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Meta-Analysis
. 2013 May 16:13:240.
doi: 10.1186/1471-2407-13-240.

Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis

Ke-Da Yu  1 , Sheng Huang, Jia-Xin Zhang, Guang-Yu Liu, Zhi-Ming Shao
Affiliations
Meta-Analysis

Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis

Ke-Da Yu et al. BMC Cancer. .

Abstract

Background: Adjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes.

Methods: PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (between January-1 1978 and January-29, 2013) were searched for eligible studies. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (β) corresponding to a continuous representation per 4-week delay of AC. Most used regimens of chemotherapy in included studies were CMF (cyclophosphamide, methotrexate, and fluorouracil) or anthracycline-based. Individual adjusted β were combined using a fixed-effects or random-effects model depending on heterogeneity.

Results: We included 7 eligible studies with 9 independent analytical groups involving 34,097 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 4 hospital-/population-based retrospective study. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.15; 95% confidence interval [CI], 1.03-1.28; random-effects model) and DFS (HR = 1.16; 95% CI, 1.01-1.33; fixed-effects model). One study caused a significant between-study heterogeneity for OS (P < 0.001; I² = 75.4%); after excluding that single study, there was no heterogeneity (P = 0.257; I² = 23.6%) and the HR was more significant (HR = 1.17; 95% CI, 1.12-1.22; fixed-effects model). Each single study did not fundamentally influence the positive outcome and no evidence of publication bias was observed in OS.

Conclusions: Longer time to AC is probably associated with worse survival in breast cancer patients.

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Figures

Figure 1
Figure 1
The literature search process. Validity required that either the comparison groups were balanced for relevant prognostic factors or the reported results were adjusted for these prognostic factors (Refer to the “Methods” section). *One study includes 3 analytical groups in overall survival.
Figure 2
Figure 2
Individual hazard ratio for overall survival according to waiting time categories. A. The relationship between waiting time categories and overall survival in the 7 independent analytical groups. The hazard ratio (HR) represents a comparison with the lowest waiting time category in each study (as reference). The first author of each study is shown. B. Conversion of HR estimates from the original studies to an HR per week of delay. The slope of each line represents the change in the log HR per week delay. The line for each individual study is located over the range of waiting times. The thick line indicates the weighted average of the HRs from the individual studies. The vertical axis is on a log scale.
Figure 3
Figure 3
Individual study and overall hazard ratios of relationships between every 4-week delay in initiation of adjuvant chemotherapy and overall survival. Individual and overall hazard ratios (HR) per 4-week of delay with 95% confidence interval (CI) for OS are shown in A. The size of each square is proportional to the weight of the study. For the combined result, the length of the diamond represents the 95% CI of the summary. B. shows the influence of individual studies on the pooled HR. The vertical axis indicates the overall HR and the two vertical axes indicate its 95% CI. Every hollow round indicates the pooled OR when the left study is omitted in this meta-analysis. The two ends of every broken line represent the respective 95% CI.
Figure 4
Figure 4
Individual study and overall hazard ratios of relationships between every 4-week delay in initiation of adjuvant chemotherapy and disease-free survival. Individual and overall hazard ratios (HR) per 4-week of delay with 95% confidence interval (CI) for DFS is shown. The size of each square is proportional to the weight of the study. For the combined result, the length of the diamond represents the 95% CI of the summary.
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