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Kawaguchi Y, De Bellis M, Panettieri E, Duwe G, Vauthey JN. Debate: Improvements in Systemic Therapies for Liver Metastases Will Increase the Role of Locoregional Treatments. Hematol Oncol Clin North Am 2025; 39:207-220. [PMID: 39510674 DOI: 10.1016/j.hoc.2024.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
The benefit of resection of liver metastases depends on primary diseases. Neuroendocrine tumors are associated with favorable prognosis after resection of liver metastases. Gastric cancer has worse tumor biology, and resection of gastric liver metastases should be performed in selected patients. A multidisciplinary approach is well established for colorectal liver metastases (CLMs). Resection remains the only curative treatment of CLM. Chemotherapy and molecular-targeted therapy have improved survival in unresectable metastatic colorectal cancer. Understanding of the following two strategies, conversion therapy and two-stage hepatectomy, are important to make this patient group to be candidates for curative-intent surgery.
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Affiliation(s)
- Yoshikuni Kawaguchi
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Mario De Bellis
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Elena Panettieri
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Gregor Duwe
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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Wu JW, Zhou CF, Han ZX, Zhang H, Yan J, Chen J, Wang CB, Qin ZQ, Mao Y, Tang XY, Zhu LJ, Wei XW, Cui DH, Yang XL, Shi M, Zhao LQ, Jiang JL, Zhu WY, Wang HM, Wang C, Zhu LJ, Zhang J. Anlotinib plus chemotherapy as a first-line treatment for gastrointestinal cancer patients with unresectable liver metastases: a multicohort, multicenter, exploratory trial. Signal Transduct Target Ther 2024; 9:344. [PMID: 39648217 PMCID: PMC11625826 DOI: 10.1038/s41392-024-02051-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/26/2024] [Accepted: 11/04/2024] [Indexed: 12/10/2024] Open
Abstract
This multicohort phase II trial (ALTER-G-001; NCT05262335) aimed to assess the efficacy of first-line anlotinib plus chemotherapy for gastrointestinal (GI) cancer patients with unresectable liver metastases. Eligible patients with colorectal cancer (Cohort A) or noncolorectal and nonesophageal GI cancer (Cohort C) received six cycles of anlotinib plus standard chemotherapeutic regimens followed by anlotinib plus metronomic capecitabine as a maintenance therapy. Liver metastasectomy can be performed when liver metastases are converted to resectable lesions. The primary outcome was the investigator-confirmed objective response rate (ORR) in the intention-to-treat population. Among the 47 patients in Cohort A, the ORR was 40.4% (95% CI 26.4-55.7), including 1 with a complete response (CR) and 18 who achieved a partial response (PR). The median progression-free survival (PFS) was 8.7 months (95% CI 7.3-NE), and the median overall survival (OS) was not reached. In Cohort C, 14 of 44 patients achieved a PR, with an ORR of 31.8% (95% CI 18.6-47.6). The PFS and OS were 5.8 months (95% CI 4.8-6.5) and 11.4 months (95% CI 5.8-19.3), respectively. The liver metastasectomy rate in patients with liver-limited disease was 22.7% (5/22) in Cohort A and 6.7% (2/30) in Cohort C. For pancreatic cancer patients, the ORR of the efficacy-evaluable population was 36.0% (9/25), and those with liver-limited metastasis had better survival. Moreover, no new safety concerns emerged. In conclusion, an anlotinib-based first-line regimen demonstrated promising antitumor activity among GI cancer patients with unresectable liver metastases and led to liver metastasectomy in selected patients.
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Affiliation(s)
- Jun-Wei Wu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen-Fei Zhou
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Xiang Han
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Huan Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Yan
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Jun Chen
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - Chun-Bin Wang
- Department of Oncology, The Third People's Hospital of Yancheng, Yancheng, China
| | - Zhi-Quan Qin
- Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xin-Yu Tang
- Department of Oncology, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Wuxi, China
| | - Liang-Jun Zhu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China
| | - Xiao-Wei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dong-Hai Cui
- Department of Internal Medicine, Anyang Tumor Hospital, Anyang, China
| | - Xiu-Li Yang
- Department of Oncology, First Affiliated Hospital of Nanyang Medical College, Nanyang, China
| | - Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Qin Zhao
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin-Ling Jiang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-You Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hong-Mei Wang
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chun Wang
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Ling-Jun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Wirsik NM, Appel PC, Braun A, Strowitzki MJ, Schleussner N, Nienhüser H, Schneider M, Schmidt T. Inhibition of the Renin-Angiotensin System Improves Response to Neoadjuvant Therapy in Patients With Liver Metastasis of Colorectal Cancers. J Surg Res 2024; 298:176-184. [PMID: 38621351 DOI: 10.1016/j.jss.2024.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 02/01/2024] [Accepted: 03/16/2024] [Indexed: 04/17/2024]
Abstract
INTRODUCTION Renin-angiotensin-aldosterone system inhibitors (RAAS-I) have been shown to prolong overall survival in patients with liver metastasized colorectal cancer in combination with antiangiogenic treatment. The effects of RAAS-I combined with neoadjuvant chemotherapy on colorectal cancer liver metastasis remain unexplored. We aimed to study the response of patients undergoing liver resection to RAAS-I in combination with neoadjuvant therapy to elucidate their potential benefits. METHODS Between February 2005 and May 2012, 62 patients fulfilled the inclusion criteria for distant metastasis (cM1) and comparable computed tomography or magnetic resonance tomography scans in the Picture Archiving Communication System of our center before and after neoadjuvant chemotherapy. Follow-up data and clinicopathological characteristics were collected from a prospective database and retrospectively investigated. The chemotherapeutic response to liver metastasis was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria 1.1. RESULTS Comparing the average reduction of measured lesions, a significant response to chemotherapy was detected in the patients receiving RAAS-I (n = 24) compared to those who did not (n = 38) (P = 0.031). Interestingly, the effect was more distinctive when the size reduction was compared between high responses with more than 50% size reduction of all measured lesions (P = 0.011). In the subgroup analysis of patients receiving bevacizumab treatment, high responses to chemotherapy were observed only in the RAAS-I cohort (28.6% versus 0%, P = 0.022). CONCLUSIONS For neoadjuvantly treated patients, concomitant antihypertensive treatment with RAAS-I showed a higher total size reduction of liver metastasis as a sign of treatment response, especially in combination with antiangiogenic treatment with bevacizumab.
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Affiliation(s)
- Naita M Wirsik
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
| | - Pia C Appel
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Braun
- Department of Radiology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Henrik Nienhüser
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Schmidt
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany.
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Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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Guo M, Jin N, Pawlik T, Cloyd JM. Neoadjuvant chemotherapy for colorectal liver metastases: A contemporary review of the literature. World J Gastrointest Oncol 2021; 13:1043-1061. [PMID: 34616511 PMCID: PMC8465453 DOI: 10.4251/wjgo.v13.i9.1043] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/17/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide, and up to 50% of patients with CRC develop colorectal liver metastases (CRLM). For these patients, surgical resection remains the only opportunity for cure and long-term survival. Over the past few decades, outcomes of patients with metastatic CRC have improved significantly due to advances in systemic therapy, as well as improvements in operative technique and perioperative care. Chemotherapy in the modern era of oxaliplatin- and irinotecan-containing regimens has been augmented by the introduction of targeted biologics and immunotherapeutic agents. The increasing efficacy of contemporary systemic therapies has led to an expansion in the proportion of patients eligible for curative-intent surgery. Consequently, the use of neoadjuvant strategies is becoming progressively more established. For patients with CRLM, the primary advantage of neoadjuvant chemotherapy (NCT) is the potential to down-stage metastatic disease in order to facilitate hepatic resection. On the other hand, the routine use of NCT for patients with resectable metastases remains controversial, especially given the potential risk of inducing chemotherapy-associated liver injury prior to hepatectomy. Current guidelines recommend upfront surgery in patients with initially resectable disease and low operative risk, reserving NCT for patients with borderline resectable or unresectable disease and high operative risk. Patients undergoing NCT require close monitoring for tumor response and conversion of CRLM to resectability. In light of the growing number of treatment options available to patients with metastatic CRC, it is generally agreed that these patients are best served at tertiary centers with an expert multidisciplinary team.
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Affiliation(s)
- Marissa Guo
- Department of Surgery, The Ohio State University Medical Center, Columbus, OH 43210, United States
| | - Ning Jin
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH 43210, United States
| | - Timothy Pawlik
- Department of Surgery, The Ohio State University, Columbus, OH 43210, United States
| | - Jordan M Cloyd
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Medical Center, Columbus, OH 43210, United States
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Kawaguchi Y, De Bellis M, Panettieri E, Duwe G, Vauthey JN. Debate: Improvements in Systemic Therapies for Liver Metastases Will Increase the Role of Locoregional Treatments. Surg Oncol Clin N Am 2021; 30:205-218. [PMID: 33220806 PMCID: PMC7709757 DOI: 10.1016/j.soc.2020.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The benefit of resection of liver metastases depends on primary diseases. Neuroendocrine tumors are associated with favorable prognosis after resection of liver metastases. Gastric cancer has worse tumor biology, and resection of gastric liver metastases should be performed in selected patients. A multidisciplinary approach is well established for colorectal liver metastases (CLMs). Resection remains the only curative treatment of CLM. Chemotherapy and molecular-targeted therapy have improved survival in unresectable metastatic colorectal cancer. Understanding of the following two strategies, conversion therapy and two-stage hepatectomy, are important to make this patient group to be candidates for curative-intent surgery.
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Affiliation(s)
- Yoshikuni Kawaguchi
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Mario De Bellis
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Elena Panettieri
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Gregor Duwe
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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Bolhuis K, Kos M, van Oijen MGH, Swijnenburg RJ, Punt CJA. Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review. Eur J Cancer 2020; 141:225-238. [PMID: 33189037 DOI: 10.1016/j.ejca.2020.09.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/07/2020] [Accepted: 09/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. METHODS Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. RESULTS Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. CONCLUSIONS Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.
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Affiliation(s)
- Karen Bolhuis
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands.
| | - Milan Kos
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Martijn G H van Oijen
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Amsterdam UMC, University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
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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: 28] [Impact Index Per Article: 5.6] [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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Hayashi H, Miyamoto Y, Higashi T, Hiyoshi Y, Yamao T, Uemura N, Matsumura K, Imai K, Yamashita YI, Baba H. CD44 expression enhances chemoresistance and implies occult micrometastases after conversion hepatectomy for initially unresectable colorectal liver metastases. Am J Transl Res 2020; 12:5955-5966. [PMID: 33042471 PMCID: PMC7540162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 07/16/2020] [Indexed: 06/11/2023]
Abstract
AIM The objective of this study was to examine the clinical and biological significance of CD44 expression in conversion hepatectomy for initially unresectable colorectal liver metastases. METHODS Fifty-four patients who received chemotherapy followed by hepatectomy (conversion hepatectomy) for initially unresectable liver metastases were enrolled. CD44 expression and its clinical significance were examined in 52 resected specimens; two specimens revealed no residual cancer cells. The biological significance of CD44 expression in the chemoresistance response to fluorouracil, oxaliplatin or irinotecan, three major anti-cancer agents for colon cancer in the clinical setting, was examined using colon cancer cell lines. RESULTS Membrane CD44 expression in the residual cancer cells after chemotherapy for colorectal liver metastases was detectable in 19 patients (37%), and was significantly associated with high proliferative activity represented by Ki-67 expression (P = 0.003). CD44 expression was also significantly associated with shorter disease-free survival and worse overall survival after hepatectomy (hazard ratio and P-values were 2.570, 0.007 and 3.457, 0.026, respectively). In SW480 and HT29 colon cancer cells, siRNA-mediated CD44 knockdown attenuated cell growth. Additionally, CD44 knockdown overcame chemoresistance in response to fluorouracil and oxaliplatin with enhanced apoptosis and p27 upregulation, respectively. For irinotecan, CD44 knockdown showed no additional effect in chemoresistance. CONCLUSIONS CD44 enhances chemoresistance in response to anti-cancer drugs (fluorouracil and oxaliplatin) in colon cancer cells. CD44 expression in liver metastases after chemotherapy implies the presence of occult micrometastases and is a worse prognostic factor in patients with conversion hepatectomy for initially unresectable colorectal liver metastases.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takanobu Yamao
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
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Ren L, Zhu D, Benson AB, Nordlinger B, Koehne CH, Delaney CP, Kerr D, Lenz HJ, Fan J, Wang J, Gu J, Li J, Shen L, Tsarkov P, Tejpar S, Zheng S, Zhang S, Gruenberger T, Qin X, Wang X, Zhang Z, Poston GJ, Xu J. Shanghai international consensus on diagnosis and comprehensive treatment of colorectal liver metastases (version 2019). EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 46:955-966. [PMID: 32147426 DOI: 10.1016/j.ejso.2020.02.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 02/17/2020] [Indexed: 12/17/2022]
Abstract
The liver is the most common anatomical site for hematogenous metastases from colorectal cancer. Therefore effective treatment of liver metastases is one of the most challenging elements in the management of colorectal cancer. However, there is rare available clinical consensus or guideline only focusing on colorectal liver metastases. After six rounds of discussion by 195 clinical experts of the Shanghai International Consensus Expert Group on Colorectal Liver Metastases (SINCE) from 29 countries or regions, the Shanghai Consensus has been finally completed, based on current research and expert experience. The consensus emphasized the principle of multidisciplinary team, provided detailed diagnosis approaches, and guided precise local and systemic treatments. This Shanghai Consensus might be of great significance to standardized diagnosis and treatment of colorectal liver metastases all over the world.
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Affiliation(s)
- Li Ren
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dexiang Zhu
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern Medical Group, Chicago, USA
| | - Bernard Nordlinger
- Surgery Department, Hospital Ambroise-Pare, Boulogne-Billancourt, France
| | | | - Conor P Delaney
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - David Kerr
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jin Gu
- Department of Colorectal Surgery, Peking University Cancer Hospital, Beijing, China; Department of Colorectal Surgery, Peking University Shougang Hospital, Beijing, China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China
| | - Petrv Tsarkov
- Clinic of Colorectal and Minimally Invasive Surgery, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Sabine Tejpar
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Shu Zheng
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Suzhan Zhang
- Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | | | - Xinyu Qin
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Graeme John Poston
- Surgery Department, Aintree University Hospital, School of Translational Studies, University of Liverpool, Liverpool, UK.
| | - Jianmin Xu
- Department of Colorectal Surgery, Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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11
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Zheng B, Wang X, Wei M, Wang Q, Li J, Bi L, Deng X, Wang Z. First-line cetuximab versus bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2019; 19:280. [PMID: 30922269 PMCID: PMC6437996 DOI: 10.1186/s12885-019-5481-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 03/15/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A first-line biologic treatment for metastatic colorectal cancer (mCRC) is still controversial. We, therefore, performed a meta-analysis to determine the efficacy of first-line cetuximab versus bevacizumab for RAS and BRAF wild-type mCRC. METHODS In March 2018, an electronic search of the following biomedical databases was performed: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov and Web of Knowledge. Randomized controlled trials (RCTs) and prospective or observational cohort studies (OCSs) were included. Subgroup analyses of all RCTs were performed in all outcomes. All statistical analyses were performed using RevMan software 5.3. RESULTS Two RCTs and three OCSs, involving a total 2576 patients, were included. The meta-analysis reported that cetuximab was associated with a longer overall survival (OS) [HR 0.89, 95% CI (0.81-0.98); p = 0.02], a higher ORR [RR 1.11, 95% CI (1.03-1.19); p = 0.006], higher complete response [RR 3.21, 95% CI (1.27-8.12); p = 0.01] and a greater median depth of response than bevacizumab. However, no significant difference was observed between cetuximab and bevacizumab groups for PFS, DCR, partial response, progressive disease, curative intent metastasectomy, EORR and incidence of grade 3 or higher adverse events. In the subgroup meta-analyses of the RCTs, inconsistent results compared to the main analysis, however, were found, in the ORR, DCR and curative intent metastasectomy. CONCLUSIONS The current evidence indicates that compared to bevacizumab treatment, cetuximab provides a clinically relevant effect in first-line treatment against mCRC, at the cost of having lower stable disease.
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Affiliation(s)
- Bobo Zheng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Wang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Mingtian Wei
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Quan Wang
- Digestive disease hospital, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jiang Li
- National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liang Bi
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiangbing Deng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ziqiang Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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12
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Xu J, Fan J, Qin X, Cai J, Gu J, Wang S, Wang X, Zhang S, Zhang Z. Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (version 2018). J Cancer Res Clin Oncol 2019; 145:725-736. [PMID: 30542791 DOI: 10.1007/s00432-018-2795-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 11/12/2018] [Indexed: 12/12/2022]
Abstract
The liver is the most common anatomical site for hematogenous metastases of colorectal cancer, and colorectal liver metastases is one of the most difficult and challenging points in the treatment of colorectal cancer. To improve the diagnosis and comprehensive treatment in China, the Guidelines have been edited and revised several times since 2008, including the overall evaluation, personalized treatment goals and comprehensive treatments, to prevent the occurrence of liver metastases, improve the resection rate of liver metastases and survival. The revised Guideline includes the diagnosis and follow-up, prevention, MDT effect, surgery and local ablative treatment, neoadjuvant and adjuvant therapy, and comprehensive treatment, and with advanced experience, latest results, detailed content, and strong operability.
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Affiliation(s)
- Jianmin Xu
- Department of Colorectal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China.
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xinyu Qin
- Department of Colorectal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Gu
- Gastrointestinal Cancer Center, Peking University Cancer Hospital, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
- Peking University Shougang Hospital, Beijing, China
| | - Shan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Xishan Wang
- Department of Colorectal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Suzhan Zhang
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, Beijing, China
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13
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Chen CH, Hsieh MC, Lao WT, Lin EK, Lu YJ, Wu SY. Multidisciplinary team intervention associated with improved survival for patients with colorectal adenocarcinoma with liver or lung metastasis. Am J Cancer Res 2018; 8:1887-1898. [PMID: 30323980 PMCID: PMC6176172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/16/2018] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND AND OBJECTIVES To investigate whether multidisciplinary team (MDT) intervention is associated with improved survival for patients with colorectal adenocarcinoma with liver or lung metastasis (CRA-LLM). METHODS We enrolled 161 consecutive patients with histologically confirmed CRA-LLM at Taipei Medical University-Wan Fang Hospital between January 2007 and December 2017. In total, 75 patients with CRA-LLM received MDT intervention, and 86 patients did not receive MDT intervention. To evaluate prognostic factors for overall death, we performed univariate and multivariate Cox regression analyses of the overall death rate in all patients. Overall survival rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test (P < .001). RESULTS A multivariate Cox regression analysis of the overall death rate in patients with CRA-LLM showed that age ≤ 65 years, systemic chemotherapy, curative-intent treatments, and MDT intervention are strong prognostic factors. The adjusted hazard ratio of death risk for age ≤ 65 years, systemic chemotherapy, curative-intent treatments, and MDT intervention were 0.60 (95% confidence interval [CI], 0.40-0.92; P = .019), 0.19 (95% CI, 0.12-0.32; P = .001), 0.25 (95% CI, 0.13-0.50; P = .001), and 0.40 (95% CI, 0.25-0.65; P = .001), respectively. The 3-year overall survival rates in patients with CRA-LLM receiving MDT intervention and not receiving MDT intervention were 48.75% and 24.21%, respectively. CONCLUSION MDT intervention is associated with improved survival for patients with CRA-LLM.
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Affiliation(s)
- Chien-Hsin Chen
- Department of Colorectal Surgery, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
| | - Mao-Chih Hsieh
- Department of General Surgery, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
| | - Wilson T Lao
- Department of Radiology, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
| | - En-Kwang Lin
- Department of Colorectal Surgery, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
| | - Yen-Jung Lu
- Department of Colorectal Surgery, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
| | - Szu-Yuan Wu
- Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical UniversityTaipei, Taiwan
- Institute of Clinical Science, Zhongshan Hospital, Fudan UniversityShanghai 200032, China
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan
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14
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Hirata F, Ishiyama K, Tanaka Y, Kobayashi T, Hashimoto M, Saeki Y, Ishida N, Taguchi K, Tanaka J, Arihiro K, Ohdan H, Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis. Ann Gastroenterol Surg 2018; 2:383-393. [PMID: 30238080 PMCID: PMC6139723 DOI: 10.1002/ags3.12195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/28/2018] [Accepted: 06/26/2018] [Indexed: 12/22/2022] Open
Abstract
AIM We investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells. METHODS We classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences. RESULTS There were no significant differences in lymphocyte fractions of either PBMC or LMNC between groups, except for the significantly lower percentage of natural killer (NK) cells in LMNC in group B than in group A. Significantly higher percentage of natural-killer group 2, member D (NKG2D)- positive NK cells in PBMC and percentage of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, NKp30-, and signal regulatory protein β (SIRPβ)-positive NK cells in LMNC were found in group B. Furthermore, significantly higher expressions of NKG2D and SIRPβ in peripheral blood NK cells and of NKp46 and CD122 in liver NK cells were found in group B. When LMNC were incubated with interleukin (IL)-2 in vitro, no difference was observed in the expression of these molecules in NK cells between groups. Consistently, there was no difference in the cytotoxic activity of those LMNC against a colon adenocarcinoma cell line between groups. CONCLUSION Colorectal cancer with liver metastasis patients treated with neoadjuvant chemotherapy showed enhanced expression of activation markers on peripheral blood and liver NK cells in comparison with patients who did not receive therapy; however, the difference in those function remains unclear. These results suggest that neoadjuvant chemotherapy does not have a negative impact on intrahepatic immune cells in resectable CRLM patients.
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Affiliation(s)
- Fumihiro Hirata
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
- Department of SurgeryNational Hospital Organization Kure Medical Center and Chugoku Cancer CenterHiroshimaJapan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Masakazu Hashimoto
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yoshihiro Saeki
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Nobuki Ishida
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kazuhiro Taguchi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Junko Tanaka
- Department of EpidemiologyInfectious Disease Control and PreventionGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Koji Arihiro
- Department of Anatomical PathologyHiroshima University HospitalHiroshimaJapan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
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15
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Oki E, Ando K, Nakanishi R, Sugiyama M, Nakashima Y, Kubo N, Kudou K, Saeki H, Nozoe T, Emi Y, Maehara Y. Recent advances in treatment for colorectal liver metastasis. Ann Gastroenterol Surg 2018; 2:167-175. [PMID: 29863162 PMCID: PMC5980283 DOI: 10.1002/ags3.12071] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
A major challenge for the management of colorectal liver metastasis (CRLM) is the multidisciplinary approach including surgery. Resection is the most important treatment strategy to prolong the survival of patients with colorectal cancer (CRC). Even when resection is not possible as a primary treatment, it may still be carried out for curative intent after effective chemotherapy. Therefore, resection should always be considered when conducting chemotherapy for CRLM. Neoadjuvant anti-epidermal growth factor receptor (EGFR) antibody has shown a high response rate for RAS wild CRC. However, whether anti-EGFR antibody is superior to antivascular endothelial growth factor antibody for all types of CRLM is yet to be determined. Recently, several randomized control trials of first-line therapy for advanced CRC have been conducted, and some of them are ongoing. The optimal chemotherapy regimen and tumor biology indicated for neoadjuvant chemotherapy as well as conversion surgery are expected to be determined in the near future.
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Affiliation(s)
- Eiji Oki
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Koji Ando
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Ryota Nakanishi
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masahiko Sugiyama
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yuichiro Nakashima
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Nobuhide Kubo
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kensuke Kudou
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Hiroshi Saeki
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Tadahiro Nozoe
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yasunori Emi
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yoshihiko Maehara
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
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16
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Wang JX, Wu HL, Zhu M, Zhou R. Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer: an Update Meta-Analysis of Randomized Clinical Trials. Pathol Oncol Res 2018; 26:159-166. [PMID: 29383654 DOI: 10.1007/s12253-017-0365-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 11/29/2017] [Indexed: 12/22/2022]
Abstract
Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have showed clinical benefit in combination with chemotherapeutic cytotoxic drugs in the first-line therapy of metastatic colorectal cancer (mCRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unknown. This study aimed to evaluate the impact of the combination of anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy on mCRC patient outcomes by combining the data from randomized clinical trials. Three trials meeting the eligibility criteria, and four randomized studies were included in the meta-analysis. For MCRC patients with KRAS wild type (KRAS-WT), the ORR was superior in patients treated with anti-EGFR compared with those who treated with anti-VEGF therapy. This effect was even better for all RAS-WT patients. Progression-free survival (PFS) rates were not significantly different for KRAS-WT mCRC and all RAS-WT mCRC between the two groups. The overall survival (OS) was higher for RAS wild-type (RAS-WT) mCRC patients who received anti-EGFR, but the KRAS-WT patients compared to the anti-VEGF therapy. The results of our research indicate that superior ORR and OS between the addition of anti-EGFR therapy VS anti-VEGF therapy in all RAS-WT patients with MCRC. There was no significant difference in OS and PFS between the two groups for KRAS-WT mCRC. These results suggest that anti- EGFR monoclonal antibodies can achieve an equivalent efficacy when compared with anti-VEGF therapy of all RAS-WT mCRC patients.
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Affiliation(s)
- Jian-Xiang Wang
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Hai-Long Wu
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Meng Zhu
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China
| | - Rui Zhou
- Department of General Surgery, Puai Hospital, Huazhong University of Science and Technology, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430033, China.
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17
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Poston G, Adam R, Xu J, Byrne B, Esser R, Malik H, Wasan H, Xu J. The role of cetuximab in converting initially unresectable colorectal cancer liver metastases for resection. Eur J Surg Oncol 2017; 43:2001-2011. [DOI: 10.1016/j.ejso.2017.07.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 07/21/2017] [Indexed: 12/15/2022] Open
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18
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Haraldsdottir S, Goldberg RM. Conversion Therapy for Initially Borderline/Unresectable Metastases in Colon Cancer: What Is the Best Neoadjuvant Chemotherapy? CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0393-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Nozawa H, Ishihara S, Kawai K, Hata K, Kiyomatsu T, Tanaka T, Nishikawa T, Otani K, Yasuda K, Sasaki K, Kaneko M, Murono K. Conversion to Resection in Patients Receiving Systemic Chemotherapy for Unresectable and/or Metastatic Colorectal Cancer-Predictive Factors and Prognosis. Clin Colorectal Cancer 2017; 17:e91-e97. [PMID: 29113730 DOI: 10.1016/j.clcc.2017.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 09/27/2017] [Accepted: 10/10/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Systemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (CRC), especially patients with hepatic metastasis. However, the predictive factors and prognosis of conversion to resection after chemotherapy in patients with various organ metastases remain largely unknown. PATIENTS AND METHODS We reviewed the data from metastatic CRC (mCRC) patients who had received oxaliplatin- or irinotecan-based systemic chemotherapy from 2005 to 2016. The predictors for conversion to surgery were assessed by multivariate analyses. Cancer-free survival and overall survival after the initiation of treatment were compared between patients who had undergone successful conversion therapy and those who had undergone surgery first for resectable stage IV CRC. RESULTS Of 99 mCRC patients receiving first-line chemotherapy, 23 underwent secondary surgical resection. Single organ metastasis, the presence of liver metastases, and the use of biologic agents were independent predictors of successful conversion therapy. The long-term survival of patients who underwent successful secondary surgery did not differ significantly from that of the 112 patients with resectable stage IV CRC who had undergone surgery first. CONCLUSION Liver metastases and single organ metastasis were more likely to be resected after chemotherapy than were other metastatic lesions in mCRC. The use of biologic agents contributed to the increased conversion rate. Successful conversion resulted in outcomes similar to those of resectable stage IV CRC.
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Affiliation(s)
- Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | | | - Toshiaki Tanaka
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kensuke Otani
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Yasuda
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Manabu Kaneko
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
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20
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Chen HH, Lin JK, Chen JB, Chuang CH, Liu MC, Wang JY, Changchien CR. Neoadjuvant therapy of bevacizumab in combination with oxaliplatin and capecitabine (XELOX) for patients with metastatic colorectal cancer with unresectable liver metastases: a phase II, open-label, single-arm, noncomparative trial. Asia Pac J Clin Oncol 2017; 14:61-68. [DOI: 10.1111/ajco.12692] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/30/2017] [Indexed: 12/17/2022]
Affiliation(s)
| | - Jen-Kou Lin
- Taipei Veterans General Hospital; Taipei Taiwan
| | - Joe-Bin Chen
- Taichung Veterans General Hospital; Taichung Taiwan
| | | | - Mei-Ching Liu
- Koo Foundation Sun Yat-Sen Cancer Center; Taipei Taiwan
| | - Jen-Yi Wang
- Chang Gung Memorial Hospital; Chai-Yi Taiwan
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21
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Tomasello G, Petrelli F, Ghidini M, Russo A, Passalacqua R, Barni S. FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis. JAMA Oncol 2017; 3:e170278. [PMID: 28542671 PMCID: PMC5824228 DOI: 10.1001/jamaoncol.2017.0278] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 01/25/2017] [Indexed: 12/22/2022]
Abstract
IMPORTANCE The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. OBJECTIVE To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. DATA SOURCES A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). STUDY SELECTION Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. DATA EXTRACTION AND SYNTHESIS Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. MAIN OUTCOMES AND MEASURES Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. RESULTS Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12). CONCLUSIONS AND RELEVANCE For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.
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Affiliation(s)
- Gianluca Tomasello
- Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale Ospedale di Cremona, Cremona, Italy
| | - Fausto Petrelli
- Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale di Bergamo Ovest, Treviglio (Bergamo), Italy
| | - Michele Ghidini
- Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale Ospedale di Cremona, Cremona, Italy
| | - Alessandro Russo
- Surgical Oncology Unit, Surgical Department, Azienda Socio Sanitaria Territoriale di Bergamo Ovest, Treviglio (Bergamo), Italy
| | - Rodolfo Passalacqua
- Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale Ospedale di Cremona, Cremona, Italy
| | - Sandro Barni
- Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale di Bergamo Ovest, Treviglio (Bergamo), Italy
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Fiorentini G, Sarti D, Aliberti C, Carandina R, Mambrini A, Guadagni S. Multidisciplinary approach of colorectal cancer liver metastases. World J Clin Oncol 2017; 8:190-202. [PMID: 28638789 PMCID: PMC5465009 DOI: 10.5306/wjco.v8.i3.190] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 04/27/2017] [Accepted: 05/03/2017] [Indexed: 02/06/2023] Open
Abstract
Large bowel cancer is a worldwide public health challenge. More than one third of patients present an advanced stage of disease at diagnosis and the liver is the most common site of metastases. Selection criteria for early diagnosis, chemotherapy and surgery have been recently expanded. The definition of resectability remains unclear. The presence of metastases is the most significant prognostic factor. For this reason the surgical resection of hepatic metastases is the leading treatment. The most appropriate resection approach remains to be defined. The two step and simultaneous resection processes of both primary and metastases have comparable survival long-term outcomes. The advent of targeted biological chemotherapeutic agents and the development of loco-regional therapies (chemoembolization, thermal ablation, arterial infusion chemotherapy) contribute to extend favorable results. Standardized evidence-based protocols are missing, hence optimal management of hepatic metastases should be single patient tailored and decided by a multidisciplinary team. This article reviews the outcomes of resection, systemic and loco-regional therapies of liver metastases originating from large bowel cancer.
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23
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Bergeat D, Rayar M, Mouchel Y, Merdrignac A, Meunier B, Lièvre A, Boudjema K, Sulpice L. Preoperative bevacizumab and surgery for colorectal liver metastases: a propensity score analysis. Langenbecks Arch Surg 2017; 402:57-67. [DOI: 10.1007/s00423-017-1551-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 01/01/2017] [Indexed: 12/25/2022]
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24
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Starlinger P, Assinger A, Brostjan C, Gruenberger T. Liver surgery for metastatic colorectal cancer: the surgical oncologist perspective. COLORECTAL CANCER 2016. [DOI: 10.2217/crc-2016-0004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Neoadjuvant/conversion chemotherapy has emerged as an indispensable tool to achieve resectability of initially unresectable metastatic colorectal cancer and improves oncological outcomes. In parallel, surgical strategy has adopted a more aggressive treatment approach to achieve complete tumor clearance. However, chemotherapy affects liver function and combined with extensive liver resection, morbidity has increased, thereby compromising oncological outcome. There is an imperative need for careful patient selection to optimize patient management. In this review, we discuss available evidence and indications for neoadjuvant treatment in the management of colorectal cancer liver metastases, on preoperative patient selection and identification of high-risk patients, potential treatment strategies to promote postoperative liver regeneration to avoid postoperative morbidity and potentially deleterious side effects of these therapies on tumor growth.
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Affiliation(s)
- Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Alice Assinger
- Center for Physiology & Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
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25
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Ongoing Adjuvant/Neoadjuvant Trials in Resectable Metastatic Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0342-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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26
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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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27
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Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJG, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27:1386-422. [PMID: 27380959 DOI: 10.1093/annonc/mdw235] [Citation(s) in RCA: 2409] [Impact Index Per Article: 267.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/31/2016] [Indexed: 02/11/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
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Affiliation(s)
- E Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - A Cervantes
- Medical Oncology Department, INCLIVA University of Valencia, Valencia, Spain
| | - R Adam
- Hepato-Biliary Centre, Paul Brousse Hospital, Villejuif, France
| | - A Sobrero
- Medical Oncology, IRCCS San Martino Hospital, Genova, Italy
| | - J H Van Krieken
- Research Institute for Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - D Aderka
- Division of Oncology, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - E Aranda Aguilar
- Medical Oncology Department, University Hospital Reina Sofia, Cordoba, Spain
| | - A Bardelli
- School of Medicine, University of Turin, Turin, Italy
| | - A Benson
- Division of Hematology/Oncology, Northwestern Medical Group, Chicago, USA
| | - G Bodoky
- Department of Oncology, St László Hospital, Budapest, Hungary
| | - F Ciardiello
- Division of Medical Oncology, Seconda Università di Napoli, Naples, Italy
| | - A D'Hoore
- Abdominal Surgery, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - E Diaz-Rubio
- Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
| | - J-Y Douillard
- Medical Oncology, Institut de Cancérologie de l'Ouest (ICO), St Herblain
| | - M Ducreux
- Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - A Falcone
- Department of Medical Oncology, University of Pisa, Pisa, Italy Division of Medical Oncology, Department of Oncology, University Hospital 'S. Chiara', Istituto Toscano Tumori, Pisa, Italy
| | - A Grothey
- Division of Medical Oncology, Mayo Clinic, Rochester, USA
| | - T Gruenberger
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria
| | - K Haustermans
- Department of Radiation Oncology, University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium
| | - V Heinemann
- Comprehensive Cancer Center, University Clinic Munich, Munich, Germany
| | - P Hoff
- Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil
| | - C-H Köhne
- Northwest German Cancer Center, University Campus Klinikum Oldenburg, Oldenburg, Germany
| | - R Labianca
- Cancer Center, Ospedale Giovanni XXIII, Bergamo, Italy
| | - P Laurent-Puig
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - B Ma
- Department of Clinical Oncology, Prince of Wales Hospital, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Shatin, Hong Kong
| | - T Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - K Muro
- Department of Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan
| | - N Normanno
- Cell Biology and Biotherapy Unit, I.N.T. Fondazione G. Pascale, Napoli, Italy
| | - P Österlund
- Helsinki University Central Hospital, Comprehensive Cancer Center, Helsinki, Finland Department of Oncology, University of Helsinki, Helsinki, Finland
| | - W J G Oyen
- The Institute of Cancer Research and The Royal Marsden Hospital, London, UK
| | - D Papamichael
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus
| | - G Pentheroudakis
- Department of Medical Oncology, University of Ioannina, Ioannina, Greece
| | - P Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - T J Price
- Haematology and Medical Oncology Unit, Queen Elizabeth Hospital, Woodville, Australia
| | - C Punt
- Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - J Ricke
- Department of Radiology and Nuclear Medicine, University Clinic Magdeburg, Magdeburg, Germany
| | - A Roth
- Digestive Tumors Unit, Geneva University Hospitals (HUG), Geneva, Switzerland
| | - R Salazar
- Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - W Scheithauer
- Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - H J Schmoll
- Department of Internal Medicine IV, University Clinic Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - J Tabernero
- Medical Oncology Department, Vall d' Hebron University Hospital, Vall d'Hebron Institute of Oncology (V.H.I.O.), Barcelona, Spain
| | - J Taïeb
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - S Tejpar
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - H Wasan
- Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - T Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - A Zaanan
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - D Arnold
- Instituto CUF de Oncologia (ICO), Lisbon, Portugal
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Lu ZH, Peng JH, Wang FL, Yuan YF, Jiang W, Li YH, Wu XJ, Chen G, Ding PR, Li LR, Kong LH, Lin JZ, Zhang RX, Wan DS, Pan ZZ. Bevacizumab with preoperative chemotherapy versus preoperative chemotherapy alone for colorectal cancer liver metastases: a retrospective cohort study. Medicine (Baltimore) 2016; 95:e4767. [PMID: 27583930 PMCID: PMC5008614 DOI: 10.1097/md.0000000000004767] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
This study aimed to assess the efficacy and safety of bevacizumab plus preoperative chemotherapy as first-line treatment for liver-only metastatic colorectal cancer in Chinese patients compared with those of preoperative chemotherapy alone.Patients with histologically confirmed liver-only metastatic colorectal cancer were sequentially reviewed, and received either preoperative chemotherapy plus bevacizumab (bevacizumab group, n = 32) or preoperative chemotherapy alone (chemotherapy group, n = 57). Progression-free survival, response rate, liver resection rate, conversion rate, and safety were analyzed.With median follow-up of 28.7 months, progression-free survival was 10.9 months (95% confidence interval: 8.7-13.1 months) in bevacizumab group and 9.9 months (95% confidence interval: 6.8-13.1 months) in chemotherapy group (P = 0.472). Response rates were 59.4% in bevacizumab group and 38.6% in chemotherapy group (P = 0.059). Overall liver resection (R0, R1, and R2) rate was 68.8% in bevacizumab group and 54.4% in chemotherapy group (P = 0.185). Conversion rate was 51.9% in bevacizumab group and 40.4% in chemotherapy group (P = 0.341). No postoperative complication was observed in all patients.Bevacizumab plus preoperative chemotherapy as first-line treatment for liver-only metastatic colorectal cancer tends to achieve better clinical benefit with controllable safety in Chinese patients.
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Affiliation(s)
| | | | | | | | - Wu Jiang
- Department of Colorectal Surgery
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China
| | | | | | | | | | | | | | | | | | - Zhi-Zhong Pan
- Department of Colorectal Surgery
- Correspondence: Zhi-Zhong Pan, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, PR China (e-mail: )
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29
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Molecular markers of prognosis and therapeutic targets in metastatic colorectal cancer. Surg Oncol 2016; 25:190-9. [PMID: 27566022 DOI: 10.1016/j.suronc.2016.05.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/19/2016] [Indexed: 12/18/2022]
Abstract
Metastatic disease ultimately occurs in approximately 50-70% of patients presenting with colorectal cancer. In patients with advanced disease, there is significant variability in individual patient outcomes. To improve understanding of tumor behavior, markers such as KRAS and BRAF mutation status are increasingly utilized. Additionally, newer surrogates of tumor biology, such as telomerase activity and the prevalence of circulating tumor cells and circulating tumor DNA, have generated increasing interest due to clinical potential. While the extent to which these newer markers can predict outcome and guide therapy is yet to be determined, KRAS mutation status is currently used to guide systemic therapy in selected patients. Furthermore, advances in our understanding of various tumorigenic pathways (such as the mitogen activated protein kinase pathway) have enabled newer targeted agents, including BRAF inhibitors. Interestingly, although inhibition of BRAF in patients has not translated into improved outcomes, characterization of BRAF mutations led to an association with microsatellite instability. A unique histologic characteristic of certain tumors in patients with microsatellite instability is the infiltration by lymphocytes at the tumor-stromal interface. This feature highlights the biology of the tumor in its microenvironment and underlies the efficacy of the programmed-death inhibitor, pembrolizumab, in patients with microsatellite unstable metastatic colorectal cancer. With an increasing number of prognostic markers and therapeutic options in metastatic colorectal cancer, the multidisciplinary approach becomes critical for appropriate treatment decisions.
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30
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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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31
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García-Alfonso P, Ferrer A, Gil S, Dueñas R, Pérez MT, Molina R, Capdevila J, Safont MJ, Castañón C, Cano JM, Lara R. Neoadjuvant and conversion treatment of patients with colorectal liver metastasis: the potential role of bevacizumab and other antiangiogenic agents. Target Oncol 2015; 10:453-65. [PMID: 25752908 PMCID: PMC4668275 DOI: 10.1007/s11523-015-0362-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 01/28/2015] [Indexed: 12/25/2022]
Abstract
More than 50 % of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metastases (CRLM). New antiangiogenic targeted therapies, such as bevacizumab, aflibercept, and regorafenib, in combination with neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The present review discusses the available data for antiangiogenic targeted agents in this setting. One of these therapies, bevacizumab, which targets the vascular endothelial growth factor (VEGF) has demonstrated good results in this setting. In patients with initially unresectable CRLM, the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab has led to high response and resection rates. This combination is also effective for patients with unresectable CRLM. Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic agents. In phase II trials, antiangiogenic therapy has demonstrated benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients.
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Affiliation(s)
- Pilar García-Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Ana Ferrer
- Medical Oncology Service, Hospital General Universitario de Albacete, Albacete, Spain
| | - Silvia Gil
- Medical Oncology Service, Hospital Universitario Carlos Haya, Málaga, Spain
| | - Rosario Dueñas
- Medical Oncology Service, Complejo Hospitalario de Jaén, Jaén, Spain
| | | | - Raquel Molina
- Medical Oncology Service, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
| | - Jaume Capdevila
- Medical Oncology Service, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - María José Safont
- Medical Oncology Service, Hospital General Universitario de Valencia, Valencia, Spain
| | - Carmen Castañón
- Medical Oncology Service, Complejo Asistencial de León, León, Spain
| | - Juana María Cano
- Medical Oncology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Ricardo Lara
- Medical Oncology Service, Hospital Obispo Polanco, Teruel, Spain
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Secondary Metastases Resection After Bevacizumab Plus Irinotecan-Based Chemotherapy in First-Line Therapy of Metastatic Colorectal Cancer in a Real-Life Setting: Results of the ETNA Cohort. Target Oncol 2015; 11:83-92. [DOI: 10.1007/s11523-015-0377-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer. Cancer Chemother Pharmacol 2015. [DOI: 10.1007/s00280-015-2825-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Current controversies in the management of metastatic colorectal cancer. Cancer Chemother Pharmacol 2015; 76:659-77. [DOI: 10.1007/s00280-015-2808-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 06/12/2015] [Indexed: 12/16/2022]
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Petrelli F, Coinu A, Ghilardi M, Cabiddu M, Zaniboni A, Barni S. Efficacy of oxaliplatin-based chemotherapy + bevacizumab as first-line treatment for advanced colorectal cancer: a systematic review and pooled analysis of published trials. Am J Clin Oncol 2015; 38:227-33. [PMID: 25806713 DOI: 10.1097/coc.0b013e3182a2d7b8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Oxaliplatin and either capecitabine or infusional/bolus 5-fluorouracil (5FU)-based chemotherapy + bevacizumab (XELOX + B and FOLFOX + B) represent 2 of the approved first-line treatments for advanced colorectal cancer (CRC). However, the addition of B did not offer a survival benefit compared with FOLFOX/XELOX alone in the phase III, NO16966 trial. The aim of this review was to aggregate all published data on the efficacy of XELOX and FOLFOX-B in prospective and retrospective studies as first-line therapy for stage IV CRC. METHODS We performed a systematic review, through PubMed and EMBASE, of all published studies exploring the efficacy of fluoropyrimidines + oxaliplatin + B-based chemotherapy as first-line chemotherapy in advanced CRC patients. Pooled estimates of the response rates, weighted medians of progression-free survival, and overall survival from all FOLFOX + B and XELOX + B arms were calculated. RESULTS A total of 25 studies were retrieved, with a total of 7878 patients. Overall, the pooled response rates (n=20 publications) was 49.1%. The median progression-free survival and overall survival (n=21 and 22 publications, respectively) were 10.3 and 23.7 months, respectively. The pooled median rate of surgical resection of metastases (n=13 publications) was 14%. CONCLUSIONS XELOX + B and FOLFOX + B are active combinations as first-line treatment of advanced CRC. The efficacy is confirmed for the first time from this pooled analysis of 25 trials. Both the XELOX + B and the FOLFOX + B arms represent 2 of the cornerstone combinations when B is used as first-line therapy.
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Affiliation(s)
- Fausto Petrelli
- *Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio (BG) †UO Oncologia, Dipartimento Oncologico, Istituto Ospedaliero Fondazione Poliambulanza, Brescia (BS), Italy
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Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A, Ishii H, Ohkawa S, Furukawa M, Maguchi H, Ikeda M, Togashi Y, Nishio K, Ohashi Y. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci 2015; 106:883-90. [PMID: 25867139 PMCID: PMC4520640 DOI: 10.1111/cas.12674] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/01/2015] [Accepted: 04/08/2015] [Indexed: 12/15/2022] Open
Abstract
Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington–Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington–Fleming P-value, 0.918; log–rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486–1.557). Median survival time was 8.36 months (95% CI, 7.46–10.18) for the Active group and 8.54 months (95% CI, 7.33–10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival. Phase II/III trial of elpamotide was performed to evaluate the clinical effect for advanced pancreatic cancer. Despite the lack of benefit in OS, sub-group analysis suggested that the patients with severe ISR might have better survival.
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Affiliation(s)
- Hiroki Yamaue
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Takuya Tsunoda
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Masaji Tani
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Motoki Miyazawa
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Kenji Yamao
- Department of Gastroenterology Aichi Cancer Center Hospital, Aichi, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology Aichi Cancer Center Hospital, Aichi, Japan
| | - Takuji Okusaka
- Hepatobiliary and Pancreatic Oncology Division National Cancer Center Hospital, Tokyo, Japan
| | - Hideki Ueno
- Hepatobiliary and Pancreatic Oncology Division National Cancer Center Hospital, Tokyo, Japan
| | - Narikazu Boku
- Department of Gastroenterology Shizuoka Cancer Center, Shizuoka, Japan
| | - Akira Fukutomi
- Department of Gastroenterology Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroshi Ishii
- Hepatobiliary and Pancreatic Division Cancer Institute Hospital, Tokyo, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology Division Kanagawa Cancer Center Hospital, Kanagawa, Japan
| | - Masayuki Furukawa
- Department of Gastroenterology National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Hiroyuki Maguchi
- Center for Gastroenterology Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Masafumi Ikeda
- Division of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital East, Chiba, Japan
| | - Yosuke Togashi
- Dept Genome Biology Kinki University School of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Dept Genome Biology Kinki University School of Medicine, Osaka, Japan
| | - Yasuo Ohashi
- Department of Integrated Science and Engineering for Sustainable society Chuo University, Tokyo, Japan
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Hatano E, Okuno M, Nakamura K, Ishii T, Seo S, Taura K, Yasuchika K, Yazawa T, Zaima M, Kanazawa A, Terajima H, Kaihara S, Adachi Y, Inoue N, Furumoto K, Manaka D, Tokka A, Furuyama H, Doi K, Hirose T, Horimatsu T, Hasegawa S, Matsumoto S, Sakai Y, Uemoto S. Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study). JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:634-45. [PMID: 25926024 DOI: 10.1002/jhbp.254] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 03/18/2015] [Indexed: 01/02/2023]
Abstract
BACKGROUND Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. METHODS We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. RESULTS Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). CONCLUSIONS This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM.
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Affiliation(s)
- Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayuki Okuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Nakamura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Seo
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kentaro Yasuchika
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takefumi Yazawa
- Department of Surgery, Shiga Medical Center for Adults, Moriyama, Shiga, Japan
| | - Masazumi Zaima
- Department of Surgery, Shiga Medical Center for Adults, Moriyama, Shiga, Japan
| | | | - Hiroaki Terajima
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Satoshi Kaihara
- Department of Surgery, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
| | | | - Naoya Inoue
- Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan
| | | | - Dai Manaka
- Department of Surgery, Kyoto Katsura Hospital, Kyoto, Japan
| | - Atsuo Tokka
- Department of Surgery, Shimane Prefectural Central Hospital, Izumo, Shimane, Japan
| | - Hiroaki Furuyama
- Department of Surgery, Tenri Yorozu Hospital, Tenri, Nara, Japan
| | - Koji Doi
- Department of Surgery, Fukui Red Cross Hospital, Fukui, Japan
| | - Tetsuro Hirose
- Department of Surgery, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Takahiro Horimatsu
- Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Suguru Hasegawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shigemi Matsumoto
- Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Hayashi H, Beppu T, Sakamoto Y, Miyamoto Y, Yokoyama N, Higashi T, Nitta H, Hashimoto D, Chikamoto A, Baba H. Prognostic value of Ki-67 expression in conversion therapy for colorectal liver-limited metastases. Am J Cancer Res 2015; 5:1225-1233. [PMID: 26046001 PMCID: PMC4449450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 12/25/2014] [Indexed: 06/04/2023] Open
Abstract
INTRODUCTION The objective of this study was to examine the prognostic value of Ki-67 expression in conversion therapy for colorectal liver-confined metastases. METHODS We enrolled a total of 96 patients including 54 patients who received oxaliplatin- or irinotecan-based chemotherapy and curative hepatectomy for initially unresectable metastases (conversion group) and 42 patients with initially resectable liver metastases (straight hepatectomy group). Ki-67 expression was examined in 96 resected specimens but excluded the 2 specimens that revealed no residual cancer cells in conversion group. RESULTS Conversion therapy leads to greater survival that is equivalent to that straight hepatectomy group. In conversion group, high Ki-67 expression (> 30%) levels were detectable in 33 patients (64%) after chemotherapy prior to conversion therapy. High Ki-67 expression was significantly associated with shorter disease-free survival and worse overall survival (P < 0.01 in both), and was an independent worse prognostic factor of disease-free survival and overall survival (hazard ratio [HR] and P-values were 5.608, 0.001 and 5.366, 0.04, respectively) in patients with conversion therapy. Interestingly, even in the patients with RECIST PR (n = 32), high Ki-67 expression was significantly shorter disease-free survival compared to low Ki-67 expression (P < 0.001). In contrast to conversion group, there was no significant difference in disease free survival and overall survival between low (n = 14, 33%) and high (n = 28, 67%) Ki-67 expressions in patients with straight hepatectomy (P = 0.14 and 0.74, respectively). CONCLUSIONS Residual Ki-67 expression is a useful biomarker for worse prognostic outcomes after conversion therapy. High Ki-67 expression may be a biomarker of micrometastases containing aggressive cancer cells.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Toru Beppu
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Naomi Yokoyama
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hidetoshi Nitta
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Daisuke Hashimoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Akira Chikamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto 860-8556, Japan
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Baba K, Oshita A, Kohyama M, Inoue S, Kuroo Y, Yamaguchi T, Nakamura H, Sugiyama Y, Tazaki T, Sasaki M, Imamura Y, Daimaru Y, Ohdan H, Nakamitsu A. Successful treatment of conversion chemotherapy for initially unresectable synchronous colorectal liver metastasis. World J Gastroenterol 2015; 21:1982-1988. [PMID: 25684967 PMCID: PMC4323478 DOI: 10.3748/wjg.v21.i6.1982] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/03/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis (CRLM), which involved the right hepatic vein (RHV) and the inferior vena cava (IVC), was referred to our hospital. The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC. After she had undergone laparoscopic sigmoidectomy for the original tumor, she consequently had 3 courses of modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus cetuximab. Computed tomography revealed a partial response, and the confluence of the RHV and IVC got free from cancer invasion. After 3 additional courses of mFOLFOX6 plus cetuximab, preoperative percutaneous transhepatic portal vein embolization (PTPE) was performed to secure the future remnant liver volume. Finally, a right hemihepatectomy was performed. The postoperative course was uneventful. The patient was discharged from the hospital on postoperative day 13. She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention. This multidisciplinary strategy, consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE, could contribute in facilitating curative hepatic resection for initially unresectable CRLM.
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Gruenberger T, Bridgewater J, Chau I, García Alfonso P, Rivoire M, Mudan S, Lasserre S, Hermann F, Waterkamp D, Adam R. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol 2014; 26:702-708. [PMID: 25538173 DOI: 10.1093/annonc/mdu580] [Citation(s) in RCA: 249] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI. CLINICALTRIALSGOV NCT00778102.
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Affiliation(s)
- T Gruenberger
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria.
| | - J Bridgewater
- Department of Oncology, University College London Cancer Institute, London
| | - I Chau
- Department of Medicine, The Royal Marsden Hospital, Sutton, UK
| | - P García Alfonso
- Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - M Rivoire
- Department of Surgical Oncology, Léon Bérard Cancer Center, Université Claude Bernard Lyon I, Lyon, France
| | - S Mudan
- Department of Surgery, The Royal Marsden Hospital, Sutton, UK
| | - S Lasserre
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - F Hermann
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - R Adam
- Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, UMR-S 776, Université Paris-Sud, Villejuif, France
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Yang YH, Lin JK, Chen WS, Lin TC, Yang SH, Jiang JK, Lan YT, Lin CC, Yen CC, Tzeng CH, Teng HW. Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: superior progression-free survival is restricted to patients with measurable tumors and objective tumor response--a retrospective study. J Cancer Res Clin Oncol 2014; 140:1927-36. [PMID: 24934725 DOI: 10.1007/s00432-014-1741-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 06/06/2014] [Indexed: 01/09/2023]
Abstract
PURPOSE We aimed to compare the treatment efficacy of cetuximab versus bevacizumab in combination with either irinotecan-based or oxaliplatin-based regimens (targeted triplet) as the first-line treatment for patients with metastatic colorectal cancer. METHODS Between April 2005 and March 2012, patients (n = 158) diagnosed with metastatic colorectal cancer after at least four courses of first-line bevacizumab-based (n = 95) or cetuximab-based triplet (n = 63) were retrospectively analyzed. The KRAS genotypes were sequenced for all patients. The Kaplan-Meier method was used for survival analysis, and Cox proportional hazards models were used for univariate and multivariate analyses. RESULTS Cetuximab-based triplet was associated with a higher objective response rate (66.0 vs. 47.2 %, p = 0.037) and a higher conversion rate to resectability (39.7 vs. 20.0 %, p = 0.007) compared to bevacizumab-based triplet. Compared with bevacizumab-based triplet, cetuximab-based triplet significantly increased progression-free survival in patients with measurable metastatic colorectal cancer who achieved objective tumor response (responders) (median 13.1 vs. 10.5 months, p = 0.023), but no significant increase was observed for overall survival. After adjustment for group differences in baseline characteristics and combined chemotherapy agents, cetuximab-based triplet remained an independent determinant of progression-free survival in responders as compared with bevacizumab-based triplet. KRAS mutation was not a prognostic factor in patients with metastatic colorectal cancer. CONCLUSIONS As compared with bevacizumab-based triplet, cetuximab-based triplet as the first-line treatment of metastatic colorectal cancer was associated with better progression-free survival in patients with measurable tumors who achieved objective tumor response to bio-chemotherapy.
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Affiliation(s)
- Yuan-Hao Yang
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan
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Brouquet A, Nordlinger B. Adjuvant Therapy in Combination with Resection of Colorectal Cancer Metastasis to the Liver or Lungs. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0239-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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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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Chok KSH, Cheung TT, Chan ACY, Dai WC, Chan SC, Fan ST, Poon RTP, Lo CM. Survival outcome of re-resection for recurrent liver metastases of colorectal cancer: a retrospective study. ANZ J Surg 2014; 84:545-549. [PMID: 23809019 DOI: 10.1111/ans.12298] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND This study aimed to investigate whether re-resection can achieve a good survival outcome in the treatment of recurrent liver metastases of colorectal cancer. METHODS Prospectively collected data of patients who underwent hepatectomy for liver tumours were reviewed. Patients whose liver tumours were metastases of colorectal cancer were included in the study provided that they had no extrahepatic metastases and received no loco-ablative treatment simultaneous with hepatectomy. Patients who did not have recurrent liver metastasis after their first liver resection (group R) and patients who underwent re-resection for recurrent liver metastasis (group RR) were compared. RESULTS In total, 321 patients were included in the study, with 307 in group R and 14 in group RR. The two groups had comparable demographics. Insignificantly more patients in group R received major resection (55.6% versus 30.8%, P = 0.079). The median blood loss volume was 0.6 (0-12.7) L in group R and 0.35 (0-15) L in group RR (P = 0.202). Group RR had a significantly smaller median tumour size (2.5 cm versus 3.5 cm, P = 0.020) and resection margin width (0.3 cm versus 0.7 cm, P = 0.037). On univariate analysis, re-resection was not a risk factor in overall survival. On multivariate analysis, post-operative complication (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.39, P = 0.007), microscopic margin involvement (HR 1.95, 95% CI 1.26-3.04, P = 0.003) and multiple tumours (HR 1.58, 95% CI 1.17-2.14, P = 0.003) were risk factors in overall survival. The two groups had no significant differences in disease-free survival and overall survival. CONCLUSION Re-resection for recurrent colorectal liver metastases can achieve a favourable survival outcome at centres with expertise.
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Affiliation(s)
- Kenneth S H Chok
- Department of Surgery, The University of Hong Kong, Hong Kong, China
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Dai F, Shu L, Bian Y, Wang Z, Yang Z, Chu W, Gao S. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig 2014; 33:779-88. [PMID: 23979925 DOI: 10.1007/s40261-013-0125-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVE The incidence rates of colorectal cancer (CRC) are increasing in a number of different regions, and recent studies have indicated that addition of bevacizumab to CRC therapy is beneficial. To better understand the relative risk (RR) of adverse events associated with use of bevacizumab, we systematically reviewed published clinical trials that studied use of bevacizumab in treatment of patients affected by metastatic CRC (mCRC). METHODS The National Library of Medicine PubMed, MEDLINE, Ovid, Cochrane Library and Chinese Biomedicine databases were searched. The RR and number needed to harm (NNH) values for major side effects with 95% confidence intervals (CIs) were calculated in a fixed-effects model and a random-effects model, where appropriate. RESULTS Fifteen controlled trials totalling 6,937 patients were eligible for this analysis. Compared with the control group, the bevacizumab treatment group had a slightly higher risk of any severe adverse event (pooled RR 1.07 [95% CI 1.02-1.12]). The pooled risk difference was 5% [95% CI 2-9%], with an NNH of 20 treated patients. Analyses showed a statistically significantly higher risk of secondary endpoints, including the discovery that bevacizumab was associated with a threefold higher risk of hypertension (pooled RR 3.06 [95% CI 2.45-3.83]), a twofold higher risk of gastrointestinal haemorrhage/perforation and a lower risk of neutropenia (pooled RR 0.75 [95% CI 0.26-2.19]). CONCLUSION Bevacizumab has efficacy in all treatment regimens for advanced CRC. However, our meta-analysis raises safety concerns regarding an increased risk of serious adverse events associated with use of bevacizumab among patients with mCRC. Our findings warrant cautious use of bevacizumab in clinical oncology.
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Affiliation(s)
- Fei Dai
- Pharmacy Department of Changhai Hospital, The First Affiliated Hospital of Second Military Medical University, Shanghai, China
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Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. Dis Colon Rectum 2014; 57:679-86. [PMID: 24807591 DOI: 10.1097/dcr.0000000000000025] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The management of asymptomatic primary tumor in patients with unresectable metastatic colorectal cancer remains inconsistent. OBJECTIVE This study aimed to determine the rate of symptom-directed surgery after systemic chemotherapy and to estimate the impact of initial primary tumor resection on survival in patients with unresectable metastatic colorectal cancer and an asymptomatic primary tumor. DESIGN This was a single-institution, retrospective observational study. SETTINGS The study was conducted in a tertiary referral hospital. PATIENTS Between 2005 and 2011, 191 consecutive patients with newly diagnosed stage IV colorectal cancer were identified. Of the 191, we analyzed 94 patients with unresectable, asymptomatic colorectal cancer. MAIN OUTCOME MEASURES We measured symptom-directed surgery and overall survival. RESULTS Forty-seven patients with an intact primary tumor received systemic chemotherapy (upfront chemotherapy group), 41 underwent primary tumor resection (upfront primary tumor resection group), and 6 underwent diversion enterostomy as first-line therapy. After excluding the 6 patients undergoing diversion enterostomy before systemic chemotherapy, this left 88 patients for final analysis. Twelve upfront chemotherapy patients required symptom-directed late surgery. Overall, 1-year and 2-year rates of symptom-directed surgery were 19.1% and 26.1%. In patients with nontraversable lesions by colonoscope at diagnosis, 64.3% required late intervention within 1 year. Competing risk regression analysis revealed that only colonoscopic traversability at diagnosis was significantly associated with symptom-directed late surgery (subhazard ratio, 7.9; p = 0.004). Median overall survival time was comparable between the 2 groups at 23.9 months for the upfront primary tumor resection group and 22.6 months for the upfront chemotherapy group (HR, 0.84; 95% CI: 0.51-1.39). LIMITATIONS This study was limited by its retrospective nature and small sample size. CONCLUSIONS Approximately 75% of upfront chemotherapy patients with unresectable, asymptomatic stage IV colorectal cancer can be spared initial resection of the primary tumor. Colonoscopic findings of nontraversable lesions at diagnosis may predict the need for late surgical intervention.
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Management of Colon Cancer and Liver Metastases: Is There a Role for Molecularly Targeted Agents? CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0213-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Connor AA, Burkes R, Gallinger S. Strategies in the Multidisciplinary Management of Synchronous Colorectal Cancer and Resectable Liver Metastases. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0222-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Beppu T, Miyamoto Y, Sakamoto Y, Imai K, Nitta H, Hayashi H, Chikamoto A, Watanabe M, Ishiko T, Baba H. Chemotherapy and targeted therapy for patients with initially unresectable colorectal liver metastases, focusing on conversion hepatectomy and long-term survival. Ann Surg Oncol 2014; 21 Suppl 3:S405-13. [PMID: 24570379 DOI: 10.1245/s10434-014-3577-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Eight years have passed since the introduction of chemotherapy (chemo) and targeted therapy regimens for colorectal liver metastases (CRLM). This study aimed to clarify the effectiveness of chemo and targeted therapy in facilitating conversion hepatectomy and improving long-term survival in Japanese patients with CRLM. METHODS A total of 199 patients with CRLM were treated between May 2005 and August 2012. Initial therapies for these patients included straightforward hepatic resection (n = 48; 24 %), induction chemotherapy (n = 148; 74 %), and radiofrequency ablation (n = 3; 2 %). RESULTS In 56 of 137 patients (40.1 %) with initially unresectable CRLM, 7.5 courses of chemo and targeted therapy downsized and converted tumors to resectable tumors. The 5-year cumulative overall survival (OS) rate and the median survival time were significantly higher for the resectable CRLM than for the unresectable CRLM (54.6 vs. 5.3 % and 77.3 vs. 21.3 months, respectively; P < .0001). Multivariate analysis revealed that conversion hepatectomy (hazard ratio [HR] 0.19; P < .001) and responder to chemo and targeted therapy (HR 0.46; P < .01) were independent prognostic factors for OS. Multivariate analysis also revealed that left-sided colon or rectal cancer (odds ratio [OR] 8.4; P < .05), H1/H2 metastases (OR 7.3; P < .05), no extrahepatic metastases (OR 52.6; P < .001), and responder to chemo and targeted therapy (OR 6.1; P < .05) were significant predictors of conversion hepatectomy. CONCLUSIONS A chemo and targeted therapy can facilitate conversion hepatectomy and allow for an excellent prognosis in patients with initially unresectable CRLM.
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Affiliation(s)
- Toru Beppu
- Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan,
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KIM SELIM, LEE SOOTEIK, TRANG KIEUTHITHU, KIM SEONGHUN, KIM INHEE, LEE SEUNGOK, KIM DAEGHON, KIM SANGWOOK. Parthenolide exerts inhibitory effects on angiogenesis through the downregulation of VEGF/VEGFRs in colorectal cancer. Int J Mol Med 2014; 33:1261-7. [DOI: 10.3892/ijmm.2014.1669] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 02/19/2014] [Indexed: 11/06/2022] Open
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