Usefulness of bevacizumab-induced hypertension in patients with metastatic colorectal cancer: an updated meta-analysis

We tested the hypothesis that bevacizumab-induced hypertension may be a useful predictor for objective response rate, progression-free and overall survival in patients with metastatic colorectal cancer via a comprehensive meta-analysis. Search process, article selection and data extraction were independently performed by two investigators. Statistical analyses were conducted using the STATA/SE software. Fourteen independent studies and 2292 study subjects were synthesized. Overall relative risk of objective response rate for bevacizumab-induced hypertension was 2.03 (95% confidence interval [CI]: 1.18-3.48, p=0.01), with significant heterogeneity and publication bias, whereas unbiased estimate was nonsignificant after considering potentially missing studies. Overall hazard ratio for progression-free survival was 0.58 (95% CI: 0.43-0.77, p<0.001), with significant heterogeneity and publication bias, and unbiased estimate was significant (hazard ratio: 0.52, 95% CI: 0.41-0.66, p<0.001). Overall hazard ratio for overall survival was 0.51 (95% CI: 0.39-0.65, p<0.001), and this estimate was not likely confounded by heterogeneity or publication bias. Subgroup and meta-regression analyses suggested that hypertension grade of controls, sample size, age and gender were possible causes of heterogeneity. Taken together, our findings indicate that bevacizumab-induced hypertension can predict progress-free survival and overall survival in patients with metastatic colorectal cancer, whereas its prediction for objective response rate was nonsignificant.


Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

Eligibility criteria
6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

Selection criteria
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

Search strategy
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Search strategy
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

Selection criteria
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Data extraction
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Statistical analysis
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Statistical analysis

Synthesis of results
14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

Statistical analysis
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Statistical analysis
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Figure 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Baseline characteristics; Table 1 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
Objective response rate; Progression-free survival; Overall survival; Figure 3 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.  Table 2 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.  Overall survival

Summary of evidence
24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

DISCUSSION
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

DISCUSSION
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Financial support