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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 571-575

The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials


1 Department of Respiratory, Affiliated Haian People’s Hospital of Nantong University, Haian, Jiangsu, Province of China
2 Department of Medical Affairs, Affiliated Haian People’s Hospital of Nantong University, Haian, Jiangsu, Province of China

Date of Web Publication25-Jul-2016

Correspondence Address:
Xia Liu
17 Cheng Zhong Ba Middle Road, Haian, Jiangsu-226 600
Province of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151950

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 > Abstract 


Purpose: Data on the role of angiogenesis inhibitors (AIs) in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC) remains limited. We aimed to assess the overall efficacy of AIs-containing regimens in the treatment of advanced NSCLC in this setting.
Materials and Methods: Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to October 31, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating therapies with or without AIs in elderly patients with advanced NSCLC. The endpoints were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using random effects models and 95% confidence intervals (CIs) were calculated.
Results: A total of 3,709 elderly patients with advanced NSCLC from 11 RCTs were identified for analysis. The pooled results demonstrated that there was a clinical benefit in PFS for AIs-containing regimens (hazard ratio (HR) 0.88, 95%CI: 0.78–1.00, P = 0.053) when compared to non-AIs-containing regimens, but not for OS (HR 0.99, 95%CI: 0.90–1.10, P = 0.89). On subgroup analysis, similar results were found based on treatment line. No publication bias was detected by Begg's and Egger's tests for OS.
Conclusions: In elderly patients with advanced NSCLC, AIs-containing therapies offer a clinical benefit in PFS but for OS. With present available data from RCTs, we are still unable to clearly set the role of specific AIs in the treatment of advanced NSCLC in this setting.

Keywords: Elderly, meta-analysis, non-small-cell lung cancer, randomized controlled trials


How to cite this article:
Tian RH, Wu X, Liu X, Yang JW, Ji HL, Yan YJ. The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials. J Can Res Ther 2016;12:571-5

How to cite this URL:
Tian RH, Wu X, Liu X, Yang JW, Ji HL, Yan YJ. The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials. J Can Res Ther [serial online] 2016 [cited 2019 Sep 20];12:571-5. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/571/151950

Rong-Hua Tian, Xia Wu
These authors contribute equally to this work





 > Introduction Top


Lung cancer is the most common cause of cancer-related mortality worldwide, accounting for almost 1.4 million deaths annually.[1] Approximately 85% of patients with lung cancer have non-small-cell lung cancer (NSCLC) and more than two-thirds are older than 65 years.[2] Demographics that are shifting toward an older population suggest that oncologists will be seeing more elderly patients with lung cancer in years to come.[3],[4] However, there are many challenges involved in the treatment of an elderly population with advanced NSCLC. Many of these patients have preexisting comorbid conditions, which, independently of cancer-related symptoms, may adversely affect organ function and functional status.[5] Moreover, only 35% of patients with regional disease and 27% with metastatic disease received guideline-recommended treatment among patients aged ≥ 65 years.[6] Therefore, the optimal treatment for NSCLC in elderly patients remains undetermined.

In current practice, there is a significant under-representation of elderly patients in most clinical trials on lung cancer.[7],[8],[9] However, previous studies demonstrated that selected elderly patients could tolerate and benefit from systemic chemotherapy if they were carefully selected.[10],[11] Subsequent two meta-analyses showed that doublet chemotherapy was superior to a single third-generation cytotoxic agent for elderly patients with advanced NSCLC.[12],[13] While these data have provided the rationale to treat fit elderly patients with standard chemotherapy regimens, the reality is that a significant number of elderly patients continue to receive suboptimaltherapy.

In recent decades, the emergence of molecularly targeted agents has provided another strategy for the treatment of elderly patients with advanced NSCLC,[8],[14],[15],[16] and antiangiogenesis therapies represent the most promising therapeutic approach being developed.[17] For patients with advanced NSCLC, several recent meta-analyses had demonstrated that angiogenesis inhibitors (AIs)-containing regimens significantly improve objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) when compared to non-AIs containing regimens.[18],[19],[20] Nonetheless, there is limited data regarding the role of AIs in NSCLC patients aged ≥ 65-years-old. Thus, we conduct this meta-analysis of all available randomized controlled trials (RCTs) to determine the overall efficacy of AIs in this setting.


 > Materials and Methods Top


Search strategy

The databases of PubMed (data from Jan 2000 to Oct 2014), Embase (data from Jan 2000 to Oct 2014), and the Cochrane Library electronic databases were searched by using the following key words:”bevacizumab”, “avastin”, “aflibercept”, “VEGFR-TKIs”, “sorafenib”, “nexavar”, “sunitinib”, “sutent”, “SU1248”, “vandetanib”,”caprelsa”, “ZD6474”, “axitinib”, “pazopanib”, “votrient”, “GW786034”, “regorafenib”, “apatinib”, “ramucirumab”, “nintedanib”, “BIBF1120”, “thalidomide”, “lenalidomide”, “angiogenesis inhibitors”, “randomized”, and “non-small-cell lung cancer”. Only studies in English were considered. The computer search was supplemented with manual searches for references of the included studies and for related citations.

Inclusion and exclusion criteria

Trials that met the following criteria were included in our analysis: (i) Prospective randomized controlled trails comparing therapies with or without AIs (bevacizumab, aflibercept, sorafenib, sunitinib, vandetanib, pazopanib, axitinib, regorafenib, apatinib, cediranib, ramucirumab, nintedanib, thalidomide, and lenalidomide); (ii) patients were pathologically confirmed of non-small-cell lung cancer; and (iii) the study had sufficient survival data of elderly patients (≥ 65) for extraction. If studies were duplicates, the study with the most up-to-date results was included. Phase 1 trials and single-group phase 2 trials were omitted from analysis because of lack of controls. The quality of reports of clinical trials was assessed and calculated using the five-item Jadad scale including randomization, double-blinding, and withdrawals as previously described.[21]

Data extraction

Data extraction was conducted independently by two investigators (Rong-Hua Tian and Xia Wu) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [22] and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: (i) Basic information, including the year of publication and the first author's name; (ii) study information, including sample size, study design, number of elderly subjects; (iii) treatment information, including treatment schedules, and dosage; and (iv) outcomes of interest, such as OS, PFS, and median follow-up.

Data analysis

OS and PFS were the primary outcome endpoints for our study. HRs and 95% confidence intervals (CIs) were estimated directly from the reported data. The analysis was undertaken on an intention-to-treat basis: Patients were analyzed according to treatment allocated, irrespective of whether they received that treatment.

Statistical analysis of the overall hazard ratio (HR) for OS and PFS was calculated using version 2 of the Comprehensive MetaAnalysis program (Biostat, Englewood, NJ). A random-effect model according to the DerSimonian and Laird method was used to calculate pooled HRs, 95% CIs, and P values. A statistical test with a P value less than 0.05 was considered significant. HR > 1 reflects more deaths or progression in AIs-containing regimens group and vice versa. Between-study heterogeneity was estimated using the χ2-based Q statistic.[23] The I 2 statistic was also calculated to evaluate the extent of variability attributable to statistical heterogeneity between trials. To investigate the sources of heterogeneity, we also conducted predefined subgroup analysis according to treatment line. The presence of publication bias was evaluated by using the Begg and Egger tests.[24] All P values were two-sided. All CIs had a two-sided probability coverage of 95%. The results of the meta-analysis were reported as classic forest plots (for OS and for PFS).


 > Results Top


Search results

The search initially provided a total of 310 potentially relevant studies, 299 of which were excluded for the reasons shown in [Figure 1]. Ten published RCTs with subgroup analysis assessing the efficacy of AIs in elderly patients were included in the meta-analysis. One additional RCT investigating the efficacy of vandetanib in elderly patients with NSCLC was also included for analysis.[25] Finally, a total of 11trials were included. The baseline characteristics of each trial were presented in [Table 1]. A total of 3,709 patients were available for the meta-analysis. Seven trials were performed in first-line settings,[25],[28],[30],[31],[33],[34],[35] and four in second-line.[26],[27],[29],[32] According to the inclusion criteria of each trial, patients were required to have an adequate renal, hepatic, and hematologic function. The quality of each included study was roughly assessed according to Jadad scale, and seven trials had Jadad score of 5, and four trials had Jadad scores of 3.
Figure 1: Studies eligible for inclusion in the meta-analysis

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Table 1: Baseline characteristic of included 11 trials for analysis

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OS

Eight of the eleven trials reported OS data of elderly patients. The pooled results demonstrated that AIs-containing regimens did not improve OS in comparison with non-AIs-containing regimens (HR 0.99, 95%CI: 0.90–1.10, P = 0.89) [Figure 2] using a random-effects model. We then performed subgroup analysis according to treatment line, and found that trials using AIs-containing regimens as first-line (HR 0.96, 95%CI: 0.84–1.09, P = 0.52) or second-line therapies (HR 1.04, 95%CI: 0.90–1.20, P = 0.62) did not improve OS when comparing to non-AIs-containing regimens.
Figure 2: Random-effects model of hazard ratio (95% CI) of overall survival (OS) associated with angiogenesis inhibitors (AIs)-containing regimens versus non-AIs-containing regimens

