Fig. 5 in Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis

RESEARCH ARTICLE Open Access Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis Tobias Engel Ayer Botrel 1,2* , Luciana Gontijo de Oliveira Clark 1 , Luciano Paladini 1 and Otávio Augusto C. Clark 1 Abstract Background: Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). Methods: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI). Results: The final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p= 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p< 0.00001) and also higher overall survival rates (HR = 0.87; 95 % CI: 0.80 to 0.95; p= 0.002) with moderate heterogeneity. Regarding adverse events and severe toxicities (grade ≥3), the group receiving the combined therapy had higher rates of hypertension (RR = 3.56 95 % CI: 2.58 to 4.92; p< 0.00001), proteinuria (RR = 1.89; 95 % CI: 1.26 to 2.84; p= 0.002), gastrointestinal perforation (RR = 3.63; 95 % CI: 1.31 to 10.09; p= 0.01), any thromboembolic events (RR = 1.44; 95 % CI: 1.20 to 1.73; p= 0.0001), and bleeding (RR = 1.81; 95 % CI: 1.22 to 2.67; p= 0.003). Conclusion: The combination of chemotherapy with bevacizumab increased the response rate, progression-free survival and overall survival of patients with mCRC without prior chemotherapy. The results of progression-free survival (PFS) and overall survival (OS) were comparatively higher in those subgroups of patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab,whencomparedtopatientstreatedwithinfusional %-FU plus bevacizumab (no difference in PFS and OS). Regarding the type of cytotoxic scheme, regimens containing irinotecan and fluoropyrimidine monotherapy showed superior efficacy results when combined to bevacizumab. Keywords: Chemotherapy, Bevacizumab, Metastatic colorectal cancer, Systematic review, Meta-analysis * Correspondence: [email protected] 1 Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil13092-123 2 CIOP - Centro Integrado de Oncologia e Pesquisa, Rua Santo Antônio 200, sala 301, Poços de Caldas, Minas Gerais, Brazil37701-036 © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Botrel et al. BMC Cancer (2016) 16:677 DOI 10.1186/s12885-016-2734-y Background Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States [1, 2]. Thus, CRC constitutes a public health problem that affects men and women in similar proportion and is more prevalent in Western countries [3]. Approximately 25 % of patients already have metastatic disease at the moment of diagnosis and nearly 50 % will develop metastases [4, 5]. Over the past 10 years, various combinations of chemotherapy were investigated for the treatment of metastatic colorectal cancer (mCRC) [6]. Since its introduction by Heidelberger in 1957, 5fluorouracil (5-FU) has become one of the most extensively used drugs in the treatment of mCRC worldwide and also the backbone of nearly all the recommended and researched chemotherapy associations [7–9]. Capecitabine, another oral fluoropyrimidine, is currently recommended as an alternative for the treatment of these patients since its similar efficacy to 5-FU was demonstrated in randomized studies [10]. Subsequently, two other cytotoxic drugs (irinotecan and oxaliplatin) had their efficacy confirmed in the treatment of mCRC, thus becoming part of treatment protocols since 1999 [7, 11–13]. Lately, the eyes of the medical community around the world have been turned to targeted molecular therapies. In February 2004, the Food and Drug Administration (FDA) approved bevacizumab - a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF) - combined with standard chemotherapy to treat mCRC [14, 15]. Less than a year later, the European Medicines Agency (EMEA) also gave the drug its approval. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin [16]. Four meta-analyses published between 2009 and 2012 compiled the results of randomized trials on standard chemotherapy with bevacizumab in the therapy of mCRC [16–19]. Results of these metaanalyses evidenced the difference in overall survival favoring the groups treated with chemotherapy plus bevacizumab. In 2014, another meta-analysis [20] showed that the addition of bevacizumab to first-line chemotherapy for mCRC did not achieve clinical benefit for overall survival. This latter study brought out questions about the real benefit of chemotherapy plus bevacizumab for these patients. Since then, the availability of new clinical studies produced uncertain or controversial results regarding the effectiveness of this treatment, particularly for the endpoint of overall survival [21–24]. In this context, we felt it was appropriate to re-assess the role of bevacizumab as a component of first-line therapy in patients with advanced colorectal cancer. This systematic review aims to evaluate the effectiveness and safety of bevacizumab associated with standard chemotherapy in the treatment of patients with mCRC without prior chemotherapy. Methods Study selection criteria Types of studies Randomized controlled clinical trials (RCTs) with parallel design that compared the use of chemotherapy regimens associated with bevacizumab against other regimens without bevacizumab. Types of participants Patients aged ≥18 years old with cytological or histological diagnosis of mCRC without prior