|Year : 2016 | Volume
| 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
Rong-Hua Tian1, Xia Wu1, Xia Liu1, Jin-Wang Yang1, Hua-Liang Ji2, Yong-Jin Yan2
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 Publication||25-Jul-2016|
17 Cheng Zhong Ba Middle Road, Haian, Jiangsu-226 600
Province of China
Source of Support: None, Conflict of Interest: None
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 2020 Apr 3];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|| |
Lung cancer is the most common cause of cancer-related mortality worldwide, accounting for almost 1.4 million deaths annually. Approximately 85% of patients with lung cancer have non-small-cell lung cancer (NSCLC) and more than two-thirds are older than 65 years. Demographics that are shifting toward an older population suggest that oncologists will be seeing more elderly patients with lung cancer in years to come., 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. Moreover, only 35% of patients with regional disease and 27% with metastatic disease received guideline-recommended treatment among patients aged ≥ 65 years. 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.,, However, previous studies demonstrated that selected elderly patients could tolerate and benefit from systemic chemotherapy if they were carefully selected., Subsequent two meta-analyses showed that doublet chemotherapy was superior to a single third-generation cytotoxic agent for elderly patients with advanced NSCLC., 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,,,, and antiangiogenesis therapies represent the most promising therapeutic approach being developed. 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.,, 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|| |
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.
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  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.
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. 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. 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|| |
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. 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,,,,,,, and four in second-line.,,, 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.
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|
Click here to view
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|
Click here to view
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.
| > Discussion|| |
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., Anti-angiogenesis targeted therapies have proven to be one of the most promising therapeutic strategies in NSCLC, with associated improvement in OS. 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|| |
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.
| > References|| |
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: Burdens upon an aging, changing nation. J Clin Oncol 2009;27:2758-65.
Gajra A, Jatoi A. Non-small-cell lung cancer in elderly patients: A discussion of treatment options. J Clin Oncol 2014;32:2562-9.
Wingo PA, Cardinez CJ, Landis SH, Greenlee RT, Ries LA, Anderson RN, et al
. Long-term trends in cancer mortality in the United States, 1930-1998. Cancer 2003;97 (12 Suppl):3133-275.
Yancik R, Ganz PA, Varricchio CG, Conley B. Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 2001;19:1147-51.
Wang S, Wong ML, Hamilton N, Davoren JB, Jahan TM, Walter LC. Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans. J Clin Oncol 2012;30:1447-55.
Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Under representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061-7.
Maione P, Rossi A, Sacco PC, Bareschino MA, Schettino C, Ferrara ML, et al
. Treating advanced non-small cell lung cancer in the elderly. Ther Adv Med Oncol 2010;2:251-60.
Blanco R, Maestu I, de la Torre MG, Cassinello A, Nunez I. A review of the management of elderly patients with non-small-cell lung cancer. Ann Oncol 2014.
Langer CJ, Manola J, Bernardo P, Kugler JW, Bonomi P, Cella D, et al
. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:173-81.
Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavole A, et al
. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011;378:1079-88.
Qi WX, Tang LN, He AN, Shen Z, Lin F, Yao Y. Doublet versus single cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer: A systematic review and meta-analysis. Lung 2012;190:477-85.
Des Guetz G, Uzzan B, Nicolas P, Valeyre D, Sebbane G, Morere JF. Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis. Crit Rev Oncol Hematol 2012;84:340-9.
Qi WX, Fu S, Zhang Q, Guo XM. Anti-epidermal-growth-factor-receptor agents and complete responses in the treatment of advanced non-small-cell lung cancer: A meta-analysis of 17 phase III randomized controlled trials. Curr Med Res Opin 2015;31:25-33.
Owonikoko TK, Ramalingam S. The role of targeted agents in the treatment of elderly patients with non-small cell lung cancer (NSCLC). Curr Treat Options Oncol 2008;9:313-25.
Qi WX, Shen Z, Lin F, Sun YJ, Min DL, Tang LN, et al
. Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: A systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:5177-82.
Qi WX, Wang Q, Jiang YL, Sun YJ, Tang LN, He AN, et al
. Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: A meta-analysis of published data. PLoS One 2013;8:e55637.
Hong S, Tan M, Wang S, Luo S, Chen Y, Zhang L. Efficacy and safety of angiogenesis inhibitors in advanced non-small cell lung cancer: A systematic review and meta-analysis. J Cancer Res Clin Oncol 2014.
Liang W, Wu X, Hong S, Zhang Y, Kang S, Fang W, et al
. Multi-targeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: Meta-analyses of 20 randomized controlled trials and subgroup analyses. PLoS One 2014;9:e109757.
Funakoshi T, Latif A, Galsky MD. Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A systematic review and meta-analysis of randomized controlled trials. Cancer Treat Rev 2014;40:636-47.
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al
. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609-13.
Moher DL, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123-37.
Vandenbroucke JP. Bias in meta-analysis detected by a simple, graphical test. Experts' views are still needed. BMJ 1998;316:469-70.
Gridelli C, Novello S, Zilembo N, Luciani A, Favaretto AG, De Marinis F, et al
. Phase II randomized study of vandetanib plus gemcitabine or gemcitabine plus placebo as first-line treatment of advanced non-small-cell lung cancer in elderly patients. J Thorac Oncol 2014;9:733-7.
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al
. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.
Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al
. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-55.
Doebele RC, Spigel D, Tehfe M, Thomas S, Reck M, Verma S, et al
. Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer. Cancer 2014.
Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al
. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: A phase III trial. J Clin Oncol 2012;30:2070-8.
Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, et al
. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 2012;30:2829-36.
Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, et al
. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: The ECOG 3598 study. J Clin Oncol 2012;30:616-22.
Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al
. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): A double-blind, placebo-controlled, phase 3 trial. Lancet 2011;377:1846-54.
Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al
. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:1835-42.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al
. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227-34.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al
. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.
Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: Power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119-29.
Lauro S, Onesti CE, Righini R, Marchetti P. The use of bevacizumab in non-small cell lung cancer: An update. Anticancer Res 2014;34:1537-45.
Crino L, Metro G. Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev 2014;23:79-91.
Meoni G, Cecere FL, Lucherini E, Di Costanzo F. Medical treatment of advanced non-small cell lung cancer in elderly patients: A review of the role of chemotherapy and targeted agents. Journal of geriatric oncology 2013;4:282-90
[Figure 1], [Figure 2], [Figure 3]