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Zhang Y, Jin Z, Wang Z, Yan L, Liu A, Li F, Li Y, Zhang Y. Trends in Colorectal Cancer Peritoneal Metastases Research: A Comprehensive Bibliometric Analysis. J Gastrointest Cancer 2025; 56:51. [PMID: 39847239 DOI: 10.1007/s12029-025-01176-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) stands as the third most prevalent malignancy globally and is recognized as the second leading cause of cancer-related mortality. Notably, nearly 50% of individuals diagnosed with CRC ultimately develop metastatic disease, with the peritoneum emerging as the second most frequent site for metastatic spread. Recent advancements in therapeutic frameworks have enhanced both survival rates and quality of life metrics for patients afflicted with colorectal cancer peritoneal metastases (CRCPM). OBJECTIVE This study endeavors to facilitate an in-depth review of the current scientific landscape surrounding CRCPM, ultimately aiming to delineate future avenues for investigative research in this realm. METHODS Employing R software through the Bibliometrix package, alongside analytical tools such as CiteSpace and VOSviewer, we performed a comprehensive bibliometric analysis. This enabled us to assess pivotal keywords, prominent authors, influential countries, notable institutions, relevant literature, and key journals pertinent to the field of CRCPM research. RESULTS Our findings illustrate a significant uptick in the volume of publications addressing CRCPM, with the USA leading in overall contribution, complemented by substantial input from distinguished scholars in the Netherlands and France. The author Ignace H. J. T. de Hingh emerged as the most prolific contributor. Current research endeavors have predominantly focused on the characterization of primary malignancies with peritoneal metastases, therapeutic interventions for CRCPM, and the orchestration of clinical trials. CONCLUSION This analysis culminates in a systematic encapsulation of the prevailing research findings concerning CRCPM, underscoring current hotspots and predicting future trends within the global research spectrum. The exploration of treatment modalities for CRCPM remains vibrant, and ongoing multicenter clinical trials are anticipated to further enrich our understanding and management of this challenging clinical issue.
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Affiliation(s)
- Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Zi Jin
- Nuclear Medicine Department, Shenyang Fifth People's Hospital, Shenyang, 110001, China
| | - Zhongqing Wang
- Department of Information Center, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Lirong Yan
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Aoran Liu
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Fang Li
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Yanke Li
- Department of Anorectal Surgery, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, China.
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Mirza MB, Smith PM, Wang Y, Naveed A, Washington MK, Xu Y, Idrees K. Intra-Patient Heterogeneity in Micro-satellite-stable Colorectal Metastases: Does Immunotherapy Have a Role in Colorectal Peritoneal Metastases? Ann Surg Oncol 2024; 31:1440-1443. [PMID: 38110752 DOI: 10.1245/s10434-023-14694-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023]
Affiliation(s)
- M B Mirza
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - P Marincola Smith
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Y Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - A Naveed
- Division of Otolaryngology, Head and Neck Surgery, Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M K Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Y Xu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - K Idrees
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
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Chen YC, Huang CW, Li CC, Chang TK, Su WC, Chen PJ, Yeh YS, Chang YT, Tsai HL, Shih MCP, Wang JY. Efficacy of transarterial chemoembolization with drug-eluting beads combined with systemic chemotherapy and targeted therapy in colorectal cancer liver metastasis. World J Surg Oncol 2023; 21:378. [PMID: 38041083 PMCID: PMC10691074 DOI: 10.1186/s12957-023-03253-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 11/13/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Systemic therapy is the standard treatment for unresectable colorectal cancer with liver metastasis (CRCLM). Transarterial chemoembolization with drug-eluting beads (DEB-TACE) is considered an effective treatment option for CRCLM. Few studies have investigated the combination of DEB-TACE, chemotherapy, and targeted therapy for CRCLM. In the present study, we evaluated the disease control rate (DCR), adverse events, and survival among patients with CRCLM who underwent the combination of DEB-TACE and chemotherapy/targeted therapy. MATERIALS We retrospectively reviewed 35 patients with CRCLM who were treated between January 2015 and January 2021. Standard systemic chemotherapy, targeted therapy, and 66 DEB-TACE procedures were administered. Data were collected on each DEB-TACE procedure, including chemotherapy agents, tumor burden of liver metastasis, number of DEB-TACE courses, and adverse events. Patients who received DEB-TACE after failure of first-line systemic therapy were categorized into the first-line failure group. Patients who received DEB-TACE after the failure of second-line, third-line, or fourth-line therapy were categorized into the other group. Subgroup analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups. RESULTS In total, 35 patients with CRCLM (34 patients with adenocarcinoma and 1 patient with neuroendocrine carcinoma) were enrolled. In total, 13 patients (37.1%) had extrahepatic metastases at initial diagnosis. In this study, 66 DEB-TACE procedures were performed. The DCR was 54.3%. The median OS period was 47.4 months, and the estimated 3-year OS rate was 59.5%. The median PFS period was 6.3 months, and the estimated 1-year PFS rate was 20.6%. The PFS period was longer in the first-line failure group than in the other group (7.2 vs. 6.3 months). No significant difference was observed in OS between the two groups. Four episodes (6.1%) of grade 3 intra-abdominal infection were observed. CONCLUSION The combination of chemotherapy, targeted therapy, and DEB-TACE can lead to a favorable DCR and survival outcomes in patients with CRCLM. Early intervention with DEB-TACE (i.e., after the failure of first-line therapy) has the potential to extend the PFS period in patients with CRCLM. Severe adverse events were rare and manageable. Further prospective, randomized controlled studies are warranted to obtain more conclusive findings.
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Affiliation(s)
- Yen-Cheng Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Chun Li
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
| | - Tsung-Kun Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wei-Chih Su
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Po-Jung Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
| | - Yung-Sung Yeh
- Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Emergency Medicine, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yu-Tang Chang
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Pediatric Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Chen Paul Shih
- Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
| | - Jaw-Yuan Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1St Road, Kaohsiung, 807, Taiwan.
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
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D'Onofrio R, Caputo F, Prampolini F, Spallanzani A, Gelsomino F, Bettelli S, Manfredini S, Reggiani Bonetti L, Carotenuto P, Bocconi A, Dominici M, Luppi G, Salati M. CtDNA-guided rechallenge with anti-EGFR therapy in RASwt metastatic colorectal cancer: Evidence from clinical practice. TUMORI JOURNAL 2023; 109:387-393. [PMID: 36113407 DOI: 10.1177/03008916221122554] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
AIM To apply extended ctDNA-based RAS genotyping to clinical criteria for improving the selection of patients eligible for anti-EGFR-based rechallenge in a real-world setting. METHODS ctDNA testing was prospectively applied to RASwt mCRC progressed after a first-line anti-EGFR-containing regimen and at least one other line. The primary endpoint was the objective response rate. RESULTS Among ten enrolled patients, the anti-EGFR rechallenge resulted in an objective response rate and disease control rate of 70% and 90%. The median progression-free survival was 11.3 months and overall survival was not reached. Compared with a historical cohort retreated with anti-EGFR agents based on clinical criteria, the ctDNA-driven approach resulted in a higher chance of achieving an objective response and longer survival. CONCLUSIONS Blood-based RASwt status may enrich metastatic colorectal cancer more likely to benefit from anti-EGFR-based rechallenge. RAS genotyping in ctDNA represents a feasible, fast, and cost-effective tool to be implemented in the clinic for advancing precision medicine.
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Affiliation(s)
- Raffaella D'Onofrio
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | | | - Luca Reggiani Bonetti
- Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Azienda Ospedaliero Universitaria Policlinico, Modena, Italy
| | - Pietro Carotenuto
- TIGEM, Telethon Institute of Genetics and Medicine, Naples, Italy
- Medical Genetics, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Alessandro Bocconi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
- PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
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Li YJ, Tang DX, Yan HT, Yang B, Yang Z, Long FX. Network pharmacology and molecular docking-based analyses to predict the potential mechanism of Huangqin decoction in treating colorectal cancer. World J Clin Cases 2023; 11:4553-4566. [PMID: 37469733 PMCID: PMC10353508 DOI: 10.12998/wjcc.v11.i19.4553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/27/2023] [Accepted: 06/13/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND To analyze the potential action mechanism of Huangqin decoction (HQD) in colorectal cancer (CRC) treatment on the basis of network pharmacology and molecular docking.
AIM To investigate the molecular mechanisms of HQD for CRC treatment by using network pharmacology and molecular docking.
METHODS All HQD active ingredients were searched using the Systematic Pharmacology and Traditional Chinese Medicine Systems Pharmacology databases and the Bioinformatics Analysis Tool for Molecular Mechanisms in traditional Chinese medicine. Then, the targets of the active ingredients were screened. The abbreviations of protein targets were obtained from the UniProt database. A “drug–compound–target” network was constructed to screen for some main active ingredients. Some targets related to the therapeutic effect of CRC were obtained from the GeneCards, DisGeNET, Therapeutic Target Database, and Online Mendelian Inheritance in Man databases. The intersection of targets of Chinese herbs and CRC was taken. A Venn diagram was drawn to construct the intersection target interactions network by referring to the STRING database. Topological analysis of the protein interaction network was performed using Cytoscape 3.7.2 software to screen the core HQD targets for CRC. The core targets were imported into the DAVID 6.8 analysis website for gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses and visualization. Finally, molecular docking was performed using AutoDockTool and PyMOL for validation.
