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1
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Merkow RP, Cavnar MJ, Gleisner AL, Mayo SC, Gholami S, Karanicolas PJ, Koerkamp BG, Homs MYV, Connell LC, Cercek A, Helft PR, Polite BN, Patel RA, Uronis HE, D'Angelica M, Lidsky ME. Minimum Requirements to Safely Establish and Sustain New Hepatic Arterial Infusion Pump Programs: An International Expert Perspective. Ann Surg Oncol 2025; 32:4408-4416. [PMID: 39962001 DOI: 10.1245/s10434-025-17009-1] [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: 01/10/2025] [Accepted: 01/28/2025] [Indexed: 05/07/2025]
Abstract
Hepatic arterial infusion (HAI) pump chemotherapy is an effective therapy for colorectal liver metastases and intrahepatic cholangiocarcinoma. In the setting of recent reports suggesting favorable outcomes in these diseases with HAI, there has been a surge in interest in this treatment worldwide, prompting the opening of many new HAI programs. While significant technical expertise is required for pump implantation, this alone is insufficient to open a safe and sustainable HAI program, and numerous other factors must be considered prior to the first pump implantation. This expert perspective, established using an anonymous web-based survey of experienced multidisciplinary international HAI providers, details the minimum required personnel, expertise, training, and infrastructure to optimize success and sustainability of a safe and effective new HAI program.
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Affiliation(s)
- Ryan P Merkow
- Department of Surgery, Division of Surgical Oncology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Michael J Cavnar
- Department of Surgery, Division of Surgical Oncology, University of Kentucky, Lexington, KY, USA
| | - Ana L Gleisner
- Department of Surgery, University of Colorado, Aurora, CO, USA
| | - Skye C Mayo
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University and Knight Cancer Institute, Portland, OR, USA
| | - Sepideh Gholami
- Department of Surgery, Division of Surgical Oncology, Northwell Health Cancer Institute, New Hyde Park, Northwell Health, NY, USA
| | - Paul J Karanicolas
- Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Bas Groot Koerkamp
- Department of Surgery, Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Marjolein Y V Homs
- Medical Oncology, Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Louise C Connell
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paul R Helft
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Blase N Polite
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Reema A Patel
- Department of Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY, USA
| | - Hope E Uronis
- Department of Medicine, Division of Medical Oncology, Duke University, Durham, NC, USA
| | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Weill Cornell School of Medicine, New York, NY, USA
| | - Michael E Lidsky
- Department of Surgery, Division of Surgical Oncology, Duke University, Durham, NC, USA.
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Messaoudi N, Vanlander A, Benhadda M, Makarian R, Kortbeek K, De Haar-Holleman A, Gumbs AA. Hepatic arterial infusion pump chemotherapy for colorectal liver metastases: Revisiting traditional techniques to explore new frontiers. World J Clin Oncol 2025; 16:101274. [PMID: 40130052 PMCID: PMC11866082 DOI: 10.5306/wjco.v16.i3.101274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/14/2024] [Accepted: 12/09/2024] [Indexed: 01/21/2025] Open
Abstract
Hepatic arterial infusion (HAI) chemotherapy, first introduced in the 1980s, has gained recognition as an effective locoregional treatment for colorectal liver metastasis (CRLM). Initially used for unresectable liver metastases, HAI's application has expanded to the adjuvant setting following hepatic resection, with early studies indicating improved hepatic disease-free survival. Recent research demonstrates that combining HAI with modern systemic therapies enhances conversion to resectability and prolongs both recurrence-free and overall survival, even in heavily pretreated patients with diverse RAS mutational statuses. Personalization through approaches like microsatellite instability status and dose modifications further optimize outcomes. However, the complexity of HAI requires expertise across multidisciplinary teams, limiting its widespread adoption to specialized centers. Ongoing clinical trials continue to investigate HAI's role in CRLM management, highlighting its potential to become a cornerstone of liver-directed therapy. We explore how HAI chemotherapy, in combination with personalized medicine, can advance treatment strategies for metastatic colorectal cancer.
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Affiliation(s)
- Nouredin Messaoudi
- Department of Hepatopancreatobiliary Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel and Europe Hospitals, Brussels 1090, Brussels-Capital Region, Belgium
| | - Aude Vanlander
- Department of Hepatopancreatobiliary Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel and Europe Hospitals, Brussels 1090, Brussels-Capital Region, Belgium
| | - Myriam Benhadda
- Department of Hepatopancreatobiliary Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel and Europe Hospitals, Brussels 1090, Brussels-Capital Region, Belgium
| | - Roza Makarian
- Department of Hepatopancreatobiliary Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel and Europe Hospitals, Brussels 1090, Brussels-Capital Region, Belgium
| | - Koen Kortbeek
- Department of Oncology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels 1090, Brussels-Capital Region, Belgium
| | - Amy De Haar-Holleman
- Department of Oncology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels 1090, Brussels-Capital Region, Belgium
| | - Andrew A Gumbs
- Service de Chirurgie Digestive Minimale Invasive, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Clamart 92140, France
- Department of Surgery, University of Magdeburg, Magdeburg 39130, Saxony-Anhalt, Germany
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Connell LC, Kemeny NE. Intraarterial Chemotherapy for Liver Metastases. Hematol Oncol Clin North Am 2025; 39:143-159. [PMID: 39510670 DOI: 10.1016/j.hoc.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.