chemotherapy (only in first-line treatment). Search strategy for identification of studies A wide search of the main computerized databases of interest was conducted, including EMBASE, LILACS, MEDLINE, SCI, CENTRAL, The National Cancer Institute Clinical Trials service, and The Clinical Trials Register. In addition, the abstracts published in the proceedings of the American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), European Society for Medical Oncology (ESMO) and World Congress on Gastrointestinal Cancer were also searched. For MEDLINE, we used the search strategy methodology for randomized controlled trials [25] recommended by the Cochrane Collaboration [26]. For EMBASE, we used adaptations of this same strategy [25], and for LILACS, we used the search strategy methodology reported by Castro et al. [27]. We performed an additional search on the SCI database looking for papers that were cited on the included studies. We added the specific terms pertinent to this review to the overall search strategy methodology for each database. The overall search strategy was: #1 “bevacizumab” (Supplementary Concept) OR “bevacizumab”(All Fields); 2# “colorectal neoplasms”(MeSH Terms) OR “colorectal”(All Fields) AND “neoplasms”(All Fields) OR “colorectal neoplasms”(All Fields) OR “colorectal” (All Fields) AND “cancer”(All Fields) OR “colorectal cancer”(All Fields); 3# Clinical Trial (ptyp). Searches of electronic databases combined the terms#1AND#2AND#3anddidnothavelanguage or date restrictions. Botrel et al. BMC Cancer (2016) 16:677 Page 2 of 19 Critical evaluation of the selected studies All the references retrieved by the search strategies had their title and abstract evaluated by two of the researchers. Every reference with the least indication of fulfilling the inclusion criteria was listed as pre-selected. We retrieved the complete article of all pre-selected references. Two different researchers analyzed the articles and included or excluded them according to the previously reported criteria. The excluded trials and the reason for their exclusion are listed in this article. Data was extracted from all the included trials. Details regarding the main methodology characteristics empirically linked to bias [28] were extracted with the methodological validity of each selected trial assessed by two reviewers (T.E.A.B and O.C). Particular attention was given to some items such as: the generation and concealment of the sequence of randomization, blinding, application of intention-to-treat analysis, sample size pre-definition, loss of follow-up description, adverse events reports, if the trial was multicentric and the source of sponsorship. Data extraction Two independent reviewers extracted the data. The name of the first author and year of publication were used to identify the study. All data were extracted directly from the text or calculated from the available information when necessary. The data of all trials were based on the intention-to-treat principle, so they compared all patients allocated in one treatment with all those allocated in the other arm. The primary endpoints were progression-free survival (defined as time from randomization to either death or disease progression, whichever occurred first) and overall survival. If data on progression-free survival were not available, data on time to progression or event free survival were assessed. Other clinical outcomes were evaluated: overall response rate (complete response + partial response) and the more frequently found adverse events (grade ≥3), both hematological (anemia, neutropenia, febrile neutropenia and thrombocytopenia) and non-hematological (diarrhea, hypertension, proteinuria, gastrointestinal perforation, nausea and vomiting and any thromboembolic and bleeding events). Analysis and presentation of results Data were analyzed using the Review Manager 5.1.2 statistical package (Cochrane Collaboration Software) [29]. Dichotomous clinical outcomes are reported as risk ratio (RR) and survival data as hazard ratio (HR) [30]. The corresponding 95 % confidence interval (95 % CI) was calculated, considering Pvalues less than 5 % (p< 0.05). A statistic for measuring heterogeneity was calculated through I 2 method (25 % was considered low-level heterogeneity, 25–50 % moderate-level heterogeneity and > 50 % high-level heterogeneity) [31, 32]. To estimate the absolute gains in progression-free survival and overall survival, we calculated the metaanalytic survival curves as suggested by Parmar et al. [30]. A pooled estimate of the HR was computed by a fixed-effect model according to the inverse-variance method [33]. Thus, for effectiveness or side effects an HR or RR > 1 favors standard arm (control), whereas an HR or RR < 1 favors bevacizumab treatment. If statistical heterogeneity was found in the metaanalysis, we performed an additional analysis using the random-effects model described by DerSimonian and Laird [34], that provides a more conservative analysis. To assess the possibility of publication bias, we performed the funnel plot test described by Egger et al. [35]. When the pooled results were significant, the number of patients needed to treat (NNT or NNH) to cause or to prevent one event was calculated by pooling absolute risk