Colorectal cancer is the third most common malignant tumor in the world, with its mortality is only inferior to that of lung cancer (1). More than 20% of patients having distant metastasis at the time of diagnosis, with another 25% of patients will have metastasis after radical surgery (2). The standard therapies for patients with metastatic colorectal cancer are mainly cytotoxic drugs and targeted drugs, including chemotherapy based on fluorouracil, oxaliplatin and irinotecan, and targeted therapy for vascular endothelial growth factor (VEGF) and epidermal growth factor receptors (EGFR). In recent years, the treatment of colorectal cancer has evolved into a multidisciplinary team (MDT) model. The quality of life of metastatic colorectal cancer patients has been significantly improved and their survival time has been significantly prolonged. Many patients have maintained good physical strength scores after the failure of first- and second-line treatment. However, at present, the drugs used in the third-line treatment of metastatic colorectal cancer are very limited. In China, fruquintinib has been approved for the third-line treatment of metastatic colorectal cancer. Fruquintinib is an efficient and highly selective oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), which has a strong inhibitory effect on a variety of metastatic tumors by inhibiting angiogenesis (3). The FRESCO study-a multicenter, randomized, double-blind, placebo-controlled phase III trial-showed that, compared with the placebo group, fruquintinib had dual benefits in overall survival (OS) (median OS 9.3 vs. 6.6 months, P<0.001) and progression-free survival (PFS) (median PFS 2.7 vs. 1.9 months, P<0.001), and safety was controllable (4). The common adverse reactions of fruquintinib include hypertension, hand-foot syndrome, albuminuria, hematuria and fatigue.
In this article, we report the first case of aortic dissection potentially caused by fruquintinib in advanced metastatic colorectal cancer and focus on the possible mechanism of fruquintinib leading to aortic dissection. We present the following case in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1872/rc).
A 61-year-old male patient with sigmoid cancer presented to our hospital for treatment in January 2017. He had quitted smoking for more than 20 years before hospitalization and had no history of drinking, hypertension, diabetes, coronary heart disease or Marfan syndrome. After diagnosis, he underwent radical sigmoidectomy. Lung metastasis was found 18 months after operation, then the patients received 10 cycles of bevacizumab with FOLFIRI (5-FU/leucovorin/irinotecan) first-line chemotherapy and 4 cycles of bevacizumab combined with ratetrexed second-line therapy. Nevertheless, none of them controlled the progress of the disease. The patient received three cycles of immunization combined with targeted third-line therapy (bevacizumab 260 mg + nivolumab 140 mg) in May 2021. Re-examination after 3 cycles indicated progressive disease (PD). In July 2021, fruquintinib (3 mg q.d.) was replaced with nivolumab. We assessed bleeding and cardiovascular risk factors before the replacement of fruquintinib, the baseline blood pressure fluctuated from 90 to 115/60 to 75 mmHg (Figure S1), and the electrocardiogram was not significantly abnormal. Furthermore, there were no signs of aortic dissection and thoracic aortic aneurysm in the baseline chest computed tomography (CT) (Figure 1A). During the treatment, the blood pressure was monitored regularly, and the highest blood pressure was in 142/80 mmHg. In September 2021, the patient experienced a sudden onset of tear-like chest pain, with back radiation pain and sweating, and his blood pressure rose to 183/100 mmHg (Figure S1), which could not be relieved after taking nitroglycerin. Emergency CT angiography showed aortic dissection (Stanford type B) (Figure 1B). Thereafter, the patient received nitroglycerin as anti-hypertensive medication in the emergency department and was transferred to vascular surgery to receive nifedipine combined with metoprolol to lower blood pressure, and stent-graft intervention was performed in September 2021 (Figure 1C). Using anticoagulants and antihypertensive drugs after operation, the blood pressure control was fair. Then, we evaluated the possible causal relationship between adverse events and drugs with reference to Naranjo probability scale, which was assessed as probable (Tables S1,S2), and therefore the patients discontinued the treatment with fruquintinib. Postoperative CT reexamination showed that the condition was stable (Figure 1D). In January 2022, the patient received 3 cycles of bevacizumab combined with S-1. By the last follow-up (February 16, 2022), the patient had no further arterial dissection. The patient’s treatment timeline is as follows (Figure 2).
