Introduction
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‐
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‐
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:
(a)
Randomized controlled trials;
(b)
Adult patients with mCRC confirmed histologically or cytologically (age > = 18 years);
(c)
The experimental group was assigned a combination of bevacizumab therapy, control group was allocated placebo or other;
(d)
Basic characteristics for patients were described, and the primary outcome were ORR, CRR, DCR, OS, PFS, etc.
The exclusion criteria were as follows:
(a)
Patients who had received adjuvant therapy in the first month of grouping were excluded;
(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;
(c)
Animal experiments, reviews, abstracts, reviews, reports;
(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 I
2 ˃ 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.
Discussion
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‐
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.
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