RESULTS In total, 280 potential drug-active ingredients were present in HQD, including 1474 targets of the drug-active ingredients. The main active ingredients identified were betulin, tetrahydropalmatine, and quercetin. In total, 10249 CRC-related targets and 1014 drug-disease intersecting targets were identified, including 28 core targets of action such as Jun proto-oncogene, AP-1 transcription factor subunit, signal transducer and activator of transcription 3, tumor protein p53, vascular endothelial growth factor, and AKT serine/threonine kinase 1. The gene ontology enrichment functional analysis yielded 503 enrichment results, including 406 biological processes that were mainly related to the positive regulation of both gene expression and transcription and cellular response to hypoxia, etc. In total, 38 cellular components were primarily related to polymer complexes, transcription factor complexes, and platelet alpha granule lumen. Then, 59 molecular functions were closely related to the binding of enzymes, homologous proteins, and transcription factors. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis yielded 139 enrichment results, involving epidermal growth factor receptor tyrosine kinase inhibitor resistance and HIF-1 and mitogen-activated protein kinase signaling pathways.
CONCLUSION HQD can play a role in CRC treatment through the “multi-component-target–pathway”. The active ingredients betulin, tetrahydropalmatine, and quercetin may act on targets such as Jun proto-oncogene, AP-1 transcription factor subunit, signal transducer and activator of transcription 3, tumor protein p53, vascular endothelial growth factor, and AKT serine/threonine kinase 1, which in turn regulate HIF-1 and mitogen-activated protein kinase signaling pathways in CRC treatment. The molecular docking junction clarified that all four key target proteins could bind strongly to the main HQD active ingredients. This indicates that HQD could slow down CRC progression by modulating multiple targets and signaling pathways.
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Affiliation(s)
- Ying-Jie Li
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550005, Guizhou Province, China
| | - Dong-Xin Tang
- Digestive Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Hong-Ting Yan
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Bing Yang
- Digestive Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Zhu Yang
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Feng-Xi Long
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Gui Yang 550001, Guizhou Province, China
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Aggarwal H, Han Y, Sheffield KM, Cui ZL. Real-world comparison between weekly versus biweekly dosing of cetuximab for metastatic colorectal cancer. J Comp Eff Res 2023; 12:e220143. [PMID: 36705061 PMCID: PMC10288952 DOI: 10.2217/cer-2022-0143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
Aim: This real-world study aims to compare overall survival (OS) associated with biweekly (Q2W) versus weekly (Q1W) cetuximab dosing regimens for metastatic colorectal cancer (mCRC) treatment in the US. Methods: Adult patients with KRAS wild-type mCRC who received cetuximab ± chemotherapy from 2013 to 2019 were selected using Flatiron Health's electronic health records database. Propensity score matching was used to balance Q2W and Q1W cohorts on baseline patient characteristics. The Kaplan-Meier method was used for survival analyses. Several sensitivity analyses were conducted to assess the robustness of findings from the main analysis. Results: Of 1075 patients in the study, 60.7% received cetuximab Q1W and 39.3% Q2W. Median OS (95% confidence interval) in months was 17.2 (15.3, 18.8) for Q2W versus 14.3 (12.8, 16.0) for Q1W; p = 0.246. Similar OS between the dosing cohorts was observed in sensitivity analyses. Conclusion: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study.
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Affiliation(s)
- Himani Aggarwal
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
| | - Yimei Han
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
| | | | - Zhanglin Lin Cui
- Eli Lilly and Company, 893 S Delaware St., Indianapolis, IN 46225, USA
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Ashique S, Garg A, Singh V, Rai G, Mishra N, Soni ML, Kumar S, Madamsetty VS. Role of Block Copolymers in Colon Cancer. BLOCK CO-POLYMERIC NANOCARRIERS: DESIGN, CONCEPT, AND THERAPEUTIC APPLICATIONS 2023:181-209. [DOI: 10.1007/978-981-99-6917-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Chen YC, Chuang CH, Miao ZF, Yip KL, Liu CJ, Li LH, Wu DC, Cheng T, Lin CY, Wang JY. Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer. Front Oncol 2022; 12:955313. [PMID: 36212420 PMCID: PMC9539537 DOI: 10.3389/fonc.2022.955313] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/19/2022] [Indexed: 12/19/2022] Open
Abstract
Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The β-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.
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Affiliation(s)
- Yen-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Zhi-Feng Miao
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kwan-Ling Yip
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Jung Liu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Deng-Chyang Wu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian−Lu Cheng
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Yen Lin
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
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Mahgoub E, Taneera J, Sulaiman N, Saber-Ayad M. The role of autophagy in colorectal cancer: Impact on pathogenesis and implications in therapy. Front Med (Lausanne) 2022; 9:959348. [PMID: 36160153 PMCID: PMC9490268 DOI: 10.3389/fmed.2022.959348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is considered as a global major cause of cancer death. Surgical resection is the main line of treatment; however, chemo-, radiotherapy and other adjuvant agents are crucial to achieve good outcomes. The tumor microenvironment (TME) is a well-recognized key player in CRC progression, yet the processes linking the cancer cells to its TME are not fully delineated. Autophagy is one of such processes, with a controversial role in the pathogenesis of CRC, with its intricate links to many pathological factors and processes. Autophagy may apparently play conflicting roles in carcinogenesis, but the precise mechanisms determining the overall direction of the process seem to depend on the context. Additionally, it has been established that autophagy has a remarkable effect on the endothelial cells in the TME, the key substrate for angiogenesis that supports tumor metastasis. Favorable response to immunotherapy occurs only in a specific subpopulation of CRC patients, namely the microsatellite instability-high (MSI-H). In view of such limitations of immunotherapy in CRC, modulation of autophagy represents a potential adjuvant strategy to enhance the effect of those relatively safe agents on wider CRC molecular subtypes. In this review, we discussed the molecular control of autophagy in CRC and how autophagy affects different processes and mechanisms that shape the TME. We explored how autophagy contributes to CRC initiation and progression, and how it interacts with tumor immunity, hypoxia, and oxidative stress. The crosstalk between autophagy and the TME in CRC was extensively dissected. Finally, we reported the clinical efforts and challenges in combining autophagy modulators with various cancer-targeted agents to improve CRC patients’ survival and restrain cancer growth.
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Affiliation(s)
- Eglal Mahgoub
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Nabil Sulaiman
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Medicine, Cairo University, Giza, Egypt
- *Correspondence: Maha Saber-Ayad,
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Tsai HL, Chen YC, Yin TC, Su WC, Chen PJ, Chang TK, Li CC, Huang CW, Wang JY. Comparison of UGT1A1 Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy. Oncol Res 2022; 29:47-61. [PMID: 35177165 PMCID: PMC9110692 DOI: 10.3727/096504022x16451187313084] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.032.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.5171.027; hazard ratio (HR), 0.729; p=0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.4101.008; HR, 0.643; p=0.054), ORR (65.3% vs. 62.7%; p=0.720), DCR (92.8% vs. 86.7%; p=0.175), metastatectomy (36.7% vs. 29.3%; p=0.307), and SAEs (p=0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p>0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.
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Affiliation(s)
- Hsiang-Lin Tsai
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- †Department of Surgery, Faculty of Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Yen-Cheng Chen
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- ‡Graduate Institute of Clinical Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Tzu-Chieh Yin
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- §Division of General and Digestive Surgery, Department of
Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical
University, Kaohsiung, Taiwan
- ¶Department of Surgery, Kaohsiung Municipal Tatung
Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Wei-Chih Su
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- ‡Graduate Institute of Clinical Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Po-Jung Chen
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Tsung-Kun Chang
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- †Department of Surgery, Faculty of Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Ching-Chun Li
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Ching-Wen Huang
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- †Department of Surgery, Faculty of Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- *Division of Colorectal Surgery, Department of Surgery,
Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung, Taiwan
- †Department of Surgery, Faculty of Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
- ‡Graduate Institute of Clinical Medicine, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
- #Graduate Institute of Medicine, College of Medicine, Kaohsiung
Medical University, Kaohsiung,
Taiwan
- **Center for Cancer Research, Kaohsiung Medical
University, Kaohsiung, Taiwan
- ††Center for Liquid Biopsy and Cohort Research,
Kaohsiung Medical University, Kaohsiung,
Taiwan
- ‡‡Pingtung Hospital, Ministry of Health and
Welfare, Pingtung, Taiwan
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11
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Xiao M, Benoit A, Hasmim M, Duhem C, Vogin G, Berchem G, Noman MZ, Janji B. Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies. Front Oncol 2021; 11:626309. [PMID: 33718194 PMCID: PMC7951055 DOI: 10.3389/fonc.2021.626309] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.
