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1
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Khan R, Ghazali FM, Mahyudin NA, Samsudin NIP. Biocontrol of Aflatoxins Using Non-Aflatoxigenic Aspergillus flavus: A Literature Review. J Fungi (Basel) 2021; 7:jof7050381. [PMID: 34066260 PMCID: PMC8151999 DOI: 10.3390/jof7050381] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/07/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Aflatoxins (AFs) are mycotoxins, predominantly produced by Aspergillus flavus, A. parasiticus, A. nomius, and A. pseudotamarii. AFs are carcinogenic compounds causing liver cancer in humans and animals. Physical and biological factors significantly affect AF production during the pre-and post-harvest time. Several methodologies have been developed to control AF contamination, yet; they are usually expensive and unfriendly to the environment. Consequently, interest in using biocontrol agents has increased, as they are convenient, advanced, and friendly to the environment. Using non-aflatoxigenic strains of A. flavus (AF−) as biocontrol agents is the most promising method to control AFs’ contamination in cereal crops. AF− strains cannot produce AFs due to the absence of polyketide synthase genes or genetic mutation. AF− strains competitively exclude the AF+ strains in the field, giving an extra advantage to the stored grains. Several microbiological, molecular, and field-based approaches have been used to select a suitable biocontrol agent. The effectiveness of biocontrol agents in controlling AF contamination could reach up to 99.3%. Optimal inoculum rate and a perfect time of application are critical factors influencing the efficacy of biocontrol agents.
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Affiliation(s)
- Rahim Khan
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Malaysia; (R.K.); (N.I.P.S.)
| | - Farinazleen Mohamad Ghazali
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Malaysia; (R.K.); (N.I.P.S.)
- Correspondence: ; Tel.: +60-12219-8912
| | - Nor Ainy Mahyudin
- Department of Food Service and Management, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Malaysia;
- Laboratory of Halal Science Research, Halal Products Research Institute, Universiti Putra Malaysia, Serdang 43400, Malaysia
| | - Nik Iskandar Putra Samsudin
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Malaysia; (R.K.); (N.I.P.S.)
- Laboratory of Food Safety and Food Integrity, Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Serdang 43400, Malaysia
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2
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Amerizadeh F, Khazaei M, Maftouh M, Mardani R, Bahrami A. miRNA Targeting Angiogenesis as a Potential Therapeutic Approach in the Treatment of Colorectal Cancers. Curr Pharm Des 2019; 24:4668-4674. [DOI: 10.2174/1381612825666190110161843] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/27/2018] [Accepted: 01/01/2019] [Indexed: 12/11/2022]
Abstract
Angiogenesis refers to the formation of recent blood vessels, which is one of the characteristics of
cancer progression and it has been deliberated as a putative target to the treatment of many kinds of cancers. The
VEGF signaling substrate is very important for angiogenesis and is commonly high-regulated in tumors. As a
result, this molecule has attracted the attention of most of the researchers to develop antiangiogenic therapies. We
have presented that VEGF blockage in neoadjuvant setting via bevacizumab, aflibercept and sunitinib not only
has revealed some promising benefits but also has shown a large negative outcome in the adjuvant trials. However,
at an advanced stage of tumors, suppression of VEGF alone is inadequate to stop advancement, encouraging
drug resistance, and probably enhancing metastasis and invasion in the tumor microenvironment, thereby suggesting
the therapeutic potential of targeting angiogenic pathways in gastrointestinal cancers.
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Affiliation(s)
- Forouzan Amerizadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Maftouh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Mardani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
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3
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Lim HY, Merle P, Weiss KH, Yau T, Ross P, Mazzaferro V, Blanc JF, Ma YT, Yen CJ, Kocsis J, Choo SP, Sukeepaisarnjaroen W, Gérolami R, Dufour JF, Gane EJ, Ryoo BY, Peck-Radosavljevic M, Dao T, Yeo W, Lamlertthon W, Thongsawat S, Teufel M, Roth K, Reis D, Childs BH, Krissel H, Llovet JM. Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma. Clin Cancer Res 2018; 24:4650-4661. [PMID: 29950351 DOI: 10.1158/1078-0432.ccr-17-3588] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC.Patients and Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS).Results: Of 1,318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and β-catenin (CTNNB1; 37.0%).Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR.
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Affiliation(s)
- Ho Yeong Lim
- Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
| | - Philippe Merle
- Service of Hepato-Gastroenterology, Hepatology Unit, Croix-Rousse Hospital, Lyon, France
| | - Karl Heinz Weiss
- Section of Transplant Hepatology, Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Paul Ross
- Cancer Centre, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplant Unit, The Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute) and University of Milan, Milan, Italy
| | - Jean-Frédéric Blanc
- Service of Hepato-Gastroenterology and Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux, France
| | - Yuk Ting Ma
- Department of Medical Oncology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Chia Jui Yen
- Division of Hematology and Oncology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Judit Kocsis
- Oncology Department, Debrecen University Clinical Center, Debrecen, Hungary
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | | | - René Gérolami
- Service of Hepato-Gastroenterology, Aix-Marseille University, Marseille, France
| | - Jean-François Dufour
- Department of Hepatology, University Clinic for Visceral Surgery and Medicine, University Hospital of Bern, Bern, Switzerland
| | - Edward J Gane
- New Zealand Liver & Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, Seoul, Korea
| | - Markus Peck-Radosavljevic
- Department of Gastroenterology and Hepatology, Endocrinology, Rheumatology and Nephrology, Medical University of Vienna, Vienna, Austria
| | - Thong Dao
- Service of Hepato-Gastroenterology and Nutrition, Caen University Hospital, Caen, France
| | - Winnie Yeo
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong
| | | | - Satawat Thongsawat
- Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand
| | - Michael Teufel
- Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey
| | | | - Diego Reis
- Medical and Data Management, Bayer S.A., São Paulo, Brazil
| | | | | | - Josep M Llovet
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York.
- Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer Group (BCLC), IDIBAPS-Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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4
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Lee DW, Lee KH, Kim HJ, Kim TY, Kim JS, Han SW, Oh DY, Kim JH, Im SA, Kim TY. A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma. BMC Cancer 2018; 18:252. [PMID: 29506478 PMCID: PMC5838934 DOI: 10.1186/s12885-018-4039-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 01/23/2018] [Indexed: 02/01/2023] Open
Abstract
Background Oxaliplatin is a platinum derivative that has shown efficacy in advanced hepatocellular carcinoma. S-1 is an oral fluoropyrimidine that has substituted for 5-fluorouracil in many cancers. This was a multicenter, open-label, single-arm phase II trial that evaluated the efficacy of S-1 and oxaliplatin (SOX) in advanced hepatocellular carcinoma. All patients included in the present study were systemic treatment-naïve. Prior treatment with sorafenib was allowed, but other treatments were not. Methods Patients received S-1 (40 mg/m2 twice daily from day 1–14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. The primary end point was time to progression (TTP). Secondary end points included progression-free survival, overall survival (OS), response rate, and safety profile. Results Thirty six patients with advanced hepatocellular carcinoma were included in this study. The median TTP was 3.0 months (95% confidence interval (CI), 0.75–5.25), and the median OS was 10.3 months (95% CI, 6.4–14.3). Bone metastasis was associated with poorer TTP and OS. The efficacy of SOX was unaffected by prior sorafenib or locoregional therapy. The objective response rate was 13.9%. No grade 4 toxicity or death from adverse events occurred. The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%). Conclusions Although this trial did not meet its primary end point, the SOX regimen showed comparable efficacy and safety to the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen. As the SOX regimen is easier for patients, SOX may be a reasonable substitute for FOLFOX in hepatocellular carcinoma. Trial registration Clinicaltrials.gov NCT01429961. Registered 7 September 2011.