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Affiliation(s)
- Louise C Connell
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, 10th floor, New York, NY 10065, USA
| | - Nancy E Kemeny
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, 10th floor, New York, NY 10065, USA.
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Schwantes IR, Patel RK, Kardosh A, Paxton J, Eil R, Chen EY, Rocha FG, Latour E, Pegna G, Lopez CD, Mayo SC. A Modified Floxuridine Reduced-Dose Protocol for Patients with Unresectable Colorectal Liver Metastases Treated with Hepatic Arterial Infusion. Ann Surg Oncol 2024; 31:6537-6545. [PMID: 38995448 DOI: 10.1245/s10434-024-15729-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/19/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection. PATIENTS AND METHODS We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts. RESULTS Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP. CONCLUSIONS A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance.
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Affiliation(s)
- Issac R Schwantes
- Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - Ranish K Patel
- Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - Adel Kardosh
- Department of Medicine, Division of Hematology and Medical Oncology, Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Jillian Paxton
- Department of Pharmacy Services, OHSU, Portland, OR, USA
| | - Robert Eil
- Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - Emerson Y Chen
- Department of Medicine, Division of Hematology and Medical Oncology, Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Flavio G Rocha
- Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - Emile Latour
- Biostatistics Shared Resource, Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Guillaume Pegna
- Department of Medicine, Division of Hematology and Medical Oncology, Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Charles D Lopez
- Department of Medicine, Division of Hematology and Medical Oncology, Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Skye C Mayo
- Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, OR, USA.
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Zheng K, Zhu X, Xu L, Cao G, Niu C, Yan X, Xu D, Liu W, Bao Q, Wang L, Wang K, Xing B, Wang X. Efficacy and safety of hepatic arterial infusion chemotherapy combined with fruquintinib and tislelizumab for patients with microsatellite stable colorectal cancer liver metastasis following failure of multiple-line therapy. Front Oncol 2024; 14:1420956. [PMID: 39234395 PMCID: PMC11372785 DOI: 10.3389/fonc.2024.1420956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND AND AIM The prognosis of microsatellite stable (MSS)-colorectal cancer liver metastasis (CRCLM) following failure of multi-line therapy remains dismal. The aim of this study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus fruquintinib and tislelizumab (HAIC-F-T treatment) for MSS-CRCLM which failed from multiple-line therapy. METHODS From February 2021 to June 2023, 45 patients with MSS-CRCLM after failure of multiple-line therapy who received HAIC combined with fruquintinib and tislelizumab (HAIC-F-T triple treatment) were enrolled. The combination therapy included HAIC regimens with oxaliplatin and 5-fluorouracil or irinotecan, oxaliplatin, and 5-fluorouracil on days 1-2, intravenous tislelizumab (200 mg) before HAIC on day 1, and oral fruquintinb (3 mg/d) on day 3-21, every 4 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS The follow-up ended on June 22, 2024, with a median follow-up time of 17.5 months. The objective response rate was 42.2%, and the disease control rate was 82.2%. The median OS was 15.3 months (95% confidence interval [CI]:12.634-17.966), and the median PFS was 7.5 months (95% CI:5.318-9.682). The independent risk factors related to worse OS were previous PD-1 immunotherapy (P = 0.021) and the number of HAIC-F-T triple treatment cycles of ≤ 2 (P = 0.007). The incidence of grade 3 or higher adverse events (AEs) was 20%, with the most frequent grade 3 or higher AEs being abdominal pain (3/45, 6.7%). CONCLUSION HAIC combined with fruquintinib and tislelizumab may be an alternative salvage treatment for patients with MSS-CRCLM following failure of multiple-line therapy.
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Affiliation(s)
- Kanglian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Liang Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Guang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Chuanxin Niu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoluan Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Da Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Wei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Quan Bao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Lijun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Kun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatic & Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaodong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, China
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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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Judge SJ, Ghalambor T, Cavnar MJ, Lidsky ME, Merkow RP, Cho M, Dominguez-Rosado I, Karanicolas PJ, Mayo SC, Rocha FG, Fields RC, Patel RA, Kennecke HF, Koerkamp BG, Yopp AC, Petrowsky H, Mahalingam D, Kemeny N, D'Angelica M, Gholami S. Current Practices in Hepatic Artery Infusion (HAI) Chemotherapy: An International Survey of the HAI Consortium Research Network. Ann Surg Oncol 2023; 30:7362-7370. [PMID: 37702903 PMCID: PMC11108096 DOI: 10.1245/s10434-023-14207-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 07/06/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.