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Affiliation(s)
- Malina Xiao
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Alice Benoit
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Meriem Hasmim
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Caroline Duhem
- Department of Hemato-oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg
| | - Guillaume Vogin
- Université de Lorraine - UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Vandoeuvre-lès-Nancy, France.,Centre François Baclesse, Esch-sur-Alzette, Luxembourg
| | - Guy Berchem
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg.,Department of Hemato-oncology, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg
| | - Muhammad Zaeem Noman
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Bassam Janji
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
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12
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Ali O, Tolaymat M, Hu S, Xie G, Raufman JP. Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22020716. [PMID: 33450835 PMCID: PMC7828259 DOI: 10.3390/ijms22020716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 01/05/2023] Open
Abstract
Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. This review examines a relatively untapped reservoir of potential therapies to target muscarinic receptor expression, activation, and signaling in colorectal cancer. Most colorectal cancers overexpress M3 muscarinic receptors (M3R), and both in vitro and in vivo studies have shown that activating these receptors stimulates cellular programs that result in colon cancer growth, survival, and spread. In vivo studies using mouse models of intestinal neoplasia have shown that using either genetic or pharmacological approaches to block M3R expression and activation, respectively, attenuates the development and progression of colon cancer. Moreover, both in vitro and in vivo studies have shown that blocking the activity of matrix metalloproteinases (MMPs) that are induced selectively by M3R activation, i.e., MMP1 and MMP7, also impedes colon cancer growth and progression. Nonetheless, the widespread expression of muscarinic receptors and MMPs and their importance for many cellular functions raises important concerns about off-target effects and the safety of employing similar strategies in humans. As we highlight in this review, highly selective approaches can overcome these obstacles and permit clinicians to exploit the reliance of colon cancer cells on muscarinic receptors and their downstream signal transduction pathways for therapeutic purposes.
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Affiliation(s)
- Osman Ali
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
| | - Mazen Tolaymat
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
| | - Shien Hu
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
| | - Guofeng Xie
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA 21201, USA
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA 21201, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA 21201, USA
- Correspondence: ; Tel.: +1-410-328-8728
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13
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Maspes A, Pizzetti F, Rossetti A, Makvandi P, Sitia G, Rossi F. Advances in Bio-Based Polymers for Colorectal CancerTreatment: Hydrogels and Nanoplatforms. Gels 2021; 7:6. [PMID: 33440908 PMCID: PMC7838948 DOI: 10.3390/gels7010006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/29/2020] [Accepted: 01/07/2021] [Indexed: 12/27/2022] Open
Abstract
Adenocarcinoma of the colon is the most common malignant neoplasia of the gastrointestinal tract and is a major contributor to mortality worldwide. Invasiveness and metastatic behavior are typical of malignant tumors and, because of its portal drainage, the liver is the closest capillary bed available in this case, hence the common site of metastatic dissemination. Current therapies forecast total resection of primary tumor when possible and partial liver resection at advanced stages, along with systemic intravenous therapies consisting of chemotherapeutic agents such as 5-fluorouracil. These cures are definitely not exempt from drawbacks and heavy side effects. Biocompatible polymeric networks, both in colloids and bulk forms, able to absorb large quantities of water and load a variety of molecules-belong to the class of innovative drug delivery systems, thus suitable for the purpose and tunable on each patient can represent a promising alternative. Indeed, the implantation of polymeric scaffolds easy to synthesize can substitute chemotherapy and combination therapies scheduling, shortening side effects. Moreover, they do not require a surgical removal thanks to spontaneous degradation and guarantees an extended and regional cargo release, maintaining high drug concentrations. In this review, we focus our attention on the key role of polymeric networks as drug delivery systems potentially able to counteract this dramatic disease.
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Affiliation(s)
- Anna Maspes
- Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milan, Italy; (A.M.); (F.P.); (A.R.)
| | - Fabio Pizzetti
- Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milan, Italy; (A.M.); (F.P.); (A.R.)
| | - Arianna Rossetti
- Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milan, Italy; (A.M.); (F.P.); (A.R.)
| | - Pooyan Makvandi
- Istituto Italiano di Tecnologia, Centre for Micro-BioRobotics, 56025 Pisa, Italy;
| | - Giovanni Sitia
- Division of Immunology, Transplantation and Infectious Diseases, Experimental Hepatology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
| | - Filippo Rossi
- Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milan, Italy; (A.M.); (F.P.); (A.R.)
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14
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Tsai HL, Huang CW, Lin YW, Wang JH, Wu CC, Sung YC, Chen TL, Wang HM, Tang HC, Chen JB, Ke TW, Tsai CS, Huang HY, Wang JY. Determination of the UGT1A1 polymorphism as guidance for irinotecan dose escalation in metastatic colorectal cancer treated with first-line bevacizumab and FOLFIRI (PURE FIST). Eur J Cancer 2020; 138:19-29. [PMID: 32829105 DOI: 10.1016/j.ejca.2020.05.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/08/2020] [Accepted: 05/21/2020] [Indexed: 12/31/2022]
Abstract
AIM Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. METHODS The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate. RESULTS Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively). CONCLUSION The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities. CLINICAL TRIAL REGISTRATION NCT02256800.
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Affiliation(s)
- Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Yi-Wen Lin
- Division of Colorectal Surgery, Department of Surgery, Tainan Municipal Hospital, Tainan, Taiwan.
| | - Jui-Ho Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
| | - Chang-Chieh Wu
- Division of Colorectal Surgery, Department of Surgery, Keelung Branch, Tri-Service General Hospital, Keelung, Taiwan.
| | - Yung-Chuan Sung
- Division of Medical Oncology, Department of Internal Medicine, Taipei Cathay General Hospital, Taipei, Taiwan.
| | - Tzu-Liang Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan.
| | - Hwei-Ming Wang
- Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan.
| | - Hsiu-Chin Tang
- Division of Colorectal Surgery, Department of Surgery, Tainan Sin-Lan Hospital, Tainan, Taiwan.
| | - Joe-Bin Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
| | - Tao-Wei Ke
- Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan.
| | - Chang-Sung Tsai
- Division of Medical Oncology, Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan.
| | - Hsuan-Yuan Huang
- Division of Colorectal Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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15
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Mele L, Del Vecchio V, Liccardo D, Prisco C, Schwerdtfeger M, Robinson N, Desiderio V, Tirino V, Papaccio G, La Noce M. The role of autophagy in resistance to targeted therapies. Cancer Treat Rev 2020; 88:102043. [PMID: 32505806 DOI: 10.1016/j.ctrv.2020.102043] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023]
Abstract
Autophagy is a self-degradative cellular process, involved in stress response such as starvation, hypoxia, and oxidative stress. This mechanism balances macro-molecule recycling to regulate cell homeostasis. In cancer, autophagy play a role in the development and progression, while several studies describe it as one of the key processes in drug resistance. In the last years, in addition to standard anti-cancer treatments such as chemotherapies and irradiation, targeted therapy became one of the most adopted strategies in clinical practices, mainly due to high specificity and reduced side effects. However, similar to standard treatments, drug resistance is the main challenge in most patients. Here, we summarize recent studies that investigated the role of autophagy in drug resistance after targeted therapy in different types of cancers. We highlight positive results and limitations of pre-clinical and clinical studies in which autophagy inhibitors are used in combination with targeted therapies.
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Affiliation(s)
- Luigi Mele
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Vitale Del Vecchio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Davide Liccardo
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Claudia Prisco
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy; The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
| | - Melanie Schwerdtfeger
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy; Department of Medicine IV -Division of Clinical Pharmacology-University of Munich, Germany
| | - Nirmal Robinson
- Centre for Cancer Biology, SA Pathology and University of South Australia, GPO Box 2471, Adelaide, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Virginia Tirino
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
| | - Gianpaolo Papaccio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy.
| | - Marcella La Noce
- Department of Experimental Medicine, University of Campania "L. Vanvitelli" Naples, Italy
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16
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Liu N, Wu C, Jia R, Cai G, Wang Y, Zhou L, Ji Q, Sui H, Zeng P, Xiao H, Liu H, Huo J, Feng Y, Deng W, Li Q. Traditional Chinese Medicine Combined With Chemotherapy and Cetuximab or Bevacizumab for Metastatic Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Front Pharmacol 2020; 11:478. [PMID: 32372960 PMCID: PMC7187887 DOI: 10.3389/fphar.2020.00478] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/26/2020] [Indexed: 12/29/2022] Open
Abstract
Background Huangci Granule is a traditional Chinese medicine for treating metastatic colorectal cancer (mCRC). Objective To evaluate the efficacy and safety of Huangci Granule combination with chemotherapy and cetuximab (CET) or bevacizumab (BV) for treating mCRC. Methods We performed a randomized, controlled, and double-blind trial and recruited patients with mCRC who were planned to undergo chemotherapy combined with CET or BV. The treatment group was treated with Huangci Granule, while the control group was treated with placebo. Continuous treatment until disease progression, death, intolerable toxicity or up to 6 months. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was quality of life and safety. Result 320 patients were randomly assigned to receive treatment, including 200 first-line patients and 120 second-line patients. In the first-line treatment, the median PFS was 9.59 months (95% CI, 6.94–13.25) vs 6.89 months (95% CI, 4.99–9.52) in treatment group and control group (HR, 0.69; 95% CI, 0.50–0.97; P = 0.027). Chinese medicine was an independent factor affecting the PFS. In the second-line treatment, the median PFS was 6.51 months (95% CI, 4.49–9.44) vs 4.53 months (95% CI, 3.12–6.57) in the treatment group and control group (HR, 0.65; 95% CI, 0.45–0.95; P = 0.020). Compared with the control group, “role function,” “social function,” “fatigue,” and “appetite loss” were significantly improved in the treatment (P < 0.05) and drug related grades 3 to 4 adverse events were less. Conclusion Huangci Granule combined with chemotherapy and CET or BV can prolong the PFS of mCRC, improve the quality of life, reduce adverse reactions, and have good safety.
