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Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Versus Bevacizumab in Metastatic Colorectal Cancer: a Systematic Review and Meta-Analysis

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Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Versus Bevacizumab in Metastatic Colorectal Cancer: a Systematic Review and Meta-Analysis MOLECULAR AND CLINICAL ONCOLOGY 3: 959-967, 2015 Vascular endothelial growth factor receptor tyrosine kinase inhibitors versus bevacizumab in metastatic colorectal cancer: A systematic review and meta-analysis ZEXIN LIN1, YILIN YANG2, YONGLIANG HUANG2, JUNJIE LIANG2, FANG LU3 and XUEJUN LAO4 1Department of General Surgery, The First Clinical Medicine School of Jinan University, Affiliated Shantou Hospital of Sun Yat‑Sen University; Departments of 2General Surgery and 3Orthopedics, The First Clinical Medicine School of Jinan University; 4Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P.R. China Received January 29, 2015; Accepted April 24, 2015 DOI: 10.3892/mco.2015.572 Abstract. Bevacizumab has demonstrated a survival benefit 95% CI, 0.85-1.05; P=0.30). VEGFR TKIs treatment showed in patients with metastatic colorectal cancer (mCRC) when a less favorable AE profile compared with bevacizumab, combined with chemotherapy. Several randomized clinical with higher rates of grade-III/IV diarrhea, fatigue, hyperten- trials comparing the efficacy and toxicity of vascular endo- sion, neutropenia and thrombocytopenia, whereas a higher thelial growth factor receptor (VEGFR) tyrosine kinase incidence of peripheral neuropathy associated with the inhibitors (TKIs) against bevacizumab have been reported. bevacizumab group was observed. In conclusion, the addition The present meta-analysis was conducted to identify the poten- of VEGFR TKIs to chemotherapy resulted in a modest but tially significant benefit of the combined treatment regimens in significantly shorter PFS but not in OS and ORR compared patients with mCRC. PubMed, Embase and Cochrane Library with bevacizumab. The VEGFR TKIs group showed a less databases were searched for the randomized controlled trials favorable AE profile with higher rates of diarrhea, fatigue, published on or before September 2014, which compared the hypertension, neutropenia and thrombocytopenia, whereas a efficacy and toxicity of VEGFR TKIs with bevacizumab in higher incidence of peripheral neuropathy associated with the combination with chemotherapy in patients with mCRC. The bevacizumab was observed. primary endpoints included progression-free survival (PFS), overall survival (OS) and overall response rate (ORR), and Introduction secondary endpoints were the toxicity profiles. Relative risks (RRs) with 95% confidence intervals (CIs) for response rate and Colorectal cancer (CRC) is the third most common cause adverse events (AEs) were calculated, as well as hazard ratios of malignancy in men and women in the United States. The (HRs) for PFS and OS. The final analysis included 4 studies prognosis is poor for patients with metastatic colorectal cancer comprising a total of 1,929 intent-to-treat patients with mCRC, (mCRC) and the 5-year survival rate for them is ~12% (1). which compared VEGFR TKIs (cediranib and axitinib) Standard first‑line chemotherapy regimens for mCRC include plus chemotherapy with bevacizumab plus chemotherapy. 5‑fluorouracil (5‑FU)/leucovorin/oxaliplatin (FOLFOX) and Results demonstrated that VEGFR TKIs plus chemotherapy 5-FU/leucovorin/irinotecan (FOLFIRI) (2). These two have significantly resulted in a modest but significantly shorter PFS incrementally led to improved overall response rates (ORR), [hazard ratio (HR), 1.12; 95% CI, 1.00-1.25; P=0.05] compared progression-free survival (PFS) and overall survival (OS) with that of bevacizumab plus chemotherapy but not in OS in first‑line regimens. However, the GERCOR study, which (HR, 1.10; 95% CI, 0.88-1.17; P=0.87) and ORR (RR, 0.95; evaluated the efficacies of FOLFOX and FOLFIRI as first‑ and second-line therapies in patients with mCRC, demonstrated that the clinical benefit was greatly reduced with second‑line treatment (3). More effective options are required to further improve outcomes. Correspondence to: Professor Xuejun Lao, Department of General As a key factor of tumor growth and metastasis, the Surgery, The First Affiliated Hospital of Jinan University, 613 West vascular endothelial growth factor (VEGF) regulates normal Huangpu Road, Guangzhou, Guangdong 510632, P.R. China E‑mail: [email protected] and pathological angiogenesis, and activates multiple signaling networks that promote endothelial cell growth, migration and Key words: advanced or metastatic colorectal cancer, bevacizumab, vascular permeability (4). A clinically validated therapeutic vascular endothelial growth factor receptor tyrosine kinase inhibitor, strategy to target the VEGF signaling axis in patients has been chemotherapy, meta-analysis