Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805

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Wendy J. Bottinor Division of Cardiovascular Medicine, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia

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Yael Flamand Department of Data Science/ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, Massachusetts

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Naomi B. Haas Division of Medical Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

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Anne M. ONeill Department of Data Science/ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, Massachusetts

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Robert S. DiPaola Division of Medical Oncology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky

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Pearl Subramanian School of Medicine, Hofstra University, New York, New York

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David Cella Department of Medical Social Sciences, Northwestern Medicine, Chicago, Illinois

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W. Gregory Hundley Division of Cardiovascular Medicine, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia

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Lynne I. Wagner Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina

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John M. Salsman Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina

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Bonnie Ky Division of Cardiology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

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Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. Methods: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. Results: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%–8.3%) versus non-AYAs (2%; 95% CI, 1.2%–2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%–33.5%) compared with non-AYAs (46%; 95% CI, 41.9%–50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%–47.5%) versus 47% (95% CI, 42.3%–51.7%), and 54% (95% CI, 33.9%–72.5%) versus 63% (95% CI, 58.6%–67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31–0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59–0.92) were each associated with a lower risk of hypertension. Conclusions: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

Background

In the United States, nearly 90,000 individuals between the ages of 15 and 39 years, often referred to as adolescents and young adults (AYAs), are diagnosed with cancer each year.1 Renal, thyroid, and colorectal cancer are among the more commonly diagnosed malignancies in this population, and the incidence of these cancers has increased over the past 4 decades.2 VEGF inhibition (VEGFi) is often used singly or as part of combination therapy for these malignancies; however, cardiovascular toxicities can be a significant limitation of VEGFi therapy, with hypertension among the most common.3 Additionally, left ventricular dysfunction has also been observed among adult and pediatric populations receiving VEGFi.46 However, the incidence and factors associated with VEGFi-mediated left ventricular systolic dysfunction (LVSD) and hypertension among the AYA population have not been determined.713

To address these knowledge gaps, we evaluated the incidence and clinical factors associated with VEGFi-mediated LVSD and hypertension among AYAs with nonmetastatic, high-risk renal cell cancer participating in a large randomized clinical trial. We hypothesized that the incidence of both LVSD and hypertension would be lower among AYAs compared with non-AYAs due to fewer comorbidities and younger age.

Methods

Data Source

This retrospective cohort analysis used data from the previously completed prospective clinical trial E2805 (ASSURE trial; ClinicalTrials.gov identifier: NCT00326898), coordinated by the ECOG-ACRIN Cancer Research Group, given a higher prevalence of AYAs than most ECOG-ACRIN clinical trials. Participants with histologically confirmed clear cell or non–clear cell renal carcinoma at high risk for recurrence (completely resected within 12 weeks prior to study entry) were randomized to receive a total of 9 six-week cycles (ie, 54 weeks) of either sunitinib, 50 mg daily for 28 days out of the 42-day cycle; sorafenib, 400 mg twice daily; or placebo therapy.

Eligibility criteria for the ASSURE trial included a baseline left ventricular ejection fraction (LVEF) of at least 50%, no cardiac events in the 6 months prior to study entry (myocardial infarction, severe or unstable angina, coronary or peripheral arterial bypass grafting, symptomatic heart failure, cerebrovascular accident, transient ischemic attack, or pulmonary embolism), a baseline blood pressure <130/90 mm Hg, a QTc interval <500 ms, and no significant arrhythmias.14 Consistent with the NCI definition and the eligibility criteria for the trial population, AYAs in our analysis included participants between the ages of 18 and 39 years.

LVEF Assessment

Per study protocol, all participants had their LVEF measured by serial multigated acquisition (MUGA) scans or echocardiograms at baseline; at 3, 6, and 12 months; or at the end of treatment. Additional MUGA scans or echocardiograms were obtained if cardiac symptoms developed or 3 months after an abnormal assessment.

