Skip to main content

Effectiveness of bevacizumab in the treatment of metastatic colorectal cancer: a systematic review and meta-analysis



To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of clinical plans.


As of October 1, 2022, the randomized controlled clinical trials of bevacizumab in combination with metastatic colorectal cancer published in PubMed, Cochrane Library and Medline databases were searched. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the short-term disease control effect and long-term survival of the treatment strategy.


21 RCTs (6665 patients; 3356 patients in the experimental group and 3309 patients in the control group; average age, 55–75 years) were treated with bevacizumab as the experimental group for metastatic colorectal cancer. BEV has stronger anti-tumor activity than the single treatment scheme (OR = 1.30, 95% CI: 1.11–1.52). And Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. The disease control of BEV combined therapy was better (OR = 1.36, 95% CI: 1.04–1.78). The same as compared with cediranib (OR = 1.94, 95% CI: 1.06–3.55). However, the long-term prognosis of BEV, including the overall survival (HRs = 0.98, 95% CI: 0.84–1.15) and progression-free survival (HRs = 1.05,95% CI: 0.97–1.13) were not prolonged. The survival benefits of cetuximab and panitumumab were not reflected.


The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability. However, it did not effectively improve the survival of patients. A more reasonable and effective treatment plan needs more clinical experimental support.

Peer Review reports


Colorectal cancer is one of the most common malignant tumors of digestive tract in the world [1]. More than 1.8 million cases of colorectal cancer were diagnosed in 2018, making it the third most common cancer in the world, accounting for 10% of all cancer diagnoses [2]. Nearly 25% of colon cancer is diagnosed as stage II in western countries [3]. Over the past 20 years, great progress has been made in the treatment of colorectal cancer. The median survival of patients with metastatic colorectal cancer (mCRC) receiving multimodal therapy can reach 30 or more months, but the prognosis of patients with metastatic colorectal cancer still need to be improved [4, 5].

For a long time, the choice of first-line treatment plan was a key step in the treatment route of every patient with mCRC. In the past few years, the combination of dual chemotherapy drugs (fluoropyrimidine plus irinotecan or oxaliplatin) and targeted drugs were the first choice for most patients [6]. In a multi-center international study, it was evaluated that the 5-year and 10-year overall survival rates (OSR) of patients with high-risk phase II CC were 88% and 75%, respectively, when oxaliplatin was added on the basis of fluorouracil and under the adjuvant folic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy [7, 8]. Several promising therapeutic methods including chemotherapy and molecular agents targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) have been reported [9,10,11,12]. These reports suggested that targeted drug combination chemotherapy can improve the rate and efficiency of hepatectomy, thereby improving the progression-free survival (PFS) and overall survival (OS) of patients.

Bevacizumab, an anti human vascular endothelial growth factor, was subsequently approved to be combined with fluorouracil in the treatment of patients with metastatic colorectal cancer [13, 14]. Bevacizumab could increase the activity of multi-drug therapy and fluoropyrimidine monotherapy in the case of metastasis. Advantage of bevacizumab combined with chemotherapy in metastatic colorectal cancer patients may be due to the increased sensitivity of tumor cells to chemotherapy, or the better distribution of chemotherapy drugs in tumors [14,15,16]. But its front-line cooperation with FOLFOX and other drugs has been questioned [17]. The comparison between BEV to placebo and BEV to CET and PAN may indeed confused. Therefore, we aim to conduct a meta-analysis of randomized controlled trials (RCTs) of bevacizumab combined with multiple protocols for the treatment of metastatic colorectal cancer, and compare the efficacy of bevacizumab compared with placebo or other drugs for the treatment of metastatic colorectal cancer, so as to provide more optional basis for the clinical treatment of metastatic colorectal cancer.

