Sungyub Lew, MD

Saint Barnabas Medical Center, Livingston, New Jersey

Saint George&rsquo;s University School of Medicine

Chairman and Surgeon-in-Chief, Department of Surgery

Saint Barnabas Medical Center, Professor of Surgery, New Jersey Medical School

Sunitinib is a multitargeted tyrosine kinase inhibitor widely used in cancer therapy that has been linked to varying degrees of treatment-related hypertension (HTN). The incidence and risk of HTN remain unclear. This study aims to assess the incidence and risk of sunitinib-associated HTN and provide a systematic review of sunitinib treatment.

A comprehensive literature search was completed of PubMed, Google Scholar, and the Cochrane Central Registry of Controlled Trials. Key words searched were: sunitinib, sutent, SU11248, cancer, and clinical trial. Eligible studies were limited to phase II and III trials of sunitinib, including safety reporting of HTN in patients with any type of malignancies. All clinical trials were analyzed for patient recruitment, intervention, and outcomes. Incidence and relative risk (RR) were calculated with 95% CI.

62 single-arm or double-arm, phase II/III clinical trials involving 11,801 patients treated with sunitinib were identified. The incidence of sunitinib-associated all-grade and high-grade (grade &ge;3) HTN was 19.3% (95% CI, 15.8-23.4) and 6.0% (95% CI, 4.6-7.8), respectively. Relative risk of sunitinib-associated allgrade and high-grade HTN was 3.13 (95% CI, 1.97-5.00;

= .001), respectively. Subgroup analysis demonstrated that the incidence and risk of severe sunitinib-associated HTN were not significantly different between 37.5-mg and 50-mg dosage regimens when monotherapy and/or concomitant chemotherapy were used, or by the type of malignancies, such as renal cell cancer, breast cancer, and non-small cell lung cancer.

Sunitinib treatment is associated with a significantly increased risk of all-grade and high-grade HTN.

Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor (TKI) that disrupts the signaling pathway activity against platelet-derived growth factor (PDGF) receptors &alpha; and &beta;, vascular endothelial growth factor (VEGF) receptors 2 and 3, FMS-like tyrosine kinase-3 (FLT3), and c-KIT, all of which are involved in angiogenesis and tumor proliferation.

The US Food and Drug Administration (FDA) has approved sunitinib for treatment of advanced renal cell carcinoma (RCC), of gastrointestinal stromal tumor (GIST) after intolerance or disease progression on imatinib mesylate, and for progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease.

Similar to other VEGF-receptor TKIs, sunitinib is associated with substantial adverse events (AEs).

These include hypertension (HTN), diarrhea, rash, fatigue, diarrhea, and mucositis.

In addition to these frequently reported AEs, previous studies with sunitinib therapy have reported an increased risk of developing hand-foot skin reaction, hematologic toxicities, arterial/venous thromboembolism, and hypothyroidism.

A meta-analysis by Zhu et al found a significantly higher risk of HTN in patients given sunitinib compared with controls: relative risk (RR), 22.72; 95% CI, 4.48-115.29;

The overall incidence of all-grade HTN was 21.6% (95% CI, 18.7-24.8) and of high-grade HTN was 6.8% (95% CI, 5.3-8.8). However, Zhu et al noted several limitations to their analysis, including an underestimation of the incidence of HTN associated with sunitinib because more than 70% of the patients included in the study were derived from the expanded access program, which did not include standardized toxicity data. Additionally, although the RR of high-grade HTN was significant, the findings were limited by the availability of very few randomized studies. The 1062 patients included in this analysis for the sunitinib arm and the 577 in the control arm came from only two randomized controlled trials, which had significant variation between them. Thus, the incidence and RR of high-grade HTN with sunitinib use have not yet been fully elucidated. Many additional randomized clinical trials have been completed since the previous meta-analysis, but with substantial variation in results. This study represents a meta-analysis of randomized controlled trials to assess the risk of high-grade HTN with sunitinib treatment and to provide a contemporary systematic review of sunitinib treatment.