Blood Pressure Assessment

Blood pressure measurements were performed in the clinic according to a standardized protocol. Home blood pressures were also accepted if a calibrated electronic device was used. Blood pressure was measured at baseline and weekly during the first cycle of therapy. For each subsequent cycle of therapy, measurements were standardized and performed on the first day of the cycle. Baseline antihypertensive medication use was also collected; however, no data regarding the initiation or titration of antihypertensive medications during the trial were available.14

Cardiac Study Endpoints

LVSD was defined per protocol as a decrease in LVEF of >15 absolute percentage points from baseline (pretreatment) to below the institutional lower limit of normal.15 Sensitivity analysis was performed using an alternative published definition of an absolute decrease from baseline LVEF by ≥10%, given the lack of strong consensus of LVSD in the setting of VEGFi therapy.16 The incidence of LVSD at any timepoint during the study treatment was determined.

Incident hypertension was defined as a systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg at any timepoint during the study treatment. Nonphysiologic blood pressure data were defined as systolic blood pressure ≥300 mm Hg, diastolic blood pressure ≤20 mm Hg, diastolic blood pressure greater than systolic blood pressure, or pulse pressure <5 mm Hg. Our criteria for a plausible range of physiologic hemodynamics were based on a population study of mean blood pressure in adults.17

Statistical Analysis

Incidence of LVSD and hypertension were reported as rates with a sensitivity analysis examining rates as events per person years of follow-up while accounting for competing risks (recurrence, second primary malignancy, or death). Chi-square and Fisher exact tests (as appropriate) were used to assess relationships between groups. Logistic regression models were used to estimate the association between AYA status and the odds of LVSD (yes vs no) or hypertension (yes vs no). The following demographic and pretreatment clinical factors were identified a priori and considered in the univariable and multivariable models: self-reported sex, race (non-white vs white), treatment arm, baseline cardiovascular medications (including the use of aspirin, statins, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, and α-blockers), and history of cardiovascular disease (CVD). Corresponding 95% confidence intervals were reported for all estimates. SAS 9.0 (SAS Institute Inc.) was used for all analyses.

Results

Patient Characteristics

E2805 accrued 1,943 participants aged ≥18 years from April 2006 through September 2010. A total of 1,572 participants had sufficient data available to form the basis of our study population (n=493, 485, and 594 in the sunitinib, sorafenib, and placebo arms, respectively). AYAs represented 7% (103/1,572) of the population. Although most AYAs were non-Hispanic white (73% [75/103]), there were more non-Hispanic Black (6.8% vs 3.3%) and Asian/Pacific Islander (5.8% vs 1.6%) participants in the AYA group compared with the non-AYA group. Baseline LVEF was similar among AYAs and non-AYAs (median LVEF, 60% among AYAs and 61% among non-AYAs).

AYAs had fewer preexisting comorbidities. For example, a history of thromboembolic events was less common among AYAs (2% [2/103]) versus non-AYAs (4% [57/1,469]); a history of CVD was less common among AYAs (10% [10/103]) versus non-AYAs (24% [354/1,469]); and at baseline, 1 AYA and 26 non-AYAs were prescribed a cardiovascular medication (β-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or calcium channel blocker) (Table 1). Censoring at off-treatment (given that endpoints were defined during the 54-week study treatment period), the duration of follow-up in person years accounting for competing risks was similar and estimated to be 95 (0.92 years per participant) among AYAs and 1,297 (0.88 years per participants) among non-AYAs.

Table 1.

Patient Characteristics

Table 1.

Incidence of LVSD

AYA status was not associated with a lower incidence of LVSD. During the 54-week study period and across all treatment types, the overall incidence of LVSD per the primary protocol definition (absolute LVEF decrease >15% from baseline to a value below the institutional lower limit of normal) was not different between AYAs and non-AYAs, at 3% (95% CI, 0.6%–8.3%) and 2% (95% CI, 1.2%–2.7%), respectively. These rates remained consistent in sensitivity analyses when examining incidence rate per participant years of follow-up (3% and 2%, respectively). Among AYAs, LVSD was observed only in the placebo arm. Of the 3 AYAs who developed LVSD, 1 had a borderline normal LVEF of 51% at baseline, and the other 2 had 58% and 65%. The incidence of LVSD was significantly higher among AYAs in the placebo arm at 8% (95% CI, 1.6%–20.4%) versus 1% (95% CI, 0.3%–2.1%) for non-AYAs. There was no significant difference between AYAs and non-AYAs for sunitinib, at 0% (95% CI, 0%–10.3%) versus 3% (95% CI, 1.5%–4.8%), and sorafenib, at 0% (95% CI, 0%–11.9%) versus 2% (95% CI, 0.9%–3.7%), respectively (Table 2).

