Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs (Review)
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- Published online on: February 23, 2021 https://doi.org/10.3892/ol.2021.12576
- Article Number: 315
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Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Angiogenesis is a crucial enabling process for tumor growth and metastasis (1). The vascular endothelial growth factor (VEGF) signaling pathway serves a key role in the angiogenesis of solid tumors. The VEGF signaling system is complex and consists of five related ligands: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PLGF). They bind with different specificities to three receptor tyrosine kinases: VEGFR1, VEGFR2 and VEGFR3 (2). VEGF pathway-targeting agents include monoclonal antibodies, such as bevacizumab and ramucirumab, and small-molecule tyrosine kinase inhibitors (TKIs), such as sunitinib, sorafenib, apatinib and regorafenib. Monoclonal antibodies block the binding of VEGF to VEGFR and prevent activation of intracellular signal transduction (3). Small-molecule TKIs act on the intracellular domain of the endothelial receptor, where they inhibit the initial phosphorylation step following the ligand-receptor interaction (4). These drugs can slow down the growth of tumors effectively and improve the progression-free survival (PFS) and overall survival (OS) of patients with cancer (2).
However, a previous study has reported that antiangiogenic therapy increased arterial blood pressure (BP), raised the risk of new-onset hypertension, or worsened existing hypertension (5). The mechanism underlying the antiangiogenic drug-induced hypertension remains controversial. The current hypotheses include decreased nitric oxide (NO) (6), increased endothelin-1 (7), capillary rarefaction (8) and activation of the renin-angiotensin-aldosterone system (RAAS) (9) (Fig. 1). According to the National Cancer Institute's common terminology criteria for adverse events (NCI CTCAE), version 5.0 (10), hypertension for adults can be classed into five categories depending on its severity (Table I). Subsequently, the presence of hypertension can lead to a reduction or interruption of antiangiogenic therapy (11).
 | Table I.Definitions of hypertension grades for adults according to the National Cancer Institute's common terminology criteria for adverse events version 5.0. |
Considering the complex relationship between antihypertensive drugs and cancer, the cancer type, the pre-existing comorbidities and the presence of contraindications should be considered when selecting antihypertensive drugs for patients with cancer (12). Currently, angiotensin-converting enzyme inhibitors (ACEIs) are the preferred first-line option in treatment of hypertension induced by anti-VEGF chemotherapy, given its improved outcome in several types of cancer (13). On the other hand, several retrospective studies (14,15) have found that the appearance of hypertension during antiangiogenic therapy might be associated with improved survival. Thus, it remains unclear whether hypertension should be considered as an adverse reaction or as a positive prognostic marker in patients with various types of cancer. The present review aimed to explore the relationship between hypertension and antiangiogenic therapy in different types of tumors.
Relationship between antiangiogenic therapy and hypertension in renal cell cancer
In total, nine studies have reported the association between hypertension and antiangiogenic drugs, including sunitinib, bevacizumab, sorafenib, axitinib and pazopanib, in renal cell carcinoma (RCC). Of these nice studies, seven were prospective studies (16–22) and two were retrospective studies (23,24), involving a total of 6,083 patients (Table II).
Hypertension as an adverse event of antiangiogenic therapy
Four phase III, randomized, double-blind, placebo-controlled trials (16–18,20) and a phase II, randomized, double-blind trial (19) demonstrated that antiangiogenic drugs increased the risk of hypertension in patients with RCC. Increased BP due to axitinib gradually dropped to baseline after the end of treatment (19). The incidence of hypertension in the TKI treatment group (33.2%) was higher compared with the group treated with monoclonal antibodies (27.4%). It is worth noting that the axitinib group had the highest incidence of severe hypertension [≥grade (G) 3 hypertension]. Compared with the aforementioned studies, hypertension was more frequently observed in the Donskov et al study (24), which could be attributed to the different definition of hypertension used. Furthermore, the risk of hypertension may be dose-dependent (19), however, no association with nephrectomy was observed (16). Thus, further research is needed to provide more evidence for the association between antiangiogenic treatment and the risk of hypertension in patients with RCC.
Hypertension as a biomarker of antiangiogenic therapy
Two studies (22,23) found that significant hypertension (≥G2) may be a potential biomarker associated with greater efficacy. In addition, another study using real-world data from Japan demonstrated that patients with hypertension have a higher 24-week OS and PFS rate (21). Donskov et al (24) found that on-treatment hypertension is an independent biomarker of sunitinib efficacy. These studies did not report the median time of hypertension-onset. However, Goldstein et al (25) found that hypertension caused by pazopanib or sunitinib was not a biomarker in the treatment of metastatic RCC.
Relationship between antiangiogenic therapy and hypertension in gastric cancer and gastroesophageal junction cancers
As an adjuvant treatment of gastric cancer, antiangiogenic drugs significantly prolong the survival of patients with advanced or metastatic gastric cancer (GC) in addition to gastroesophageal junction carcinoma (GEJ), and hypertension is a common adverse reaction that cannot be ignored. Five studies have reported the association between hypertension and antiangiogenic drugs, including apatinib and ramucirumab, of which, four were prospective studies (26–29) and one was a retrospective study (15). In total, 1,700 patients were included (Table III).
| Table III.Association between anti-angiogenic drugs and hypertension in gastric and gastroesophageal junction cancer. |
Hypertension as an adverse event of antiangiogenic therapy
Two double-blind, randomized, placebo-controlled, phase III trials for ramucirumab (27,28) and the phase II and III studies for apatinib (26,29) showed that ramucirumab and apatinib increased the risk of ≥G3 hypertension in patients with GC or GEJ carcinoma. The incidence of hypertension in the TKI treatment group (36.80%) was higher compared with the group treated with monoclonal antibodies (22.78%). However, the incidence of severe hypertension in the monoclonal antibody treatment group (11.37%) was higher compared with the TKI-treated group (6.32%). Of note, the incidence of severe hypertension was higher in the dose of 425 mg twice daily compared with the dose of 850 mg once-daily regimen (26), but this comparison lacked statistical significance.
Hypertension as a biomarker of effective antiangiogenic therapy
A retrospective cohort study of 269 patients demonstrated that the presence of hypertension within the first four weeks of antiangiogenic therapy was associated with prolonged median overall survival (15), suggesting that hypertension is an early prognostic marker. However, further studies are required to support this conclusion.
Relationship between antiangiogenic therapy and hypertension in lung cancer
Bevacizumab is the most widely used antiangiogenic drug for lung cancer treatment. Twelve studies have reported the association between hypertension and approved antiangiogenic drugs, including fruquintinib, crediranib anlotinib and bevacizumab. There are seven prospective studies (30–36), two retrospective studies (14,37) and three meta-analyses (38–40). A total of 1,1291 patients were included (Table IV).
Hypertension as an adverse event of antiangiogenic therapy
Bevacizumab increased the risk of severe hypertension in the high-dose group (15 mg/kg) (32,39) and amongst female patients (41). There was no significant difference between different races (30), pathological types (38) and age (42). Discontinuation of medication due to hypertension was extremely rare (30,39). Based on these data, it was found in the present study that the incidence of hypertension in the TKI treatment group (59.72%) was higher compared with the group treated with the monoclonal antibodies (28.61%). The incidence of hypertension was the highest in the anlotinib group (67.3%). A total of 13.6% patients developed severe hypertension during therapy. Notably, 23% of patients developed severe hypertension when receiving bevacizumab plus erlotinib (34).
Hypertension as a biomarker of antiangiogenic therapy
Two studies of bevacizumab (14,37) and one study of cediranib (36) suggested that the early development of hypertension was associated with clinical benefit.
Relationship between antiangiogenic therapy and hypertension in colorectal cancer
Antiangiogenic therapy improved the overall survival of patients with colorectal cancer, but its benefit is offset partially by adverse events, such as hypertension. Thirteen studies have reported significant associations between hypertension and antiangiogenic drugs, including bevacizumab, ramucirumab and fruquintinib. There are six prospective studies (43–48), three retrospective studies (14,49,50), three meta-analyses (51–53) and one cohort study (54), including a total of 22,639 patients (Table V).
Hypertension as an adverse event of antiangiogenic therapy
A meta-analysis of 10,180 participants treated with bevacizumab (51), two randomized controlled studies for regorafenib (47) and a phase III controlled trial for ramucirumab (55) showed that these drugs increased the incidence of severe hypertension in patients with colorectal cancer. Hypertension caused by antiangiogenic drugs was associated with age (43,56,57) and regimen (58), but no association was observed with VEGF-D levels (55), race (59), cancer stage (45) or treatment line (47,48). Based on the aforementioned studies, the incidence of severe hypertension in the monoclonal antibodies group (13.11%) was higher than the TKI group (9.14%). Notably, bevacizumab was less likely to induce severe hypertension in elderly patients (age, ≥75 years) (43,56,57).
Hypertension as a biomarker of antiangiogenic therapy
Three retrospective studies (14,49,50) and a cohort study (54) of bevacizumab showed that early developing hypertension may be a predictive marker for the efficacy of bevacizumab.
Examples of trials that did not increase the risk of hypertension
Other studies have reported that bevacizumab did not significantly increase the risk of severe hypertension in patients receiving the drug (60,61) and patients who were aged ≥70 (57). However, the former conclusion may have selection bias, because amongst the patients who have previously received bevacizumab treatment, only patients who have not developed severe hypertension receive bevacizumab treatment again.
Relationship between antiangiogenic therapy and hypertension in hepatocellular carcinoma
Antiangiogenic drugs have an important role in the treatment of hepatocellular carcinoma (62). Five studies have reported the association between hypertension and antiangiogenic drugs, including cabozantinib, regorafenib, sorafenib and ramucirumab, in hepatocellular carcinoma. There are four prospective studies (63–66) and one retrospective study (67). A total of 2,272 patients were included (Table VI).
Hypertension as an adverse event of antiangiogenic therapy
Four phase III, randomized, double-blind, placebo-controlled trials of antiangiogenic drugs, including cabozantinib, regorafenib and ramucirumab, reported an increasing risk of severe hypertension in the drug-treated group, with an incidence of 13–16% (63–66). Based on the given data, it was found in the present study that the incidence of severe hypertension in the TKI-treated group (14.51%) was moderately greater compared with the monoclonal antibodies-treated group (13.66%).
Hypertension as a biomarker of antiangiogenic therapy
One retrospective study of 38 patients suggested that hypertension within two weeks of therapy initiation may be a positive predictor of the anticancer efficacy of sorafenib in patients with hepatocellular carcinoma (67).
Examples of trials that did not increase the risk of hypertension
Three multicenter, phase III, double-blind, placebo-controlled trials showed that sorafenib did not significantly increase the risk of severe hypertension in patients with advanced hepatocellular carcinoma (68–70). This may be a unique manifestation of sorafenib in hepatocellular carcinoma.
Relationship between antiangiogenic therapy and hypertension in breast cancer
Antiangiogenic agents have been used extensively for the treatment of breast cancer, but high rates of treatment-induced hypertension have been reported (71). Six studies have reported the association between hypertension and antiangiogenic drugs including, bevacizumab and axitinib, in breast cancer. There are four prospective studies (72–75), one retrospective study (76) and one meta-analysis (77), with a total of 7,414 patients included (Table VII).
Hypertension as an adverse event of antiangiogenic therapy
A meta-analysis of five clinical trials reported that bevacizumab increased the risk of severe hypertension (77). Severe hypertension was more frequent in the high-dose group (73) and in some specific genotypes (76). In specific, Schneider et al (76) demonstrated that those with VEGF-1498TT and VEGF-634CC genotypes were largely protected from severe hypertension. There was no clear correlation between severe hypertension and baseline blood pressure (78). Based on the given data, it was found in the present study that the incidence of severe hypertension in the TKI-treated group (17.5%) was higher compared with the monoclonal antibodies-treated group (6.6%).
Hypertension as a biomarker of antiangiogenic therapy
Biomarker analysis of the Eastern Cooperative Oncology Group clinical trial E2100 demonstrated that patients with severe hypertension had a superior median overall survival, and that the VEGF-2578 AA genotype was associated with improved outcome (76). Another study of apatinib showed that the predictive effect of hypertension was not related to the grade of hypertension (75).
Discussion
The present brief review examined the association between hypertension and antiangiogenic therapy in different types of cancer. There are several key findings reported in the present review. First, the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancer. Based on the analyzed data, the incidence of hypertension (33.39%) was the highest in lung cancer. In addition, the incidence of severe hypertension was the highest in hepatocellular carcinoma (13.48%) and the lowest in breast cancer (7.1%). Second, there was no significant difference in the incidence of hypertension between monoclonal antibodies and small molecule TKI treatments. Of note, the use of several novel TKIs has been associated with a higher incidence of severe hypertension, such as axitinib in renal cell cancer (18%) (19), fruquintinib in colorectal cancer (29.8%) (48), apatinib in breast cancer (17.5%) (75), and combination of bevacizumab with erlotinib in lung cancer (23%) (34). However, this effect was not observed in the combined antiangiogenic immunotherapy arm (79). In addition, hypertension as an adverse event was more common in patients receiving high doses (41), however, the effect of frequency of administration on the occurrence of hypertension remains unclear. Third, hypertension was more likely to occur in patients younger than 75 years old (43,56,57), those who have not previously used bevacizumab (60,61), and female patients (41). Fourth, the effect of baseline blood pressure levels on the development of hypertension is controversial. Pivot et al (78) reported that there was no clear correlation between baseline hypertension and its development during study treatment. By contrast, Yang et al (80) found that a history of hypertension was an independent risk factor for predicting hypertension during the treatment period. Fifth, discontinuation or death caused by hypertension was rare. Nevertheless, hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke, with the grade of hypertension associated with mortality (77,81). Finally, early development of significant hypertension may be a biomarker associated with greater efficacy of antiangiogenic therapy and improved survival (14,49,50).
Large doses of antiangiogenic agents are generally associated with greater inhibitory effects on VEGF. We speculate that higher sensitivity to angiogenesis inhibitors may be an explanation, due to different levels of VEGF expression. Patients with RCC have increased levels of VEGF and VEGFR expression (82), which is accompanied by higher rates of hypertension development, compared with hepatocellular carcinoma patients treated with sorafenib (83). Frey et al (84) have shown that bevacizumab-induced hypertension is related to genetic variation in WNK lysine deficient protein kinase 1, kallikrein B1 and G protein-coupled receptor kinase 4. The performance of sunitinib in patients with non-small cell lung cancer (85), bevacizumab in Chinese patients with locally progressed GC (86), as well as sorafenib (87) and sunitinib (88) in patients with breast cancer, confirms our hypothesis: These drugs did not increase the risk of serious hypertension, but at the same time, they did not improve survival.
As an adverse event, hypertension caused by antiangiogenic drugs should be monitored regularly by physicians. There is a role for home or ambulatory blood pressure monitoring, which can increase the sensitivity of diagnosing hypertension (89). Nevertheless, blood pressure monitoring in the clinic is recommended for the first cycle of therapy (90). When blood pressure remains <140/90 mmHg, lifestyle intervention is recommended, which includes lower salt intake, reduced alcohol consumption, normalization of the body mass index, no cigarette smoking and increased physical activity (91). Antihypertensive therapy should be initiated when blood pressure is >140/90 mmHg or 20 mmHg greater than the baseline blood pressure (90). The association between antihypertensive drugs and cancer is a matter of large debate in the last several years. At present, renin inhibitors, including ACEIs and angiotensin receptor blockers, are the first-line agents preferred for antiangiogenetic therapy, since they can improve remodeling by reducing left ventricular afterload and by direct inhibition of angiotensin II type 1 receptor-mediated hypertrophy and fibrosis (13). After the end of antiangiogenic drug treatment, blood pressure should be regularly monitored, and antihypertensive treatment should be discontinued if it normalizes.
On the other hand, the presence of hypertension has been reported as a positive prognostic biomarker of improved survival in patients receiving antiangiogenic therapy. However, the underlying mechanisms, the timing and value of blood pressure that best predicts survival needs to be elucidated. Previous studies have shown that significant hypertension [≥G2 (22,23) or ≥G3 (76)] and early occurrence of hypertension [in the first two (67), four (15) or six weeks of treatment initiation (21)] may be associated with improved survival. However, it is unclear whether patients who do not develop significant hypertension in the early stage need alterations in the medication regimen (15).
Conclusion
In conclusion, the use of antiangiogenic drugs is associated with an increased risk of hypertension in most types of solid cancer. Early development of significant hypertension may be a potential biomarker of improved survival. Prospective studies are needed to support these findings.
Acknowledgements
The authors would like to thank Dr Sharen Lee (Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong) for his contribution to the revision of the manuscript and data interpretation.
Funding
No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
GT, PS and LZ designed and arranged the manuscript. MD and RW wrote the article. DZ, ZZ and JZ found and analyzed the references in Medline, and participated in writing the article. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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