Materials and methods

Search Strategy

We follow the Preferred Report Item for Systematic Reviews and Meta-analyses statement to perform the meta-analysis. As of October 1, 2022, we have conducted a systematic search on medical databases (PubMed, Medline and Cochrane Library). Language was restricted English only. The following search keywords were used: “Colorectal Neoplasm”, “Colorectal Tumors”, “Colorectal Cancers”, “Rectal Neoplasms” and “Bevacizumab”, “Antineoplastic Chemotherapy Protocol”, “Antineoplastic Drug Combinations”, “Combined Antineoplastic Agent”. We also searched the bibliography of confirmed reports for more references. Two researchers jointly completed this search process.

Inclusion and exclusion criteria

The inclusion criteria were as follows:

  1. (a)

    Randomized controlled trials;

  2. (b)

    Adult patients with mCRC confirmed histologically or cytologically (age > = 18 years);

  3. (c)

    The experimental group was assigned a combination of bevacizumab therapy, control group was allocated placebo or other;

  4. (d)

    Basic characteristics for patients were described, and the primary outcome were ORR, CRR, DCR, OS, PFS, etc.

The exclusion criteria were as follows:

  1. (a)

    Patients who had received adjuvant therapy in the first month of grouping were excluded;

  2. (b)

    History of stroke, transient ischemic attacks, myocardial infarction/unstable angina, significant peripheral vascular disease, bleeding diathesis, uncontrolled hypertension, grade > 1 neuropathy, and allergy to platinum compounds;

  1. (c)

    Animal experiments, reviews, abstracts, reviews, reports;

  1. (d)

    Specific patient population (elderly or patients with liver metastasis only) or treatment methods (induction therapy with anti EGFR (epidermal growth factor receptor) antibody).

Data extraction and Quality Assessment

Screening and data extraction were conducted in duplicate by two investigators (Hu and Liu) independently. Any differences were resolved through discussion or consultation with other researchers. The data was wxtracted including name of the first author, year of publication, sample size, average age of patients, disease stage, intervention and control strategies, follow-up and main results such as objective response rate (ORR), disease control rate (DCR), overall survival (OS) and median progression-free survival (PFS). For those studies that did not give a specific effect value, it was calculated based on the effect and number of people given the treatment. In order to get enough information, we downloaded the full text. If in doubt, please ask the original author for help. Jadad scale, which assessing data related to randomization, blinding, and study withdrawal, was used to evaluate the methodological quality of selected randomized clinical trials [18]. The evaluation content of the scale are generation of random sequence, randomized hiding, blind methods and withdrawal and loss of interview. Full score of a randomized controlled trial was 7. Randomized controlled trials with scores > = 4 were considered to be of good quality and can be included in the meta-analysis.

Statistical analysis

Based on the recommendations of the Cochrane collaboration, quantitative synthesis of the indicators were included in the study. The data was pooled by conducting meta-analysis. If data were allowed, Stata 16.0 software(Stata Corporation, College Station, TX) would be used. We summarized the main results of the experimental group and the control group to obtain the efficacy of bevacizumab in multiple comprehensive therapies. Random-effects model was used for meta-analysis considering potential sources of clinical heterogeneity. When I2 ˃ 50%, subgroup analysis based on baseline, intervention and/or sensitivity analysis eliminate studies one by one would be conducted to explore the source of heterogeneity [19, 20]. Small sample effect and publication bias were detected by funnel plots and statistical tests, respectively.


Search results

According to the pre-screening strategy, 21 randomized clinical trial were included in this study by two researchers [14, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40]. Figure 1 showed the whole process of selecting documents. The main characteristics of each study were summarized in Table 1. There were 6665 participants, including 3356 in the experimental group and 3309 in the control group. Their overall average age was between 55 and 75 years. We also checked the gender ratio, Tumor site (colon/rectum), BRAS mutation status (mutant/wild type) and ECOG (Eastern Cooperative Oncology Group) status (An important index for evaluating the general health status of tumor patients) of the selected personnel, and identified the comparability. FOLFIRI scheme and FOLFOX scheme were the most commonly used schemes, in addition to CAP and CT therapy. The experimental group only added appropriate dose of bevacizumab on the basis of the control group. In addition, cetuximab (CET), vanucizumab (VAN), cediranib (CED), panitumumab (PAN) were also used as the control group for comparison with bevacizumab (Table 2). Supplement Table 1 showed all results of our evaluation on the methodological quality of the randomized clinical trials. Randomization concealment, loss of interview and withdrawal were their main defects. However, Jadad rated them all at or above 4. Therefore, they entered the meta comprehensive analysis.