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Affiliation(s)
- Sean J Judge
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tara Ghalambor
- Department of Surgery, University of California, Davis, Sacramento, CA, USA
| | - Michael J Cavnar
- Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Michael E Lidsky
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Ryan P Merkow
- Department of Surgery, Northwestern University, Chicago, IL, USA
| | - May Cho
- Department of Medicine, University of California Irvine, Orange, CA, USA
| | - Ismael Dominguez-Rosado
- Department of Surgery, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Tlalpan, Mexico City, Mexico
| | - Paul J Karanicolas
- Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Skye C Mayo
- Division of Surgical Oncology, Department of Surgery, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Flavio G Rocha
- Division of Surgical Oncology, Department of Surgery, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Ryan C Fields
- Division of Surgical Oncology, Department of Surgery, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St Louis, MO, USA
| | - Reema A Patel
- Department of Medical Oncology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Hagen F Kennecke
- GI Oncology, Providence Health Cancer Institute, Portland, OR, USA
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Adam C Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Henrik Petrowsky
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | | | - Nancy Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sepideh Gholami
- Department of Surgery, Northwell Health Cancer Institute, New Hyde Park, NY, USA.
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8
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Walker BS, Billingsley KG, Sutton TL, Kolbeck KJ, Korngold EK, Nabavizadeh N, Dewey EN, Herzig DO, Lopez CD, Mayo SC. Hepatic arterial infusion pump chemotherapy combined with systemic therapy for patients with advanced colorectal liver metastases: Outcomes in a newly established program. J Surg Oncol 2022; 126:513-522. [PMID: 35522249 DOI: 10.1002/jso.26911] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND OBJECTIVES Colorectal liver metastasis (CRLM) is a leading cause of morbidity and mortality in patients with colorectal cancer. Hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve survival in patients with resected CRLM and to facilitate conversion of technically unresectable disease. METHODS Between 2016 and 2018, n = 22 HAI pumps were placed for CRLM. All patients received systemic chemotherapy concurrently with HAI floxuridine/dexamethasone. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. RESULTS HAI pumps were placed in seven patients with completely resected CRLM and 15 patients with unresectable disease. Twenty-one patients received HAI floxuridine with a median of 5 total HAI cycles (interquartile range: 4-7). Biliary sclerosis was the most common HAI-related complication (n = 5, 24%). Of the 13 patients treated to convert unresectable CRLM, 3 (23%) underwent hepatic resection with curative intent after a median of 7 HAI cycles (range: 4-10). For all HAI patients, the mean OS was 26.7 months from CRLM diagnosis, while the median PFS and hepatic PFS from pump placement were 9 and 13 months, respectively. CONCLUSION Concomitant HAI and systemic therapy can be utilized at multidisciplinary programs for patients with advanced CRLM, both in the adjuvant setting and to facilitate conversion of unresectable disease.
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Affiliation(s)
- Brett S Walker
- Oregon Health & Science University (OHSU), Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Portland, Oregon, USA
| | | | - Thomas L Sutton
- Oregon Health & Science University (OHSU), Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Portland, Oregon, USA
| | - Kenneth J Kolbeck
- OHSU, Department of Interventional Radiology, Dotter Institute, Portland, Oregon, USA
| | | | | | | | - Daniel O Herzig
- OHSU, Division of Colorectal Surgery, Department of Surgery, Portland, Oregon, USA
| | - Charles D Lopez
- OHSU, Division of Hematology and Medical Oncology, Department of Medicine, Portland, Oregon, USA.,The Knight Cancer Institute at OHSU, Portland, Oregon, USA
| | - Skye C Mayo
- Oregon Health & Science University (OHSU), Department of Surgery, Division of Surgical Oncology, Knight Cancer Institute, Portland, Oregon, USA.,The Knight Cancer Institute at OHSU, Portland, Oregon, USA
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Torres-Jiménez J, Esteban-Villarrubia J, Ferreiro-Monteagudo R, Carrato A. Local Treatments in the Unresectable Patient with Colorectal Cancer Metastasis: A Review from the Point of View of the Medical Oncologist. Cancers (Basel) 2021; 13:5938. [PMID: 34885047 PMCID: PMC8656541 DOI: 10.3390/cancers13235938] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/18/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022] Open
Abstract
For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, such as radiofrequency, microwave hyperthermia and cryotherapy. Locoregional therapies are delivered through the hepatic artery, such as chemoinfusion, chemoembolization or selective internal radiation with Yttrium 90 radioembolization. The purpose of this review is to describe the different interventional therapies that are available for these patients in routine clinical practice, the most important clinical trials that have tried to demonstrate the effectiveness of each therapy and recommendations from principal medical oncologic societies.
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Affiliation(s)
- Javier Torres-Jiménez
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
| | - Jorge Esteban-Villarrubia
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
| | - Reyes Ferreiro-Monteagudo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (R.F.-M.)
| | - Alfredo Carrato
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain;
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Zhao J, Zheng Y, Liu T, Chang J, Shan H, Cong K. Comparison between fluoropyrimidine-hepatic arterial infusion and systemic chemotherapy for unresectable liver metastases: A protocol for systematic review and meta-analysis based on 16 observational studies. Medicine (Baltimore) 2021; 100:e27483. [PMID: 34731127 PMCID: PMC8519215 DOI: 10.1097/md.0000000000027483] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/01/2021] [Accepted: 09/16/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The benefit of loco-regional treatments such as hepatic arterial infusion (HAI) in terms of survival and response rate is unclear. The aim of this work is to quantitatively summarize the results of both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing fluoropyrimidine-HAI (F-HAI) to systemic chemotherapy (SCT) for the treatment of colorectal liver metastases (CRLMs). METHODS We searched the Cochrane Library, PubMed, EMBASE, and Web of Science up to July 1, 2021. The outcome measures were tumor response rate and overall survival (OS). Both RCTs and NRSIs comparing HAI to SCT for patients with unresectable CRLMs were included. The outcome measures were tumor response rate and OS. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2. RESULTS A total of 16 studies including 11 RCTs and 5 NRSIs were identified for the present meta-analysis. Nine RCTs compared F-HAI to SCT for patients with unresectable CRLMs and the pooled result indicated that patients who received F-HAI experienced more than twofold response rate than SCT, with a pooled risk ratio of 2.10 (95%CI 1.59-2.79; P < .00001). In addition, the pooled result based on RCTs showed that F-HAI had a significant benefit regarding OS, with a pooled HR of 0.83 (95% CI 0.70-0.99; P = .04). Similarly, the benefit of F-HAI in terms of OS was also observed in the results of NRSIs. CONCLUSIONS Our results indicated that the F-HAI regimen had a greater tumor response rate and survival advantage than SCT for patients with unresectable CRLMs. Future propensity score-matched analyses with a large sample size should be conducted to support the evidence of our results based on RCTs and NRSIs.
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11
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Fohlen A, Bordji K, Assenat E, Gongora C, Bazille C, Boulonnais J, Naveau M, Breuil C, Pérès EA, Bernaudin M, Guiu B. Anticancer Drugs for Intra-Arterial Treatment of Colorectal Cancer Liver Metastases: In-Vitro Screening after Short Exposure Time. Pharmaceuticals (Basel) 2021; 14:ph14070639. [PMID: 34358065 PMCID: PMC8308869 DOI: 10.3390/ph14070639] [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: 06/18/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/24/2022] Open
Abstract
To treat colorectal liver metastases, intra-arterial chemotherapies may complete therapeutic arsenal. Drugs using intra-arterially are very heterogeneous. The aim of this study was to select the most efficient drug on a panel of colorectal cancer (CRC) cell lines (Caco-2, HCT 116, HT 29, SW 48, SW 480, SW 620) exposed for 30 min to 12 cytotoxic agents (doxorubicin, epirubicin, idarubicin, 5-FU, raltitrexed, gemcitabine, cisplatin, oxaliplatin, mitomycin C, irinotecan, streptozocin, paclitaxel) at different concentrations. The effect on cell viability was measured using the WST-1 cell viability assay. For each drug and cell line, the IC50 and IC90 were calculated, which respectively correspond to the drug concentration (mg/mL) required to obtain 50% and 90% of cell death. We also quantified the cytotoxic index (CyI90 = C Max/IC90) to compare drug efficacy. The main findings of this study are that idarubicin emerged as the most cytotoxic agent to most of the tested CRC cell lines (Caco-2, HT29, HCT116, SW620 and SW480). Gemcitabine seemed to be the most efficient chemotherapy for SW48. Interestingly, the most commonly used cytotoxic agents in the systemic and intra-arterial treatment of colorectal liver metastasis (CRLM) (oxaliplatin, 5-FU, irinotecan) showed very limited cytotoxicity to all the cell lines.
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Affiliation(s)
- Audrey Fohlen
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
- Urodigestive Imagery and Interventional Radiology Department, University Hospital of Caen, CEDEX, 14000 Caen, France
- Correspondence: ; Tel.: +33-616702414
| | - Karim Bordji
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
| | - Eric Assenat
- Medical Oncology Department, Montpellier School of Medicine, Saint-Eloi University Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier, France;
| | - Céline Gongora
- IRCM, Montpellier Cancerology Research Center, INSERM U1194, Montpellier University, Montpellier Regional Institute of Cancer, 34298 Montpellier, France;
| | - Céline Bazille
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
- Department of Pathology, University Hospital of Caen, CEDEX, 14000 Caen, France
| | - Jérémy Boulonnais
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
| | - Mikaël Naveau
- UNICAEN, CNRS, UMS 3408, GIP CYCERON, Normandie University, 14000 Caen, France;
| | - Cécile Breuil
- Pharmacy Department, University Hospital of Caen, CEDEX, 14000 Caen, France;
| | - Elodie A. Pérès
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
| | - Myriam Bernaudin
- UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Normandie University, 14000 Caen, France; (K.B.); (C.B.); (J.B.); (E.A.P.); (M.B.)
| | - Boris Guiu
- Radiology Department, Montpellier School of Medicine, Saint-Eloi University Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier, France;
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12
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Zhao JJ, Tan E, Sultana R, Syn NL, Da Zhuang K, Leong S, Tai DWM, Too CW. Intra-arterial therapy for unresectable colorectal liver metastases: A meta-analysis. J Vasc Interv Radiol 2021; 32:1536-1545.e38. [PMID: 34166803 DOI: 10.1016/j.jvir.2021.05.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 05/09/2021] [Accepted: 05/31/2021] [Indexed: 11/19/2022] Open
Abstract
PURPOSE To evaluate the efficacy of hepatic arterial infusion (HAI), conventional trans-arterial chemoembolization (cTACE), drug-eluting embolic trans-arterial chemoembolization (DEE-TACE), trans-arterial radioembolization (TARE) and their combinations with systemic chemotherapy (SCT) for unresectable colorectal liver metastases. METHODS A search was conducted on EMBASE, Scopus, PubMed and Web of Science for prospective non-randomized studies and randomized controlled trials (RCTs) from inception to 20th June 2020. Survival data of patients were recovered from original Kaplan-Meier curves by exploiting a graphical reconstructive algorithm. One-stage meta-analyses were conducted for median overall survival (OS), survival rates (SR), and restricted mean survival time (RMST), while two-stage meta-analyses of proportions were conducted to determine response rates (RR) and conversion-to-resection rates (CRR). RESULTS 71 prospective non-randomized studies and 21 RCTs were identified comprising 6,695 patients. Among patients treated beyond first line, DEE-TACE+SCT (n=152) had the best survival outcomes of median OS of 26.5 (95%-CI: 22.5-29.1) months and 3-year RMST of 23.6 (95%-CI: 21.8-25.5) months. Upon further stratification by publication year, DEE-TACE+SCT appears to consistently have the highest pooled survival rates at 1-year (81.9%) and 2-years (66.1%) in recent publications (2015-2020). DEE-TACE+SCT and HAI+SCT had the highest pooled-RRs of 56.7% (I2=0.90) and 62.6% (I2=0.87) respectively and pooled-CRRs of 35.5% (I2=0.00) and 30.3% (I2=0.80) respectively. CONCLUSION Albeit significant heterogeneity, paucity of high-quality evidence and the non-comparative nature of all analyses, the overall evidence suggests that patients treated with DEE-TACE+SCT may have the best oncological outcomes and greatest potential to be converted for resection.
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Affiliation(s)
- Joseph J Zhao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Eelin Tan
- Department of Vascular and Interventional Radiology, Division of Radiological Sciences; Radiological Sciences Academic Clinical Program, SingHealth- Duke-National University of Singapore Academic Medical, Singapore General Hospital, Singapore
| | - Rehena Sultana
- Centre for Quantitative Medicine, Duke-National University of Singapore Graduate Medical School, Singapore
| | - Nicholas L Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kun Da Zhuang
- Department of Vascular and Interventional Radiology, Division of Radiological Sciences; Radiological Sciences Academic Clinical Program, SingHealth- Duke-National University of Singapore Academic Medical, Singapore General Hospital, Singapore
| | - Sum Leong
- Department of Vascular and Interventional Radiology, Division of Radiological Sciences; Radiological Sciences Academic Clinical Program, SingHealth- Duke-National University of Singapore Academic Medical, Singapore General Hospital, Singapore
| | - David W M Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Chow Wei Too
- Department of Vascular and Interventional Radiology, Division of Radiological Sciences; Radiological Sciences Academic Clinical Program, SingHealth- Duke-National University of Singapore Academic Medical, Singapore General Hospital, Singapore.
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Massani M, Bonariol L, Stecca T. Hepatic Arterial Infusion Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma, a Comprehensive Review. J Clin Med 2021; 10:2552. [PMID: 34207700 PMCID: PMC8228250 DOI: 10.3390/jcm10122552] [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: 05/24/2021] [Revised: 06/02/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials.
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Affiliation(s)
- Marco Massani
- HPB Hub Reference Center, First General Surgery Unit, Department of Surgery, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (L.B.); (T.S.)
