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Jin Z, Zhou F, Wang Z, Li H. First-Line Treatment of Icaritin and Thalidomide in a Patient With Hepatocellular Carcinoma With PR: A Case Report. Cancer Rep (Hoboken) 2025; 8:e70136. [PMID: 40035422 PMCID: PMC11877328 DOI: 10.1002/cnr2.70136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 12/30/2024] [Accepted: 01/26/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains a significant global health burden, with unmet clinical needs despite the availability of multiple therapeutic options. CASE We present the case of an 85-year-old male diagnosed with HCC and bilateral lung metastases following hepatectomy. The patient responded favorably to treatment with icaritin and thalidomide, which resulted in a reduction in alpha-fetoprotein (AFP) levels and tumor size. This treatment achieved partial remission, with a progression-free survival (PFS) of 24 months and an overall survival (OS) of 33 months. Unfortunately, the patient ultimately passed away due to a cerebral infarction unrelated to cancer progression. CONCLUSION This case underscores the potential of icaritin as a therapeutic option for HCC patients with compromised health status. The combination of icaritin and thalidomide demonstrated promising efficacy in this real-world scenario. Multidisciplinary combination treatment strategies incorporating icaritin merit further exploration, given its immunomodulatory effects and favorable safety profile.
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Affiliation(s)
- Zaiyong Jin
- Department of Hepatological SurgeryJilin City Central HospitalJilinChina
| | - Fei Zhou
- Medical Image Central, Jilin City Central HospitalJilinChina
| | - Zhuo Wang
- Department of Abdominal Imaging DiagnosticJilin City Central HospitalJilinChina
| | - Hongji Li
- Department of Traditional and Western OncologyJilin City Central HospitalJilinChina
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Chen SC, Ho HL, Liu CA, Hung YP, Chiang NJ, Chen MH, Chao Y, Yang MH. PIVKA-II as a surrogate biomarker for therapeutic response in Non-AFP-secreting hepatocellular carcinoma. BMC Cancer 2025; 25:199. [PMID: 39905360 PMCID: PMC11792300 DOI: 10.1186/s12885-025-13568-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Alpha-fetoprotein (AFP) is a key biomarker for hepatocellular carcinoma (HCC), but 30-40% of cases are AFP-negative. Prothrombin induced by vitamin K absence II (PIVKA-II) is more sensitive for HCC detection, though its role in systemic therapy remains underexplored. This study aimed to evaluate PIVKA-II in non-AFP-secreting HCC treated with systemic therapy. METHODS Patients with unresectable HCC undergoing systemic therapy were enrolled. Baseline imaging and PIVKA-II levels were recorded. After 8-12 weeks of treatment, response was evaluated through imaging and repeat PIVKA-II measurements. RESULTS A total of 116 treatment assessments from 61 cases were analyzed. Baseline PIVKA-II levels correlated with tumor size, but not tumor number or liver function. PIVKA-II regression (≥ 50% reduction) and progression (≥ 50% increase) were defined using ROC analysis. Imaging showed 71.0% objective response in the regression group, 50.0% stable disease in the stable group, and 83.7% progressive disease in the progression group (p < 0.001). This association held for targeted therapies, immune checkpoint inhibitors, and chemotherapy. Progression-free survival (PFS) for the regression, stable, and progression groups was non-reached, 6.7, and 3.2 months (p = 0.0002), and overall survival (OS) was non-reached, non-reached, and 18.5 months (p = 0.02). CONCLUSIONS This study is the first to establish the "50-50 rule" for PIVKA-II response in non-AFP-secreting HCC treated with systemic therapy, highlighting its value as a surrogate marker for radiological outcomes and prognosis.
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Affiliation(s)
- San-Chi Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-An Liu
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ping Hung
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Nai-Jung Chiang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Huang Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- Department of Internal Medicine, Central Clinical & Hospital, Taipei, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan.
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
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Zhang D, Cai Y, Sun Y, Zeng P, Wang W, Wang W, Jiang X, Lian Y. A real-world pharmacovigilance study of Sorafenib based on the FDA Adverse Event Reporting System. Front Pharmacol 2024; 15:1442765. [PMID: 39741633 PMCID: PMC11685139 DOI: 10.3389/fphar.2024.1442765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 12/02/2024] [Indexed: 01/03/2025] Open
Abstract
Aims The primary objective of this study was to closely monitor and identify adverse events (AEs) associated with Sorafenib, a pharmacological therapeutic agent used to treat hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. The ultimate goal was to optimize patient safety and provide evidence-based guidance for the appropriate use of this drug. Methods Reports from the FDA Adverse Event Reporting System (FAERS) database were comprehensively collected and analyzed, covering the first quarter of 2004 to the first quarter of 2024. Disproportionality analysis was performed using robust algorithms for effective data mining to quantify the signals associated with Sorafenib-related AEs. Results In total, we identifued 18,624 patients (82,857 AEs in the Sorafenib population) from the collected reports and examined, the occurrence of Sorafenib-induced AEs in 26 organ systems. The study results revealed the presence of the expected AEs, including Diarrhoea, Palmar-plantar erythrodysaesthesia syndrome, Hepatocellular carcinoma, Fatigue, and Rash, which was consistent with the information provided in the drug insert. In addition, unexpected significant AEs, such as Gait inability, Palmoplantar keratoderma and Hyperkeratosis were observed at the preferred term (PT) level. These findings suggest the potential occurrence of adverse reactions not currently documented in drug descriptions. Conclusion This study successfully detected new and unforeseen signals associated with Sorafenib-related AEs related to Sorafenib administration, providing important insights into the complex correlations between AEs and Sorafenib use. The results of this study emphasize the critical importance of continuous and vigilant surveillance for the timely identification and effective management of AEs to improve the overall patient safety and wellbeing in the context of Sorafenib therapy.
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Affiliation(s)
- Dongdong Zhang
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Digestive Disease, School of Medicine, Institute for Microbial Ecology, Xiamen University, Xiamen, Fujian, China
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Cai
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Digestive Disease, School of Medicine, Institute for Microbial Ecology, Xiamen University, Xiamen, Fujian, China
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yixin Sun
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Peiji Zeng
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Wei Wang
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Wenhui Wang
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Xiaohua Jiang
- Department of Orthopedics, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yifan Lian
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Digestive Disease, School of Medicine, Institute for Microbial Ecology, Xiamen University, Xiamen, Fujian, China
- School of Medicine, Xiamen University, Xiamen, Fujian, China
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Colloca GA, Venturino A. Radiographic and serologic response in patients with unresectable hepatocellular carcinoma receiving systemic antineoplastic treatments: A trial-level analysis. Cancer 2024; 130:1773-1783. [PMID: 38231887 DOI: 10.1002/cncr.35199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND In a disease like unresectable hepatocellular carcinoma, overall survival is an inadequate outcome measure for evaluating the effectiveness of treatments given the high risk of death from liver failure. There is an unmet need for reliable alternative end points for clinical trials and daily clinical practice. To evaluate treatment response in patients with unresectable or metastatic hepatocellular carcinoma (mHCC), imaging-related end points are often used, whereas serologic end points have been developed for patients with serum alpha-fetoprotein levels >20 ng/mL. The objective of this study was to evaluate clinical trials that report concomitant assessment of radiographic and serologic response in patients with mHCC. METHODS After a systematic review, studies that evaluated response according to radiographic and serologic criteria were selected. A correlation between progression-free survival (PFS) and overall survival (OS) was performed, and a linear regression of each response-related outcome measure with OS was reported. Finally, the effect of eight baseline variables on OS and response-related measures was evaluated. RESULTS Twenty-six studies were included, including 16 first-line studies and 10 second-line studies. PFS and response rates demonstrated a significant relationship with OS, whereas disease control rates did not. The responses were correlated with OS, particularly in the first-line setting, after targeted therapy, and whenever assessment was early. Among the baseline variables, only performance status had a prognostic role, whereas hepatitis B virus-related liver disease was associated with higher radiographic response rates. CONCLUSIONS PFS and radiographic and serologic response rates appear to be reliable intermediate end points in patients with mHCC who are undergoing systemic antineoplastic therapy. However, the serologic response is available earlier.
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McEneaney LJ, Vithayathil M, Khan S. Screening, Surveillance, and Prevention of Hepatocellular Carcinoma. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:271-290. [DOI: 10.1002/9781119756422.ch16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abou-Alfa GK, Wang X, Parrinello CM, Gossai A, Kim R, Magee K, Miksad RA. Association between posttreatment α-fetoprotein reduction and outcomes in real-world US patients with advanced hepatocellular carcinoma. Cancer 2023; 129:2064-2074. [PMID: 36942492 DOI: 10.1002/cncr.34754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND Clinical trials suggest α-fetoprotein (AFP) reduction may be prognostic among patients with advanced hepatocellular carcinoma. However, the association of AFP reduction with outcomes in real-world settings is unclear. METHODS Patients with advanced hepatocellular carcinoma between January 1, 2011, and June 30, 2021, first-line tyrosine kinase inhibitor, and baseline and posttreatment AFP values (closest to 8 ± 2 weeks after first-line initiation) were included. AFP reduction was defined as ≥20% decrease from baseline vs <20% or no decrease. Real-world overall survival and progression-free survival (rwPFS) were defined as time from posttreatment AFP measurement to death, and the first progression event or death, respectively. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification by baseline AFP and hepatocellular carcinoma risk factors was assessed. RESULTS Among 533 patients, median baseline AFP was higher in those with AFP reduction than those without (N = 166, 210 µg/L vs N = 367, 150 µg/L). There was a 35% decrease in hazard of death for patients with reduction vs without (aHR = 0.65; 95% CI, 0.52-0.81; median, 10.3 vs 5.9 months). Results were similar for rwPFS (aHR = 0.66; 95% CI, 0.54-0.81; median, 4.6 vs 2.6 months). AFP reduction was associated with better outcomes among patients with baseline AFP ≥400 µg/L or with history of hepatitis B virus, hepatitis C virus, or alcohol use. Only the interaction between baseline AFP and reduction in association with rwPFS was statistically significant. CONCLUSIONS For certain etiologies, posttreatment AFP change may be more important than baseline AFP for prognosis. Further work should characterize the prognostic implications of longitudinal AFP changes during treatment. PLAIN LANGUAGE SUMMARY The prognostic value of the change in α-fetoprotein (AFP) concentration after treatment initiation is less established, particularly in real-world settings. Longitudinal data from a large nationwide cohort of patients with advanced hepatocellular carcinoma (HCC) treated with first-line tyrosine kinase inhibitor in routine practice revealed that ≥20% reduction in posttreatment AFP levels was associated with better real-world overall survival and progression-free survival after adjusting for baseline AFP levels and other factors. The results also suggested that the associations may be stronger among patients with a history of HCC risk factors (e.g., hepatitis C virus, alcohol) or with higher baseline AFP levels.
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Affiliation(s)
- Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, New York, USA
| | | | - Christina M Parrinello
- Flatiron Health, Inc., New York, New York, USA
- Pine Mountain Consulting, LLC, Redding, Colorado, USA
| | | | - Richard Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Kelly Magee
- Flatiron Health, Inc., New York, New York, USA
| | - Rebecca A Miksad
- Flatiron Health, Inc., New York, New York, USA
- Department of Hematology and Oncology, Boston Medical Center, Boston, Massachusetts, USA
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Kopystecka A, Patryn R, Leśniewska M, Budzyńska J, Kozioł I. The Use of ctDNA in the Diagnosis and Monitoring of Hepatocellular Carcinoma-Literature Review. Int J Mol Sci 2023; 24:ijms24119342. [PMID: 37298294 DOI: 10.3390/ijms24119342] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/18/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important limitations, especially in very small nodules and those which show atypical imaging features. In recent years, liquid biopsy and molecular analysis of tumor breakdown products have become an attractive source of new biomarkers. Patients with liver and biliary malignancies, including hepatocellular carcinoma (HCC), may greatly benefit from ctDNA testing. These patients are often diagnosed at an advanced stage of the disease, and relapses are common. Molecular analysis may indicate the best cancer treatment tailored to particular patients with specific tumor DNA mutations. Liquid biopsy is a minimally invasive technique that facilitates the early detection of cancer. This review summarizes the knowledge of ctDNA in liquid biopsy as an indicator for early diagnosis and monitoring of hepatocellular cancer.
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Affiliation(s)
- Agnieszka Kopystecka
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Rafał Patryn
- Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Magdalena Leśniewska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Julia Budzyńska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ilona Kozioł
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
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Tian BW, Yan LJ, Ding ZN, Liu H, Meng GX, Xue JS, Han CL, Dong ZR, Hong JG, Chen ZQ, Wang DX, Li T. Early alpha-fetoprotein response predicts prognosis of immune checkpoint inhibitor and targeted therapy for hepatocellular carcinoma: a systematic review with meta-analysis. Expert Rev Gastroenterol Hepatol 2023; 17:73-83. [PMID: 36476076 DOI: 10.1080/17474124.2022.2156859] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The prognostic value of alpha-fetoprotein (AFP) response for efficacy of targeted therapy or immune checkpoint inhibitors (ICIs) has not been established. The purpose of this meta-analysis is to elucidate the relationship between AFP response and survival outcomes in hepatocellular carcinoma (HCC) patients who received targeted therapy or ICIs. METHODS The hazard ratio (HR) with 95% confidence interval (CI) was used to evaluate the relationship between AFP response and overall survival (OS)/progression-free survival (PFS). RESULTS Twenty-six articles containing 3056 HCC patients were finally included in the study. The pooled results showed that after targeted therapy or ICIs, patients with decrease in AFP had better prognosis (OS:HR = 0.48, 95%CI:0.40-0.56; PFS:HR = 0.39, 95%CI:0.33-0.46), while patients with increase in AFP had worse prognosis (OS:HR = 2.30, 95%CI:1.82-2.89; PFS:HR = 2.34, 95%CI = 1.69-3.24). Subgroup analysis revealed that compared to AFP decrease >50%, AFP decrease >20% can better predict the prognosis of patients who received targeted therapy (OS:HR = 0.51, 95%CI:0.41-0.62; PFS:HR = 0.39, 95%CI:0.30-0.51) or ICIs treatment (OS:HR = 0.34, 95%CI:0.16-0.71; PFS:HR = 0.22, 95%CI:0.10-0.47), and 8 weeks after targeted therapy may be the appropriate time point for AFP assessment. CONCLUSION AFP decrease >20% within 8 weeks may be the appropriate definition for early AFP response which probably works best in predicting the efficacy of therapy. REGISTRATION The review was not registered.
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Affiliation(s)
- Bao-Wen Tian
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Jun-Shuai Xue
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital, Shandong University, 250012, Jinan, P.R. China
| | - Tao Li
- Department of Hepatobiliary Surgery, the Second Hospital of Shandong University, 250012, Jinan P.R. China
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Shao G, Bai Y, Yuan X, Chen X, Gu S, Gu K, Hu C, Liang H, Guo Y, Wang J, Yen CJ, Lee VHF, Wang C, Widau RC, Zhang W, Liu J, Zhang Q, Qin S. Ramucirumab as second-line treatment in Chinese patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib (REACH-2 China): A randomised, multicentre, double-blind study. EClinicalMedicine 2022; 54:101679. [PMID: 36247923 PMCID: PMC9562926 DOI: 10.1016/j.eclinm.2022.101679] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND In the global REACH-2 study, ramucirumab significantly improved overall survival (OS) compared with placebo in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). REACH-2 China study aimed to evaluate the efficacy and safety of ramucirumab in Chinese patients with advanced HCC (NCT02435433). METHODS REACH-2 China was a randomised, double-blind, placebo-controlled, phase 3 study done at 31 centres in China between Sep 16, 2015, and March 15, 2021. Patients with advanced HCC and AFP ≥400 ng/mL after first-line sorafenib were randomly assigned (2:1) to receive ramucirumab 8 mg/kg intravenously or placebo Q2W, until disease progression or unacceptable toxicity. The primary endpoint was OS. Efficacy was assessed per intention-to-treat, and safety in patients who received any treatment. FINDINGS Of 104 Chinese patients enrolled (44 in the global study and 60 in the China extension study), 70 received ramucirumab and 34 received placebo. Median OS was 9·1 months in the ramucirumab group and 6·2 months in the placebo group (HR = 0·854 [95% CI: 0·536, 1·359]). The most common grade 3 or worse treatment-emergent adverse event were hypertension (5 [7·1%] of 70 patients in the ramucirumab group vs 1 [2.9%] of 34 in the placebo group), pneumonia (5 [7·1%] vs 1 [2·9%]), and hyponatraemia (4 [5·7%] vs 0 [0%]). INTERPRETATION Ramucirumab demonstrated clinically meaningful improvement in OS compared to placebo for Chinese patients with advanced HCC and elevated AFP, although lacking statistical superiority. Ramucirumab was well tolerated, with a manageable safety profile. The results are consistent with those of the global REACH-2 study, supporting a favourable risk-benefit profile for ramucirumab in this population. FUNDING Eli Lilly and Company, USA.
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Affiliation(s)
- Guoliang Shao
- Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yuxian Bai
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaomin Chen
- Department of Intervention Therapy, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Shanzhi Gu
- Department of Interventional Radiology, Hunan Cancer Hospital, Changsha, China
| | - Kangsheng Gu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Houjie Liang
- Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yabing Guo
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jufeng Wang
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | | | | | | | | | | | - Shukui Qin
- Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
- Corresponding author at: Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing 210002, China.
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Zhu AX, Dayyani F, Yen CJ, Ren Z, Bai Y, Meng Z, Pan H, Dillon P, Mhatre SK, Gaillard VE, Hernandez S, Kelley RK, Sangro B. Alpha-Fetoprotein as a Potential Surrogate Biomarker for Atezolizumab + Bevacizumab Treatment of Hepatocellular Carcinoma. Clin Cancer Res 2022; 28:3537-3545. [PMID: 35435967 PMCID: PMC9662926 DOI: 10.1158/1078-0432.ccr-21-3275] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/15/2021] [Accepted: 04/13/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Atezolizumab + bevacizumab is the new standard of care for systemic treatment-naïve, unresectable hepatocellular carcinoma (HCC). This exploratory study investigated on-treatment alpha-fetoprotein (AFP) response as a potential surrogate biomarker of prognosis for the combination therapy. EXPERIMENTAL DESIGN Data from Group A of the phase Ib GO30140 study were used to identify the optimal time for AFP measurement and AFP cutoffs to differentiate patients by their best confirmed response per independent review facility-assessed RECIST (IRF-RECIST) version 1.1: responders from nonresponders and patients with disease control from primary progressors. We applied these cutoffs to independent data from the atezolizumab + bevacizumab arm of the phase III IMbrave150 trial to distinguish patients based on (i) overall survival (OS) and progression-free survival (PFS) per IRF-RECIST 1.1 and (ii) best confirmed response per IRF-RECIST 1.1. RESULTS We derived AFP cutoffs of ≥75% decrease and ≤10% increase from baseline at 6 weeks to identify responders and those who had disease control, respectively. These cutoffs had high sensitivity and specificity in GO30140. In IMbrave150 patients, sensitivity was 0.59 and specificity was 0.86 for the ≥75% decrease AFP cutoff; the sensitivity was 0.77 and specificity was 0.44 for the ≤10% increase AFP cutoff. Both AFP cutoffs were associated with longer OS and PFS, particularly in patients with hepatitis B virus etiology (HR < 0.5; P < 0.01). CONCLUSIONS AFP response at 6 weeks after initiating treatment is a potential surrogate biomarker of prognosis for patients with HCC receiving atezolizumab + bevacizumab. See related commentary by Cappuyns and Llovet, p. 3405.
