Characteristics of the included studies
After an initial literature search on PubMed, Web of science, Embase, ScienceDirect, Google scholar and clinicaltrials.gov databases, 189 articles were identified. After excluding duplicates and obvious irrelevant studies, 59 potentially relevant articles were remained. Among these, 32 articles were further excluded due to mis-matching contents (21 studies did not report the comparison between sequential and concurrent regimens; 8 reviews; 3 case reports). For the rest 27 articles, another 21 studies were excluded for the following reasons: no available data (n=7); no comparison between sequential and concurrent regimens(n=4); regimens did notcontain both anthracycline and taxane(n=8); duplicates(n=2). Finally, 6 articles wereincluded in this meta-analysis [8-13](Figure 1).
In these 6 studies, 6866 breast cancer patients after surgery were given sequential regimen of anthracyclines and taxanes as adjuvant chemotherapy, while 6847 patients were received concurrent treatment(Table 1). The publication year ranged from 2010 to 2017. All these studies were phase III randomized control trials.
Quality assessment
The details of the risk of bias summary wasoutlined( Figure 2).All studies were considered to be at median risk of bias.Randomized sequence generation was implemented in all 6 studies,and 4 studies implemented allocation concealment.All studies were performed on the intention-to-treat principle.None of these 6 studies reported blind to the participants or the outcome assessment.
Comparison of DFS between sequential and concurrent regimens
Significant heterogeneity among studies (I2 =59%, P =0.03, Figure 3) was found in analysis for DFS between sequential and concurrent regimens, so we used the random effects model to pool the RR. The meta-analysis showed that sequential regimens of anthracycline and taxane seems not to add any significant improvement in DFS over to the concurrent regimens(RR: 1.05; 95%CI:0.97-1.14; P=0.22, Figure 3).
Comparison of DFS between sequential and concurrent regimens
As shown in Figure 4, significant heterogeneity among studies was observed for OS in comparison between sequential and concurrent regimens (I2=55%, P =0.05, Figure 4), so the randomized effects model should be used. The pooled estimate showed that there are no significant different OS between sequentialregimens compared withconcurrent regimens(RR: 1.03, 95% CI: 0.94 to 1.13, P =0.51, Figure 4).
Sub-analysis in node status for DFS and OS
Eligible patients in HORG trial[11]were early breast cancer patients with high risk and node-negative, while the other trials included patients with node-positive.We conducted a sub-analysis according to the axillary lymph node status. The pooled estimate showed that there wasa significant better DFS in patients with node-positive administrated with sequential regimens (RR: 1.08;95%CI:1.02-1.14, P=0.004, Figure 5A),yet the OS were approximate between both regimens (RR: 1.07;95%CI:0.96-1.19, P=0.24, Figure 5B).
The cycles of concurrent regimen with doxorubicin and taxanes also seemed to affect the heterogenity. The patients in Big02-98[10]and NSABP B-30[9] trials only received 4 cycles of doxorubicin and taxanes. Whilepatients in the other two trials [8, 12]weretreated for six cycles. So we then conducted another sub-analysis for this. The pooled estimate showed that less cycles (4 cycles) of concurrent treatment had worse DFS(RR:1.16;95%CI:1.06-1.27, P=0.0009, Figure 7A) and OS (RR:1.18;95%CI:1.05-1.33, P=0.007, Figure 7B) compared to sequential regimen, whereas more cycles(6 cycles) may rescue the loss.
Comparison of toxicity between sequential and concurrent regimens
Both hematologic and non-hematologic grades 3 and 4 adverse events were described in the six studies. Using prophylactic Granulocyte colony stimulating factor(G-CSF),patients with concurrent treatment did not show any significant higher risk of hematologic complications, such as febrile neutropenia and anemia.There was also no significant difference for fatigue or diarrhea.Nevertheless, the incidence of neuropathyoccuered more frequentlyin the sequential regimen(RR = 0.17, 95% CI: 0.12 to 0.24, P <0.00001, Table 2).
Sensitivity analysis and publication bias
Sensitivity analysis showed that there was no significantly different incidence through omitting each study. No significant publication bias was found based on the Egger’s and Begg’s test (P > 0.05, Figure 8).