demonstrated with advanced mCRC. The VEGF monoclonal antibody bevacizumab (Avastin®; Genentech, San Francisco, CA, USA), has demonstrated a clinical benefit in patients with 960 LIN et al: VEGFR TKIs VERSUS BEVACIZUMAB IN METASTATIC CRC: A META-ANALYSIS mCRC when combined with chemotherapy in a randomized, ii) quasi-randomized studies that were considered to possess phase III study, in which the addition of bevacizumab to oxali- insufficient quality; and iii) trials included adjuvant chemo- platin, fluorouracil and leucovorin (FOLFOX4) significantly therapy within 6 months or concomitant interventions were prolonged PFS [7.3 vs. 4.7 months; hazard ratio (HR), 0.61; excluded. P<0.0001] and OS (12.9 vs. 10.8 months; HR, 0.75; P=0.0011) compared with FOLFOX4 alone (5). Quality assessment. Quality of study methodology was VEGF receptors (VEGFR) tyrosine kinase inhibi- scored using the methods reported by Jadad et al (15) and tors (TKIs), such as cediranib and axitinib, have shown Kjaergard et al (16). This is a five‑point scale, with one point antitumor activity in patients with mCRC. Cediranib is awarded for each quality criterion (17). an oral, highly potent VEGF TKI with activity against all three VEGFRs (6,7). A randomized, phase III study Data extraction and statistical analysis. Two investigators (HORIZON II) of cediranib + FOLFOX/CAPOX versus (Y.L Huang and F. Lu) independently extracted the data from placebo + FOLFOX/CAPOX for mCRC demonstrated that all the included studies according to the inclusion criteria the addition of cediranib to chemotherapy prolonged PFS, but listed. Disagreements were resolved by discussion with an did not significantly improve OS (8). Axitinib, a potent and independent expert (Y.L. Yang). The following informa- selective second-generation inhibitor of VEGFRs 1-3 (9), has tion was sought: First author, year of publication, number of shown promising single-agent activity against a variety of patients, number of patients eligible for response, gender rate, tumor types, including metastatic renal cell carcinoma, mela- mean age, ORR, median OS and PFS, and data on AEs/toxici- noma, thyroid cancer and non-small-cell lung cancer (10-14). ties, such as hypertension, vomiting, diarrhea, fatigue and As opposed to bevacizumab, it specifically binds VEGF‑A, neutropenia, thrombocytopenia and peripheral neuropathy. and cediranib and axitinib act directly at VEGFR 1‑3 and Meta-analysis was carried out by RevMan 5.0 provided by may result in a more complete blockade of VEGF signaling. the Cochrane Collaboration (Oxford, UK). HR for PFS and Several RTCs have been conducted to investigate efficacy and OS, relative risks (RR) for ORR and AEs with 95% confidence toxicity of VEGFR TKIs versus bevacizumab in combina- intervals (CI) were calculated. To test the statistical heteroge- tion with chemotherapy in patients with mCRC. However, neity for each trial, a Cochrane's Q test was performed, and if the conclusions are not consistent. Therefore, the present P<0.1, the assumption of homogeneity was considered invalid meta-analysis was performed to evaluate the randomized and the random effect model was used. HR>1 for PFS and controlled trials (RCTs) and compare the efficacy and toxicity OS indicated that the anti-VEGF TKI treatment group derived of VEGFR TKIs plus chemotherapy with bevacizumab plus more progression or fatalities. RR>1 for ORR and AEs indi- chemotherapy in patients with mCRC. cated that the anti-VEGF TKI treatment group derived more overall response or more toxicities. The potential presence of Materials and methods publication bias was evaluated visually by inspecting funnel plots and statistically using the Egger's test. Search criteria. PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library were searched Results for all the relevant trials on or before September 2014, which compared efficacy and toxicity of VEGFR TKIs with Included studies. A total of 273 potentially relevant citations bevacizumab in combination with chemotherapy in patients were reviewed, and following exclusion of 264 as they were with mCRC. The following keywords were used: ‘Advanced reviews studies, basic researches or case reports, 9 potential colorectal cancer’ OR ‘metastatic colorectal cancer’ AND RCTs were identified and the full text for each study was ‘randomized controlled trial’ AND ‘bevacizumab’ AND screened. Of these, 5 studies were excluded due to incomplete ‘VEGFR TKIs’ OR ‘cediranib’ OR ‘axitinib’ OR ‘sunitinib’. data, phase I pharmacokinetics and tolerability or irrelevant Abstracts presented at the annual meeting of the American data to compare VEGFR TKI with bevacizumab in mCRC. Society of Clinical Oncology (ASCO) and the European Finally, 4 randomized trials were eligible for inclusion in the Society for Medical Oncology (ESMO) were also searched, meta-analysis. The study search process is shown in Fig. 1. Four and the
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