Both New-Onset and Pre-Existing Hypertension Indicate Favorable Clinical Outcomes in Patients Treated With Anti-Vascular Endothelial Growth Factor Therapy

Shohei Moriyama; Michinari Hieda; Megumi Kisanuki; Shotaro Kawano; Taku Yokoyama; Mitsuhiro Fukata; Hitoshi Kusaba; Toru Maruyama; Eishi Baba; Koichi Akashi; Haruhisa Fukuda

doi:10.1253/circj.CJ-22-0628

Abstract

Background: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.

Methods and Results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133–567) and 170 (72–358) days, respectively, compared with 146 (70–309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50–0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73–0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62–0.76; P<0.001).

Conclusions: This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.

Vascular endothelial growth factor (VEGF) regulates and maintains angiogenesis during normal blood vessel formation.¹ Recent studies demonstrated that abnormalities in angiogenesis were critical to the process of tumor growth, invasion, and metastasis in patients with cancer.²^–⁴ Indeed, VEGF ligands and receptors are overexpressed in the tumor microenvironment, promoting tumor growth and metastasis.⁵ Tumor blood vessels induced by VEGF have increased permeability because of immature and disorganized vasculature.³ This environment around the tumor cannot remedy hypoxia, which leads to persistent angiogenesis, and high interstitial pressure is maintained in the tumor tissue.⁵ Therefore, VEGF inhibitors are widely used to suppress tumor growth by normalizing the tumor vasculature.⁶^–⁸ The recent development of VEGF inhibitors has improved the prognosis of patients with advanced cancer.⁷^–⁹

Editorial p 226

However, VEGF signaling pathway (VSP) inhibitors cause drug-specific anti-angiogenesis vascular toxicities.¹⁰^,¹¹ Among the adverse events, hypertension (HTN) is one of the most frequent complications, occurring in up to two-thirds of patients treated with VSP inhibitors.¹²^,¹³ VSP inhibitors increase vasoconstriction cytokines¹⁴^,¹⁵ and decrease microvascular density,¹⁶ thereby increasing blood pressure. In addition, VSP inhibitors suppress the differentiation of mesangial cells in the kidney, affecting the glomerular filtration rate.¹⁷^,¹⁸

To date, a few studies have reported an association between VSP inhibitor-related HTN and enhanced efficacy.¹⁹^–²¹ However, the cohorts in those studies were small, and there are conflicting studies reported that VSP inhibitor-related HTN did not affect clinical outcomes in cancer patients.²²^,²³ VSP inhibitors are widely used in various types of cancer, and the relationship between VSP inhibitor-induced HTN and clinical outcomes remains controversial. Moreover, the clinical effect of pre-existing HTN before VSP inhibitor administration is not fully understood.

Taking all these reports into consideration, we hypothesized that VSP inhibitor-induced HTN and pre-existing HTN before VSP inhibitor therapy may provide favorable clinical outcomes in patients with advanced cancers. Therefore, the aim of this study was to elucidate the effects of new-onset and pre-existing HTN on clinical outcomes in patients treated with VSP inhibitors, using a Japanese claims database.

Methods

Data Sources and Study Design

The Longevity Improvement and Fair Evidence (LIFE) Study is a multiregion community-based database project conducted by Kyushu University (Fukuoka, Japan).²⁴ The database comprises healthcare claims data collected from 14 municipalities between 2016 and 2020. The LIFE study database includes the National Health Insurance system, in which more than 80% of those aged 65–74 years old are enrolled, and the Latter-Stage Older Persons Health Care System, which covers all citizens aged ≥75 years. The LIFE Study has agreements with participating municipalities to collect and process anonymized claims data for secondary analysis.

From the LIFE Study database, comprising 1,588,335 patients, 4,331 patients met the following inclusion criteria: age ≥18 years, received a VSP inhibitor for the corresponding primary cancer lesion, and received a single VSP inhibitor during cancer therapy. The combinations of primary cancer lesions and VSP inhibitors used were as follows: colorectal and bevacizumab, ramucirumab, or regorafenib; gastric and ramucirumab; liver and lenvatinib, regorafenib, bevacizumab, ramucirumab, or sorafenib; lung and bevacizumab or ramucirumab; kidney and axitinib, pazopanib, sunitinib, or sorafenib; and thyroid and lenvatinib or sorafenib. This study excluded patients who had been treated with a VSP inhibitor for <4 weeks because many of these patients discontinued cancer treatment for specific reasons, such as poor performance status or sudden death. After excluding 871 patients, the final cohort comprised 3,460 patients (Figure 1).

