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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 109-115

A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials


1 Department of Hematology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China
2 Department of Nephrology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China
3 Department of Urology and Andragogy, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China

Date of Web Publication7-Oct-2016

Correspondence Address:
Jingfeng Zhang
Department of Hematology, Nephrology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191617

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 > Abstract 


Purpose: The purpose of this study was to conduct network meta-analysis to assess drug resistances of the Food and Drug Administration-approved drugs for advanced renal cell carcinoma.
Materials and Methods: Database searches were conducted to identify randomized controlled trials reporting results for eligible treatments. After searching for PubMed, MEDLINE, EMBASE, and ISI Web of Science, 22 studies (n = 7854 patients) were included for the comparison of drug resistance in the present meta-analysis.
Results: For overall present, the mean 6-month progression-free survival rates were 65.4%, 49.3%, 60.6%, 70.3%, 62.6%, 41.6%, 38.2%, 66.1%, 43.1%, and 17.9% for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab plus interferon (IFN)-a, everolimus, temsirolimus, temsirolimus plus bevacizumab, IFN-a, and placebo, respectively. For indirect comparison, two combined therapies (bevacizumab plus IFN-a and temsirolimus plus bevacizumab) and sunitinib were of less ability of drug resistance. The risk ratio of sunitinib therapy was 3.64 (95% confidence interval [CI] [3.12, 4.25]), the risk ratio of temsirolimus plus bevacizumab therapy was 3.68 (95% CI [3.14, 4.33]), and the risk ratio of bevacizumab plus IFN-a therapy was 3.49 (95% CI [2.99, 4.06]).
Conclusions: Our results support that combination of targeted therapies might be a novel strategy against advanced renal cell carcinomas.

Keywords: Drug resistance, meta-analysis, molecular targeted drugs, renal cell cancer


How to cite this article:
Guo M, Cao Y, Yang J, Zhang J. A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials. J Can Res Ther 2016;12:109-15

How to cite this URL:
Guo M, Cao Y, Yang J, Zhang J. A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials. J Can Res Ther [serial online] 2016 [cited 2018 Nov 16];12:109-15. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/109/191617




 > Introduction Top


Renal cell carcinoma (RCC) is the most common form of kidney cancer and accounts for ~2%–3% of adult cancers worldwide.[1] In general, patients have a poor prognosis, and 12%–25% of patients with a new diagnosis of RCC will have metastatic disease at presentation.[2] About 70% of patients were present with localized or locally advanced RCC (ARCC); unfortunately, 20%–40% of these patients would experience recurrence and metastasis.[3] It affects mainly an elderly population with the peak incidence occurring between the ages of 60 and 70 years.[4] Renal cancer cells are insensitive to chemotherapy and radiotherapy and of great ability of multidrug resistance.[5]

Before 2005, the standard of care was limited to cytokine therapy with interleukin-2 and/or interferon (IFN)-a. These treatments are associated with limited efficacy and high toxicity.[6] Several newer targeted treatments are now available, and survival rates have improved in recent years following the introduction of tyrosine kinase inhibitors (TKIs) and other targeted treatments.[7] Targeted therapies have improved disease control rates and outcomes for patients with advanced conventional (clear cell) RCC.[8] Four multitargeted TKIs: sorafenib,[9] sunitinib,[10] pazopanib,[11] and axitinib;[12] the humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab with IFN-a,[13] and two mammalian target of rapamycin (mTOR) complex 1 kinase inhibitors (temsirolimus [14] and everolimus [15]). Sunitinib is currently the standard of care in the first-line treatment.[10]

In this article, we conducted a network meta-analysis (NMA) to assess drug resistances of the Food and Drug Administration (FDA)-approved drugs for ARCC. We presented a pool of overall survival (OS), progression-free survival (PFS), and 6-month progression-free survival from all studies enrolled in the meta-analysis with corresponding data to show an impression on all seven drugs. Finally, we utilized 6-months PFS as an indicator of drug resistance, comparing the drug resistance of the FDA-approved seven drugs.


 > Materials and Methods Top


Search strategy

We conducted a bibliographic search for original research articles, using multiple electronic databases, including PubMed, MEDLINE, EMBASE, and ISI Web of Science. We used the search terms “Sunitinib,” “Sorafenib,” “Pazopanib,” “Axitinib,” “Bevacizumab,” “Everolimus,” “Temsirolimus,” “advanced renal cell carcinomas,” and “advanced renal cancer” from 2007 onward. We also hand-searched the reference sections of all obtained publications to find out any study missed by the search strategies. For comparison, studies were retrieved from the same databases within the same publication period. To effectively identify relevant articles, a protocol for structured literature retrieval was followed, and retrieval result in each step is given in [Figure 1].
Figure 1: Selection strategy of studies enrolled in the current meta-analysis

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Selection criteria

The following eligibility criteria were applied: (1) Original articles published in English between January 2007 and January 2016; (2) eligibility criteria included randomized controlled trials (RCTs) conducted in adult patients (>18 years old) undergoing any line of treatment for ARCC; (3) ARCC was strictly limited to Stage III/IV or metastatic disease with reference to the 7th edition of cancer staging by the American Joint Committee on Cancer; (4) primary outcomes of interest were 6-month PFS, PFS, and OS, which were reported or could be extrapolated based on published results; (5) relevant treatments included but were not restricted to sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, and IFN-a (according to the European licensed indication). Some authors had more than one report meeting the inclusion criteria. To minimize data overlap, each report was analyzed to ensure that only the report with latest results and largest patient number was enrolled. If the patient population was from a different time period or different outcomes were reported, both reports were included in this study for analysis.

Data extraction

Two reviewers independently extracted data from all studies. Additional data obtained from the studies included the first author, publication year, research phase, treatment arms, patients per arm, median age (year range), number of males (percent), ECOG performance status, Memorial Sloan-Kettering Cancer Center (MSKCC) score, median OS, median PFS, and 6-month PFS. Disagreements were resolved by consensus between the two readers. Survival data (median OS, median PFS, and 6-month PFS), not available within the context, were extracted from the survival curve using Engauge Digitizer V4.1 (Slashdot Media, Torrance, California, USA). At the same time, the extracted data of survival were confirmed with the data available in the context in the same year. The acceptable error is ± 0.05. The risk of bias (RoB) assessment was performed using the standard Cochrane Collaboration RoB tool for RCTs.

Statistical analysis

All patients were filtrated in sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, IFN-a, or combination treat group. The results of the study were considered statistically significant when the P < 0.05 in univariate analysis. Relative risk (RR) with 95% confidence interval (CI) synthesized was used to assess the strength of association. Considering the many sources of heterogeneity between studies and consequently between their individual RR estimates, we calculated the overall RR according to the DerSimonian and Laird method,[16] with a random effect model when homogeneity was not fine (P > 0.10, I2 > 50%). An observed RR >1 indicated better outcomes for the targeted treatment to placebo group and would be considered statistically significant if the 95% CI did not overlap 1, with P < 0.05. Forest plots were used to estimate the relationship between the targeted treatment to placebo group, created by RevMan 5.3 (Cochrane Collaboration, Oxford, UK) in our NMA.


 > Results Top


Literature search and characteristics

Our electronic search algorithm retrieved a total of 2781 references for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, and advanced renal cell cancer. After removal of duplicated articles, studies of tumors from other origins, animal and laboratory studies, and studies on other pathway, 137 candidate studies were retrieved for abstract reading. After further evaluation, 33 studies were retrieved for full-text assessment. Of all the 32 reports, 11 were excluded: one in Chinese,[17] Three in German,[18],[19],[20],[21] one is molecular biology study,[22] and three are reviews [23],[24],[25],[26],[27] [Figure 1]. Finally, 22 studies (n = 7854 patients) were eligible for the present meta-analysis.

Characteristics of the 22 eligible studies are listed in [Table 1]. All the eligible studies were clinical trials. Nine reports belong to Phase II study, and thirteen belong to Phase III study. All except two studies reported MSKCC score. According to the information, the clinical trials are reported ranged from the year 2005 to 2015; the percentage of male is nearly 70% [Table 1]. Twenty studies reported PFS and/or 6-month PFS [Table 2].
Table 1: 22 studies on targeted drugs for advanced renal cancer included in the current meta-analysis

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Table 2: Final progression-free survival and/or 6-month progression-free survival data for included trials

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Systematic review of included literature

A pooled presentation of OS, PFS, and 6-months PFS from all studies enrolled in this meta-analysis with corresponding data available is shown in [Figure 2]. The mean 6-month PFS rates were 65.4%, 49.3%, 60.6%, 70.3%, 62.6%, 41.6%, 38.2%, 66.1%, 43.1%, and 17.9% for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab plus IFN-a, everolimus, temsirolimus, temsirolimus plus bevacizumab, IFN-a, and placebo, respectively.
Figure 2: Mean overall survival, progression-free survival, and 6-month progression-free survival (6-month progression-free survival) comparison of the Food and Drug Administration-approved targeted drugs for advanced renal cell cancer. A pooled presentation of overall survival, progression-free survival, and 6-month progression-free survival from all studies enrolled in this meta-analysis with corresponding data available

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[Figure 3] illustrates the network diagram used to compare treatments. The median PFS (with 95% CI) or 6-month PFS for the studies included in the meta-analysis (reported by independent and investigator assessment) is reported in [Table 2]. The RoB was generally low across most studies [Figure 4].
Figure 3: Network diagram for studies that report progression-free survival and/or 6-month progression-free survival

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Figure 4: Risk of bias assessment of included studies. Green: low risk of bias; yellow: unclear risk of bias; red: high risk of bias

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Indirect comparison of the treatment effects for 6-month progression-free survival by independent assessment

To compare the drug resistance, placebo was defined as a control for all other targeted treatments. The meta-analysis showed that two combined therapies (bevacizumab plus IFN-a and temsirolimus plus bevacizumab) and sunitinib were of less ability of drug resistance, which was contrast to the previous studies. The risk ratio of sunitinib therapy was 3.64 (95% CI [3.12, 4.25]), the risk ratio of temsirolimus plus bevacizumab therapy was 3.68 (95% CI [3.14, 4.33]), and the risk ratio of bevacizumab plus IFN-a therapy was 3.49 (95% CI [2.99, 4.06]) [Figure 5].
Figure 5: Meta-analysis of 6-month progression-free survival for nine targeted therapies

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 > Discussion Top


The lack of suitable studies that evaluate the efficiency of target cell therapies (TCTs) for ARCC was noted during the systematic review and only a few were submitted to meta-analysis. It was also observed difficult to collect data from the studies since some presented neither clear nor objective results. Among the revised studies, there were several difficulties regarding the interpretation of results, such as randomization and 6-month PFS that impaired precision. Many selected works were excluded since they were not prospective, randomized, and with the necessary information for analysis. Subgroup analysis studies were also excluded as well as those with duplicated populations.

At present, there are several available treatments with TCT: four multitargeted TKIs: sorafenib,[9] sunitinib,[10] pazopanib,[11] and axitinib;[12] the humanized anti-VEGF monoclonal antibody bevacizumab with IFN-a [13] and two mTOR complex 1 kinase inhibitors (temsirolimus [14] and everolimus [15]). Targeted therapies have improved disease control rates and outcomes for patients with advanced conventional (clear cell) RCC [8] although the drug resistances exist. Recently, a combination of multitarget drugs was highlighted for its outstanding effects on advanced renal cell cancer. After conducting an NMA, we support this strategy. In this meta-analysis, we have to use 6-month PFS as a substitution of drug resistance for the complexity in the generalization of renal cancer cell drug resistance.


 > Conclusion Top


Our results support that combination of targeted therapies might be a novel strategy against advanced renal cell carcinomas. Specially, temsirolimus plus bavacizumab and bavacizumab plus IFN-a therapies are suitable for the treatment of advanced renal cell cancer.[46]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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