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Stefanini B, Bucci L, Santi V, Reggidori N, Lani L, Granito A, Pelizzaro F, Cabibbo G, Di Marco M, Ghittoni G, Campani C, Svegliati-Baroni G, Foschi FG, Giannini EG, Biasini E, Saitta C, Magalotti D, Sangiovanni A, Guarino M, Gasbarrini A, Rapaccini GL, Masotto A, Sacco R, Vidili G, Mega A, Azzaroli F, Nardone G, Brandi G, Sabbioni S, Vitale A, Trevisani F. Sorafenib and Metronomic Capecitabine in Child-Pugh B patients with advanced HCC: A real-life comparison with best supportive care. Dig Liver Dis 2024; 56:1582-1591. [PMID: 38341377 DOI: 10.1016/j.dld.2024.01.199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/29/2023] [Accepted: 01/23/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND AND AIMS The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated both with tyrosine kinase inhibitors (TKIs) and with metronomic capecitabine (MC). This study aimed to compare sorafenib and MC outcomes versus best supportive care (BSC) in C-P B patients. METHOD Between 2008 and 2020, among 774 C-P B patients with aHCC not amenable/responsive to locoregional treatments, 410 underwent sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors. RESULTS In the unmatched population, median OS was 9.7 months in patients treated with sorafenib, 8.0 with MC, and 3.9 months with BSC. In sorafenib vs. BSC-matched patients (135 couples), median OS was 7.3 (4.9-9.6) vs. 3.9 (2.6-5.2) months (p<0.001). ECOG-Performance Status, tumor size, macrovascular invasion, AFP, treatment-naive, and sorafenib were independent predictors of survival. In MC vs. BSC-matched patients (40 couples), median OS was 9.0 (0.2-17.8) vs.3.0 (2.2-3.8) months (p<0.001). Median OS did not differ (p = 0.283) in sorafenib vs. MC-matched patients (55 couples). CONCLUSION C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis.
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Affiliation(s)
- Benedetta Stefanini
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Laura Bucci
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Valentina Santi
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nicola Reggidori
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Lorenzo Lani
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary Diseases and Immunoallergology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Unit, University of Padua, Padua, Italy
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | | | | | - Claudia Campani
- Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Florence, Florence, Italy
| | | | | | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; Gastroenterology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Elisabetta Biasini
- Infectious Diseases and Hepatology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy
| | - Donatella Magalotti
- Division of Internal Medicine, Neurovascular and Hepatometabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale maggiore Policlinico and C.R.C. "A.M. & A. Migliavacca Center for Liver Disease", Milan, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Diseases of the Liver and Biliary System Unit, University of Naples "Federico II", Naples, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome - Università Cattolica del Sacro Cuore, Rome
| | | | - Alberto Masotto
- Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy
| | - Gianpaolo Vidili
- Department of Medical, Surgical and Experimental Sciences, Clinica Medica Unit, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy
| | - Andrea Mega
- Gastroenterology Unit, Bolzano Regional Hospital, Bolzano, Italy
| | - Francesco Azzaroli
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Gerardo Nardone
- Department of Clinical Medicine and Surgery, Hepato-Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Giovanni Brandi
- Unit of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Simone Sabbioni
- Unit of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology Unit, University of Padua, Padua, Italy
| | - Franco Trevisani
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-related diseases, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.
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Kang M, Xue F, Xu S, Shi J, Mo Y. Effectiveness and safety of anlotinib with or without S-1 in the treatment of patients with advanced hepatocellular carcinoma in a Chinese population: a prospective, phase 2 study. Radiol Oncol 2023; 57:405-410. [PMID: 37494583 PMCID: PMC10476909 DOI: 10.2478/raon-2023-0036] [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: 02/16/2023] [Accepted: 06/15/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND The aim of the study was to observe the safety and efficacy of anlotinib (ANL) alone or combined with S-1 in the first-line treatment of advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS Fifty-four patients with untreated advanced HCC who could not be resected were randomly divided into the ANL group (n = 27) and ANL+S-1 group (n = 27). The ANL group was given 10 mg ANL orally once a day for 14 consecutive days, stopped for 1 week, and repeated every 21 days. The ANL+S-1 group was given 10 mg ANL once a day orally and 40 mg S-1 twice a day orally for 14 consecutive days, stopped for 1 week, repeated every 21 days. All patients were treated until the disease progressed or toxicity became unacceptable. For patients who could not tolerate adverse reactions, the ANL dose should be reduced to 8 mg per day. CT or MRI was reviewed every 6 weeks to evaluate the efficacy. RESULTS A total of 44 patients were included in the results analysis, including 22 patients in the ANL group and 22 patients in the ANL+S-1 group. In the ANL group, the objective response rate (ORR) was 4.5% (1/22), the disease control rate (DCR) was 77.3% (17/22), the median progression-free survival (PFS) was 4.2 months (95% CI: 3.6-6.0) and the median overall survival (mOS) was 7.0 months (95% CI: 6.3-9.0). In the ANL+S-1 group, the ORR was 18.2% (4/22), the DCR was 59.1% (13/22), the median PFS was 4.0 months (95% CI: 3.6-5.4) and the mOS was 6.0 months (95% CI: 5.5-7.4). There was no significant difference in ORR (p = 0.345) or DCR (p = 0.195) between the two groups. Adverse reactions were mainly hypertension, anorexia, fatigue, liver transaminase heightened and hand and foot skin reaction. CONCLUSIONS ANL monotherapy was effective in the treatment of advanced HCC, and adverse reactions have been able to tolerated.
