Circulating tumor cells are an indicator for the administration of adjuvant transarterial chemoembolization in hepatocellular carcinoma: A single-center, retrospective, propensity-matched study

Peng-Xiang Wang, Yun-Fan Sun, Kai-Qian Zhou, Jian-Wen Cheng, Bo Hu, Wei Guo, Yue Yin, Jun-Feng Huang, Jian Zhou, Jia Fan, Tan To Cheung, Xu-Dong Qu, Xin-Rong Yang, Peng-Xiang Wang, Yun-Fan Sun, Kai-Qian Zhou, Jian-Wen Cheng, Bo Hu, Wei Guo, Yue Yin, Jun-Feng Huang, Jian Zhou, Jia Fan, Tan To Cheung, Xu-Dong Qu, Xin-Rong Yang

Abstract

Background: High rates of postoperative tumor recurrence contribute to poor outcome in hepatocellular carcinoma (HCC). Here, we investigated whether circulating tumor cells (CTCs) status can predict the benefit of adjuvant transcatheter arterial chemoembolization (TACE) in patients with HCC.

Methods: The retrospective study enrolled 344 HCC patients with preoperative CTCs analysis. Clinical outcomes including recurrence and survival were compared between those who received and who did not receive adjuvant TACE. Similar comparisons were made for patients stratified according to CTC status (CTC-negative [CTC = 0], n = 123; CTC-positive [CTC ≥ 1], n = 221). Propensity score matching (PSM) strategy was adopted to offset differences between two groups.

Results: In the study cohort as a whole or in CTC-negative cohort, there were no observable differences in overall survival (OS) or time to recurrence (TTR) between TACE and control group (P > .05). In CTC-positive patients, PSM generated 64 patient pairs, and patients with adjuvant TACE had significantly better clinical outcomes (OS: not reached vs 36.4 months, P < .001; TTR: 45.8 vs 9.8 months, P < .001). Adjuvant TACE significantly reduced early recurrence (≤2 years) (64.1% vs 31.7%, P < .001) in CTC-positive patients. Notably, adjuvant TACE influenced TTR and OS even in subgroups of CTC-positive patients with low risk of recurrence according to traditional evaluation.

Conclusions: Preoperative CTC status could serve as an indicator for the administration of adjuvant TACE in HCC patients. Adjuvant TACE benefits CTC-positive HCC patients mainly by reducing early recurrence.

Keywords: a propensity score matching analysis; adjuvant transcatheter arterial chemoembolization; circulating tumor cells; hepatocellular carcinoma.

Conflict of interest statement

The authors declare that they have no conflict of interest.

© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Figures

FIGURE 1
FIGURE 1
Flow chart for patient selection in this study
FIGURE 2
FIGURE 2
Comparison of recurrence rates and OS between CTC‐stratified HCC patients in TACE and control groups before PSM. Recurrence rates (A) and OS (B) for CTC‐negative patients in TACE and control groups before PSM. Recurrence rates (C) and OS (D) for CTC‐positive patients in TACE and control groups before PSM
FIGURE 3
FIGURE 3
Comparison of recurrence rates and OS between CTC‐stratified HCC patients in TACE and control groups after PSM. Recurrence rates (A) and OS (B) for CTC‐negative patients in TACE and control groups after PSM. Recurrence rates (C) and OS (D) for CTC‐positive patients in TACE and control groups after PSM
FIGURE 4
FIGURE 4
Associations between adjuvant TACE and early recurrence in CTC‐stratified HCC patients. A, Proportions CTC‐positive patients in TACE and control groups that experienced early recurrence or nonearly recurrence. Kaplan‐Meier analysis of rates of early recurrence (B) and late recurrence (C) for CTC‐positive patients in TACE and control groups. D, Proportions of CTC‐negative patients in TACE and control groups that experienced early recurrence or nonearly recurrence. Kaplan‐Meier analysis of rates of early recurrence (E) and late recurrence (F) for CTC‐negative patients in TACE and control groups
FIGURE 5
FIGURE 5
Kaplan‐Meier analysis of early recurrence rates in subgroups of CTC‐positive HCC patients after PSM. Recurrence rates in CTC‐positive patients in the following subgroups: (A) single tumor, (B) tumor diameter 

FIGURE 6

Subgroups analyses for time to…

FIGURE 6

Subgroups analyses for time to early recurrence (A), and OS (B) by Cox…

FIGURE 6
Subgroups analyses for time to early recurrence (A), and OS (B) by Cox regression model based on independent assessment in CTC‐positive HCC patients after PSM Abbreviations: AFP, alpha fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CNLC, Liver Cancer Guidelines in China; CT, computed tomography; CTC, circulating tumor cell; DSA, digital subtraction angiography; HCC, hepatocellular carcinoma; OS, overall survival; PSM, propensity score matching; TACE, transcatheter arterial chemoembolization.
FIGURE 6
FIGURE 6
Subgroups analyses for time to early recurrence (A), and OS (B) by Cox regression model based on independent assessment in CTC‐positive HCC patients after PSM Abbreviations: AFP, alpha fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CNLC, Liver Cancer Guidelines in China; CT, computed tomography; CTC, circulating tumor cell; DSA, digital subtraction angiography; HCC, hepatocellular carcinoma; OS, overall survival; PSM, propensity score matching; TACE, transcatheter arterial chemoembolization.

