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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 775-781

Incidence and risk of hypertension associated with ramucirumab in cancer patients: A systematic review and meta-analysis


1 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Pudong New District, China
2 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Pudong New District; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

Date of Web Publication25-Jul-2016

Correspondence Address:
Shen Fu
Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, 4365 Kang Xin Road, Pudong New District, Shanghai - 201 321; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai-200 032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148700

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 > Abstract 


Background: Ramucirumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has been approved for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma. Hypertension has been described as a common adverse event with ramucirumab, but the incidence and risk have not been well determined. We conduct this meta-analysis to investigate the overall incidence and risk of developing hypertension associated with use of ramucirumab.
Materials and Methods: Databases from PubMed, Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) meeting up to May 31, 2014, were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating ramucirumab in cancer patients with adequate data on hypertension. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% confidence intervals (CIs) by using either random--effect or fixed--effect models according to the heterogeneity of included studies.
Results: A total of 2,649 patients with a variety of solid tumors from eight prospective clinical trials were included in our analysis. The incidence of all--grade and high-grade hypertension associated with ramucirumab was 16.4% (95%CI: 11.9–22.3%) and 9.8% (95%CI: 7.2–13.0%), respectively. Patients treated with ramucirumab had a significantly increased risk of developing all-grade (RR: 2.28, 95%CI: 1.61–3.24, P < 0.001) and high-grade (RR: 3.59, 95%CI: 2.32–5.53, P < 0.001) hypertension compared with patients treated with control medication. No evidence of publication bias was observed.
Conclusions: The use of ramucirumab is associated with a significantly increased risk of developing hypertension when compared with controls. Close monitoring and appropriate managements are recommended during the therapy.

Keywords: Cancer, hypertension, meta-analysis, ramucirumab


How to cite this article:
Qi WX, Fu S, Zhang Q, Guo XM. Incidence and risk of hypertension associated with ramucirumab in cancer patients: A systematic review and meta-analysis. J Can Res Ther 2016;12:775-81

How to cite this URL:
Qi WX, Fu S, Zhang Q, Guo XM. Incidence and risk of hypertension associated with ramucirumab in cancer patients: A systematic review and meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Dec 11];12:775-81. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/775/148700




 > Introduction Top


Angiogenesis, the formation of new blood vessels, plays a critical role in the tumor growth, invasion, and metastasis, and thus the tumor vasculature is a good target for cancer therapy.[1],[2],[3],[4] During the past decade, multiple clinical trials demonstrated that angiogenesis inhibitors, principally targeting the vascular endothelial growth factor (VEGF) pathway, had been associated with a survival benefit in a variety of solid tumors including colorectal cancer (CRC),[5],[6] non–small-cell lung cancer (NSCLC),[7],[8] renal cell carcinoma (RCC),[9],[10],[11],[12],[13] and hepatocellular carcinoma (HCC).[14] The VEGF family comprises VEGF-A, -B, -C, -D, and -E,[15] placenta growth factors (PlGF)-1 and -2, VEGF receptors (VEGFR)-1 (also referred to as fms-like tyrosine kinase 1 [Flt-1]), -2 (also referred to as kinase insert domain receptor [KDR]),[16] and -3, and co-receptors neuropilin1/2.[17] Recent data suggest that VEGF-A has a major role in angiogenesis, and its actions are mainly mediated by VEGFR-2.[1],[17] Therefore, inhibition of VEGFR-2 activation is expected to prevent the formation of new blood vessels and thereby limit the supply of nutrients to the tumour, thus causing the death of the tumour cells. Ramucirumab (Cyramza ), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that targets the VEGFR-2, was approved by the US Food and Drug Administration (FDA) on April 21, 2014, for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma in patients who experienced disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy.[11] The approval of ramucirumab is based on the results from the REGARD trial (NCT00917384). Patients in this study, all of whom had experienced disease progression after first-line platinum- or fluoropyrimidine-containing chemotherapy, were randomized to treatment with ramucirumab 8 mg/kg (n = 238) or placebo (n = 117) by infusion every 2 weeks, in addition to BSC (best support care). Median overall survival (OS) duration rates for the ramucirumab and placebo groups were 5.2 months and 3.8 months, respectively (hazard ratio [HR]: 0.776, 95% confidence interval [CI]: 0.603–0.998; P = 0.047). The median progression-free survival (PFS) duration was also significantly increased with ramucirumab (2.1 vs. 1.3 months; HR: 0.483, 95%CI: 0.376–0.620; P < 0.0001). Disease control rates for ramucirumab and placebo were 49% and 23%, respectively (P < 0.0001). Another large phase III randomized controlled trials for NSCLC also demonstrated that ramucirumab and docetaxel significantly improved median PFS duration compared with placebo and docetaxel (4.5 vs. 3.0 months, HR: 0.76, 95%CI: 0.68–0.86; P < 0.0001). The median OS duration was also significantly increased with ramucirumab (10.5 vs. 9.1 months; HR: 0.86, 95%CI: 0.75–0.98; P = 0.023).[18] Additionally, the efficacy of ramucirumab in other malignancies such as metastatic breast cancer,[19] CRC,[20] HCC,[21] and RCC.[22] has been also under investigation. Therefore, an increase in the use of ramucirumab is expected in the near future.

