Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study

Jun Sik Yoon; Dong Hyun Sinn; Jeong Hoon Lee; Hwi Young Kim; Cheol Hyung Lee; Sun Woong Kim; Hyo Young Lee; Joon Yeul Nam; Young Chang; Yun Bin Lee; Eun Ju Cho; Su Jong Yu; Hyo Cheol Kim; Jin Wook Chung; Yoon Jun Kim; Jung Hwan Yoon

doi:10.3390/cancers11111721

Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study

Jun Sik Yoon, Dong Hyun Sinn, Jeong Hoon Lee, Hwi Young Kim, Cheol Hyung Lee, Sun Woong Kim, Hyo Young Lee, Joon Yeul Nam, Young Chang, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Hyo Cheol Kim, Jin Wook Chung, Yoon Jun Kim, Jung Hwan Yoon

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre-and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×^√protein induced by vitamin K absence-II + 2×^√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (∆MoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ∆MoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ∆MoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

Original language	English
Article number	1721
Journal	Cancers
Volume	11
Issue number	11
DOIs	https://doi.org/10.3390/cancers11111721
State	Published - Nov 2019

Bibliographical note

Funding Information:
Funding: This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (No. 2019R1A2C2010311), from the Seoul National University Hospital Research Fund (03-2016-0380), and from Liver Research Foundation of Korea as part of Bio Future Strategies Research Project. Funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. The corresponding authors had full access to all study data and had final responsibility for the decision to submit for publication.

Funding Information:
Acknowledgments: The database used in this study was provided by the Korean Central Cancer Registry, Ministry of Health and Welfare, South Korea, and the Korean Liver Cancer Association.

Funding Information:
This study was conducted in accordance with the World Medical Association Declaration of Helsinki and was approved by the Institutional Review Board of each participating center (SNUH No. 1702-067-831, SMC No. 2018-08-137, and EUMC No. 2016-07-081-015), and by the Korean Central Cancer Registry, Ministry of Health and Welfare Korea, and the Korean Liver Cancer Association.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Alpha-fetoprotein
Hepatocellular carcinoma
Protein induced by vitamin K absence-II
Tumor biology
Tumor marker

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10.3390/cancers11111721

Cite this

Yoon, J. S., Sinn, D. H., Lee, J. H., Kim, H. Y., Lee, C. H., Kim, S. W., Lee, H. Y., Nam, J. Y., Chang, Y., Lee, Y. B., Cho, E. J., Yu, S. J., Kim, H. C., Chung, J. W., Kim, Y. J., & Yoon, J. H. (2019). Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study. Cancers, 11(11), Article 1721. https://doi.org/10.3390/cancers11111721

@article{b4157d61500b46d392fb83d62441edb7,

title = "Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study",

abstract = "Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-na{\"i}ve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre-and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (∆MoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ∆MoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ∆MoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.",

keywords = "Alpha-fetoprotein, Hepatocellular carcinoma, Protein induced by vitamin K absence-II, Tumor biology, Tumor marker",

author = "Yoon, {Jun Sik} and Sinn, {Dong Hyun} and Lee, {Jeong Hoon} and Kim, {Hwi Young} and Lee, {Cheol Hyung} and Kim, {Sun Woong} and Lee, {Hyo Young} and Nam, {Joon Yeul} and Young Chang and Lee, {Yun Bin} and Cho, {Eun Ju} and Yu, {Su Jong} and Kim, {Hyo Cheol} and Chung, {Jin Wook} and Kim, {Yoon Jun} and Yoon, {Jung Hwan}",

note = "Funding Information: Funding: This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (No. 2019R1A2C2010311), from the Seoul National University Hospital Research Fund (03-2016-0380), and from Liver Research Foundation of Korea as part of Bio Future Strategies Research Project. Funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. The corresponding authors had full access to all study data and had final responsibility for the decision to submit for publication. Funding Information: Acknowledgments: The database used in this study was provided by the Korean Central Cancer Registry, Ministry of Health and Welfare, South Korea, and the Korean Liver Cancer Association. Funding Information: This study was conducted in accordance with the World Medical Association Declaration of Helsinki and was approved by the Institutional Review Board of each participating center (SNUH No. 1702-067-831, SMC No. 2018-08-137, and EUMC No. 2016-07-081-015), and by the Korean Central Cancer Registry, Ministry of Health and Welfare Korea, and the Korean Liver Cancer Association. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = nov,

doi = "10.3390/cancers11111721",

language = "English",

volume = "11",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "11",

}

Yoon, JS, Sinn, DH, Lee, JH, Kim, HY, Lee, CH, Kim, SW, Lee, HY, Nam, JY, Chang, Y, Lee, YB, Cho, EJ, Yu, SJ, Kim, HC, Chung, JW, Kim, YJ & Yoon, JH 2019, 'Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study', Cancers, vol. 11, no. 11, 1721. https://doi.org/10.3390/cancers11111721

TY - JOUR

T1 - Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma

T2 - A multi-cohort study

AU - Yoon, Jun Sik

AU - Sinn, Dong Hyun

AU - Lee, Jeong Hoon

AU - Kim, Hwi Young

AU - Lee, Cheol Hyung

AU - Kim, Sun Woong

AU - Lee, Hyo Young

AU - Nam, Joon Yeul

AU - Chang, Young

AU - Lee, Yun Bin

AU - Cho, Eun Ju

AU - Yu, Su Jong

AU - Kim, Hyo Cheol

AU - Chung, Jin Wook

AU - Kim, Yoon Jun

AU - Yoon, Jung Hwan

N1 - Funding Information: Funding: This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (No. 2019R1A2C2010311), from the Seoul National University Hospital Research Fund (03-2016-0380), and from Liver Research Foundation of Korea as part of Bio Future Strategies Research Project. Funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. The corresponding authors had full access to all study data and had final responsibility for the decision to submit for publication. Funding Information: Acknowledgments: The database used in this study was provided by the Korean Central Cancer Registry, Ministry of Health and Welfare, South Korea, and the Korean Liver Cancer Association. Funding Information: This study was conducted in accordance with the World Medical Association Declaration of Helsinki and was approved by the Institutional Review Board of each participating center (SNUH No. 1702-067-831, SMC No. 2018-08-137, and EUMC No. 2016-07-081-015), and by the Korean Central Cancer Registry, Ministry of Health and Welfare Korea, and the Korean Liver Cancer Association. Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2019/11

Y1 - 2019/11

N2 - Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre-and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (∆MoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ∆MoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ∆MoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

AB - Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre-and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (∆MoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ∆MoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ∆MoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

KW - Alpha-fetoprotein

KW - Hepatocellular carcinoma

KW - Protein induced by vitamin K absence-II

KW - Tumor biology

KW - Tumor marker

UR - http://www.scopus.com/inward/record.url?scp=85074659149&partnerID=8YFLogxK

U2 - 10.3390/cancers11111721

DO - 10.3390/cancers11111721

M3 - Article

AN - SCOPUS:85074659149

SN - 2072-6694

VL - 11

JO - Cancers

JF - Cancers

IS - 11

M1 - 1721

ER -

Tumor marker-based definition of the transarterial chemoembolization-refractoriness in intermediate-stage hepatocellular carcinoma: A multi-cohort study

Abstract

Bibliographical note

Keywords

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