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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 96-103

Meta-analysis of therapeutic effects and the risks of hypertension and hyperglycemia in patients with renal cell carcinoma who were receiving antiangiogenic drugs


1 Department of Kidney Internal Medicine, Yidu Central Hospital of Weifang, Weifang 262500, China
2 Department of Endocrinology, Yidu Central Hospital of Weifang, Weifang 262500, China

Date of Web Publication7-Oct-2016

Correspondence Address:
Lingling Chang
Department of Kidney Internal Medicine, Yidu Central Hospital of Weifang, Weifang 262500
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191614

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 > Abstract 


Purpose: A meta-analysis of published data was conducted to investigate the therapeutic effects in patients with renal cell carcinoma (RCC) who were receiving antiangiogenic drugs.
Methods: A computerized search through electronic databases, including PubMed (until February 2016), was performed to obtain eligible randomized controlled trials that compared the effectiveness of antiangiogenic with control groups (everolimus, placebo, and interferon [IFN] alfa) in patients with RCC. The data of progressive disease, objective response rate (ORR), stable disease rate (SDR), progressive disease rate (PDR), progression-free survival (PFS), and overall survival (OS) were extracted to assess therapeutic effects, hypertension, and hyperglycemia. Relative risk and 95% confidence interval were calculated and pooled using a fixed effects model.
Results: According to the meta-analysis, antiangiogenic agents have advantages in ORR (odds ratio [OR] =2.93, P < 0.00001), SDR (OR = 1.45, P < 0.00001), PDR (OR = 0.25, P < 0.00001, PFS (OR = 0.65, P < 0.00001), and median OS (OR = 0.88, P < 0.00001) compared with control group; in the subway group, sorafenib and pazopanib have advantages in median PFS compared with placebo (OR = 0.52, P < 0.00001); sunitinib and pazopanib have advantages in median OS compared with IFN (OR = 0.87, P = 0.03). Sunitinib, sorafenib, and pazopanib have greater risk of hypertension compared with control group (OR = 8.40, P < 0.00001); sunitinib and pazopanib did not have greater risk of hypertension compared with control group (OR = 1.26, P = 0.25).
Conclusions: Sorafenib, sunitinib, and the combination of bevacizumab and IFN are more effective in stabilizing disease, but they have higher risk of hypertension.

Keywords: Hypertension, pazopanib, sorafenib, sunitinib


How to cite this article:
Chang L, An Y, Yang S, Zhang X. Meta-analysis of therapeutic effects and the risks of hypertension and hyperglycemia in patients with renal cell carcinoma who were receiving antiangiogenic drugs. J Can Res Ther 2016;12:96-103

How to cite this URL:
Chang L, An Y, Yang S, Zhang X. Meta-analysis of therapeutic effects and the risks of hypertension and hyperglycemia in patients with renal cell carcinoma who were receiving antiangiogenic drugs. J Can Res Ther [serial online] 2016 [cited 2018 Nov 14];12:96-103. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/96/191614




 > Introduction Top


Renal cell carcinoma (RCC) has long been a chemotherapy-refractory malignancy. The biology of RCC is thought to be influenced by the immune system, and thus, interferon-alfa (IFN-α), an immunotherapeutic cytokine, has been investigated, and response rates have been between 10% and 15%. The addition of interleukin-2, hormonal therapy, or antiproliferative agents such as cis-retinoic acid to IFN has not demonstrated significant advantages over IFN monotherapy in randomized trials.[1] Based on a better understanding of pathogenesis mechanisms of RCC, in recent years, more and more targeting drugs are discovered by investigators, including multikinase inhibitors, i.e., sorafenib [2] and sunitinib,[3] the combination of antivascular endothelial growth factor agent bevacizumab with IFN-α.[4] However, therapeutic effect and adverse events, such as hypertension of antiangiogenic drugs, are unknown. In this study, a meta-analysis of randomized trials was performed to evaluate the therapeutic effect and the risk of hypertension and hyperglycemia treatments for RCC.


 > Methods Top


Study design

This study was a meta-analysis based on data collected from previous randomized controlled trials (RCTs) of chemotherapies for patients with RCC. Two reviewers selected and reviewed the evidence. Discrepancies were handled through group discussion.

Search strategy

Studies were searched among PubMed using the terms: “Antiangiogenic OR antiangiogenesis agents,” “angiogenesis inhibitor,” “sorafenib,” “sunitinib,” “bevacizumab,” “interferon (OR IFN),” “Renal cell carcinoma OR RCC,” and “randomized trials (random* OR randomized trials)” in title and abstract. The databases were searched for studies published till February 2016. Only trails published in English were involved. Reference lists of related articles were manually checked to search for additional eligible publications. All references of relevant articles were scanned, and all additional studies of potential interest were retrieved for further analysis.

Inclusion criteria

Eligible trails have to meet the following criteria: Patients involved were diagnosed with RCC through cytological diagnosis or pathological diagnosis; RCTs using antiangiogenic agents individually or in combination with IFN to treat RCC, without surgery or other nonantiangiogenic treatment; trails with patients who previously had received cancer immunotherapy or other molecular targeted therapy were excluded.

Data extraction and quality assessment

For each candidate trial, two reviewers independently recorded the characteristics of the studies, including the first author, publication year, Jadad scale, study designation, intervention, control, and stage of patients. Discrepancies were handled through group discussion. Analytical data that would be included in our meta-analysis but were missing from the original published studies were requested from their authors. The methodological quality of each included study was evaluated using the Jadad scale.[5] A trial score of ≤2 indicates low quality whereas a score of ≥3 indicates high quality.[6]

Statistical analysis

Our study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement.[7] Significant differences between studies were reported in terms of odds ratio (OR), with a 95% confidence interval (CI) for dichotomous outcomes.[8] Heterogeneity of the results of the trials was assessed with the I2 statistic using the Chi-square test at α = 0.1. Primary assessment was done with a fixed model. When P ≥ 0.05 and I2 ≤50%, it was considered that the trials are without heterogeneity and a fixed effect model was used to perform meta-analysis. When P < 0.05 and I2 >50%, it was considered that the trials are with significant heterogeneity.[9] The source of the heterogeneity was further analyzed. P ≤ 0.05 was considered statistically significant. If there was no significant clinical heterogeneity, a secondary confirmatory analysis was done with a random effects model. Otherwise, descriptive analysis was performed. If necessary, sensitivity analyses were performed to test the stability of identified outcomes. All data and statistical analyses, except for publication bias, were combined and performed using RevMan 5.3.0 (The Cochrane Collaboration, Copenhagen, Denmark).


 > Results Top


Literature search

A total of 10 RCTs [4],[10],[11],[12],[13],[14],[15],[16],[17],[18] from 160 potential articles were selected for our meta-analysis [Figure 1].
Figure 1: Literature screening process

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The principal characteristics of the selected articles are listed in [Table 1]. The ten trials, with a total of 5787 patients, were published in English between 2007 and 2016. The trials are all multicenter, randomized, controlled, and Phase II or III trails. Three studies assessed the combination treatment of bevacizumab with IFN-α,[16],[17],[18] three evaluated sunitinib,[10],[11],[12] three evaluated sorafenib,[4],[13],[14] and one studied pazopanib.[16]
Table 1: Patient characteristics

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Objective response rate

Seven studies evaluated the effect of multikinase inhibitors such as sorafenib (999 patients),[4],[13],[14] pazopanib (290 patients),[15] and sunitinib (606 patients)[10],[11],[12] in objective response rate (ORR). According to the meta-analysis, antiangiogenic agents such as sorafenib, sunitinib, and pazopanib have advantages in ORR compared with IFN, placebo, and everolimus (OR = 2.93, 95% CI: 2.42–3.55, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in ORR compared with IFN, placebo, and everolimus. However, I2 = 95%, it was implied that the trials are with significant heterogeneity. Next, heterogeneity analyzed was performed. When we remove the Escudier 2009, Motzer 2014, and Melichar 2008, I2 is 0. Thus, Escudier 2009, Motzer 2014, and Melichar 2008 are the sources of heterogeneity [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8].
Figure 2: Meta-analysis of effect in objective response rate

