Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib

M Rimini¹, M Kudo², T Tada³, S Shigeo⁴, W Kang⁵, G Suda⁶, A Jefremow⁷, V Burgio⁸, M Iavarone⁹, R Tortora¹⁰, F Marra¹¹, S Lonardi¹², E Tamburini¹³, F Piscaglia¹⁴, G Masi¹⁵, G Cabibbo¹⁶, F G Foschi¹⁷, M Silletta¹⁸, T Kumada¹⁹, H Iwamoto⁴, T Aoki², M J Goh²⁰, N Sakamoto⁶, J Siebler⁷, A Hiraoka²¹, T Niizeki⁴, K Ueshima², T Sho⁶, M Atsukawa²², M Hirooka²³, K Tsuji²⁴, T Ishikawa²⁵, K Takaguchi²⁶, K Kariyama²⁷, E Itobayashi²⁸, K Tajiri²⁹, N Shimada³⁰, H Shibata³¹, H Ochi³², S Yasuda³³, H Toyoda³³, S Fukunishi³⁴, H Ohama³⁴, K Kawata³⁵, J Tani³⁶, S Nakamura³, K Nouso²⁷, A Tsutsui²⁶, T Nagano²⁶, T Takaaki²¹, N Itokawa²², T Okubo²², T Arai²², M Imai²⁵, K Joko²¹, Y Koizumi²¹, Y Hiasa²¹, A Cucchetti³⁷, F Ratti³⁸, L Aldrighetti³⁹, S Cascinu⁴⁰, A Casadei-Gardini⁴¹

Affiliations

¹ Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy.
² Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Higashi-osaka, Japan.
³ Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.
⁴ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
⁵ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
⁶ Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷ Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nuremberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
⁸ Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁹ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Division of Gastroenterology and Hepatology, Milan, Italy.
¹⁰ Liver Unit, Department of Transplantation, Cardarelli Hospital, Naples, Italy.
¹¹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
¹² Medical Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹³ Department of Medical Oncology, Card. G. Panico Hospital of Tricase, Tricase, Italy.
¹⁴ Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹⁵ Unit of Medical Oncology, Pisa University Hospital, Pisa, Italy.
¹⁶ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
¹⁷ Azienda Unità Sanitaria della Romagna, Ospedale degli Infermi, Faenza, Italy.
¹⁸ Medical Oncology Unit, University Campus Bio-Medico, Rome, Italy.
¹⁹ Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan.
²⁰ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
²¹ Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.
²² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
²³ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan.
²⁴ Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
²⁵ Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.
²⁶ Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
²⁷ Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.
²⁸ Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.
²⁹ Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.
³⁰ Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.
³¹ Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan.
³² Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.
³³ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
³⁴ Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan.
³⁵ Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
³⁶ Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan.
³⁷ Department of Medical and Surgical Sciences-DIMEC, Alma Mater Studiorum - University of Bologna, Bologna, Italy; Department of Surgery, Morgagni - Pierantoni Hospital, Forlì, Italy.
³⁸ Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁹ Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
⁴⁰ Vita-Salute San Raffaele University, Milan, Italy; Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁴¹ Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: casadeigardini@gmail.com.

PMID: 34847382
PMCID: PMC8710492
DOI: 10.1016/j.esmoop.2021.100330

Multicenter Study

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib

M Rimini et al. ESMO Open. 2021 Dec.

. 2021 Dec;6(6):100330.

doi: 10.1016/j.esmoop.2021.100330. Epub 2021 Nov 27.

Authors

Affiliations

¹ Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy.
² Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Higashi-osaka, Japan.
³ Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.
⁴ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
⁵ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
⁶ Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷ Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nuremberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
⁸ Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁹ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Division of Gastroenterology and Hepatology, Milan, Italy.
¹⁰ Liver Unit, Department of Transplantation, Cardarelli Hospital, Naples, Italy.
¹¹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
¹² Medical Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹³ Department of Medical Oncology, Card. G. Panico Hospital of Tricase, Tricase, Italy.
¹⁴ Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹⁵ Unit of Medical Oncology, Pisa University Hospital, Pisa, Italy.
¹⁶ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
¹⁷ Azienda Unità Sanitaria della Romagna, Ospedale degli Infermi, Faenza, Italy.
¹⁸ Medical Oncology Unit, University Campus Bio-Medico, Rome, Italy.
¹⁹ Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan.
²⁰ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
²¹ Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.
²² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
²³ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan.
²⁴ Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
²⁵ Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.
²⁶ Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
²⁷ Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.
²⁸ Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.
²⁹ Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.
³⁰ Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.
³¹ Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan.
³² Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.
³³ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
³⁴ Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan.
³⁵ Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
³⁶ Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan.
³⁷ Department of Medical and Surgical Sciences-DIMEC, Alma Mater Studiorum - University of Bologna, Bologna, Italy; Department of Surgery, Morgagni - Pierantoni Hospital, Forlì, Italy.
³⁸ Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁹ Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
⁴⁰ Vita-Salute San Raffaele University, Milan, Italy; Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁴¹ Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: casadeigardini@gmail.com.

PMID: 34847382
PMCID: PMC8710492
DOI: 10.1016/j.esmoop.2021.100330

Abstract

Background: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes.

Patients and methods: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed.

Results: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047).

Conclusion: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Keywords: advanced hepatocarcinoma; atezolizumab; bevacizumab; hepatitis C; hepatocellular carcinoma; immunotherapy; lenvatinib; nonalcoholic steatohepatitis; sorafenib.

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Conflict of interest statement

Disclosure AC-G has received grants and personal fees from MSD, Eisai and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. MK has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma and Bristol-Myers Squibb; has received grants and personal fees from MSD, Eisai and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly and ONO Pharmaceutical. AJ reports personal fees from Eisai. All other authors have declared no conflicts of interest. Data sharing Data available on request from the authors.

Figures

**Figure 1**
Kaplan–Meier curves for (A) overall survival to lenvatinib and (B) progression-free survival to lenvatinib in patients with nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) and no NASH-related HCC.

See this image and copyright information in PMC

References

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Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib

Affiliations

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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