Figure 1.

Patient selection from the Longevity Improvement and Fair Evidence (LIFE) Study database. The LIFE Study database comprises 1,588,335 patients. The 3,460 patients meeting the study criteria were analyzed in this study: 569 in the new-onset hypertension (HTN) group, 1,790 in the pre-existing HTN group, and 1,101 in the non-HTN group. VSP, vascular endothelial growth factor signaling pathway.

Participants were classified into 3 groups according to the timing of HTN onset: (1) new-onset HTN, in which HTN developed after VSP inhibitor administration; (2) pre-existing HTN, in which HTN was present at baseline and included patients in whom VSP inhibitor initiation aggravated HTN; and (3) no HTN. The diagnosis of HTN was based on the following criteria: new disease registration for HTN and new prescription of antihypertension drugs. The timing of HTN onset was determined by the date of the first administration of antihypertension drugs. As an indicator of clinical outcomes, the time to treatment failure (TTF), defined as the time between the first and last administration of VSP inhibitors, was used as the primary endpoint. Past medical history was extracted according to the Elixhauser Comorbidity Index.²⁵

The Internal Review Board at Kyushu University approved this study protocol (Approval no. 2021-399), and patient consent was obtained via an opt-out method. All procedures performed in this study followed the principles of the updated Declaration of Helsinki (2013).

Statistical Analysis

Continuous variables are presented as the median with interquartile range (IQR) and were compared using the Mann-Whitney U test (2 groups) or Kruskal-Wallis test (multiple groups). Categorical variables were compared using the Chi-squared test. Event-free survival was analyzed using the Kaplan-Meier method with the log-rank test. Individual subgroup comparisons were conducted when P<0.05 for comparisons among the 3 groups. P values of post hoc analyses in particular subgroups are described as adjusted P values (P_adjusted) corrected using the Holm-Bonferroni method. In addition, unadjusted and adjusted Cox proportional hazard models were used to evaluate the impact of HTN on clinical outcomes, with results presented as hazard ratios (HR) and 95% confidence intervals (CIs). The adjusted model used age, sex, primary cancer lesion, type of VSP inhibitor, and all past medical histories as covariates.

In all cases, two-sided P values <0.05 was considered statistically significant. All preprocessing from the LIFE database and statistical calculations were performed using Python version 3.8.5 (Python Software Foundation, Beaverton, OR, US). The time-to-event analyses were performed using the LIFELINES 0.27.0 package in Python.

Results

Clinical Characteristics

Data for 3,460 patients were available for analysis: 569 (16.4%) patients in the new-onset HTN group, 1,790 (51.7%) patients in the pre-existing HTN group, and 1,101 (31.8%) patients in the non-HTN group (Figure 1). The clinical characteristics of the patients are presented in Table 1. Patients in both the new-onset and pre-existing HTN groups were older than those in the non-HTN group (median [IQR] age 71 [50–84] and 74 [54–87] vs. 69 [44–83] years, respectively; P<0.001). Patients with pre-existing HTN were older than those with new-onset HTN (P_adjusted<0.001). The distribution of primary cancer sites and types of VSP inhibitors differed among the 3 groups (P<0.001 and P<0.001, respectively; Table 1; Supplementary Table).

Table 1.

Patient Characteristics

	Total (n=3,460)	HTN (n=2,359)		Non-HTN (n=1,101)	P value
	Total (n=3,460)	New-onset (n=569)	Pre-existing (n=1,790)	Non-HTN (n=1,101)	P value
Age (years)	72 [67–77]	71 [50–84]**	74 [54–87]**^,††	69 [44–83]	<0.001
Age group					<0.001
<50 years	104 (3.0)	13 (2.3)	17 (0.9)	74 (6.7)
50–70 years	1,201 (34.7)	232 (40.8)	460 (25.7)	509 (46.2)
≥70 years	2,155 (62.3)	324 (56.9)	1,313 (73.4)	518 (47.0)
Male sex	2,057 (59.5)	306 (53.8)	1,152 (64.4)**^,††	599 (54.4)	<0.001
Cancer site					<0.001
Colorectal	1,477 (42.7)	257 (45.2)	713 (39.8)	507 (46.0)
Stomach	487 (14.1)	79 (13.9)	230 (12.8)	178 (16.2)
Liver	691 (20.0)	106 (18.6)	422 (23.6)	163 (14.8)
Lung	598 (17.3)	96 (16.9)	278 (15.5)	224 (20.3)
Kidney	170 (4.9)	22 (3.9)	122 (6.8)	26 (2.4)
Thyroid	37 (1.1)	9 (1.6)	25 (1.4)	3 (0.3)
VSP inhibitor					<0.001
Ramucirumab	663 (19.2)	93 (16.3)	325 (18.2)	245 (22.3)
Bevacizumab	2,168 (62.7)	391 (68.7)	1,008 (56.3)	769 (69.8)
Lenvatinib	203 (5.9)	31 (5.4)	159 (8.9)	13 (1.2)
Pazopanib	55 (1.6)	6 (1.1)	38 (2.1)	11 (1.0)
Sorafenib	229 (6.6)	26 (4.6)	169 (9.4)	34 (3.1)
Sunitinib	51 (1.5)	7 (1.2)	33 (1.8)	11 (1.0)
Axitinib	52 (1.5)	9 (1.6)	40 (2.2)	3 (0.3)
Regorafenib	39 (1.1)	6 (1.1)	18 (1.0)	15 (1.4)
Type of VSP inhibitor^A					<0.001
VEGFR inhibitor	2,831 (81.8)	484 (85.1)	1,333 (74.5)	1,014 (92.1)
Multikinase inhibitor	630 (18.2)	85 (14.9)	457 (25.5)	87 (7.9)
Antihypertensive drugs^B
CCB	1,288 (37.2)	296 (52.0)**	956 (53.4)**	36 (3.3)	<0.001
RAS inhibitors	884 (25.6)	213 (37.4)**	654 (36.5)**	17 (1.5)	<0.001
ACEI	59 (1.7)	18 (3.2)**	40 (2.2)**	1 (0.1)	<0.001
ARB	834 (24.1)	196 (34.5)**	621 (34.7)**	17 (1.5)	<0.001
β-blockers	200 (5.8)	22 (3.9)**	168 (9.4)**^,††	10 (0.9)	<0.001
α-blockers	98 (2.8)	7 (1.2)*	90 (5.0)**^,††	1 (0.1)	<0.001
Thiazides	53 (1.5)	5 (0.9)	46 (2.6)**	2 (0.2)	<0.001
MRA	178 (5.1)	40 (7.0)*	92 (5.1)^†	46 (4.2)	0.044
Past medical history
Pulmonary disease	1,435 (41.5)	221 (38.8)	798 (44.6)*^,†	416 (37.8)	<0.001
Psychoses	478 (13.8)	86 (15.1)	211 (11.8)*	181 (16.4)	0.001
CHF	882 (25.5)	123 (21.6)*	583 (32.6)**^,††	176 (16.0)	<0.001
Valvular disease	410 (11.8)	59 (10.4)	257 (14.4)**^,†	94 (8.5)	<0.001
Cardiac arrhythmias	606 (17.5)	78 (13.7)	381 (21.3)**^,††	147 (13.4)	<0.001
Depression	563 (16.3)	102 (17.9)	269 (15.0)	192 (17.4)	0.118
Diabetes	838 (24.2)	131 (23.0)**	546 (30.5)**^,†	161 (14.6)	<0.001
Renal failure	316 (9.1)	46 (8.1)*	223 (12.5)**^,†	47 (4.3)	<0.001
Peripheral vascular	450 (13.0)	50 (8.8)	318 (17.8)**^,††	82 (7.4)	<0.001
Hypothyroidism	442 (12.8)	74 (13.0)*	281 (15.7)**	87 (7.9)	<0.001
Liver disease	1,776 (51.3)	260 (45.7)	1,034 (57.8)**^,††	482 (43.8)	<0.001

Unless indicated otherwise, data are given as median [interquartile range] or n (%). *P_adjusted<0.05, **P_adjusted<0.001 compared with the non-hypertension group; ^†P_adjusted<0.05, ^††P_adjusted<0.001 compared with the new-onset HTN group. ^AVascular endothelial growth factor receptor (VEFGR) inhibitors are ramucirumab and bevacizumab; multikinase inhibitors are axitinib, lenvatinib, pazopanib, sorafenib, sunitinib, and regorafenib. ^BIncluding prescriptions for non-hypertensive disease. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; CCB, calcium channel blockers; CHF, congestive heart failure; HTN, hypertension; MRA, mineralocorticoid receptor antagonists; RAS, renin-angiotensin system inhibitors; VSP, vascular endothelial growth factor signaling pathway.

Impact of New-Onset and Pre-Existing HTN on Clinical Outcome

The median (IQR) TTF in the new-onset HTN and pre-existing HTN groups was 301 (133–567) and 170 (72–358) days, respectively (Figure 2), compared with 146 (70–309) days in the non-HTN group. There was a significant difference among groups in the event-free survival analysis (log-rank test, P<0.001). In post hoc analyses, TTF was longer in both the new-onset and pre-existing HTN groups than in the non-HTN group (P_adjusted<0.001 and P_adjusted=0.004, respectively). In addition, new-onset HTN was associated with significantly more prolonged TTF than pre-existing HTN (P_adjusted<0.001).

Figure 2.

Time to treatment failure (TTF) among the new-onset, pre-existing, and non-hypertension (HTN) groups. The median TTF in each group differed significantly (P<0.001). In post hoc analyses, median TTF was substantially longer in new-onset and pre-existing HTN groups than in the non-HTN group (P_adjusted<0.001 and P_adjusted=0.004, respectively). In addition, new-onset HTN was significantly associated with a more prolonged TTF than pre-existing HTN (P_adjusted<0.001). IQR, inter quartile range.

The Cox proportional hazard model adjusted for baseline characteristics revealed that new-onset (HR 0.60; 95% CI 0.54–0.67; P<0.001) and pre-existing (HR 0.88; 95% CI 0.81–0.96; P=0.002) HTN were related to longer TTF compared with no HTN (reference group; Table 2). Moreover, TTF was longer in the new-onset HTN than pre-existing HTN group (HR 0.68; 95% CI 0.62–0.75; P<0.001).

Table 2.

Cox Proportional Hazard Models of Evaluating the Effect of HTN on the TTF

	Unadjusted model		Adjusted model^A
	HR (95% CI)	P value	HR (95% CI)	P value
Non-HTN	Reference		Reference
New-onset HTN	0.61 (0.55–0.67)	<0.001	0.58 (0.50–0.68)	<0.001
Pre-existing HTN	0.89 (0.83–0.96)	0.003	0.85 (0.73–0.98)	0.026
Pre-existing HTN	Reference		Reference
New-onset HTN	0.68 (0.62–0.75)	<0.001	0.68 (0.62–0.76)	<0.001

^AAdjusted for baseline characteristics, including age, sex, primary cancer lesion, type of vascular endothelial growth factor signaling pathway (VSP) inhibitor, antihypertensive drugs, and past medical history. CI, confidence interval; HR, hazard ratio; HTN, hypertension; TTF, time to treatment failure.

TTF among the 3 groups and event-free analyses in each subgroup are summarized in Table 3. In the age <70 years old, female sex, VEGF receptor inhibitors, chronic heart failure and renal failure subgroups, new-onset and pre-existing HTN were related to prolonged TTF compared with the non-HTN group. TTFs for different cancer sites and VSP inhibitors are shown in Supplementary Figures 1,2.

Table 3.

TTF Analysis in Subgroups

	TTF (days)			P value (all groups)	P_adjusted (post hoc)
	New-onset HTN (a)	Pre-existing HTN (b)	Non-HTN (c)	P value (all groups)	(a) vs. (c)	(b) vs. (c)	(a) vs. (b)
All patients	301 [133–567]	170 [72–358]	146 [70–309]	<0.001	<0.001	0.004	<0.001
Age [years]
<70	308 [154–574]	182 [76–402]	154 [70–296]	<0.001	<0.001	<0.001	<0.001
≥70	296 [127–567]	168 [72–336]	134 [70–319]	<0.001	<0.001	0.131	<0.001
Sex
Male	271 [124–556]	168 [70–355]	147 [70–314]	<0.001	<0.001	0.200	<0.001
Female	324 [146–588]	182 [82–368]	143 [63–286]	<0.001	<0.001	0.002	<0.001
Cancer site
Colorectal	434 [229–686]	217 [98–466]	187 [84–386]	<0.001	<0.001	0.099	<0.001
Stomach	147 [69–249]	98 [49–170]	98 [49–181]	<0.001	0.002	0.844	0.001
Liver	261 [120–455]	168 [64–335]	135 [60–294]	0.014	0.009	0.319	0.030
Lung	239 [144–486]	149 [70–297]	108 [62–244]	<0.001	<0.001	0.095	<0.001
Kidney	258 [62–614]	243 [106–606]	297 [110–551]	0.715	–	–	–
Thyroid	233 [194–315]	266 [80–605]	198 [153–244]	0.454	–	–	–
VSP inhibitor^A
VEGFR inhibitors	323 [144–587]	172 [78–363]	146 [70–309]	<0.001	<0.001	0.004	<0.001
Multikinase inhibitors	224 [90–380]	160 [64–349]	142 [64–301]	0.718
Antihypertensive drugs
CCB	312 [134–566]	168 [72–348]	131 [61–253]	<0.001	<0.001	0.064	<0.001
RAS inhibitors	324 [148–588]	174 [70–380]	105 [77–189]	<0.001	<0.001	0.107	<0.001
Past medical history
Pulmonary disease	313 [144–602]	176 [81–385]	148 [77–357]	<0.001	<0.001	0.135	<0.001
CHF	399 [164–630]	175 [82–371]	142 [84–261]	<0.001	<0.001	0.019	<0.001
Renal failure	297 [117–504]	189 [84–458]	140 [58–228]	0.001	0.001	0.002	0.451

TTF is presented as the median (interquartile range). ^AVEFGR inhibitors are ramucirumab and bevacizumab; multikinase inhibitors are axitinib, lenvatinib, pazopanib, sorafenib, sunitinib, and regorafenib. Abbreviations as in Tables 1,2.

Discussion

Using a large cohort database, the present study demonstrated that: (1) new-onset HTN induced by VSP inhibitors was an independent factor for prolonged TTF as a clinical indicator of the effectiveness of VSP inhibitors; and (2) even pre-existing HTN, before initiation of VSP inhibitors, was a significant indicator of favorable clinical outcomes (Figure 3).

Figure 3.

Hypertension (HTN) is a predictor of favorable outcomes during treatment with vascular endothelial growth factor signaling pathway (VSP) inhibitors. The present cohort-based study analyzed the impact of HTN on clinical outcomes. Overall 3,460 patients were included, and these were divided into the pre-existing HTN (52%), new-onset HTN (14%), and non-HTN (32%) groups. New-onset HTN reduced the hazard ratio for treatment failure by 42% compared with non-HTN, whereas pre-existing HTN reduced the risk by 15%.

Implication of New-Onset HTN Induced by VSP Inhibitors

This study demonstrated that, compared with the non-HTN group, new-onset HTN decreases the risk of treatment failure by nearly 40% in patients treated with VSP inhibitors. This result confirmed the findings of previous studies. For example, Dahlberg et al reported that new-onset HTN was related to superior clinical outcomes compared with no HTN during combination chemotherapy with bevacizumab and cytotoxic agents for non-small-cell lung cancer.²⁰ In addition, a meta-analysis by Cai et al revealed an association between bevacizumab-related HTN and prolonged progression-free survival (HR 0.57; 95% CI 0.46–0.72) and overall survival (HR 0.50; 95% CI 0.37–0.68) in patients with metastatic colorectal cancer.²⁶ HTN induced by other VSP inhibitors has also been reported as a favorable indicator of clinical outcome.²⁷ However, to the best of our knowledge, there is only 1 small study in Japan referring to the relationship between new-onset HTN and VSP inhibitors.²¹ Therefore, the present study is the first to comprehensively clarify the significance of new-onset HTN in patients treated with VSP inhibitors in a Japanese cohort.

Implications of Pre-Existing HTN

To date, the implication of pre-existing HTN before initiation of VSP inhibitor therapy has been rarely explored. To the best of our knowledge, the study of Izzedine et al is the only one that suggests a clinical benefit of pre-existing HTN in cancer treatment with VSP inhibitors.¹⁹ In that study, a history of HTN before the administration of sunitinib significantly affected both overall and progression-free survival. Although recent studies reported that renin–angiotensin system inhibitors before or early after VSP inhibitor therapy prolonged overall survival, the clinical impact of HTN itself has not been fully explored.²⁸^,²⁹ The present study confirms that pre-existing HTN has clinically beneficial effects in cancer patients treated with VSP inhibitors. Further studies are required to confirm the effect of pre-existing HTN; based on the results of the present study, VSP inhibitors should be useful in patients with HTN.

