|Year : 2018 | Volume
| Issue : 8 | Page : 79-84
Meta-analysis of molecular targeted agents in the treatment of elderly patients with metastatic colorectal cancer: Does the age matter?
Chuan Jie Zhao1, ShuLiang Li1, Qiang Liu2
1 Department of Gastrointestinal Surgery, The Second People's Hospital of Liao Cheng, Liao Cheng, Shandong Province, China
2 Department of Surgical Oncology Surgery, The First Hospital of HeBei Medical Univeristy, Shi Jia Zhuang, He Bei Province, China
|Date of Web Publication||26-Mar-2018|
Chuan Jie Zhao
Department of Gastrointestinal Surgery, No. 306 JianKang Road, Liao Cheng, ShanDong-252600
Source of Support: None, Conflict of Interest: None
Aim: Patients aged 65 years and older are often underrepresented in clinical trials of metastatic colorectal cancer (mCRC) and probably undertreated in clinical practice. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of molecular targeted agents (MTAs) in this population.
Materials and Methods: A comprehensive literature search for studies published up to December 2014 was performed. The endpoints were overall survival (OS) and progression-free survival (PFS). The pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.
Results: Eleven RCTs involving 8,488 patients were ultimately identified. The pooled analysis demonstrated that the use of MTAs in elderly patients with mCRC significantly improve OS (HR 0.84, 95% CI: 0.76–0.92, P < 0.001) and PFS (HR 0.78, 95% CI: 0.64–0.96, P = 0.017) when compared to MTAs-free therapies. Similar results of OS were observed in subgroup analysis according to treatment line, therapy regimes, and approval status of MTAs. No publication bias was detected by Begg's and Egger's tests.
Conclusions: The introduction of MTAs to therapies offered a survival benefit in elderly patients with mCRC. Further studies aimed at this specific patient population were still needed to watchfully monitor potential treatment-related toxicities to optimize the use of these drugs.
Keywords: Advanced colorectal cancer, elderly, molecular targeted agents, meta-analysis, randomized controlled trials
|How to cite this article:|
Zhao CJ, Li S, Liu Q. Meta-analysis of molecular targeted agents in the treatment of elderly patients with metastatic colorectal cancer: Does the age matter?. J Can Res Ther 2018;14, Suppl S1:79-84
|How to cite this URL:|
Zhao CJ, Li S, Liu Q. Meta-analysis of molecular targeted agents in the treatment of elderly patients with metastatic colorectal cancer: Does the age matter?. J Can Res Ther [serial online] 2018 [cited 2019 Aug 24];14:79-84. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/79/158031
| > Introduction|| |
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, with around 136,830 new cases diagnosed in 2014., Most CRC patients are over 65 years old. Of the old patients, approximately 82% of CRC survivors (approximately 1 million men and women) are aged 60 years and older, while only 5% (67,120 individuals) are aged younger than 50 years. Although patients ≥65 years of age represent the majority of patients with CRC, this patient population is often underrepresented in clinical trials and very likely undertreated in the clinical practice. With continued population aging and an increasing life expectancy, oncologists will confront increasing numbers of older CRC patients in the near future. Therefore, a critical reevaluation of the role and potential options of systemic therapies in elderly patients with CRC is warranted.
However, there are many challenges involved in the treatment of an elderly population with metastatic CRC (mCRC). As many of these patients have preexisting comorbid conditions, it might increase the risk of side effects associated with the use of specific anti-cancer agents. Moreover, disease history, aims of treatment, and both patient's and physician's perceptions of the balance between treatment associated risk and gain in survival/quality of life in elderly people may differ significantly from those in younger individuals. As a result, it is uncertain whether the treatment strategies for these patients coincide with those classically used for the general population.