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Affiliation(s)
- Mafei Kang
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Feng Xue
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Shengyuan Xu
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Jieqiong Shi
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Yunyan Mo
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
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Wang H, Wang ZL, Zhang S, Kong DJ, Yang RN, Cao L, Wang JX, Yoshida S, Song ZL, Liu T, Fan SL, Ren JS, Li JH, Shen ZY, Zheng H. Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients’ T cell ferroptosis. World J Gastroenterol 2023; 29:3084-3102. [PMID: 37346150 PMCID: PMC10280797 DOI: 10.3748/wjg.v29.i20.3084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/19/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation.
AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.
METHODS A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy.
RESULTS With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells.
CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.
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Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zheng-Lu Wang
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
| | - Sai Zhang
- School of Medicine, Nankai University, Tianjin 300190, China
| | - De-Jun Kong
- School of Medicine, Nankai University, Tianjin 300190, China
| | - Rui-Ning Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jian-Xi Wang
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
| | - Zhuo-Lun Song
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Shun-Li Fan
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Jia-Shu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Jiang-Hong Li
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zhong-Yang Shen
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Hong Zheng
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
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Ong BAG, Rocimo AMR, King REC, Yasay EB. Capecitabine Maintenance Chemotherapy in the Treatment of Metastatic Colorectal Cancer: A Meta-Analysis. ASIAN JOURNAL OF ONCOLOGY 2022. [DOI: 10.1055/s-0042-1744439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
AbstractMany agents have been evaluated as maintenance therapy for metastatic colorectal cancer (mCRC), but there is no consensus on the optimal regimen. This study assessed the effect of single-agent capecitabine maintenance therapy on the survival outcomes of mCRC patients. A comprehensive literature search was performed according to prespecified inclusion and exclusion criteria for randomized controlled trials (RCTs) comparing capecitabine as maintenance monotherapy versus active monitoring for mCRC patients. Data on overall survival (OS), progression-free survival (PFS), time to tumor progression (TTP), adverse events, and quality of life (QoL) scores were extracted. Three RCTs with a total of 576 patients were included. Pooled analyses found neither OS benefit (HR:0.85, 95% CI:0.64–1.13) nor reduction in mortality at 24 months (RR:0.88, 95% CI:0.66–1.17) with capecitabine maintenance. Compared with active monitoring, capecitabine maintenance therapy improved PFS (HR:0.36, 95% CI:0.26–0.61) and reduced the risk of progression at 6 months (HR:0.78, 95% CI:0.56–1.10). The incidence of any grade ≥ 3 toxicity was higher with maintenance therapy than with observation (OR:2.02, 95% CI:1.42–2.88). No difference in terms of QoL was observed. Single-agent capecitabine as maintenance for patients with mCRC provides no OS benefit but results in statistically significant improvement in PFS with increased risk of toxicity. Hence, it may be considered particularly for patients who wish to delay the need for second-line treatment and who can tolerate it well.
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Affiliation(s)
| | | | - Rich Ericson Chan King
- Department of Medicine, Section of Medical Oncology, Philippine General Hospital, University of the Philippines, Manila, Philippines
| | - Eric Baldivino Yasay
- Department of Medicine, Section of Gastroenterology, Philippine General Hospital, University of the Philippines, Manila, Philippines
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Brandi G, Di Federico A, Rizzo A, De Lorenzo S, Vasuri F, Brocchi S, Golfieri R, Morelli MC, Frega G, Palloni A. The power of kindness: curative treatment with metronomic combination in advanced hepatocellular carcinoma. Anticancer Drugs 2022; 33:e781-e783. [PMID: 34407053 DOI: 10.1097/cad.0000000000001202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The administration of approved systemic treatments for advanced hepatocellular carcinoma (HCC) is limited to patients with preserved liver function (Child-Pugh A/B7) and performance status. Conversely, metronomic chemotherapy can be safely administered to patients with poor clinical conditions and severe liver impairment. The metronomic schedule demonstrated to exert different anticancer mechanisms compared to that of the same agent administered at its standard schedule, including immune stimulation and the inhibition of angiogenesis and vasculogenesis. Nevertheless, metronomic chemotherapy is a nearly neglected option for the treatment of advanced HCC patients, even among those who cannot afford standard treatments. Herein, we report the case of a 40-year-old patient affected by HBV-HDV-related cirrhosis who was diagnosed with advanced HCC. The severe liver impairment (Child-Pugh B9) did not allow to administer first-line treatment with tyrosine kinase inhibitors so that the patient received metronomic capecitabine as upfront therapy. Due to the suspect of progressive disease at the first radiologic assessment, metronomic cyclophosphamide was added to capecitabine aiming to enhance its efficacy. After 4 months of treatment, complete tumor response, alpha-fetoprotein (AFP) normalization and the recovery of a Child-Pugh A were achieved. The patient was then able to undergo liver transplantation, and, after 18 months from the diagnosis, he is still free of disease recurrence. This experience emphasizes the reliability of metronomic capecitabine as a well-tolerated and effective treatment when patient's conditions prevent the administration of standard first-line treatments. In fact, metronomic capecitabine demonstrated its effectiveness in advanced HCC in retrospective and prospective analyses, leading to median progression-free survival and overall survival of, respectively, 6.03 and 14.47 months in phase II single-arm trial. Moreover, in consideration of the raising interest in immune-checkpoint inhibition in HCC, we believe that the immunomodulating effects of metronomic chemotherapy, either capecitabine or cyclophosphamide, warrant future trials exploring its combination with immunotherapy.
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Affiliation(s)
- Giovanni Brandi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
| | - Alessandro Di Federico
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
| | - Alessandro Rizzo
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
| | - Stefania De Lorenzo
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
| | - Francesco Vasuri
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
- Pathology Unit
| | - Stefano Brocchi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
- Radiology Unit
| | - Rita Golfieri
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
- Radiology Unit
| | - Maria Cristina Morelli
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giorgio Frega
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
| | - Andrea Palloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna
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Pelizzaro F, Gambato M, Gringeri E, Vitale A, Cillo U, Farinati F, Burra P, Russo FP. Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2021; 13:cancers13194882. [PMID: 34638365 PMCID: PMC8508053 DOI: 10.3390/cancers13194882] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/19/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is an increasingly important indication for liver transplantation (LT) worldwide. However, LT in the setting of liver cancer is burdened by the risk of tumor recurrence. The prognosis of patients with post-LT HCC recurrence is still very poor and several areas of uncertainty remain in the management of these patients. In this paper, we provide a comprehensive evaluation of available evidence regarding the management of HCC recurrence after LT, starting from the pre- and post-transplant stratification criteria and encompassing post-LT surveillance, preventive strategies and treatment. Much work has been done in the last several years but further effort is still needed in order to improve the outcome of these patients. Abstract Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10–15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Martina Gambato
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Patrizia Burra
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
- Correspondence:
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Zhang S, Wang Z, Fan S, Liu T, Yoshida S, Yang S, Liu L, Hou W, Cao L, Wang J, Song Z, Li S, Zhang S, Wang H, Li J, Zheng H, Shen Z. Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect. Front Immunol 2021; 12:737849. [PMID: 34557199 PMCID: PMC8452994 DOI: 10.3389/fimmu.2021.737849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.
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Affiliation(s)
- Sai Zhang
- School of Medicine, Nankai University, Tianjin, China
| | - Zhenglu Wang
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Shunli Fan
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Shuang Yang
- School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Lei Liu
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Wen Hou
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Lei Cao
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Jianxi Wang
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Zhuolun Song
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Shanni Li
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Sirui Zhang
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Hao Wang
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Jianghong Li
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Hong Zheng
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zhongyang Shen
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
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8
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Suzuki H, Iwamoto H, Nakano M, Nakamura T, Masuda A, Sakaue T, Tanaka T, Nakano D, Kuromatsu R, Niizeki T, Okamura S, Shimose S, Shirono T, Noda Y, Kamachi N, Yano H, Kawaguchi A, Koga H, Torimura T. Efficacy and tolerability of Sorafenib plus metronomic chemotherapy S-1 for advanced hepatocellular carcinoma in preclinical and clinical assessments. Transl Oncol 2021; 14:101201. [PMID: 34388691 PMCID: PMC8363883 DOI: 10.1016/j.tranon.2021.101201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/28/2021] [Accepted: 08/09/2021] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib. METHODS Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015. RESULTS In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p < 0.05); however, there were no significant differences in overall survival and time to progression. Adverse events including alopecia, thrombocytopenia, and pancreatic enzymes elevation in the combination chemotherapy were higher than those of sorafenib. No patient treated with the combination chemotherapy discontinued treatment due to severe adverse events. CONCLUSIONS Sorafenib plus MC S-1 seems to be effective and tolerable for patients with advanced HCC and could be considered a treatment option for these patients.
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Affiliation(s)
- Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Iwamoto Internal Medicine Clinic, Kitakyushu, Japan.
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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9
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El Darsa H, El Sayed R, Abdel-Rahman O. What is the real value of metronomic chemotherapy in the treatment of gastrointestinal cancer? Expert Opin Pharmacother 2021; 22:2297-2302. [PMID: 34165012 DOI: 10.1080/14656566.2021.1940953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Haidar El Darsa
- Division of Medical Oncology, Department of Oncology Cross Cancer Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Rola El Sayed
- Global Health Institute, American University of Beirut, Beirut, Lebanon
| | - Omar Abdel-Rahman
- Division of Medical Oncology, Department of Oncology Cross Cancer Centre, University of Alberta, Edmonton, Alberta, Canada
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10
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Schipilliti FM, Garajová I, Rovesti G, Balsano R, Piacentini F, Dominici M, Gelsomino F. The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review. Pharmaceuticals (Basel) 2021; 14:43. [PMID: 33429973 PMCID: PMC7827379 DOI: 10.3390/ph14010043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/13/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.
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Affiliation(s)
- Francesca Matilde Schipilliti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Giulia Rovesti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Federico Piacentini
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Massimo Dominici
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Fabio Gelsomino
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
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11
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Geng R, Wang G, Qiu L, Liu B, Yang F, Zhang J, Miao Y. Metronomic capecitabine as maintenance treatment after first line induction with XELOX for metastatic colorectal cancer patients. Medicine (Baltimore) 2020; 99:e23719. [PMID: 33371122 PMCID: PMC7748176 DOI: 10.1097/md.0000000000023719] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 11/16/2020] [Indexed: 01/05/2023] Open
Abstract
Maintenance treatment after first-line chemotherapy for patients with metastatic colorectal cancer (mCRC) is a priority strategy. However, which medicine is chosen is controversial. This study aimed to determine the efficacy and safety of maintenance treatment with metronomic capecitabine vs observation.In this randomized controlled trial, patients who completed 18 weeks of induction chemotherapy with XELOX and achieved disease control were randomly assigned centrally (1:1) to receive maintenance therapy with metronomic chemotherapy or observation until disease progression. The primary endpoint was progression-free survival from randomization; secondary endpoints included overall survival and safety. Analyses were performed by intention to treat.Between January 1st, 2017 and December 31th 2018, 48 patients were enrolled and randomly assigned to receive maintenance treatment with metronomic capecitabine (n = 25) or only observation (n = 23). The median progression-free survival in the metronomic capecitabine group was 5.66 (95% confidence interval [CI] 5.25-6.07) months vs 3.98 (95%CI 3.71-4.24) months in the observation group (hazard ratio 0.11, 95% [CI] 0.04-0.26, P = .000). There was no statistically significant difference in median overall survival: 23.82 (95% CI 22.38-25.25) months in the metronomic capecitabine group vs 21.81 (95% CI 20.23-23.38) months in the observation group (hazard ratio 0.49, 95% CI 0.21-1.11, P = .087). Subgroup analyses were generally consistent with the primary finding. Similar safety profiles were observed in both arms. The most frequent adverse events in metronomic capecitabine group included neutropenia, diarrhea, hand-foot skin reaction, and mucositis.Maintenance therapy with metronomic capecitabine can be considered an alternative option following first-line chemotherapy of XELOX in patients with metastatic colorectal cancer with controlled toxicities.
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Affiliation(s)
- Rui Geng
- School of Public Health, Nanjing Medical University, Nanjing
| | - Gang Wang
- Department of gastrointestinal surgery, the Second People's Hospital of Lianyungang, Lianyungang
| | - Lei Qiu
- Department of gastrointestinal surgery, the Second People's Hospital of Lianyungang, Lianyungang
| | - Bing Liu
- Department of gastrointestinal oncology, the Second People's Hospital of Lianyungang, Lianyungang, China
| | - Fan Yang
- Department of gastrointestinal oncology, the Second People's Hospital of Lianyungang, Lianyungang, China
| | - Jingyu Zhang
- Department of gastrointestinal oncology, the Second People's Hospital of Lianyungang, Lianyungang, China
| | - Yongchang Miao
- Department of gastrointestinal surgery, the Second People's Hospital of Lianyungang, Lianyungang
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12
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Orsi G, Tovoli F, Dadduzio V, Vivaldi C, Brunetti O, Ielasi L, Conti F, Rovesti G, Gramantieri L, Rizzato MD, Pecora I, Argentiero A, Teglia F, Lonardi S, Salani F, Granito A, Zagonel V, Marisi G, Cabibbo G, Foschi FG, Benevento F, Cucchetti A, Piscaglia F, Cascinu S, Scartozzi M, Casadei-Gardini A. Prognostic Role of Blood Eosinophil Count in Patients with Sorafenib-Treated Hepatocellular Carcinoma. Target Oncol 2020; 15:773-785. [PMID: 33044683 DOI: 10.1007/s11523-020-00757-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. OBJECTIVE The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. PATIENTS AND METHODS A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6-216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24-16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83-5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. CONCLUSIONS Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.
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Affiliation(s)
- Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Via del Pozzo 71, Modena, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Vincenzo Dadduzio
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Caterina Vivaldi
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
- Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Via Savi 6, Pisa, 56126, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Luca Ielasi
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Fabio Conti
- Department of Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Via del Pozzo 71, Modena, Italy
| | - Laura Gramantieri
- Center for Applied Biomedical Research (CRBa), St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Mario Domenico Rizzato
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Irene Pecora
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
| | | | - Federica Teglia
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Francesca Salani
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
| | - Alessandro Granito
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifco Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | | | - Francesca Benevento
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Stefano Cascinu
- Vita-Salute San Rafaele University, Milan, Italy
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Vita-Salute San Rafaele University, Milan, Italy.
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy.
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13
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Lai E, Astara G, Ziranu P, Pretta A, Migliari M, Dubois M, Donisi C, Mariani S, Liscia N, Impera V, Persano M, Tolu S, Balconi F, Pinna G, Spanu D, Pireddu A, Saba G, Camera S, Musio F, Puzzoni M, Pusceddu V, Madeddu C, Casadei Gardini A, Scartozzi M. Introducing immunotherapy for advanced hepatocellular carcinoma patients: Too early or too fast? Crit Rev Oncol Hematol 2020; 157:103167. [PMID: 33271389 DOI: 10.1016/j.critrevonc.2020.103167] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Simona Tolu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Annagrazia Pireddu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Silvia Camera
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy. Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, via Olgettina 60, Milan, Italy.
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy. Oncologia Medica, Azienda Ospedaliera Universitaria di Cagliari, Presidio Policlinico Universitario "Duilio Casula" S.S. 554, Km 4,500 Bivio per Sestu, 09042 Monserrato, Cagliari, Italy.
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14
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Xu Y, Li X, Gong W, Huang HB, Zhu BW, Hu JN. Construction of Ginsenoside Nanoparticles with pH/Reduction Dual Response for Enhancement of Their Cytotoxicity Toward HepG2 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8545-8556. [PMID: 32686932 DOI: 10.1021/acs.jafc.0c03698] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The aim of this study is to construct a pH- and reduction-responsive nanodrug delivery system to effectively deliver a ginsenoside (Rh2) and enhance its cytotoxicity against human hepatocarcinoma cells (HepG2). Here, pullulan polysaccharide was grafted by urocanic acid and α-lipoic acid (α-LA) to obtain a copolymer, α-LA-conjugated N-urocanyl pullulan (LA-URPA), which was expected to have pH and redox dual response. Then, the copolymer LA-URPA was used to encapsulate ginsenoside Rh2 to form Rh2 nanoparticles (Rh2 NPs). The results showed that Rh2 NPs exhibited an average size of 119.87 nm with a uniform spherical morphology. Of note, Rh2 NPs showed a high encapsulation efficiency of 86.00%. Moreover, Rh2 NPs possessed excellent pH/reduction dual-responsive drug release under acidic conditions (pH 5.5) and glutathione (GSH) stimulation with a low drug leakage of 14.8% within 96 h. Furthermore, Rh2 NPs with pH/reduction dual response had higher cytotoxicity than Rh2 after incubation with HepG2 cells for 72 h, indicating that Rh2 NPs had a longer circulation time. After the treatment with Rh2 NPs, the excessive increase of reactive oxygen species and the decrease of superoxide dismutase, glutathione (GSH), and mitochondrial membrane potential suggested that the mitochondrial pathway mediated by oxidative stress played a role in this Rh2 NP-induced apoptosis. In conclusion, this study provides a new strategy for improving the application of ginsenoside Rh2 in the food and pharmaceutical fields.
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Affiliation(s)
- Yu Xu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Xiang Li
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Wei Gong
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Hai-Bo Huang
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Bei-Wei Zhu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
| | - Jiang-Ning Hu
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China
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15
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Marconato L, Sabattini S, Marisi G, Rossi F, Leone VF, Casadei-Gardini A. Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs. Cancers (Basel) 2020; 12:cancers12051272. [PMID: 32443457 PMCID: PMC7281367 DOI: 10.3390/cancers12051272] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 12/20/2022] Open
Abstract
Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191–535) in dogs treated with sorafenib versus 27 days (95% CI, 0–68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0–909) in dogs receiving sorafenib, while 32 days (95% CI, 0–235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy.
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Affiliation(s)
- Laura Marconato
- Department of Veterinary Medical Sciences, University of Bologna, via Tolara di Sopra 50, Ozzano dell’Emilia, 40064 Bologna, Italy;
- Correspondence:
| | - Silvia Sabattini
- Department of Veterinary Medical Sciences, University of Bologna, via Tolara di Sopra 50, Ozzano dell’Emilia, 40064 Bologna, Italy;
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, Meldola, 47014 Forlì-Cesena, Italy;
| | - Federica Rossi
- Centro Oncologico Veterinario, via San Lorenzo 1-4, Sasso Marconi, 40037 Bologna, Italy; (F.R.); (V.F.L.)
| | - Vito Ferdinando Leone
- Centro Oncologico Veterinario, via San Lorenzo 1-4, Sasso Marconi, 40037 Bologna, Italy; (F.R.); (V.F.L.)
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, 41124 Modena, Italy;
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16
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Faloppi L, Puzzoni M, Casadei Gardini A, Silvestris N, Masi G, Marisi G, Vivaldi C, Gadaleta CD, Ziranu P, Bianconi M, Loretelli C, Demurtas L, Lai E, Giampieri R, Galizia E, Ulivi P, Battelli N, Falcone A, Cascinu S, Scartozzi M. Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE-2 Study. Target Oncol 2020; 15:115-126. [DOI: 10.1007/s11523-020-00698-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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17
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Rovesti G, Orsi G, Kalliopi A, Vivaldi C, Marisi G, Faloppi L, Foschi FG, Silvestris N, Pecora I, Aprile G, Molinaro E, Riggi L, Ulivi P, Canale M, Cucchetti A, Tamburini E, Ercolani G, Fornaro L, Andreone P, Zavattari P, Scartozzi M, Cascinu S, Casadei-Gardini A. Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience. Gastrointest Tumors 2019; 6:92-107. [PMID: 31768353 DOI: 10.1159/000502714] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 07/29/2019] [Indexed: 12/24/2022] Open
Abstract
Background Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS). Method Univariate/multivariate analyses were conducted to retrospectively identify the impact of baseline characteristics on the OS of 398 advanced HCC patients treated with sorafenib. Results Based on univariate analysis, α-fetoprotein (AFP), albumin, AST, bilirubin, Child-Pugh, ECOG, systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) grade, and portal vein thrombosis were significantly associated with shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP, age, etiology, albumin, aspartate transaminase (AST), bilirubin, Child-Pugh, LDH, platelet-to-lymphocyte ratio, ECOG, ALBI grade, portal vein thrombosis, SII, and BCLC stage identified increase in LDH, age >70 years, no viral etiologies, ECOG >0, albumin <35, ALBI grade 2, and AST >40 as prognostic factors for poorer OS based on the 5% significance level. Conclusion Our study highlights that baseline hepatic function, patient-centered variables, and etiology have prognostic value. These findings might have implications in terms of therapeutic decision-making and patient counseling.
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Affiliation(s)
- Giulia Rovesti
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Giulia Orsi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrikou Kalliopi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Caterina Vivaldi
- Department of Medical Oncology, Pisa University Hospital, Pisa, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Luca Faloppi
- Oncology Unit, Macerata Hospital, Macerata, Italy
| | | | | | - Irene Pecora
- Department of Medical Oncology, Pisa University Hospital, Pisa, Italy
| | | | - Eleonora Molinaro
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Laura Riggi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences-DIMEC, S. Orsola-Malpighi Hospital, Alma Mater Studiorum-University of Bologna, Bologna, Italy.,General Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy
| | | | - Giorgio Ercolani
- Medical Oncology Unit, Hospital of Vicenza, Vicenza, Italy.,Department of Medical and Surgical Sciences-DIMEC, S. Orsola-Malpighi Hospital, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Lorenzo Fornaro
- Department of Medical Oncology, Pisa University Hospital, Pisa, Italy
| | - Pietro Andreone
- Division of Internal and Metabolic Medicine, Baggiovara Hospital, University of Modena and Reggio Emilia, Modena, Italy
| | - Patrizia Zavattari
- Unit of Biology and Genetics, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
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18
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Nenu I, Breaban I, Pascalau S, Bora CN, Stefanescu H. The future is now: beyond first line systemic therapy in hepatocellular carcinoma. Transl Cancer Res 2019; 8:S261-S274. [PMID: 35117106 PMCID: PMC8797356 DOI: 10.21037/tcr.2018.11.23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is becoming a worldwide concern due to its rising incidence. Although for the incipient stages there are curative therapies, the advanced disease represents a major provocation for the clinicians. 2008 marked as an important year for the hepatology community with the administration of sorafenib for late stages of HCC. Six years after this major discovery, the multikinase inhibitor still represents an important pillar, the first line treatment for the advanced liver cancer. Lenvatinib may represent a new promising first line strategy, but it is still unavailable in many countries. The last years represented an explosion in the research of HCC. Beyond the first line treatments there are a plethora of new emerging therapies. By far immunotherapy represents the major revolution in oncology. While adoptive immunotherapy is still at the beginning, immune check-point inhibitors bursted in many clinical trials with very encouraging results. This review summarises the major discoveries in the field of HCC with an emphasis on immunotherapy. It also briefly describes the important aspects of primary liver cancer immunology and the major ongoing clinical trials.
