0.311
<6	1.000
≥6	1.337 (0.762-2.347)
NA
Tumor pathological type		0.259
NEC	1.000
MiNEN	1.267 (0.840-1.910)
Histopathology		0.891
Large cell	1.000
Small cell	0.876 (0.489-1.571)	0.658
Mixed	0.894 (0.518-1.543)	0.687
Ki-67 proliferation index		0.141
20%-55%	1.000
>55%	1.379 (0.899-2.115)
T stage		0.255
T₁	1.000
T₂	1.153 (0.312-4.268)	0.831
T₃	2.055 (0.644-6.559)	0.224
T₄	2.064 (0.629-6.773)	0.232
N stage		0.029	1.145 (0.898-1.461)	0.276
N₀	1.000
N₁	1.062 (0.657-1.717)	0.805
N₂	0.783 (0.350-1.752)	0.552
N₃	2.457 (1.230-4.911)	0.011
M stage		<0.001	2.754 (1.703-4.454)	<0.001
M₀	1.000
M₁	2.818 (1.938-4.098)
TNM stage		<0.001
Ⅰ	1.000
Ⅱ	1.717 (0.604-4.879)	0.310
Ⅲ	2.170 (0.754-6.241)	0.151
Ⅳ	5.047 (1.821-13.989)	0.002
Surgery		<0.001	0.378 (0.229-0.626)	<0.001
No	1.000
Yes	0.224 (0.149-0.339)
Surgery mode		0.153
Radical surgery	1.000
Palliative surgery	1.844 (0.797-4.267)
Chemotherapy		<0.001	0.347 (0.215-0.559)	<0.001
No	1.000
Yes	0.481 (0.319-0.726)
Chemotherapy regimen		0.836
EP, IP	1.000
XELOX, SOX, FOLFOX	0.889 (0.520-1.520)	0.668
FOLFIRI, CAPTEM, taxol	0.719 (0.174-2.967)	0.648
Severe adverse reactions to chemotherapy occurred		0.736
No	1.000
Yes	0.923 (0.580-1.470)
Comprehensive treatment model		<0.001
Surgery+chemotherapy	1.000
Surgery alone	2.120 (1.273-3.529)	0.004
Chemotherapy alone	4.476 (2.783-7.197)	<0.001
Without treatment	14.693 (7.083-30.479)	<0.001

表2

图1

表3

图2

图3

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辅助化疗对胃神经内分泌癌患者预后的意义

Prognostic significance of adjuvant chemotherapy in patients with gastric neuroendocrine carcinoma

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Clinicopathological data	n (%)	Clinicopathological data	n (%)
Age/year		N₂	16 (8.7)
<60	54 (29.3)	N₃	22 (12.0)
≥60	130 (70.7)	NA	9 (4.9)
Gender		M stage
Male	148 (80.4)	M₀	114 (62.0)
Female	36 (19.6)	M₁	70 (38.0)
Tumor site		TNM stage
Upper stomach	85 (46.2)	Ⅰ	11 (6.0)
Middle stomach	66 (35.9)	Ⅱ	60 (32.6)
Lower stomach	33 (17.9)	Ⅲ	43 (23.4)
Tumor size/cm		Ⅳ	70 (38.0)
<6	76 (41.3)	Surgery
≥6	30 (16.3)	No	47 (25.5)
NA	78 (42.4)	Yes	137 (74.5)
Tumor pathological type		Surgery mode
NEC	141 (76.6)	Radical	129 (70.1)
MiNEN	43 (23.4)	Palliative	8 (4.3)
Histopathology		Without surgery	47 (25.5)
Large cell	35 (19.0)	Chemotherapy
Small cell	33 (17.9)	No	41 (22.3)
Mixed	43 (23.4)	Yes	143 (77.7)
Unknown	73 (39.7)	Chemotherapy regimen
Ki-67 proliferation index		EP, IP	91 (49.5)
20%-55%	43 (23.4)	XELOX, SOX, FOLFOX	31 (16.8)
>55%	127 (69.0)	FOLFIRI, CAPTEM, taxol	5 (2.7)
NA	14 (7.6)	No chemotherapy or protocol unknown	57 (31.0)
T stage		Severe adverse reactions to chemotherapy occurred
T₁	6 (3.3)	No	49 (34.3)
T₂	22 (12.0)	Yes	94 (65.7)
T₃	98 (53.3)	Comprehensive treatment model
T₄	48 (26.1)	Surgery+chemotherapy	109 (59.2)
NA	10 (5.4)	Surgery alone	28 (15.2)
N stage		Chemotherapy alone	34 (18.5)
N₀	42 (22.8)	Without treatment	13 (7.1)
N₁	95 (51.6)

Variable	Total	3-year cum survival rate/%	Median survival time/month	HR (95% CI)	P value
Surgery mode
Radical surgery	129	52.7	40	1
Palliative surgery	8	18.8	13	1.831 (0.792-4.235)	0.157
Without surgery	47	8.3	11	4.624 (3.047-7.016)	<0.001
Adjuvant chemotherapy
No	27	33.3	17	1
Yes	102	58.5	47	0.467 (0.275-0.790)	0.008
Different TNM stages (adjuvant chemotherapy)
Ⅰstage (adjuvant chemotherapy)
No	5	NA	NA	1
Yes	5	NA	NA	0.500 (0.045-5.514)	0.535
Ⅱ stage (adjuvant chemotherapy)
No	8	NA	11	1
Yes	50	60.9	50	0.371 (0.156-0.882)	0.018
Ⅲ stage (adjuvant chemotherapy)
No	13	16.7	15	1
Yes	24	50.1	37	0.390 (0.167-0.911)	0.023
Ⅳstage (chemotherapy)
No	11	0	3	1
Yes	59	27.7	14	0.160 (0.073-0.351)	<0.001
Chemotherapy regimen					0.836
EP, IP	91	42.6	27	1
XELOX, SOX, FOLFOX	31	42.7	27	0.889 (0.520-1.520)	0.668
FOLFIRI, CAPTEM, taxol	5	NA	NA	0.719 (0.174-2.967)	0.648
Comprehensive treatment model					<0.001
Surgery+chemotherapy	109	59.0	43	1
Surgery alone	28	32.1	16	2.120 (1.273-3.529)	0.004
Chemotherapy alone	34	10.9	13	4.476 (2.783-7.197)	<0.001
Without surgery	13	0	4	14.693 (7.083-30.479)	<0.001