Potential Underlying Mechanism

VEGF Family and On-Target Toxicity The pathologies of VSP inhibitor-related HTN are called on-target toxicity, which can be a clinical indicator of the effect of VSP inhibitors on cancer.³⁰ The human VEGF family consists of 5 glycoproteins and 3 VEGF receptors (VEGFR-1, -2, and -3) corresponding to these ligands. VEGFR-2 is primarily expressed in vascular and lymphatic endothelial cells. Once VEGF ligands bind to their receptors, VEGFR-2 autophosphorylates and activates endothelial nitric oxide synthase, increasing the production of nitric oxide.³¹ VSP inhibitors affect the normal microvasculature and kidney through VEGF signaling, which also contributes to the development of new-onset HTN.³² In addition, VSP inhibitors reduce the number of vessels and endothelial fenestrations, leading to increased afterload and contributing to the development and maintenance of HTN.¹⁶ Inhibition of VEGF and VEGFR, expressed in the kidneys, damages mesangial and endothelial cells and decreases the glomerular filtration rate, leading to HTN.¹⁷^,¹⁸ In addition, VSP inhibitors increase serum concentrations of endothelin-1, one of the most potent vasoconstrictive cytokines, which may be derived from the kidneys.¹⁵ Therefore, elevated blood pressure after VSP inhibitors is attributed to the fact that VSP inhibitors act on normal organs through VEGF and VEGFR-mediated mechanisms, which extends their actions beyond antitumor effects. That is, VSP inhibitor-induced HTN can be an indicator of reactivity to VSP inhibitors in individuals. These mechanisms of action of VSP inhibitors can explain the relationship between new-onset HTN and favorable clinical outcomes.

VEGF Expression and Pre-Existing HTN Although the pathogenesis of pre-existing HTN on favorable clinical outcomes is not yet fully elucidated, the VEGF family may play a role in exerting a positive clinical effect. HTN is an independent risk factor for the development of cancer.³³ In addition, prior to the VSP inhibitor era, and in contrast to the findings of the present study, pre-existing HTN prior to a cancer diagnosis was reported to be associated with a poor prognosis.³⁴ The differential response to cytotoxic cancer therapy and VSP inhibitors suggests that cancer development in hypertensive patients may be influenced by the VEGF family. Suzuma et al reported that VEGF expression and VEGF receptors were increased in a HTN mouse model.³⁵ Indeed, serum concentrations of VEGF and soluble VEGF receptor were higher in HTN patients than in healthy controls.³⁶ Interestingly, in colorectal cancer patients treated with VSP inhibitors, an elevated plasma VEGF concentration was a potential biomarker of response to cancer therapy.³⁷ Considering this finding and the results of the present study, elevated serum VEGF in patients with HTN may affect the development of cancers with favorable sensitivity to VSP inhibitors.

Inflammatory cytokines, including interleukin (IL)-6 or tumor necrosis factor, may also be involved in the clinical consequences. In the development of HTN, chronic inflammation, hypoxia, and reactive oxygen species generated by HTN lead to further exacerbation of HTN in a vicious cycle.³⁸ In addition, these inflammatory cytokines are linked to cancer development.³⁹ IL-6, a proinflammatory cytokine, increases VEGF expression and promotes angiogenesis in the tumor microenvironment in a concentration-dependent manner.⁴⁰ Hypoxia-inducible factors and reactive oxygen species are also linked to VEGF expression, leading to angiogenesis in the cancer microenvironment.⁴¹ The mechanisms of inflammation- and oxidative stress-mediated carcinogenesis in patients with HTN support our findings that pre-existing HTN has a clinical impact in patients treated with VSP inhibitor therapy.

Other Possible Underlying Mechanisms The exacerbation of blood pressure control in the pre-existing HTN group, through the same mechanisms as new-onset HTN, may have influenced the results of the present study. Pre-existing HTN, older age, and obesity were risk factors for increased blood pressure after VSP inhibitor administration.⁴²^,⁴³ Half the patients with 2 of the above risk factors and 60% of those with all 3 risk factors developed HTN after anti-VEGF therapy.⁴² In the present study, 62% of the total study population and >70% of those with pre-existing HTN were aged ≥70 years, and the age distribution in the present study was higher than in other clinical trials.¹³^,⁴⁴ Older patients with a history of HTN have a higher risk of increased blood pressure after VSP inhibitor administration. Our results may reflect the effect of HTN exacerbation as on-target toxicity.