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Yokoyama D, Mukai M, Uda S, Kishima K, Koike T, Hasegawa S, Izumi H, Yamamoto S, Tajima T, Nomura E, Makuuchi H. Efficacy of modified bevacizumab-XELOX therapy in Japanese patients with stage IV recurrent or non-resectable colorectal cancer. J Gastrointest Oncol 2021; 12:527-534. [PMID: 34012646 DOI: 10.21037/jgo-20-350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background Neoadjuvant chemotherapy (NAC) has been conducted for patients with non-resectable colorectal cancer; however, few reports of a systematic approach to NAC exist. At our hospital, bevacizumab with capecitabine and oxaliplatin (B-mab XELOX) has been used as chemotherapy for Stage IV colorectal cancer since 2014. We aimed to evaluate the efficacy and safety of NAC with a molecular-targeting agent for Stage IV colorectal cancer. Methods A retrospective, single-institute analysis was performed including 27 patients with advanced recurrent cancer following primary tumor resection and 43 patients with non-resectable tumors and remote metastasis. At the time of resection, 17 were receiving chemotherapy. All 70 patients received at least 3 cycles of B-mab XELOX (total: 920 cycles). We determined the 1-year progression-free survival (1Y-PFS), 1-year overall survival (1Y-OS), 3Y-PFS, 3Y-OS, and number of treatment cycles. The objective response rate, clinical benefit rate, and adverse events were assessed. The number of chemotherapy cycles, survival time, and R0 surgery rate were determined for patients who underwent RO conversion surgery. Results The 1Y-PFS was 28.5% [median survival time (MST): 7.4 months], 1Y-OS was 76.6% (MST not reached), 3Y-PFS was 5.5% (MST: 7.4 months), and 3Y-OS was 26.4% (MST: 25.2 months). The mean and median number of cycles of B-mab XELOX was 13.1 and 10.5, respectively. The objective response rate was 28.6%, and the clinical benefit rate was 58.6%. Grade 1 or Grade 2 adverse events occurred in 60 patients (85.7%); however, they all resolved without intervention. A single Grade 4 event (perforation of the primary tumor) occurred in 1 patient (1.4%). RO conversion surgery was performed in 7 patients (10.0%; primary + liver in 2 patients, primary + lung in 1 patient, liver in 3 patients, and primary in 1 patient). These patients received 3 to 10 cycles preoperatively (mean: 7.3; median: 6.5). R0 surgery was achieved in 5 of the 7 patients (71.4%). Postoperative survival ranged from 1 to 26 months (MST: 8 months). Conclusions This modified regimen was safe and effective in Japanese patients, and a high quality of life/quality-adjusted life-year was achieved. To further evaluate PFS and OS, more patients are being investigated.
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Affiliation(s)
- Daiki Yokoyama
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Masaya Mukai
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Shuji Uda
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Kyouko Kishima
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Takuya Koike
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Sayuri Hasegawa
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Hideki Izumi
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Souichirou Yamamoto
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Takayuki Tajima
- Department of Surgery, Tokai University Tokyo Hospital, Shibuya, Tokyo, Japan
| | - Eiji Nomura
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Hiroyasu Makuuchi
- Department of Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
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15
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Napier KJ, Lidsky ME, James OG, Wildman-Tobriner B. Hepatic Arterial Infusion Pumps: What the Radiologist Needs to Know. Radiographics 2021; 41:895-908. [PMID: 33769890 DOI: 10.1148/rg.2021200130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatic arterial infusion (HAI) entails the surgical implantation of a subcutaneous pump to deliver chemotherapeutic agents directly to the liver in the setting of primary or secondary liver cancer. The purpose of HAI chemotherapy is to maximize hepatic drug concentrations while minimizing systemic toxicity, facilitating more effective treatment. HAI is used in combination with systemic chemotherapy and can be considered in several clinical scenarios, including adjuvant therapy, conversion of unresectable disease to resectable disease, and unresectable disease. Radiologists are key members of the multidisciplinary team involved in the selection and management of these patients with complex liver disease. As these devices begin to be used at more sites across the country, radiologists should become familiar with the guiding principles behind pump placement, expected imaging appearances of these devices, and potential associated complications. The authors provide an overview of HAI therapy, with a focus on the key imaging findings associated with this treatment that radiologists may encounter. ©RSNA, 2021.