Fig. 1
figure 1

Screening flow chart of included studies

Table 1 The characteristic of included studies
Table 2 Effect and prognosis of colorectal cancer patients compared to BEV addition

Objective remission rate (ORR)

18 randomized clinical trials described objective remission rates for metastatic colorectal cancer in the experimental and control groups. Heterogeneity analysis showed that I2 = 66.1%, P < 0.05. Random effect model was used for meta-analysis. OR = 1.04, 95% CI: 0.83–1.30, P = 0.747 (Fig. 2). This showed that the experimental group only adding bevacizumab did not have complete advantages, which enhanced the anti-tumor activity of the comprehensive treatment scheme. Subsequently, we used a fixed-effect model to pool estimates of those placebo-controlled studies except when significant heterogeneity was found according to a random-effects model. The results of fixed effects showed that OR = 1.29, 95% CI: 1.10–1.50, P = 0.001 (Fig. 3). Advantage was found in the experimental group. It was worth noting that the study of Dotan was confirmed that the experimental group was a double antibody group (BEV + CET) with poor therapeutic effect. After removing this study, OR = 1.30, 95% CI: 1.11–1.52, P = 0.001. This showed that bevacizumab can indeed enhance the anti-tumor activity of drug therapy.

Fig. 2
figure 2

ORR to the combination of bevacizumab for Metastatic colorectal cancer

Fig. 3
figure 3

ORR to the bevacizumab combination compared with placebo for Metastatic colorectal cancer

We also conducted a meta-analysis of studies that were controlled by other drugs. The results of random effects showed that OR = 0.77, 95% CI: 0.52–1.14, P = 0.186 (Fig. 4). No advantage of the experimental group was found. Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. It meant that the addition of CET and PAN is more effective than that of BEV alone. No advantages were found in VAN and CED compared to BEV. We also used fixed effect model and random effect model for mutual verification to ensure the stability and accuracy of the above analysis results. Egger’s test showed that there was no publication bias (P > 0.05).

Fig. 4
figure 4

ORR to the bevacizumab combination compared with other drugs for Metastatic colorectal cancer

Disease control rate (DCR)

Data on disease control rates from eight studies were extracted for meta-analysis. The fixed effect model was used for fitting (I2 = 0%, p = 0.712). OR = 1.36, 95% CI: 1.04–1.78, P = 0.024 (Fig. 5). The experimental group added bevacizumab performed better than the control group in disease control. Benefits of BEV were 1.13 (0.77, 1.66), 1.71 (0.97, 3.00), 1.94 (1.06, 3.55) and 0.92 (0.36, 2.31) compared with Placebo, CET, CED and PAN. This meant that The addition of BEV is better than the addition of CED. However, the impact of PAN, CET and BEV on the anti-tumor ability was not different compared to the addition of BEV. The use of random effects models mutually confirms the above conclusions. No publication bias and small sample bias were found through statistical tests.

Fig. 5
figure 5

DCR to the bevacizumab combination compared with other drugs for Metastatic colorectal cancer

Overall survival(OS)

11 studies described differences in overall survival between experimental and control groups. Heterogeneity analysis showed that I2 = 58.5%, P = 0.010. Therefore, the random effect model was used to fit the final results. HRs = 0.98, 95% CI: 0.84–1.15, P = 0.822, Fig. 6. This indicated that the total survival period has not been prolonged by the addition of BEV. HRs of placebo, CET and PAN as controls were 1.13 (0.91, 1.42), 0.84 (0.75, 0.94) and 0.86 (0.56, 1.32), respectively. This meant that CET had a longer overall survival than BEV alone, and BEV was not better than placebo and PAN. No publication bias and small sample bias were found through statistical tests.