Regarding new-onset HTN, a previous study reported that the relationship between favorable outcomes and new-onset HTN during bevacizumab therapy was detected only in patients with metastatic cancer and not in those without metastatic disease.⁴⁵ The use of VSP inhibitors was limited to metastatic or inoperable cancers in the present study, which may be one reason why new-onset HTN had a substantial impact on TTF in this study.

Hypertensive drugs may also have contributed to our results. Previous studies have suggested that renin-angiotensin system inhibitors may normalize tumor vessels and enhance the delivery of chemotherapy, leading to a favorable clinical outcome among cancer patients.⁴⁶^,⁴⁷ Although the present study demonstrated that pre-existing HTN was related to favorable clinical outcomes independent of antihypertensive drugs, further studies evaluating the effects of antihypertensive drugs in patients with VSP inhibitor-related HTN are required.

Study Strengths and Limitations

This is one of the largest studies to clarify the clinical impact of new-onset and pre-existing HTN during cancer therapy with VSP inhibitors, with robust results incorporating multiple primary cancer sites and VSP inhibitors.

We acknowledge that this study has inherent limitations. First, the study was limited to the 14 Japanese municipalities enrolled in the LIFE Study. This cohort may not represent all cancer patients treated with VSP inhibitors. However, the LIFE Study spans a large region, from urban to rural, covering many populations. Second, this was a cohort-based retrospective study and we could not evaluate laboratory data, chemotherapy dose, and actual changes in blood pressure. In fact, the elevation of blood pressure in the pre-existing HTN group was not assessed. However, to accurately assess blood pressure trends, the onset of hypertension was defined as the time when antihypertensive drugs were administered, and not only when the ICD-10 code for HTN was registered. In fact, during chemotherapy for cancer treatment, blood pressure is calculated during each course, and the criteria for blood pressure control are established.⁴⁸ Therefore, the timing of the initiation of antihypertensive drugs matches that of blood pressure elevation. Moreover, it is difficult to include such a large population in a prospective clinical study, but the large amount of cohort-based data compensated for this weakness. Indeed, the present study has sufficient statistical power (both new-onset and pre-existing HTN vs. non-HTN, >0.95). Third, the difference in the line of chemotherapy may affect TTF. Generally, the duration of late-line chemotherapy is shorter than that of first- or second-line chemotherapy. In addition, the combination of cancer sites and type of VSP inhibitors was unevenly distributed, and VSP inhibitors included both VEGFR inhibitors and multikinase inhibitors. We eliminated this bias as far as possible by incorporating the primary cancer lesion, baseline characteristics, and the type of VSP inhibitors as covariates. Finally, TTF was assessed as a clinical indicator because the LIFE Study database did not contain information on mortality and image examinations for all patients. In fact, it was not possible to assess whether the reason for cancer treatment discontinuation was disease progression or treatment intolerance. However, TTF can be one of the essential composite real-world outcomes because it is a treatment duration that considers the efficacy of anticancer drugs and their toxicity.⁴⁹ In addition, these patients have well-documented higher rates of severe adverse events, which can prompt the premature discontinuation of chemotherapy. Furthermore, many patients with advanced cancer may opt to transition to palliative care sooner. Therefore, in advanced cancer patients, TTF can be an invaluable endpoint.

Global prospective studies may compensate for the limitations of this study and contribute to the investigation of appropriate treatment of HTN during VSP inhibitor therapy.

Conclusions

This study highlighted that HTN induced by VSP inhibitors is a pivotal indicator of favorable clinical outcomes in patients with advanced cancer. In addition, pre-existing HTN is predictive of a favorable response to VSP inhibitors. Therefore, VSP inhibitors can potentially improve mortality in patients with advanced cancer with new-onset and pre-existing HTN.

Acknowledgments

The authors gratefully acknowledge all staff associated with the LIFE Study.

Sources of Funding

This work was supported by grants provided by the Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST) Program (Grant no. JPMJFR205J) and the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) Program (Grant no. JP20H00563 and JP19K21590).

Disclosures

The authors have no conflicts of interest relevant to the content of this article.

IRB Information

This study was approved by the Institutional Review Board of Kyushu University (Reference no. 2021-399).

Data Availability

Public access to the registry cannot be provided due to limitations in data use agreements.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0628

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