Postoperative circulating tumor cells: An early predictor of extrahepatic metastases in patients with hepatocellular carcinoma undergoing curative surgical resection

Abstract

BACKGROUND: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. METHODS: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. RESULTS: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P < .001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P < .001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α-fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α-fetoprotein level during postoperative follow-up (all P < .05). The results were confirmed in the validation cohort. CONCLUSIONS: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM.

Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal

“…The only CTC detection system approved by the Food-and-Drug Administration is the CellSearch ® system (Menarini-Silicon Biosystems, Bologna, Italy), which is based on immunocapture (positive enrichment) of CTCs expressing epithelial-to-cell adhesion molecule (EpCAM + CTCs). Although the CellSearch ® system has been widely used in HCC research with promising results [ 26 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], novel methodologies are in the pipeline claiming for increased CTC detection rate, sensitivity, and specificity [ 30 , 35 , 63 , 64 ]. Thus, CTC analysis by the IsoFlux ® system [ 64 ] or by negative enrichment and iFISH [ 30 ] showed an increased sensitivity in HCC candidates for LT compared to the CellSearch ® system (90.5% vs. 4.7% and 70% vs. 26.67%, respectively).…”

Measurement of Circulating Tumor Cells Determines Treatment Response and Exitus in Patients with Hepatocellular Carcinoma Submitted to Transarterial Chemoembolization

“…The procedure used in the present study, IsoFlux, has resulted more sensitive in detecting CTCs than CellSearch in patients in the waiting list for OLT (21) list (22). A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of postoperative extrahepatic metastases after curative surgical resection of HCC (23). The CanPatrol CTC enrichment system based on cellular filtration using membranes with 8 µm diameter pores and tricolor RNA hybridization in situ (RNA-ISH) was not able to find any correlation between CTCs counts and tumor recurrence after OLT (24).…”

Clearance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection or Liver Transplantation

“…EpCAM is a well-characterized surface marker of liver cancer cells, and the presence of EpCAM-positive CTCs has been previously associated with vascular invasion, increased serum AFP [21,34,35], more advanced HCC stage, and increased recurrence rates after surgery [21,36]. There are several approaches to enumerate EpCAMpositive CTCs, the most widely known being the CellSearch TM system, which was used in some preliminary studies including HCC patients who underwent surgical resection of HCC [19,30,33]. However, the CellSearch TM system has shown reduced sensitivity in patients with early HCC [37].…”