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Affiliation(s)
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Hee-Jun Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jin-Soo Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea. .,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
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5
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The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma. Ann Hematol 2018; 97:839-849. [DOI: 10.1007/s00277-018-3237-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
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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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7
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Dika IE, Abou-Alfa GK. Treatment options after sorafenib failure in patients with hepatocellular carcinoma. Clin Mol Hepatol 2017; 23:273-279. [PMID: 29151326 PMCID: PMC5760005 DOI: 10.3350/cmh.2017.0108] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 09/19/2017] [Indexed: 12/20/2022] Open
Abstract
Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma.
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Affiliation(s)
- Imane El Dika
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
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8
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Pinter M, Weinmann A, Wörns MA, Hucke F, Bota S, Marquardt JU, Duda DG, Jain RK, Galle PR, Trauner M, Peck-Radosavljevic M, Sieghart W. Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United European Gastroenterol J 2017; 5:987-996. [PMID: 29163965 PMCID: PMC5676550 DOI: 10.1177/2050640617695698] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/01/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies. OBJECTIVE The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC). METHODS Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses. RESULTS In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4-0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76). CONCLUSION RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A.
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Affiliation(s)
- Matthias Pinter
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA
| | - Arndt Weinmann
- Department of Medicine I, University Medical Center Johannes Gutenberg University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center Johannes Gutenberg University, Mainz, Germany
- Clinical Registry Unit (CRU), University Medical Center Johannes Gutenberg University, Mainz, Germany
| | - Marcus-Alexander Wörns
- Department of Medicine I, University Medical Center Johannes Gutenberg University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center Johannes Gutenberg University, Mainz, Germany
| | - Florian Hucke
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Department of Gastroenterology & Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Simona Bota
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Department of Gastroenterology & Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Johannes Gutenberg University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center Johannes Gutenberg University, Mainz, Germany
| | - Dan G Duda
- Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA
| | - Rakesh K Jain
- Department of Radiation Oncology, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA
| | - Peter R Galle
- Department of Medicine I, University Medical Center Johannes Gutenberg University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center Johannes Gutenberg University, Mainz, Germany
| | - Michael Trauner
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Department of Gastroenterology & Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Wolfgang Sieghart
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Wang EA, Stein JP, Bellavia RJ, Broadwell SR. Treatment options for unresectable HCC with a focus on SIRT with Yttrium-90 resin microspheres. Int J Clin Pract 2017; 71. [PMID: 28758319 DOI: 10.1111/ijcp.12972] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 05/10/2017] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the second leading cause of cancer-related deaths across the globe. Only a small percentage of HCC patients (~20%-30%) are diagnosed at an early stage when first-line treatment options may be effective. The majority of HCC patients (>70%) are diagnosed with unresectable disease and given a poor overall prognosis. Current treatment guidelines recommend locoregional therapy with transarterial chemoembolisation (TACE) and systemic therapy with sorafenib as first-line treatment for patients with intermediate and advanced stage HCC. However, multiple factors including contraindications, technical considerations and treatment-related toxicities pose significant challenges in achieving favourable treatment outcomes, underscoring the need for a paradigm shift in managing these patients. In 2002, yttrium-90 (Y-90) resin microspheres was approved by the U.S. Food and Drug Administration (FDA) for the treatment of unresectable metastatic colorectal cancer to the liver with adjuvant floxuridine chemotherapy. However, thousands of patients with unresectable HCC have also been treated with resin Y-90. For over two decades, several small-scale prospective trials and retrospective studies have investigated and reported on the efficacy of locoregional selective internal radiation therapy (SIRT) with Y-90 microspheres in treating unresectable HCC. Although it is currently a treatment option for intermediate-stage HCC patients, mainstream clinical application of resin Y-90 has been largely limited because of the lack of sufficient clinical data from a randomised controlled trial. This could change with the imminent announcement of results from the phase 3 Sorafenib vs Radioembolization in Advanced Hepatocellular carcinoma (SARAH) trial. To provide the foundation and context for interpreting results from the SARAH trial, this article provides an overview of treatment modalities and current challenges in managing unresectable HCC. There is also a review of key prospective and retrospective studies evaluating the use of Y-90 SIRT, specifically Y-90 resin microspheres in unresectable HCC, which led to the development of the SARAH trial. METHODS To identify relevant publications, the PubMed database was queried using one or more of the following search terms alone or in combination with Boolean operators: epidemiology, hepatocellular, hepatocellular cancer, hepatocellular carcinoma, unresectable, radioembolisation, selective internal radiation therapy, SIR-Spheres, yttrium 90, TACE, and sorafenib. The results were sorted or filtered by "Author", "Publication dates" or "Article types" to identify articles relevant to each section of the review. To ensure that information on ongoing clinical trials involving Y-90 resin was included, we conducted a search on "ClinicalTrials.gov", by combining the search terms "HCC" OR "hepatocellular carcinoma" with "Y 90" OR "yttrium 90" OR "radioembo", and screened for studies that involved treatment with Y-90 resin microspheres.
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Affiliation(s)
- Eric A Wang
- Charlotte Radiology, Carolinas Medical Center, Charlotte, NC, USA
| | - Jeff P Stein
- Charlotte Radiology, Carolinas Medical Center, Charlotte, NC, USA
| | - Ross J Bellavia
- Charlotte Radiology, Carolinas Medical Center, Charlotte, NC, USA
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10
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Ascierto PA, Daniele B, Hammers H, Hirsh V, Kim J, Licitra L, Nanda R, Pignata S. Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge", Napoli, November 30th 2016. J Transl Med 2017; 15:205. [PMID: 29020960 PMCID: PMC5637331 DOI: 10.1186/s12967-017-1309-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 09/30/2017] [Indexed: 12/26/2022] Open
Abstract
The complex interactions between the immune system and tumors lead the identification of key molecules that govern these interactions: immunotherapeutics were designed to overcome the mechanisms broken by tumors to evade immune destruction. After the substantial advances in melanoma, immunotherapy currently includes many other type of cancers, but the melanoma lesson is essential to progress in other type of cancers, since immunotherapy is potentially improving clinical outcome in various solid and haematologic malignancies. Monotherapy in pre-treated NSCLC is studied and the use of nivolumab, pembrolizumab and atezolizumab as second-line of advanced NSCLC is demonstrated as well as first line monotherapy and combination therapy in metastatic NSCLC studied. Patients with HNSCC have immunotherapeutic promises as well: the FDA recently approved moAbs targeting immune checkpoint receptors. Nivolumab in combination with ipilumumab showed acceptable safety and encouraging antitumor activity in metastatic renal carcinoma. HCCs have significant amounts of genomic heterogeneity and multiple oncogenic pathways can be activated: the best therapeutic targets identification is ongoing. The treatment of advanced/relapsed EOC remain clearly an unmet need: a better understanding of the relevant immuno-oncologic pathways and their corresponding biomarkers are required. UC is an immunotherapy-responsive disease: after atezolizumab, three other PD-L1/PD-L1 inhibitors (nivolumab, durvalumab, and avelumab) were approved for treatment of platinum-refractory metastatic urothelial carcinoma. Anti-PD-1/PD-L1 monotherapy is associated with a modest response rate in metastatic breast cancer; the addition of chemotherapy is associated with higher response rates. Immunotherapy safety profile is advantageous, although, in contrast to conventional chemotherapy: boosting the immune system leads to a unique constellation of inflammatory toxicities known as immune-related Adverse Events (irAEs) that may warrant the discontinuation of therapy and/or the administration of immunosuppressive agents. Research should explore better combination with less side effects, the right duration of treatments, combination or sequencing treatments with target therapies. At present, treatment decision is based on patient's characteristics.
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Affiliation(s)
- Paolo A. Ascierto
- Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori “Fondazione G. Pascale”, Via Mariano Semmola, 80131 Naples, Italy
| | - Bruno Daniele
- Department of Oncology and Medical Oncology Unit, G. Rummo Hospital, Benevento, Italy
| | | | - Vera Hirsh
- McGill Department of Oncology, McGill University, Montreal, Canada
| | - Joseph Kim
- Medical Oncology, Yale School of Medicine, New Haven, CT USA
| | - Lisa Licitra
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Rita Nanda
- Section of Hematology–Oncology, Department of Medicine, The University of Chicago, Chicago, IL USA
| | - Sandro Pignata
- Department of Urology and Gynecology, Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy
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11
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Sahin B. Enlighting the Shadow for Advanced Hepatocellular Carcinoma: Immunotherapy with Immune Checkpoint Inhibitors. J Gastrointest Cancer 2017; 48:288-290. [PMID: 28836129 DOI: 10.1007/s12029-017-9996-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma has still been one of the cancer with increasing incidence and highest mortality rate in the world. Although many new promising developments have been defined in hepatocarcinogenesis, with a short survival the treatment of patients with advanced hepatocellular carcinoma is an emerging issue. On the recent decade, only one anti-angiogenic agent sorafenib improved overall survival with costing a hardly manageable toxicity. Novel immunotherapeutic agents, especially immune checkpoint inhibitors are on the edge of more effective but less toxic treatments for these patients. In this article the activity of immune checkpoint inhibitors, anti-CTLA-4 and anti-PD1 antibodies for the treatment of patients with advanced hepatocellular cancer will be reviewed.
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Affiliation(s)
- Berksoy Sahin
- Medical Oncology Department, Cukurova University, Balcali, 01330, Adana, Turkey.
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12
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Crocetti L, Bargellini I, Cioni R. Loco-regional treatment of HCC: current status. Clin Radiol 2017; 72:626-635. [PMID: 28258743 DOI: 10.1016/j.crad.2017.01.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/18/2017] [Accepted: 01/25/2017] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) represents one of the few cancers for which locoregional treatments are recognised as being able to cure and/or prolong survival and are included in international guidelines. This is due to the unique nature of HCC, in most cases occurring in patients with underlying virus- or alcohol-related cirrhosis. The treatment choice in patients with HCC is therefore driven not only by tumour staging, as in the great majority of cancers, but also by careful evaluation of liver function and physical status. Another specific feature of HCC is that it is the only tumour that can be cured by organ transplantation, with the aim of treating both the cancer and underlying liver disease. These characteristics configure a complex scenario and prompt the need for close cooperation among interventional oncologists, surgeons, hepatologists, and anaesthesiologists. In patients with limited hepatic disease, preserved hepatic function and good performance status, categorised as very early and early-stage HCC according to the Barcelona Clinic Liver Cancer (BCLC) classification, image-guided tumour ablation is included among the curative treatments. More than half of patients with HCC are, however, diagnosed late, despite the widespread implementation of surveillance programmes, when curative treatments cannot be applied. For patients presenting with multinodular HCC and relatively preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread transcatheter arterial chemoembolisation (TACE) is the current standard of care. Although anti-tumour activity and promising survival results has been reported in cohorts of patients with advanced HCC treated with radio-embolisation, systemic treatment with the multi-kinase inhibitor, sorafenib, is still recommended for patients at this stage. In this article, current treatment strategies for HCC according to tumour stage are discussed, underlining the latest advances in the literature and technical developments.
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Affiliation(s)
- L Crocetti
- Division of Interventional Radiology, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Cisanello University Hospital, Pisa, Italy.
| | - I Bargellini
- Division of Interventional Radiology, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Cisanello University Hospital, Pisa, Italy
| | - R Cioni
- Division of Interventional Radiology, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Cisanello University Hospital, Pisa, Italy
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13
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Casadei Gardini A, Santini D, Aprile G, Silvestris N, Felli E, Foschi FG, Ercolani G, Marisi G, Valgiusti M, Passardi A, Puzzoni M, Silletta M, Brunetti O, Cardellino GG, Frassineti GL, Scartozzi M. Antiangiogenic agents after first line and sorafenib plus chemoembolization: a systematic review. Oncotarget 2017; 8:66699-66708. [PMID: 29029548 PMCID: PMC5630448 DOI: 10.18632/oncotarget.19449] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 04/27/2017] [Indexed: 12/31/2022] Open
Abstract
Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage, although the combination of TACE with sorafenib may theoretically benefit HCC patients in intermediate stage. Owing to the significant antiangiogenic effect of sorafenib and the limitation of TACE, it is rational to combine them. Though the strategy of combining TACE and sorafenib has been increasingly used in patients with unresectable HCC but the current evidence is controversial and its clinical role has not been determined yet. In first-line therapy, patients receiving sorafenib had increased overall survival and progression free survival. Therefore several antiangiogenic agents have entered clinical studies on HCC, many with negative results. This review discusses the current drug development for patients with HCC and role of TACE plus sorafenib.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Daniele Santini
- Medical Oncology Department, University Campus Bio-Medico, Via Álvaro del Portillo, Rome, Italy
| | - Giuseppe Aprile
- Department of Medical Oncology, University Hospital, Udine, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Emanuele Felli
- Hôpital Hautepierre Service de Chirurgie Générale, Hépatique, Endocrinienne et Transplantation Université de Strasbourg, Strasbourg, France
| | | | - Giorgio Ercolani
- Department of General Surgery, Morgagni-Pierantoni Hospiatal, AUSL Romagna, Forli, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Marco Puzzoni
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Marianna Silletta
- Medical Oncology Department, University Campus Bio-Medico, Via Álvaro del Portillo, Rome, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | | | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
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14
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Gaba RC, Lokken RP, Hickey RM, Lipnik AJ, Lewandowski RJ, Salem R, Brown DB, Walker TG, Silberzweig JE, Baerlocher MO, Echenique AM, Midia M, Mitchell JW, Padia SA, Ganguli S, Ward TJ, Weinstein JL, Nikolic B, Dariushnia SR. Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy. J Vasc Interv Radiol 2017; 28:1210-1223.e3. [PMID: 28669744 DOI: 10.1016/j.jvir.2017.04.025] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 04/29/2017] [Indexed: 02/07/2023] Open
Affiliation(s)
- Ron C Gaba
- Division of Interventional Radiology, Department of Radiology, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612.
| | - R Peter Lokken
- Division of Interventional Radiology, Department of Radiology, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612
| | - Ryan M Hickey
- Section of Vascular and Interventional Radiology, Department of Radiology, Northwestern Memorial Hospital, Chicago, Illinois
| | - Andrew J Lipnik
- Division of Interventional Radiology, Department of Radiology, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612
| | - Robert J Lewandowski
- Section of Vascular and Interventional Radiology, Department of Radiology, Northwestern Memorial Hospital, Chicago, Illinois
| | - Riad Salem
- Section of Vascular and Interventional Radiology, Department of Radiology, Northwestern Memorial Hospital, Chicago, Illinois
| | - Daniel B Brown
- Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - T Gregory Walker
- Division of Interventional Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | | | - Ana Maria Echenique
- Department of Interventional Radiology, University of Miami School of Medicine, Coral Gables, Florida
| | - Mehran Midia
- Interventional Radiology, McMaster University, Hamilton, Ontario, Canada
| | - Jason W Mitchell
- Interventional Radiology and Image Guided Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Siddharth A Padia
- Division of Interventional Radiology, Department of Radiology, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Suvranu Ganguli
- Division of Interventional Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Center for Image Guided Cancer Therapy, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Thomas J Ward
- Vascular and Interventional Radiology, Florida Hospital, Orlando, Florida
| | - Jeffrey L Weinstein
- Vascular and Interventional Radiology, Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Boris Nikolic
- Department of Radiology, Stratton Medical Center, Albany, New York
| | - Sean R Dariushnia
- Interventional Radiology and Image Guided Medicine, Emory University School of Medicine, Atlanta, Georgia
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15
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Ziogas IA, Tsoulfas G. Evolving role of Sorafenib in the management of hepatocellular carcinoma. World J Clin Oncol 2017; 8:203-213. [PMID: 28638790 PMCID: PMC5465010 DOI: 10.5306/wjco.v8.i3.203] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/03/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.
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16
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Hubbard JM, Mahoney MR, Loui WS, Roberts LR, Smyrk TC, Gatalica Z, Borad M, Kumar S, Alberts SR. Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group Trial N0745 (Alliance). Target Oncol 2017; 12:201-209. [PMID: 27943153 PMCID: PMC5586602 DOI: 10.1007/s11523-016-0467-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis. OBJECTIVE To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC. PATIENTS AND METHODS Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID. RESULTS Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively. CONCLUSIONS The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.).
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Affiliation(s)
| | | | | | - Lewis R Roberts
- Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA
| | - Thomas C Smyrk
- Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA
| | | | | | - Shaji Kumar
- Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA
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17
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Kolly P, Dufour JF. Patients with hepatocellular carcinoma: Your address matters! J Hepatol 2017; 66:480-481. [PMID: 27965157 DOI: 10.1016/j.jhep.2016.11.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 11/28/2016] [Indexed: 12/04/2022]
Affiliation(s)
- Philippe Kolly
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
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18
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Archbold J. Recent Developments in Regorafenib Treatment for Gastrointestinal Cancers: Presentations at the Meeting of the European Society for Medical Oncology (ESMO) Congress 2016. EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10311298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023] Open
Abstract
The European Society for Medical Oncology (ESMO) Congress was held in Copenhagen, Denmark from 7th–11th October 2016. The use of the promiscuous multikinase inhibitor regorafenib (Stivarga®, BAY 73-4506) in the treatment of cancers of the gastrointestinal (GI) tract was strongly featured at this meeting. Regorafenib targets multiple kinases involved in oncogenesis and angiogenesis, and is US Food and Drug Administration (FDA)-approved for the treatment of advanced metastatic colorectal cancer and GI stromal tumours, following progression on standard therapies. In this review, we summarise the results of completed clinical trials on the use of regorafenib alone or in combination with other therapies for the treatment of GI cancers. We highlight the results of the Phase III RESORCE study which demonstrated the efficacy of regorafenib as a second-line therapy in patients with advanced hepatocellular carcinoma who have progressed on sorafenib. We review some promising preliminary data on the use of regorafenib in other GI cancers, such as gastric cancer, oesophageal cancer, pancreatic cancer, and soft tissue carcinomas, and provide a brief overview of ongoing and planned trials. Finally, we discuss the incidence and management of regorafenib-related toxicities and summarise attempts to identify predictive biomarkers of regorafenib sensitivity.
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19
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TTP as a surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy: meta-analysis of randomised controlled trials. Br J Cancer 2016; 115:1201-1205. [PMID: 27736843 PMCID: PMC5104893 DOI: 10.1038/bjc.2016.322] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 09/01/2016] [Accepted: 09/07/2016] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Time to progression (TTP) is suggested as a reliable endpoint compared with the progression-free survival in the clinical trials of hepatocellular carcinoma (HCC). However, the correlation between TTP and overall survival (OS) has never been studied. METHODS We searched PubMed and Embase data to obtain data source. Eligible studies were randomised controlled phase III trials, which evaluated the efficacy of systemic chemotherapy or molecular targeted therapy in advanced HCC. The association of treatment effects as shown by the hazard ratio (HR) of TTP and OS in each trial was assessed by the Spearman rank correlation coefficient (rs) and linear regression analysis. The association between median TTP and OS was also investigated. RESULTS Nine studies with a total of 18 treatment arms and 6318 patients were included. Incremental benefit from the study treatment in TTP from each trial was correlated with incremental benefit in OS. The rs value and R2 value between log (HRTTP) and log (HROS) was 0.73 (95% confidence interval (CI) 0.12-0.94, P=0.024) and 0.57. The minimum TTP effect to predict a treatment effect on OS was 0.63. Median TTP was associated with median OS. The rs value between TTP and OS was 0.73 (95% CI 0.40-0.89, P<0.001) and the corresponding R2 was 0.42. CONCLUSIONS Our study results suggest that TTP could be used as a surrogate marker for OS in the clinical trials of advanced HCC. However, the results suggest modest correlation between treatment effects on TTP and OS.
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