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Affiliation(s)
- Ningning Liu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chaojun Wu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ru Jia
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guoxiang Cai
- Department of Colorectal Cancer Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lihong Zhou
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Ji
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Sui
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Puhua Zeng
- Cancer Research Institute, Hunan Academy of Traditional Chinese Medicine, Changsha, China
| | - Haijuan Xiao
- Department of Oncology, Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, China
| | - Huaimin Liu
- Department of Integrated Chinese and Western Medicine, Henan Provincial Cancer Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Feng
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanli Deng
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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17
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Lau DK, Burge M, Roy A, Chau I, Haller DG, Shapiro JD, Peeters M, Pavlakis N, Karapetis CS, Tebbutt NC, Segelov E, Price TJ. Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019. Expert Rev Anticancer Ther 2020; 20:251-270. [PMID: 32186929 DOI: 10.1080/14737140.2020.1744439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype.Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping.Expert opinion: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended RAS wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor RAS, BRAF, HER2 and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with KRAS G12 C mutation and gene TRK fusion defects.
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Affiliation(s)
- David K Lau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | - Matthew Burge
- Medical Oncology, Royal Brisbane Hospital, Brisbane, Australia.,University of Queensland, Brisbane, Australia
| | - Amitesh Roy
- Medical Oncology, Flinders Centre for Innovation in Cancer, Bedford Park, Australia
| | - Ian Chau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | - Daniel G Haller
- Abramson Cancer Center at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeremy D Shapiro
- Monash University, Melbourne, Australia.,Medical Oncology, Cabrini Medical Centre, Melbourne, Australia
| | - Marc Peeters
- Medical Oncology, University Hospital Antwerp, Edegem, Belgium
| | - Nick Pavlakis
- Medical Oncology, Royal North Shore Hospital, St Leonards, Australia.,Sydney University, Camperdown, Sydney, Australia
| | | | - Niall C Tebbutt
- Medical Oncology, Austin Health, Heidelberg, Australia.,Department of Surgery, University of Melbourne, Melbourne, Australia
| | - Eva Segelov
- Monash University, Melbourne, Australia.,Medical Oncology, Monash Medical Centre, Clayton, Australia
| | - Timothy J Price
- Medical Oncology, The Queen Elizabeth Hospital, Woodville, Australia
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18
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Ceelen W, Ramsay RG, Narasimhan V, Heriot AG, De Wever O. Targeting the Tumor Microenvironment in Colorectal Peritoneal Metastases. Trends Cancer 2020; 6:236-246. [PMID: 32101726 DOI: 10.1016/j.trecan.2019.12.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/01/2023]
Abstract
Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma.
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Affiliation(s)
- Wim Ceelen
- Department of Human Structure and Repair, Ghent University, B-9000 Ghent, Belgium; Department of GI Surgery, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
| | - Robert G Ramsay
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Vignesh Narasimhan
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Alexander G Heriot
- Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Olivier De Wever
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium; Laboratory for Experimental Cancer Research, Ghent University, Ghent, Belgium
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19
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The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression. Cancers (Basel) 2019; 11:cancers11030308. [PMID: 30841571 PMCID: PMC6468573 DOI: 10.3390/cancers11030308] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 02/22/2019] [Accepted: 02/27/2019] [Indexed: 02/08/2023] Open
Abstract
Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and protein are over-expressed in colon cancer, and M3R can be activated by both traditional (e.g., acetylcholine) and non-traditional (e.g., bile acids) muscarinic ligands. In this review, we weigh the data supporting a prominent role for key protein kinases downstream of M3R activation in promoting colon cancer progression and dissemination. Specifically, we explore the roles that downstream activation of the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK), protein kinase C, p38 MAPK, and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways play in mediating colon cancer cell proliferation, survival, migration and invasion. We assess the impact of M3R-stimulated induction of selected matrix metalloproteinases germane to these hallmarks of colon cancer progression. In this context, we also critically review the reproducibility of findings derived from a variety of in vivo and in vitro colon cancer models, and their fidelity to human disease. Finally, we summarize the therapeutic potential of targeting various steps from ligand-M3R interaction to the activation of key downstream molecules.
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20
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Siravegna G, Bardelli A. Failure is not final: ctDNA-guided rechallenge therapy in colorectal cancer. Ann Oncol 2019; 30:157-159. [PMID: 30475974 DOI: 10.1093/annonc/mdy525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- G Siravegna
- Department of Oncology, University of Torino, Turin, Italy; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
| | - A Bardelli
- Department of Oncology, University of Torino, Turin, Italy; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
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21
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Wang J, Lu Y, Zeng Y, Zhang L, Ke K, Guo Y. Expression profile and biological function of miR-455-5p in colorectal carcinoma. Oncol Lett 2018; 17:2131-2140. [PMID: 30675279 PMCID: PMC6341642 DOI: 10.3892/ol.2018.9862] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 10/17/2018] [Indexed: 01/19/2023] Open
Abstract
Underexpression of microRNA-455-5p (miR-455-5p) in medullary thyroid carcinoma, melanoma, gastric cancer and additional cancer types has been reported, which may be associated with carcinoma development. The present study aimed to evaluate the expression profile and biological role of miR-455-5p in colorectal carcinoma. Carcinoma tissues and adjacent tissue specimens from 40 patients with colorectal cancer were randomly collected. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was conducted to detect the expression levels of miR-455-5p in colorectal carcinoma and adjacent normal tissues. The biological effects of miR-455-5p on selected colorectal cancer cells were assessed using bromodeoxyuridine assays, wound healing migration assays and flow cytometry. Bioinformatics analysis was implemented to predict the potential target genes of miR-455-5p in colorectal cancer. The expression levels of target genes were further validated by RT-qPCR and western blot analysis of the mRNA and protein levels. The results of the experiments demonstrated that miR-455-5p expression was downregulated in colorectal cancer tissues compared with adjacent normal tissues. In colorectal cancer cells (SW-480, HT-29 and HCT-116), miR-455-5p was observed to inhibit cell proliferation and migration while promoting cell apoptosis. Bioinformatics analysis predicted that the oncogene phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was one of the top ranked target genes of miR-455-5p in colorectal cancer cells. This association was validated by RT-qPCR and western blotting. In vivo studies revealed that the expression level of miR-455-5p was significantly downregulated in human colorectal cancer. Further in vitro studies suggested that miR-455-5p may prevent the development of colorectal cancer by downregulating the oncogene PIK3R1. It was concluded that miR-455-5p may target and downregulate PIK3R1 in colorectal cancer.
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Affiliation(s)
- Jinqiu Wang
- Department of Breast Surgery, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Yang Lu
- Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Yiyong Zeng
- Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Leming Zhang
- Department of Proctology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Kongliang Ke
- Department of Proctology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Yu Guo
- Department of Breast Surgery, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
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22
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Yeatman TJ, Yang M, Coppola D. Whole Genome Sequencing Analysis of a Stage IV Colon Cancer Patient with a 10-Year Disease-Free Survival following Systemic Chemotherapy/Bevacizumab. Case Rep Gastroenterol 2018; 12:729-736. [PMID: 30631260 PMCID: PMC6323361 DOI: 10.1159/000494751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 10/15/2018] [Indexed: 12/14/2022] Open
Abstract
It is rare that stage IV colon cancer is cured with chemotherapy. Here we report the long-term survival of a patient who presented with highly advanced disease characterized by a papillary architecture as well as porta hepatis lymph nodes but responded extremely well to FOLFIRI/bevacizumab. His original tumor underwent comprehensive genomic testing that included whole genome DNA sequencing, targeted sequencing, and RNA sequencing. These genetic results suggest the patient's tumor harbored mutations in APC, KRAS, and TP53 as well as in PIK3CB. Moreover, the RNA-seq data suggested that the tumor belonged to the consensus molecular subtype 4, the "inflamed, immune phenotype," with increased angiogenesis. Deep sequencing of highly responsive cancers may yield molecular insights into mechanisms underpinning a remarkable response.
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Affiliation(s)
- Timothy J. Yeatman
- Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina, USA
| | - Mingli Yang
- Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina, USA
| | - Domenico Coppola
- Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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23
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Price TJ, Tang M, Gibbs P, Haller DG, Peeters M, Arnold D, Segelov E, Roy A, Tebbutt N, Pavlakis N, Karapetis C, Burge M, Shapiro J. Targeted therapy for metastatic colorectal cancer. Expert Rev Anticancer Ther 2018; 18:991-1006. [PMID: 30019590 DOI: 10.1080/14737140.2018.1502664] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Outcomes in metastatic colorectal cancer are improving, with better understanding and use of targeted therapies. Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This article reviews the current evidence for targeted therapies in advanced colorectal cancer, including up-to-date data regarding anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor (VEGF) agents, the relevance of primary tumor location and novel subgroups such as BRAF mutated, HER2 amplified, and mismatch-repair-deficient cancers. Expert commentary: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for metastatic colorectal cancer (mCRC). The use of EGFR-targeted antibodies should be restricted to patients with extended RAS wild-type profiles, and there is evidence that they should be further restricted to patients with left-sided tumors. Clinically, mCRC can be divided into subgroups based on RAS, BRAF, HER2, and MMR status, each of which have distinct treatment pathways.