All procedures performed in this study were in accordance with the ethical standards of the Zhejiang Provincial People’s Hospital research committee(s) (approval No. QT2022269) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
VEGF, VEGFR, c-kit, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) expressed on the surface of vascular endothelial cells play an important role in maintaining normal vascular endothelial cell development and homoeostasis (5-8). Targeting these molecules can inhibit the formation of new blood vessels, and also produce different side effects. Aortic dissection associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) has been reported in Japan as early as 2017 that increases the risk of aortic dissection during systemic exposure to vascular endothelial growth factor receptor pathway inhibitors (VPIs) (9). In December 2018, Health Canada also issued a warning of the potential risk of abnormal structural changes (dissection and aneurysm, including ruptured) in the arterial wall of VEGFR TKIs, and updated product safety information for all VEGFR TKIs drugs in June 2020 to inform them of this risk (https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/june-2020.html). However, as far as we know, this is the first report of fruquintinib-associated aortic dissection.
Aortic dissection is a very serious cardiovascular disease. Within 48 hours after onset, the mortality rate of untreated aortic dissection is close to 1% per hour (10). Even after surgical repair, the mortality rate of acute aortic dissection is still high. Hypertension is one of the main causes of aortic dissection (11). Meanwhile, hypertension is also the main adverse reaction of vascular endothelial growth factor inhibitors (VEGFIs). VEGFIs can increase hypertension in a variety of ways (Figure 3). It is reported that up to 80% of patients who use VEGFIs for the first time have elevated blood pressure (12). In order to find out the relationship between these factors, we reviewed all reports of VEGFI-associated aortic dissection and found that not all cases describing TKI-induced aortic dissection had hypertension before the onset of aortic dissection (Table 1), which was consistent with this case we reported. Based on this fact, we speculated that VEGF-VEGFR signal pathway (VSP) may also play an important role in fruquintinib-related aortic dissection in addition to hypertension.
|Drug class||Agent||Publication time||Region||Authors||Tumor type||History of hypertension||Blood pressure during TKI treatment||Target(s)||Indications||Reference|
|Tyrosine kinase inhibitor||Sunitinib||2015||Brazil||Formiga et al.||Renal cell carcinoma||No||<140/90 mmHg||VEGFR-1, -2, -3; PDGFR; c-Kit; RET; FLT3||Gastrointestinal stromal tumour, renal cell carcinoma, pancreatic neuroendocrine tumour||(13)|
|Sunitinib||2010||France||Edeline et al.||Renal cell carcinoma||Yes||>140/90 mmHg; long-term control of blood pressure with nebivolol||VEGFR-1, -2, -3; PDGFR; c-Kit; RET; FLT3||Gastrointestinal stromal tumour, renal cell carcinoma, pancreatic neuroendocrine tumour||(14)|
|Axitinib||2015||Japan||Niwa et al.||Renal cell carcinoma||No||<140/90 mmHg||VEGFR-1, -2, -3; PDGFR; c-Kit||Renal cell carcinoma||(15)|
|Anlotinib||2020||China||Jiang et al.||Lung squamous cell carcinoma||No||<140/90 mmHg||VEGFR-2, -3; PDGFR; FGFR1-4; c-Kit; RET||Thyroid cancer, renal cell carcinoma, gastric cancer, esophageal squamous cell carcinoma||(16)|
|Sorafenib||2017||China||Xu et al.||Hepatocellular carcinoma||Yes||>140/90 mmHg; long-term use of calcium channel blockers to lower blood pressure||VEGFR-2, -3; PDGFR; FlT3; c-Kit; Raf||Hepatocellular carcinoma, renal cell carcinoma, melanoma||(17)|
|Sunitinib||2017||Canada||Hatem et al.||Gastrointestinal stromal tumor||No||<140 mmHg||VEGFR-1, -2, -3; PDGFR; c-Kit; RET; FLT3||Gastrointestinal stromal tumor, renal cell carcinoma, pancreatic neuroendocrine tumour||(18)|
|Sorafenib and axitinib||2018||Japan||Takada et al.||Renal cell carcinoma||No||<140/90 mmHg; control of blood pressure by irbesartan and azelnidipine||VEGFR-2, -3; PDGFR; FlT3; c-Kit; Raf||Hepatocellular carcinoma, renal cell carcinoma, melanoma||(19)|
|Monoclonal antibody||Bevacizumab (+ docetaxel, thalidomide, and prednisone)||2008||USA||Aragon-Ching et al.||Prostate cancer||Yes||>160/100 mmHg; blood pressure is controlled by diuretics, calcium channel blockers and hydrazine||VEGF-A||Colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, renal cell carcinoma, cervical carcinoma||(20)|
TKI, tyrosine kinase inhibit.