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Affiliation(s)
- Kyle J Napier
- From the Departments of Radiology (K.J.N., O.G.J., B.W.T.) and Surgery (M.E.L.), Duke University Medical Center, Box 3808, Durham, NC 27710
| | - Michael E Lidsky
- From the Departments of Radiology (K.J.N., O.G.J., B.W.T.) and Surgery (M.E.L.), Duke University Medical Center, Box 3808, Durham, NC 27710
| | - Olga G James
- From the Departments of Radiology (K.J.N., O.G.J., B.W.T.) and Surgery (M.E.L.), Duke University Medical Center, Box 3808, Durham, NC 27710
| | - Benjamin Wildman-Tobriner
- From the Departments of Radiology (K.J.N., O.G.J., B.W.T.) and Surgery (M.E.L.), Duke University Medical Center, Box 3808, Durham, NC 27710
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16
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Combined Systemic and Hepatic Artery Infusion Pump Chemo-Therapy as a Liver-Directed Therapy for Colorectal Liver Metastasis-Review of Literature and Case Discussion. Cancers (Basel) 2021; 13:cancers13061283. [PMID: 33805846 PMCID: PMC7998495 DOI: 10.3390/cancers13061283] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Liver metastasis is a major therapeutic challenge and common cause of death for patients with colorectal cancer. While systemic treatment especially chemotherapy remains the mainstay of treatment, selected patients with liver-only metastasis may further benefit from liver-directed therapies. Direct infusion of chemotherapy into the liver metastases via an implantable hepatic arterial infusion pump (HAIP) is potentially an effective way to improve treatment response and survival in selected patients. Here, we reviewed the literature utilizing HAIP as a liver-directed modality alone and in combination with systemic chemotherapy. We discussed two cases who were successfully treated with this combinatorial approach and achieved remission or prolongation of disease control. We discussed the limitations, toxicities of combined systemic and HAIP modalities. Lastly, we provided insights on the use of HAIP in the modern era of systemic treatment for colorectal cancer patients with liver metastasis. Abstract Colorectal cancer (CRC) is the third most prevalent malignancy and the second most common cause of death in the US. Liver is the most common site of colorectal metastases. About 13% of patients with colorectal cancer have liver metastasis on initial presentation and 50% develop them during the disease course. Although systemic chemotherapy and immunotherapy are the mainstay treatment for patients with metastatic disease, for selected patients with predominant liver metastasis, liver-directed approaches may provide prolonged disease control when combined with systemic treatments. Hepatic artery infusion pump (HAIP) chemotherapy is an approach which allows direct infusion of chemotherapeutic into the liver and is especially useful in the setting of multifocal liver metastases. When combined with systemic chemotherapy, HAIP improves the response rate, provides more durable disease control, and in some patients leads to successful resection. To ensure safety, use of HAIP requires multidisciplinary collaboration between interventional radiologists, medical oncologists, hepatobiliary surgeons and treatment nurses. Here, we review the benefits and potential risks with this approach and provide our single institution experience on two CRC patients successfully treated with HAIP in combination with systemic chemotherapy. We provide our recommendations in adopting this technique in the current era for patient with colorectal liver metastases.
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17
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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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18
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Anteby R, Kemeny NE, Kingham TP, D'Angelica MI, Wei AC, Balachandran VP, Drebin JA, Brennan MF, Blumgart LH, Jarnagin WR. Getting Chemotherapy Directly to the Liver: The Historical Evolution of Hepatic Artery Chemotherapy. J Am Coll Surg 2021; 232:332-338. [PMID: 33387624 PMCID: PMC8320676 DOI: 10.1016/j.jamcollsurg.2020.11.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 01/14/2023]
Affiliation(s)
- Roi Anteby
- School of Public Health, Harvard University, Boston, MA; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
| | - Nancy E Kemeny
- Departments of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T Peter Kingham
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Alice C Wei
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Jeffrey A Drebin
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Murray F Brennan
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Leslie H Blumgart
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William R Jarnagin
- Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
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19
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Connell LC, Kemeny NE. Intraarterial Chemotherapy for Liver Metastases. Surg Oncol Clin N Am 2021; 30:143-158. [PMID: 33220802 PMCID: PMC8594481 DOI: 10.1016/j.soc.2020.08.005] [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: 10/23/2022]
Abstract
Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.
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Affiliation(s)
- Louise C Connell
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, 10th floor, New York, NY 10065, USA
| | - Nancy E Kemeny
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, 10th floor, New York, NY 10065, USA.
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20
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Muaddi H, D'Angelica M, Wiseman JT, Dillhoff M, Latchana N, Roke R, Ko YJ, Carpizo D, Spencer K, Fields RC, Williams G, Aucejo F, Acevedo-Moreno LA, Billingsley KG, Walker BS, Mayo SC, Karanicolas PJ. Safety and feasibility of initiating a hepatic artery infusion pump chemotherapy program for unresectable colorectal liver metastases: A multicenter, retrospective cohort study. J Surg Oncol 2020; 123:252-260. [PMID: 33095919 DOI: 10.1002/jso.26270] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Hepatic artery infusion pump (HAIP) chemotherapy is a specialized therapy for patients with unresectable colorectal liver metastases (uCRLM). Its effectiveness was demonstrated from a high volume center, with uncertainty regarding the feasibility and safety at other centers. Therefore, we sought to assess the safety and feasibility of HAIP for the management of uCRLM at other centers. METHODS We conducted a multicenter retrospective cohort study of patients with uCRLM treated with HAIP from January 2003 to December 2017 at six North American centers initiating the HAIP program. Outcomes included the safety and feasibility of HAIP chemotherapy. RESULTS We identified 154 patients with HAIP insertion and the median age of 54 (48-61) years. The burden of disease was >10 intra-hepatic metastatic foci in 59 (38.3%) patients. Patients received at least one cycle of systemic chemotherapy before HAIP insertion. Major complications occurred in 7 (4.6%) patients during their hospitalization and 13 (8.4%) patients developed biliary sclerosis during follow-up. A total of 148 patients (96.1%) received at least one-dose of HAIP chemotherapy with a median of 5 (4-7) cycles. 78 patients (56.5%) had a complete or partial response and 12 (7.8%) received a curative liver resection. CONCLUSION HAIP programs can be safely and effectively initiated in previously inexperienced centers with good response.