References

    1. European Association for the Study of the Liver . EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182‐236.
    1. Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2015;261(5):947‐955.
    1. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358‐380.
    1. Pantel K, Alix‐Panabieres C. Tumour microenvironment: informing on minimal residual disease in solid tumours. Nat Rev Clin Oncol. 2017;14(6):325‐326.
    1. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205‐218.
    1. Ren ZG, Lin ZY, Xia JL, et al. Postoperative adjuvant arterial chemoembolization improves survival of hepatocellular carcinoma patients with risk factors for residual tumor: a retrospective control study. World J Gastroenterol. 2004;10(19):2791‐2794.
    1. Wang Z, Ren Z, Chen Y, et al. Adjuvant transarterial chemoembolization for HBV‐Related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res. 2018;24(9):2074‐2081.
    1. Liao M, Zhu Z, Wang H, Huang J. Adjuvant transarterial chemoembolization for patients after curative resection of hepatocellular carcinoma: a meta‐analysis. Scand J Gastroenterol. 2017;52(6‐7):624‐634.
    1. Sun YF, Xu Y, Yang XR, et al. Circulating stem cell‐like epithelial cell adhesion molecule‐positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 2013;57(4):1458‐1468.
    1. Staffa SJ, Zurakowski D. Five steps to successfully implement and evaluate propensity score matching in clinical research studies. Anesth Analg. 2018;127(4):1066‐1073.
    1. Bruix J, Sherman M. American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020‐1022.
    1. Zhou J, Sun HC, Wang Z, et al. Guidelines for diagnosis and treatment of primary liver cancer in China (2017 Edition). Liver Cancer. 2018;7(3):235‐260.
    1. Sarin SK, Kumar M, Lau GK, et al. Asian‐Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1‐98.
    1. Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243(2):229‐235.
    1. Chen X, Zhang B, Yin X, Ren Z, Qiu S, Zhou J. Lipiodolized transarterial chemoembolization in hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol. 2013;139(5):773‐781.
    1. Qu XD, Chen CS, Wang JH, et al. The efficacy of TACE combined sorafenib in advanced stages hepatocellullar carcinoma. BMC Cancer. 2012;12:263.
    1. Zheng Z, Liang W, Wang D, et al. Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: a meta‐analysis. Int J Cancer. 2015;136(6):E751‐E759.
    1. Jiang JH, Guo Z, Lu HF, et al. Adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma: propensity score analysis. World J Gastroenterol. 2015;21(15):4627‐4634.
    1. Lin E, Cao T, Nagrath S, King MR. Circulating tumor cells: diagnostic and therapeutic applications. Annu Rev Biomed Eng. 2018;20:329‐352.
    1. Bluthner E, Bednarsch J, Malinowski M, et al. Dynamic liver function is an independent predictor of recurrence‐free survival after curative liver resection for HCC ‐ a retrospective cohort study. Int J Surg. 2019;71:56‐65.
    1. Qi LN, Xiang BD, Wu FX, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma. Cancer Res. 2018;78(16):4731‐4744.
    1. Guo W, Yang XR, Sun YF, et al. Clinical significance of EpCAM mRNA‐positive circulating tumor cells in hepatocellular carcinoma by an optimized negative enrichment and qRT‐PCR‐based platform. Clin Cancer Res. 2014;20(18):4794‐4805.
    1. Guo W, Sun YF, Shen MN, et al. Circulating tumor cells with stem‐like phenotypes for diagnosis, prognosis, and therapeutic response evaluation in hepatocellular carcinoma. Clin Cancer Res. 2018;24(9):2203‐2213.
    1. Ben Lassoued A, Nivaggioni V, Gabert J. Minimal residual disease testing in hematologic malignancies and solid cancer. Expert Rev Mol Diagn. 2014;14(6):699‐712.
    1. Lencioni R. Loco‐regional treatment of hepatocellular carcinoma. Hepatology. 2010;52(2):762‐773.
    1. Sun JJ, Wang K, Zhang CZ, et al. Postoperative adjuvant transcatheter arterial chemoembolization after R0 hepatectomy improves outcomes of patients who have hepatocellular carcinoma with microvascular invasion. Ann Surg Oncol. 2016;23(4):1344‐1351.
    1. Andree KC, van Dalum G, Terstappen LW. Challenges in circulating tumor cell detection by the CellSearch system. Mol Oncol. 2016;10(3):395‐407.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe