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Identification of Regorafenib Prognostic Index (REP Index) via Recursive Partitioning Analysis in Patients with Advanced Hepatocellular Carcinoma Receiving Systemic Treatment: A Real-World Multi-Institutional Experience

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Abstract

Background

The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce.

Objective

The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib.

Methods

We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system.

Results

At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (n  =  59) and patients with a PFS < 6 months (n = 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (n = 22) and patients with no HBV-related liver disease (n = 37). In the subpopulation of patients presenting ALP >122 U/L (n = 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (n = 48) and patients with AST > 56 U/L (n = 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into “low-risk,” “medium-risk,” and “high-risk” groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval [CI] 10.0–46.3) in the “low-risk” group, 8.4 months (95% CI 7.2–1435.8) in the “medium-risk” group, and 5.5 months (95% CI 3.5–13.2) in the “high risk” group. The median PFS was 7.7 months (95% CI 3.7–19.3), 2.5 months (95% CI 2.1–28.8), and 2.4 months (95% CI 1.6–9.1) for the “low-risk,” “medium-risk,” and “high-risk” groups, respectively.

Conclusion

The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.

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Authors and Affiliations

  1. Department of Medical Oncology, Hospital Policlinico of Modena, Via Del Pozzo n.71, 41122, Modena, Italy

    Margherita Rimini

  2. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Changhoon Yoo, Yeonghak Bang, Hyung-Don Kim, Baek-Yeol Ryoo & Min-Hee Ryoo

  3. Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

    Sara Lonardi

  4. Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

    Sara Lonardi, Mario Domenico Rizzato & Francesca Bergamo

  5. U.O. Oncologia Medica 2 Universitaria Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Gianluca Masi, Caterina Vivaldi & Francesca Salani

  6. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

    Alessandro Granito, Luca Ielasi & Simona Leoni

  7. Unit of Oncology, IRCCS-San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy

    Valentina Burgio, Stefano Cascinu & Andrea Casadei-Gardini

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  1. Margherita Rimini
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  2. Changhoon Yoo
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  3. Sara Lonardi
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  4. Gianluca Masi
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  5. Alessandro Granito
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  7. Mario Domenico Rizzato
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  11. Francesca Bergamo
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  15. Min-Hee Ryoo
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  17. Stefano Cascinu
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  18. Andrea Casadei-Gardini
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Corresponding author

Correspondence to Margherita Rimini.

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Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

CY receives research grants from Bayer, ONO, Ipsen, and AstraZeneca and honoraria from Bayer, MSD, BMS, Ipsen, and AstraZeneca. Margherita Rimini, Sara Lonardi, Gianluca Masi, Alessandro Granito, Yeonghak Bang, Mario Domenico Rizzato, Caterina Vivaldi, Luca Ielasi, Hyung-Don Kim, Francesca Bergamo, Francesca Salani, Simona Leoni, Baek-Yeol Ryoo, Min-Hee Ryoo, Valentina Burgio, Stefano Cascinu, and Andrea Casadei-Gardini have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

The ethical review board of each institutional hospital approved the present study. This study was performed in line with the principles of the Declaration of Helsinki.

Consent

Written informed consent was obtained from all patients.

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Data are available on request from the authors.

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Author contributions

Conception and design: AC-G, MR. Acquisition of data (acquired and managed patients): all authors. Analysis and interpretation of data: AC-G, MR. Writing, review, and/or revision of the manuscript: AC-G, MR. Final approval of manuscript: all authors.

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Rimini, M., Yoo, C., Lonardi, S. et al. Identification of Regorafenib Prognostic Index (REP Index) via Recursive Partitioning Analysis in Patients with Advanced Hepatocellular Carcinoma Receiving Systemic Treatment: A Real-World Multi-Institutional Experience. Targ Oncol 16, 653–661 (2021). https://doi.org/10.1007/s11523-021-00834-1

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