西妥昔单抗联合mFOLFOX6化疗方案治疗晚期结直肠癌患者的临床疗效及安全性分析

摘要/Abstract

摘要：

目的分析西妥昔单抗联合mFOLFOX6化疗方案治疗晚期结直肠癌的临床疗效，探讨其对T淋巴细胞亚群分布、患者体能状况、肿瘤标志物水平的影响，并进行安全性分析。方法选择2020年4月至2022年4月海南省肿瘤医院收治的晚期结直肠癌患者90例，采用随机数字表法将患者随机分为观察组（n=45）和对照组（n=45）。对照组采用mFOLFOX6化疗方案治疗，观察组采用西妥昔单抗联合mFOLFOX6化疗方案治疗。比较两组治疗后客观缓解率（ORR）、疾病控制率（DCR）、T淋巴细胞亚群水平（CD3⁺、CD4⁺、CD8⁺占比）、Karnofsky功能状态（KPS）评分、肿瘤标志物血管内皮生长因子（VEGF）、内皮细胞特异分子1（ESM1）、癌胚抗原（CEA）水平及不良反应发生率。结果治疗4周期后，观察组ORR为66.67%（30/45），对照组为42.22%（19/45），差异有统计学意义（χ²=5.42，P=0.020）。观察组DCR为86.67%（39/45），对照组为66.67%（30/45），差异有统计学意义（χ²=5.03，P=0.025）。观察组T淋巴细胞亚群CD3⁺、CD4⁺、CD8⁺占比分别为（63.35±6.71）%、（35.67±3.96）%、（17.03±2.11）%，对照组分别为（52.23±5.92）%、（30.55±3.51）%、（20.64±2.83）%，观察组CD3⁺、CD4⁺占比均较对照组高（t=8.34，P<0.001；t=6.49，P<0.001），CD8⁺占比低（t=6.86，P<0.001）。观察组KPS评分为（95.55±9.74）分，对照组为（85.03±8.92）分，差异有统计学意义（t=5.34，P<0.001）。观察组VEGF、ESM1、CEA水平分别为（303.45±33.21）ng/L、（75.66±8.36）pg/ml、（7.73±0.98）ng/ml，对照组分别为（364.53±39.07）ng/L、（92.53±9.91）pg/ml、（9.95±1.13）ng/ml，观察组VEGF、ESM1、CEA均较对照组低（t=7.99，P<0.001；t=8.73，P<0.001；t=9.96，P<0.001）。观察组不良反应总发生率为75.56%（34/45），对照组为66.67%（30/45），差异无统计学意义（χ²=0.87，P=0.352）。结论采用西妥昔单抗联合mFOLFOX6化疗方案治疗晚期结直肠癌患者，临床疗效显著，可改善患者免疫功能，缓解临床症状，调节患者血清肿瘤标志物水平，且不增加不良反应，安全性较好。

关键词:结直肠肿瘤,西妥昔单抗,药物疗法，联合,治疗结果,T淋巴细胞亚群

Abstract:

ObjectiveTo analyze the clinical efficacy of cetuximab combined with mFOLFOX6 chemotherapy regimen in the treatment of advanced colorectal cancer， to explore its effects on the distribution of T lymphocyte subsets， patients' physical status and tumor marker levels， and to analyze its safety.MethodsA total of 90 patients with advanced colorectal cancer admitted to the Hainan Cancer Hospital from April 2020 to April 2022 were selected and randomly divided into observation group （n=45） and control group （n=45） according to random number table method. The control group was treated with the mFOLFOX6 chemotherapy regimen， while the observation group was treated with cetuximab combined with the mFOLFOX6 chemotherapy regimen. Objective response rate （ORR）， disease control rate （DCR）， T lymphocyte subsets levels （percentages of CD3⁺， CD4⁺， CD8⁺）， Karnofsky performance status （KPS） score， tumor marker vascular endothelial growth factor （VEGF）， endothelial cell-specific molecule 1 （ESM1）， carcino-embryonic antigen （CEA） levels and the incidence of adverse reactions were compared between the two groups after treatment.ResultsAfter 4 cycles of treatment， the ORR was 66.67% （30/45） in the observation group and 42.22% （19/45） in the control group， and there was a statistically significant difference （χ²=5.42，P=0.020）. The DCR of the observation group was 86.67% （39/45） and that of the control group was 66.67% （30/45）， and there was a statistically significant difference （χ²=5.03，P=0.025）. The percentages of T lymphocyte subsets CD3⁺， CD4⁺and CD8⁺in the observation group were （63.35±6.71） %，（35.67±3.96） % and （17.03±2.11） %， respectively， while those in the control group were （52.23±5.92） %，（30.55±3.51） % and （20.64±2.83） %， respectively. The percentages of CD3⁺and CD4⁺in the observation group were significantly higher than those in the control group （t=8.34，P<0.001；t=6.49，P<0.001）， while the percentage of CD8⁺ratio was significantly lower （t=6.86，P<0.001）. The KPS score of the observation group was （95.55±9.74） points， and that of the control group was （85.03±8.92） points， and there was a statistically significant difference （t=5.34，P<0.001）. VEGF， ESM1 and CEA levels in the observation group were （303.45±33.21） ng/L，（75.66±8.36） pg/ml and （7.73±0.98） ng/ml， respectively， while those in the control group were （364.53±39.07） ng/L，（92.53±9.91） pg/ml and （9.95±1.13） ng/ml， respectively. VEGF， ESM1 and CEA levels in observation group were significantly lower compared with control group （t=7.99，P<0.001；t=8.73，P<0.001；t=9.96，P<0.001）. The total incidence of adverse reactions was 75.56% （34/45） in the observation group and 66.67% （30/45） in the control group， and there was no statistically significant difference （χ²=0.87，P=0.352）.ConclusionCetuximab combined with mFOLFOX6 chemotherapy regimen in the treatment of advanced colorectal cancer patients has significant clinical efficacy， can improve the immune function of patients， alleviate clinical symptoms， regulate the level of serum tumor markers in patients without increasing adverse reactions， and has good safety.

