Incidence and Risk of Cardiovascular Toxicity with Fruquintinib in Metastatic Colorectal Cancer: a Meta-analysis

doi:10.12114/j.issn.1007-9572.2024.0203

Abstract

Abstract:

Background

38.4% of patients with colorectal cancer died from non-cancer disease, with cardiovascular disease being the most important cause, accounting for 20.3% of the total deaths. Cardiovascular toxicity associated with targeted therapy is not uncommon, most notably hypertension.

Objective

The study aimed to determine the overall incidence and risk of cardiovascular toxicity associated with fruquintinib in metastatic colorectal cancer.

Methods

We searched CNKI, Wanfang Data, CBM, PubMed, Embase, Web of Science and Cochrane Library databases for single-arm clinical trials and randomized controlled trials (RCTs) relevant to fuquintinib therapy in patients with metastatic colorectal cancer. The search time limit was from the establishment of the databases to May 2024. Literature screening, data extraction, and quality evaluation were performed independently by two investigators. The meta-analysis was conducted using R 4.3.3 software.

Results

Eight articles involving six single-arm clinical trials and three randomized controlled trials were included. The meta-analysis results showed that the incidence rates of all-grade hypertension and hemorrhage were 35% (95%CI=0.25-0.45) and 24% (95%CI=0.10-0.37), respectively. For high-grade events, the rates were 15% for hypertension (95%CI=0.10-0.20), 1% for hemorrhage (95%CI=0-0.02), 3% for embolic and thrombotic events (95%CI=0.02-0.05), and 1% for cardiac diseases (95%CI=0-0.02). Fruquintinib was associated with increased risks for both all-grade and high-grade hypertension, as well as all-grade hemorrhage, with RR of 3.93 (95%CI=2.95-5.24), 12.33 (95%CI=5.31-28.63), and 1.84 (95%CI=1.36-2.50) respectively, but not for high-grade hemorrhage (RR=1.06, 95%CI=0.35-3.23), embolic and thrombotic events (RR=3.35, 95%CI=0.89-12.55), or cardiac diseases (RR=0.62, 95%CI=0.18-2.14) .

Conclusion

The use of fruquintinib is associated with a significantly increased risk of developing cardiovascular toxicity, primarily for lower-grade events, in patients with metastatic colorectal cancer.

Key words: Metastatic colorectal cancer, Fruquintinib, Cardiovascular toxicity, Meta-analysis

摘要：

背景

38.4%的结直肠癌患者死于非癌症疾病，其中心血管疾病是最主要原因，占总死亡人数的20.3%。靶向治疗相关的心血管毒性并不少见，最突出的为高血压。

目的

本研究旨在探讨转移性结直肠癌患者呋喹替尼治疗相关心血管毒性的发生率和风险。

方法

系统检索中国知网、万方数据知识服务平台、中国生物医学文献数据库、Web of Science、PubMed、Cochrane Library、Embase数据库中有关转移性结直肠癌患者呋喹替尼治疗的单臂临床试验和随机对照试验，检索时限为建库至2024年5月。由2名研究者独立进行文献筛选、资料提取及质量评价，使用R 4.3.3软件进行Meta分析。

结果

共纳入8篇文献，涉及6项单臂临床试验、3项随机对照试验。Meta分析结果显示：全级别高血压和出血的发生率为35%（95%CI=0.25~0.45）和24%（95%CI=0.10~0.37）。在高级别事件中，高血压发生率为15%（95%CI=0.10~0.20），出血发生率为1%（95%CI=0~0.02），血栓栓塞发生率为3%（95%CI=0.02~0.05），心脏疾病发生率为1%（95%CI=0~0.02）。呋喹替尼与全级别、高级别高血压及全级别出血的风险增加相关，RR分别为3.93（95%CI=2.95~5.24）、12.33（95%CI=5.31~28.63）及1.84（95%CI=1.36~2.50），但与高级别的出血（RR=1.06，95%CI=0.35~3.23）、血栓栓塞事件（RR=3.35，95%CI=0.89~12.55）及心脏疾病（RR=0.62，95%CI=0.18~2.14）无关。

结论

呋喹替尼与转移性结直肠癌患者心血管毒性发生率和风险增加显著相关，但主要针对的是低级别事件。

关键词: 转移性结直肠癌, 呋喹替尼, 心血管毒性, Meta分析

CLC Number:

R 735.34

WANG Xiaolin,LI Qiuyue,ZHOU Yanjun, et al. Incidence and Risk of Cardiovascular Toxicity with Fruquintinib in Metastatic Colorectal Cancer: a Meta-analysis[J]. Chinese General Practice, 2025, 28(23): 2934-2940. DOI: 10.12114/j.issn.1007-9572.2024.0203.
王笑林,李秋月,周彦君等. 转移性结直肠癌患者呋喹替尼治疗相关心血管毒性发生率和风险的Meta分析[J]. 中国全科医学, 2025, 28(23): 2934-2940. DOI: 10.12114/j.issn.1007-9572.2024.0203.

Figures/Tables 15

Figure 1 Literature screening flowchart

Table 1 Characteristics of the included studies

第一作者	发表时间（年）	试验阶段	治疗方案	暴露时间[M（P₂₅，P₇₅）或M（Min，Max），月]	样本量（例）	随访时间（月）	中位年龄[M（P₂₅，P₇₅）或M（Min，Max），岁]	NCI-CTCAE版本	MINORS分数（分）	结局指标
LI^[2]	2018	Ⅲ期	呋喹替尼+BSC	3.7（0.1~21.9）	278	13.3	55（23~75）	5.0		①②③④
			安慰剂+BSC	1.8（0.1~11.1）	137	13.2	57（24~74）
DASARI^[4]	2023	Ⅲ期	呋喹替尼+BSC	3.1（1.8~5.6）	456	11.3	64（56~70）	5.0		①②③ ④⑤⑥
			安慰剂+BSC	1.8（1.0~2.3）	230	11.2	64（56~69）
XU^[9]	2017	Ⅱ期	呋喹替尼+BSC	3.2	47	NR	50（25~69）	4.03		①②⑤⑥
			安慰剂+BSC	0.8	24	NR	54（38~70）
TAN^[10]	2023	Ⅱ期	呋喹替尼	NR	29	NR	69（65~77）	4.0	14	①②③④
ZHAO^[11]	2023	Ⅱ期	呋喹替尼+PD-1	7.5（3~18）	20	13.7	52（30~71）	5.0	14	①②
MA^[12]	2023	Ⅱ期	呋喹替尼+PD-1+粪便移植	NR	19	NR	62（42~79）	5.0	12	①②
GUO^[13]	2023	Ⅱ期	呋喹替尼+PD-1	NR	44	NR	50（25~69）	4.03	13	①②
XU^[9]	2017	Ⅰb期	呋喹替尼	NR	42	NR	55.5（33~70）	4.03	13	①②⑤⑥
LI^[3]	2024	Ⅳ期	呋喹替尼或呋喹替尼+PD-1或呋喹替尼+化疗	2.7（1.4~5.7）	2798	NR	60（52~67）	4.03	12	①②

Table 2 Quality assessment of the randomized controlled trials

第一作者	随机化过程中产生的偏倚	偏离预期干预措施而导致的偏倚	由于结果数据缺失引起的偏倚	结果测量偏倚	报告结果选择偏倚	总体偏倚
LI^[2]	存在一定风险	低	低	低	低	低
DASARI^[4]	存在一定风险	低	低	低	低	低
XU^[9]	存在一定风险	低	低	低	低	低

Figure 2 Forest plot of all-grade hypertension incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 3 Forest plot for comparing RR of all-grade hypertension between trial group and control group

Figure 4 Forest plot of high-grade hypertension incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 5 Forest plot for comparing RR of high-grade hypertension between trial group and control group

Figure 6 Forest plot of all-grade hemorrhage incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 7 Forest plot for comparing RR of all-grade hemorrhage between trial group and control group

Figure 8 Forest plot of high-grade hemorrhage incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 9 Forest plot for comparing RR of high-grade hemorrhage between trial group and control group

Figure 10 Forest plot of high-grade embolic and thrombotic events incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 11 Forest plot for comparing RR of high-grade embolic and thrombotic events between trial group and control group

Figure 12 Forest plot of high-grade cardiac disease incidence for fuquintinib therapy in patients with metastatic colorectal cancer

Figure 13 Forest plot for comparing RR of high-grade cardiac disease between trial group and control group

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