The histopathological features of aortic dissection are mainly media degeneration, which is composed of smooth muscle cells (SMCs) and extracellular matrix (ECM), which mainly produces aortic tension and elasticity. The pathological process of aortic dissection includes the decrease of vascular SMCs, the rupture of elastic fibers and the degradation of ECM (21). These processes are related to oxidative stress involved in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (22,23). Recent research has found that inhibition of VSP may increase the production of reactive oxygen species (ROS) by inducing the activation of NADPH oxidase (NOX) and down-regulation of antioxidants in endothelial cells (7). The continuously increasing level of ROS will eventually induce apoptosis of vascular SMCs (24). NOX1 can inhibit TIMP-1 expression induced by angiotensin II (Ang-II), change the balance of protease/antiprotease, promote the degradation of elastin and basement membrane of vascular wall, and negatively regulate the expression of Fibulin-5 (25). Fibulin-5 is an extracellular protein, which is reported to be related to the polymerization and assembly of elastin (26). Previous study has found that decreased expression of Fibulin-5 in patients with thoracic aortic dissection (TAD) may lead to elastic fiber breakage and reduced elastin content, which in turn promotes the progression of aortic dissection (27). Furthermore, the production of ROS can inhibit the binding of Fibulin-5 and elastin, so it is easy to cause disordered arrangement of elastic fibers, loose structure, which can affect the structure of aortic media, and make the weakened aorta easy to spontaneously tear and form aortic dissection (25). VSP can not only affect the formation of elastic fibers through Fibulin-5, but also degrade ECM through matrix metalloproteinases (MMPs), destroy elastic fibers and vascular SMCs, damage aortic media and induce aortic dissection (28). The normal physiological structure of ECM must rely on the balance and coordination of MMPs and tissue inhibitors of metalloproteinases (TIMPs), and the imbalance between MMPs and TIMPs will lead to excessive degradation of ECM (29). MMPs is a kind of zinc-dependent endopeptidase protein (30). Only after being activated by enzyme can various components of ECM begin to be degraded, which are secreted in vascular endothelial cells, SMCs, macrophages, neutrophils and so on. MMP2 and MMP9 have been found to be key factors in the occurrence of aortic dissection (31). The expression of MMP9 is regulated by fork head box protein O1 (FOXO1). The expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) is regulated by GATA1. Protein Kinase B (AKT) can phosphorylate FOXO1 and GATA1 and regulate their transcriptional activity to MMP9 and TIMP-1 (Figure 4). In Akt-2 gene deficient mice, the expression of MMP9 was significantly increased, the expression of TIMP-1 was significantly decreased, the elastic fibers of aortic wall were abnormal, and the medial thickness was decreased. When challenged with Ang-II, these mice developed aortic aneurysms, dissections, and ruptures similar to those in the human thorax and abdomen (32). At the same time, targeting AKT signal can also inhibit the proliferation and migration of vascular SMCs (33). In addition, inhibition of VSP would impair nitric oxide-mediated vasodilation, leading to arterial stiffness and making it more prone to aortic dissection (34).
Here, we reported the first case of fruquintinib-associated aortic dissection, and discussed the possible mechanism of VSP inhibitors leading to aortic dissection. As a new drug, fruquintinib brings not only clinical benefits, but also brings some adverse reactions. How to manage these adverse reactions, especially serious cardiovascular toxicity, such as aortic dissection, is still a problem that needs further exploration.
Funding: This work was supported by
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1872/rc
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1872/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1872/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Zhejiang Provincial People’s Hospital research committee(s) (approval No. QT2022269) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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