Table 2.

Incidence of Left Ventricular Systolic Dysfunction Among Treatment Groups

Table 2.

Sensitivity analysis using a definition of an absolute decrease in LVEF from baseline by ≥10% at any time during treatment suggested that the overall incidence of LVSD among AYAs and non-AYAs was not statistically significantly different, at 18% (95% CI, 10.7%–26.2%) versus 15% (95% CI, 13.3%–17.0%), respectively. The incidence between AYAs and non-AYAs was also not different according to treatment arm at 12% (95% CI, 3.3%–27.4%) versus 17% (95% CI, 13.5%–20.5%) for sunitinib; 21% (95% CI, 8.0%–39.7%) versus 15% (95% CI, 12.2%–19.0%) for sorafenib; and 20% (95% CI, 9.1%–35.7%) versus 13% (95% CI, 10.6%–16.5%) for placebo, respectively (supplemental eTable 1, available with this article at www.jnccn.org).

Association of AYA Status and LVSD, Adjusted for Clinical Factors

In both the univariable and multivariable settings, AYA status was not significantly associated with LVSD; in addition, the magnitude of effect for AYA status did not change after adjustment for the other factors. There were also no differences according to sex (Figure 1, Table 3).

Figure 1.
Figure 1.

Incidence of LVSD and hypertension among AYAs and females. Overall incidence of LVSD (absolute LVEF decrease >15% to a value below the institutional lower limit of normal from baseline during the 54-week study period) is not significantly different between AYAs and non-AYAs or between female and male sex. Incidence of hypertension (≥140/90 mm Hg), although prevalent overall, is lower among AYAs compared with non-AYAs and female sex compared with male sex.

Abbreviations: AYA, adolescent and young adult; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction.

Citation: Journal of the National Comprehensive Cancer Network 21, 7; 10.6004/jnccn.2023.7018

Table 3.

Clinical Factors Associated With LVSD

Table 3.

Incidence of Hypertension

AYAs had a lower incidence of hypertension compared with non-AYAs. The overall incidence of hypertension during the 54-week study period and across all treatment types was significantly less among AYAs compared with non-AYAs, at 32% (95% CI, 22.8%–42.7%) versus 52% (95% CI, 49.0%–54.3%), respectively. When examining incidence rate per participant years of follow-up in sensitivity analyses, rates of hypertension were 44% for AYAs and 89% for non-AYAs. Thus, the rate among AYAs was still substantial.

In the placebo group, the incidence of hypertension was lower among AYAs compared with non-AYAs, at 18% (95% CI, 7.5%–33.5%) versus 46% (95% CI, 41.9%–50.4%), respectively. In the VEGFi groups, the incidence for AYAs versus non-AYAs was 29% (95% CI, 15.1%–47.5%) versus 47% (95% CI, 42.3%–51.7%) with sunitinib and 54% (95% CI, 33.9%–72.5%) versus 63% (95% CI, 58.6%–67.7%) with sorafenib, respectively. Overall, hypertension was quite prevalent among AYAs (Table 4).

Table 4.

Incidence of Hypertension Among Treatment Groups

Table 4.

