The Systemic Inflammatory Response Identifies Patients with Adverse Clinical Outcome from Immunotherapy in Hepatocellular Carcinoma

被引：55

作者：

Muhammed, Ambreen ^{[1
]}

Fulgenzi, Claudia Angela Maria ^{[1
,2
]}

Dharmapuri, Sirish ^{[3
]}

Pinter, Matthias ^{[4
]}

Balcar, Lorenz ^{[4
]}

Scheiner, Bernhard ^{[4
]}

Marron, Thomas U. ^{[3
]}

Jun, Tomi ^{[3
]}

Saeed, Anwaar ^{[5
]}

Hildebrand, Hannah ^{[5
]}

Muzaffar, Mahvish ^{[6
]}

Navaid, Musharraf ^{[6
]}

Naqash, Abdul Rafeh ^{[6
]}

Gampa, Anuhya ^{[7
]}

Ozbek, Umut ^{[8
]}

Lin, Junk-Yi ^{[8
]}

Perone, Ylenia ^{[1
]}

Vincenzi, Bruno ^{[2
]}

Silletta, Marianna ^{[2
]}

Pillai, Anjana ^{[7
]}

Wang, Yinghong ^{[9
]}

Khan, Uqba ^{[10
]}

Huang, Yi-Hsiang ^{[11
]}

Bettinger, Dominik ^{[12
]}

Abugabal, Yehia I. ^{[13
]}

Kaseb, Ahmed ^{[13
]}

Pressiani, Tiziana ^{[14
]}

Personeni, Nicola ^{[14
,15
]}

Rimassa, Lorenza ^{[14
,15
]}

Nishida, Naoshi ^{[16
]}

Di Tommaso, Luca ^{[17
]}

Kudo, Masatoshi ^{[16
]}

Vogel, Arndt ^{[18
]}

Mauri, Francesco A. ^{[1
]}

Cortellini, Alessio ^{[1
]}

Sharma, Rohini ^{[1
]}

D'Alessio, Antonio ^{[1
,15
]}

Ang, Celina ^{[3
]}

Pinato, David J. ^{[1
]}

机构：

[1] Imperial Coll London, Hammersmith Hosp, Dept Surg & Canc, Du Cane Rd, London W12 0HS, England

[2] Univ Campus Biomed, Dept Med Oncol, I-00128 Rome, Italy

[3] Mt Sinai Hosp, Tisch Canc Inst, Div Hematol Oncol, Dept Med, New York, NY 10029 USA

[4] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, A-1090 Vienna, Austria

[5] Univ Kansas, Dept Med, Div Med Oncol, Canc Ctr, Westwood, KS 66205 USA

[6] East Carolina Univ, Div Hematol Oncol, 600 Moye Blvd, Greenville, NC 27834 USA

[7] Univ Chicago Med, Sect Gastroenterol Hepatol & Nutr, 5841 S Maryland Ave, Chicago, IL 60637 USA

[8] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[10] Weill Cornell Med, New York Presbyterian Hosp, Div Hematol & Oncol, 1305 York Ave,Room Y1247, New York, NY 10021 USA

[11] Natl Yang Ming Chiao Tung Univ, Taipei Vet Gen Hosp, Div Gastroenterol & Hepatol, Inst Clin Med,Sch Med, Taipei 11217, Taiwan

[12] Univ Freiburg, Med Ctr, Fac Med, Dept Med 2, D-79106 Freiburg, Germany

[13] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[14] IRCCS Humanitas Res Hosp, Humanitas Canc Ctr, Med Oncol & Hematol Unit, Via Manzoni 56, I-20089 Milan, Italy

[15] Humanitas Univ, Dept Biomed Sci, Via R Levi Montalcini 4, I-20072 Milan, Italy

[16] Kindai Univ, Fac Med, Dept Gastroenterol & Hepatol, Osakasayama, Osaka 5898511, Japan

[17] Humanitas Clin & Res Ctr IRCCS, Pathol Unit, I-20089 Rozzano, Italy

[18] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany

来源：

CANCERS | 2022年 / 14卷 / 01期

关键词：

hepatocellular carcinoma; inflammatory biomarkers; neutrophil-lymphocyte ratio; platelet-lymphocyte ratio; prognostic nutritional index; PHASE-III; INDEX;

D O I：

10.3390/cancers14010186

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary The investigation of predictive and prognostic markers is pivotal in patients affected by hepatocellular carcinoma treated with immune-checkpoint-inhibitors. Inflammation has a central role in hepatocellular carcinoma development and progression; however, its role in influencing outcomes in the context of immunotherapy has not been fully elucidated yet. In the following study, we investigated the prognostic role of bloods derived inflammatory markers and we found that they predict survival and response of patients treated with immunotherapy for advanced hepatocellular carcinoma. Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR >= 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR >= 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45-2.64, p < 0.001; HR 1.73, 95%CI 1.23-2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6-2.40, p = 0.020; HR 1.99, 95%CI 1.11-3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

引用

页数：15

共 31 条

[21] The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma [J].

Sanghera, Chandan ;

Teh, Jhia J. ;

Pinato, David J. .

LIVER INTERNATIONAL, 2019, 39 (11) :2008-2023

[22] Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma [J].

Sangro, Bruno ;

Melero, Ignacio ;

Wadhawan, Samir ;

Finn, Richard S. ;

Abou-Alfa, Ghassan K. ;

Cheng, Ann-Lii ;

Yau, Thomas ;

Furuse, Junji ;

Park, Joong-Won ;

Boyd, Zachary ;

Tang, Hao Tracy ;

Shen, Yun ;

Tschaika, Marina ;

Neely, Jaclyn ;

El-Khoueiry, Anthony .

JOURNAL OF HEPATOLOGY, 2020, 73 (06) :1460-1469

[23] MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-a, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial [J].

Sarker, Debashis ;

Plummer, Ruth ;

Meyer, Tim ;

Sodergren, Mikael H. ;

Basu, Bristi ;

Chee, Cheng Ean ;

Huang, Kai-Wen ;

Palmer, Daniel H. ;

Ting, Yuk ;

Evans, T. R. Jeff ;

Spalding, Duncan R. C. ;

Pai, Madhava ;

Sharma, Rohini ;

Pinato, David J. ;

Spicer, James ;

Hunter, Sarah ;

Kwatra, Vineet ;

Nicholls, Joanna P. ;

Collin, David ;

Nutbrown, Robert ;

Glenny, Helen ;

Fairbairn, Sonia ;

Reebye, Vikash ;

Voutila, Jon ;

Dorman, Stephanie ;

Andrikakou, Pinelopi ;

Lloyd, Peter ;

Felstead, Steve ;

Vasara, Jenni ;

Habib, Robert ;

Wood, Chris ;

Saetrom, Pal ;

Huber, Hans E. ;

Blakey, David C. ;

Rossi, John J. ;

Habib, Nagy .

CLINICAL CANCER RESEARCH, 2020, 26 (15) :3936-3946

[24] Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features [J].

Sia, Daniela ;

Jiao, Yang ;

Martinez-Quetglas, Iris ;

Kuchuk, Olga ;

Villacorta-Martin, Carlos ;

de Moura, Manuel Castro ;

Putra, Juan ;

Camprecios, Genis ;

Bassaganyas, Laia ;

Akers, Nicholas ;

Losic, Bojan ;

Waxman, Samuel ;

Thung, Swan N. ;

Mazzaferro, Vincenzo ;

Esteller, Manel ;

Friedman, Scott L. ;

Schwartz, Myron ;

Villanueva, Augusto ;

Llovet, Josep M. .

GASTROENTEROLOGY, 2017, 153 (03) :812-826

[25] Onodera's prognostic nutritional index is a strong prognostic indicator for patients with hepatocellular carcinoma after initial hepatectomy, especially patients with preserved liver function [J].

Tanemura, Akihiro ;

Mizuno, Shugo ;

Hayasaki, Aoi ;

Gyoten, Kazuyuki ;

Fujii, Takehiro ;

Iizawa, Yusuke ;

Kato, Hiroyuki ;

Murata, Yasuhiro ;

Kuriyama, Naohisa ;

Kishiwada, Masashi ;

Sakurai, Hiroyuki ;

Isaji, Shuji .

BMC SURGERY, 2020, 20 (01)

[26] Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis [J].

van der Windt, Dirk J. ;

Sud, Vikas ;

Zhang, Hongji ;

Varley, Patrick R. ;

Goswami, Julie ;

Yazdani, Hamza O. ;

Tohme, Samer ;

Loughran, Patricia ;

O'Doherty, Robert M. ;

Minervini, Marta I. ;

Huang, Hai ;

Simmons, Richard L. ;

Tsung, Allan .

HEPATOLOGY, 2018, 68 (04) :1347-1360

[27]

Yamamoto H, 2000, INT J ONCOL, V16, P543

[28]

Yau T, 2019, ANN ONCOL, V30, P874

[29] Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial [J].

Yau, Thomas ;

Kang, Yoon-Koo ;

Kim, Tae-You ;

El-Khoueiry, Anthony B. ;

Santoro, Armando ;

Sangro, Bruno ;

Melero, Ignacio ;

Kudo, Masatoshi ;

Hou, Ming-Mo ;

Matilla, Ana ;

Tovoli, Francesco ;

Knox, Jennifer J. ;

He, Aiwu Ruth ;

El-Rayes, Bassel F. ;

Acosta-Rivera, Mirelis ;

Lim, Ho-Yeong ;

Neely, Jaclyn ;

Shen, Yun ;

Wisniewski, Tami ;

Anderson, Jeffrey ;

Hsu, Chiun .

JAMA ONCOLOGY, 2020, 6 (11)

[30] Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment [J].

Yegin, Ender Gunes ;

Oymaci, Erkan ;

Karatay, Emrah ;

Coker, Ahmet .

HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, 2016, 15 (03) :234-256

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