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Affiliation(s)
- Andrew X. Zhu
- Jiahui International Cancer Center, Jiahui International Hospital, Shanghai, P.R. China.,Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.,Corresponding Author: Andrew X. Zhu, Jiahui International Cancer Center, Jiahui International Hospital, Shanghai 200233, P.R. China. Phone: 86 (21) 5339 3217; E-mail:
| | - Farshid Dayyani
- Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, California
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Zhenggang Ren
- Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yuxian Bai
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, P.R. China
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Paul Dillon
- Personalized Health Care Real World Data Oncology, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Shivani K. Mhatre
- Personalized Health Care Real World Data Oncology, Genentech, Inc., South San Francisco, California
| | - Vincent E. Gaillard
- Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Sairy Hernandez
- US Medical Affairs, Genentech, Inc., South San Francisco, California
| | - Robin Kate Kelley
- Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, California
| | - Bruno Sangro
- Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
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11
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Zhang S, Zhong BY, Zhang L, Wang WS, Ni CF. Transarterial chemoembolization failure/refractoriness: A scientific concept or pseudo-proposition. World J Gastrointest Surg 2022; 14:528-537. [PMID: 35979416 PMCID: PMC9258238 DOI: 10.4240/wjgs.v14.i6.528] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/08/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Abstract
Multi-session transarterial chemoembolization (TACE) is usually needed for the treatment of intermediate-stage hepatocellular carcinoma (HCC), but it may not always have a positive influence on prognosis due to high heterogeneity of HCC. To avoid ineffective repeated TACE, the concept of TACE failure/refractoriness has been proposed by several organizations and is being addressed using tyrosine kinase inhibitors. The concept of TACE failure/refractoriness is controversial due to ambiguous definitions and low evidence-based data. To date, only a few studies have examined the rationality concerning the definition of TACE failure/refractoriness, although the concept has been introduced and applied in many TACE-related clinical trials. This review focuses on some of the issues related to different versions of TACE failure/refractoriness, the rationality of related definitions, and the feasibility of continuing TACE after so-called failure/refractoriness based on published evidence. A suggestion to re-define TAEC failure/refractoriness is also put forward.
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Affiliation(s)
- Shen Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Bin-Yan Zhong
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Lei Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Wan-Sheng Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Cai-Fang Ni
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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12
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Zhai J, Liu J, Fu Z, Bai S, Li X, Qu Z, Sun Y, Ge R, Xue F. Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study. J Gastrointest Oncol 2022; 13:1278-1288. [PMID: 35837155 DOI: 10.21037/jgo-22-404] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/09/2022] [Indexed: 12/24/2022] Open
Abstract
Background There is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients. Methods This study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared. Results The incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1-30.9) vs. 29.7 (95% CI: 21.4-38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1-16.3) vs. 15.9 (95% CI: 8.3-23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9-9.2) vs. 8.0 (95% CI: 5.1-10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380). Conclusions Regorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14-22% and 62-60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.
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Affiliation(s)
- Jian Zhai
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jianwei Liu
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zhigang Fu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Shilei Bai
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xiaowei Li
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zengqiang Qu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yanfu Sun
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ruiliang Ge
- Department of Outpatient, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Feng Xue
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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13
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Falette Puisieux M, Pellat A, Assaf A, Ginestet C, Brezault C, Dhooge M, Soyer P, Coriat R. Therapeutic Management of Advanced Hepatocellular Carcinoma: An Updated Review. Cancers (Basel) 2022; 14:cancers14102357. [PMID: 35625962 PMCID: PMC9139863 DOI: 10.3390/cancers14102357] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/06/2022] [Accepted: 05/08/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child-Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy.
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Affiliation(s)
- Manon Falette Puisieux
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
- Correspondence: ; Tel.: +33-1-58-41-19-52
| | - Anna Pellat
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
| | - Antoine Assaf
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
| | - Claire Ginestet
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
| | - Catherine Brezault
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
| | - Marion Dhooge
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
| | - Philippe Soyer
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
- Radiology Department, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Unit, Cochin Hospital, AP-HP Centre, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (A.A.); (C.G.); (C.B.); (M.D.); (R.C.)
- Faculté de Médecine, Université Paris Cité, 75006 Paris, France;
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14
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Song S, Bai M, Li X, Gong S, Yang W, Lei C, Tian H, Si M, Hao X, Guo T. Early Predictive Value of Circulating Biomarkers for Sorafenib in Advanced Hepatocellular Carcinoma. Expert Rev Mol Diagn 2022; 22:361-378. [PMID: 35234564 DOI: 10.1080/14737159.2022.2049248] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. AREAS COVERED This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to Aug 15, 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. EXPERT OPINION The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or non-invasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future.
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Affiliation(s)
- Shaoming Song
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Mingzhen Bai
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xiaofei Li
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Shiyi Gong
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Wenwen Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Caining Lei
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Hongwei Tian
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Moubo Si
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Tiankang Guo
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
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15
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Choucair K, Kamran S, Saeed A. Clinical Evaluation of Ramucirumab for the Treatment of Hepatocellular Carcinoma (HCC): Place in Therapy. Onco Targets Ther 2022; 14:5521-5532. [PMID: 35002257 PMCID: PMC8721285 DOI: 10.2147/ott.s268309] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma remains one of the leading causes of death from cancer worldwide as most cases are diagnosed at an advanced disease stage. Ramucirumab, a human anti-VEGFR-2 monoclonal antibody, is approved as a monotherapy for the treatment of patients with hepatocellular carcinoma and α-fetoprotein levels ≥400 ng/mL previously treated with sorafenib. As most patients present with an advanced disease, patients with α-fetoprotein levels ≥400 ng/mL have an aggressive disease and a poor prognosis, making ramucirumab an important treatment option for this subgroup of patients. This article provides a comprehensive review of the clinical efficacy of ramucirumab as highlighted in the two major trials that lead to its approval. We also briefly review the agent pharmacologic properties, as well as its safety and toxicity profile, before discussing certain limitations and challenges associated with ramucirumab use. Finally, we review completed and ongoing clinical trials and focus on those involving ramucirumab-based combinations, namely with immune therapy.
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Affiliation(s)
- Khalil Choucair
- Department of Medicine, Kansas University School of Medicine, Wichita, KS, USA
| | - Syed Kamran
- Department of Medicine, Kansas University School of Medicine, Wichita, KS, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS, USA
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16
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Moldogazieva NT, Zavadskiy SP, Sologova SS, Mokhosoev IM, Terentiev AA. Predictive biomarkers for systemic therapy of hepatocellular carcinoma. Expert Rev Mol Diagn 2021; 21:1147-1164. [PMID: 34582293 DOI: 10.1080/14737159.2021.1987217] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers.Areas covered: Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy.Expert opinion: There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.
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Affiliation(s)
- Nurbubu T Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.m. Sechenov First Moscow State Medical University (Sechenov University);, Moscow, Russia
| | - Sergey P Zavadskiy
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Susanna S Sologova
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Innokenty M Mokhosoev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
| | - Alexander A Terentiev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
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17
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Yang DS, Park S, Rim CH, Yoon WS, Shin IS, Lee HA. Salvage External Beam Radiotherapy after Incomplete Transarterial Chemoembolization for Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1000. [PMID: 34684036 PMCID: PMC8539441 DOI: 10.3390/medicina57101000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/18/2021] [Accepted: 09/19/2021] [Indexed: 12/12/2022]
Abstract
Background and objective: Although transarterial chemoembolization (TACE) has been the commonest local modality for hepatocellular carcinoma (HCC), incomplete repsonse occurs especially for tumors with a large size or difficult tumor accessment. The present meta-analysis assessed the efficacy and feasibility of external beam radiotherapy (EBRT) as a salvage modality after incomplete TACE. Materials and Methods: We systematically searched the PubMed, Embase, Medline, and Cochrane databases. The primary endpoint was overall survival (OS), and the secondary endpoints included the response ratem toxicity of grade 3, and local control. Results: Twelve studies involving 757 patients were included; the median of portal vein thrombosis rate was 25%, and the pooled median of tumor size was 5.8 cm. The median prescribed dose ranged from 37.3 to 150 Gy (pooled median: 54 Gy in *EQD2). The pooled one- and two-year OS rates were 72.3% (95% confidence interval (CI): 60.2-81.9%) and 50.5% (95% CI: 35.6-65.4%), respectively; the pooled response and local control rates were 72.2% (95% CI: 65.4-78.1%) and 86.6 (95% CI: 80.1-91.2%) respectively. The pooled rates of grade ≥3 gastrointestinal toxicity, radiation-induced liver disease, hepatotoxicity, and hematotoxicity were 4.1%, 3.5%, 5.7%, and 4.9%, respectively. Local control was not correlated with intrahepatic (p = 0.6341) or extrahepatic recurrences (p = 0.8529) on meta-regression analyses. Conclusion: EBRT was feasible and efficient in regard to tumor response and control; after incomplete TACE. Out-field recurrence, despite favorable local control, necessitates the combination of EBRT with systemic treatments. *Equivalent dose in 2 Gy per fraction scheme.
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Affiliation(s)
- Dae Sik Yang
- Department of Radiation Oncology, Korea University Medical College, Seoul 02841, Korea; (D.S.Y.); (W.S.Y.)
- Department of Radiation Oncology, Korea University Guro Hospital, Seoul 08308, Korea
| | - Sunmin Park
- Department of Radiation Oncology, Korea University Ansan Hospital, Ansan 15355, Korea;
| | - Chai Hong Rim
- Department of Radiation Oncology, Korea University Medical College, Seoul 02841, Korea; (D.S.Y.); (W.S.Y.)