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Affiliation(s)
- Iuliana Nenu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Iulia Breaban
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
| | - Sorana Pascalau
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina-Nelida Bora
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
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19
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Simsek C, Esin E, Yalcin S. Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. JOURNAL OF ONCOLOGY 2019; 2019:5483791. [PMID: 31015835 PMCID: PMC6446118 DOI: 10.1155/2019/5483791] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/24/2018] [Accepted: 02/05/2019] [Indexed: 02/07/2023]
Abstract
Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts' immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
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Affiliation(s)
- Cem Simsek
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
| | - Ece Esin
- Department of Medical Oncology, A.Y. Ankara Training Hospital, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University, Ankara, Turkey
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20
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Zhang J, Fang C, Qu M, Wu H, Wang X, Zhang H, Ma H, Zhang Z, Huang Y, Shi L, Liang S, Gao Z, Song W, Wang X. CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents. Front Pharmacol 2018; 9:1042. [PMID: 30258365 PMCID: PMC6144529 DOI: 10.3389/fphar.2018.01042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 08/27/2018] [Indexed: 12/20/2022] Open
Abstract
Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.
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Affiliation(s)
- Jian Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Chunyan Fang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Meihua Qu
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Huina Wu
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xuejuan Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hongan Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hui Ma
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zhaolin Zhang
- Weifang Bochuang International Biological Medicinal Institute, Weifang, China
| | - Yongxue Huang
- Weifang Bochuang International Biological Medicinal Institute, Weifang, China
| | - Lihong Shi
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Shujuan Liang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zhiqin Gao
- School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Weiguo Song
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xuejian Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
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21
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Filippi R, Lombardi P, Depetris I, Fenocchio E, Quarà V, Chilà G, Aglietta M, Leone F. Rationale for the use of metronomic chemotherapy in gastrointestinal cancer. Expert Opin Pharmacother 2018; 19:1451-1463. [PMID: 30161003 DOI: 10.1080/14656566.2018.1512585] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Metronomic chemotherapy (mCT) is endowed with various properties, ranging from antiangiogenic to immunomodulation, and may revert tumor resistance to conventional drug administration. A variety of antineoplastic agents displayed activity when administered with metronomic schedules in preclinical models of gastrointestinal cancers. However, most of the field is still unexplored. AREAS COVERED Herein, the authors review the existing literature from PubMed, concerning the use of mCT in gastrointestinal oncology. EXPERT OPINION A mounting body of evidence is emerging in support of mCT as a treatment option for gastrointestinal tumors, but the frequent signs of clinical activity inconsistently translate into a benefit for survival. Research in this field should focus on providing high-quality evidence on the safety and efficacy of mCT, with more prospective, comparative trials; identifying the subgroups of patients for whom mCT would be the best approach; establishing standardized protocols based on mCT pharmacokinetics and pharmacodynamics; developing drug activity biomarkers. mCT is also potentially suitable for combinations with targeted antiangiogenic drugs and may be incorporated with conventional administration into dual regimens.
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Affiliation(s)
- Roberto Filippi
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Pasquale Lombardi
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Ilaria Depetris
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Elisabetta Fenocchio
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Virginia Quarà
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Giovanna Chilà
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Massimo Aglietta
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
| | - Francesco Leone
- a Department of Oncology , University of Turin , Candiolo , Italy.,b Medical Oncology , Candiolo Cancer Institute FPO-IRCCS , Candiolo , Italy
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22
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Bonomini F, Borsani E, Favero G, Rodella LF, Rezzani R. Dietary Melatonin Supplementation Could Be a Promising Preventing/Therapeutic Approach for a Variety of Liver Diseases. Nutrients 2018; 10:nu10091135. [PMID: 30134592 PMCID: PMC6164189 DOI: 10.3390/nu10091135] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 02/07/2023] Open
Abstract
In the therapeutic strategies, the role of diet is a well-established factor that can also have an important role in liver diseases. Melatonin, identified in animals, has many antioxidant properties and it was after discovered also in plants, named phytomelatonin. These substances have a positive effect during aging and in pathological conditions too. In particular, it is important to underline that the amount of melatonin produced by pineal gland in human decreases during lifetime and its reduction in blood could be related to pathological conditions in which mitochondria and oxidative stress play a pivotal role. Moreover, it has been indicated that melatonin/phytomelatonin containing foods may provide dietary melatonin, so their ingestion through balanced diets could be sufficient to confer health benefits. In this review, the classification of liver diseases and an overview of the most important aspects of melatonin/phytomelatonin, concerning the differences among their synthesis, their presence in foods and their role in health and diseases, are summarized. The findings suggest that melatonin/phytomelatonin supplementation with diet should be considered important in preventing different disease settings, in particular in liver. Currently, more studies are needed to strengthen the potential beneficial effects of melatonin/phytomelatonin in liver diseases and to better clarify the molecular mechanisms of action.