differences in trials included in meta-analyses [36–38]. For all analyses, a forest plot was generated to display results. In the efficacy assessment, a subgroup analysis was planned to evaluate the influence of the type of fluoropyrimidine (bolus or infusional 5-FU or capecitabine) and cytotoxic agents used (only fluoropyrimidine monotherapy, oxaliplatin-based and irinotecan-based regimens). Results The diagram represents the flow of identification and inclusion of trials, as recommended by the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) statement [39] (Fig. 1). In the first search, 228 references were identified and screened. Nineteen were considered of potential interest and selected for analysis in full. Of these, 10 were excluded for different reasons as described in Table 1. The final analysis included 9 trials comprising 3,914 patients (Table 2). A comprehensive analysis was performed regarding the presence of relevant biomarkers, such as VEGF-A isoform or KRAS status, which might have predicted superior efficacy for patients treated with bevacizumab or other particular regimens. Three studies reported separateddataofefficacyforpatientswithwildtype (WD) or mutated (MT) KRAS. Mutation status KRAS was determined for patients participating in the ITACA trial [21, 23], also for 315 (66,9 %) of those on MAX trial [22, 40, 41] and 230 patients (28.3 %) on the AVF2107 study [14, 42, 43]. Quality assessments for eligible trials were evaluated and performed by extracting key methodological Botrel et al. BMC Cancer (2016) 16:677 Page 3 of 19 characteristics from published trials (Additional file 1: Table S1). Characteristics and results of included studies Studies containing chemotherapy (irinotecan-based) + bevacizumab Bevacizumab was associated with irinotecan in 3 randomized studies [14, 24, 42, 44]. AVF 2107 trial This multicenter, placebo-controlled study [14] analyzed patients with mCRC and measurable disease. Patients were initially randomized 1:1:1 to 3 groups: placebo combined with chemotherapy (IFL regimen: irinotecan + fluorouracil + leucovorin); bevacizumab (5 mg/kg) every 15 days combined with chemotherapy (IFL regimen); and bevacizumab combined with 5-FU and leucovorin (abandoned after the safety of bevacizumab + irinotecan was well established). Treatment continued until progression of disease. The primary endpoint was overall survival (Table 2). In the ITT analysis, 411 patients were randomized to the group IFL + placebo and 402 patients to the group IFL + bevacizumab. The association of bevacizumab to the IFL regimen significantly increased the objective response rate, compared to IFL + placebo (44.8 % vs. 34.8 %; p= 0.004) (Table 3). Progression-free survival (10.6 months vs. 6.2 months; p< 0.001) and overall survival (20.3 months vs. 15.6 months; p< 0.001) were higher in the group receiving bevacizumab (Table 3). The combination of IFL + bevacizumab was well tolerated. In general, toxicity levels ≥3werehigherinthe group treated with bevacizumab (84.9 % vs. 74 %; p< 0.01). There was no significant difference in the rate of thromboembolic events, proteinuria, and bleeding or gastrointestinal perforation. Hypertension (grade ≥3) was more frequent in the group treated with bevacizumab (11 % vs. 2.3 %; p<0.01) (Table 5). ARTIST trial This prospective, multicenter study [24] assessed patients diagnosed with mCRC and measurable disease. The trial included Chinese patients and randomized (2:1) 139 patients to receive bevacizumab (5 mg/kg every 15 days) combined with chemotherapy (IFL regimen) and 64 patients to receive only IFL. The treatment continued until progression of disease. Rate of progression-free survival at 6 months and duration of progression-free survival were co-primary endpoints (Table 2). The combination of IFL + bevacizumab significantly increased the objective response rate, compared with IFL alone (35.3 % vs. 17.2 %; p= 0.013) (Table 3). Progressionfree survival (8.3 months vs. 4.2 months; p<0.001) and overall survival (18.7 months vs. 13.4 months; p=0.014) Fig. 1 Trial selection flow Table 1 Characteristics of excluded studies Reasons for exclusion Lee 2012 [72] Nonrandomized (cost-effectiveness analysis) Shiroiwa 2010 [73] Nonrandomized (cost-effectiveness analysis) Zhang 2012 [74] Nonrandomized Allegra 2009/2011 [75,76] Adjuvant treatment Ducreux 2009 [77] Different comparison (bevacizumab in both arms) Pectasides 2012 [78] Different comparison (bevacizumab in both arms) Souglakos 2012 [79] Different comparison (bevacizumab in both arms) Díaz-Rubio 2012 [80] Different comparison (bevacizumab in both arms) Price 2012 [81] Subgroup analysis of another study Moehler 2009 [82] Nonrandomized Botrel et al. BMC Cancer (2016) 16:677 Page 4 of 19 Table 2 Characteristics of randomized studies evaluating bevacizumab plus chemotherapy in patients with mCRC in first line chemotherapy Study nType of study Patients Comparison Primary endpoint Regimens containing irinotecan with/without bevacizumab Hurwitz 2004/2005 [14,42] (AVF 2107) 813 Randomized, multicenter, phase III mCRC, ECOG PS 0–1, ≥18 years IFL/Bev (5 mg/kg) OS IFL/placebo Guan 2011 [24] (ARTIST) 203 Randomized, multicenter, phase III mCRC, ECOG PS 0–1, ≥18 years IFL/Bev (5 mg/kg) PFS and PFS rate in 6 months IFL Stathopoulos 2010 [44] 222 Randomized, phase III mCRC, ECOG PS 0–2, ≥18 years IFL/Bev (7.5 mg/kg) OS IFL Regimens containing oxaliplatin with/without bevacizumab Saltz/Cassidy 2008/2011 [45,46] (NO16966) 1400 Randomized, multicenter, phase III mCRC, ECOG PS 0–1, ≥18 years XELOX or FOLFOX/Bev (5 mg/kg or 7.5 mg/kg) PFS XELOX or FOLFOX/ placebo Regimens containing oxaliplatin or irinotecan with/without bevacizumab Passardi 2013/2015 [21,23] (ITACA) b 370 Randomized, multicenter, phase III mCRC, ECOG PS 0–2, ≥18 years FOLFOX or FOLFIRI/Bev (5 mg/kg) PFS FOLFOX or FOLFIRI Regimens containing only 5-FU with/without bevacizumab Kabinnavar 2003 [47] 104 Randomized, multicenter, phase III mCRC, ECOG PS 0–1, ≥18 years 5-FU/LV TTP and ORR 5-FU/LV/Bev (5 mg/kg) 5-FU/LV/Bev (10 mg/kg) Kabinnavar 2005 [48] 209 Randomized, multicenter, phase III mCRC, ECOG PS 1–2, ≥65 years 5-FU/LV/Bev (5 mg/kg) OS 5-FU/LV/placebo Regimens containing only capecitabine with/without bevacizumab Tebutt 2010 [40] (MAX) 313 a Randomized, multicenter, phase III mCRC, ECOG PS 0–2, ≥18 years Capecitabine/Bev (7.5 mg/kg) PFS Capecitabine Cunningham 2013 [22] (AVEX) 280 Randomized, multicenter, phase III mCRC, ECOG PS 0–2, ≥70 years Capecitabine/Bev (7.5 mg/kg) PFS Capecitabine Chemotherapy protocols: Hurwitz 2004/2005 [14,42] - (AVF 2107) IFL/Placebo: 5-FU: 500 mg/m 2 ,bolus + LV: 20 mg/m 2 , during 2 h + irinotecan: 125 mg/m 2 , once/week for 4 weeks every 6 weeks. IFL/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg intravenously every 15 days until progression. Guan 2011 [24] - (ARTIST) IFL/Placebo: 5-FU: 500 mg/m 2 + LV: 20 mg/m 2 (infusion: 6–8 h) + irinotecan: 125 mg/m 2 , once/week for 4 weeks every 6 weeks. IFL/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg intravenously every 15 days until progression. Stathopoulos 2010 [44] IFL: 5-FU: 500 mg/m 2 + LV: 200 mg/m 2 + irinotecan: 135 mg/m 2 , in Day 1 (D1) every 3 weeks. IFL/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg intravenously every 3 weeks until progression. Saltz/Cassidy 2008/2011 [45,46] - (NO16966) FOLFOX/placebo: LV: 200 mg/m 2 /day intravenously in 2 h + 5-FU: 400 mg/m 2 /day in bolus, followed by 600 mg/m 2 /dayin22hinDays1 and 2 + oxaliplatin: 85 mg/m 2 ,in2h,inD1; FOLFOX/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1; every 15 days; XELOX/placebo: capecitabine: 1000 mg/m 2 orally, twice/day, for 14 days + oxaliplatin: 130 mg/m 2 intravenously in D1; XELOX/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg in D1; every 21 days, until progression. Botrel et al. BMC Cancer (2016) 16:677 Page 5 of 19 were also higher in the group treated with bevacizumab (Table 3). Patients tolerated well the association of bevacizumab and IFL. The proportion of adverse events (grade ≥3) was comparable between groups (IFL: 61 % vs. IFL + bevacizumab: 69 %). Stathopoulos et al. trial This study [44] analyzed 222 patients with mCRC and measurable disease. The trial randomized 144 patients to receive bevacizumab (7.5 mg/kg) plus chemotherapy (IFL regimen) every 3 weeks and 108 patients to receive IFL alone. The primary endpoint was overall survival. Treatment continued until progression of disease (Table 2). Response rate was similar between groups (IFL + bevacizumab: 36.8 % vs. IFL: 35.2 %; p= NS). Overall survival was also similar between groups (IFL + bevacizumab: IFL: 22 months vs. 25 months; p= 0.1391) (Table 3). In this trial, the authors reported only the overall adverse events (without stratifying by degree). Hematologic toxicities were similar between groups (leukopenia, IFL + bevacizumab: 34.2 % vs. IFL: 36.1 %; anemia, IFL + bevacizumab: 31.6 % vs. IFL: 33.3 %; thrombocytopenia, IFL + bevacizumab: 3.5 % vs. IFL: 4.6 %). Regarding nonhematological toxicities, four adverse events were more frequent in patients treated with IFL + bevacizumab than with IFL alone (hypertension: 20.2 % vs. 0 %; proteinuria: 6.1 % vs. 0 %; bleeding: 2.6 % vs. 0 %; and gastrointestinal perforation: 0.9 % vs. 0 %). Rates of nausea, vomiting and diarrhea were similar between the groups. Studies containing chemotherapy (oxaliplatin-based) + bevacizumab One randomized trial analyzed the combination of bevacizumab with oxaliplatin-based regimens in the therapy of previously untreated mCRC [45, 46]. NO16966 trial This multicenter study [46] associated bevacizumab with 2 chemotherapy regimens (FOLFOX or XELOX) in patients with mCRC. In the bevacizumab + FOLFOX combination, patients received bevacizumab (5 mg/kg) on day 1 of chemotherapy every 15 days. In bevacizumab + XELOX combination, patients received bevacizumab (7.5 mg/kg) on day 1 of chemotherapy every 21 days. The trial randomized 701 patients to receive XELOX/ FOLFOX + bevacizumab and 699 patients to receive XELOX/FOLFOX + placebo (Table 2). Table 2 Characteristics of randomized studies evaluating bevacizumab plus chemotherapy in patients with mCRC in first line chemotherapy (Continued) Passardi 2013/2015 [21,23] - (ITACA) FOLFOX: LV: 100 mg/m 2 /day intravenously D1 and D2 + 5-FU: 400 mg/m 2 /day in bolus D1andD2,followedby600mg/m 2 in 22 h in Days 1 and 2 + oxaliplatin: 85 mg/m 2 ,in2h,inD1; FOLFIRI: LV: 100 mg/m 2 /day intravenously D1 and D2 + 5-FU: 400 mg/m 2 /day in bolus D1 and D2, followed by 600 mg/m 2 in 22 h in Days 1 and 2 + irinotecan 180 mg/m 2 ,inD1; FOLFOX or FOLFIRI/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1; every 15 day; Kabinnavar 2003 [47] 5-FU/LV: 5-FU: 500 mg/m 2 /LV: 500 mg/m 2 , weekly for 6 weeks every 8 weeks. 