- Department of Radiation Oncology, Korea University Ansan Hospital, Ansan 15355, Korea;
| | - Won Sup Yoon
- Department of Radiation Oncology, Korea University Medical College, Seoul 02841, Korea; (D.S.Y.); (W.S.Y.)
- Department of Radiation Oncology, Korea University Ansan Hospital, Ansan 15355, Korea;
| | - In-Soo Shin
- Graduate School of Education, AI Convergence Education, Dongguk University, Seoul 04620, Korea;
| | - Han Ah Lee
- Department of Gastroenterology, Anam Hospital, Korea University Medical College, Seoul 02841, Korea;
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18
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Reductions in AFP and PIVKA-II can predict the efficiency of anti-PD-1 immunotherapy in HCC patients. BMC Cancer 2021; 21:775. [PMID: 34218801 PMCID: PMC8254996 DOI: 10.1186/s12885-021-08428-w] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 05/27/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Few biomarkers can predict the efficiency of PD-1 blockade in patients with hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic role of AFP and PIVKA-II in HCC patients receiving anti-PD-1 immunotherapy. METHODS A total of 235 HCC patients treated with PD-1 blockade were enrolled. Serum AFP and PIVKA-II levels were collected before and after treatments. The patients were divided into groups based on the reduction in AFP and PIVKA-II: AFP reduction ≤50% vs AFP reduction > 50% and PIVKA-II reduction ≤50% vs PIVKA-II reduction > 50%. The primary endpoints included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Binary logistic regression analyses were used to explore the related factors of ORR. A Cox proportional hazards model was employed to identify the potential prognostic factors of PFS and OS. RESULTS Among all the patients, 34.9% (82/235) achieved a complete or partial response. There was a positive correlation between AFP reduction > 50% or PIVKA-II reduction> 50% and the ORR of PD-1 blockade (P < 0.001 and = 0.003). PFS was significantly improved in patients with AFP reduction > 50% and PIVKA-II reduction > 50% (p < 0.001 and = 0.021). In addition, AFP reduction > 50% and PIVKA-II reduction> 50% were positively correlated with longer OS (p = 0.003 and 0.006). CONCLUSION Early reductions in AFP and PIVKA-II can be predictors of the efficacy of PD-1 blockade in HCC patients.
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19
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Meng Z, Ren Q, Zhong G, Li S, Chen Y, Wu W, Feng Y, Mao M, Zhang F, Long G. Noninvasive Detection of Hepatocellular Carcinoma with Circulating Tumor DNA Features and α-Fetoprotein. J Mol Diagn 2021; 23:1174-1184. [PMID: 34182124 DOI: 10.1016/j.jmoldx.2021.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 04/27/2021] [Accepted: 06/08/2021] [Indexed: 01/05/2023] Open
Abstract
Liver cancer is the fifth-most common cancer worldwide, with the third-highest rate of cancer-related mortality. Hepatocellular carcinoma (HCC) is the leading pathologic subtype, contributing 85% to 90% of cases of primary liver cancer. Most HCC patients are diagnosed at an advanced stage at which treatment is not curative. This study assessed the performance of a newly developed blood-based assay that utilizes genomic features and protein markers for the early detection of HCC. Two cancer-associated hallmarks, copy-number aberrations (CNA) and fragment size (FS), were characterized by shallow whole-genome sequencing of cell-free DNA and utilized to differentiate cancer patients from healthy subjects. As a clinically implemented biomarker of HCC, plasma α-fetoprotein (AFP) was also used with the genomic surrogates to optimize the detection of HCCs. The sensitivity of AFP ≥20.0 μg/L in detecting HCC was 57.9%. The combined genomic classifier CNA + FS via cell-free DNA shallow whole-genome sequencing identified nearly half of AFP-negative HCC patients (43.8%). By integrating CNA, FS as well as AFP (HCCseek), 75.0% sensitivity was achieved at 98.0% specificity, resulting in 92.6% accuracy, with 58.6% sensitivity in stage I HCC. The quantitative output of HCCseek was correlated with the severity of the disease (tumor size, stage, and recurrence-free survival). In summary, this study describes an efficient, noninvasive, and cost-effective method to detect HCC.
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Affiliation(s)
- Zuowei Meng
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Qingqi Ren
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Guolin Zhong
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Shiyong Li
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Yan Chen
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Wei Wu
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Yumin Feng
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Mao Mao
- Research & Development, SeekIn Inc., Shenzhen, China; Yonsei Song-Dang Institute for Cancer Research, Yonsei University, Seoul, Republic of Korea.
| | - Feng Zhang
- Research & Development, SeekIn Inc., Shenzhen, China.
| | - Guanghui Long
- Peking University Shenzhen Hospital, Shenzhen, China
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Cho YY, Yu SJ, Lee HW, Kim DY, Kang W, Paik YH, Sung PS, Bae SH, Park SC, Doh YS, Kim KM, Jang ES, Kim IH, Kim W, Kim YJ. Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study. J Hepatocell Carcinoma 2021; 8:613-623. [PMID: 34169044 PMCID: PMC8219232 DOI: 10.2147/jhc.s304439] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIM Sorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment. METHODS This multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles. RESULTS The patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001). CONCLUSION This large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.
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Affiliation(s)
- Young Youn Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Pil Soo Sung
- Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Su Cheol Park
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Young Seok Doh
- Department of Internal Medicine, Eulji University Hospital, Daejeon, Korea
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Sun Jang
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Cheongju-si, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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21
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Marasco G, Poggioli F, Colecchia A, Cabibbo G, Pelizzaro F, Giannini EG, Marinelli S, Rapaccini GL, Caturelli E, Di Marco M, Biasini E, Marra F, Morisco F, Foschi FG, Zoli M, Gasbarrini A, Svegliati Baroni G, Masotto A, Sacco R, Raimondo G, Azzaroli F, Mega A, Vidili G, Brunetto MR, Nardone G, Alemanni LV, Dajti E, Ravaioli F, Festi D, Trevisani F. A Nomogram-Based Prognostic Model for Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib: A Multicenter Study. Cancers (Basel) 2021; 13:2677. [PMID: 34072309 PMCID: PMC8199276 DOI: 10.3390/cancers13112677] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Patients in the ITA.LI.CA database treated with Sorafenib and updated on 30 June 2019 were included. Demographic and clinical data before starting Sorafenib treatment were considered. For the evaluation of predictive factors for OS, a time-dependent Cox proportional hazard model was used. A total of 1107 patients were included in our analysis. The mean age was 64.3 years and 81.7% were male. Most patients were staged as BCLC B (205, 18.9%) or C (706, 65.1%). The median time of Sorafenib administration was 4 months (interquartile range (IQR) 2-12), and the median OS was 10 months (IQR: 4-20). A total of 263 patients (33.8%) out of 780 with available evaluation experienced objective tumoral response to Sorafenib. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (hazard ratio (HR) 1.284), maximum tumoral diameter (HR 1.100), plasma total bilirubin (HR 1.119), aspartate amino transferase assessed as multiple of the upper normal value (HR 1.032), alpha-fetoprotein ≥200 ng/mL (HR 1.342), hemoglobin (HR 0.903) and platelet count (HR 1.002) were associated with OS at multivariate Cox regression analysis. Drug response was predicted by maximum tumoral diameter and platelet count. A novel prognostic nomogram for patients undergoing Sorafenib is hereby proposed. The novelty introduced is the comprehensive patient's assessment using common markers of patient's general status, liver damage and function and HCC biology. Further studies are required to test its accuracy and provide external validation.
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Affiliation(s)
- Giovanni Marasco
- Division of Internal Medicine and Digestive Pathophysiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Francesco Poggioli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Antonio Colecchia
- Gastroenterology Unit, Borgo Trento University Hospital Verona, 37126 Verona, Italy;
| | - Giuseppe Cabibbo
- Gastroenterology & Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, University of Palermo, 90133 Palermo, Italy;
| | - Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy;
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Gian Ludovico Rapaccini
- Division of Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | | | | | - Elisabetta Biasini
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy;
| | - Fabio Marra
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50139 Florence, Italy;
| | - Filomena Morisco
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Napoli “Federico II”, 80138 Napoli, Italy;
| | | | - Marco Zoli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Internal Medicine, Neurovascular and Hepatometabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine and Gastroenterology, Policlinico Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | | | - Alberto Masotto
- Gastroenterology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, 37024 Verona, Italy;
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, 71100 Foggia, Italy;
| | - Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University of Messina, 98124 Messina, Italy;
| | - Francesco Azzaroli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Mega
- Division of Gastroenterology, Bolzano Regional Hospital, 39100 Bolzano, Italy;
| | - Gianpaolo Vidili
- U.O.C. Clinica Medica, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, 07100 Sassari, Italy;
| | - Maurizia Rossana Brunetto
- Hepatology and Liver Physiopathology Laboratory and Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy;
| | - Gerardo Nardone
- Hepato-Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Luigina Vanessa Alemanni
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Elton Dajti
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Davide Festi
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Franco Trevisani
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Semeiotics, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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22
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Hong YM, Yoon KT, Cho M. Systemic immune-inflammation index predicts prognosis of sequential therapy with sorafenib and regorafenib in hepatocellular carcinoma. BMC Cancer 2021; 21:569. [PMID: 34006248 PMCID: PMC8130266 DOI: 10.1186/s12885-021-08124-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 03/29/2021] [Indexed: 12/26/2022] Open
Abstract
Background Regorafenib has shown promising results as a second-line therapy for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib. Although there have been several data regarding the efficacy of sequential therapy with sorafenib and that of regorafenib in real-life, specific inflammation markers for predicting the prognosis have not been studied. This study aimed to investigate prognostic value of systemic inflammatory markers in patients with HCC who received sorafenib-regorafenib sequential therapy. Methods We retrospectively analyzed medical data of patients who received regorafenib for the treatment of HCC after sorafenib failure. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier survival curves. Univariate and multivariate analyses were performed to analyze the factors associated with survival. Results A total of 58 patients who received at least one dose of regroafenib and fulfilled the eligibility criteria, good performance status (Eastern Cooperative Oncology Group [ECOG] 0–1) and preserved liver function (Child-Pugh-A), were included in the analysis. The median PFS was 3 months (95% confidence interval [CI] = 0.981–5.019) and the median OS was 8 months (95% CI = 5.761–10.239). Elevated systemic immune-inflammation index (SII ≥340) was independently associated with poor OS. In multivariate analysis, the SII (hazard ratio [HR] = 2.211, 95% CI = 1.089–4.489, P = 0.028) and alpha-fetoprotein (AFP) (HR = 2.750, 95% CI = 1.259–6.010, P = 0.011) were independent predictors of OS. Conclusion Elevated SII is associated with poor OS in patients with HCC who received sequential therapy with sorafenib and regorafenib. In addition, when selecting a treatment strategy, the SII can be used in combination with the AFP level as a promising prognostic tool for HCC.