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Affiliation(s)
- Timothy J Price
- a Medical Oncology , The Queen Elizabeth Hospital, Woodville, and University of Adelaide , Adelaide , Australia
| | - Monica Tang
- b Medical Oncology , NHMRC Clinical Trials Centre, University of Sydney , Sydney , Australia
| | - Peter Gibbs
- c Medical Oncology , Western Hospital , Melbourne , Australia.,d Medical Oncology , Walter and Eliza Hall Institute , Melbourne , Australia
| | - Daniel G Haller
- e Medical Oncology , Abrahamson Cancer Centre at the Perelman School of Medicine, University of Pennsylvania , Philadelphia , USA
| | - Marc Peeters
- f Medical Oncology , University Hospital Antwerp, Edegem, Belgiumg Asklepios Tumorzentrum Hamburg , Hamburg , Germany
| | - Dirk Arnold
- g Medical Oncology , Asklepios Tumorzentrum Hamburg , Germany
| | - Eva Segelov
- h Medical Oncology , Monash University School of Clinical Sciences at Monash Health, Monash Medical Centre , Clayton , Australia
| | - Amitesh Roy
- i Medical Oncology , Flinders Centre for Innovation in Cancer , Bedford Park , Australia.,j Medical Oncology , Flinders University , Bedford Park , Australia
| | - Niall Tebbutt
- k Medical Oncology , Austin Health , Heidelberg , Australia
| | - Nick Pavlakis
- l Medical Oncology , Royal North Shore Hospital , St Leonards , Australia
| | - Chris Karapetis
- i Medical Oncology , Flinders Centre for Innovation in Cancer , Bedford Park , Australia
| | - Matthew Burge
- m Medical Oncology , Royal Brisbane Hospital , Brisbane , Australia
| | - Jeremy Shapiro
- n Medical Oncology , Cabrini Hospital and Monash University , Melbourne , Australia
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24
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McGregor M, Price TJ. Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC. Future Oncol 2018; 14:2437-2459. [PMID: 29737864 DOI: 10.2217/fon-2017-0711] [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: 12/21/2022] Open
Abstract
The humanized monoclonal antibody panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of panitumumab continues to evolve as understanding of sequencing of therapies grows. There is evidence for use as maintenance therapy and conversion therapy for unresectable liver metastases. Future research is likely to focus on biomarkers for improved patient selection and the development of novel therapeutic strategies to overcome resistance.
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Affiliation(s)
- Mark McGregor
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, Flinders Medical Centre, Adelaide, Australia
| | - Timothy J Price
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, The Queen Elizabeth Hospital & University of Adelaide, Woodville, Adelaide, Australia
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25
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Geng F, Wang Z, Yin H, Yu J, Cao B. Molecular Targeted Drugs and Treatment of Colorectal Cancer: Recent Progress and Future Perspectives. Cancer Biother Radiopharm 2018. [PMID: 28622036 DOI: 10.1089/cbr.2017.2210] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ∼50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab. The development of these drugs marked significant advancement in the field of mCRC therapy. The addition of biologic agents to chemotherapy has prolonged the median overall survival. Now, many investigational drugs are under clinical trials, of which programmed death (PD)-1/L1 has drawn much attention. In this review, new biologic agents under clinical trials such as MEK/MET/RAS/RAF/PD-1 inhibitors with potentials for mCRC treatment are concluded by describing targeted drugs approved by FDA, to offer new insights into global trends and future development.
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Affiliation(s)
- Fang Geng
- 1 Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University , Beijing, China .,2 Cancer Center, Beijing Friendship Hospital, Capital Medical University , Beijing, China
| | - Zheng Wang
- 1 Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University , Beijing, China
| | - Hang Yin
- 1 Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University , Beijing, China
| | - Junxian Yu
- 1 Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University , Beijing, China
| | - Bangwei Cao
- 2 Cancer Center, Beijing Friendship Hospital, Capital Medical University , Beijing, China
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26
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Rangasamy L, Chelvam V, Kanduluru AK, Srinivasarao M, Bandara NA, You F, Orellana EA, Kasinski AL, Low PS. New Mechanism for Release of Endosomal Contents: Osmotic Lysis via Nigericin-Mediated K +/H + Exchange. Bioconjug Chem 2018; 29:1047-1059. [PMID: 29446616 DOI: 10.1021/acs.bioconjchem.7b00714] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although peptides, antibodies/antibody fragments, siRNAs, antisense DNAs, enzymes, and aptamers are all under development as possible therapeutic agents, the breadth of their applications has been severely compromised by their inability to reach intracellular targets. Thus, while macromolecules can often enter cells by receptor-mediated endocytosis, their missions frequently fail due to an inability to escape their entrapping endosomes. In this paper, we describe a general method for promoting release of any biologic material from any entrapping endosome. The strategy relies on the fact that all nascent endosomes contain extracellular (Na+-enriched) medium, but are surrounded by intracellular (K+-enriched) fluid in the cytoplasm. Osmotic swelling and rupture of endosomes will therefore be facilitated if the flow of K+ down its concentration gradient from the cytosol into the endosome can be facilitated without allowing downhill flow of Na+ from the endosome into the cytosol. While any K+ selective ionophore can promote the K+ specific influx, the ideal K+ ionophore will also exchange influxed K+ for an osmotically inactive proton (H+) in order to prevent buildup of an electrical potential that would rapidly halt K+ influx. The only ionophore that catalyzes this exchange of K+ for H+ efficiently is nigericin. We demonstrate here that ligand-targeted delivery of nigericin into endosomes that contain an otherwise impermeable fluorescent dye can augment release of the dye into the cell cytosol via swelling/bursting of the entrapping endosomes. We further show that nigericin-facilitated escape of a folate-targeted luciferase siRNA conjugate from its entrapping endosomes promotes rapid suppression of the intended luciferase reporter gene. Taken together, we propose that ionophore-catalyzed entry of K+ into endosomal compartments can promote the release of otherwise impermeable contents from their encapsulating endosomes.
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Affiliation(s)
- Loganathan Rangasamy
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States
| | - Venkatesh Chelvam
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States.,Discipline of Chemistry, Centre for Biosciences and Biomedical Engineering , Indian Institute of Technology , Indore , Madhya Pradesh , 453552 , India
| | - Ananda Kumar Kanduluru
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States
| | - Madduri Srinivasarao
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States
| | - N Achini Bandara
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States
| | - Fei You
- Endocyte, Inc. , 3000 Kent Avenue, Suite A1-100 , West Lafayette , Indiana 47906 , United States
| | - Esteban A Orellana
- Department of Biological Sciences, Bindley Bioscience Center , Purdue University , West Lafayette , Indiana 47907 , United States
| | - Andrea L Kasinski
- Department of Biological Sciences, Bindley Bioscience Center , Purdue University , West Lafayette , Indiana 47907 , United States
| | - Philip S Low
- Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette Indiana 47907 , United States
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27
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Li F, Li Q, Wu X. Construction and analysis for differentially expressed long non-coding RNAs and MicroRNAs mediated competing endogenous RNA network in colon cancer. PLoS One 2018; 13:e0192494. [PMID: 29420609 PMCID: PMC5805314 DOI: 10.1371/journal.pone.0192494] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 01/24/2018] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNA (lncRNA) has been confirmed to act as a key regulatory molecule in different types of cancers and play a significant role in tumors initiation and progression. LncRNA can be as acompeting endogenous RNA(ceRNA) to regulate the expression of targeted genes by sponging miRNA. In the present study, we explore the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in colon cancer and their potential implications for prognosis.The lncRNAs, miRNAs and mRNAs expression profiles of 341 colon cancer tissues and 27 non-tumor colon tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the “DESeq” bioconductor package in R. PPI network of differentially expressed genes was constructed using the STRING database. Survival analysis was estimated based on Kaplan-Meier curve analysis. We used KOBAS 3.0 to analyze the KEGG pathway of DEGs. The dysregulated lncRNA-associated ceRNA network was constructed in colon cancer based on bioinformatics generated from miRanda, PicTar, TargetScan, miRDB and miRcode. A total of 791 DElncRNAs and 200 DEmiRNAs were identified in colon cancer compared with matched normal tissues with thresholds of |log2foldChange (FC)| >3.0and adjusted P value<0.05.Twenty DElncRNAs were identified, may be related to tumorigenesis and/or progression of colon cancer. Nine out of 20 dysregulated lncRNA were found to be significantly associated with overall survival (P value<0.05). Finally, we successfully constructed colon cancer-associated ceRNA network, including 9 colon cancer-specific lncRNAs, 13 miRNAS and 70 mRNAs. In conclusion, our study will contribute to improve the understanding of ceRNA network regulatory mechanisms in colon cancer. These identified novel lncRNAs can be as candidate prognostic biomarkers or potential therapeutic targets.
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Affiliation(s)
- Fengxi Li
- Department of Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qian Li
- Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xianghua Wu
- Department of Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- * E-mail:
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28
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Nakanishi R, Kitao H, Kiniwa M, Morodomi Y, Iimori M, Kurashige J, Sugiyama M, Nakashima Y, Saeki H, Oki E, Maehara Y. Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication. Sci Rep 2017; 7:16969. [PMID: 29208954 PMCID: PMC5717244 DOI: 10.1038/s41598-017-17282-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 11/23/2017] [Indexed: 12/14/2022] Open
Abstract
Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients.
