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Review |

Association Between Time to Initiation of Adjuvant Chemotherapy and Survival in Colorectal Cancer: A Systematic Review and Meta-analysis

James J. Biagi, MD; Michael J. Raphael; William J. Mackillop, MB, ChB; Weidong Kong, MD, MSC; Will D. King, PhD; Christopher M. Booth, MD
JAMA. 2011;305(22):2335-2342. doi:10.1001/jama.2011.749.
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Published online

Context Adjuvant chemotherapy (AC) improves survival among patients with resected colorectal cancer. However, the optimal timing from surgery to initiation of AC is unknown.

Objective To determine the relationship between time to AC and survival outcomes via a systematic review and meta-analysis.

Data Sources MEDLINE (1975 through January 2011), EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched to identify studies that described the relationship between time to AC and survival.

Study Selection Studies were only included if the relevant prognostic factors were adequately described and either comparative groups were balanced or results adjusted for these prognostic factors.

Data Extraction  Hazard ratios (HRs) for overall survival and disease-free survival from each study were converted to a regression coefficient (β) and standard error corresponding to a continuous representation per 4 weeks of time to AC. The adjusted β from individual studies were combined using a fixed-effects model. Inverse variance (1/SE2) was used to weight individual studies. Publication bias was investigated using the trim and fill approach.

Results We identified 10 eligible studies involving 15 410 patients (7 published articles, 3 abstracts). Nine of the studies were cohort or population based and 1 was a secondary analysis from a randomized trial of chemotherapy. Six studies reported time to AC as a binary variable and 4 as 3 or more categories. Meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both overall survival (HR, 1.14; 95% confidence interval [CI], 1.10-1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10-1.18). There was no significant heterogeneity among included studies. Results remained significant after adjustment for potential publication bias and when the analysis was repeated to exclude studies of largest weight.

Conclusion In a meta-analysis of the available literature on time to AC, longer time to AC was associated with worse survival among patients with resected colorectal cancer.

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Figure 1. Flow Diagram of Search Strategy
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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.)

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Figure 2. Hazard Ratio Data for Overall Survival According to Waiting Time Categories
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A, The relationship between waiting time (WT) categories and overall survival in the 10 studies. Data markers correspond to the midpoint assigned to each WT category. The hazard ratio (HR) represents a comparison with the lowest WT category in each study (reference). Numbers indicate references for the original studies. B, Conversion of HR estimates from the original studies to an HR per unit time of delay. The slope of each line represents the change in the HR per unit of WT. The line for each individual study is located over the range of WTs considered in the study. The blue line and shading indicate the weighted average of the HRs from the individual studies (eg, combined meta-analysis result) and the 95% confidence interval, respectively.

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Figure 3. Individual Trial and Overall Hazard Ratios of Relationships Between Waiting Times for Adjuvant Chemotherapy and Overall Survival and Disease-Free Survival
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The size of each data marker represents the weighting factor (1/SE2) assigned to the study. For the combined result, the length of the diamond represents the 95% confidence interval (CI) of the summary.

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Figure 4. Funnel Plot of the Relationship Between the Hazard Ratio and Standard Error of the Log HR for Overall Survival
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Hazard ratio (HR) estimates are the effect per 4 weeks of waiting time. The dotted line indicates the combined HR for all studies of overall survival. Filled circles represent the 10 studies and open circles the studies generated artificially to account for potential publication bias.

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