5-FU/LV/Bev (5 mg/kg): same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1, every 15 day; 5-FU/LV/Bev (10 mg/kg): same chemotherapy regimen + bevacizumab: 10 mg/kg, Day 1, every 15 day; Kabinnavar 2005 [48] 5-FU/LV: 5-FU: 500 mg/m 2 /LV: 500 mg/m 2 , weekly for 6 weeks every 8 weeks + placebo every 15 day. 5-FU/LV/Bev (5 mg/kg): same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1, every 15 day; Tebutt 2010 [40] (MAX) a Capecitabine: 1000–1250 mg/m 2 orally, twice/day, for 14 days; Capecitabine/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg D1; every 21 days, until progression. Cunningham 2013 [22] - (AVEX) Capecitabine: 1000 mg/m 2 orally, twice/day, for 14 days; Capecitabine/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg D1; every 21 days, until progression. Abbreviations:mCRC metastatic colorectal cancer, Bev bevacizumab, IFL fluorouracil/leucovorin + irinotecan, 5-FU fluorouracil, LV leucovorin, OS overall survival, PFS progression-free survival, FOLFOX bolus and infusional fluorouracil/leucovorin + oxaliplatin, XELOX oxaliplatin + capecitabine, ECOG Eastern Cooperative Oncology Group, PS performance status, TTP time to progression, ORR overall response rate a Excluded patients with mitomycin; b FOLFOX4 was used in 60 % of the patients and FOLFIRI in 40 % Botrel et al. BMC Cancer (2016) 16:677 Page 6 of 19 Overall response rate was similar between groups (XELOX/FOLFOX + bevacizumab: 47 % vs. XELOX/ FOLFOX + placebo: 49 %; p= 0.31) and progression-free survival was higher in the group treated with XELOX/ FOLFOX + bevacizumab (9.4 months vs. 8.0 months; p = 0.0023). Overall survival was also similar between groups (XELOX/FOLFOX + bevacizumab: 21.3 months vs. XELOX/FOLFOX + placebo: 19.9 months; p= 0.0769) (Table 3). Hematologic toxicities were not reported. Nonhematological toxicities (grade ≥3) were generally 5 % higher in patients treated with XELOX/FOLFOX + Table 3 Efficacy results of randomized studies evaluating bevacizumab plus chemotherapy in patients with mCRC in first-line treatment Study n (ITT) Comparison Response rate PFS OS HR (95 % CI) HR (95 % CI) Regimens containing irinotecan with/without bevacizumab Hurwitz 2004/2005 [14,42] (AVF 2107) 402 IFL/Bev 44.8 % 10.6 months 20.3 months 411 IFL/placebo 34.8 % 6.2 months 15.6 months p= 0.004 HR: 0.54 (0.37–0.78) HR: 0.66 (0.52–0.85) Guan 2011 [24] (ARTIST) 139 IFL/Bev 35.3 % 8.3 months 18.7 months 64 IFL 17.2 % 4.2 months 13.4 months p= 0.013 HR: 0.44 (0.31–0.63) HR: 0.62 (0.41–0.95) Stathopoulos 2010 [44] 114 IFL/Bev 36.8 % NR 22 months 108 IFL 35.2 % 25 months p= NS HR: 1.05 (0.81–1.36) b Regimens containing oxaliplatin with/without bevacizumab Saltz/Cassidy 2008/2011 [45,46] (NO16966) 699 XELOX or FOLFOX/Bev 47 % 9.4 months 21.3 months 701 XELOX or FOLFOX/placebo 49 % 8.0 months 19.9 months p= 0.31 HR: 0.83 (0.72–0.95) a HR: 0.89 (0.76–1.03) Regimens containing oxaliplatin or irinotecan with/without bevacizumab Passardi 2013/2015 [21,23] (ITACA) c 176 FOLFOX or FOLFIRI/Bev 50.6 % 9.6 months 20.8 months 194 FOLFOX or FOLFIRI 50 % 8.4 months 21.3 months p= 0.865 HR: 0.86 (0.70-1.07) HR: 1.13 (0.89-1.43) Regimens containing only 5-FU with/without bevacizumab Kabinnavar 2003 [47] (AVF0780) 35 5-FU/LV/Bev (5 mg/kg) 40 % 9.0 months 21.5 months 33 5-FU/LV/Bev (10 mg/kg) 24 % 7.2 months 16.1 months 36 5-FU/LV 17 % 5.2 months 13.8 months (p= 0.08) HR: 0.54 (0.33–0.88) HR: NR Kabinnavar 2005 [48] (AVF2192) 104 5-FU/LV/Bev 26 % 9.2 months 16.6 months 105 5-FU/LV 15.2 % 5.5 months 12.9 months p= 0.055 HR: 0.50 (0.35–0.73) HR: 0.79 (0.56–1.10) Regimens containing only capecitabine with/without bevacizumab Tebutt 2010 [40] (MAX) 157 Capecitabine/Bev 38.1 % 8.5 months NR 156 Capecitabine 30.3 % 5.7 months p= 0.16 HR: 0.63 (0.50–0.79) HR: 0.88 (0.68–1.13) Cunningham 2013 [22] (AVEX) 140 Capecitabine/Bev 19 % 9.1 months 20.7 months 140 Capecitabine 10 % 5.1 months 16.8 months p= 0.04 HR: 0.53 (0.41–0.69) HR: 0.79 (0.57–1.09) Abbreviations:mCRC metastatic colorectal cancer, Bev bevacizumab, IFL fluorouracil/leucovorin + irinotecan, 5-FU fluorouracil, LV leucovorin, OS overall survival, PFS progression-free survival, FOLFOX bolus and infusional fluorouracil/leucovorin + oxaliplatin, XELOX oxaliplatin + capecitabine, ITT intent to treat, NR not reported, HR hazard ratio, CI confidence interval, NS not significant a 97.5 % IC; b calculated by the method of Parmar; c FOLFOX4 was used in 60 % of the patients and FOLFIRI in 40 % Botrel et al. BMC Cancer (2016) 16:677 Page 7 of 19 bevacizumab compared with XELOX/FOLFOX + placebo. Studies containing chemotherapy (irinotecan or oxaliplatin-based) + bevacizumab ITACA trial This multicenter study [21] was presented at ASCO in 2013 and published in full afterwards [23]. A total of 370 (ITT) mCRC patients were randomized to receive firstline chemotherapy (FOLFOX4 or FOLFIRI) plus bevacizumab (5 mg/kg) or chemotherapy alone. The primary endpoint was progression-free survival. FOLFOX4 regimen was used by 60 % of the patients and FOLFIRI by 40 %. Results showed no statistically significant differences in progression-free survival, overall survival and overall response rate (Table 3). Hematologic toxicities were similar between the groups. Regarding nonhematological toxicities, five adverse events were more frequently found in patients treated with chemotherapy + bevacizumab than with chemotherapy alone (hypertension: 27.8 % vs. 10.8 %; fatigue: 10.3 % vs. 3.1 %; proteinuria: 22.2 % vs. 13.4 %; bleeding: 17.0 % vs. 4.6 %; and thrombosis: 21 % vs. 12.9 %). Rates of nausea, vomiting and diarrhea were similar between the groups. Studies containing chemotherapy (only 5-FU) + bevacizumab Two randomized studies investigated the use of bevacizumab with chemotherapy containing only 5-FU [47, 48]. AVF0780 trial This randomized study [47] evaluated the use of bevacizumab combined with chemotherapy (“Roswell Park” scheme) in 104 patients with mCRC. Patients were randomly assigned to one of three treatment groups: 36 to receive chemotherapy alone, 35 to receive chemotherapy plus low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to receive chemotherapy plus high-dose bevacizumab (10 mg/kg every 2 weeks) (Table 2). The group treated with bevacizumab presented better overall response rate (control arm: 17 %; low-dose arm: 40 %; high-dose arm: 24 %), longer time to disease progression (control arm: 5.2 months; low-dose arm: 9.0 months; high-dose arm: 7.2 months) and longer overall survival (control arm: 13.8 months; low-dose arm: 21.5 months; high-dose arm: 16.1 months) (Table 3). Toxicity profiles are described in Tables 4 and 5. The study did not report the degree of proteinuria, however none of the patients developed nephrotic syndrome. AVF2192 trial This study [48] randomized patients to receive chemotherapy (“Roswell Park”scheme) plus placebo (n= 105) or chemotherapy plus bevacizumab (n= 104). The primary endpoint was overall survival. The trial included patients (aged ≥65 years) who were not optimal candidates for treatment with irinotecan [41] (Table 2). The addition of bevacizumab to chemotherapy increased the overall response rate (5-FU + leucovorin + bevacizumab: 26.0 % vs. 5-FU + leucovorin + placebo: 15.2 %; p= 0.055) and progression-free survival (5-FU + leucovorin + bevacizumab: 9.2 months vs. 5-FU + leucovorin + placebo: 5.5 months; p= 0.0002), but had no difference in overall survival (5-FU + leucovorin + bevacizumab: 16.6 months vs. 5-FU + leucovorin + placebo: 12.9 months; p= 0:16) (Table 3). Regarding adverse events, grade 3 hypertension was more frequent in the bevacizumab arm (16 % vs.3 %), (Table 5). Studies containing chemotherapy (capecitabine only) + bevacizumab Two randomized studies assessed bevacizumab plus chemotherapy compared to capecitabine alone [22, 40]. MAX trial This multicenter phase III trial evaluated bevacizumab plus chemotherapy versus capecitabine alone [40]. The trial analyzed patients with mCRC without prior chemotherapy. Overall, 471 patients were randomly assigned to receive capecitabine; capecitabine plus bevacizumab (7.5 mg/kg); or capecitabine plus bevacizumab and mitomycin. The primary endpoint was progression-free survival. Since the chemotherapy regimen including mitomycin is not considered standard for mCRC according to the main international guidelines, that particular group was not evaluated in this meta-analysis. Overall response rate (capecitabine + bevacizumab: 56 % vs. 43 %; p= 0.16) and overall survival were similar between groups (Table 3). Progression-free survival was higher in the group treated with capecitabine + bevacizumab (8.5 months vs. 5.7 months; p< 0.001). Hand-foot syndrome (also known as palmar-plantar erythrodysesthesia) and diarrhea were the most common grades ≥3 toxicities (Table 5). AVEX trial This phase III trial [22] included patients (aged ≥70 years) with previously untreated mCRC, who were not fit candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens. Patients were randomly assigned to receive bevacizumab plus capecitabine (n= 140) or capecitabine alone (n= 140). The primary endpoint was progressionfree survival. Chemotherapy plus bevacizumab achieved higher overall response rate (19 % vs. 10 %; p = 0.04) and Botrel et al. BMC Cancer (2016) 16:677 Page 8 of 19 progression-free survival (9.1 months vs. 5.1 months; p< 0.0001). Median overall survival was 20.7 months in the combination arm and 16.8 months in the capecitabine alone group (p=0.18)(Table3). The frequencies of grade ≥3 adverse events related to chemotherapy, with the exception of hand-foot syndrome, remained similar between the groups as seen on Tables 4 and 5. Meta-analyses The meta-analyses performed found that the combination of bevacizumab with chemotherapy resulted in higher overall response rate, progression-free survival and overall survival. Overall response rate was higher in patients who received chemotherapy plus bevacizumab (RR = 0.89; 95 % CI: 0.82 to 0.96; 0.003; NNT = 20). Nevertheless, Table 4 Results of hematological adverse events (grade > 3) of the included studies that evaluated bevacizumab plus chemotherapy in mCRC nAnemia Neutropenia Febrile neutropenia Thrombocytopenia Regimens containing irinotecan with/without bevacizumab Hurwitz 2004/2005 [14,42] (AVF 2107) IFL/Bev 393 NR 37.0 % NR NR IFL/placebo 