Data abstraction, meta-analysis, and systematic review have been performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,

and a comprehensive literature search of PubMed, Google Scholar, and the Cochrane Central Registry of Controlled Trials from January 1966 to August 2014 was conducted. Key words included in the search were: sunitinib, Sutent, SU11248, cancer, and clinical trial. The search was restricted to clinical trials in English. In case of duplicate publications, only the most recent and updated report of the clinical trial was included.

Study Selection, Data Extraction, and Clinical Endpoints

Clinical trials that met the following conditions were included in this study: (a) phase II or III trials in patients with cancer; (b) participants assigned to treatment with sunitinib; (c) events and sample size available for all-grade or high-grade HTN (grade 3 and 4); (d) participants assigned to treatment with only sunitinib at a dosage of either oral 25 mg, 37.5 mg, or 50 mg with either continuous daily dosing or intermittent treatment-free schedule; (e) safety reporting of all-grade or high-grade HTN available. To analyze the incidence of HTN associated with sunitinib, only trials with participants who were assigned to sunitinib as a monotherapy were used.

The incidence of HTN events in most of the included trials were recorded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 3, which defines HTN as the following: (a) grade 1, asymptomatic, transient (<24 h) increase in blood pressure (BP) of >20 mm Hg (diastolic) or to >150/100 mm Hg if previously within normal limits, intervention not indicated; (b) grade 2, recurrent or persistent (>24 h) or symptomatic increase by >20 mm Hg (diastolic) or to >150/100 mm Hg if previously within normal limits, monotherapy might be indicated; (c) grade 3, requiring more than one drug or more intensive treatment than used previously; (d) grade 4, life-threatening consequences; and (e) grade 5, death.

For RR analysis, randomized controlled trials were included in the study when participants were randomly assigned to sunitinib versus placebo, sunitinib plus best supportive care versus placebo plus best supportive care, or sunitinib plus concurrent immunotherapy and/or chemotherapy versus immunotherapy and/or chemotherapy alone. In case of crossover studies, only data available prior to crossover were used. If the data prior to crossing over were not available, the study was excluded.

Incidence, RR, and 95% CIs for all-grade (grades 1-2) and high-grade (grades 3-4) HTN were calculated. Relative risk and CIs were calculated with data extracted only from randomized controlled studies, and the HTN events in patients assigned to sunitinib were compared with those assigned to control treatment in the same trial. To calculate 95% CIs, the variance of a log-transformed study-specific RR was derived using the delta method.

To calculate the incidence, clinical trials with sunitinib as a monotherapy were included in the analysis. The trials with concomitant chemotherapy and/or immunotherapy in addition to sunitinib were excluded from analysis to minimize the effect of other medications. The number of patients who developed HTN and the number of patients who received sunitinib were extracted from the selected single-arm and randomized controlled trials. The rate of AEs and 95% CIs were extracted from each trial. Traditional continuity corrections using a factor of 0.5 was adopted to calculate the RR and variance for the studies reporting zero events in any arm. In case of zero events in both groups, the RR was not calculable, and the study was excluded from the meta-analysis. Depending on the heterogeneity of included studies, fixed-effect or random-effects models were used for the calculation of RRs and summary incidence. Cochrane&rsquo;s Q statistics with I

statistic was used to estimate statistical heterogeneity. An assumption of homogeneity was considered invalid for

>50%. When substantial heterogeneity was not observed, the pooled estimate was calculated based on the fixed-effect model. When significant heterogeneity was observed, the pooled estimate was calculated with a random-effects model. The publication bias regarding the primary endpoint (RR of high-grade HTN) was evaluated using Funnel plot, Begg&rsquo;s test, and Egger&rsquo;s test. A two-tailed

value of <.05 was considered statistically significant. Statistical analysis was performed using the Comprehensive Meta-Analysis software Version 3 (Biostat, Englewood, New Jersey).