Key words:Colorectal neoplasms,Cetuximab,Drug therapy， combination,Treatment outcome,T-lymphocyte subsets

刘佳奇, 王文君, 钟萍, 杨敏, 赵心恺. 西妥昔单抗联合mFOLFOX6化疗方案治疗晚期结直肠癌患者的临床疗效及安全性分析[J]. 国际肿瘤学杂志, 2024, 51(12): 763-768.

Liu Jiaqi, Wang Wenjun, Zhong Ping, Yang Min, Zhao Xinkai. Clinical efficacy and safety analysis of cetuximab combined with mFOLFOX6 chemotherapy in the treatment of advanced colorectal cancer patients[J]. Journal of International Oncology, 2024, 51(12): 763-768.

图/表6

组别	性别	年龄（岁）	分化类型		肿瘤类型		结肠原发肿瘤部位
观察组（n=45）	28	17	57.44±6.22	10	15	20		25	20	13	7
对照组（n=45）	30	15	57.16±6.15	13	14	18		27	18	11	7
χ²/t值	0.19	0.22		0.53			0.18		0.06
P值	0.660	0.830		0.767			0.670		0.804

表1

组别	CR	PR	SD	PD	客观缓解	疾病控制
观察组（n=45）	4（8.89）	26（57.78）	9（20.00）	6（13.33）	30（66.67）	39（86.67）
对照组（n=45）	1（2.22）	18（40.00）	11（24.44）	15（33.33）	19（42.22）	30（66.67）
χ²值					5.42	5.03
P值					0.020	0.025

表2

组别	CD3⁺占比			CD8⁺占比
观察组（n=45）	49.42±5.37	63.35±6.71^a	24.27±3.28	35.67±3.96^a	25.12±3.05	17.03±2.11^a
对照组（n=45）	49.38±5.34	52.23±5.92^a	24.33±3.31	30.55±3.51^a	25.16±3.08	20.64±2.83^a
t值	0.04	8.34	0.09	6.49	0.06	6.86
P值	0.972	<0.001	0.931	<0.001	0.951	<0.001

表3

组别	治疗前	治疗后	t值	P值
观察组（n=45）	77.65±8.01	95.55±9.74	9.52	<0.001
对照组（n=45）	77.71±8.05	85.03±8.92	4.09	<0.001
t值	0.04	5.34
P值	0.972	<0.001

表4

组别	VEGF（ng/L）			CEA（ng/ml）
观察组（n=45）	437.22±45.35	303.45±33.21^a	111.25±13.28	75.66±8.36^a	13.72±2.02	7.73±0.98^a
对照组（n=45）	435.98±45.14	364.53±39.07^a	110.83±13.01	92.53±9.91^a	13.69±2.05	9.95±1.13^a
t值	0.13	7.99	0.15	8.73	0.07	9.96
P值	0.897	<0.001	0.880	<0.001	0.944	<0.001

表5

表6

参考文献19

[1]	Novillo A, Gaibar M, Romero-Lorca A, et al. Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: six case reports[J].World J Gastroenterol,2020,26(16): 1979-1986. DOI:10.3748/wjg.v26.i16.1979.
[2]	Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics[J].Trends Pharmacol Sci,2023,44(4): 222-236. DOI:10.1016/j.tips.2023.01.003. pmid:36828759
[3]	Patel SG, Karlitz JJ, Yen T, et al. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection[J].Lancet Gastroenterol Hepatol,2022,7(3): 262-274. DOI:10.1016/S2468-1253(21)00426-X.
[4]	Yun SH, Park JI. PGC-1α regulates cell proliferation and invasion via AKT/GSK-3β/β-catenin pathway in human colorectal cancer SW620 and SW480 cells[J].Anticancer Res,2020,40(2): 653-664. DOI:10.21873/anticanres.13995.
[5]	Cremolini C, Antoniotti C, Rossini D, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial[J].Lancet Oncol,2020,21(4): 497-507. DOI:10.1016/S1470-2045(19)30862-9. pmid:32164906
[6]	Okumura M, Ichihara H, Matsumoto Y. Hybrid liposomes showing enhanced accumulation in tumors as theranostic agents in the orthotopic graft model mouse of colorectal cancer[J].Drug Deliv,2018,25(1): 1192-1199. DOI:10.1080/10717544.2018.1475517. pmid:29790374
[7]	Holch JW, Held S, Stintzing S, et al. Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306)[J].Ann Oncol,2020,31(1): 72-78. DOI:10.1016/j.annonc.2019.10.001. pmid:31912799
[8]	中华人民共和国国家卫生健康委员会. 中国结直肠癌诊疗规范(2020年版)[J].中华外科杂志,2020,58(8): 561-585. DOI:10.3760/cma.j.cn112139-20200518-00390.
[9]	杨学宁, 吴一龙. 实体瘤治疗疗效评价标准—RECIST[J].循证医学,2004,4(2): 85-90, 111. DOI:10.3969/j.issn.1671-5144.2004.02.012.
[10]	Zhou L, Zhan ML, Tang Y, et al. Effects of β-caryophyllene on arginine ADP-ribosyltransferase 1-mediated regulation of glycolysis in colorectal cancer under high-glucose conditions[J].Int J Oncol,2018,53(4): 1613-1624. DOI:10.3892/ijo.2018.4506. pmid:30066849
[11]	Diaz LA Jr, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study[J].Lancet Oncol,2022,23(5): 659-670. DOI:10.1016/S1470-2045(22)00197-8. pmid:35427471
[12]	Kanemitsu Y, Shimizu Y, Mizusawa J, et al. Hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver-only metastatic colorectal cancer (JCOG0603): a phase Ⅱ or Ⅲ randomized controlled trial[J].J Clin Oncol,2021,39(34): 3789-3799. DOI:10.1200/JCO.21.01032.
[13]	林淑君, 蓝佳琦, 沈惠群, 等. 伊立替康联合西妥昔单抗治疗老年晚期结直肠癌临床研究[J].中国医药科学,2023,13(8): 150-153, 166. DOI:10.3969/j.issn.2095-0616.2023.08.040.
[14]	韩如意, 孙丽, 王媛, 等. 西妥昔单抗联合FOLFOX化疗方案对晚期结直肠癌患者血清VEGF、IGF-1水平的影响[J].中国处方药,2020,18(12): 115-116. DOI:10.3969/j.issn.1671-945X.2020.12.058.
[15]	Zheng Z, Wieder T, Mauerer B, et al. T cells in colorectal cancer: unravelling the function of different T cell subsets in the tumor microenvironment[J].Int J Mol Sci,2023,24(14): 11673. DOI:10.3390/ijms241411673.
[16]	Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C[J].N Engl J Med,2023,388(1): 44-54. DOI:10.1056/NEJMoa2212419.
[17]	Mohamed SY, Mohammed HL, Ibrahim HM, et al. Role of VEGF, CD105, and CD31 in the prognosis of colorectal cancer cases[J].J Gastrointest Cancer,2019,50(1): 23-34. DOI:10.1007/s12029-017-0014-y. pmid:29110224
[18]	Bakshi HA, Quinn GA, Nasef MM, et al. Crocin inhibits angiogene-sis and metastasis in colon cancer via TNF-α /NF-κ B/VEGF pathways[J].Cells,2022,11(9): 1502. DOI:10.3390/cells11091502.
[19]	常伟纳, 王璇, 楚盼盼, 等. 西妥昔单抗联合FOLFIRI方案治疗结直肠癌疗效及对血清ESM1、SRPX2、VEGF水平的影响[J].淮海医药,2021,39(6): 586-590. DOI:10.14126/j.cnki.1008-7044.2021.06.009.

组别	消化道反应		心脏毒性		肝功能异常		骨髓抑制		合计
组别	1~2级	3~4级	1~2级	3~4级	1~2级	3~4级	1~2级	3~4级	合计
观察组（n=45）	9	2	7	1	4	1	9	1	34
对照组（n=45）	6	2	6	0	4	1	10	1	30
χ²值									0.87
P值									0.352