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Affiliation(s)
- Francesca Bonomini
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Elisa Borsani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - Luigi F Rodella
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
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23
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De Lorenzo S, Tovoli F, Barbera MA, Garuti F, Palloni A, Frega G, Garajovà I, Rizzo A, Trevisani F, Brandi G. Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept. Sci Rep 2018; 8:9997. [PMID: 29968763 PMCID: PMC6030080 DOI: 10.1038/s41598-018-28337-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/18/2018] [Indexed: 02/07/2023] Open
Abstract
There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naïve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8-9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733-11.267]in MC-patients and 5.1 months [95% CI: 4.098-6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5-6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370-0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations.
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Affiliation(s)
- Stefania De Lorenzo
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Internal Medicine Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Maria Aurelia Barbera
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Francesca Garuti
- Medical Semeiotics Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Andrea Palloni
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giorgio Frega
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Ingrid Garajovà
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Alessandro Rizzo
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Franco Trevisani
- Medical Semeiotics Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giovanni Brandi
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
- "G.Prodi" Interdepartmental Centre for Cancer Research, University of Bologna, Bologna, Italy.
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Brandi G, Venturi M, De Lorenzo S, Garuti F, Frega G, Palloni A, Garajovà I, Abbati F, Saccoccio G, Golfieri R, Pantaleo MA, Barbera MA. Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases. Cancer Commun (Lond) 2018; 38:41. [PMID: 29941039 PMCID: PMC6020209 DOI: 10.1186/s40880-018-0312-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 06/08/2018] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death. Sorafenib, a multitarget angiogenesis inhibitor, is an approved frontline treatment for advanced HCC in Western countries, although a complete response (CR) to treatment is infrequently reported. Capecitabine, an oral fluoropyrimidine, has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib. To date, however, only one case of sustained CR to metronomic capecitabine has been reported. Case presentation We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained. In the first case, capecitabine was administered as first line therapy; in the second case, capecitabine was used after intolerance to sorafenib; while in the third case, capecitabine was administered after sorafenib failure. Conclusion Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.
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Affiliation(s)
- Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy.
| | - Michela Venturi
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Francesca Garuti
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, 40138, Bologna, Italy
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Ingrid Garajovà
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Francesca Abbati
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | | | - Rita Golfieri
- Department of Digestive Diseases and Internal Medicine, St. Orsola-Malpighi Hospital, University of Bologna, 40138, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi Hospital, Haematological and Oncological Institute, University of Bologna, 9 Massarenti street, 40138, Bologna, Italy
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Trevisani F, Brandi G, Garuti F, Barbera MA, Tortora R, Casadei Gardini A, Granito A, Tovoli F, De Lorenzo S, Inghilesi AL, Foschi FG, Bernardi M, Marra F, Sacco R, Di Costanzo GG. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J Cancer Res Clin Oncol 2018; 144:403-414. [PMID: 29249005 DOI: 10.1007/s00432-017-2556-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023]
Abstract
PURPOSE Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.
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Affiliation(s)
- Franco Trevisani
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy.
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Francesca Garuti
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Raffaella Tortora
- Department of Transplantation, Liver Unit, Cardarelli Hospital, Naples, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Granito
- Department of Medical and Surgical Sciences, Internal Medicine, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, Internal Medicine, University of Bologna, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Andrea Lorenzo Inghilesi
- Department of Clinical and Experimental Medicine, Internal Medicine and Hepatology, University of Florence, Florence, Italy
| | | | - Mauro Bernardi
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy
| | - Fabio Marra
- Department of Clinical and Experimental Medicine, Internal Medicine and Hepatology, University of Florence, Florence, Italy
| | - Rodolfo Sacco
- Gastroenterology and Metabolic Diseases, University Hospital of Pisa, Pisa, Italy
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Tovoli F, Negrini G, Benevento F, Faggiano C, Goio E, Granito A. Systemic treatments for hepatocellular carcinoma: challenges and future perspectives. Hepat Oncol 2018; 5:HEP01. [PMID: 30302192 PMCID: PMC6168042 DOI: 10.2217/hep-2017-0020] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC.
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Affiliation(s)
- Francesco Tovoli
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulia Negrini
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Francesca Benevento
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Chiara Faggiano
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Elisabetta Goio
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Alessandro Granito
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
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Zhang X, Chen Y, Cai G, Li X, Wang D. Carnosic acid induces apoptosis of hepatocellular carcinoma cells via ROS-mediated mitochondrial pathway. Chem Biol Interact 2017; 277:91-100. [PMID: 28918123 DOI: 10.1016/j.cbi.2017.09.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/30/2017] [Accepted: 09/08/2017] [Indexed: 01/06/2023]
Abstract
Carnosic acid (CA), an important bioactive phenolic diterpene mainly found in labiate plants, exerts various biological functions, including antioxidant, anti-inflammatory, antitumor, and neuroprotective activities. In the present study, we proved the deleterious effects of CA against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. In vitro, CA significantly decreased cell viability, inhibited cell proliferation and migration, enhanced apoptosis, and increased caspase-3, -8, and -9 activities in HepG2 and SMMC-7721 cells. Specifically, CA led to a decreased mitochondrial membrane potential (MMP) and increases in intracellular reactive oxygen species (ROS) levels and apoptosis-related protein expression. Pre-incubation of HCC cells with N-Acetyl-l-cysteine (NAC), a ROS inhibitor, strongly suppressed CA-induced apoptotic phenomena, including reduced cell viability, excessive ROS levels, MMP decreases, and abnormal protein expression, suggesting an association of CA-induced apoptosis with oxidative stress-mediated mitochondrial pathways. In HepG2-and SMMC-7721-xenograft tumor mouse models, treatment with CA inhibited tumor growth and modulated apoptosis-related protein expression, confirming the anti-HCC effects of this chemical. Moreover, the CA-mediated anti-HCC effects associated with oxidative stress provide experimental evidence to support the potential use of CA as a drug therapy for HCC.