397 31.1 % Guan 2011 [24] (ARTIST) IFL/Bev 141 4 % 33 % 2 % 3 % IFL 70 1 % 19 % 2 % 4 % Stathopoulos 2010 [44] IFL/Bev 114 NR NR NR NR IFL 108 Regimens containing oxaliplatin with/without bevacizumab Saltz/Cassidy 2008/2011 [45,46] (NO16966) XELOX or FOLFOX/Bev 694 NR NR NR NR XELOX or FOLFOX/placebo 675 Regimens containing oxaliplatin or irinotecan with/without bevacizumab Passardi 2013/2015 [21,23] (ITACA) FOLFOX or FOLFIRI/Bev 176 1.1 % 39.6 % 0.6 % 2.3 % FOLFOX or FOLFIRI 194 2.6 % 42.3 % 2.1 % 1.0 % Regimens containing only 5-FU with/without bevacizumab Kabinnavar 2003 [47] (AVF0780) 5-FU/LV/Bev (5 mg/kg) 35 NR 5.7 % NR NR 5-FU/LV/Bev (10 mg/kg) 32 3.1 % 5-FU/LV 35 2.85 % Kabinnavar 2005 [48] (AVF2192) 5-FU/LV/Bev 100 NR 5 % NR NR 5-FU/LV 104 7 % Regimens containing only capecitabine with/without bevacizumab Tebutt 2010 [40] (MAX) Capecitabine/Bev 157 NR 0 % 2.5 % 0 % Capecitabine 156 1.3 % 1.9 % 0 % Cunningham 2013 [22] (AVEX) Capecitabine/Bev 134 NR 1 % NR NR Capecitabine 136 1 % Abbreviations:mCRC metastatic colorectal cancer, Bev bevacizumab, IFL fluorouracil/leucovorin + irinotecan, FOLFOX bolus and infusional fluorouracil/leucovorin + oxaliplatin, XELOX oxaliplatin + capecitabine, NR not reported Botrel et al. BMC Cancer (2016) 16:677 Page 9 of 19 results demonstrated that the overall response rate, progression-free survival and overall survival were higher in patients who received the combination of chemotherapy plus bevacizumab in a fixed effects model analysis, but with heterogeneity. These results remain favorable to the same combination with bevacizumab, even after a random-effects model analysis was performed. One hypothesis that may explain the heterogeneity found in this and other systematic reviews is the difference in bevacizumab doses and individual inclusion criteria – as age and ECOG PS of patients –for each study. The wide range regarding mean age of patients detected on the included trials might have contributed to the heterogeneity seen in all meta-analyses performed to this date. Two trials included patients with mean age between 50 and 60 years [14, 24, 42]; four had patients with mean age between 60 and 70 years [21, 23, 40, 44–46] and two included patients with mean age over 70 years [22, 48]. Levels of ECOG performance status of included patients were also distinct along the trials, varying from PS 0–1 [14, 24, 42, 45–47]; PS 0–2[21–23, 40, 44] and PS 1–2 [48]. The mode of chemotherapy administration and type of cytotoxic drug also seemed to influence the results, since in the subgroups analysis the response rate was higher in patients who received bolus fluoropyrimidine plus bevacizumab and in those treated with irinotecancontaining regimens or fluoropyrimidine monotherapy plus bevacizumab. Progression-free survival and the overall survival were also influenced by the same variables, as better results were seen in patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab. Regarding the type of cytotoxic regimen, all subgroups (irinotecan-containing, oxaliplatin-containing and fluoropyrimidine monotherapy) had favorable results on progression-free survival with the addition of bevacizumab. However, only patients treated with irinotecan-containing regimens (IFL) or fluoropyrimidine monotherapy had statistically significant results in overall survival with the association of bevacizumab. Oxaliplatin might not be an ideal partner for bevacizumab, as pointed out by Macedo et al. [18]. Both studies that combined oxaliplatin-based chemotherapy [21, 23, 45, 46] plus bevacizumab failed to show benefit in overall survival. In the trial by Passardi [21, 23] FOLFOX4 was used in 60 % of the patients. Separate data on overall survival FOLFIRI or FOLFOX were not reported, however. The bevacizumab dose in studies using oxaliplatin-based chemotherapy was similar to those seen in studies with irinotecan regimens. Also, the ECOG PS of patients was comparable to that seen in irinotecan-based or 5FU monotherapy regimens. The efficacy results of our meta-analysis were similar to those found by Macedo et al. [18], who also assessed the addition of bevacizumab in different settings, albeit with fewer studies included. To our knowledge, ours is the only meta-analysis that evaluated subgroups of patients by type of cytotoxic treatment and mode of administration. This systematic review is comprised by trials published through a span of more than 10 years. This opens issues regarding the appropriateness of pooling the results of older trials from the standpoint of current standards of care in advanced colorectal cancer. Sensitivity analyses were performed excluding AVF 2107 [14, 42] and Kabinnavar et al. [47, 48] trials, both with patient accrual taking place in the early 2000s (data not shown). Although overall survival data didn’t statistically favor bevacizumab-containing regimens (HR = 0.92; 95 % CI 0.83, 1.01), benefits in PFS persisted in the same magnitude as observed in the main analysis (HR = 0.72; 95 % CI 0.66, 0.79). It should be noted that this exploratory analysis carries some potential biases: Most trials included were conducted with sample calculation taking into account that the primary endpoint was PFS, limiting the chance for identification of an overall survival benefit