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1
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Yohanathan L, Chopra A, Simo K, Clancy TE, Khithani A, Anaya DA, Maegawa FA, Sheikh M, Raoof M, Jacobs M, Aleassa E, Boff M, Ferguson B, Tan-Tam C, Winslow E, Qadan M, D’Angelica MI. Assessment and treatment considerations for patients with colorectal liver metastases: AHPBA consensus guideline and update for surgeons. HPB (Oxford) 2025; 27:263-278. [PMID: 39828468 DOI: 10.1016/j.hpb.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/20/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Colorectal cancer most commonly metastasizes to the liver. While various treatment strategies have been developed, surgical management of these patients has vital implications on the prognosis and survival of this group of patients. There remains a need for a consensus guideline regarding the surgical evaluation and management of patients with colorectal liver metastases (CRLM). METHODS This review article is a consensus guideline established by the members of the AHPBA Professional Standards Committee, as an amalgamation of existent literature and a guide to surgeons managing this complex disease. RESULTS These guidelines reports the benefits and shortcomings of various diagnostic modalities including imaging and next-generation sequencing in the management of patients with CRLM. While surgery has established survival benefits in patients with resectable disease, this report notes the importance of treatment sequencing with non-surgical modalities as well as between colon and liver resection. Finally, the guidelines address the various treatment modalities for patients with unresectable disease, that may have significant impact on survival. CONCLUSION CRLM is a complex diagnosis which warrants multidisciplinary approach with early surgical involvement in both assessment and management of the disease, to optimize patient outcomes and survival.
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2
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Pat Fong W, Li ZJ, Ren C, Guan WL, Zuo MX, Zhang TQ, Li BK, Zheng Y, Wu XJ, Ding PR, Chen G, Pan ZZ, Yuan YF, Tan Q, Wang ZQ, Li YH, Wang DS. Percutaneous hepatic artery infusion chemotherapy with oxaliplatin and fluoropyrimidines in treatment-resistant colorectal cancer patients with unresectable liver metastases: a retrospective cohort study. HPB (Oxford) 2025; 27:289-298. [PMID: 39668070 DOI: 10.1016/j.hpb.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Subsequent lines of therapy for chemotherapy-resistant metastatic colorectal cancer (CRC) have shown limited efficacy. Herein, we retrospectively investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) using oxaliplatin plus 5-FU/FUDR in patients with unresectable colorectal liver metastases (CRLM) who progressed following standard chemotherapy regimens. METHODS From March 2017 to April 2023, CRC patients with unresectable CRLM who progressed following standard chemotherapy and subsequently received HAIC oxaliplatin plus 5-FU/FUDR were evaluated. Objective response rate (ORR), disease control rate (DCR), median depth of tumor response (DpR), no evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. RESULTS A total of 21 patients who progressed after a median of two (range: 1-4) lines of standard systemic chemotherapy were included. The ORR and DCR were 28.6 % and 95.2 %, respectively, with six patients reaching partial response. Additionally, the median DpR was 10.6 %, and seven patients underwent successful conversion surgery. Stratification revealed significantly better PFS in patients with liver-limited metastases compared to those with concurrent hepatic and extrahepatic metastases (P = 0.0003). CONCLUSION HAIC oxaliplatin plus 5-FU/FUDR is a robust regimen for treatment-resistant CRC patients with unresectable CRLM, particularly those with liver-limited disease.
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Affiliation(s)
- William Pat Fong
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zi-Jing Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Meng-Xuan Zuo
- Department of Minimally Invasive & Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tian-Qi Zhang
- Department of Minimally Invasive & Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Bin-Kui Li
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yun Zheng
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao-Jun Wu
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Gong Chen
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-Zhong Pan
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yun-Fei Yuan
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qiong Tan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-Qiang Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - De-Shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Rao D, Ellis CS, Kemeny N, Cercek A. Case-Based Clinical Guidance on Dosing and Management of the Hepatic Artery Infusion Chemotherapy Pump. JCO Oncol Pract 2024; 20:187-194. [PMID: 37883732 DOI: 10.1200/op.23.00374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatic artery infusion (HAI) delivers localized high-dose floxuridine directly to liver tumors through an implanted pump. While patients are undergoing active treatment, the pump is refilled with chemotherapy alternating with saline every 2 weeks using a specialized noncoring needle. Numerous clinical scenarios influence the dosing of floxuridine, which do not conform to the usual dose modification schema for systemic chemotherapy. This article aims to provide practical clinical management solutions to overcome the common challenges faced by oncologists in the real-world management of HAI pump therapy.
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Affiliation(s)
- Devika Rao
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Nancy Kemeny
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrea Cercek
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Clinical Oncology Pharmacy, College of Pharmacy, University of Kentucky, Lexington, KY
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4
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Ding M, Wang C, Hu J, She J, Shi R, Liu Y, Sun Q, Xu H, Zhou G, Wu W, Xia H. PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-α/ NF-κB pathway. J Transl Med 2024; 22:30. [PMID: 38184566 PMCID: PMC10771005 DOI: 10.1186/s12967-023-04809-w] [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: 07/16/2023] [Accepted: 12/16/2023] [Indexed: 01/08/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC. METHODS Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. RESULTS We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway. CONCLUSIONS This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis.
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Affiliation(s)
- Min Ding
- Department of Pathology & Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission && Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, 211166, China
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, 210009, China
- Department of General Surgery & High Talent & Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Cheng Wang
- Department of Pathology & Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission && Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, 211166, China
| | - Junhong Hu
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Junjun She
- Department of General Surgery & High Talent & Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ruoyu Shi
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, 169856, Singapore
| | - Yixuan Liu
- Department of Pathology & Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission && Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, 211166, China
| | - Qi Sun
- Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Haojun Xu
- Department of Pathology & Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission && Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, 211166, China
| | - Guoren Zhou
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, 210009, China.
| | - Wenlan Wu
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, 210009, China.
| | - Hongping Xia
- Department of Pathology & Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission && Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, 211166, China.
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, 210009, China.
- Department of General Surgery & High Talent & Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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5
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Franssen S, Holster JJ, Jolissaint JS, Nooijen LE, Cercek A, D'Angelica MI, Homs MYV, Wei AC, Balachandran VP, Drebin JA, Harding JJ, Kemeny NE, Kingham TP, Klümpen HJ, Mostert B, Swijnenburg RJ, Soares KC, Jarnagin WR, Groot Koerkamp B. Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2024; 31:115-124. [PMID: 37814188 PMCID: PMC10695893 DOI: 10.1245/s10434-023-14409-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. METHODS We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. RESULTS In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0-13.6%) in the gem-cis group versus 34.3% (95% CI 28.1-41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19-0.39). CONCLUSIONS This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.
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Affiliation(s)
- Stijn Franssen
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Jessica J Holster
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Joshua S Jolissaint
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lynn E Nooijen
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marjolein Y V Homs
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Alice C Wei
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey A Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - James J Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nancy E Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Bianca Mostert
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Rutger-Jan Swijnenburg
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Kevin C Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
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6
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Chitkara A, Kaur N, Desai A, Mehta D, Anamika F, Sarkar S, Gowda N, Sethi P, Thawani R, Chen EY. Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis. Cancer Med 2023; 12:21579-21591. [PMID: 38069531 PMCID: PMC10757147 DOI: 10.1002/cam4.6662] [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: 05/22/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. METHODS Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. RESULTS The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. CONCLUSION BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.
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Affiliation(s)
- Akshit Chitkara
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Nirmaljot Kaur
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Aditya Desai
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Devanshi Mehta
- Loma Linda UniversityCalifornia in Internal MedicineCaliforniaUSA
| | - Fnu Anamika
- Internal MedicineHackensack Meridian Ocean UniversityBrickNew JerseyUSA
| | - Srawani Sarkar
- Research LabAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Nandini Gowda
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Prabhdeep Sethi
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Rajat Thawani
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
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7
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Elijah J, Schepers AJ, Krauss JC, McDevitt RL. Evaluation of biliary toxicity in patients with hepatic artery infusion pumps. J Oncol Pharm Pract 2023; 29:1915-1920. [PMID: 36823961 DOI: 10.1177/10781552231158744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
PURPOSE Identify risk factors for biliary toxicity in patients with colorectal liver metastases who received floxuridine (FUDR) via a surgically implanted hepatic artery infusion pump (HAIP). Describe the incidence of biliary toxicity and evaluate relevant patterns in the biliary toxicity cohort. METHODS A single center, retrospective, case-control study included adult colorectal cancer patients with liver metastases who received at least one cycle of FUDR via a surgically implanted HAIP from 1 January 2017, to 1 October 2021. Patients were excluded if they had incomplete records, cholangiocarcinoma diagnosis, or received concurrent mitomycin and FUDR. Biliary toxicity criteria derived from existing HAIP literature were utilized to determine whether patients experienced biliary toxicity. Multiple variables were compared by univariate statistical analysis between the biliary toxicity and non-biliary toxicity cohorts to identify potential risk factors for development of FUDR-induced biliary toxicity. RESULTS Out of 50 patients who had a HAIP implanted, 39 met the inclusion criteria. Five of the 39 patients (12.7%) included in the analysis met the pre-specified biliary toxicity criteria. No risk factors for biliary toxicity were identified. All five patients who developed biliary toxicity demonstrated elevations in alkaline phosphatase (ALP) prior to meeting the toxicity criteria. CONCLUSION Biliary toxicity remains a significant and therapy-limiting consequence of FUDR administration. Rising ALP may be an early indicator of subsequent biliary toxicity. Future studies with more patients may identify risk factors that can facilitate risk mitigation strategies.
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Affiliation(s)
- Joseph Elijah
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
- Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA
| | - Allison J Schepers
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
- Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA
| | - John C Krauss
- Department of Hematology/Oncology, Michigan Medicine, Ann Arbor, MI, USA
| | - Rachel L McDevitt
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
- Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA
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8
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Téllez T, Martin-García D, Redondo M, García-Aranda M. Clusterin Expression in Colorectal Carcinomas. Int J Mol Sci 2023; 24:14641. [PMID: 37834086 PMCID: PMC10572822 DOI: 10.3390/ijms241914641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer.
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Affiliation(s)
- Teresa Téllez
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
| | - Desirée Martin-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
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9
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Kim JS, Kim H, Lee SY, Han YD, Han K, Min BS, Kim MD, Won JY, Beom SH, Shin SJ, Kim HS, Han DH, Ahn JB. Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol. BMC Cancer 2023; 23:691. [PMID: 37481515 PMCID: PMC10363309 DOI: 10.1186/s12885-023-11085-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 06/16/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.
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Affiliation(s)
- Ji Su Kim
- Division of Hepatobiliary and Pancreas Surgery, Incheon St. Mary's Hospital, The Catholic University College of Medicine, Incheon, Korea
| | - Hyunwook Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Seo Young Lee
- Department of Medical Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Dae Han
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kichang Han
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Soh Min
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Man-Deuk Kim
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Yun Won
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Hoon Beom
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Sang Joon Shin
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Han Sang Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
- Graduate School of Medical Science, Brain Korea 21 Project, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
| | - Dai Hoon Han
- Department of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
| | - Joong Bae Ahn
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
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10
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Georgilis E, Gavriatopoulou M, Tsilimigras DI, Malandrakis P, Theodosopoulos T, Ntanasis-Stathopoulos I. Optimizing Adjuvant Therapy after Surgery for Colorectal Cancer Liver Metastases: A Systematic Review. J Clin Med 2023; 12:jcm12062401. [PMID: 36983401 PMCID: PMC10051548 DOI: 10.3390/jcm12062401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/09/2023] [Accepted: 03/19/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is the most common site of colorectal cancer metastatic spread. Although metastasectomy is the gold standard for fit patients with resectable colorectal cancer liver metastases (CRLMs), their management after surgical treatment remains controversial. The objective of this systematic review was to collate the currently available data of the agents used in the adjuvant setting in order to define the most optimal therapeutic strategy. A systematic review of the literature was conducted by searching PubMed/Medline and Cochrane library databases. We included studies that evaluated the efficacy, the tolerability and the safety profile of various chemotherapeutic agents that are used as adjuvant treatment after surgical resection of CRLMs. The outcomes of interest were regression-free survival (RFS), disease-free survival (DFS), overall survival (OS) and severe toxicities. From 543 initial articles, 29 publications with 7028 patients were finally included. In general, the results of the eligible studies indicated that adjuvant therapy after resection of CRLMs led to improved RFS/DFS rates, but this benefit did not contribute to a statistically significant prolongation of OS. Moreover, the choice of the therapeutic strategy, namely systematic or regional chemotherapy or the combination of both, did not seem to have a differential impact on patient outcomes. However, these results should be interpreted with caution since the majority of the chosen studies are of low or moderate quality. In this context, further high-quality clinical trials conducted on patient sub-populations with modern therapies are required in order to reduce in-study and between-study heterogeneity and determine which patients are expected to derive the maximum benefit from adjuvant therapy after surgery for CRLMs.
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Affiliation(s)
- Emmanouil Georgilis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Panagiotis Malandrakis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Theodosios Theodosopoulos
- Second Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
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11
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Leowattana W, Leowattana P, Leowattana T. Systemic treatment for metastatic colorectal cancer. World J Gastroenterol 2023; 29:1569-1588. [PMID: 36970592 PMCID: PMC10037252 DOI: 10.3748/wjg.v29.i10.1569] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/14/2023] Open
Abstract
Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.
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Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pathomthep Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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12
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Leowattana W, Leowattana P, Leowattana T. Systemic treatment for metastatic colorectal cancer. World J Gastroenterol 2023; 29:1425-1444. [DOI: 10.3748/wjg.v29.i10.1425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Abstract
Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.
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Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pathomthep Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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13
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Narayan RR, Datta J, Goldman DA, Aveson VG, Walch HS, Sanchez-Vega F, Gönen M, Balachandran VP, Drebin JA, Jarnagin WR, Kingham TP, Wei AC, Schultz N, Kemeny NE, D'Angelica MI. Genomic Predictors of Recurrence Patterns After Complete Resection of Colorectal Liver Metastases and Adjuvant Hepatic Artery Infusion Chemotherapy. Ann Surg Oncol 2022; 29:7579-7588. [PMID: 35896920 PMCID: PMC9561013 DOI: 10.1245/s10434-022-12085-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/09/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.
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Affiliation(s)
- Raja R Narayan
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Jashodeep Datta
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Debra A Goldman
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Victoria G Aveson
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Henry S Walch
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco Sanchez-Vega
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey A Drebin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alice C Wei
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nancy E Kemeny
- Gastrointestinal Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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14
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Feng AW, Guo JH, Gao S, Kou FX, Liu SX, Liu P, Chen H, Wang XD, Xu HF, Cao G, Zhu X. A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases. Front Oncol 2022; 12:913017. [PMID: 36212504 PMCID: PMC9532863 DOI: 10.3389/fonc.2022.913017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM). METHODS Patients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events. RESULTS 113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838-6.762]) and 4.6 months [95% CI, 3.419-5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828-21.372] and 13.1 months [95% CI, 11.215-14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms. CONCLUSION HAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/, identifier NCT02557490.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xu Zhu
- Department of Interventional Therapy, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
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15
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Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin 2022; 72:372-401. [PMID: 35472088 DOI: 10.3322/caac.21728] [Citation(s) in RCA: 287] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.
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Affiliation(s)
- Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Davide Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- Division of Medical Oncology, IRCCS Foundation Home for the Relief of Suffering, San Giovanni Rotondo, Italy
| | - Giulia Martini
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Stefania Napolitano
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus, Barcelona, Spain
- Institute of Oncology, University of Vic/Central University of Catalonia, Barcelona, Spain
- Oncology Institute of Barcelona-Quironsalud, Biomedical Research Center in Cancer, Barcelona, Spain
| | - Andres Cervantes
- Medical Oncology Department, Instituto de Investigación Sanitaria Valencia Biomedical Research Institute, University of Valencia, Valencia, Spain
- Carlos III Institute of Health, Biomedical Research Center in Cancer, Madrid, Spain
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16
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Pernot S, Pellerin O, Mineur L, Monterymard C, Smith D, Lapuyade B, Gallois C, Khemissa Akouz F, De Baere T, Tougeron D, Thirot-Bidault A, Audemar F, Simon M, Lecaille C, Louafi S, Lepage C, Ducreux M, Taieb J. Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49. Dig Liver Dis 2022; 54:324-330. [PMID: 35027324 DOI: 10.1016/j.dld.2021.12.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy. AIM The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM. MATERIALS AND METHODS Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1. ENDPOINT The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life. CONCLUSION This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753).
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Affiliation(s)
- Simon Pernot
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
| | - Olivier Pellerin
- Department of Interventional Radiology, Hopital Européen Georges-Pompidou, Université de Paris, SIRIC CARPEM, France
| | - Laurent Mineur
- Department of Medical Oncology, Institut Sainte Catherine, Avignon, France
| | - Carole Monterymard
- Federation Francophone de Cancérologie Digestive (FFCD), EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - Denis Smith
- Department of Gastroenterology and GI Oncology, CHU Haut-Leveque, Université de Bordeaux, Pessac, France
| | - Bruno Lapuyade
- Department of Interventional Radiology, CHU Haut-Leveque, Université de Bordeaux, Pessac, France
| | - Claire Gallois
- Department of Gastroenterology and GI Oncology, Hopital Européen Georges-Pompidou, Université de Paris, SIRIC CARPEM, France
| | - Faiza Khemissa Akouz
- Department of Gastroenterology and GI Oncology, CH Saint-Jean, Perpignan, France
| | - Thierry De Baere
- Department of Interventional Radiology, Gustave Roussy, BIOTHERIS, Université Paris-Saclay, Villejuif, France
| | - David Tougeron
- Université de Poitiers, Department of Gastroenterology and Hepatology, CHU La Milétrie, Poitiers, France
| | | | - Franck Audemar
- Department of Gastroenterology and GI Oncology, CH de la Côte-Basque, Bayonne, France
| | - Mireille Simon
- Department of Gastroenterology and GI Oncology, CH Pau, Pau, France
| | - Cedric Lecaille
- Department of Gastroenterology and GI Oncology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France
| | - Sami Louafi
- Department of Medical Oncology, CH Corbeille Essonne, France
| | - Come Lepage
- Federation Francophone de Cancérologie Digestive (FFCD), EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France; Department of Gastroenterology and GI Oncology, CHU Haut-Leveque, Université de Bordeaux, Pessac, France; Department of Interventional Radiology, CHU Haut-Leveque, Université de Bordeaux, Pessac, France; Department of Gastroenterology and GI Oncology, Hopital Européen Georges-Pompidou, Université de Paris, SIRIC CARPEM, France; Department of Gastroenterology and GI Oncology, CH Saint-Jean, Perpignan, France; Department of Interventional Radiology, Gustave Roussy, BIOTHERIS, Université Paris-Saclay, Villejuif, France; Université de Poitiers, Department of Gastroenterology and Hepatology, CHU La Milétrie, Poitiers, France; Department of Medical Oncology, Hôpital Privé d'Antony, Antony, France; Department of Gastroenterology and GI Oncology, CH de la Côte-Basque, Bayonne, France; Department of Gastroenterology and GI Oncology, CH Pau, Pau, France; Department of Gastroenterology and GI Oncology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France; Department of Medical Oncology, CH Corbeille Essonne, France; Department of Gastroenterology and GI oncology, CHU Le Bocage, University of Burgundy and Franche Comté, Dijon, France
| | - Michel Ducreux
- Department of Medical Oncology, Gustave Roussy, Inserm U1279, Université Paris-Saclay, Villejuif, France
| | - Julien Taieb
- Department of Gastroenterology and GI Oncology, Hopital Européen Georges-Pompidou, Université de Paris, SIRIC CARPEM, France
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Kemeny NE, Chou JF, Capanu M, Chatila WK, Shi H, Sanchez-Vega F, Kingham TP, Connell LC, Jarnagin WR, D'Angelica MI. A Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer. Ann Surg 2021; 274:248-254. [PMID: 33938493 PMCID: PMC9351589 DOI: 10.1097/sla.0000000000004923] [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] [Indexed: 11/26/2022]
Abstract
OBJECTIVE/BACKGROUND The purpose was to determine whether adding Pmab versus no Pmab to an adjuvant regimen of hepatic arterial infusion (HAI) of floxuridine (FUDR) plus systemic (SYS) leucovorin, fluorouracil, and irinotecan (FOLFIRI) improves 15-month recurrence-free survival for patients with RAS wild-type colorectal cancer. Secondary endpoints included overall survival, toxicity, and influence of predictive biomarkers. METHODS This phase II trial randomized patients with KRAS wild-type resected colorectal liver metastases to adjuvant HAI FUDR + SYS FOLFIRI +/- Pmab (NCT01312857). Patients were stratified by clinical risk score and previous chemotherapy. Based on an exact binomial design, if one arm had ≥24 patients alive and disease-free at 15 months that regimen was considered promising for further investigation. RESULTS Seventy-five patients were randomized. Patient characteristics and toxicity were not different in the 2 arms, except for rash in +Pmab arm. Grade 3/4 elevation in bilirubin or alkaline phosphatase did not differ in the 2 arms. Twenty-five (69%; 95% CI, 53-82) patients in the Pmab arm versus 18 (47%; 95% CI, 32-63) patients in the arm without Pmab were alive and recurrence-free at 15 months. Only the Pmab arm met the decision rule, while the other arm did not. After median follow-up of 56.6 months, 3-year recurrence-free survival was 57% (95% CI, 43-76) and 42% (95% CI, 29-61), and 3-year overall survival was 97% (95% CI, 90-99) and 91% (95% CI, 83-99), +/- Pmab, respectively. CONCLUSIONS The addition of Pmab to HAI FUDR + SYS FOLFIRI showed promising activity without increased biliary toxicity and should be further investigated in a larger trial.
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Affiliation(s)
- Nancy E Kemeny
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Joanne F Chou
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marinela Capanu
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Walid K Chatila
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hongyu Shi
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Francisco Sanchez-Vega
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Thomas Peter Kingham
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Louise Catherine Connell
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William R Jarnagin
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
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Molla M, Fernandez-Plana J, Albiol S, Fondevila C, Vollmer I, Cases C, Garcia-Criado A, Capdevila J, Conill C, Fundora Y, Fernandez-Martos C, Pineda E. Limited Liver or Lung Colorectal Cancer Metastases. Systemic Treatment, Surgery, Ablation or SBRT. J Clin Med 2021; 10:jcm10102131. [PMID: 34069240 PMCID: PMC8157146 DOI: 10.3390/jcm10102131] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/07/2021] [Indexed: 12/25/2022] Open
Abstract
The prognosis for oligometastatic colorectal cancer has improved in recent years, mostly because of recent advances in new techniques and approaches to the treatment of oligometastases, including new surgical procedures, better systemic treatments, percutaneous ablation, and stereotactic body radiation therapy (SBRT). There are several factors to consider when deciding on the better approach for each patient: tumor factors (metachronous or synchronous metastases, RAS mutation, BRAF mutation, disease-free interval, size and number of metastases), patient factors (age, frailty, comorbidities, patient preferences), and physicians' factors (local expertise). These advances have presented major challenges and opportunities for oncologic multidisciplinary teams to treat patients with limited liver and lung metastases from colorectal cancer with a curative intention. In this review, we describe the different treatment options in patients with limited liver and lung metastases from colorectal cancer, and the possible combination of three approaches: systemic treatment, surgery, and local ablative treatments.
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Affiliation(s)
- Meritxell Molla
- Department of Radiation Oncology, Hospital Clinic Barcelona, Barcelona 08036, Spain; (M.M.); (C.C.); (C.C.)
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain
| | | | - Santiago Albiol
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona 08036, Spain;
| | - Constantino Fondevila
- Department of General and Digestive Surgery, Hospital Clinic de Barcelona, Barcelona 08036, Spain; (C.F.); (Y.F.)
| | - Ivan Vollmer
- Department of Radiology, Hospital Clinic Barcelona, Barcelona 08036, Spain; (I.V.); (A.G.-C.)
| | - Carla Cases
- Department of Radiation Oncology, Hospital Clinic Barcelona, Barcelona 08036, Spain; (M.M.); (C.C.); (C.C.)
| | - Angeles Garcia-Criado
- Department of Radiology, Hospital Clinic Barcelona, Barcelona 08036, Spain; (I.V.); (A.G.-C.)
| | - Jaume Capdevila
- Department of Medical Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona 08035, Spain;
| | - Carles Conill
- Department of Radiation Oncology, Hospital Clinic Barcelona, Barcelona 08036, Spain; (M.M.); (C.C.); (C.C.)
| | - Yliam Fundora
- Department of General and Digestive Surgery, Hospital Clinic de Barcelona, Barcelona 08036, Spain; (C.F.); (Y.F.)
| | | | - Estela Pineda
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona 08036, Spain;
- Correspondence:
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19
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Zhang Y, Wang K, Yang T, Cao Y, Liang W, Yang X, Xiao T. Meta-Analysis of Hepatic Arterial Infusion for Liver Metastases From Colorectal Cancer. Front Oncol 2021; 11:628558. [PMID: 33777775 PMCID: PMC7989965 DOI: 10.3389/fonc.2021.628558] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 02/11/2021] [Indexed: 12/24/2022] Open
Abstract
The aim of the present study was to evaluate the potential benefits of hepatic arterial infusion chemotherapy (HAIC) in the management of colorectal liver metastases (CRLM). Electronic databases, including PubMed, EMBASE, Medline, Web of Science, and Cochrane Library, were comprehensively searched from inception to November 2020. Prospective randomized trials with HAIC vs. systemic chemotherapy (SC) were selected. The overall survival (OS), tumor response rates (RRs), progression-free survival (PFS), and corresponding 95% confidence intervals (CIs) were assessed in the meta-analysis. Subsequently, the heterogeneity between studies, sensitivity, publication bias, and meta-regression analyses were performed. Finally, 18 studies, which contained 1,766 participants (922 in the HAIC group and 844 in the SC group) were included. There was a significantly higher OS rate in the HAIC as palliative treatment group (HR, 0.17; 95% CI, 0.08–0.26; P = 0.000) and HAIC as adjuvant treatment group compared with SC group (HR, 0.63; 95% CI, 0.38–0.87; P = 0.000). The complete and partial tumor RRs were also increased significantly in the HAIC as palliative treatment group (RR = 2.09; 95% CI, 1.36–3.22; P = 0.001) and as adjuvant treatment group compared with SC group (RR = 2.14; 95% CI, 1.40–3.26; P = 0.000). However, PFS did not differ significantly between the HAIC and SC groups (P > 0.05). Meta-regression analysis showed potential covariates did not influence on the association between HAIC and OS outcomes (P > 0.05). The results of the present study suggested that HAIC may be a potential therapeutic regimen that may improve the outcomes of patients with CRLM. The present meta-analysis has been registered in PROSPERO (no. CRD 42019145719).
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Affiliation(s)
- Yan Zhang
- The Second Clinical School, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Kaili Wang
- The Second Clinical School, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.,China Academy of Chinese Medical Sciences, Beijing, China
| | - Tao Yang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yibo Cao
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Wanling Liang
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China.,Colorectal and Anal Surgery, Chengdu Anorectal Hospital, Chengdu, China
| | - Xiangdong Yang
- Colorectal and Anal Surgery, Chengdu Anorectal Hospital, Chengdu, China
| | - Tianbao Xiao
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
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Anaya DA, Dogra P, Wang Z, Haider M, Ehab J, Jeong DK, Ghayouri M, Lauwers GY, Thomas K, Kim R, Butner JD, Nizzero S, Ramírez JR, Plodinec M, Sidman RL, Cavenee WK, Pasqualini R, Arap W, Fleming JB, Cristini V. A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases. Cancers (Basel) 2021; 13:cancers13030444. [PMID: 33503971 PMCID: PMC7866038 DOI: 10.3390/cancers13030444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 01/21/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary It is known that drug transport barriers in the tumor determine drug concentration at the tumor site, causing disparity from the systemic (plasma) drug concentration. However, current clinical standard of care still bases dosage and treatment optimization on the systemic concentration of drugs. Here, we present a proof of concept observational cohort study to accurately estimate drug concentration at the tumor site from mathematical modeling using biologic, clinical, and imaging/perfusion data, and correlate it with outcome in colorectal cancer liver metastases. We demonstrate that drug concentration at the tumor site, not in systemic circulation, can be used as a credible biomarker for predicting chemotherapy outcome, and thus our mathematical modeling approach can be applied prospectively in the clinic to personalize treatment design to optimize outcome. Abstract Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 (p < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.
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Affiliation(s)
- Daniel A. Anaya
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (M.H.); (J.E.); (R.K.); (J.B.F.)
- Correspondence: (D.A.A.); (V.C.); Tel.: +1-813-745-1432 (D.A.A.); +1-505-934-1813 (V.C.); Fax: +1-813-745-7229 (D.A.A.)
| | - Prashant Dogra
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
| | - Zhihui Wang
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
| | - Mintallah Haider
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (M.H.); (J.E.); (R.K.); (J.B.F.)
| | - Jasmina Ehab
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (M.H.); (J.E.); (R.K.); (J.B.F.)
| | - Daniel K. Jeong
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (D.K.J.); (M.G.); (G.Y.L.); (K.T.)
| | - Masoumeh Ghayouri
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (D.K.J.); (M.G.); (G.Y.L.); (K.T.)
| | - Gregory Y. Lauwers
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (D.K.J.); (M.G.); (G.Y.L.); (K.T.)
| | - Kerry Thomas
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (D.K.J.); (M.G.); (G.Y.L.); (K.T.)
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (M.H.); (J.E.); (R.K.); (J.B.F.)
| | - Joseph D. Butner
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
| | - Sara Nizzero
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
| | - Javier Ruiz Ramírez
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
| | - Marija Plodinec
- Biozentrum and the Swiss Nanoscience Institute & ARTIDIS AG, University of Basel, 4056 Basel, Switzerland;
| | - Richard L. Sidman
- Department of Neurology, Harvard Medical School, Boston, MA 02115, USA;
| | - Webster K. Cavenee
- Ludwig Institute for Cancer Research, University of California-San Diego, La Jolla, CA 92093, USA;
| | - Renata Pasqualini
- Rutgers Cancer Institute of New Jersey & Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Wadih Arap
- Rutgers Cancer Institute of New Jersey & Division of Hematology/Oncology, Department of Medicine Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Jason B. Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (M.H.); (J.E.); (R.K.); (J.B.F.)
| | - Vittorio Cristini
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (P.D.); (Z.W.); (J.D.B.); (S.N.); (J.R.R.)
- Correspondence: (D.A.A.); (V.C.); Tel.: +1-813-745-1432 (D.A.A.); +1-505-934-1813 (V.C.); Fax: +1-813-745-7229 (D.A.A.)
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21
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Huang C, Gu X, Zeng X, Chen B, Yu W, Chen M. Cetuximab versus bevacizumab following prior FOLFOXIRI and bevacizumab in postmenopausal women with advanced KRAS and BRAF wild-type colorectal cancer: a retrospective study. BMC Cancer 2021; 21:30. [PMID: 33413175 PMCID: PMC7789412 DOI: 10.1186/s12885-020-07770-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/26/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC. METHODS Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs). RESULTS At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001). CONCLUSIONS CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.
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Affiliation(s)
- Chunlong Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Xiaoyuan Gu
- Department of Oncology, Shibei Hospital of Shanghai, No. 4500, Goughexin Road, Jing’ an District, Shanghai, 200443 China
| | - Xianshang Zeng
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Baomin Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Weiguang Yu
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Meiji Chen
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
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22
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Kurilova I, Bendet A, Petre EN, Boas FE, Kaye E, Gonen M, Covey A, Brody LA, Brown KT, Kemeny NE, Yarmohammadi H, Ziv E, D'Angelica MI, Kingham TP, Cercek A, Solomon SB, Beets-Tan RGH, Sofocleous CT. Factors Associated With Local Tumor Control and Complications After Thermal Ablation of Colorectal Cancer Liver Metastases: A 15-year Retrospective Cohort Study. Clin Colorectal Cancer 2020; 20:e82-e95. [PMID: 33246789 DOI: 10.1016/j.clcc.2020.09.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 09/03/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The purpose of this study was to identify risk factors associated with local tumor progression-free survival (LTPFS) and complications after colorectal liver metastases (CLM) thermal ablation (TA). PATIENTS AND METHODS This retrospective analysis included 286 patients with 415 CLM undergoing TA (radiofrequency and microwave ablation) in 378 procedures from January 2003 to July 2017. Prior hepatic artery infusion (HAI), bevacizumab, pre-existing biliary dilatation, ablation modality, minimal ablation margin (MM), prior hepatectomy, CLM number, and size were analyzed as factors influencing complications and LTPFS. Statistical analysis included the Kaplan-Meier method, Cox proportional hazards model, competing risk analysis, univariate/multivariate logistic/exact logistic regressions, and the Fisher exact test. Complications were reported according to modified Society of Interventional Radiology guidelines. RESULTS The median follow-up was 31 months. There was no LTP for MM > 10 mm. Smaller tumor size, increased MM, and prior hepatectomy correlated with longer LTPFS. The major complications occurred following 28 (7%) of 378 procedures. There were no biliary complications in HAI-naive patients, versus 11% in HAI patients (P < .001), of which 7% were major. Biliary complications predictors in HAI patients included biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, ablation with 6 to 10 mm and > 10 mm MM resulted in major biliary complication rates of 4% and 21% (P = .0011), with corresponding LTP rates of 24% and 0% (P = .0033). In HAI-naive patients, the LTP rates for 6 to 10 mm and > 10 mm MM were 27% and 0%, respectively. CONCLUSIONS No LTP was seen for MM > 10 mm. Biliary complications occurred only in HAI patients, especially in those with biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, MM of 6 to 10 mm resulted in 76% local tumor control and 4% major biliary complications incidence.
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Affiliation(s)
- Ieva Kurilova
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Achiude Bendet
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elena N Petre
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Franz E Boas
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elena Kaye
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anne Covey
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lynn A Brody
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Karen T Brown
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nancy E Kemeny
- Department of Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hooman Yarmohammadi
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Etay Ziv
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T Peter Kingham
- Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrea Cercek
- Department of Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Steven B Solomon
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Regina G H Beets-Tan
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Constantinos T Sofocleous
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
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23
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Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases. Eur J Cancer 2020; 138:89-98. [PMID: 32871526 DOI: 10.1016/j.ejca.2020.07.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 07/19/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. METHODS Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. RESULTS A total of 89 patients (median age 55 years (range, 26-76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0-5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1-28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. CONCLUSION Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.
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Datta J, Narayan RR, Kemeny NE, D'Angelica MI. Role of Hepatic Artery Infusion Chemotherapy in Treatment of Initially Unresectable Colorectal Liver Metastases: A Review. JAMA Surg 2020; 154:768-776. [PMID: 31188415 DOI: 10.1001/jamasurg.2019.1694] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Importance Although liver metastasis develops in more than half of patients with colorectal cancer, only 15% to 20% of these patients have resectable liver metastasis at presentation. Moreover, patients with initially unresectable colorectal liver metastasis (IU-CRLM) who progress on first-line systemic chemotherapy have limited treatment options. Hepatic arterial infusion chemotherapy (HAIC), in combination with systemic chemotherapy, leverages a multimodality approach to achieving control of hepatic disease and/or expanding resectability in patients with liver-only disease or liver-dominant disease. Observations Intra-arterial delivery of agents with high first-pass hepatic extraction (eg, floxuridine) limits systemic toxic effects and allows for administration of systemic chemotherapy at near-full doses. Hepatic arterial infusion chemotherapy in conjunction with systemic chemotherapy augments response rates up to 92% in patients who are chemotherapy naive, and up to 85% in pretreated patients with IU-CRLM. In turn, these responses translate into encouraging rates of conversion to resectability (CTR). Prospective trials have reported CTR rates as high as 52% in heavily pretreated patients with IU-CRLM who have an extensive hepatic disease burden. As such, CTR remains a compelling indication for liver-directed chemotherapy in this subset of patients. This review discusses the biological rationale for HAIC, evolution of rational combinations with systemic chemotherapy, contemporary evidence for CTR using HAIC and systemic chemotherapy, juxtaposition with rates of CTR using systemic chemotherapy alone, and morbidity and toxic effect profiles of HAIC. Conclusions and Relevance The argument is made for consideration of earlier initiation of HAIC in patients with IU-CRLM who are chemotherapy naive and for adoption of HAIC strategies to augment rates of resectability in patients who have failed first-line systemic chemotherapy before proceeding to second-line or third-line regimens.
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Affiliation(s)
- Jashodeep Datta
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Raja R Narayan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy E Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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Coadjuvant Anti-VEGF A Therapy Improves Survival in Patients with Colorectal Cancer with Liver Metastasis: A Systematic Review. GASTROINTESTINAL DISORDERS 2020. [DOI: 10.3390/gidisord2020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: the presence of liver metastasis in colorectal cancer (CRC) remains one of the most significant prognostic factors. Objective: systematically review the results of studies evaluating the benefit of adding bevacizumab to a normal chemotherapy regime in the survival of patients with colorectal-cancer liver metastasis (CRLM). Search methods: Pubmed and Google Scholar databases were searched for eligible articles (from inception up to the 2 April 2019). Inclusion criteria: studies including patients with CRLM receiving anti-vascular endothelial growth factor (VEGF; bevacizumab) as treatment, overall survival as an outcome; regarding language restrictions, only articles in English were accepted. Main results: Eleven studies met the inclusion criteria. In 73% of these cases, chemotherapy with bevacizumab was an effective treatment modality for treating CRLM, and its administration significantly extended both overall survival (OS) and/or progression-free survival (PFS). Nevertheless, three articles showed no influence on survival rates of bevacizumab-associated chemotherapy. Author conclusions: It is necessary to standardize methodologies that aim to evaluate the impact of bevacizumab administration on the survival of patients with CRLM. Furthermore, follow-up time and the cause of a patient’s death should be recorded, specified, and cleared in order to better calculate the survival rate and provide a comparison between the produced literature.
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Huang C, Huang J, Luo H, Zong Z, Zhu Z. Comparative Efficacy of Preoperative, Postoperative, and Perioperative Treatments for Resectable Colorectal Liver Metastases: A Network Meta-Analysis. Front Pharmacol 2019; 10:1052. [PMID: 31619998 PMCID: PMC6759603 DOI: 10.3389/fphar.2019.01052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 08/20/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Several treatment strategies are used for management of resectable colorectal liver metastases. We performed a Bayesian network meta-analysis to compare preoperative, postoperative, or perioperative treatments, identifying the optimal approach. Methods: We searched reports of randomized controlled trials through the relevant databases. The primary outcome criterion was overall survival (OS). The secondary outcome measure was disease-free survival (DFS). We calculated the hazard ratio (HR) with the 95% credible interval (Crl) of the time-to-event data. Rank probabilities were evaluated by the probability of treatment rankings. Multiple treatment comparisons based on a Bayesian network integrated the efficacy of all included approaches. Results: Twenty-two eligible randomized controlled trials with 6,115 patients were included in the network meta-analysis. One treatment that resulted in a significant improvement in OS compared with surgery alone was hepatic arterial infusion (HAI) plus postoperative chemotherapy (CT) [HR = 0.74 with 95% Crl: (0.60, 0.94)]. With regard to the secondary outcome measure, three approaches that led to a significant improvement in DFS compared with surgery alone were HAI plus postoperative CT [HR = 1.44 with 95% Crl: (1.19, 1.75)], postoperative CT [HR = 1.14 with 95% Crl: (1.01, 1.29)], preoperative hepatic and regional arterial chemotherapy (PHRAC) plus preoperative CT [HR = 1.41 with 95% Crl: (1.03, 1.89)]. According to the results for the rank probabilities of the 11 treatments, the combination of HAI and bevacizumab plus postoperative CT showed the highest probability of benefitting OS, and PHRAC plus preoperative CT was most likely to benefit DFS. Conclusions: The combination of HAI and bevacizumab plus postoperative CT exhibited the greatest odds of being the most effective treatment for improving OS, and PHRAC plus preoperative CT exhibited the greatest odds of improving DFS. Further clinical studies are needed and justified.
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Affiliation(s)
| | | | | | | | - Zhengming Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Saad AM, Abdel-Rahman O. Initial systemic chemotherapeutic and targeted therapy strategies for the treatment of colorectal cancer patients with liver metastases. Expert Opin Pharmacother 2019; 20:1767-1775. [PMID: 31314604 DOI: 10.1080/14656566.2019.1642324] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: The liver is the most common metastatic site in colorectal cancer with more than half the patients developing a liver metastasis either at the time of their diagnosis (synchronous) or later (metachronous). Surgical resection remains the principal curative approach that offers significant survival improvements. However, upfront surgery is only possible in about 10-20% of patients at the time of diagnosis, making the consideration of other treatment modalities essential. Areas covered: In this review, the authors provide an overview of the standard approaches for the initial management of patients with colorectal cancer with liver metastases. They then provide an up-to-date discussion of first-line systemic chemotherapy/targeted therapy options in the contexts of initially resectable and unresectable disease and review toxicities and complications following these options. Expert opinion: Advances in chemotherapeutic agents and biological targeted therapies have improved the prognosis of colorectal cancer with liver metastases. However, there is still no 'single best approach', making further trials necessary to provide more evidence.
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Affiliation(s)
| | - Omar Abdel-Rahman
- Clinical Oncology Department, Ain Shams University , Cairo , Egypt.,Department of Oncology, University of Alberta, Cross Cancer Institute , Edmonton , Alberta , Canada
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28
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When oncologic treatment options outpace the existing evidence: Contributing factors and a path forward. J Cancer Policy 2019. [DOI: 10.1016/j.jcpo.2019.100188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019; 11:150-172. [PMID: 30820266 PMCID: PMC6393711 DOI: 10.4254/wjh.v11.i2.150] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/24/2018] [Accepted: 12/04/2018] [Indexed: 02/06/2023] Open
Abstract
Liver metastasis is the commonest form of distant metastasis in colorectal cancer. Selection criteria for surgery and liver-directed therapies have recently been extended. However, resectability remains poorly defined. Tumour biology is increasingly recognized as an important prognostic factor; hence molecular profiling has a growing role in risk stratification and management planning. Surgical resection is the only treatment modality for curative intent. The most appropriate surgical approach is yet to be established. The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach; these two strategies have comparable long-term outcomes. For patients with a limited future liver remnant, portal vein embolization, combined ablation and resection, and associating liver partition and portal vein ligation for staged hepatectomy have been advocated, and each has their pros and cons. The role of neoadjuvant and adjuvant chemotherapy is still debated. Targeted biological agents and loco-regional therapies (thermal ablation, intra-arterial chemo- or radio-embolization, and stereotactic radiotherapy) further improve the already favourable results. The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials. Evidence-based protocols are missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.
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Affiliation(s)
| | - Kenneth Siu-Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, the University of Hong Kong, Hong Kong, China.
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Chakedis J, Beal EW, Sun S, Galo J, Chafitz A, Davidson G, Reardon J, Dillhoff M, Pawlik TM, Abdel-Misih S, Bloomston M, Schmidt CR. Implementation and early outcomes for a surgeon-directed hepatic arterial infusion pump program for colorectal liver metastases. J Surg Oncol 2018; 118:1065-1073. [DOI: 10.1002/jso.25249] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Jeffery Chakedis
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Eliza W. Beal
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Steven Sun
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Jason Galo
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Aaron Chafitz
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Gail Davidson
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Joshua Reardon
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Mary Dillhoff
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Timothy M. Pawlik
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Sherif Abdel-Misih
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | | | - Carl R. Schmidt
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
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Johnson BW, Wright GP. Regional therapies for the treatment of primary and metastatic hepatic tumors: A disease-based review of techniques and critical appraisal of current evidence. Am J Surg 2018; 217:541-545. [PMID: 30782316 DOI: 10.1016/j.amjsurg.2018.10.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/05/2018] [Accepted: 10/09/2018] [Indexed: 12/24/2022]
Abstract
The practice of hepatic surgery has become increasingly complex as additional therapeutic options emerge to treat both primary and metastatic tumors of the liver. Liver-directed therapy options include selective internal radiation therapy (SIRT), stereotactic body radiation therapy, chemoembolization, bland embolization, hepatic artery infusion chemotherapy (HAIC), and ablative techniques such as microwave or radiofrequency ablation. Hepatocellular carcinoma has been treated with many of these therapies for palliation of symptoms, definitive treatment, and as a bridge to transplantation. Intrahepatic cholangiocarcinoma, particularly patients with unresectable disease, have demonstrated clinical responses to both SIRT as well as HAIC. Colorectal liver metastases have been treated with all of these techniques with varying degrees of success depending on the clinical scenario. A detailed understanding of these technologies and the evidence supporting their use is essential for the modern hepatic surgeon to properly sequence therapies and provide salvage options when first-line treatment has failed. This review describes these techniques and their appropriate usage based on the disease of interest and the respective evidence currently available.
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Affiliation(s)
- Benjamin W Johnson
- Spectrum Health General Surgery Residency Program, Grand Rapids, MI, USA; Michigan State University College of Human Medicine, Department of Surgery, Grand Rapids, MI, USA
| | - G Paul Wright
- Spectrum Health General Surgery Residency Program, Grand Rapids, MI, USA; Michigan State University College of Human Medicine, Department of Surgery, Grand Rapids, MI, USA; Spectrum Health Medical Group, Division of Surgical Oncology, Grand Rapids, MI, USA.
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Tan HL, Lee M, Vellayappan BA, Neo WT, Yong WP. The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2018; 14:129-137. [PMID: 30294248 PMCID: PMC6153585 DOI: 10.1007/s11888-018-0409-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Purpose of Review Colorectal cancer liver metastasis is a major clinical problem, and surgical resection is the only potentially curative treatment. We seek to discuss various liver-directed therapy modalities and explore their roles in the evolving realm of treatment strategies for metastatic colorectal cancer. Recent Findings Clinical outcomes for patients with colorectal cancer liver metastases have improved as more patients undergo potentially curative resection and as the armamentarium of systemic treatment and liver-directed therapies continues to expand. Liver-directed therapies have been developed as adjuncts to improve resectability, employed in the adjuvant setting to potentially reduce local recurrence rates, and utilized in the palliative setting with the aim to improve overall survival. Summary Ongoing research is expected to validate the role of these evolving therapeutic options, and determine how best to sequence and when to apply these therapies.
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Affiliation(s)
- Hon Lyn Tan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 1E Kent Ridge Road, Singapore, 119228 Singapore
| | - Matilda Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 1E Kent Ridge Road, Singapore, 119228 Singapore
| | - Balamurugan A Vellayappan
- Department of Radiation Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 1E Kent Ridge Road, Singapore, 119228 Singapore
| | - Wee Thong Neo
- 3Department of Diagnostic Imaging, National University Health System, 1E Kent Ridge Road, Singapore, 119228 Singapore
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 1E Kent Ridge Road, Singapore, 119228 Singapore
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Gavriilidis P, Tobias A, Sutcliffe RP, Azoulay D, Roberts KJ. Network Meta-Analysis of Adjuvant Chemotherapy following Resection of Colorectal Liver Metastases. Gastrointest Tumors 2018; 5:21-31. [PMID: 30574478 PMCID: PMC6288637 DOI: 10.1159/000490763] [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: 05/09/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Six principal adjuvant chemotherapy treatments (ACTs) are currently available for patients with resected colorectal liver metastases. This meta-analysis was designed to determine the optimal ACT, as evaluated by 2-year disease-free survival (DFS) and 5-year overall survival (OS) rates as well as by hepatic recurrences and adverse events (AEs). METHODS A systematic literature search of the PubMed, EMBASE, Medline, Cochrane Library, and Google Scholar databases was performed. The probability of the optimal therapeutic scheme and the mean ranking were estimated for each treatment using network meta-analysis. RESULTS Systemic chemotherapy (SCT) had the best 2-year DFS rate (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.48-1.27, 95% prediction interval [PI] = 0.17-3.56, surface under the cumulative ranking area [SUCRA] = 73) and the lowest AE rate (estimated SUCRA = 65 and predicted SUCRA = 62). Hepatic arterial infusion (HAI) plus SCT had the best 5-year OS rate (HR = 0.81, 95% CI = 0.64-1.01, 95% PI = 0.50-1.29) and the lowest hepatic recurrence rate (odds ratio = 2.87, 95% CI = 1.56-5.30, 95% PI = 0.61-13.62). CONCLUSION Both SCT and HAI plus SCT showed superior efficacy and safety. Clinical trials in homogeneous populations with strict selection criteria are needed to compare these two ACTs.
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Affiliation(s)
- Paschalis Gavriilidis
- Department of Hepato-Pancreato-Biliary and Liver Transplant Surgery, Queen Elizabeth University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Aurelio Tobias
- Biostatistician in the Spanish Council for Scientific Research (CSIC), Barcelona, Spain
| | - Robert P. Sutcliffe
- Department of Hepato-Pancreato-Biliary and Liver Transplant Surgery, Queen Elizabeth University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Daniel Azoulay
- Department of Hepato-Pancreato-Biliary and Liver Transplantation, Henri Mondor University Hospital, Créteil, France
| | - Keith J. Roberts
- Department of Hepato-Pancreato-Biliary and Liver Transplant Surgery, Queen Elizabeth University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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34
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Pak LM, Kemeny NE, Capanu M, Chou JF, Boucher T, Cercek A, Balachandran VP, Kingham TP, Allen PJ, DeMatteo RP, Jarnagin WR, D'Angelica MI. Prospective phase II trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. J Surg Oncol 2017; 117:634-643. [PMID: 29165816 DOI: 10.1002/jso.24898] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/09/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND/OBJECTIVES Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study. METHOD The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS). RESULTS From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention. CONCLUSION Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure.
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Affiliation(s)
- Linda M Pak
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy E Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne F Chou
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Taryn Boucher
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vinod P Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter J Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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Gouverneur A, Salvo F, Berdaï D, Moore N, Fourrier-Réglat A, Noize P. Inclusion of elderly or frail patients in randomized controlled trials of targeted therapies for the treatment of metastatic colorectal cancer: A systematic review. J Geriatr Oncol 2017; 9:15-23. [PMID: 28844343 DOI: 10.1016/j.jgo.2017.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/23/2017] [Accepted: 08/09/2017] [Indexed: 01/20/2023]
Abstract
Treatment of metastatic colorectal cancer (mCRC) has been modified since the launching of targeted therapies. Colorectal cancer (CRC) is common in elderly patients; their representation in randomized controlled trials (RCTs) is thus crucial. This study aimed to evaluate and quantify the inclusion of elderly/frail patients in RCTs of targeted therapies in mCRC. A systematic review using Medline, Scopus, Cochrane Database and ISI Web of Science was performed to identify all phase II/III RCTs of bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept in mCRC until January 2015. Two reviewers independently performed studies selection, and data extraction. The protocol was registered in Prospero (CRD42015016163). Among 1,369, identified publications, 54 RCTs were selected. Nine RCTs (17%) excluded elderly patients; median age of the included population was <65years old in 50 RCTs (93%). Twenty RCTs (37%) excluded frail patients, and many RCTs excluded patients with uncontrolled hypertension or heart failure, patients treated with specific drugs (mainly anticoagulants), and patients with inadequate creatinine clearance. Elderly/frail patients are underrepresented in RCTs studying targeted therapies in mCRC, and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria. RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects.
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Affiliation(s)
- Amandine Gouverneur
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France.
| | - Francesco Salvo
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Driss Berdaï
- CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Nicholas Moore
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Annie Fourrier-Réglat
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Pernelle Noize
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
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Abstract
INTRODUCTION Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions. Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization. Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence.
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Affiliation(s)
- Ciara M Kelly
- a Department of Graduate Medical Education , Memorial Sloan Kettering Cancer Center , New York , USA
| | - Nancy E Kemeny
- b Memorial Sloan-Kettering Cancer Center , Weill Medical College of Cornell University , New York , USA
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Bielčiková Z, Jakabová A, Pinkas M, Zemanová M, Kološtová K, Bobek V. Circulating tumor cells: what we know, what do we want to know about them and are they ready to be used in clinics? Am J Transl Res 2017; 9:2807-2823. [PMID: 28670371 PMCID: PMC5489883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 05/30/2017] [Indexed: 06/07/2023]
Abstract
Circulating tumor cells (CTC) present in peripheral blood are assigned precursors of advanced tumor disease. Simplicity of blood withdrawal procedure adds practically an unlimited possibility of the CTC-monitoring and the advantages of the repeated biopsies over time. CTC got prognostic, predictive and diagnostic status with the technologic advance. Although the clinical utility of CTC has reached the high evidence, the significance of CTC testing was presented in the treatment strategy mostly with palliative intention. We report on the experiences with the CTC-testing in the CLIA-like laboratory working with the size-based CTC separation and in vitro culture. The data is presented in the form of case reports in patients with breast (BC), colorectal (CRC), prostate (PC) and lung cancer (NSCLC) to support the clinical utility of CTC during the neoadjuvant, adjuvant and palliative treatment. The presented findings support the evidence for liquid biopsy clinical implementation and enhance the ability of malignant disease monitoring and the treatment efficacy prediction.
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Affiliation(s)
- Zuzana Bielčiková
- Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 499/212808 Prague, Czech Republic
| | - Anna Jakabová
- Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Srobarova 5010034 Prague, Czech Republic
| | - Michael Pinkas
- Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Srobarova 5010034 Prague, Czech Republic
| | - Milada Zemanová
- Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 499/212808 Prague, Czech Republic
| | - Katarína Kološtová
- Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Srobarova 5010034 Prague, Czech Republic
| | - Vladimír Bobek
- Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Srobarova 5010034 Prague, Czech Republic
- Third Department of Surgery, First Faculty of Medicine, Charles University in Prague and University Hospital MotolPrague, V Uvalu 84, 15006 Prague
- Department of Thoracic Surgery, Masaryk’s Hospital in Usti nad Labem, Krajska Zdravotni a.s., Socialni Pece 3316/12A40113 Usti nad Labem, Czech Republic
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Zampino M, Magni E, Ravenda P, Cella C, Bonomo G, Della Vigna P, Galdy S, Spada F, Varano G, Mauri G, Fazio N, Orsi F. Treatments for colorectal liver metastases: A new focus on a familiar concept. Crit Rev Oncol Hematol 2016; 108:154-163. [DOI: 10.1016/j.critrevonc.2016.11.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 10/09/2016] [Accepted: 11/13/2016] [Indexed: 11/17/2022] Open
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Stang A, Donati M, Weilert H, Oldhafer KJ. Impact of Systemic Therapy and Recurrence Pattern on Survival Outcome after Radiofrequency Ablation for Colorectal Liver Metastases. J Cancer 2016; 7:1939-1949. [PMID: 27877209 PMCID: PMC5118657 DOI: 10.7150/jca.15656] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Background: Most patients undergoing radiofrequency ablation (RFA) of colorectal liver metastasases (CLM) develop disease recurrence, but little is known about the effect of recurrence patterns and/or systemic therapy on outcome. In this study, we examined the recurrence patterns and survival after systemic therapy plus RFA in patients with unresectable CLM without extrahepatic disease. The aims were to analyze the effect of recurrence patterns on survival and to assess the relative benefit contributed by systemic therapy and local ablation to disease control and patient outcome. Methods: From January 2002 to December 2012, 113 patients underwent RFA of liver-limited CLM after systemic therapy. Univariate and multivariate analyses for associations between clinical and/or treatment-related variables, recurrence-free survival (RFS), recurrence patterns, and overall survival (OS) were carried out. Results: Of 113 patients, 105 (92.8%) had disease recurrence (median RFS: 6.1 months). Lower post-recurrence OS was observed after early (≤6 months) than after late recurrence (8.5 versus 24.0 months, p < 0.001). Recurrence sites were RFA-sites only (4.8%), liver-only (57.1%), lung-only (10.5%), or multiple (27.6%); the corresponding post-recurrence OS was 21, 19, 39, and 7 months (p < 0.001), respectively. Response to pre-RFA systemic therapy was the strongest predictor for OS (hazard ratio [HR] 5.28), RFS (HR 3.30), early (odds ratio [OR] 6.34) and multiple-site recurrence (OR 3.83) (p < 0.01), respectively; only responders achieved 5-year OS and RFS (29% and 12% versus 0% and 0% for non-responders, p < 0.001, respectively). Conclusions: Survival after RFA for liver-limited CLM is strongly linked to the timing and pattern of non-local disease recurrence. Local ablation efficacy is necessary but not sufficient to obtain long-term disease control. Effective pre-RFA systemic therapy does favourably affect the incidence, timing and patterns of recurrence and long-term survival and appears essential for the tailoring of RFA application to maximize patient benefit.
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Affiliation(s)
- Axel Stang
- Department of Hematology, Oncology, & Palliative Care, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Asklepios Campus Hamburg, Germany
| | - Marcello Donati
- Department of Surgery & Medical-Surgical Specialities, General & Oncologic Surgery Unit, Vittorio-Emanuele University Hospital, University of Catania, Italy
| | - Hauke Weilert
- Department of Hematology & Oncology, Asklepios Hospital Altona, Semmelweis University of Medicine, Asklepios Campus Hamburg, Germany
| | - Karl Jürgen Oldhafer
- Department of General & Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Asklepios Campus, Germany
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Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Shantakumar S, Nordstrom BL, Djousse L, Hall SA, Gagnon DR, Fraeman KH, van Herk-Sukel M, Chagin K, Nelson J. Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network. Cancer Chemother Pharmacol 2016; 78:559-66. [PMID: 27438066 PMCID: PMC5010603 DOI: 10.1007/s00280-016-3112-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 07/13/2016] [Indexed: 01/20/2023]
Abstract
PURPOSE To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients. METHODS A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists. RESULTS In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib. CONCLUSIONS Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.
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Affiliation(s)
- Sumitra Shantakumar
- Worldwide Epidemiology, R&D, GlaxoSmithKline, 150 Beach Road, #26-00 Gateway West, Singapore, 189720, Singapore.
| | - Beth L Nordstrom
- Center of Excellence in Epidemiology, Evidera, Lexington, MA, USA
| | - Luc Djousse
- Department of Veteran's Affairs, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston VA Healthcare System, Boston, MA, USA
| | - Susan A Hall
- New England Research Institutes, Inc., Watertown, MA, USA
| | - David R Gagnon
- Department of Veteran's Affairs, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston VA Healthcare System, Boston, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Kathy H Fraeman
- Center of Excellence in Epidemiology, Evidera, Lexington, MA, USA
| | | | - Karen Chagin
- Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Collegeville, PA, USA
| | - Jeanenne Nelson
- Worldwide Epidemiology Department, R&D, GlaxoSmithKline, Research Triangle Park, NC, USA
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Escalante CP, Chang YC, Liao K, Rouleau T, Halm J, Bossi P, Bhadriraju S, Brito-Dellan N, Sahai S, Yusuf SW, Zalpour A, Elting LS. Meta-analysis of cardiovascular toxicity risks in cancer patients on selected targeted agents. Support Care Cancer 2016; 24:4057-74. [PMID: 27344327 DOI: 10.1007/s00520-016-3310-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/07/2016] [Indexed: 12/18/2022]
Abstract
PURPOSE The purpose was to estimate the risk and severity of cardiovascular toxicities associated with selected targeted agents. METHODS We searched English-language literature for randomized clinical trials published between January 1, 2000 and November 30, 2013 of targeted cancer therapy drugs approved by the FDA by November 2010. One hundred ten studies were eligible. Using meta-analytic methods, we calculated the relative risks of several cardiovascular toxicities [congestive heart failure (CHF), decreased left ventricular ejection fraction (DLVEF), myocardial infarction (MI), arrhythmia, and hypertension (HTN)], adjusting for sample size using the inverse-variance technique. For each targeted agent and side effect, we calculated the number needed to harm. RESULTS Regarding CHF, trastuzumab showed significantly greater risk of all-grade and high-grade CHF. There was significant increased risk of all-grade DLVEF with sorafenib, sunitinib, and trastuzumab and high-grade DLVEF with bevacizumab and trastuzumab. Sorafenib was associated with significant increased all-grade risk of MI based on one study. None was associated with high-grade risk of MI or increased risk of arrhythmia. Bevacizumab, sorafenib, and sunitinib had significant increased risk of all-grade and high-grade HTN. CONCLUSIONS Several of the targeted agents were significantly associated with increased risk of specific cardiovascular toxicities, CHF, DLVEF, and HTN. Several had significant increased risk for high-grade cardiovascular toxicities (CHF, DLVEF, and HTN). Patients receiving such therapy should be closely monitored for these toxicities and early and aggressive treatment should occur. However, clinical experience has demonstrated that some of these toxicities may be reversible and due to secondary effects.
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Affiliation(s)
- C P Escalante
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Y C Chang
- Houston Independent School District, Houston, TX, USA
| | - K Liao
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - T Rouleau
- Carolinas Medical Center, Charlotte, NC, USA
| | - J Halm
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - P Bossi
- Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - S Bhadriraju
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - N Brito-Dellan
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - S Sahai
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - S W Yusuf
- Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - A Zalpour
- Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - L S Elting
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Khoo E, O'Neill S, Brown E, Wigmore SJ, Harrison EM. Systematic review of systemic adjuvant, neoadjuvant and perioperative chemotherapy for resectable colorectal-liver metastases. HPB (Oxford) 2016; 18:485-93. [PMID: 27317952 PMCID: PMC4913134 DOI: 10.1016/j.hpb.2016.03.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/02/2016] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The role of systemic chemotherapy in patients with resectable colorectal liver metastases (CRLM) is ambiguous. The aim of this review was to compare the outcomes of regimens using systemic neoadjuvant, adjuvant or perioperative (combination of pre and postoperative) chemotherapy, for the treatment of resectable CRLM. METHODS MEDLINE was searched for articles investigating the use of chemotherapy for adults with resectable CRLM. Randomized controlled trials reporting overall survival (OS), disease-free survival (DFS) and grade 3-4 adverse events (AEs) were screened for inclusion. PROSPERO record: CRD42015020609. RESULTS Four trials met the inclusion criteria (1098 patients). No significant improvement in median OS was achieved with chemotherapy/surgery compared with surgery-alone. Two trials demonstrated a significant improvement in DFS with chemotherapy/surgery compared to surgery-alone (Hazard ratio 0.78 (0.61-0.99) p = 0.04 and HR 0.66 (0.46-0.96) p = 0.03). Fluorouracil/folinic acid alone had a lower incidence of AEs than combination therapies, and the addition of cetuximab shortened DFS in one trial (HR 1.48 (1.04-2.12) p = 0.03). CONCLUSION There is a lack of adequately powered trials of chemotherapy in combination with liver resection for CRLM, partly due to difficulties in recruitment. In an unselected patient group, FOLFOX in combination with liver resection appears to improve DFS compared to surgery-alone, but trials are underpowered for OS. Future trials will require prospective stratification of patients based on biomarkers predictive of response.
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Affiliation(s)
- Emily Khoo
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Stephen O'Neill
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Ewan Brown
- Edinburgh Cancer Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
| | - Stephen J. Wigmore
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Ewen M. Harrison
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK,Correspondence: Ewen M. Harrison, Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK. Tel.: +44 7974420495.Department of Clinical SurgeryUniversity of EdinburghRoyal Infirmary of Edinburgh51 Little France CrescentEdinburghEH16 4SAUK
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Alahmari AK, Almalki ZS, Alahmari AK, Guo JJ. Thromboembolic Events Associated with Bevacizumab plus Chemotherapy for Patients with Colorectal Cancer: A Meta-Analysis of Randomized Controlled Trials. AMERICAN HEALTH & DRUG BENEFITS 2016; 9:221-32. [PMID: 27688834 PMCID: PMC5004819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 04/29/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Bevacizumab is a recombinant, humanized monoclonal antibody that hinders the proliferation of new blood vessels required for malignant progression. The drug is considered safe and tolerable; however, some controversy remains about whether it is linked to venous and arterial thromboembolic events (TEEs). OBJECTIVE To evaluate the risk for overall, venous, and arterial TEEs in patients with colorectal cancer (CRC) who are administered bevacizumab plus chemotherapy in randomized controlled trials (RCTs). METHODS We searched PubMed and CENTRAL databases to extract reports of relevant trials that were published in English between January 1, 2003, and December 31, 2014. All RCTs in which bevacizumab plus chemotherapy was compared with standard chemotherapy or with placebo plus chemotherapy for the treatment of CRC, and TEEs were reported, were included in a meta-analysis. Risk ratios (RRs) with 95% confidence intervals (CIs) of TEEs were calculated for each RCT. Because the between-study heterogeneities (I2) were insignificant, a fixed-effect model was used to determine the effect size of each TEE. A funnel plot was created to assess publication bias, and 2 forms of sensitivity analyses were performed for each outcome. RESULTS This meta-analysis included 22 RCTs with a total of 13,185 patients. Overall, compared with the control groups, patients with CRC who received bevacizumab were at significant risk for overall TEEs (RR, 1.334; 95% CI, 1.191-1.494; P <.001; I2 = 1.37%). Regarding venous TEEs, a significant risk was observed for patients who received bevacizumab versus control patients (RR, 1.244; 95% CI, 1.091-1.415; P = .001; I2 = 0.0%). Similarly, the risk for arterial TEEs was significant in bevacizumab-treated patients (RR, 1.627; 95% CI, 1.162-2.279; P = .005; I2 = 0.0%). Sensitivity analyses did not affect the level of significance of the effect size for each outcome, and no significant publication bias was observed. CONCLUSION In all the studies reviewed in this meta-analysis, the risk for venous or arterial TEEs was associated with bevacizumab use in patients with CRC. Healthcare providers are encouraged to consider thromboprophylaxis agents, periodically monitor their patients who receive bevacizumab, and carefully manage patients who are at increased risk for those complications.
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Affiliation(s)
| | - Ziyad S Almalki
- Graduate student, University of Cincinnati, College of Pharmacy, OH
| | - Ahmed K Alahmari
- Student, King Khalid University, College of Medicine, Abha, Kingdom of Saudi Arabia
| | - Jeff J Guo
- Professor, Pharmacoepidemiology & Pharmacoeconomics, College of Pharmacy, University of Cincinnati Academic Health Center, OH
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Kemeny NE, Chou JF, Boucher TM, Capanu M, DeMatteo RP, Jarnagin WR, Allen PJ, Fong YC, Cercek A, D'Angelica MI. Updated long-term survival for patients with metastatic colorectal cancer treated with liver resection followed by hepatic arterial infusion and systemic chemotherapy. J Surg Oncol 2016; 113:477-84. [PMID: 26830685 DOI: 10.1002/jso.24189] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 01/16/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVES Patients who undergo liver resection for metastatic colorectal cancer (mCRC) have reported 5-year survivals ranging from 25% to 50%. The current study updated long-term survival for patients with resected liver metastases treated with adjuvant hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy. METHODS Updated survival and recurrence free survival for patients treated on four consecutive adjuvant protocols with HAI and SYS from 1991 to 2009. Patients were divided into two groups: those treated on protocols before 2003 and after 2003. Median follow-up for all patients was 11 years. RESULTS All 287 patients enrolled in four prospective protocols after liver resection are included. Patients treated before 2003 had a median follow-up of 15 years, 5 and 10-year survivals of 56% [95%CI: 49-64%] and 40% [95%CI: 32-47%], respectively, and median survival of 71 months. Patients treated after 2003 had a median follow-up of 9 years, 5 and 10-year survivals of 78% [95%CI: 70-84%] and 61% [95%CI: 51-70%], respectively, and median survival has not been reached. CONCLUSIONS Survival is improving for patients with mCRC who undergo liver resection. These data support the durability of long-term survival in patients who undergo resection followed by adjuvant HAI and SYS therapy. J. Surg. Oncol. 2016;113:477-484. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nancy E Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne F Chou
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Taryn M Boucher
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter J Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yuman C Fong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Surgery, City of Hope, Duarte, California
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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Brandi G, De Lorenzo S, Nannini M, Curti S, Ottone M, Dall’Olio FG, Barbera MA, Pantaleo MA, Biasco G. Adjuvant chemotherapy for resected colorectal cancer metastases: Literature review and meta-analysis. World J Gastroenterol 2016; 22:519-533. [PMID: 26811604 PMCID: PMC4716056 DOI: 10.3748/wjg.v22.i2.519] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/06/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Surgical resection is the only option of cure for patients with metastatic colorectal cancer (CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent site of relapse. The current international guidelines recommend an adjuvant therapy after surgical resection of CRC metastases despite the lower level of evidence (based on the quality of studies in this setting). However, there is still no standard treatment and the effective role of an adjuvant therapy remains controversial. The aim of this review is to report the state-of-art of systemic chemotherapy and regional chemotherapy with hepatic arterial infusion in the management of patients after resection of metastases from CRC, with a literature review and meta-analysis of the relevant randomized controlled trials.
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Cho M, Gong J, Fakih M. The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Rev Anticancer Ther 2016; 16:229-45. [PMID: 26652741 DOI: 10.1586/14737140.2016.1129277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the United States. Most colorectal cancer patients die from advanced disease, and two-thirds of CRC deaths are due to liver metastases. Liver resection provides the best curative option for patients with colorectal liver metastases (CRLM), yet only 20% of those patients are eligible for liver metastases resection for curative intent. Loco-regional treatment of CRLM may provide additional benefits in terms of down-staging for resection and prolonged hepatic disease control. This review focusses on hepatic arterial infusion, radioembolization and chemoembolization.
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Affiliation(s)
- May Cho
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
| | - Jun Gong
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
| | - Marwan Fakih
- a Department of Medical Oncology , City of Hope National Medical Center , Duarte , CA , USA
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Konstantinidis IT, Groot Koerkamp B, Do RKG, Gönen M, Fong Y, Allen PJ, D'Angelica MI, Kingham TP, DeMatteo RP, Klimstra DS, Kemeny NE, Jarnagin WR. Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer 2015; 122:758-65. [PMID: 26695839 DOI: 10.1002/cncr.29824] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/23/2015] [Accepted: 11/12/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone. METHODS Consecutive patients with ICC were retrospectively reviewed. Clinicopathologic data were reviewed. Survival rates were compared by Kaplan-Meier analysis and log-rank testing. RESULTS Between January 2000 and August 2012, 525 patients with ICC were evaluated at Memorial Sloan Kettering Cancer Center, and 236 patients with unresectable tumors (locally advanced or metastatic) were analyzed. Disease was confined to the liver in 104 patients, who underwent treatment with combined HAI and SYS (n = 78 or 75%) or SYS alone (n = 26 or 25%). The response rate in the combined group was better than the rate in the group receiving SYS alone, although this did not reach statistical significance (59% vs 39%, P = .11). Overall survival for the combined group was longer than overall survival for the patients who received SYS alone (30.8 vs 18.4 months, P < .001), and this difference was maintained when patients with portal lymph node disease were included in the survival analysis (29.6 months with HAI and SYS [n = 93] vs 15.9 months with SYS [n = 74], P < .001). Eight patients who initially presented with unresectable tumors responded enough to undergo complete resection and had a median overall survival of 37 months (range, 10.4-92.3 months). CONCLUSIONS In patients with unresectable ICC confined to the liver or with limited regional nodal disease, a combination of SYS and HAI chemotherapy is associated with greater survival than SYS alone. Cancer 2016;122:758-765. © 2015 American Cancer Society.
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Affiliation(s)
| | - Bas Groot Koerkamp
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Richard K G Do
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yuman Fong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter J Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David S Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy E Kemeny
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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Subramanian M, Choti MA, Yopp AC. Hepatic Arterial Infusion Pump Chemotherapy for Colorectal Liver Metastases: Making a Comeback? CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0277-2] [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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Ahmadizar F, Onland-Moret NC, de Boer A, Liu G, Maitland-van der Zee AH. Efficacy and Safety Assessment of the Addition of Bevacizumab to Adjuvant Therapy Agents in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One 2015; 10:e0136324. [PMID: 26331473 PMCID: PMC4558033 DOI: 10.1371/journal.pone.0136324] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 08/02/2015] [Indexed: 12/13/2022] Open
Abstract
AIM To evaluate the efficacy and safety of bevacizumab in the adjuvant cancer therapy setting within different subset of patients. METHODS & DESIGN/ RESULTS PubMed, EMBASE, Cochrane and Clinical trials.gov databases were searched for English language studies of randomized controlled trials comparing bevacizumab and adjuvant therapy with adjuvant therapy alone published from January 1966 to 7th of May 2014. Progression free survival, overall survival, overall response rate, safety and quality of life were analyzed using random- or fixed-effects models according to the PRISMA guidelines. We obtained data from 44 randomized controlled trials (30,828 patients). Combining bevacizumab with different adjuvant therapies resulted in significant improvement of progression free survival (log hazard ratio, 0.87; 95% confidence interval (CI), 0.84-0.89), overall survival (log hazard ratio, 0.96; 95% CI, 0.94-0.98) and overall response rate (relative risk, 1.46; 95% CI: 1.33-1.59) compared to adjuvant therapy alone in all studied tumor types. In subgroup analyses, there were no interactions of bevacizumab with baseline characteristics on progression free survival and overall survival, while overall response rate was influenced by tumor type and bevacizumab dose (p-value: 0.02). Although bevacizumab use resulted in additional expected adverse drug reactions except anemia and fatigue, it was not associated with a significant decline in quality of life. There was a trend towards a higher risk of several side effects in patients treated by high-dose bevacizumab compared to the low-dose e.g. all grade proteinuria (9.24; 95% CI: 6.60-12.94 vs. 2.64; 95% CI: 1.29-5.40). CONCLUSIONS Combining bevacizumab with different adjuvant therapies provides a survival benefit across all major subsets of patients, including by tumor type, type of adjuvant therapy, and duration and dose of bevacizumab therapy. Though bevacizumab was associated with increased risks of some adverse drug reactions such as hypertension and bleeding, anemia and fatigue were improved by the addition of bevacizumab.
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Affiliation(s)
- Fariba Ahmadizar
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
| | | | - Anthonius de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
| | - Geoffrey Liu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, Ontario, Canada
- Division of Epidemiology, Dalla Lana School of Public Health, Toronto, Ontario, Canada
| | - Anke H. Maitland-van der Zee
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
- * E-mail:
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