The search yielded 357 potentially relevant citations. The selection process excluded 295 citations; the reasons for study exclusion are detailed in

. In all, 62 phase II and phase III clinical trials were considered eligible for the meta-analysis; 21 trials involved randomized treatment allocation, while 41 trials were single-arm trials. Of the 21 randomized treatment trials, 11 had placebo as a control and 10 had active treatment as the control arms. The HTN events in the included trials were reported in accordance with CTCAE version 2, 3, or 4. Two trials used version 2, 55 trials used version 3, two trials used version 4, and three trials did not specify the CTCAE version. The baseline characteristics of each trial are depicted in (

Characteristics of All Sunitinib Clinical Trials Included in the Meta-analysis.

FIGURE 1. CONSORT diagram of selection process for the clinical trials.

Only arms with sunitinib monotherapy were considered for the HTN incidence analysis. The trials that involved concomitant chemotherapy and/or immunotherapy were excluded because of the possibility of confounding effect on blood pressure from the concomitant therapy. A total of 4276 patients who were treated with sunitinib from both randomized and nonrandomized studies were included. All-grade HTN occurred in 807 of 3981 patients, 19.3% (95% CI, 15.8-23.4). The overall incidence of all-grade HTN was 3.7% (95% CI, 1.7-5.8) in the placebo arm. High-grade HTN occurred in 285 of 4276 patients, 6.0% (95% CI, 4.6-7.8). The overall incidence of high-grade HTN was 0.8% (95% CI, 0.0-1.7) in the placebo arm. In all-grade and high-grade HTN in sunitinib therapy, the heterogeneity test was significant (

= 71%) and a random-effects model was used.

For meta-analysis of the overall RR for all-grade and high-grade HTN events, 20 randomized clinical trials were included. The control arm was best supportive care or chemotherapy and/or immunotherapy. The treatment arm was sunitinib in addition to best supportive care or chemotherapy and/or immunotherapy. The RR of all-grade and high-grade HTN associated with sunitinib compared with control was 3.13 (95% CI, 1.97-5.00;

Click here, to download a PDF of FIGURES 2 and 3

). A random-effects model was used for both all-grade and high-grade HTN because heterogeneity was found to be significant in both cases (

Because of the potential risk of BP elevation from the use of concomitant chemotherapeutic or immunotherapeutic agents, the impact of the control arm on RR of high-grade HTN with sunitinib treatment was investigated. Among 20 randomized controlled trials, 10 involved sunitinib as a single agent and 10 used sunitinib in combination with chemotherapeutic and/or immunotherapeutic agents. The RR of high-grade HTN in combination therapy was 2.20 (95% CI, 1.00-4.88;

= .051) and was 3.01 in sunitinib monotherapy (95% CI, 1.34-6.75;

= .007). Although RR of high-grade HTN in combination therapy was not significant, there was no difference observed in the RR of high-grade HTN between sunitinib monotherapy and combination therapy (P = .588) (

). The incidence and RR of high-grade HTN were further investigated by malignancy type and by dosage regimen. The stratified malignancy types were RCC, breast cancer (BC), and non small cell lung cancer (NSCLC). There was no difference in the incidence of the high-grade HTN among the malignancies studied. There was no difference in the RR of high-grade HTN between RCC and non-RCC, between BC and non-BC, or between NSCLC and non- NSCLC. No differences in the RR of high-grade HTN were observed between a 37.5-mg dosage regimen and a 50-mg dosage regimen. The duration of therapy for 50-mg dosage regimen also showed no statistical difference whether treatment duration was shorter or longer than 4 months

TABLE 2. Incidence and Relative Risk of High-Grade HTN Stratified by Type of Malignancy Treated and by Treatment Regimen

BC indicates breast cancer; NSCLC, nonsmall cell lung cancer; RCC, renal cell carcinoma.

Publication bias for the all-grade HTN was significant via the Egger&rsquo;s test (

= .51). Regarding high-grade HTN, Egger&rsquo;s test was significant (

= .54). Three trials compared sunitinib with the same VEGF class medications: bevacizumab,

After adjusting for VEGF inhibitor class trials, publication bias was not observed for both all-grade and high-grade HTN: Begg&rsquo;s test,

All-grade and high-grade HTN occurs about 19% and 6% of patients, respectively, in sunitinib treatment.

