Clinical and Prognostic Biomarker Value of Blood-Circulating Inflammatory Cytokines in Hepatocellular Carcinoma

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Abstract

Introduction

Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients.

Methods

We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% confidence interval [CI]: 52.5, 83.3). Biomarker association with OS was evaluated by the log-rank method.

Results

The median OS in this cohort was 14.2 months (95% CI: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18.

Conclusion

Our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC.

Related collections

Most cited references 35

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Hepatocellular carcinoma: a review

Julius Balogh, David Victor, Emad H. Asham … (2016)

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.

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Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.

P. Wagner, Yinghui Wang, Ashvini Reddy … (2009)

Alpha-fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with cirrhosis. Des-gamma carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The aims of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels. We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory. A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77-0.84), followed by DCP (0.72, 95% CI: 0.68-0.77) and AFP-L3% (0.66, 95% CI: 0.62-0.70) for early stage HCC. The optimal AFP cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72-0.85) leading to a sensitivity of 65% at the same cutoff. AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL.

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Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.

Andrew X Zhu, Dushyant V Sahani, Dan G Duda … (2009)

To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome. Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

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Author and article information

Journal

Journal ID (nlm-ta): Oncology

Journal ID (iso-abbrev): Oncology

Journal ID (hwp): OCL

Journal ID (publisher-id): OCL

Title: Oncology

Publisher: S. Karger AG (Basel, Switzerland )

ISSN (Print): 0030-2414

ISSN (Electronic): 1423-0232

Publication date (Electronic): 23 August 2023

Publication date (Print): October 2023

Volume: 101

Issue: 11

Pages: 730-737

Affiliations

[a ]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[b ]Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[c ]Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[d ]Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

[e ]Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[f ]Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

[g ]Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

[h ]Division of Hematology/Oncology, Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

[i ]Department of Surgery, Emory University, Atlanta, GA, USA

[j ]Department of Internal Medicine University of Texas Health Science Center at Houston, Houston, TX, USA

[k ]Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Author notes

Correspondence to: Ahmed O. Kaseb, akaseb@ 123456mdanderson.org

Article

Publisher ID: 531870

DOI: 10.1159/000531870

PMC ID: 10614568

PubMed ID: 37467732

SO-VID: dd5b464a-7138-4aea-8e9b-1a3f91bdba96

License:

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

History

Date received : 14 March 2023

Date accepted : 20 June 2023

Date: 2023

Page count

Tables: 4, References: 36, Pages: 8

Funding

The University of Texas MD Anderson Cancer Center, SPORE in HCC, Grant #NCI, P50 CA217674-01A1 (to AOK), NCI R01CA260872 (to AOK, HMA, DGD). D.G.D.’s research is also funded through NIH (Grant No. R01CA260857 and R01CA247441) and by Department of Defense PRCRP (Grant No. W81XWH-19–1-0284, W81XWH1910482, and W81XWH-21–1–0738). All other authors report no competing financial interests related to this work.

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Clinical and Prognostic Biomarker Value of Blood-Circulating Inflammatory Cytokines in Hepatocellular Carcinoma

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Abstract

Introduction

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 35

Hepatocellular carcinoma: a review

Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.

Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.

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