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Affiliation(s)
- Young Mi Hong
- Department of Internal Medicine, Liver Center, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, 20 Geumo-ro, Gyeongnam, 50612, Yangsan, South Korea
| | - K T Yoon
- Department of Internal Medicine, Liver Center, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, 20 Geumo-ro, Gyeongnam, 50612, Yangsan, South Korea
| | - Mong Cho
- Department of Internal Medicine, Liver Center, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, 20 Geumo-ro, Gyeongnam, 50612, Yangsan, South Korea.
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23
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Zhu AX, Finn RS, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Motomura K, Ohno I, Daniele B, Vogel A, Yamashita T, Hsu CH, Gerken G, Bilbruck J, Hsu Y, Liang K, Widau RC, Wang C, Abada P, Kudo M. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer 2021; 124:1388-1397. [PMID: 33531690 PMCID: PMC8039038 DOI: 10.1038/s41416-021-01260-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/11/2020] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). METHODS Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. RESULTS Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001). CONCLUSIONS AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Boston, MA, USA.
- Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
| | - Richard S Finn
- Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Chia-Jui Yen
- National Cheng Kung University Hospital, Tainan, Taiwan
| | | | - Josep M Llovet
- Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institut d'Investigations Biomèdiques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Eric Assenat
- Department of Medical Oncology, CHU de Montpellier, Montpellier, France
| | | | | | - Izumi Ohno
- National Cancer Center Hospital East-Hepatobiliary and Pancreatic Oncology, Kashiwa, Japan
| | - Bruno Daniele
- Azienda Ospedaliera Gaetano Rummo, Benevento, Italy
- Ospedale del Mare, Napoli, Italy
| | - Arndt Vogel
- Medizinische Hochschule Hannover, Hannover, Germany
| | | | - Chih-Hung Hsu
- National Taiwan University Hospital, Taipei, Taiwan, ROC
| | | | | | - Yanzhi Hsu
- Eli Lilly and Company, New York, NY, USA
| | - Kun Liang
- Eli Lilly and Company, Branchburg, NJ, USA
| | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, IN, USA
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24
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Reig M, Galle PR, Kudo M, Finn R, Llovet JM, Metti AL, Schelman WR, Liang K, Wang C, Widau RC, Abada P, Zhu AX. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int 2021; 41:598-607. [PMID: 33188713 PMCID: PMC7898500 DOI: 10.1111/liv.14731] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/23/2020] [Accepted: 11/08/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. METHODS Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. RESULTS Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. CONCLUSIONS The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.
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Affiliation(s)
- Maria Reig
- Barcelona Clinic Liver Cancer Group, Liver UnitHospital Clínic of Barcelona. IDIBAPS. CIBERehd. University of BarcelonaBarcelonaSpain
| | - Peter R. Galle
- Department of Internal MedicineMainz University Medical CenterMainzGermany
| | - Masatoshi Kudo
- Departments of Gastroenterology and HepatologyKindai University Faculty of MedicineOsakaJapan
| | - Richard Finn
- Division of Hematology/OncologyUniversity of CaliforniaLos AngelesCAUSA
| | - Josep M. Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNYUSA
- Translational Research in Hepatic Oncology, Liver UnitIDIBAPS, Hospital Clinic Barcelona, University of BarcelonaBarcelonaSpain
- Institució Catalana d’Estudis Avançats (ICREA)BarcelonaSpain
| | | | | | - Kun Liang
- Eli Lilly and CompanyBranchburgNJUSA
| | | | | | | | - Andrew X. Zhu
- Massachusetts General Hospital Cancer CenterHarvard Medical SchoolBostonMAUSA
- Jiahui International Cancer CenterJiahui HealthShanghaiChina
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25
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Risk Factors and Biomarkers for Chronic Hepatitis B Associated Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22020479. [PMID: 33418899 PMCID: PMC7825109 DOI: 10.3390/ijms22020479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 02/08/2023] Open
Abstract
Globally, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality. This is, in part, due to delayed diagnosis and limited therapeutic options with more advanced stages of the disease. Given the prognostic importance of early diagnosis, novel methods for early detection are in need. Unlike most other cancer types, tissue is not required to diagnose HCC and is frequently avoided given the inherent risks of liver biopsy, so less invasive methods of obtaining tumor material are currently under investigation. Material shed from tumors into the periphery are being investigated for their potential to both surveil and diagnose patients for HCC. These materials include circulating tumor cells, DNA, RNA, and exosomes, and are collectively termed a “liquid biopsy”. In this review article, we discuss the evolving literature regarding the different risk factors for HCC and the types of emerging novel biomarkers that show promise in the prevention and early diagnosis of HCC within the context of HBV infection.
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26
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Ahmed S, Gordon L, Dueck DA, Souied O, Haider K. Current status of systemic therapy in hepatocellular cancer. Dig Liver Dis 2020; 53:S1590-8658(20)30933-6. [PMID: 34756361 DOI: 10.1016/j.dld.2020.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022]
Abstract
Hepatocellular cancer (HCC) is a common cancer and an important cause of cancer-related death globally. Although surgery is the primary curative treatment, most patients at diagnosis are not surgical candidates and are treated with liver-directed therapy and or systemic therapy. Over the past decade, the systemic treatment options for patients with advanced HCC have evolved. This paper reviews recent progress in systemic therapy and the results of major clinical trials involving novel compounds in patients with HCC. A literature search was performed using keywords related to HCC and systemic therapy. The evidence shows that at the present time an effective adjuvant systemic therapy is not available for patients with early-stage HCC following surgery. In patients with advanced HCC, in addition to sorafenib at least four other targeted agents and several immune checkpoint inhibitors, alone or in combination have been shown to be associated with improved progression-free and overall survival. The optimal sequence of agents, is currently not known, and is determined by patient characteristics, toxicities profile, patients and physicians preference. The future identification of novel active agents and predictive biomarkers are vital to personalize systemic therapy in HCC.
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Affiliation(s)
- Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK Canada.
| | - Lexis Gordon
- Department of Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK Canada
| | - Dorie-Anna Dueck
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK Canada
| | - Osama Souied
- Allan Blair Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Regina, SK, Canada
| | - Kamal Haider
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK Canada
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27
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Yen CJ, Kudo M, Lim HY, Hsu CH, Vogel A, Brandi G, Cheng R, Nitu IS, Abada P, Hsu Y, Zhu AX, Kang YK. Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies. Liver Cancer 2020; 9:440-454. [PMID: 32999870 PMCID: PMC7506228 DOI: 10.1159/000506946] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/29/2020] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH. METHODS We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model. RESULTS In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive ramucirumab (n = 168) or placebo (n = 123), and 251 non-Asian patients received ramucirumab (n = 148) or placebo (n = 103). The median OS was significantly longer in the ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56-0.95], p = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49-0.86], p = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients. DISCUSSION AND CONCLUSION This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.
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Affiliation(s)
- Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ho-Yeong Lim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chih-Hung Hsu
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | - Giovanni Brandi
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Yanzhi Hsu
- TG Therapeutics Inc., New York, New York, USA
| | - Andrew X. Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,*Yoon-Koo Kang, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505 (South Korea),
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Brunetti O, Gnoni A, Licchetta A, Longo V, Calabrese A, Argentiero A, Delcuratolo S, Solimando AG, Casadei-Gardini A, Silvestris N. Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib. ACTA ACUST UNITED AC 2019; 55:medicina55100707. [PMID: 31640191 PMCID: PMC6843290 DOI: 10.3390/medicina55100707] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/16/2019] [Accepted: 10/16/2019] [Indexed: 12/13/2022]
Abstract
Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.
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Affiliation(s)
- Oronzo Brunetti
- Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonio Gnoni
- Medical Oncology Unit, "S. Cuore di Gesù" Hospital, 73014 Gallipoli, Italy.
| | | | - Vito Longo
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
| | - Angela Calabrese
- Radiology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonella Argentiero
- Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
| | - Sabina Delcuratolo
- Scientific Direction, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonio Giovanni Solimando
- Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine "G. Baccelli", University of Bari Medical School, 70124 Bari, Italy.
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, IstitutoScientifico Romagnolo per Lo Studio e Cura Dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
- Department of Oncology and Haematology, University Hospital of Modena, 41125 Modena, Italy.
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", 70124 Bari, Italy.
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Mokdad AA, Zhu H, Beg MS, Arriaga Y, Dowell JE, Singal AG, Yopp AC. Efficacy and Safety of Bavituximab in Combination with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Clinical Trial. Target Oncol 2019; 14:541-550. [DOI: 10.1007/s11523-019-00663-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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He C, Peng W, Liu X, Li C, Li X, Wen TF. Post-treatment alpha-fetoprotein response predicts prognosis of patients with hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2019; 98:e16557. [PMID: 31374020 PMCID: PMC6709300 DOI: 10.1097/md.0000000000016557] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Post-treatment alpha-fetoprotein (AFP) response has been reported to be associated with prognosis of hepatocellular carcinoma (HCC) patients, but the results were not consistent. This meta-analysis aimed to explore the relationship between AFP response and clinical outcomes of HCC. METHODS PubMed, Embase, Medline and Cochrane library were searched for relevant articles published before March 20, 2019. The data were analyzed using RevMan5.3 software. RESULTS Twenty-nine articles with 4726 HCC patients were finally included for analysis. The pooled results showed that post-treatment AFP response was significantly associated with overall survival (OS) (hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.35-0.47, P <.001), progression free survival (PFS) (HR = 0.46, 95% CI: 0.39-0.54, P <.001) and recurrence free survival (RFS) (HR = 0.41, 95% CI: 0.29-0.56, P <.001) of HCC patients. CONCLUSION post-treatment AFP response might be a useful prognostic marker for HCC patients.
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Affiliation(s)
- Chao He
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University
| | - Wei Peng
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University
| | - Xiaojuan Liu
- Department of Anesthesia, West China Hospital of Sichuan University
| | - Chuan Li
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University
| | - Xueting Li
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, China
| | - Tian-Fu Wen
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University
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Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20:282-296. [PMID: 30665869 DOI: 10.1016/s1470-2045(18)30937-9] [Citation(s) in RCA: 1219] [Impact Index Per Article: 203.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 12/01/2018] [Accepted: 12/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. METHODS REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. FINDINGS Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). INTERPRETATION REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma. FUNDING Eli Lilly.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital Tainan, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Richard S Finn
- Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Josep M Llovet
- Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institut d'Investigations Biomèdiques, August Pi i Sunyer-Hospital Clinic Barcelona, Barcelona, Spain
| | | | | | | | - Ho Yeong Lim
- Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Kun-Ming Rau
- Chang Gung Memorial Hospital-Kaohsiung Branch, Kaohsiung City, Taiwan; Hematology-Oncology Department, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | | | - Izumi Ohno
- National Cancer Center Hospital East-Hepatobiliary and Pancreatic Oncology, Kashiwa, Chiba, Japan
| | | | - Bruno Daniele
- Azienda Ospedaliera G Rummo, Benevento, Benevento, Italy; Ospedale del Mare, Naples, Italy
| | - Dong Bok Shin
- Gachon University Gil Medical Center, Incheon, South Korea
| | - Guido Gerken
- Universtitätsklinikum Essen AöR, Essen, North Rhine-Westphalia, Germany
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Marisi G, Cucchetti A, Ulivi P, Canale M, Cabibbo G, Solaini L, Foschi FG, De Matteis S, Ercolani G, Valgiusti M, Frassineti GL, Scartozzi M, Casadei Gardini A. Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers? World J Gastroenterol 2018; 24:4152-4163. [PMID: 30271080 PMCID: PMC6158485 DOI: 10.3748/wjg.v24.i36.4152] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/06/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) since 2007 and numerous studies have investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology, DI.BI.M.I.S., University of Palermo, Palermo 35628, Italy
| | - Leonardo Solaini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Francesco G Foschi
- Department of Internal Medicine, Degli Infermi Hospital, Faenza 48018, Italy
| | - Serena De Matteis
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
| | - Giovanni L Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
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Saeki I, Yamasaki T, Maeda M, Hisanaga T, Iwamoto T, Fujisawa K, Matsumoto T, Hidaka I, Marumoto Y, Ishikawa T, Yamamoto N, Suehiro Y, Takami T, Sakaida I. Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy. World J Hepatol 2018; 10:571-584. [PMID: 30310535 PMCID: PMC6177565 DOI: 10.4254/wjh.v10.i9.571] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/30/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.
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Affiliation(s)
- Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Masaki Maeda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takuro Hisanaga
- Department of Medical Education, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Koichi Fujisawa
- Center of Research and Education for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, 755-8505, Japan
| | - Toshihiko Matsumoto
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Isao Hidaka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Yoshio Marumoto
- Center for Clinical Research, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan
| | - Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Naoki Yamamoto
- Yamaguchi University Health Administration Center, Yamaguchi 753-8511, Japan
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
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Lipid profiling of pre-treatment plasma reveals biomarker candidates associated with response rates and hand-foot skin reactions in sorafenib-treated patients. Cancer Chemother Pharmacol 2018; 82:677-684. [PMID: 30062555 DOI: 10.1007/s00280-018-3655-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/23/2018] [Indexed: 12/17/2022]
Abstract
Sorafenib is a multi-kinase inhibitor for treatment of advanced hepatocellular carcinoma (HCC). Beyond its clinical benefit against advanced HCC, the efficacy and safety of sorafenib chemotherapy are critical concerns. In this study, we addressed the lipid profiles associated with the efficacy and safety of sorafenib chemotherapy. Plasma samples from HCC patients before sorafenib chemotherapy (N = 44) were collected and subjected to lipidomic analysis. We measured the levels of 176 lipids belonging to 8 classes of phosphoglycerolipids, 2 classes of sphingolipids, 3 classes of neutral lipids, and 4 other classes of lipids. To characterize lipids associated with efficacy, we compared the responder group (N = 21; partial response and stable disease) with non-responder group (N = 22; progressive disease). To characterize lipids associated with hand-foot skin reaction (HFSR), we compared the susceptible group (N = 12; grade 2 and 3) with non-susceptible group (N = 32; grade 0 and 1). The levels of 8 lipids, including phosphatidylcholine (PC)[34:2], PC[34:3]a, PC[35:2], PC[36:4]a, PC[34:3e], acylcarnitine (Car)[18:0], cholesterol ester[20:2], and diacylglycerol (DG)[34:2], were significantly lower in the responder group, and 6 out of 8 these lipids contained FA(18:2). In addition, the levels of 7 lipids (Car[12:0], Car[18:0], Car[18:1], Car[20:1] and fatty acid amides (FAA[16:0], FAA[18:0], and FAA[18:1]b)) were significantly lower in the group susceptible to HFSR. Our comprehensive lipidomics study using samples from sorafenib-treated patients with HCC revealed that significant differences in the lipid profiles of pre-treatment plasma were associated with sorafenib efficacy and sorafenib-induced HFSR. Validation using another set of patient plasma samples and elucidating the molecular basis of these changes will lead to better treatment with sorafenib chemotherapy.
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Chou WC, Lee CL, Yang TS, Huang CY, Teng W, Tseng YT, Chen JS, Lin YC, Hou MM, Chang HH, Chia-Hsun Hsieh J. Changes in serum α-fetoprotein level predicts treatment response and survival in hepatocellular carcinoma patients and literature review. J Formos Med Assoc 2018; 117:153-163. [PMID: 28392193 DOI: 10.1016/j.jfma.2017.03.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 03/11/2017] [Accepted: 03/16/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Oxaliplatin-based chemotherapy is an alternative systemic treatment for patients with metastatic hepatocellular carcinoma (HCC) who were refractory or intolerant to sorafenib. To date, there have been no biomarkers reported to monitor the therapeutic efficacy and to predict the outcomes of HCC patients receiving oxaliplatin-based chemotherapy. METHODS Eighty-one HCC patients with elevated baseline α-fetoprotein (AFP) levels and extrahepatic spreading who received oxaliplatin-based chemotherapy between 2012 and 2014 were retrospectively enrolled in this study. Two AFP tests were performed, at baseline and 2-4 weeks after the initiation of chemotherapy. The change in AFP levels was calculated for survival analysis. RESULTS In the AFP decline group (decreased compared to baseline), the median progression-free survival (PFS) and overall survival (OS) were 7.0 months and 12.3 months, respectively. In the AFP nondecline group, the median PFS and OS were 2.3 months and 3.0 months, respectively. The difference in OS between the two groups was significant (p < 0.005). In the multivariate analysis for disease progression, the best response to chemotherapy and AFP decline were independent factors, with p values of 0.004 and 0.009, respectively. In the multivariate analysis for OS, the baseline Child-Pugh score, best response to chemotherapy, and AFP decline were independent prognostic factors, with p values of 0.01, 0.001, and 0.008, respectively. Additionally, the unit change in AFP level was predictive of PFS and OS with p values of 0.007 and 0.001, respectively. CONCLUSION The change in AFP levels 2-4 weeks after initiating oxaliplatin-based chemotherapy is useful to predict treatment response and survival.
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Affiliation(s)
- Wen-Chi Chou
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Chia-Lin Lee
- Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tsai-Sheng Yang
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Chen-Yang Huang
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Wei Teng
- Chang Gung University, Taoyuan, Taiwan; Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ya-Ting Tseng
- Chang Gung University, Taoyuan, Taiwan; Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jen-Shi Chen
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Lin
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Ming-Mo Hou
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung University, Taoyuan, Taiwan
| | - Ho-Hsiang Chang
- Chang Gung University, Taoyuan, Taiwan; Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan
| | - Jason Chia-Hsun Hsieh
- Division of Medical Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Chemical and Materials Engineering, Chang Gung University, Taoyuan, Taiwan.
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Kong Y, Sun L, Hou Z, Zhang Y, Chen P, Cui Y, Zhu X, Song T, Li Q, Li H, Zhang T, Qin L. Apatinib is effective for treatment of advanced hepatocellular carcinoma. Oncotarget 2017; 8:105596-105605. [PMID: 29285275 PMCID: PMC5739662 DOI: 10.18632/oncotarget.22337] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 09/21/2017] [Indexed: 12/31/2022] Open
Abstract
As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow-up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy.