Fig. 6
figure 6

OSR to the bevacizumab combination compared with other drugs for Metastatic colorectal cancer

Progression-free survival (PFS)

10 studies described differences in progression-free survival between experimental and control groups. Heterogeneity analysis showed that I2 = 27.0%, P = 0.187. Therefore, the fixed effect model was used to fit the final results. HRs = 1.05, 95% CI: 0.97–1.13, P = 0.238, Fig. 7. This indicated that the addition of BEV did not prolong the progression-free survival. HRs of placebo, CET, CED and PAN as controls were 1.20 (1.06, 1.37), 0.93 (0.83, 1.04), 1.22 (0.91, 1.64) and 0.88 (0.60, 1.29), respectively. This meant that the addition of BEV will prolong the progression-free survival. There was no difference between CED and PAN compared with CET.

Fig. 7
figure 7

PFSR to the bevacizumab combination compared with other drugs for Metastatic colorectal cancer

Sensitivity analysis

Some of the included research methodologies had low quality evaluation. It was restricted that studies with a study quality ≥ 5 can be included in the meta-analysis as sensitivity analysis. Hazard ratio for objective remission rate and disease control rate were OR = 1.00 (95% CI: 0.80–1.24) and OR = 1.55 (95% CI: 1.13–2.12) respectively. Which was consistent with the initial research results. The addition of BEV made disease control profitable. We also analyzed the hazard ratio for overall survival and progression-free survival, OR = 0.89 (95% CI: 0.80–0.99) and OR = 1.02 (95% CI: 0.94–1.11) respectively. This even meant that the addition of BEV cannot improve the overall survival period. There was no difference between fixed effect and random effect models. These results are recorded in the supplementary materials.


Chemotherapy has become the first choice of treatment when colorectal cancer can not be eradicated or distant metastasis occurs [41]. However, it is said that only 30% of patients receiving chemotherapy can achieve the desired effect, and most patients often have poor prognosis [42]. Therefore, it is inevitable for clinicians to choose more beneficial treatment strategies. BEV is the first monoclonal antibody used to treat metastatic colorectal cancer, which can specifically bind VEGF to inhibit the production of vascular endothelial growth [43, 44]. Previous studies have shown that FOLFOX + BEV treatment strategy is superior to a single FOLFOX strategy [45]. However, the benefit of bevacizumab in a broader comprehensive treatment scheme was not clear.

In this study, we found that the anti-tumor activity of BEV added to the comprehensive treatment strategy does not always occupy an absolute advantage (OR = 1.04, 95% CI: 0.83–1.30). As the first certified monoclonal antibody, bevacizumab has certain advantages. Bevacumab maintained its benefits under any treatment regimen (OR = 1.29, 95% CI: 1.10–1.50). It should be noted that the treatment strategy of double antibody is not recommended (OR = 0.41, 95% CI: 0.08–2.19).Trial was forced to stop due to the continuous progress of tumor. In our study, we found that compared with bevacizumab, cetuximab (OR = 0.73, 95% CI: 0.55–0.96) and panitumumab (OR = 0.07, 0.02–0.25) were more effective in anti-tumor treatment. In particular, cetuximab can enhance the efficacy of irinotecan and radiotherapy in experimental systems [46]. On the basis of this, paniximab has potential therapeutic value [47,48,49]. However, the dosage of bevacizumab is different even under different treatment strategies. This makes the use and benefit of antibody controversial. The same is true for the ability to control disease progression, and bevacizumab still has great benefits (OR = 1.36, 1.04–1.78). Even in the face of cetuximab and paniximab, it is not inferior.

The marginal benefit of combination with oxaliplatin, which has no effect on PFS but no effect on OS, seems to be applicable to other trials involving VEGF inhibitors. Our research evidence may reinforce the impression that oxaliplatin may not be an ideal partner for such target inhibitors, which is similar to the results of the recent two studies [50, 51]. Therefore, the available data are insufficient to draw a conclusion on whether the addition of bevacizumab (especially FOLFOX) to oxaliplatin based protocols is beneficial to patients who have not received chemotherapy [52].