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PFS

Six trials with seven comparisons reported PFS data. The pooled HR for PFS demonstrated that there was a clinical benefit in PFS for AIs-containing regimens giving HR 0.88 (95% CI: 0.78–1.00, P = 0.053) [Figure 3], compared with non-AIs containing therapy. There was moderate heterogeneity between trials (I 2 = 46.32%, P = 0.083), and the pooled HR for PFS was performed by using random-effects model. We then did subgroup analysis according to treatment line and found that AIs-containing regimens had a tendency to improve PFS as first-line therapy (HR 0.81; 95% CI: 0.63–1.05, P = 0.11) and second-line therapy (HR, 0.90; 95% CI: 0.77–1.06, P = 0.21) in elderly patients with advanced NSCLC.
Figure 3: Random-effects model of hazard ratio (95%CI) of progression-free survival (PFS) associated with AIs-containing regimens versus non-AIs-containing regimens

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Risk of bias across the studies

For the pooled estimate of OS, both Begger and Egger were not significant (P = 0.90 and 0.99, respectively). For the pooled estimate of PFS, Begger test did not detect any evidence of obvious asymmetry (P = 0.07), but not for Egger test (P = 0.007). The difference in the results obtained from the two methods might be due to a greater statistical power of the regression methods.[36]


 > Discussion Top


During the past decades, the introduction of targeted biological agents represents the most promising approach to improve the disease control and outcome for patients with NSCLC.[37],[38] Anti-angiogenesis targeted therapies have proven to be one of the most promising therapeutic strategies in NSCLC, with associated improvement in OS.[39] Although the trials that established the efficacy of these agents allowed the enrollment of patients older than 70 years, the elderly patients constituted the minority. Given the stringent enrolment criteria in terms of organ function and performance status for most clinical trials, the elderly patients on clinical trials are not entirely representative of the overall elderly patient population. Therefore, the applicability of these data to the overall patient population deserves critical appraisal in the absence of trials dedicated specifically to the elderly. Preplanned and unplanned subset analysis of registration trial data is becoming increasingly common as a substitute measure to provide valuable information to guide the use of targeted agents in the elderly. We therefore conduct this meta-analysis of RCTs with preplanned and unplanned subset analysis of elderly patients (≥65) to investigate the overall efficacy of AIs in the treatment of advanced NSCLC in this setting.

To our best knowledge, this is the first meta-analysis focusing specifically on efficacy of AIs in elderly patients with advanced NSCLC. Our study, including 3,709 patients from 11 RCTs, demonstrates that there is a clinical benefit in PFS for antiangiogenesis therapy when compared to non-antiangiogenesis therapies (P = 0.053), but not for OS. Similar results are also observed in subgroup analysis based on treatment line. Based on our results, we could conclude that the addition of AIs to treatment therapies could improve PFS in unselected elderly patients with advanced NSCLC, but it does not translate into survival benefit. And we still could not clearly set the role of each antiangiogenesis agent in the treatment of elderly patients with advanced NSCLC due to limited RCTs included for analysis. Thus, further studies are still needed to identify patients who will most likely benefit from specific antiangiogenesis therapy.

The meta-analysis is a powerful statistical tool that, by a predetermined method, identifies, appraises, synthesizes, and aggregates relevant clinical studies to reduce bias. However, this review has a number of limitations that should be acknowledged. First, inherent assumptions are made for all meta-analyses, because the analyses used pooled data, either published or provided by the individual study; individual patient data or original data are unavailable, which precludes us to perform a more comprehensive analysis such as adjusting for baseline factors and other differences that existed between the trials. Second, we include patients treated with different antiangiogenesis agents. While each of these molecules inhibits angiogenesis, these drugs have different potencies, and have inhibitory properties against a range of non overlapping targeted receptors. Given the limited sample size of patients treated with any single AIs, we decide to include patients treated with all of these drugs in this class with adequate data on survival of elderly patients with NSCLC, which would increase the clinical heterogeneity among included trials. Third, our study pools trials with heterogeneous dosage and administration schedule of AIs, periods of study conduct, treatment line, and study investigators. All of these factors would increase the clinical heterogeneity among included trials, although we pooled the meta-analysis by using random-effects model. Finally, in the meta-analysis of published studies, publication bias is important because trials with positive results are more likely to be published and trials with null results tend not to be published. Our research detects no publication bias using Begg and Egger tests for OS, but not for PFS.


 > Conclusion Top


In conclusion, this is the first-meta-analysis to specifically assess the role of AIs in the treatment of elderly patients with advanced NSCLC. The results of our study suggest that the addition of AIs to the treatment therapies of elderly patients with NSCLC offered a clinical benefit in PFS but not for OS, when compared to non-AIs-containing regimens. With present available data from randomized clinical trials, we could not clearly set the role of specific AIs in the treatment of advanced NSCLC in this setting. Further studies are recommended to identify patients who could derive greater benefits from specific AIs.

 
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