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Affiliation(s)
- Xinrui Zhang
- School of Life Sciences, Jilin University, Jilin, 130012, China.
| | - Yiling Chen
- School of Life Sciences, Jilin University, Jilin, 130012, China; Zhuhai College of Jilin University, Jilin University, Zhuhai, 519000, China; Southern Research Institute, Jilin University, Zhuhai, 519000, China.
| | - Guangsheng Cai
- School of Life Sciences, Jilin University, Jilin, 130012, China.
| | - Xin Li
- Zhuhai College of Jilin University, Jilin University, Zhuhai, 519000, China; Southern Research Institute, Jilin University, Zhuhai, 519000, China.
| | - Di Wang
- School of Life Sciences, Jilin University, Jilin, 130012, China; Zhuhai College of Jilin University, Jilin University, Zhuhai, 519000, China.
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Ravaioli M, Cucchetti A, Pinna AD, De Pace V, Neri F, Barbera MA, Maroni L, Frega G, Palloni A, De Lorenzo S, Ripoli MC, Pantaleo MA, Cescon M, Del Gaudio M, Brandi G. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. Sci Rep 2017; 7:11305. [PMID: 28900245 PMCID: PMC5595852 DOI: 10.1038/s41598-017-11810-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/14/2017] [Indexed: 12/17/2022] Open
Abstract
The management of recurrent hepatocellular carcinoma untreatable with surgical options is based on systemic therapy with sorafenib. Due to the high rates of adverse events connected to the therapy with sorafenib, metronomic capecitabine seems a promising strategy for these patients. We analyzed the data of 38 patients with hepatocellular carcinoma recurrent after liver transplantation performed at our center. We compared the outcome of 17 patients receiving metronomic capecitabine versus 20 patients experiencing best supportive care and versus the data of the literature about treatment with sorafenib. In the group treated with metronomic capecitabine we observed an increased survival after tumor recurrence at the univariate and multivariate analysis compared to the group of best supportive care (median 22 months vs. 7 months, p < 0.01). Data from the literature on the use of sorafenib showed outcomes like our study group, with similar patient and tumoral features. The episodes of acute rejection and the tumor stage at the recurrence showed a correlation with patient survival at the univariate analysis. The metronomic capecitabine for hepatocellular cancer recurrent after liver transplantation seems effective without important adverse events and comparable results to sorafenib.
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Affiliation(s)
- Matteo Ravaioli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy.
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Vanessa De Pace
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Flavia Neri
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Lorenzo Maroni
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Cristina Ripoli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Massimo Del Gaudio
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
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Takahashi K, Putchakayala KG, Safwan M, Kim DY. Extrahepatic metastasis of hepatocellular carcinoma to the paravertebral muscle: A case report. World J Hepatol 2017; 9:973-978. [PMID: 28839518 PMCID: PMC5550763 DOI: 10.4254/wjh.v9.i22.973] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/29/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
Identification of extrahepatic metastases (EHM) of hepatocellular carcinoma (HCC) has been paradoxically increasing due to an increase in the survival of HCC patients. However, metastasis of HCC to the skeletal muscle tissue is extremely rare. We describe a unique case of HCC metastasizing to the paravertebral muscle. A 55-year-old man with a history of hepatitis B cirrhosis underwent partial liver resection with complete removal of HCC. Three months later, a computed tomography (CT) scan showed intrahepatic recurrence. The tumors were treated with yttrium-90 microspheres, trans-catheter arterial chemoembolization, and sorafenib. Six months later, a CT scan showed an enhancing lesion of the left paravertebral muscle that on biopsy were consistent with metastatic HCC. The tumor was treated with stereotactic hypo-fractionated image-guided radiation therapy (SHFRT). A follow-up scan 3 mo post-radiotherapy revealed a stable appearance of the paravertebral muscle metastasis. Because of the progression in the intrahepatic tumors, the patient was treated with capecitabine, which was changed to dasatinib 6 mo later. The patient passed away three years after the primary surgical resection. Management of EHM poses an extreme challenge. This is the first case of HCC with EHM to the paravertebral muscle in which stability of disease was achieved using SHFRT. This case highlights the importance of early detection of hepatitis B viral infection and initiation of anti-viral therapy to decrease recurrence of HCC and prevent EHM.
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Rimassa L, Pressiani T, Personeni N, Santoro A. Regorafenib for the treatment of unresectable hepatocellular carcinoma. Expert Rev Anticancer Ther 2017; 17:567-576. [PMID: 28580808 DOI: 10.1080/14737140.2017.1338955] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions.
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Affiliation(s)
- Lorenza Rimassa
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy
| | - Tiziana Pressiani
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy
| | - Nicola Personeni
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy.,b Department of Medical Biotechnology and Translational Medicine , University of Milan , Milan , Italy
| | - Armando Santoro
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy.,c Humanitas University , Rozzano ( Milan ), Italy
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