First line treatment should also be considered as a potential source of bias. A trial of oxaliplatin based first-line therapy versus maintenance versus observation alone demonstrated: maintenance therapy had no significant effect on prolonging OS. The irinotecan based combination bevacizumab maintenance therapy prolonged OS. However the use of oxaliplatin has cumulative toxicity, especially neurotoxicity. The use of irinotecan based chemotherapy may be more feasible than oxaliplatin based chemotherapy, and more clinical trials on maintenance therapy are needed for further confirmation.

Although this study did not show higher fatal adverse events, a recent meta-analysis involving 16 clinical trials of bevacizumab in solid tumors showed a significant increase in treatment-related mortality (2.5% vs. 1.7%; P = 0.01), particularly associated with taxanes and platinum agents (OR = 3.49; 95% CI: 1.82–6.66; incidence, 3.3% vs. 1.0%) [53].

The present study also has certain shortcomings that warrant attention. First, we restricted the search engines and databases to Pubmed, MEDLINE, and the Cochrane Library, which may have limited the number of high-quality rcts searched, thereby weakening the reliability of the results. Second, the included articles were not of high quality and lacked detailed description of allocation concealment and blinding, warranting further studies with rigorous design.Third, the included studies lacked data on indicators such as OS and PFS and could not be included in the comprehensive analysis. Fourth, because the genotypes of Ras and BRAF patients closely related to targeted therapy were not examined in the included studies, the relationship between genotypes and chemotherapy could not be further analyzed, and the potential relationship between genotypes and chemotherapy needs to be further investigated in the future.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.


  1. Siegel RL, Jakubowski CD, Fedewa SA, Davis A, Azad NS. Colorectal Cancer in the Young: Epidemiology, Prevention, Management. Am Soc Clin Oncol Educ Book. 2020;40:1–14.

    PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6), 394–424.

  3. Chen VW, Hsieh MC, Charlton ME, Ruiz BA, Karlitz J, Altekruse SF, Ries LA, Jessup JM. Analysis of stage and clinical/prognostic factors for colon and rectal cancer from SEER registries: AJCC and collaborative stage data collection system. Cancer. 2014;120(0 0):3793–806.

    Article  PubMed  Google Scholar 

  4. Golshani G, Zhang Y. Advances in immunotherapy for colorectal cancer: a review. Th Adv Gastroenterol. 2020;13:1756284820917527.

    CAS  Google Scholar 

  5. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D’Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422.

    Article  PubMed  Google Scholar 

  6. Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer. 2019;109:70–83.

    Article  CAS  PubMed  Google Scholar 

  7. : Adjuvant chemotherapy with oxaliplatin, in combination with fluorouracil plus leucovorin prolongs disease-free survival, but causes more adverse events in people with stage II or III colon cancer Abstracted from, Andre T, Boni C, Mounedji-Boudiaf L et al. Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51. Cancer Treat Rev. 2004;30(8):711-3.

  8. André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III Colon cancer: updated 10-Year survival and outcomes according to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol. 2015;33(35):4176–87.

    Article  PubMed  Google Scholar 

  9. Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, Levitt R, Rowland K, Nair S, Sargent DJ, Donohue JH. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol. 2005;23(36):9243–9.

    Article  CAS  PubMed  Google Scholar 

  10. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Köhne CH. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  11. Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, Vennarecci G, Mottolese M, Sperduti I, Cognetti F. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010;103(10):1542–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wong R, Cunningham D, Barbachano Y, Saffery C, Valle J, Hickish T, Mudan S, Brown G, Khan A, Wotherspoon A, Strimpakos AS, Thomas J, Compton S, Chua YJ, Chau I. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol. 2011;22(9):2042–8.

    Article  CAS  PubMed  Google Scholar 

  13. Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, Bordonaro R, Latiano TP, Tamburini E, Santini D, Passardi A, Marmorino F, Grande R, Aprile G, Zaniboni A, Murgioni S, Granetto C, Buonadonna A, Moretto R, Corallo S, Cordio S, Antonuzzo L, Tomasello G, Masi G, Ronzoni M, Di Donato S, Carlomagno C, Clavarezza M, Ritorto G, Mambrini A, Roselli M, Cupini S, Mammoliti S, Fenocchio E, Corgna E, Zagonel V, Fontanini G, Ugolini C, Boni L, Falcone A. GONO Foundation Investigators. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus Bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(4):497–507.

    Article  CAS  PubMed  Google Scholar 

  14. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus Irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  15. Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP. AVEX study investigators. 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(11):1077–85.

    Article  CAS  PubMed  Google Scholar 

  16. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. 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(16):3697–705.

    Article  CAS  PubMed  Google Scholar 

  17. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.

    Article  CAS  PubMed  Google Scholar 

  18. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, Klassen TP. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352(9128):609–13.

    Article  CAS  PubMed  Google Scholar 

  19. MANTEL N, HAENSZEL W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    PubMed  Google Scholar 

  20. Irwig L, Macaskill P, Berry G, et al. Bias in meta-analysis detected by a simple, graphical test. Graphical test is itself biased. BMJ. 1998;316(7129):470. author reply 470-1.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Salazar R, Capdevila J, Laquente B, Manzano JL, Pericay C, Villacampa MM, López C, Losa F, Safont MJ, Gómez A, Alonso V, Escudero P, Gallego J, Sastre J, Grávalos C, Biondo S, Palacios A, Aranda E. A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features. BMC Cancer. 2015;15:60.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Salazar R, Capdevila J, Manzano JL, Pericay C, Martínez-Villacampa M, López C, Losa F, Safont MJ, Gómez-España A, Alonso-Orduña V, Escudero P, Gallego J, García-Paredes B, Palacios A, Biondo S, Grávalos C, Aranda E. Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results. BMC Cancer. 2020;20(1):1164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qin S, Li J, Bai Y, Shu Y, Li W, Yin X, Cheng Y, Sun G, Deng Y, Zhong H, Li Y, Qian X, Zhang L, Zhang J, Chen K, Kang W. HLX04-mCRC03 investigators. Efficacy, Safety, and immunogenicity of HLX04 Versus Reference Bevacizumab in Combination with XELOX or mFOLFOX6 as First-Line treatment for metastatic colorectal Cancer: results of a Randomized, double-blind phase III study. BioDrugs. 2021;35(4):445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oki E, Emi Y, Yamanaka T, Uetake H, Muro K, Takahashi T, Nagasaka T, Hatano E, Ojima H, Manaka D, Kusumoto T, Katayose Y, Fujiwara T, Yoshida K, Unno M, Hyodo I, Tomita N, Sugihara K, Maehara Y. Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial). Br J Cancer. 2019;121(3):222–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Moehler M, Scheithauer W, Held S, Miller-Phillips L, Modest DP, Jung A, Kirchner T, Stintzing S. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer. 2021;124(3):587–94.

    Article  CAS  PubMed  Google Scholar 

  26. Fischer LE, Stintzing S, von Weikersthal LF, Modest DP, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Giessen-Jung C, Uhlig J, Peuser B, Denzlinger C, Stahler A, Weiss L, Heinrich K, Held S, Jung A, Kirchner T, Heinemann V. Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3. Br J Cancer. 2022;127(5):836–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5–6):376–81.

