Prognostic and Clinicopathological Significance of Circulating Tumor Cells Detected by RT-PCR in Non-metastatic Colorectal Cancer: a Meta-analysis and Systematic Review

Background: Circulating tumor cells (CTCs) have been accepted as a prognostic marker in patients with metastatic colorectal cancer (mCRC, UICC stage IV). However, the prognostic value of CTCs in patients with non-metastatic colorectal cancer (non-mCRC, UICC stage I-III) still remains in dispute. A meta-analysis was performed to investigate the prognostic significance of CTCs detected by the RT-PCR method in patients diagnosed with non-mCRC patients.

Methods: A comprehensive literature search for relevant articles was performed in the EmBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar databases. The studies were selected according to predetermined inclusion/exclusion criteria. Using the random-effects model of Stata software, version12.0 (2011) (Stata Corp, College Station, TX, USA), to conduct the meta-analysis, and the hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were regarded as the effect measures. Subgroup analyses and meta-regression were also conducted to clarify the heterogeneity.

Results: Twelve eligible studies, containing 2363 patients with non-mCRC, were suitable for final analyses. The results showed that the overall survival (OS) (HR = 3.07, 95% CI: [2.05-4.624], P < 0.001; I = 55.7%, P = 0.008) and disease-free survival (DFS) (HR = 2.58, 95% CI: [2.00-3.32], P < 0.001; I = 34.0%, P = 0.085) were poorer in patients with CTC-positive, regardless of the sampling time, adjuvant therapy and TNM stage. CTC-positive was also significantly associated with regional lymph nodes (RLNs) metastasis (RR = 1.62, 95% CI: [1.17-2.23], P = 0.003; I = 74.6%, P<0.001), depth of infiltration (RR = 1.41, 95% CI: [1.03-1.92], P = 0.03; I = 38.3%, P = 0.136), vascular invasion (RR = 1.66, 95% CI: [1.17-2.36], P = 0.004; I = 46.0%, P = 0.135), tumor grade (RR = 1.19, 95% CI: [1.02-1.40], P = 0.029; I = 0%, P = 0.821) and tumor-node-metastasis (TNM) stage(I, II versus III) (RR = 0.76, 95% CI 0.71-0.81, P < 0.001; I = 0%, P = 0.717). However, there was no significant relationship between CTC-positive and tumor size (RR = 1.08, 95% CI: [0.94-1.24], P = 0.30; I = 0%, P = 0.528).

Conclusions: Detection of CTCs by RT-PCR method has prognostic value for non-mCRC patients, and CTC-positive was associated with poor prognosis and poor clinicopathological prognostic factors. However, the prognostic value of CTCs supports the use of CTCs as an indicator of metastatic disease prior to the current classification of mCRC meaning it is detectable by CT/MRI.