Association of AYA Status and Hypertension, Adjusted for Clinical Factors

In both the univariable and multivariable settings, AYA status was significantly associated with a lower odds of developing hypertension (odds ratio [OR], 0.43 [95% CI, 0.28–0.67] and 0.48 [95% CI, 0.31–0.75], respectively). Females were less likely to develop hypertension at any time relative to males (OR, 0.70 [95% CI, 0.57–0.88] and 0.74 [95% CI, 0.59–0.92], respectively). The odds of hypertension were similar with sunitinib (OR, 1.06 [95% CI, 0.83–1.35] and 1.08 [95% CI, 0.85–1.39], respectively) but higher with sorafenib (OR, 2.12 [95% CI, 1.65–2.71] and 2.18 [95% CI, 1.69–2.80], respectively) relative to placebo, although we were not able to account for antihypertension medication use during treatment in these models (Figure 1, Table 5).

Table 5.

Clinical Factors Associated With Hypertension

Table 5.

Discussion

AYAs are an underrepresented group in cancer research, with a significant CVD burden. Our study specifically examines the influence of VEGFi therapy (sunitinib and sorafenib) on LVSD and blood pressure among AYAs undergoing adjuvant therapy for unfavorable, high-risk renal cell carcinoma. Our main findings are as follows: (1) AYA status was not associated with a reduced risk of LVSD; (2) independent of VEGFi therapy, AYAs with high-risk renal cell carcinoma had a quantifiable risk of LVSD; and (3) one-third of AYAs treated with sunitinib and one-half of AYAs treated with sorafenib developed hypertension.

Survival rates among AYAs diagnosed with cancer exceed all other age groups, with an 85% 5-year survival rate.1820 However, survival improvement has been relatively static during the last quarter century because AYAs have not demonstrated the same improvement in survival as older or younger cohorts.21 The reasons for this limited improvement are multifactorial; cancer treatment–related diseases, such as CVD, are potential factors. The risk for CVD is >2-fold higher for AYAs when compared with age-matched peers without cancer.22,23 Among AYAs with CVD, the mortality risk is 8 to 11 times higher compared with AYAs without CVD.22,24

Left ventricular dysfunction related to VEGFi therapy has been observed in both adult and pediatric populations.46 Among adults, the risk for VEGFi-mediated left ventricular dysfunction is approximately 10% in the setting of metastatic renal cancer.7,9,10 In the adjuvant setting, the incidence is closer to 1%.15 A previous history of heart failure, coronary artery disease, lower body mass index, female sex, and concomitant CTCAE grade 3 hypertension have been suggested as potential risk factors in the adult population; however, this has not been confirmed across all studies.7,911

In this study, we found no difference in the incidence of LVSD in AYAs versus non-AYAs with either the primary definition (>15% absolute decrease in LVEF from baseline to below the lower limit of normal) or secondary definition (≥10% absolute decrease from baseline). LVSD during VEGFi therapy was not associated with baseline CVD. The incidence of LVSD was greatest among AYAs not receiving VEGFi. These results may reflect an inherently higher risk for CVD among individuals with cancer due to common pathophysiologic pathways, such as chronic inflammation and oxidative stress, that can increase the risk for CVD irrespective of the absence of other risk factors.2527 Cancer biology may also contribute to an increased burden of CVD. For example, mutations related to clonal hematopoiesis of indeterminate potential are associated with a higher risk of cardiovascular events.28,29

Hypertension is the most common VEGFi-mediated cardiovascular toxicity, occurring in 20% to 90% of adult patients, depending on the specific VEGFi used.3 Preexisting hypertension, older age, and elevated body mass index have been identified as potential risk factors for VEGFi-mediated hypertension; however, these associations have not been found in all studies.12,13 The incidence and risk factors for VEGFi-mediated hypertension among AYAs are poorly defined. Within our population, the incidence of hypertension was influenced by traditional risk factors, including older age and male sex.30 Although these factors may identify individuals with an increased likelihood of developing hypertension during treatment with VEGFi, the large number of AYAs (29%–54%) who developed hypertension with either sunitinib or sorafenib therapy suggests that even individuals without identifiable preexisting factors are also at risk for developing VEGFi-mediated hypertension.