Previous data indicated that the tolerance and effectiveness of standard chemotherapy including 5-fluorouracil, oxaliplatin, and irinotecan in elderly patients with mCRC were acceptable and not significantly different from younger populations.,, Therefore, standardized palliative chemotherapy should generally be offered to elderly patients. In recent decades, the emergence of molecular targeted agents (MTAs) has provided another strategy for the treatment of elderly patients with mCRC.,,,,, However, less information is available on the safety and efficacy of MTAs in mCRC patients aged ≥65 years. Thus, we perform this meta-analysis of all available randomized controlled trials (RCTs) to determine the overall efficacy of MTAs in this population.
| > Materials and Methods|| |
Selection of studies
We searched the PubMed, Embase, and the Cochrane Library electronic databases. The search end date was January 2014, with no specified start date. The search criteria included only RCTs and published in English language, and the key words “aflibercept”, “sorafenib”, “nexavar”, “sunitinib”, “sutent”, “SU1248”, “vandetanib”, “caprelsa”, “ZD6474”, “axitinib”, “pazopanib”, “votrient”, “GW786034”, “regorafenib”, “apatinib”, “ramucirumab”, “nintedanib”, “BIBF1120”, “thalidomide”, “lenalidomide”, “bevacizumab”, “cetuximab”, “panitumumab”, “molecular targeted agents”, “randomized”, and “colorectal cancer”. Each publication was reviewed and in cases of duplicate publication only the most complete, recent, and updated report of the clinical trial was included in the meta-analysis.
Data extraction was conducted independently by two investigators 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:First author's name, year of publication, number of elderly patients, treatment arms, primary endpoints, and median follow-up. Phase 1 trials and single-group phase 2 trials were omitted from analysis because of lack of controls.
Trials that met the following criteria were included in our analysis: (i) Prospective randomized controlled trails comparing therapies with or without targeted agents; (ii) patients were pathologically confirmed of CRC; and (iii) the study had sufficient survival data of elderly patients with mCRC. 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.
The analysis was undertaken on an intention-to-treat basis: Patients were analyzed according to treatment allocated, irrespective of whether they received that treatment. The outcomes used were: (i) Overall survival (OS), defined as the time from random assignment to death from any cause, censoring patients who had not died at the date last known alive; (ii) Progression-free survival (PFS), defined as the time from random assignment to first documented progression.
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 statistical test with a P value less than 0.05 was considered significant. HR > 1 reflects more deaths or progression in aromatase inhibitors (AIs)-containing regimens group, and vice versa. Between-study heterogeneity was estimated using the χ2-based Q statistic. The I2 statistic was also calculated to evaluate the extent of variability attributable to statistical heterogeneity between trials. Heterogeneity was considered statistically significant when Pheterogeneity < 0.05 or I2 > 50%. If heterogeneity existed, data was analyzed using a random-effects model using the inverse variance method. Otherwise, the pooled estimate was calculated according to the random-effects model using the DerSimonian method. To investigate the sources of heterogeneity, we also conducted predefined subgroup analysis according to treatment line and regimens. The presence of publication bias was evaluated by using the Begg and Egger tests. Additionally, sensitivity analyses were performed to assess the influence of each study on overall estimate for HR by sequential removal of individual studies. All P values were two-sided. Allconfidence intervals (CIs) had two-sided probability coverage of 95%.
| > Results|| |
A total of 270 potentially relevant studies were retrieved electronically, 217 of which were excluded for the reasons shown in [Figure 1]. Eleven published RCTs with subgroup analysis assessing the efficacy of MTAs in elderly mCRC patients were included. The baseline characteristics of each trial were listed in [Table 1]. A total of 8,488 patients were available for the meta-analysis. 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. Six of the included trials were double-blind, placebo-controlled randomized trials, and thus had Jadad score of 5,,,,,, and five trials had Jadad scores of 3.,,,,
|Figure 1: Studies eligible for inclusion in the meta-analysis. MTA = Mineral trioxide aggregate, CRC = Colorectal cancer|
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|Table 1: Baseline characteristic of included 11 clinical trials for analysis|
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Ten of the eleven trials reported OS data of targeted agents in elderly mCRC patients. The pooled results demonstrated that the use of MTAs significantly improve OS in comparison with targeted agents-free regimens (HR 0.84, 95% CI: 0.76–0.92, P < 0.001) [Figure 2] using a fixed-effects model (I2 = 0%, P= 0.95). We then performed subgroup analysis according to treatment line, and found that the use of MTAs as first-line (HR 0.83, 95% CI: 0.71–0.97, P= 0.016) and second-line (HR 0.84, 95% CI: 0.75–0.94, P= 0.003) therapy in elderly mCRC patients significantly improve OS when compared to MTAs-free regimens. We also did subgroup analysis according to concurrent therapy with MTAs, and the combined results showed that both MTAs plus chemotherapy (HR 0.84, 95% CI: 0.75–0.93, P= 0.001) or MTAs alone (HR 0.84, 95% CI: 0.71–0.98, P= 0.032) regimens significantly increased OS when compared to controlled therapies. Additionally, we performed subgroup analysis based on approval status of targeted agents. Our results show that the addition of approved targeted agents to chemotherapy in mCRC significantly improve OS (HR 0.81, 95% CI: 0.72–0.90, P < 0.001), but not for unapproved targeted agents (HR 0.90, 95% CI: 0.76–1.05, P= 0.18). No statistically significant difference between those subgroups (data not shown). We also performed a sensitivity analysis to examine the stability and reliability of pooled HRs by sequential omission of individual studies. The results indicated that the significance estimate of pooled HRs was not significantly influenced by omitting any single study [Figure 3].
|Figure 2: Fixed-effects model of hazard ratio (95% CI) of OS associated with MTAs-containing regimens versus MTAs-free regimens. CI = Confidence interval, OS = Overall survival|
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|Figure 3: Meta-analysis hazard ratio of OS associated with MTAs-containing regimens versus MTAs-free regimens: “Leave-one-out” sensitivity analysis|
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Six trials reported PFS data. The pooled HR for PFS demonstrated that the use of MTAs in elderly patients with mCRC significantly improve PFS by giving HR 0.78 (95% CI: 0.64–0.96, P= 0.017) [Figure 4], compared with MTAs-free therapies. There was significant heterogeneity between trials (I2 = 70.7%, P= 0.004), 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 the use of MTAs as second-line therapy (HR 0.73, 95% CI: 0.62–0.85, P < 0.001) in elderly patients significantly improve PFS, but not for MTAs used as first-line therapy (HR 0.82, 95% CI: 0.58–1.16, P= 0.26).
|Figure 4: Random-effects model of hazard ratio (95%CI) of PFS associated with MTAs-containing regimens versus MTAs-free regimens. PFS = Progression-free survival|
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Begg's funnel plot and Egger's test were performed to assess the publication bias of literatures. The Begg's funnel plots did not reveal any evidence of obvious asymmetry (P= 0.93 for OS and P= 0.06 for PFS, respectively). Then, Egger's test still did not suggest any evidence of publication bias for OS (P= 0.17) and PFS (P= 0.95).
| > Discussion|| |
In a continuously aging population, the burden of mCRC is rising among older patients. Despite the fact that almost half of the cases occur in patients over 75 years, this age group is subjected to disparities regarding diagnostic and therapeutic options. During the past decades, the introduction of MTAs represents the most promising approach to improve the disease control and outcome for patients with mCRC. At present, there are five targeted agents approved for the treatment of patients with CRC: The two monoclonal antibodies against the epidermal growth factor receptor (EGFR)–cetuximab and panitumumab; two monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) –bevacizumab and aflibercept; and a multi-kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR). Subgroup analyses and observational cohort studies have suggested that elderly patients benefit from the addition of bevacizumab to standard chemotherapy and the safety profile of bevacizumab in this population does not significantly differ from that observed in younger patients.,, A recent prospective, randomized, phase III trial also confirms that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly patients with mCRC. However, the efficacy of other MTAs in elderly patients with mCRC remains unknown. For lack 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 MTAs 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 MTAs in the treatment of mCRC in this setting.
To our best knowledge, this is the first meta-analysis focusing specifically on efficacy of MTAs in elderly patients with mCRC. Our study, included 8,488 patients from 11 RCTs, demonstrates that the use of MTAs in elderly mCRC patients significantly improve OS (P < 0.001) and PFS (P= 0.017) when compared to MTAs-free therapies. Similar results for OS were also observed in sub-group analysis based on treatment line and regimens. Sensitivity analysis demonstrated that the significance estimate of pooled HRs was not significantly influenced by omitting any single study. Based on our results, we could conclude that the addition of MTAs to treatment therapies could improve OS and PFS in unselected elderly patients with mCRC. However, we still could not clearly set the role of each MTAs in the treatment of elderly patients with mCRC due to limited RCTs included for analysis. Additionally, we could not assess the toxicity of MTAs in elderly mCRC patients because reports of adverse events from each subgroup were unavailable. Thus, further studies aimed at this specific patient population are still needed to identify patients who will most likely benefit from specific MTAs and monitor potential toxicities of MTAs to optimize the use of these drugs.
Meta-analysis and systematic reviews assist in developing evidence-based treatment protocols and healthcare decision making. They are good tools that objectively gather and summarize all available evidence for decision makers. However, there are several limitations needed to be considered. First, although most of these trials were carried out the randomization process adequately, an imbalance of patient characteristics between the two treatment groups of the MTAs subgroup in elderly patients could exist. Therefore, these data should be interpreted cautiously, because the extracted data used for this analysis could not be considered randomized, which somehow compromised the evidence level. Second, we include patients treated with different MTAs, and these drugs have different potencies, and have inhibitory properties against a range of nonoverlapping targeted receptors. Given the limited sample size of elderly patients treated with any single MTAs, we decide to include patients treated with all of these drugs in this class with adequate data on survival of elderly patients with mCRC, which would increase the clinical heterogeneity among included trials. Third, the toxicity profile is another important factor for choosing treatment options. However, it is not possible to perform an analysis to deal with such a concern because reports of adverse events from each subgroup were not available. 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 and PFS.
| > Conclusion|| |
In conclusion, this is the first-meta-analysis to specifically assess the role of MTAs in the treatment of elderly patients with mCRC. Our study confirms that the addition of MTAs to the treatment therapies in elderly patients with mCRC offer an improved survival benefits comparing to MTAs-free regimens. Moreover, chemotherapy regimens and treatment line does not appear to influence the efficacy of MTAs in this population. Further studies are still needed to watchfully monitor potential treatment-related toxicities to optimize the use of these drugs in this population.
| > Acknowledgement|| |
CJ Z and SL L designed research; Q L conducted research; CJ Z and Q L analyzed data; CJ Z wrote the draft; all authors read, reviewed and approved the final manuscript. CJ Z had primary responsibility for final content.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al
. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014;64:252-71.
Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061-7.
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.
Sclafani F, Cunningham D. Bevacizumab in elderly patients with metastatic colorectal cancer. J Geriatr Oncol 2014;5:78-88.
Folprecht G, Seymour MT, Saltz L, Douillard JY, Hecker H, Stephens RJ, et al
. Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol 2008;26:1443-51.
Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, et al
. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006;24:4085-91.
Folprecht G, Cunningham D, Ross P, Glimelius B, Di Costanzo F, Wils J, et al
. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: A pooled analysis of clinical trials. Ann Oncol 2004;15:1330-8.
Joulain F, Proskorovsky I, Allegra C, Tabernero J, Hoyle M, Iqbal SU, et al
. Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer. Br J Cancer 2013;109:1735-43.
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al
. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44.
Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al
. Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005;23:3502-8.
Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al
. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563-72.
Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al
. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-8.
Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al
. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672-80.
Moher DL, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
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.
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.
Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, et al
. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: Prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014;50:320-31.
Tabernero J, Garcia-Carbonero R, Cassidy J, Sobrero A, Van Cutsem E, Kohne CH, et al
. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: The RESPECT trial. Clin Cancer Res 2013;19:2541-50.
Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, et al
. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol 2013;31:2477-84.
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al
. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-12.
Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, et al
. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: A randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 2012;30:3596-603.
Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al
. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 2005;23:3697-705.
Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al
. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1077-85.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al
. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 2013;14:29-37.
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al
. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet 2011;377:2103-14.
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al
. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 2010;28:4697-705.
Kordatou Z, Kountourakis P, Papamichael D. Treatment of older patients with colorectal cancer: A perspective review. Ther Adv Med Oncol 2014;6:128-40.
Kyriakou F, Kountourakis P, Papamichael D. Targeted agents: Review of toxicity in the elderly metastatic colorectal cancer patients. Target Oncol 2011;6:245-51.
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