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Affiliation(s)
- Yinlong Kong
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Lin Sun
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Zhenyu Hou
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yongqiang Zhang
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Ping Chen
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yunlong Cui
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiaolin Zhu
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Tianqiang Song
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Qiang Li
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Huikai Li
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Ti Zhang
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
- Cancer Research Center, Institute of Biomedical Science, Fudan University, Shanghai 200032, China
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Changes of alpha-fetoprotein levels could predict recurrent hepatocellular carcinoma survival after trans-arterial chemoembolization. Oncotarget 2017; 8:85599-85611. [PMID: 29156744 PMCID: PMC5689634 DOI: 10.18632/oncotarget.20343] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 07/18/2017] [Indexed: 02/05/2023] Open
Abstract
Background There is paucity of information concerning whether AFP change is a predictor of prognosis for recurrent hepatocellular carcinoma (RHCC) patients after trans-arterial chemoembolization (TACE). Methods A total of 177 RHCC patients who received TACE as first-line therapy were retrospectively analyzed. The patients were classified into three groups according to their pre-TACE and post-TACE AFP levels (group A: AFP decreased, group B: AFP consistent normal, and group C: AFP increased). The recurrence to death survival (RTDS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared by the log-rank test. Multivariate analyses were performed to identify prognostic factors for OS and RTDS. Results There was no significant difference among the three groups concerning the baseline characteristics. The median overall survival (OS) was 74.5 months in group A (95% confidence interval (CI): 63.5, 85.6), 64.0 months in group B (95% CI: 52.3, 75.7) and 29.0 months in group C (95% CI: 24.1, 33.9; P<0.001). The median recurrence to death survival (RTDS) was 66.5 months (95% CI: 53.4, 79.6) in group A, 50.4 months (95% CI: 39.5, 61.4) in group B and 17.7 months (95% CI: 13.4, 22.1; P<0.001) in group C. Multivariate analysis revealed that tumor size at resection stage, tumor number at recurrent stage, cycles of TACE, mRECIST response and AFP change after TACE were significant independent risk factors for RTDS and OS. Conclusions AFP change could predict the prognoses of patients with RHCC who received trans-arterial chemoembolization, which may help clinicians make subsequent treatment decision.
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Guarino M, Di Costanzo GG, Gallotta A, Tortora R, Paneghetti L, Auriemma F, Tuccillo C, Fassina G, Caporaso N, Morisco F. Circulating SCCA-IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients. Scandinavian Journal of Clinical and Laboratory Investigation 2017; 77:448-453. [PMID: 28609160 DOI: 10.1080/00365513.2017.1336569] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) develops in about 3-4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy. MATERIALS AND METHODS From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T0) and after one month of treatment (T1). RESULTS At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th + 75th percentile] at T0:115.1 AU/mL [50.0 + 174.4] vs. 149.1 AU/mL [111.3 + 198.8]; median SCCA-IgM level [25th + 75th percentile] at T1: 113.4 AU/mL [50.0 + 194.2] vs. 170.6 AU/mL [111.7 + 344.2]). CONCLUSION Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC.
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Affiliation(s)
- Maria Guarino
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | | | | | - Raffaella Tortora
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | | | - Francesco Auriemma
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | - Concetta Tuccillo
- d Department of Clinical and Experimental Medicine 'F. Magrassi and A. Lanzara', Gastroenterology Unit , Second University of Naples , Naples , Italy
| | | | - Nicola Caporaso
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | - Filomena Morisco
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
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Tarakanovskaya MG, Chinburen J, Batchuluun P, Munkhzaya C, Purevsuren G, Dandii D, Hulan T, Oyungerel D, Kutsyna GA, Reid AA, Borisova V, Bain AI, Jirathitikal V, Bourinbaiar AS. Open-label Phase II clinical trial in 75 patients with advanced hepatocellular carcinoma receiving daily dose of tableted liver cancer vaccine, hepcortespenlisimut-L. J Hepatocell Carcinoma 2017; 4:59-69. [PMID: 28443252 PMCID: PMC5396941 DOI: 10.2147/jhc.s122507] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])—an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis. Methods The outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively. Over a period of 5 years, 75 patients with advanced HCC were enrolled, consisting of 29 (38.7%) females and 46 (61.3%) males with a median age of 60 years (mean 61.6±8.1 years). Out of these, 23 (30.7%) had hepatitis B and 34 (45.3%) had hepatitis C infections, including 9 (12%) with dual infection, 4 (5.3%) negative for both viruses, and 5 (6.7%) without established viral diagnosis. Most patients (94.7%) had underlying liver cirrhosis of varying severity. Results After a median of 2 months of treatment, 50 out of 75 patients had experienced a decline in serum levels of the tumor marker, alpha-fetoprotein (AFP) (66.7%; P=0.006 by Wilcoxon signed rank test). Baseline median AFP levels were 245.2 IU/mL (mean 4,233; range 7.2–92,407; 95% confidence interval [CI] 1,186–7,280) and post-treatment values were 102.3 IU/mL (mean 2,539; range 0.9–54,478; 95% CI 503–4,575). The decrease in AFP was correlated either with tumor clearance or regression on computed tomography scans. The median overall survival time could not be established since 68 out of 75 (90.7%) patients were still alive after median follow-up of 12 months (mean 15±9.7; range 7–59; 95% CI 12.8–17.2). The first patient in this study received immunotherapy 5 years ago and still remains in complete remission. None of the patients experienced any serious adverse effects or toxicity. Conclusion The results indicate that hepcortespenlismut-L is a safe, effective, and fast-acting immunomodulatory intervention for HCC. The Phase III, randomized, double-blind, placebo-controlled trial is now initiated at the Mongolian National Cancer Center to confirm these promising findings.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Galyna A Kutsyna
- Department of Infectious Diseases, Luhansk State Medical University, Luhansk, Ukraine
| | - Alan A Reid
- Immunitor China Ltd, Beijing, People's Republic of China
| | - Vika Borisova
- Immunitor China Ltd, Beijing, People's Republic of China
| | | | | | - Aldar S Bourinbaiar
- Immunitor China Ltd, Beijing, People's Republic of China.,Immunitor Inc, Vancouver, BC, Canada.,Immunitor LLC, Ulaanbaatar, Mongolia
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40
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Wu FX, Lu HR, Zhu SL, Li ZH, Zou L, Bai T, Chen J, Yang TB, Liang SX. Efficacy of three-dimensional conformal radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus. Onco Targets Ther 2016; 9:7141-7147. [PMID: 27942219 PMCID: PMC5138039 DOI: 10.2147/ott.s113161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Objective The current study aimed to evaluate the efficacy and outcomes of three-dimensional conformal radiotherapy (3DCRT) combined with transarterial chemoembolization (TACE) for treating patients with hepatocellular carcinoma involving portal vein tumor thrombus. Methods Between January 2000 and December 2013, a total of 182 hepatocellular carcinoma patients with portal vein tumor thrombus were retrospectively analyzed: 68 patients were treated by 3DCRT alone (group A), 74 by TACE alone (group B), and 40 by a combination of 3DCRT + TACE (group C). The overall survival (OS) of the three groups was compared using the Kaplan–Meier method. The independent predictors of survival were identified using multivariate analysis. Results The total effective rate (complete response + partial response) among all patients was 44% (80/182). The objective response rate (complete response + partial response) was higher in group C than in group A or B, but the differences were not significant. OS rates at 1, 2, and 3 years were significantly higher in group C than in group A or B (P<0.05), while OS rates were similar between groups A and B. Multivariate analysis identified serum levels of alpha-fetoprotein <400 ng/mL and the use of 3DCRT + TACE as independent predictors of better OS. Conclusion These results suggest that combining 3DCRT with TACE may provide better OS than either technique alone in hepatocellular carcinoma patients with portal vein tumor thrombus.
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Affiliation(s)
- Fei-Xiang Wu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning; Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Shanghai
| | - Hui-Rong Lu
- Department of Radiation Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Shao-Liang Zhu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Zi-Hui Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Ling Zou
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Tao Bai
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Jie Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Tian-Bo Yang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning
| | - Shi-Xiong Liang
- Department of Radiation Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning; Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Shiozawa K, Watanabe M, Ikehara T, Shimizu R, Shinohara M, Igarashi Y, Sumino Y. Evaluation of sorafenib for advanced hepatocellular carcinoma with low α-fetoprotein in arrival time parametric imaging using contrast-enhanced ultrasonography. J Med Ultrason (2001) 2016; 44:101-107. [PMID: 27837395 PMCID: PMC5222904 DOI: 10.1007/s10396-016-0757-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 10/11/2016] [Indexed: 02/06/2023]
Abstract
PURPOSE To determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating early response to sorafenib for hepatocellular carcinoma (HCC). METHODS Twenty-one advanced HCC patients with low α-fetoprotein (AFP) levels (≤35 ng/ml) who received sorafenib for at least 4 weeks were enrolled in this study. CEUS was performed before and 2 weeks after treatment, and the images of the target lesion in the arterial phase were analyzed by AtPI. In the color mapping images obtained by AtPI, the mean arrival time of the contrast agent in the target lesion from the reference point (mean time: MT) was calculated. In each patient, differences between MT before and MT 2 weeks after treatment were compared. MT (+) and MT (-) groups were defined as difference of 0 s or greater and less than 0 s, respectively. Overall survival was evaluated between the two groups. RESULTS In the MT (+) (11 patients) and MT (-) (10 patients) groups, the median survival time was 792 and 403 days, respectively, which was statistically significant. CONCLUSIONS The results suggested that AtPI was useful for evaluating early response to sorafenib for advanced HCC with low AFP level.
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Affiliation(s)
- Kazue Shiozawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Manabu Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.
| | - Takashi Ikehara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Ryo Shimizu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Mie Shinohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yasukiyo Sumino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Medical Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
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Sauzay C, Petit A, Bourgeois AM, Barbare JC, Chauffert B, Galmiche A, Houessinon A. Alpha-foetoprotein (AFP): A multi-purpose marker in hepatocellular carcinoma. Clin Chim Acta 2016; 463:39-44. [PMID: 27732875 DOI: 10.1016/j.cca.2016.10.006] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/05/2016] [Accepted: 10/06/2016] [Indexed: 12/13/2022]
Abstract
Alpha-foetoprotein (AFP), one of the first protein tumour markers discovered, is widely used today in clinical practice. Its application for the screening and diagnosis of hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, is a matter of extensive debate. In addition to the studies focused on the role of the AFP in the diagnosis of HCC, in recent years AFP has been used to guide the therapeutic choice in HCC and monitor the treatment. Here, we summarize the latest studies that show the interest of AFP quantification in determining the suitability of liver transplantation or to follow-up on patients receiving the targeted treatment sorafenib. We also highlight the recent studies showing the active role of AFP in tumour progression, and the new modes of regulation of this tumour marker. Among these is the regulation of AFP through tumour proteostasis and the Unfolded Protein Response (UPR). We discuss the implications of this new knowledge in the therapeutic context, in terms of interpreting serum levels of AFP, and the new perspectives offered by AFP for the study of tumour proteostasis.
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Affiliation(s)
- Chloé Sauzay
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France
| | - Alexandra Petit
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France
| | | | | | | | - Antoine Galmiche
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
| | - Aline Houessinon
- Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France
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Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G. Hepatocellular carcinoma. Nat Rev Dis Primers 2016; 2:16018. [PMID: 27158749 DOI: 10.1038/nrdp.2016.18] [Citation(s) in RCA: 1832] [Impact Index Per Article: 203.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies - resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches.
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Affiliation(s)
- Josep M Llovet
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, Madison Avenue 1425, 11F-70, Box 1123, New York, New York 10029, USA.,Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IDIBAPS - Hospital Clinic, CIBERehd, University of Barcelona, Catalonia, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Jessica Zucman-Rossi
- INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Haematologie, Paris, France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France.,Université Paris Diderot, Paris, France
| | - Eli Pikarsky
- Lautenberg Center for Immunology and Cancer Research and Department of Pathology, Hebrew University Hadassah-Medical School, Jerusalem, Israel
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IDISNA) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
| | - Myron Schwartz
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, Madison Avenue 1425, 11F-70, Box 1123, New York, New York 10029, USA
| | - Morris Sherman
- Department of Gastroenterology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gregory Gores
- Mayo Clinic, Mayo College of Medicine, Rochester, Minnesota, USA
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Song PP, Xia JF, Inagaki Y, Hasegawa K, Sakamoto Y, Kokudo N, Tang W. Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma. World J Gastroenterol 2016; 22:262-274. [PMID: 26755875 PMCID: PMC4698491 DOI: 10.3748/wjg.v22.i1.262] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/27/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.
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Effects of sorafenib combined with low-dose interferon therapy for advanced hepatocellular carcinoma: a pilot study. Int J Clin Oncol 2015; 21:676-683. [PMID: 26701173 DOI: 10.1007/s10147-015-0942-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 12/12/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND Sorafenib is a standard of care for advanced hepatocellular carcinoma (HCC). An in vitro study showed the synergistic effects of sorafenib and interferon for HCC. To clarify the efficacy, combination therapy with sorafenib and interferon was performed for patients with advanced HCC. METHODS Pegylated interferon α-2a was administered every 2 weeks for the initial 4 weeks. Subsequently, it was combined with sorafenib. We evaluated the anti-tumor effect and biomarkers during treatment period. RESULTS The subjects were 13 patients with advanced HCC complicated by hepatitis C virus (HCV)-related liver cirrhosis. A partial response, stable disease and progressive disease were noted in 4, 6, and 3 patients, respectively. The response rate, the disease control rate, the mean time to progression and the median survival time (MST) were 30.8 % (4/13), 76.9 % (10/13), 12.2 months, and 17.5 months, respectively. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001). In plasma vascular endothelial growth factor (VEGF), serum alpha-fetoprotein (AFP), AFP-L3, a protein induced by vitamin K absence or antagonist-II (PIVKA II), and hepatocyte growth factor (HGF), there was no pretreatment factor and no biomarker during the combination therapy to predict therapeutic effect in the present study. CONCLUSIONS The results of this study suggest that combination therapy with sorafenib and interferon could be effective and safe in advanced HCC patients with HCV-related liver cirrhosis.
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Takada J, Hidaka H, Nakazawa T, Kondo M, Numata K, Tanaka K, Matsunaga K, Okuse C, Kobayashi S, Morimoto M, Ohkawa S, Koizumi W. Modified response evaluation criteria in solid tumors is superior to response evaluation criteria in solid tumors for assessment of responses to sorafenib in patients with advanced hepatocellular carcinoma. BMC Res Notes 2015; 8:609. [PMID: 26502722 PMCID: PMC4624170 DOI: 10.1186/s13104-015-1565-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 10/05/2015] [Indexed: 01/16/2023] Open
Abstract
Background Modified response evaluation criteria in solid tumors (mRECIST) and RECIST are used to assess the effect of treatment with targeted agents for hepatocellular carcinoma (HCC). The aim of this study was to determine which set of criteria is superior in patients with advanced HCC treated with sorafenib. Methods A multicenter retrospective study to assess the tumor response and patient prognosis of 191 patients with HCC who had been treated with sorafenib from May 2009 through December 2011. We analyzed tumor responses as shown by contrast-enhanced computed tomography scan images according to RECIST 1.1 and mRECIST and compared the findings. Results The median duration of follow-up was 9.7 months and median overall survival was 10.8 months. Twenty-five patients (13.1 %) were assessed as responders by mRECIST and 15 (7.8 %) by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST (P = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 (P = 0.0722). Sixteen patients (8.4 %) had no measurable enhanced target lesions that could be assessed as required by mRECIST; however, these patients could be assessed by RECIST 1.1. According to RECIST 1.1, eight of them had stable disease (SD) and eight had progressive disease (PD). There was a significant difference in OS between these SD and PD patients (P = 0.0312). Conclusions Patients treated with sorafenib for HCC should be evaluated by mRECIST; RECIST 1.1 is preferable only for assessment of patients with lesions that are non-measurable according to mRESIST.
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Affiliation(s)
- Juichi Takada
- Department of Gastroenterology, Internal Medicine, Kitasato University Hospital, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University Hospital, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University Hospital, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.
| | - Masaaki Kondo
- Department of Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
| | - Kazushi Numata
- Department of Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
| | - Katsuaki Tanaka
- Department of Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
| | - Kotaro Matsunaga
- Department of Gastroenterology and Hepatology, St Marianna University School of Medicine, Kawasaki, Japan.
| | - Chiaki Okuse
- Department of Gastroenterology and Hepatology, St Marianna University School of Medicine, Kawasaki, Japan.
| | - Satoshi Kobayashi
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
| | - Manabu Morimoto
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University Hospital, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.
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Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma. PLoS One 2015; 10:e0138776. [PMID: 26421430 PMCID: PMC4589320 DOI: 10.1371/journal.pone.0138776] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/03/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma. METHODS Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated. RESULTS After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively). CONCLUSIONS Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.
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Shao YY, Hsu CH, Cheng AL. Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there? World J Gastroenterol 2015; 21:10336-10347. [PMID: 26420960 PMCID: PMC4579880 DOI: 10.3748/wjg.v21.i36.10336] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/26/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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Hidaka H, Nakazawa T, Fujii S, Yanagihara M, Minamino T, Takada J, Tanaka Y, Okuwaki Y, Shibuya A, Koizumi W. Early evaluation of response to sorafenib for hepatocellular carcinoma by duplex Doppler ultrasonography. Hepatol Res 2015; 45:976-985. [PMID: 25336196 DOI: 10.1111/hepr.12440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 09/30/2014] [Accepted: 10/19/2014] [Indexed: 01/18/2023]
Abstract
AIM Early evaluation of the response to sorafenib for patients with hepatocellular carcinoma (HCC) remains unclear. This prospective study investigated the early evaluation of the efficacy of sorafenib in patients with advanced HCC using duplex Doppler ultrasonography (DDU). METHODS Thirty-seven Child-Pugh class-A advanced HCC patients treated with sorafenib 400 mg b.i.d. were enrolled. Changes in portal venous area (PVA) and portal venous flow velocity (PVV) revealed by DDU before and after 2 weeks of sorafenib treatment were evaluated. The relation between the congestion index (PVA/PVV), which reflects the pathophysiological hemodynamics of the portal venous system and the tumor response, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), was also assessed. RESULTS The median progression-free survival and overall survival of all the patients was 2.8 months (95% confidence interval [CI], 2.6-3.2) and 12.8 months (95% CI, 8.7-17.0), respectively. Overall, three patients (8%) had a partial response (PR), 15 (41%) stable disease (SD) and 17 (46%) progressive disease, according to the mRECIST, and two patients (6%) could not be evaluated because of worsened conditions. The decrease in the congestion index was significantly larger in the disease control group (PR/SD) after the sorafenib treatment (P = 0.035); furthermore, the congestion index was the only significant independent predictor of disease control (P = 0.033; hazard ratio, 8.456; 95% CI, 1.182-60.484). CONCLUSION A decrease in the congestion index revealed by DDU provides an early evaluation of response in patients taking sorafenib for advanced HCC.
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Affiliation(s)
- Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shigeru Fujii
- Department of Ultrasonography, Kitasato University East Hospital, Sagamihara, Japan
| | - Michiko Yanagihara
- Department of Ultrasonography, Kitasato University East Hospital, Sagamihara, Japan
| | - Tsutomu Minamino
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Juichi Takada
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yoshiaki Tanaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yusuke Okuwaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akitaka Shibuya
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
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