Another factor to consider is the molecular targets of VEGFi therapy. Small-molecule tyrosine kinase inhibitors in particular may have several molecular targets, leading to distinct cardiovascular toxicity profiles. For example, the incidence of hypertension is lower among individuals receiving bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor A) compared with those receiving lenvatinib (a tyrosine kinase inhibitor targeting VEGF receptors 1–3, FGF receptors, PDGFR-α, RET, and KIT).3

Although previous studies have suggested a similar overall incidence of hypertension among individuals treated with sunitinib and sorafenib,3 in our study, the incidence of hypertension was significantly greater among individuals treated with sorafenib, regardless of AYA status. Although it is unclear whether this observation is related to the inhibition of BRAF and MEK among individuals using sorafenib, BRAF and MEK inhibitors have been associated with hypertension.31

Limitations of our study include the relatively small size of our AYA cohort. We attempted to address these differences in cohort sizes by using proportions in our analysis and comparing the proportions using chi-square and Fisher exact tests. Although larger sample sizes would result in a greater precision in the estimate, this may not necessarily result in a greater proportion of detectable dysfunction. Nonetheless, because AYAs account for 5% of cancer cases in the United States overall, small sample sizes are a pervasive limitation in AYA research and further highlight the unmet need for AYA-focused clinical research.20,32 Complete data on cardiovascular risk factors, such as diabetes, obesity, and hyperlipidemia, and the use of antihypertensives during the study were not available and limit our ability to fully determine the impact of cardiovascular risk factors on VEGFi-mediated LVSD and hypertension. This needs to be considered in future prospective studies. The generalizability of these results may also be limited because all participants were screened for CVD and hypertension at baseline and were undergoing treatment in the adjuvant setting for high-risk renal carcinoma.

Conclusions

In the analysis of data from this trial, AYAs with fewer comorbidities had a similar incidence of LVSD as non-AYAs, independent of VEGFi exposure, and a significant burden of hypertension in the setting of VEGFi exposure. These results suggest that younger age and lower comorbidity burden may not reduce the incident risk for cardiovascular toxicities among AYAs receiving VEGFi therapy and suggest a need for further research to understand and mitigate the factors that influence cardiovascular risk in this population. Given the high survival rates and the anticipation of an extended survivorship period among AYAs, understanding the relationship between cancer diagnosis, treatment, and CVD is imperative to promoting cardiovascular health over the entire lifetime of AYAs.20

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Submitted August 9, 2022; final revision received March 3, 2023; accepted for publication March 6, 2023.

Author contributions: Conceptualization: Bottinor, Flamand, Haas, ONeill, Salsman, Ky. Data curation: Haas, Subramanian. Formal analysis: Flamand, ONeill. Validation: Flamand, ONeill. Writing—original draft: Bottinor, Flamand, Salsman, Ky. Writing—review and editing: Haas, ONeill, DiPaola, Cella, Hundley, Wagner.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by ECOG-ACRIN (award number UG1CA189828-06-VCU1). This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD, and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180820, U10CA180794, UG1CA189828, UG1CA233270, UG1CA233196, UG1CA233320, and UG1CA189869. The research reported in this publication was also supported by CTSA award No. KL2TR002648 from the National Center for Advancing Translational Sciences, Tomorrow’s Research Fund St. Baldrick’s Scholar Award (award number 636214), and American Heart Association (award number 19CDA34760181).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the supporting institutions.

Correspondence: Wendy J. Bottinor, MD, MSCI, Virginia Commonwealth University, Department of Internal Medicine, Division of Cardiovascular Medicine, Gateway Building, 1200 East Marshall Street, Richmond, VA 23298. Email: wendy.bottinor@vcuhealth.org

Supplementary Materials

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  • Figure 1.

    Incidence of LVSD and hypertension among AYAs and females. Overall incidence of LVSD (absolute LVEF decrease >15% to a value below the institutional lower limit of normal from baseline during the 54-week study period) is not significantly different between AYAs and non-AYAs or between female and male sex. Incidence of hypertension (≥140/90 mm Hg), although prevalent overall, is lower among AYAs compared with non-AYAs and female sex compared with male sex.

    Abbreviations: AYA, adolescent and young adult; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction.

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