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Affiliation(s)
- Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hiroyuki Kitao
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan. .,Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
| | - Mamoru Kiniwa
- Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.,Taiho Pharmaceutical Co. Ltd.,, Tokushima and Ibaraki, Japan
| | - Yosuke Morodomi
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Makoto Iimori
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan
| | - Junji Kurashige
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Masahiko Sugiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka, Japan
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29
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Olmedillas-López S, Lévano-Linares DC, Alexandre CLA, Vega-Clemente L, Sánchez EL, Villagrasa A, Ruíz-Tovar J, García-Arranz M, García-Olmo D. Detection of KRAS G12D in colorectal cancer stool by droplet digital PCR. World J Gastroenterol 2017; 23:7087-7097. [PMID: 29093617 PMCID: PMC5656456 DOI: 10.3748/wjg.v23.i39.7087] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 09/15/2017] [Accepted: 09/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess KRAS G12D mutation detection by droplet digital PCR (ddPCR) in stool-derived DNA from colorectal cancer (CRC) patients.
METHODS In this study, tumor tissue and stool samples were collected from 70 patients with stage I-IV CRC diagnosed by preoperative biopsy. KRAS mutational status was determined by pyrosequencing analysis of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The KRAS G12D mutation was then analyzed by ddPCR in FFPE tumors and stool-derived DNA from patients with this point mutation. Wild-type (WT) tumors, as determined by pyrosequencing, were included as controls; analysis of FFPE tissue and stool-derived DNA by ddPCR was performed for these patients as well.
RESULTS Among the total 70 patients included, KRAS mutations were detected by pyrosequencing in 32 (45.71%), whereas 38 (54.29%) had WT tumors. The frequency of KRAS mutations was higher in left-sided tumors (11 located in the right colon, 15 in the left, and 6 in the rectum). The predominant point mutation was KRAS G12D (14.29%, n = 10), which was more frequent in early-stage tumors (I-IIA, n = 7). In agreement with pyrosequencing results, the KRAS G12D mutation was detected by ddPCR in FFPE tumor-derived DNA, and only a residual number of mutated copies was found in WT controls. The KRAS G12D mutation was also detected in stool-derived DNA in 80% of all fecal samples from CRC patients with this point mutation.
CONCLUSION ddPCR is a reliable and sensitive method to analyze KRAS G12D mutation in stool-derived DNA from CRC patients, especially at early stages. This non-invasive approach is potentially applicable to other relevant biomarkers for CRC management.
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Affiliation(s)
- Susana Olmedillas-López
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Dennis César Lévano-Linares
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | | | - Luz Vega-Clemente
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Edurne León Sánchez
- Department of Biomedicine and Biotechnology, Universidad de Alcalá, Madrid 28805, Spain
| | - Alejandro Villagrasa
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Jaime Ruíz-Tovar
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | - Mariano García-Arranz
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damián García-Olmo
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
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Ntavatzikos A, Spathis A, Patapis P, Machairas N, Peros G, Konstantoudakis S, Leventakou D, Panayiotides IG, Karakitsos P, Koumarianou A. Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer. World J Gastroenterol 2017; 23:5913-5924. [PMID: 28932083 PMCID: PMC5583576 DOI: 10.3748/wjg.v23.i32.5913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/22/2017] [Accepted: 07/22/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed. RESULTS The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively). CONCLUSION The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.
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Affiliation(s)
- Anastasios Ntavatzikos
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Aris Spathis
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Paul Patapis
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Nikolaos Machairas
- 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - George Peros
- Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, 11528 Athens, Greece
| | - Stefanos Konstantoudakis
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Danai Leventakou
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Ioannis G Panayiotides
- 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Petros Karakitsos
- Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
| | - Anna Koumarianou
- Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
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Yang M, Yeatman TJ. Molecular stratification of colorectal cancer populations and its use in directing precision medicine. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1362316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Mingli Yang
- Gibbs Research Institute, Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA
| | - Timothy J Yeatman
- Gibbs Research Institute, Gibbs Cancer Center & Research Institute, Spartanburg, SC 29303, USA
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Ma CJ, Huang CW, Yeh YS, Tsai HL, Hu HM, Wu IC, Cheng TL, Wang JY. Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated According to Uridine Diphosphate Glucuronosyltransferase 1A1 Genotyping in Patients With Metastatic Colorectal Cancer. Oncol Res 2017; 25:673-679. [PMID: 27938508 PMCID: PMC7840952 DOI: 10.3727/97818823455816x14786040691928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.
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Affiliation(s)
- Cheng-Jen Ma
- *Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- †Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- ‡Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- *Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- ‡Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- §Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yung-Sung Yeh
- *Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- †Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- ¶Division of Trauma and Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- *Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- §Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- #Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- **Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huang-Ming Hu
- ††Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- ‡‡Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Chen Wu
- ††Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- ‡‡Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- §§Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
- ¶¶Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- *Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- †Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- ‡Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- §Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- **Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- ¶¶Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
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Price TJ, Thavaneswaran S, Burge M, Segelov E, Haller DG, Punt CJ, Arnold D, Karapetis CS, Tebbutt NC, Pavlakis N, Gibbs P, Shapiro JD. Update on optimal treatment for metastatic colorectal cancer from the ACTG/AGITG expert meeting: ECCO 2015. Expert Rev Anticancer Ther 2017; 16:557-71. [PMID: 27010906 DOI: 10.1586/14737140.2016.1170594] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The treatment of metastatic CRC (mCRC) has evolved over the last 20 years, from fluoropyrimidines alone to combination chemotherapy and new biologic agents. Median overall survival is now over 24 months for RAS mutated (MT) patients and over 30 months for RAS wild-type (WT) patients. However, there are subgroups of patients with BRAF V600E MT CRC who have a significantly poorer outlook. Newer treatment options are also being explored in select subgroups of patients (anti-HER 2 in HER2 positive mCRC and immunotherapy in patients with defective mismatch repair (dMMR)). The best use of these systemic treatment options, as well as surgery in well-selected patients requires careful consideration of predictive biomarkers and importantly, the optimal sequence in which therapies should be given to derive maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, USA, The Netherlands and Germany met during ECCO 2015 in Vienna to review current practice.
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Affiliation(s)
- Timothy J Price
- a Medical Oncology, The Queen Elizabeth Hospital , Adelaide Colorectal Tumour Group and University of Adelaide , Adelaide , Australia
| | | | - Matthew Burge
- c Medical Oncology, Royal Brisbane Hospital , Brisbane , Australia
| | - Eva Segelov
- d St Vincent's Clinical School, Faculty of Medicine , University of NSW , Sydney , Australia
| | - Daniel G Haller
- e Abramson Cancer Centre , University of Pennsylvania , Philadelphia , USA
| | - Cornelis Ja Punt
- f Academic Medical Center , University of Amsterdam , Amsterdam, The Netherlands
| | - Dirk Arnold
- g Medical Oncology, Klinik für Tumorbiologie , Freiburg , Germany
| | - Christos S Karapetis
- h Medical Oncology, Flinders Medical Centre , Flinders University and Adelaide Colorectal Tumour Group , Adelaide , Australia
| | | | - Nick Pavlakis
- j Medical Oncology, Royal Melbourne and Western Hospitals , Melbourne , Australia
| | - Peter Gibbs
- k Medical Oncology, Royal North Shore Hospital , Sydney University , Sydney , Australia
| | - Jeremy D Shapiro
- l Cabrini Medical Centre , Monash University , Melbourne , Australia
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Canavese M, Ngo DTM, Maddern GJ, Hardingham JE, Price TJ, Hauben E. Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer. Int J Cancer 2017; 140:2183-2191. [PMID: 27943279 DOI: 10.1002/ijc.30567] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/16/2016] [Accepted: 11/30/2016] [Indexed: 12/30/2022]
Abstract
Tumor growth, dissemination and metastasis are dependent on angiogenesis. The predominant vascular endothelial growth factor (VEGF) isoform that plays a major role in angiogenesis is VEGF-A. Indeed, VEGF-A is implicated in promoting angiogenesis of numerous solid malignancies, including colorectal cancer (CRC). A large body of preclinical and clinical evidence indicates that the expression of specific VEGF-A isoforms represents a predominant pro-angiogenic factor, which is associated with formation of metastases and poor prognosis in CRC patients. Different isoforms of human VEGF-A have been identified, all of which arise from alternative splicing of the primary transcript of a single gene. Notably, it has been recently demonstrated that expression of type 3 isoform pattern is significantly correlated with venous involvement in CRC as well as in progression to metastatic colorectal cancer (mCRC), although it remains unclear what proportion of CRC tumors express these isoforms. This review highlights the importance of investigating the genetic and the epigenetic variations in VEGF-A pathways in CRC, the functions of different VEGF-A isoforms and their potential application as prognostic markers and/or therapeutic targets. Better understanding of the mechanisms controlling angiogenesis in liver metastases is necessary to address the limitations of current anti-angiogenic therapies.
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Affiliation(s)
- Miriam Canavese
- The Basil Hetzel Institute for Translational Health Research, Liver Metastasis Research Group, Discipline of Surgery, University of Adelaide, Adelaide, Australia
| | - Doan T M Ngo
- Cardiology Unit, the Queen Elizabeth Hospital and Basil Hetzel Institute, University of Adelaide, Adelaide, Australia
| | - Guy J Maddern
- Department of Surgery, University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Jennifer E Hardingham
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, South Australia and School of Medicine, University of Adelaide, Adelaide
| | - Timothy J Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, South Australia and School of Medicine, University of Adelaide, Adelaide
| | - Ehud Hauben
- The Basil Hetzel Institute for Translational Health Research, Liver Metastasis Research Group, Discipline of Surgery, University of Adelaide, Adelaide, Australia
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Sartore-Bianchi A, Siena S, Tonini G, Bardelli A, Santini D. Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer: Multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR. Cancer Treat Rev 2016; 51:54-62. [PMID: 27865140 DOI: 10.1016/j.ctrv.2016.10.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 12/25/2022]
Abstract
In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting.