Sunitinib therapy increases the risk of HTN.

Sunitinib-associated HTN does not differ by dosage regimen, by malignancy type, or when monotherapy and/or concomitant chemotherapy are used.

Hypertension is a common adverse event observed in clinical trials associated with VEGF-inhibitor class medications. VEGF inhibitors, such as sunitinib, sorafenib, pazopanib, and bevacizumab have all been associated with increased risk of HTN.

In a recent meta-analysis, HTN developed in 23.6% (95% CI, 20.5-27.1) of patients treated with bevacizumab, 23.1% (95% CI, 19.3-26.9) of patients treated with sorafenib, and 35.9% (95% CI, 31.5-40.6) of patients treated with pazopanib.

This study demonstrated that there was a high incidence of HTN associated with sunitinib therapy in patients with cancer: all-grade: 19.3% (95% CI, 15.8-23.4). Most HTN associated with sunitinib are grades 1 or 2, but high-grade HTN in association with sunitinib use is not infrequent (high-grade: 6.0% [95% CI, 4.6-7.8]). Chu et al studied 75 patients treated with sunitinib for GIST and reported that 8% of patients experienced congestive heart failure and more than 10% experienced a 28% reduction of left ventricular ejection fraction.

VEGF-inhibitorinduced HTN is associated with decrease in nitric oxide (NO) production and endothelin signaling pathway activation.

Kruzliak et al described bioavailability of NO by direct inhibition of endothelial NO synthase through VEGFR-2 leading to reduced vasodilation, and NO-deficiencymediated cell proliferation in tunica media leading to fixation of HTN.

In addition, Wheeler et al has shown that treatment-associated HTN is related to interference in prostacyclin production in human umbilical endothelium cells.

The study by Robinson et al of urinary biomarkers from 80 patients with metastatic RCC showed the association between antiangiogenic therapy and suppression of metabolites of the NO pathway and cyclic guanosine monophosphate (cGMP).

Hypertension is a dose-limiting toxicity in VEGF inhibitor therapy. However, there are no evidence-based guidelines for the management of VEGF inhibitor-induced HTN. Traditionally, most patients are managed with standard antihypertensive medications, and in the case of severe or persistent HTN, the VEGF inhibitor is temporarily or permanently discontinued until proper control of the HTN is achieved. Angiotensin-converting enzyme inhibitors have been most commonly used because proteinuria may also be associated with VEGF inhibitor use.

Because of the mechanism of VEGF inhibition, Kruzliak et al have suggested a possible role for long-acting NO donors such as molsidomine,

administered as a pretreatment 7 to 10 days before starting VEGF inhibitor therapy in patients whose baseline BP is &ge;140/90 mm Hg or who have other cardiovascular risk factors. Further study is necessary to evaluate the benefit of pretreatment of NO donors in patients with pre-existing HTN treated with sunitinib.

In addition to managing VEGF-inhibitorinduced HTN, there is increasing evidence that elevation of blood pressure (BP) in patients who are on antiangiogenic therapy may predict better outcome. Rini et al investigated four studies of patients with metastatic RCC who were treated with sunitinib 50 mg daily on a 4-week-on, 2-week-off cycle. Patients with BP &ge;140/90 had improved overall survival, progression-free survival, and hazard ratio for survival compared with patients who did not develop HTN after the sunitinib treatment.

Similar results were observed for bevacizumab, sorafenib, and apatinib as well.

Hypertension may reflect the effectiveness of the inhibition of VEGF-signaling pathway and tumor response.

Articles

Sunitinib treatment is associated with a significantly increased risk of all-grade and high-grade hypertension.

Sungyub Lew, MD | Authors

Articles

Hypertension Risk Among Cancer Patients Treated With Sunitinib: A Meta-analysis and Systematic Review