    Article  CAS  PubMed  Google Scholar 

  28. Chibaudel B, Henriques J, Rakez M, Brenner B, Kim TW, Martinez-Villacampa M, Gallego-Plazas J, Cervantes A, Shim K, Jonker D, Guerin-Meyer V, Mineur L, Banzi C, Dewdney A, Dejthevaporn T, Bloemendal HJ, Roth A, Moehler M, Aranda E, Van Cutsem E, Tabernero J, Schmoll HJ, Hoff PM, André T, de Gramont A. Association of Bevacizumab Plus Oxaliplatin-based Chemotherapy with Disease-Free Survival and overall survival in patients with stage II Colon cancer: a secondary analysis of the AVANT Trial. JAMA Netw Open. 2020;3(10):e2020425.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bendell JC, Sauri T, Gracián AC, Alvarez R, López-López C, García-Alfonso P, Hussein M, Miron ML, Cervantes A, Montagut C, Vivas CS, Bessudo A, Plezia P, Moons V, Andel J, Bennouna J, van der Westhuizen A, Samuel L, Rossomanno S, Boetsch C, Lahr A, Franjkovic I, Heil F, Lechner K, Krieter O, Hurwitz H. McCAVE Study Group. The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal carcinoma (mCRC). Oncologist. 2020;25(3):e451–9.

    Article  CAS  PubMed  Google Scholar 

  30. Chakravarthy AB, Zhao F, Meropol NJ, Flynn PJ, Wagner LI, Sloan J, Diasio RB, Mitchell EP, Catalano P, Giantonio BJ, Catalano RB, Haller DG, Awan RA, Mulcahy MF, O’Brien TE, Santala R, Cripps C, Weis JR, Atkins JN, Leichman CG, Petrelli NJ, Sinicrope FA, Brierley JD, Tepper JE, O’Dwyer PJ, Sigurdson ER, Hamilton SR, Cella D, Benson AB 3. rd. Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for patients with stage II or III rectal Cancer receiving preoperative chemoradiation: a trial of the ECOG-ACRIN Research Group (E5204). Oncologist. 2020;25(5):e798–e807.

    Article  CAS  PubMed  Google Scholar 

  31. Cunningham D, Wong RP, D’Haens G, Douillard JY, Robertson J, Stone AM, Van Cutsem E. HORIZON I study group. Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer. Br J Cancer. 2013;108(3):493–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shitara K, Yonesaka K, Denda T, Yamazaki K, Moriwaki T, Tsuda M, Takano T, Okuda H, Nishina T, Sakai K, Nishio K, Tokunaga S, Yamanaka T, Boku N, Hyodo I, Muro K. Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild-type KRAS colorectal cancer-WJOG 6210G. Cancer Sci. 2016;107(12):1843–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, Tollenaar RA, Verheul HM, van der Sijp J, Borel Rinkes IH, Voest EE. Hepatica study group. Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in patients after Resection of Colorectal Liver metastases: HEPATICA study. Neoplasia. 2017;19(2):93–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Aparicio T, Bouché O, Taieb J, Maillard E, Kirscher S, Etienne PL, Faroux R, Khemissa Akouz F, El Hajbi F, Locher C, Rinaldi Y, Lecomte T, Lavau-Denes S, Baconnier M, Oden-Gangloff A, Genet D, Paillaud E, Retornaz F, François E, Bedenne L. For PRODIGE 20 investigators. Bevacizumab + chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results. Ann Oncol. 2018;29(11):2270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lipsyc-Sharf M, Ou FS, Yurgelun MB, Rubinson DA, Schrag D, Dakhil SR, Stella PJ, Weckstein DJ, Wender DB, Faggen M, Zemla TJ, Heying EN, Schuetz SR, Noble S, Meyerhardt JA, Bekaii-Saab T, Fuchs CS, Ng K. Cetuximab and Irinotecan with or without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial. Oncologist. 2022;27(4):292–8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O’Neil BH, Atkins JN, Berry S, Polite BN, O’Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined with Cetuximab or Bevacizumab on overall survival in patients with KRAS Wild-Type Advanced or metastatic colorectal Cancer: a Randomized Clinical Trial. JAMA. 2017;317(23):2392–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of Bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26(6):1201–7.

    Article  CAS  PubMed  Google Scholar 

  38. Dotan E, Meropol NJ, Burtness B, Denlinger CS, Lee J, Mintzer D, Zhu F, Ruth K, Tuttle H, Sylvester J, Cohen SJ. A phase II study of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as frontline therapy for metastatic colorectal cancer. A Fox Chase extramural research study. J Gastrointest Cancer. 2012;43(4):562–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009;15(4):449–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cremolini C, Loupakis F, Masi G, Lonardi S, Granetto C, Mancini ML, Chiara S, Moretto R, Rossini D, Vitello S, Allegrini G, Tonini G, Bergamo F, Tomasello G, Ronzoni M, Buonadonna A, Bustreo S, Barbara C, Boni L, Falcone A. FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials. Ann Oncol. 2016;27(5):843–9.

    Article  CAS  PubMed  Google Scholar 

  41. Bradbury KE, Murphy N, Key TJ. Diet and colorectal cancer in UK Biobank: a prospective study. Int J Epidemiol. 2020;49(1):246–58.

    Article  PubMed  Google Scholar 

  42. Chen HD, Dai M. [On prevention and control strategy of colorectal cancer in China]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(10):1627–32. Chinese.

    CAS  PubMed  Google Scholar 

  43. Antoniotti C, Borelli B, Rossini D, Pietrantonio F, Morano F, Salvatore L, Lonardi S, Marmorino F, Tamberi S, Corallo S, Tortora G, Bergamo F, Brunella DS, Boccaccino A, Grassi E, Racca P, Tamburini E, Aprile G, Moretto R, Boni L, Falcone A, Cremolini C. AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus Bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer. BMC Cancer. 2020;20(1):683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Limagne E, Euvrard R, Thibaudin M, Rébé C, Derangère V, Chevriaux A, Boidot R, Végran F, Bonnefoy N, Vincent J, Bengrine-Lefevre L, Ladoire S, Delmas D, Apetoh L, Ghiringhelli F. Accumulation of MDSC and Th17 cells in patients with metastatic colorectal Cancer predicts the efficacy of a FOLFOX-Bevacizumab Drug Treatment Regimen. Cancer Res. 2016;76(18):5241–52.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang H, You J, Liu W, Chen D, Zhang S, Wang X. The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: a systematic review and meta-analysis. Med (Baltim). 2021;100(30):e26714.

    Article  CAS  Google Scholar 

  46. Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 2002;8:994–1003.

    CAS  PubMed  Google Scholar 

  47. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229–37.

    Article  CAS  PubMed  Google Scholar 

  48. Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C. Gruppo Oncologico Dell’Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005;23(22):4866–75.

    Article  CAS  PubMed  Google Scholar 

  49. Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016;27(8):1539–46.

    Article  CAS  PubMed  Google Scholar 

  50. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):1997–2003.

    Article  CAS  PubMed  Google Scholar 

  51. Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):2004–10.

    Article  PubMed  Google Scholar 

  52. Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. 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(29):3596–603.

    Article  CAS  PubMed  Google Scholar 

  53. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 2011;305(5):487–94.

    Article  CAS  PubMed  Google Scholar 

Download references


Not applicable.


No Funding.

Author information

Authors and Affiliations



Yu Song, Li Kong and Cheng-Jiang Liu designed the study and developed the retrieve strategy. Qianqian Mao and Ting Hu executed the systematic evaluation as the first and second reviewers, searching and screening the summaries and titles, assessing the inclusion and exclusion criteria, generating data collection forms and extracting data, and evaluating the quality of the study. Yu Song, Li Kong, Manling Zhou and Cheng-Jiang Liu performed meta-analysis. Yu Song drafted the article, which was reviewed and revised by Li Kong.

Corresponding authors

Correspondence to Cheng-Jiang Liu or Li Kong.

Ethics declarations

Ethics approval and consent to participate

This is a systematic review and meta-analysis, ethics approval and consent to participate are not applicable.

Consent for publication

Not applicable. This study does not involve human participants.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, Y., Mao, Q., Zhou, M. et al. Effectiveness of bevacizumab in the treatment of metastatic colorectal cancer: a systematic review and meta-analysis. BMC Gastroenterol 24, 58 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: