Efficacy and influencing factors of DEBIRI-TACE combined with regorafenib in the third-line or above treatment of colorectal cancer liver metastases

doi:10.3760/cma.j.cn371439-20220318-00077

Abstract

Abstract:

Objective To 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. Methods From 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. Results After 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）. Conclusion DEBIRI-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

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.

Figures/Tables 7

References 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)30054-3 pmid: 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/s12094-018-1902-8 pmid: 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.28443 pmid: 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)30737-3 pmid: 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

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）

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）

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