even if this was a true effect of bevacizumab containing regimens. Furthermore, crossover to bevacizumab was not allowed in some trials [14, 42, 48] but it did occur in others [22, 46, 47], while some studies did not explicitly report such information [24, 40, 44]. Nevertheless, PFS lengthening have been shown to strongly correlate with improvements in overall survival in advanced colorectal cancer [66, 67]. Since bevacizumab is an antibody against VEGF, another aspect that needs further clarification is the potential benefit of VEGF-A isoform plasma levels in patients who are eligible for this targeted therapy. It is known that VEGF is overexpressed in various human malignancies [68] and it is considered to be an important regulator of physiologic and pathologic angiogenesis [44, 69]. In many instances, VEGF is correlated with an adverse prognosis (increased risk of tumor recurrence and metastasis and decreased survival) [48]. Recently, a systematic review with meta-analysis presented at the ESMO Meeting [70] explored this correlation and, despite the small number of included studies, showed that VEGF-A plasma levels seemed to predict benefit with bevacizumab in early and advanced breast cancer. Appraisal of VEGF-A levels in patients with mCRC might similarly help to select those with the greatest potential for treatment response. None of the meta-analyses evaluating the addition of bevacizumab to standard chemotherapy in patients with mCRC was able to identify the potential benefit of VEGF-A isoform plasma levels, or other efficacy Botrel et al. BMC Cancer (2016) 16:677 Page 16 of 19 biomarkers, since the included studies did not report on that outcome. KRAS gene mutation status was not predictive of bevacizumab outcome in patients with mCRC. Efficacy results of chemotherapy alone versus chemotherapy plus bevacizumab did not differ in regard to biomarker status. Regarding adverse events and severe toxicities (grade ≥3), the group receiving chemotherapy plus bevacizumab had higher rates of hypertension, proteinuria, gastrointestinal perforation and any thromboembolic events. This profile of toxicity warrants a greater level of attention to those patients at an increased risk for thromboembolic events and gastrointestinal perforation (such as the elderly or debilitated patients with Speritoneal carcinomatosis). As seen in another systematic review with meta-analysis evaluating the use of bevacizumab plus chemotherapy in lung cancer [71], hypertension and proteinuria are usually controllable events and do not require permanent discontinuation of therapy. Conclusion The combination of chemotherapy plus bevacizumab increased the response rate, progression-free survival and overall survival of previously untreated patients diagnosed with mCRC. Regarding the mode of fluoropyrimidine administration, both bolus (IFL) and capecitabine-based regimens combined with bevacizumab presented better results in survival outcomes. As for the type of systemic therapy associated with bevacizumab, regimens containing irinotecan and therapy with fluoropyrimidine monotherapy showed better efficacy results. Thus, patients who are not candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens may benefit from the treatment with bevacizumab plus fluoropyrimidine monotherapy regimen. Additional files Additional file 1: Quality assessment (risk of bias) of randomized studies evaluating bevacizumab plus chemotherapy in patients with mCRC in first line chemotherapy. (DOCX 46 kb) Additional file 2: Figure S1. Comparative effect in hematologic toxicities of chemotherapy with bevacizumab versus chemotherapy alone. (PDF 503 kb) Additional file 3: Figure S2. Comparative effect in non-hematologic toxicities of chemotherapy with bevacizumab versus chemotherapy alone. (PDF 864 kb) Additional file 4: Assessment of publication bias. Funnel plot for objective response rates, progression-free survival and overall survival in this meta-analysis. (DOCX 352 kb) Acknowledgements The authors would like to acknowledge Ms. Christiane Bueno’s contribution to the proper formatting of this paper and her support in medical writing. Funding None. Availability of data and material All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Authors’contributions TEAB designed the paper’s structure, extracted the data, performed the analyses and wrote the manuscript. LGOC Selected complementary references and wrote and revised the manuscript. LMP extracted data and revised the manuscript. OACC extracted data and revised the manuscript. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Consent for publication Since this is a systematic review and only public data were used, this item is not applicable. Ethics approval and consent to participate Since this is a systematic review and only public data were used, this item is not applicable. Received: 2 February 2015 Accepted: 30 June 2016 References 1. 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World J Gastroenterol. 2009;15(4):449–56. • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal • We provide round the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit Submit your next manuscript to BioMed Central and we will help you at every step: Botrel et al. BMC Cancer (2016) 16:677 Page 19 of 19