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Affiliation(s)
- Andrea Sartore-Bianchi
- Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy
| | - Salvatore Siena
- Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy; Department of Oncology, Università degli Studi di Milano, 20122 Milan, Italy
| | - Giuseppe Tonini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, 10043 Torino, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy.
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Huang CW, Yeh YS, Ma CJ, Tsai HL, Chen CW, Huang MY, Lu CY, Wu JY, Wang JY. Patients with Metastatic Colorectal Cancer and Hyperbilirubinemia Treated with FOLFIRI plus Bevacizumab as First-Line Treatment. Chemotherapy 2016; 62:80-84. [PMID: 27654129 DOI: 10.1159/000447118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 05/25/2016] [Indexed: 11/19/2022]
Abstract
Metastatic colorectal cancer (mCRC) combined with hyperbilirubinemia is typically considered a contraindication to irinotecan-based therapy, a proven first-line treatment of mCRC. Herein, we present 6 consecutive patients with mCRC combined with hyperbilirubinemia who underwent UGT1A1 genotyping before receiving FOLFIRI plus bevacizumab. Dose escalation of irinotecan was performed according to the results of UGT1A1 genotyping in all patients. Improvement in the serum total bilirubin level to a normal range was noted in all 6 patients. Disease control was 100%. The median progression-free survival was 7.5 months and the median overall survival was 8.5 months. FOLFIRI plus bevacizumab as a first-line chemotherapy may achieve effective disease control and be safe in patients with mCRC and hyperbilirubinemia based on UGT1A1 genotyping. More prospective clinical studies are necessary to evaluate the clinical benefits and safety of this treatment approach.
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Affiliation(s)
- Ching-Wen Huang
- Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
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Ohhara Y, Fukuda N, Takeuchi S, Honma R, Shimizu Y, Kinoshita I, Dosaka-Akita H. Role of targeted therapy in metastatic colorectal cancer. World J Gastrointest Oncol 2016; 8:642-55. [PMID: 27672422 PMCID: PMC5027019 DOI: 10.4251/wjgo.v8.i9.642] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/21/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.
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De Greef K, Rolfo C, Russo A, Chapelle T, Bronte G, Passiglia F, Coelho A, Papadimitriou K, Peeters M. Multisciplinary management of patients with liver metastasis from colorectal cancer. World J Gastroenterol 2016; 22:7215-7225. [PMID: 27621569 PMCID: PMC4997640 DOI: 10.3748/wjg.v22.i32.7215] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 06/21/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent (25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twenty-thirty per cent (20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and anti-EGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.
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Lo Nigro C, Ricci V, Vivenza D, Granetto C, Fabozzi T, Miraglio E, Merlano MC. Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy. World J Gastroenterol 2016; 22:6944-6954. [PMID: 27570430 PMCID: PMC4974592 DOI: 10.3748/wjg.v22.i30.6944] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/27/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling.
METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21st, 2016 using these following terms: ‘‘colorectal cancer’’, “predictive biomarkers’’, “anti-EGFR therapy”, “KRAS”, “NRAS’’, “PIK3CA”, “TP53”, “PTEN”, ‘‘EGFR”, “MET”, “HER2”, “epiregulin”, “amphiregulin”, “prognostic biomarkers”, “BRAF”, “miRNA” and “antibody-dependent cell-mediated cytotoxicity (ADCC) activity”. Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion.
RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mRNA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3CA. The prognostic value of selected microRNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial.
CONCLUSION: This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.
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The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat Med 2016; 22:624-31. [PMID: 27135741 DOI: 10.1038/nm.4078] [Citation(s) in RCA: 218] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 03/07/2016] [Indexed: 12/13/2022]
Abstract
Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.
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Yeh YS, Tsai HL, Huang CW, Wang JH, Lin YW, Tang HC, Sung YC, Wu CC, Lu CY, Wang JY. Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting: study protocol for a randomized controlled trial. Trials 2016; 17:46. [PMID: 26811156 PMCID: PMC4727397 DOI: 10.1186/s13063-016-1153-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 01/04/2016] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Irinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group. METHODS/DESIGN This trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups. DISCUSSION Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice. TRIAL REGISTRATION NCT02256800 . Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015.
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Affiliation(s)
- Yung-Sung Yeh
- Division of Trauma, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Hsiang-Lin Tsai
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Ching-Wen Huang
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jui-Ho Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
| | - Yi-Wen Lin
- Department of Surgery, Tainan Municipal Hospital, Tainan, Taiwan.
| | - Hsiu-Chih Tang
- Colon and Rectal Surgery, Tainan Sin-Lau Hospital, Tainan, Taiwan.
| | - Yung-Chuan Sung
- Division of Hematology-Oncology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan.
| | - Chang-Chieh Wu
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Chien-Yu Lu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jaw-Yuan Wang
- Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Willaert W, Van Der Speeten K, Liberale G, Ceelen W. BEV-IP: Perioperative chemotherapy with bevacizumab in patients undergoing cytoreduction and intraperitoneal chemoperfusion for colorectal carcinomatosis. BMC Cancer 2015; 15:980. [PMID: 26673788 PMCID: PMC4682259 DOI: 10.1186/s12885-015-1954-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 11/24/2015] [Indexed: 12/29/2022] Open
Abstract
Background Selected patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) benefit from cytoreductive surgery (CRS) combined with intraperitoneal chemoperfusion (IPC). However, even after optimal cytoreduction, systemic and locoregional recurrence are common. Perioperative chemotherapy with bevacizumab (BEV) may improve the outcome of these patients. Methods/Design The BEV-IP study is a phase II, single-arm, open-label study aimed at patients with colorectal or appendiceal adenocarcinoma with synchronous or metachronous PC. This study evaluates whether perioperative chemotherapy including BEV in combination with CRS and oxaliplatin-based IPC results in acceptable morbidity and mortality (primary composite endpoint). Secondary endpoints are treatment completion rate, chemotherapy-related toxicity, pathological response, progression free survival, and overall survival. Discussion The BEV-IP trial is the first prospective assessment of the safety and efficacy of perioperative chemotherapy combined with anti-angiogenic treatment in patients undergoing CRS and IPC for colorectal peritoneal metastases. Trial registration ClinicalTrials.gov Identifier: NCT02399410 EudraCT number: 2015-001187-19 (registered March 9, 2015).
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Affiliation(s)
- Wouter Willaert
- Department of Gastrointestinal Surgery, Ghent University Hospital, 2K12 IC UZ De Pintelaan 185, B-9000, Ghent, Belgium.
| | | | - Gabriel Liberale
- Clinic of Digestive Surgical Oncology, Jules Bordet Institute, Brussels, Belgium.
| | - Wim Ceelen
- Department of Gastrointestinal Surgery, Ghent University Hospital, 2K12 IC UZ De Pintelaan 185, B-9000, Ghent, Belgium.
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Lu CY, Huang CW, Wu IC, Tsai HL, Ma CJ, Yeh YS, Chang SF, Huang ML, Wang JY. Clinical Implication of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated with Bevacizumab Combined with FOLFIRI in the First-line Setting. Transl Oncol 2015; 8:474-479. [PMID: 26692528 PMCID: PMC4700286 DOI: 10.1016/j.tranon.2015.11.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/01/2015] [Accepted: 11/02/2015] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study aimed to identify the efficacy and toxicity of the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) with irinotecan dose escalation plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC) via UGT1A1 genotyping. METHODS We administered bevacizumab plus FOLFIRI with irinotecan dose escalation to treat 70 mCRC patients. The UGT1A1 *1/*1 and *1/*28 genotypes started with a 180-mg/m(2) dose of irinotecan, and UGT1A1 *28/*28 genotype started with a dose of 120 mg/m(2). The dose of irinotecan was escalated at increasing intervals of 20 to 30 mg/m(2) until grade 3/4 adverse events (AEs) occurred. The clinical response rate, toxicity, and survival were analyzed. RESULTS The clinical response and disease control rates of mCRC patients treated with FOLFIRI plus bevacizumab were significantly better in patients with UGT1A1 *1/*1 and *1/*28 genotypes than in patients with UGT1A1 *28/*28 (P = .006 and P < .001, respectively). Grade 3/4 AEs were significantly more common in mCRC patients with the UGT1A1 *28/*28 genotype (P < .001). Progression-free survival was significantly higher in UGT1A1 *1/*1 and *1/*28 patients (P = .002). mCRC patients who underwent metastasectomy achieved better overall survival than those who did not undergo metastasectomy (P = .015). CONCLUSIONS Our study showed that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive escalated doses of irinotecan to obtain a more favorable clinical outcome without significant AEs.
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Affiliation(s)
- Chien-Yu Lu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Chen Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Program of Bachelor of Health Beauty, School of Medical and Health Sciences, Fooyin University, Kaohsiung, Taiwan
| | - Cheng-Jen Ma
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yung-Sung Yeh
- Division of Trauma, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Emergency Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Se-Fen Chang
- Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Lin Huang
- Division of Colorectal Surgery, Department of Surgery, ZuoYing Armed Forces General Hospital, Kaohsiung, Taiwan.
| | - Jaw-Yuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.
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Del Prete M, Giampieri R, Faloppi L, Bianconi M, Bittoni A, Andrikou K, Cascinu S. Panitumumab for the treatment of metastatic colorectal cancer: a review. Immunotherapy 2015; 7:721-38. [PMID: 26250414 DOI: 10.2217/imt.15.46] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
In recent years, the treatment of metastatic colorectal cancer (mCRC) has evolved significantly with the increase of new therapeutic options, leading to an improved median survival for these patients. In particular, the identification of molecular targets in tumor cells has led to the introduction of biological drugs for the treatment of mCRC. Panitumumab is a fully human monoclonal antibody that binds the EGF receptor of tumor cells and inhibits downstream cell signaling with antitumor effect on inhibition of tumor growth. Its use has been approved by randomized clinical trials as monotherapy in chemorefractory patients or combined with chemotherapy in the treatment of RAS wild-type mCRC, where it demonstrated a significant improvement in survival and response rate. The purpose of this review is to analyze the use and efficacy profile of panitumumab, particularly focusing on recently reported data on its use, and future perspectives in patients with mCRC.
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Affiliation(s)
- M Del Prete
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - R Giampieri
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - L Faloppi
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - M Bianconi
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - A Bittoni
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - K Andrikou
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - S Cascinu
- Medical Oncology, AOU Ospedali Riuniti-Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
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First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2015; 96:156-66. [PMID: 26088456 DOI: 10.1016/j.critrevonc.2015.05.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 03/17/2015] [Accepted: 05/19/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated. METHODS MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS Seven eligible RCTs were identified. In the overall RAS wild-type population (N=2719), anti-EGFR MoAbs significantly improved OS (HR=0.81; 95%CI, 0.71-0.92; p=0.002), PFS (HR=0.77; 95%CI, 0.60-0.98; p=0.03) and objective response rate (ORR) (RR=1.33; 95%CI, 1.09-1.62; p=0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p<0.001) and ORR (p<0.001) with a trend toward longer OS (p=0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR=0.80; 95%CI, 0.69-0.92; p=0.003), but not PFS (HR=0.94; 95%CI, 0.74-1.19; p=0.59) or ORR (RR=1.10; 95%CI, 0.97-1.25; p=0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based). CONCLUSIONS The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.
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Gibbs P, Gebski V, Van Buskirk M, Thurston K, Cade DN, Van Hazel GA. Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study. BMC Cancer 2014; 14:897. [PMID: 25487708 PMCID: PMC4289171 DOI: 10.1186/1471-2407-14-897] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 12/01/2014] [Indexed: 12/29/2022] Open
Abstract
Background In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia). Methods/Design SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy ± SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naïve patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of ≥3 months and a WHO performance status of 0–1. Patients will be randomised to receive either mFOLFOX6 or SIRT + mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1–3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting ≥450 patients will be sufficient for 80% power and 95% confidence. Discussion The SIRFLOX trial will establish the potential role of SIRT + standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases. Trial registration SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-897) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Peter Gibbs
- Royal Melbourne Hospital, Melbourne, Victoria, Australia.
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Lien K, Berry S, Ko YJ, Chan KKW. The use of EGFR inhibitors in colorectal cancer: is it clinically efficacious and cost-effective? Expert Rev Pharmacoecon Outcomes Res 2014; 15:81-100. [PMID: 25400031 DOI: 10.1586/14737167.2015.982100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies to the EGFR. They are used as monotherapy or in combination with cytotoxic chemotherapy and increase both progression-free survival and overall survival in patients with wild-type RAS metastatic colorectal cancer. The most common side effects of therapy are dermatological, including skin (acneiform) rash, pruritus and hair changes. Despite their clinical activity, cost-effectiveness of the two drugs should be addressed in a discussion of their usage in everyday care. This study provides an up-to-date review of the clinical efficacy and cost-effectiveness of anti-EGFR inhibitors.
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Affiliation(s)
- Kelly Lien
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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Price TJ, Segelov E, Burge M, Haller DG, Tebbutt NC, Karapetis CS, Punt CJA, Pavlakis N, Arnold D, Gibbs P, Shapiro JD. Current opinion on optimal systemic treatment for metastatic colorectal cancer: outcome of the ACTG/AGITG expert meeting ECCO 2013. Expert Rev Anticancer Ther 2014; 14:1477-93. [PMID: 25138900 DOI: 10.1586/14737140.2014.949678] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The treatment of metastatic colorectal cancer has evolved greatly in the last 15 years, involving combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of targeted therapy with bevacizumab, aflibercept, cetuximab, panitumumab and regorafenib in the treatment of metastatic colorectal cancer is now well established with median overall survival accepted as over 24 months, and with super selection for extended RAS patients higher again. The optimal timing of treatment options requires careful consideration of predictive biomarkers, and importantly the potential for interactions, to derive the maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, the USA, the Netherlands and Germany met during ECCO 2013 to discuss current practice. Subsequent new data from the American Society of Clinical Oncology were also reviewed. This article reviews the evidence discussed in support of modern treatments for colorectal cancer and the decision-making behind the treatment choices, with their benefits and risks.
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Affiliation(s)
- Timothy J Price
- The Queen Elizabeth Hospital, Adelaide Colorectal Tumour Group and University of Adelaide, Adeaide, Australia
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Lu CY, Huang CW, Hu HM, Tsai HL, Huang CM, Yu FJ, Huang MY, Chang SF, Huang ML, Wang JY. Prognostic advantage of irinotecan dose escalation according to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping in patients with metastatic colorectal cancer treated with bevacizumab combined with 5-fluorouracil/leucovorin with irinotecan in a first-line setting. Transl Res 2014; 164:169-176. [PMID: 24462762 DOI: 10.1016/j.trsl.2013.12.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 12/22/2013] [Accepted: 12/27/2013] [Indexed: 02/08/2023]
Abstract
This study compared the clinical responses of patients with metastatic colorectal cancer (mCRC) with 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) plus bevacizumab therapy either with or without uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping and irinotecan dose escalation. Of 107 total patients with mCRC, 79 were classified as the study group and 28 as the control group. The study group received irinotecan dose escalation based on UGT1A1 genotyping whereas the control group did not. Clinicopathologic features, response rates, and survival were compared for the 2 groups. The clinical response rate of patients with mCRC treated with FOLFIRI plus bevacizumab under UGT1A1 genotyping and irinotecan dose escalation was significantly better than that of those without these prospective tests and dose escalation (P = 0.028). Both progression-free survival (PFS) and overall survival were significantly greater in clinical responders than nonresponders (both, P < 0.001), and PFS was significantly greater among the study group patients than among the control group patients, with a median PFS of 12.2 months vs 9.4 months (P = 0.025). Grade 3/4 adverse events were not significantly different between the 2 groups (P = 0.189). Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan to obtain a better clinical response/outcome with comparable toxicities.
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Affiliation(s)
- Chien-Yu Lu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huang-Ming Hu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical, University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Ming Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Radiation Oncology, Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fang-Jung Yu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yii Huang
- Department of Radiation Oncology, Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Radiation Oncology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Se-Fen Chang
- Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Lin Huang
- Division of Colorectal Surgery, Department of Surgery, ZuoYing Armed Forces General Hospital, Kaohsiung, Taiwan; Department of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jaw-Yuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Dutton SJ, Kenealy N, Love SB, Wasan HS, Sharma RA. FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer. BMC Cancer 2014; 14:497. [PMID: 25011439 PMCID: PMC4107961 DOI: 10.1186/1471-2407-14-497] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/30/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death. Almost 50% of patients with CRC develop liver metastases, which heralds a poor prognosis unless metastases can be downsized to surgical resection or ablation. The FOXFIRE trial examines the hypothesis that combining radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia) as a first-line treatment for liver-dominant metastatic CRC will improve clinical outcomes when compared to OxMdG chemotherapy alone. METHODS/DESIGN FOXFIRE is an open-label, multicentre, randomised controlled trial of OxMdG with or without the addition of SIRT (1:1 randomisation). Eligible adult patients have histologically confirmed colorectal adenocarcinoma, liver metastases measurable on computed tomography scan and untreatable by either surgical resection or local ablation, and they may have limited extra-hepatic disease, defined as ≤5 nodules in the lung and/or one other metastatic site which is amenable to future definitive treatment. Eligible patients may have received adjuvant chemotherapy following resection of the primary tumour, but are not permitted to have previously received chemotherapy for metastatic disease, and must have a life expectancy of ≥3 months and a WHO performance status of 0-1. The primary outcome is overall survival. Secondary outcomes include progression free survival (PFS), liver-specific PFS, patient-reported outcomes, safety, response rate, resection rate and cost-effectiveness. FOXFIRE shares a combined statistical analysis plan with an international sister trial called SIRFLOX. DISCUSSION This trial is establishing a network of SIRT centres and 'feeder' chemotherapy-only centres to standardise the delivery of SIRT across the whole of the UK and to provide greater equity of access to this highly specialised liver-directed therapy. The FOXFIRE trial will establish the potential role of adding SIRT to first-line chemotherapy for unresectable liver metastatic colorectal cancer, and the impact on current treatment paradigms for metastatic CRC. TRIAL REGISTRATION ISRCTN83867919.
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Affiliation(s)
- Susan J Dutton
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Nicola Kenealy
- Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UK
| | - Sharon B Love
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Harpreet S Wasan
- Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK
| | - Ricky A Sharma
- CRUK-MRC Oxford Institute for Radiation Oncology, NIHR Biomedical Research Centre Oxford, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK
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