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Figure 3: Meta-analysis of effect in objective response rate after removing source of heterogeneity

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Figure 4: Meta-analysis of effect in stable disease

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Figure 5: Meta-analysis of effect in stable disease after removing source of heterogeneity

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Figure 6: Meta-analysis of effect in progressive disease

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Figure 7: Meta-analysis of effect in progressive disease after removing source of heterogeneity

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Figure 8: Meta-analysis of effect in progression-free survival

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Stable disease rate

Six studies evaluated the effect of multikinase inhibitors such as sorafenib (999 patients),[4],[13],[14] pazopanib (290 patients),[15] and sunitinib (375 patients)[10],[11],[12] in stable disease rate (SDR). According to the meta-analysis, antiangiogenic agents such as sorafenib, sunitinib, and pazopanib have advantages in SDR compared with IFN and placebo (OR = 1.45, 95% CI: 1.25–1.68, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in SDR compared with IFN and placebo. However, I2 = 95%, it was implied that the trials are with significant heterogeneity. Next, heterogeneity analyzed was performed. When we remove the Motzer 2009 and Sternberg 2010, I2 is 0. Thus, Motzer 2009 and Sternberg 2010 are the sources of heterogeneity [Figure 9], [Figure 10], [Figure 11], [Figure 12].
Figure 9: Meta-analysis of effect in progression-free survival after removing source of heterogeneity

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Figure 10: Meta-analysis of effect in overall survival

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Figure 11: Meta-analysis of effect in progression-free survival compared with placebo

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Figure 12: Meta-analysis of effect in overall survival compared with interferon

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Progressive disease rate

Six studies evaluated the effect of multikinase inhibitors such as sorafenib (999 patients),[4],[13],[14] pazopanib (290 patients),[15] and sunitinib (375 patients)[10],[11],[12] in progressive disease rate (PDR). According to the meta-analysis, antiangiogenic agents such as sorafenib, sunitinib, and pazopanib have advantages in PDR compared with IFN and placebo (OR = 0.25, 95% CI: 0.21–0.30, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in PDR compared with IFN and placebo. However, I2 = 55%, it was implied that the trials are with significant heterogeneity. Next, heterogeneity analyzed was performed. When we remove the Escudier 2009, I2 is 0. Thus, Escudier 2009 is the source of heterogeneity.

Median progression-free survival

Four studies evaluated the effect of multikinase inhibitors such as sorafenib (548 patients),[13],[14] pazopanib (290 patients),[15] and sunitinib (51 patients)[10] in median progression-free survival (PFS). According to the meta-analysis, antiangiogenic agents such as sorafenib, sunitinib, and pazopanib have advantages in median PFS compared with IFN and placebo (OR = 0.65, 95% CI: 0.58–0.74, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in median PFS compared with IFN, placebo, and everolimus. However, I2 = 92%, it was implied that the trials are with significant heterogeneity. Next, heterogeneity analyzed was performed. When we remove the Escudier 2009 and Andrew 2016, I2 is 0. Thus, Escudier 2009 and Andrew 2016 are the sources of heterogeneity.

Median overall survival

Four studies evaluated the effect of multikinase inhibitors such as sunitinib (426 patients)[10],[11] and combination of bevacizumab with IFN [16],[17] in median overall survival (OS). According to the meta-analysis, antiangiogenic agents such as sunitinib and combination of bevacizumab and IFN have advantages in median OS compared with IFN, placebo, and everolimus (OR = 0.88, 95% CI: 0.77–1.00, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in median OS compared with IFN, placebo, and everolimus.

Subgroup analysis

Two studies evaluated the effect of multikinase inhibitors such as sorafenib (451 patients)[13] and pazopanib (290 patients)[15] in median PFS. According to the meta-analysis, antiangiogenic agents such as sorafenib and pazopanib have advantages in median PFS compared with placebo (OR = 0.52, 95% CI: 0.45–0.60, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in median PFS compared with placebo.

Three studies evaluated the effect of multikinase inhibitors such as sunitinib (375 patients)[11] and combination of bevacizumab with IFN (696 patients)[16],[17] in median OS. According to the meta-analysis, antiangiogenic agents such as sunitinib and pazopanib have advantages in median OS compared with IFN (OR = 0.87, 95% CI: 0.76–0.99, P = 0.03). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in median OS compared with IFN.

Risk of hypertension

Three studies evaluated the risk of multikinase inhibitors such as sunitinib (657 patients),[4],[13],[14] pazopanib (290 patients),[15] and combination of bevacizumab with IFN (369 patients)[17] in hypertension. According to the meta-analysis, antiangiogenic agents such as sunitinib, pazopanib, and combination of bevacizumab with IFN have greater risk of hypertension compared with IFN, placebo, and everolimus (OR = 8.40, 95% CI: 6.41–11.00, P < 0.00001). Therefore, it is obvious that antiangiogenic agents can achieve better outcomes in median OS compared with IFN, everolimus, and placebo.

Risk of hyperglycemia

Two studies evaluated the risk of multikinase inhibitors such as sunitinib (51 patients),[10] pazopanib (290 patients)[15] in hyperglycemia. According to the meta-analysis, antiangiogenic agents such as sunitinib and pazopanib did not have a greater risk of hyperglycemia compared with placebo and everolimus (OR = 1.26, 95% CI: 0.85–1.88, P = 0.25) [Figure 12], [Figure 13], [Figure 14].
Figure 13: Meta-analysis of risk in hypertension

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Figure 14: Meta-analysis of risk in hyperglycemia

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 > Discussion Top


This meta-analysis intended to identify the therapeutic effect, associated with adverse events, including hypertension and hyperglycemia, of RCC. The study demonstrates that individual use of sorafenib, sunitinib, pazopanib, and combination of bevacizumab with IFN is more effective in ORR, SDR, and PDR compared with traditional IFN, everolimus, and placebo treatments. The results suggest that most significant advantage of sorafenib, sunitinib, pazopanib, and combination of bevacizumab with IFN compared with IFN is their effectiveness in preventing tumor progression. In addition, the results also show that the PFS and OS of sorafenib, sunitinib, pazopanib, and combination of bevacizumab with IFN are longer than traditional IFN, everolimus, and placebo treatments. In the subgroup analysis, the individual use of sorafenib and pazopanib is more effective in PFS compared with placebo treatment. Moreover, it also shows that sunitinib and pazopanib have advantages in median OS compared with IFN.

However, there is a significant risk in hypertension of antiangiogenic agents compared with IFN, everolimus, and placebo treatments although there is no significant risk in hyperglycemia of antiangiogenic agents compared with IFN, everolimus, and placebo treatments.

Although great progress has been achieved in understanding of molecular mechanism of RCC and development of targeting drugs in recent years, prognosis is still far from satisfactory. Combined administration is clearly a treatment option to be considered for patients with RCC, which can offer additive or synergistic effects to blockade aberrant signaling. However, current combinations actually do not show much advantage in therapeutic effects. Some of the combinations even brought severe adverse events, such as hypertension and hyperglycemia. Further investigation is necessary to exploit therapeutic benefit. Due to the poor physical conditions of patients with advanced RCC, the key is to improve their quality of life. Although antiangiogenic agents have advantage in PFS and OS, the severe adverse events, such as hypertension and hyperglycemia, cannot be ignored. In clinical practice, the balance between therapeutic effect and associated adverse events should be carefully evaluated before the final selection.

It is important to note some limitations of our study. This meta-analysis found no difference in hyperglycemia. This may be caused by fewer studies. Therefore, more studies with large sample size are required to identify the root reason of this phenomenon.


 > Conclusion Top


In this study, a meta-analysis of randomized trials was performed to evaluate the therapeutic effect and the risk of hypertension and hyperglycemia treatments for RCC

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]
 
 
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