As with many other approved VEGF-targeted agents (bevacizumab, aflibercept, sorafenib, sunitinib, pazopanib, axitinib, and vandetanib), ramucirumab is also associated with unique VEGF-related class adverse events, including proteinuria, hemorrhage, thrombosis, and gastrointestinal perforation.[23] Specially, hypertension is a major side-effect that has been reported to be associated with ramucirumab, with its incidence ranging from 10.8-40.5%.[18],[21] Poorly controlled ramucirumab-induced hypertension may lead to serious cardiovascular events, treatment disruption, and dose reduction. Therefore, the recognition and management of hypertension might be an important issue in patients treated with ramucirumab. However, to our best knowledge, the incidence and risk of hypertension with the use of ramucirumab has not been systematically defined. Therefore, we conduct a systematic review and a meta-analysis to determine the overall incidence and risk of hypertension associated with ramucirumab in cancer patients.


 > Materials and Methods Top


Search strategy

We searched the Pubmed (data from 2000 to May 2014), Embase (data from 2000 to May 2014), and the Cochrane Library electronic databases without language restriction. We used the following words treated as title/abstract or MeSH terms for the literature search: (“cancer,” OR “carcinoma,” OR “neoplasm,” OR “tumor,” OR “sarcoma,” OR “malignant,” OR “carcinosarcoma,” OR “soft-tissue sarcoma,” OR “melanoma, OR “ leiomyosarcoma”) And (“ramucirumab,” OR “IMC-1121B”) And (“clinical trial,” OR “randomized controlled trials as topic,” OR “randomized controlled trials,” OR “study,” OR “prospective study”). We also searched abstracts containing the term “ramucirumab” that were presented at the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) annual meetings between 2004 and 2014 to identify relevant studies. Additionally, we searched the clinical trial registration Web site (http://www. ClinicalTrials.gov) to obtain information on the registered clinical trials. Updated manufacturer package insert of aflibercept was also reviewed for related information.

Study selection

Two investigators (Qi W.X. and Fu S.) independently assessed the eligibility of the articles and abstracts identified by the search, and discrepancies were resolved by consensus. The clinical trials that met the following criteria were selected for the final analysis: (1) prospective phase II and III clinical trails in cancer patients; (2) participants assigned to treatment with ramucirumab alone or in combination; and (3) events or event rate and sample size available for hypertension. Only the most recent publication (and the most informative) was included if multiple publications of the same trial were retrieved or if there was a case mix among publications.

Clinical end points

Hypertension was extracted from the safety profile in each trial. These clinical end points were recorded according to versions III of the Common Terminology Criteria for Adverse Events (CTCAE) of National Cancer Institute ([24]%3C/sup%3E%20The%20CTC%203.0%20version%20described%20the%20grading%20of%20HTN%20(hypertension)%20as:%20Grade%20I,%20asymptomatic,%20transient%20(<24%20hrs)%20increase%20of%20blood%20pressure%20by%20>20%20mmHg%20(diastolic">http://ctep.cancer.gov/reporting/ctc_archive.html).[24] The CTC 3.0 version described the grading of HTN (hypertension) as: Grade I, asymptomatic, transient (<24 hrs) increase of blood pressure by >20 mmHg (diastolic), or to > 150/100 mmHg if previously within normal limit (WNL), intervention not indicated; grade II, recurrent or persistent (>24 hrs) or symptomatic increase by >20 mmHg (diastolic) or to > 150/100 mmHg if previously WNL, monotherapy might be indicated; grade III, requiring more than one drug or more intensive therapy than before; and grade IV, hypertensive crisis. We included all incidences of HTN of grade 1 or above in our analysis.

Data analysis

The number of patients with all-grade and high grade (grades 3-4) of hypertension and the number of patients receiving ramucirumab were extracted from the adverse event outcomes. For each study, we derived the proportion and 95%CI of patients with hypertension. For studies with a control group in the same trial, we also calculated and compared the RR of hypertension. For one study that reported zero events in the control arm, we applied the classic half-integer correction to calculate the RR and variance.[25] Between-study heterogeneity was estimated using the χ2-based Q statistic.[26] Heterogeneity was considered statistically significant when Pheterogeneity < 0.05 or I2 > 50%. If heterogeneity existed, data were analyzed using a random-effect model. In the absence of heterogeneity, a fixed-effect model was used. To calculate the pooled incidence, an inverse variance statistical method was used. A statistical test with a P > 0.05 was considered significant. The presence of publication bias was evaluated by using the Begg's and Egger's tests.[27],[28] The quantitative 5-point Jadad scale was used to assess the quality of included trials based on the reporting of the studies' methods and results.[29] All statistical analyses were performed by using Version 2 of the Comprehensive MetaAnalysis program (Biostat, Englewood, NJ).


 > Results Top


Search results

Our search yielded a total of 152 articles on ramucirumab from the literature. After reviewing each publication, we identified six original studies and two abstracts that met our inclusion criteria, including three phase III trials and five phase II trials [Figure 1]. A total of 2,649 patients from eight clinical trials were available for analysis. The baseline characteristics of patients in the included studies are listed [Table 1]. Underlying malignancies including advanced gastric or gastroesophageal junction adenocarcinoma (two trials),[23],[30] metastatic CRC (one trial),[20] advanced NSCLC (one trial),[18] metastatic RCC (one trial),[22] metastatic melanoma (one trial),[31] advanced HCC (one trial),[21] and metastatic breast cancer (one trial).[19] The quality of the four randomized controlled trials was high. Three of them had Jadad score of 5, which mentioned the concealment of allocation clearly in the randomization process, and provided the number of patients who withdrew from the trials. One trial was an open-label trial and did not mention the number of patients who withdrew from the trials, and thus had Jadad scores of 2. We performed this meta-analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement.[32]
Figure 1: Selection process for prospective clinical trials included in the meta-analysis

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Table 1: Baseline characteristics of eight included clinical trials in the meta-analysis (n=)

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Incidence of all-grade hypertension

Data for all-grade hypertension were available for analysis from a total of 1,117 patients. The incidence of all-grade hypertension ranged between 10.8 and 40.5%, with the highest incidence observed in a prospective clinical trial in patients with advanced hepatocellular cancer,[21] and the lowest in a randomized controlled phase III trial in patients with NSCL cancer. On the basis of the data from six trials, the overall incidence of all-grade hypertension was 16.4% (95%CI: 11.9–22.3%) according to the random-effects model [Figure 2]. We then performed sub-group analysis according to ramucirumab-based regimen. The incidence of all-grade hypertension for ramucirumab monotherapy was higher than that of ramucirumab-based combination therapy (25.1 vs. 14.2%), but the incidence difference between monotherapy and combination therapy was not statistically significant (P = 0.12).
Figure 2: Incidence of all- and high-grade hypertension associated with ramucirumab

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Incidence of high-grade hypertension

High-grade hypertension is associated with increased morbidity and can result in dose modification or treatment interruption. The incidence of high-grade hypertension ranged from 4.2 to 16.7%, with the highest incidence observed in a single-arm phase II trials in patients with colorectal cancer.[20] and the lowest in a randomized phase II trial in patients with breast cancer.[19] On the basis of the data from eight trials with a total of 1,493 patients, the overall incidence of high-grade hypertension was 9.8% (95%CI: 7.2–13.0%) according to the random-effect model [Figure 2]. Sub-group analysis according to ramucirumab-based regimen showed that the incidence of high-grade hypertension for ramucirumab monotherapy was comparable with that of ramucirumab-based combination therapy (9.8 vs. 9.6%), and no significant difference was found between these two groups (P = 0.96).

Relative risk of hypertension

To investigate the specific contribution of ramucirumab to the development of hypertension and exclude the influence of confounding factors such as underlying malignancy and history of other therapeutic interventions, we determined the RR of hypertension associated with ramucirumab. A meta-analysis of the RR for all-grade hypertension attributable to ramucirumab compared with controls was performed on three randomized controlled trials. The overall RR for all-grade hypertension was 2.28 (95% CI: 1.61–3.24, P < 0.001) [Figure 3], according to the fixed-effect model. As for high-grade hypertension in patients prescribed ramucirumab, the combined RR demonstrated that the use of ramucirumab significantly increased the risk of developing high-grade hypertension (RR: 3.59, 95% CI: 2.32–5.54, P < 0.001) [Figure 3] using a fixed-effect model.
Figure 3: Relative risk of all- and high-grade hypertension associated with ramucirumab vs. control

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Publication bias

No evidence of publication bias was detected for the RR of all-grade and high-grade hypertension in this study by the funnel plot [Figure 4], Egger's test, and Begg' test (RR of all-grade hypertension: Egger's test P = 0.36, Begg's test P = 0.60; RR of high-grade hypertension: Egger's test P = 0.94, Begg's test P = 0.50).
Figure 4: Funnel plot of standard error by log-odds ratio for hypertension

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 > Discussion Top


During the past decade, there has been considerable progress in the understanding of the molecular mechanism of VEGF signaling pathways in oncology, which led to the discovery of a variety of anti-VEGF agents. Although anti-VEGF agents present a favorable toxicity profiles and are generally tolerable, hypertension is an emerging complication associated with the use of these drugs. Indeed, the incidence and risk of hypertension with anti-VEGF monoclonal antibody (bevacizumab.[33],[34] and aflibercept.[35]) and anti-VEGFR-tyrosine kinase inhibitors (sorafenib,[36],[37],[38] sunitinib,[39] vandetanib,[40] pazopanib,[41] axitinib,[42] and regorafenib.[43]) has been previously well determined. However, the overall incidence and risk of hypertension with ramucirumab, a novel monoclonal antibody targeting VEGFR-2, is still unknown.

Our study includes a total of 2,694 patients from eight prospective clinical trials. To our best knowledge, this is the first large meta-analysis study demonstrating a significant increase in the risk of all-grade and high-grade hypertension with the use of ramucirumab. The overall incidence of all-grade hypertension associated with ramucirumab is 16.4% (95%CI: 11.9–22.3%), which is lower than other anti-VEGF agents, whereas the incidence of high-grade hypertension (9.8%, 95%CI: 7.2–13.0%) with ramucirumab is comparable with other anti-VEGF agents.[35] We then performed sub-group analysis according to ramucirumab-based regimen and found that the incidence of hypertension with ramucirumab monotherapy is comparable with that of ramucirumab combination therapies, which suggests that the concomitant drugs may not affect the incidence of hypertension associated with ramucirumab. Our analysis of data from four randomized controlled trials also demonstrates that the risk of developing a hypertension of any grade is 2.28-fold higher in patients treated with ramucirumab. And, more importantly, there is a 3.59-fold increase in the risk of high-grade hypertension associated with the use of ramucirumab.

With an increased RR of treatment-related hypertension, it is clear that proper monitoring, immediate intervention, and effective management are crucial to achieve the maximal therapeutic benefit of ramucirumab. However, there are no specific guidelines for the treatment of ramucirumab-induced hypertension because there is a lack of controlled studies addressing the subject. According to the manufacturer package insert for ramucirumab,[44] clinicians should control hypertension before initiating treatment with ramucirumab. Lifestyle modification may be considered for patients with hypertension. All patients receiving ramucirumab should be monitored for blood pressure every 2 weeks or more frequently as indicated during treatment. The packet insert also recommends to permanently discontinue ramucirumab if medically significant hypertension cannot be controlled with anti-hypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. No clear recommendation for an anti-hypertensive agent can be made because there is a lack of controlled studies addressing the subject. Calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and angiotensin 2 receptor antagonist (ARA) have been recommended to treat hypertension secondary to anti-angiogenesis therapy. Further studies are needed to identify the mechanisms and optimize treatment of this hypertension.

Despite the size of this meta-analysis, our study has several limitations. First, all included studies are conducted at major academic institutions among patients with adequate major organ function, and thus the results may not entirely apply to the general patient population in the community or patients with organ dysfunction. Second, the sample size is not large and may have affected our analysis. Third, the prevalence of baseline hypertension is not described in these trials, which may lead to an overestimation of the incidence of hypertension associated with ramucirumab. Fourth, different versions of CTCAE are used for grading hypertension in the included trials, which could contribute to variability in hypertension grading among the different investigators. Finally, this is a meta-analysis at study level; therefore, confounding factors at the patient level cannot be assessed properly and incorporated into the analysis.


 > Conclusion Top


In conclusion, this study has demonstrated that the use of ramucirumab significantly increases the risk of developing hypertension in cancer patients. Early detection and effective management of hypertension with ramucirumab is crucial for safer use of this drug.

 
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