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Response to the letter to the editor by Weberpals et al. on our article entitled 'β-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies'.

(1) In our study, postdiagnostic β-blocker use was defined as any use of β-blockers after diagnosis. However, Weberpals and colleagues believe that studies assessing β-blocker use at diagnosis and during treatment should not be lumped together with studies analyzing time-dependent β-blocker use assessed over many years after diagnosis. Indeed, a cohort study with inappropriate accounting of follow-up time and treatment status in the design and analysis can be subject to immortal time bias (Levesque et al., 2010), which was mentioned in our study (Zhong et al., 2015). Timedependent analysis is one of the methods used to correct the misclassified immortal time (Levesque et al., 2010). To explore whether this contributed toward the heterogeneity in the findings in our metaanalysis, a further subgroup meta-analysis was carried out for postdiagnostic use. The result showed that the heterogeneity was still significant (Supplementary Fig. S1, Supplemental digital content 1, http://links.lww.com/ EJCP/A62). Weberpals and colleagues also mention that the study by Grytli et al. (2014) defining exposure as use of β-blockers before diagnosis and reuse after diagnosis should be only categorized as prediagnostic use, but not postdiagnostic use. Although the cohort was exposed to β-blockers before diagnosis, most of the other studies did not restrict patients to new users of βblockers after diagnosis, which has also been mentioned in our study (Zhong et al., 2015). This was why we included the study in the analysis of the association between postdiagnostic β-blocker use and mortality in cancer patients, which was still significant after removing this study. (2) Weberpals and colleagues question how we calculated a summary risk estimate for mortality by combining the risk estimates of the different β-blocker use categories. However, we presented the method in our study. The summary estimate of hazard ratio (HR) and the 95% confidence interval (CI) were calculated using a random-effects model (Raudenbush, 2009). (3) Indeed, we have not referred to the previous metaanalysis published by Choi et al. (2014), which found that β-blocker use can be associated with the prolonged survival of cancer patients, which was consistent with our results. However, there are several limitations in their meta-analysis. First, not all of the published studies available at the time of their compilations were included. Second, the authors used a random-effects model to combine the effect estimates; however, they did not correctly interpret the summary result as an estimate of the average effect rather than the common effect (Riley et al., 2011). Third, Choi et al. (2014) combined cancer-specific mortality and all-cause mortality, but arrived at a summary estimate for overall survival. Fourth, they did not differentiate prediagnostic use and postdiagnostic use of β-blockers. Considering the above-mentioned aspects, a markedly improved methodological approach was used in our study. (4) Weberpals and colleagues question that we excluded studies comparing β-blocker use with use of other antihypertensives, and included studies with selected patient populations such as patients with myocardial infarction and patients with hypertension. In our meta-analysis, we explored the effect of β-blocker use on mortality of cancer patients by comparing βblocker users to nonusers. Although studies in patients with myocardial infarction and patients with hypertension were included, all these studies compared β-blocker users with nonusers. These users and nonusers had the same characteristics, except βblocker use. Studies comparing β-blocker use with the use of other antihypertensives do not reflect the effect of β-blockers solely, but reflect the different treatment effects between the two drugs. If these studies were to be included, the overall results would be biased. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.eurjcancerprev.com). Letter to the Editor 179