DEBIRI-TACE联合瑞戈非尼三线以上治疗结直肠癌肝转移的疗效及影响因素分析

摘要/Abstract

摘要：

目的探讨CalliSpheres载药微球加载伊立替康经肝动脉化疗栓塞（DEBIRI-TACE）联合瑞戈非尼三线以上治疗不可切除结直肠癌肝转移的疗效及影响因素。方法回顾性分析2018年6月至2020年6月山东省临沂市肿瘤医院收治的53例至少接受二线全身化疗失败的不可切除结直肠癌肝转移患者,依据治疗方案不同分为观察组（n=24）和对照组（n=29）。对照组仅接受瑞戈非尼单药治疗,观察组接受瑞戈非尼联合DEBIRI-TACE治疗。依据改良的实体瘤疗效评价标准评价患者的客观缓解率（ORR）、疾病控制率（DCR）,采用Kaplan-Meier法估算患者无进展生存期（PFS）、总生存期（OS）。Cox比例风险模型分析观察组患者OS的影响因素,观察治疗相关不良反应。结果治疗2个月后,观察组的ORR为75.0%（18/24）,DCR为91.7%（22/24）,均高于对照组的6.9%（2/29）、51.7%（15/29）,差异均有统计学意义（χ²=25.92,P<0.001;χ²=9.94,P=0.002）。两组与瑞戈非尼相关不良反应手足皮肤反应[62.5%（15/24）vs.65.5%（19/29）,χ²=0.05,P=0.819]、乏力[41.7%（10/24）vs.44.8%（13/29）,χ²=0.05,P=0.817]、高血压[29.2%（7/24）vs.34.5%（10/29）,χ²=0.17,P=0.679]、腹泻[25.0%（6/24）vs.27.6%（8/29）,χ²=0.04,P=0.832]、声音嘶哑[16.7%（4/24）vs.17.2%（5/29）,χ²=0.01,P=0.956]、蛋白尿[8.3%（2/24）vs.10.3%（3/29）,χ²=0.06,P=0.803]发生率比较,差异均无统计学意义。观察组与DEBIRI-TACE相关的不良反应主要为发热、疼痛、恶心呕吐等,均经对症治疗后缓解,未出现CalliSpheres载药微球异位栓塞等严重并发症。至随访结束,观察组24例患者中,同时性肝转移患者的中位OS为12个月,异时性肝转移患者为22个月,差异有统计学意义（χ²=4.29,P=0.026）;肝转移癌数目3~5个的患者中位OS为21个月,肝转移癌数目>5个的患者为14个月,差异有统计学意义（χ²=3.35,P=0.040）;肝功能分级Child-Pugh A级患者中位OS为22个月,Child-Pugh B级患者为13个月,差异有统计学意义（χ²=4.22,P=0.027）;伴有肝外转移患者中位OS为16个月,不伴有肝外转移患者为23个月,差异有统计学意义（χ²=7.68,P=0.013）。Cox比例风险模型分析显示,同时性肝转移（HR=1.59,95%CI为1.02~2.47,P=0.031）、肝外转移（HR=1.61,95%CI为1.29~2.01,P=0.020）是观察组患者OS的独立危险因素。观察组中位PFS为9个月,对照组为5个月,差异有统计学意义（χ²=7.78,P=0.005）;观察组中位OS为17个月,对照组为11个月,差异有统计学意义（χ²=16.81,P<0.001）。结论DEBIRI-TACE联合瑞戈非尼三线以上治疗全身化疗失败的不可切除结直肠癌肝转移的疗效较好,不良反应可耐受,是一种安全可行的治疗方式;同时性肝转移、合并肝外转移的患者预后更差。

关键词:结直肠肿瘤,治疗结果,经导管动脉化疗栓塞,肝转移,瑞戈非尼

Abstract:

ObjectiveTo explore the efficacy and influencing factors of irinotecan-loaded CalliSpheres drug-eluting bead-transcatheter arterial chemoembolization （DEBIRI-TACE） combined with regorafenib in the third-line or above treatment of unresectable colorectal cancer liver metastases.MethodsFrom June 2018 to June 2020, 53 patients with unresectable colorectal cancer liver metastases admitted to Linyi Cancer Hospital of Shandong Province who had failed at least second-line systemic chemotherapy were retrospectively analyzed. The patients were divided into observation group （24 cases） and control group （29 cases） according to different treatment regimes. The control group only received regorafenib monotherapy, and the observation group received regorafenib combined with DEBIRI-TACE. According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate （ORR） and disease control rate （DCR） were evaluated, and the progression-free survival （PFS） and overall survival （OS） were estimated by Kaplan-Meier method. The Cox proportional hazards model was used to analyze the OS influencing factors in the observation group. The treatment related adverse reactions were observed.ResultsAfter 2 months of treatment, the ORR of the observation group was 75.0% （18/24）, and the DCR was 91.7% （22/24）, both were higher than those of the control group [6.9% （2/29） and 51.7% （15/29） respectively], with statistically significant differences （χ²=25.92,P<0.001;χ²=9.94,P=0.002）. There were no statistically significant differences in the incidences of regorafenib-related adverse reactions such as hand-foot skin reaction [62.5% （15/24）vs.65.5% （19/29）,χ²=0.05,P=0.819], fatigue [41.7% （10/24）vs.44.8% （13/29）,χ²=0.05,P=0.817], hypertension [29.2% （7/24）vs.34.5% （10/29）,χ²=0.17,P=0.679], diarrhea [25.0% （6/24）vs.27.6% （8/29）,χ²=0.04,P=0.832], hoarseness [16.7% （4/24）vs.17.2% （5/29）,χ²=0.01,P=0.956] and proteinuria [8.3% （2/24）vs.10.3% （3/29）,χ²=0.06,P=0.803] between the two groups. The main adverse reactions related to DEBIRI-TACE in the observation group were fever, pain, nausea and vomiting,etc., which were relieved after symptomatic treatment. No serious complications such as ectopic embolism of CalliSpheres drug eluting bead occurred. By the end of the follow-up,among the 24 patients in the observation group, the median OS of patients with simultaneous liver metastases was 12 months, and that of patients with metachronous liver metastases was 22 months, with a statistically significant difference （χ²=4.29,P=0.026）. The median OS of patients with 3-5 liver metastases was 21 months, and that of patients with more than 5 liver metastases was 14 months, with a statistically significant difference （χ²=3.35,P=0.040）. The median OS of Child-Pugh grade A patients was 22 months, and that of Child-Pugh grade B patients was 13 months, with a statistically significant difference （χ²=4.22,P=0.027）. The median OS was 16 months in patients with extrahepatic metastases and 23 months in patients without extrahepatic metastases, with a statistically significant difference （χ²=7.68,P=0.013）. Cox proportional hazards model analysis showed that simultaneous liver metastases （HR=1.59, 95%CI： 1.02-2.47,P=0.031） and extrahepatic metastases （HR=1.61, 95%CI： 1.29-2.01,P=0.020） were independent risk factors influencing OS of patients in the observation group. The median PFS of the observation group was 9 months, and that of the control group was 5 months, with a statistically significant difference （χ²=7.78,P=0.005）. The median OS of the observation group was 17 months, and that of the control group was 11 months, with a statistically significant difference （χ²=16.81,P<0.001）.ConclusionDEBIRI-TACE combined with regorafenib is effective in the third-line or above treatment of unresectable colorectal cancer liver metastases, with tolerable adverse reactions. It is a safe and feasible treatment method. The prognosis of patients with simultaneous liver metastases or extrahepatic metastases is worse.

Key words:Colorectal neoplasms,Treatment outcome,Transcatheter arterial chemoembolization,Liver metastases,Regorafenib

刘松, 于广计, 王庆东. DEBIRI-TACE联合瑞戈非尼三线以上治疗结直肠癌肝转移的疗效及影响因素分析[J]. 国际肿瘤学杂志, 2022, 49(7): 400-407.

Liu Song, Yu Guangji, Wang Qingdong. Efficacy and influencing factors of DEBIRI-TACE combined with regorafenib in the third-line or above treatment of colorectal cancer liver metastases[J]. Journal of International Oncology, 2022, 49(7): 400-407.

图/表7

表1

53例CRLM患者的临床资料[$\bar{x}\pm s$±s/例（%）]"

临床特征	观察组（n=24）	对照组（n=29）	t/χ²值	P值
年龄（岁）	58.6±6.9	59.2±7.1	0.31	0.379
性别
男	15（62.5）	17（58.6）	0.08	0.773
女	9（37.5）	12（41.4）	0.08	0.773
肝转移类型
同时性	6（25.0）	7（24.1）	0.01	0.942
异时性	18（75.0）	22（75.9）	0.01	0.942
肝转移癌数目（个）
3~5	7（29.2）	9（31.0）	0.02	0.883
>5	17（70.8）	20（69.0）	0.02	0.883
肿瘤大小（cm）
<5	11（45.8）	13（44.8）	0.01	0.942
≥5	13（54.2）	16（55.2）	0.01	0.942
肝外转移
是	13（54.2）	15（51.7）	0.03	0.859
否	11（45.8）	14（48.3）	0.03	0.859
肝功能分级
Child-Pugh A	21（87.5）	25（86.2）	0.02	0.889
Child-Pugh B	3（12.5）	4（13.8）	0.02	0.889
ECOG评分（分）
0	18（75.0）	21（72.4）
1	5（20.8）	6（20.7）	0.19	0.192
2	1（4.2）	2（6.9）
原发肿瘤位置
直肠	10（41.7）	12（41.4）
左结肠	6（25.0）	7（24.1）	0.01	0.955
右结肠	8（33.3）	10（34.5）

表1

不良反应	1级	2级
发热	13（54.2）	6（25.0）
疼痛	11（45.8）	3（12.5）
恶心呕吐	8（33.3）	3（12.5）
肝功能损害	6（25.0）	1（4.2）
骨髓抑制	2（8.3）	1（4.2）
迟发型腹泻	1（4.2）	0（0）

表2

表3

两组CRLM患者使用瑞戈非尼治疗期间不良反应发生情况"

不良反应	观察组（n=24）			对照组（n=29）			χ²值	P值
不良反应	1~2级（例）	3~4级（例）	发生率（%）	1~2级（例）	3~4级（例）	发生率（%）	χ²值	P值
手足皮肤反应	13	2	62.5	16	3	65.5	0.05	0.819
乏力	8	2	41.7	12	1	44.8	0.05	0.817
高血压	7	0	29.2	10	0	34.5	0.17	0.679
腹泻	5	1	25.0	6	2	27.6	0.04	0.832
声音嘶哑	4	0	16.7	5	0	17.2	0.01	0.956
蛋白尿	2	0	8.3	3	0	10.3	0.06	0.803

表3

表4

影响24例使用DEBIRI-TACE联合瑞戈非尼治疗CRLM患者OS的单因素分析"

影响因素	例数	中位OS（月）	χ²值	P值
年龄（岁）
<60	14	16	1.57	0.163
≥60	10	19	1.57	0.163
性别
男	15	18	0.39	0.768
女	9	15	0.39	0.768
肝转移类型
同时性	6	12	4.29	0.026
异时性	18	22	4.29	0.026
肝转移癌数目（个）
3~5	7	21	3.35	0.040
>5	17	14	3.35	0.040
肿瘤大小（cm）
<5	11	20	1.38	0.194
≥5	13	18	1.38	0.194
肝外转移
是	13	16	7.68	0.013
否	11	23	7.68	0.013
肝功能分级
Child-Pugh A	21	22	4.22	0.027
Child-Pugh B	3	13	4.22	0.027
ECOG评分（分）
0	18	20	1.03	0.516
1	5	15
2	1	14
原发肿瘤位置
直肠	10	23	1.00	0.691
左结肠	6	19
右结肠	8	17

表4

因素	HR值	95%CI	P值
肝转移类型（异时性/同时性）	1.59	1.02~2.47	0.031
肝转移癌数目（3~5个/>5个）	1.21	0.93~1.56	0.174
肝功能分级（Child-Pugh A/Child-Pugh B）	0.96	0.82~1.12	0.865
肝外转移（否/是）	1.61	1.29~2.01	0.020

表5

图1

图2

参考文献22

[1]	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版)[J]. 中华消化外科杂志, 2020, 19(6): 536-588. DOI: 10.3760/cma.j.cn115610-20200504-00348. doi:10.3760/cma.j.cn115610-20200504-00348
[2]	李佳, 马晓捷, 王宇翔. 射频消融后辅助mFOLFOX6联合贝伐珠单抗方案在结直肠癌肝转移瘤中的疗效和安全性评价[J]. 国际肿瘤学杂志, 2021, 48(12): 729-734. DOI: 10.3760/cma.j.cn371439-20210416-00144. doi:10.3760/cma.j.cn371439-20210416-00144
[3]	Slesser AA, Georgiou P, Brown G, et al. The tumour biology of synchronous and metachronous colorectal liver metastases: a systematic review[J]. Clin Exp Metastasis, 2013, 30(4): 457-470. DOI: 10.1007/s10585-012-9551-8. doi:10.1007/s10585-012-9551-8
[4]	林榕生, 吴楚海, 郭颖梅, 等. 特瑞普利单抗联合贝伐珠单抗二线以上治疗MSI-H型转移性结直肠癌的疗效及安全性[J]. 国际肿瘤学杂志, 2022, 49(2): 100-105. DOI: 10.3760/cma.j.cn371439-20210409-00016. doi:10.3760/cma.j.cn371439-20210409-00016
[5]	Walter T, Hawkins NS, Pollock RF, et al. Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer[J]. J Cancer Res Clin Oncol, 2020, 146(10): 2575-2587. DOI: 10.1007/s00432-020-03315-6. doi:10.1007/s00432-020-03315-6
[6]	Akinwande O, Dendy M, Ludwig JM, et al. Hepatic intra-arterial injection of irinotecan drug eluting beads (DEBIRI) for patients with unresectable colorectal liver metastases: a systematic review[J]. Surg Oncol, 2017, 26(3): 268-275. DOI: 10.1016/j.suronc.2017.05.003. doi:S0960-7404(17)30054-3pmid:28807246
[7]	Zhang G, Tang R, Wu J, et al. Initial experience of drug-eluting bead transarterial chemoembolization with CalliSpheres^®microspheres in treating liver metastases patients[J]. Transl Cancer Res, 2020, 9(3): 1630-1639. DOI: 10.21037/tcr.2020.01.61. doi:10.21037/tcr.2020.01.61
[8]	Grathey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastati colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial[J]. Lancet, 2013, 381(9863): 303-312. DOI: 10.1016/S0140-6736(12)61900-X. doi:10.1016/S0140-6736(12)61900-X
[9]	Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with pre-viously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2015, 16(6): 619-629. DOI: 10.1016/S1470-2045(15)70156-7. doi:10.1016/S1470-2045(15)70156-7
[10]	Sutphin PD, Ganguli S. Interventional treatment of hepatic metastases from colorectal cancer[J]. Semin Intervent Radiol, 2020, 37(5): 492-498. DOI: 10.1055/s-0040-171919. doi:10.1055/s-0040-171919
[11]	Zhang X, Zhou J, Zhu DD, et al. CalliSpheres^®drug-eluting beads (DEB) transarterial chemoembolization (TACE) is equally efficient and safe in liver cancer patients with different times of previous conventional TACE treatments: a result from CTILC study[J]. Clin Transl Oncol, 2019, 21(2): 167-177. DOI: 10.1007/s12094-018-1902-8. doi:10.1007/s12094-018-1902-8pmid:30003530
[12]	Zhao GS, Li C, Liu Y, et al. 350-560 μm gelatin sponge particles combined with transcatheter arterial chemoembolization for the treatment of elderly hepatocellular carcinoma: the safety and efficacy[J]. Medicine (Baltimore), 2017, 96(16): e6629. DOI: 10.1097/MD.0000000000006629. doi:10.1097/MD.0000000000006629
[13]	Gruber-Rouh T, Naguib NN, Eichler K, et al. Transarterial chemoembolization of unresectable systemic chemotherapy-refractory liver metastases from colorectal cancer: long-term results over a 10-year period[J]. Int J Cancer, 2014, 134(5): 1225-1231. DOI: 10.1002/ijc.28443. doi:10.1002/ijc.28443pmid:23960002
[14]	Li J, Wang N, Shi C, et al. Short-term efficacy and safety of callispheres drug-loaded microsphere embolization in primary hepatocellular carcinoma[J]. J Cancer Res Ther, 2021, 17(3): 733-739. DOI: 10.4103/jcrt.JCRT_1848_20. doi:10.4103/jcrt.JCRT_1848_20
[15]	Zhao G, Liu S, Chen S, et al. Assessment of efficacy and safety by CalliSpheres versus HepaSpheres for drug-eluting bead transarterial chemoembolization in unresectable large hepatocellular carcinoma patients[J]. Drug Deliv, 2021, 28(1): 1356-1362. DOI: 10.1080/10717544.2021.1943057. doi:10.1080/10717544.2021.1943057
[16]	Szemitko M, Golubinska-Szemitko E, Warakomski M, et al. Evalua-tion of CRC-metastatic hepatic lesion chemoembolization with irinotecan-loaded microspheres, according to the site of embolization[J]. J Pers Med, 2022, 12(3): 414. DOI: 10.3390/jpm12030414. doi:10.3390/jpm12030414
[17]	Cao F, Zheng JP, Luo J, et al. Treatment efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization versus regorafenib monotherapy in colorectal cancer liver metastasis patients who fail standard treatment regimens[J]. J Cancer Res Clin Oncol, 2021, 147(10): 2993-3002. DOI: 10.1007/s00432-021-03708-1. doi:10.1007/s00432-021-03708-1
[18]	Patel AK, Abhyankar R, Brais LK, et al. Trifluridine/tipiracil and regorafenib in patients with metastatic colorectal cancer: a retrospective study at a tertiary oncology center[J]. Oncologist, 2021, 26(12): e2161-e2169. DOI: 10.1002/onco.13942. doi:10.1002/onco.13942
[19]	Ducreux M, Petersen LN, Öhler L, et al. Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study[J]. Eur J Cancer, 2019, 123: 146-154. DOI: 10.1016/j.ejca.2019.09.015. doi:S0959-8049(19)30737-3pmid:31698328
[20]	Alexander BM, Othus M, Caglar HB, et al. Tumor volume is a prognostic factor in non-small-cell lung cancer treated with chemoradiotherapy[J]. Int J Radiat Oncol Biol Phys, 2011, 79(5): 1381-1387. DOI: 10.1016/j.ijrobp.2009.12.060. doi:10.1016/j.ijrobp.2009.12.060
[21]	Dane F, Ozgurdal K, Yalçın Ş, et al. Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study[J]. BMJ Open, 2020, 10(3): e027665. DOI: 10.1136/bmjopen-2018-027665. doi:10.1136/bmjopen-2018-027665
[22]	Peng Z, Cao G, Hou Q, et al. The comprehensive analysis of efficacy and safety of CalliSpheres^®Drug-Eluting beads transarterial chemoembolization in 367 liver cancer patients: a multiple-center, cohort study[J]. Oncol Res, 2020, 28(3): 249-271. DOI: 10.3727/096504019X15766663541105. doi:10.3727/096504019X15766663541105