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Affiliation(s)
- Hala Muaddi
- Division of General Surgery, Sunnybrook Health Science Centre, Toronto, Ontario, Canada
| | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jason T Wiseman
- Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Mary Dillhoff
- Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Nicholas Latchana
- Department of Surgery, Novant Health Carolina Surgical, Charlotte, North Carolina, USA
| | - Rachel Roke
- Division of General Surgery, Sunnybrook Health Science Centre, Toronto, Ontario, Canada
| | - Yoo-Joung Ko
- Division of General Surgery, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.,St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Darren Carpizo
- Department of Surgery, Division of Surgical Oncology, Rochester's School of Medicine and Dentistry and Wilmot Cancer Center, Rochester, New York, USA
| | - Kristen Spencer
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine and the Alvin J. Siteman Comprehensive Cancer Center, St. Louis, Missouri, USA
| | - Gregory Williams
- Department of Surgery, Washington University School of Medicine and the Alvin J. Siteman Comprehensive Cancer Center, St. Louis, Missouri, USA
| | - Federico Aucejo
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Lou-Anne Acevedo-Moreno
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kevin G Billingsley
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA
| | - Brett S Walker
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA
| | - Skye C Mayo
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA
| | - Paul J Karanicolas
- Division of General Surgery, Sunnybrook Health Science Centre, Toronto, Ontario, Canada
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21
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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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22
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Boilève A, Maillard A, Wagner M, Dromain C, Laurent C, Dupont Bierre E, Le Sourd S, Audemar F, Ulusakarya A, Guerin-Meyer V, Smisth D, Pezzella V, De Baere T, Goere D, Gelli M, Taieb J, Boige V. Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy - a randomized phase II study -- SULTAN UCGI 30/PRODIGE 53 (NCT03164655)- study protocol. BMC Cancer 2020; 20:74. [PMID: 32000724 PMCID: PMC6990591 DOI: 10.1186/s12885-020-6571-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 01/23/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10-15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low (< 10%). Hepatic arterial infusion (HAI) oxaliplatin may represent a salvage therapy in patients with CRLM unresectable after one or more sys-CT regimens with ORRs and CRRs up to 60 and 30%, respectively. This study is designed to evaluate the efficacy of an intensification strategy based on HAI oxaliplatin combined with sys-CT as a salvage treatment in patients with CRLM unresectable after at least 2 months of first-line induction sys-CT. OBJECTIVES AND ENDPOINTS OF THE PHASE II STUDY Our main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0). METHODS This study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients. TRIAL REGISTRATION ClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.
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Affiliation(s)
- Alice Boilève
- Department of Medical Oncology, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France.
| | - Aline Maillard
- Department of statistics and epidemiology, Villejuif, France.,Centre for Research in Epidemiology and Population Health (team 2), INSERM U1018, Paris-Saclay University, Villejuif, France
| | - Mathilde Wagner
- Department of radiology, CHU Pitié Salpétrière, Paris, France
| | - Clarisse Dromain
- Department of radiology, Centre Hospitalier et Universitaire Vaudois, Lausanne, Switzerland
| | - Christophe Laurent
- Department of hepatogastroenterology, Hôpital Haut Levêque, Pessac, France
| | - Eric Dupont Bierre
- Department of digestive surgery, CHP Saint Grégoire, Saint-Grégoire, France
| | - Samuel Le Sourd
- Department of medical oncology, Centre Eugène-Marquis, Rennes, France
| | - Franck Audemar
- Department of hepatogastroenterology, Centre hospitalier Côte Basque, Bayonne, France
| | - Ayhan Ulusakarya
- Department of medical oncology, Hôpital Paul Brousse, Villejuif, France
| | | | - Denis Smisth
- Department of hepatogastroenterology, Hôpital Haut Levêque, Pessac, France
| | | | - Thierry De Baere
- Department of interventional radiology, Gustave Roussy, Villejuif, France
| | - Diane Goere
- Department of Surgical Oncology, Hôpital Saint Louis, Paris, France
| | | | - Julien Taieb
- Department of digestive oncology, Hôpital Européen Georges-Pompidou, Sorbonne Paris Cite/Paris Descartes University, Paris, France
| | - Valérie Boige
- Department of Medical Oncology, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France
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23
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Smith JJ, Chatila WK, Sanchez-Vega F, Datta J, Connell LC, Szeglin BC, Basunia A, Boucher TM, Hauser H, Wasserman I, Wu C, Cercek A, Hechtman JF, Madden C, Jarnagin WR, Garcia-Aguilar J, D'Angelica MI, Yaeger R, Schultz N, Kemeny NE. Genomic stratification beyond Ras/B-Raf in colorectal liver metastasis patients treated with hepatic arterial infusion. Cancer Med 2019; 8:6538-6548. [PMID: 31503397 PMCID: PMC6825986 DOI: 10.1002/cam4.2415] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/28/2019] [Accepted: 06/28/2019] [Indexed: 12/15/2022] Open
Abstract
Background Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. Methods We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. Results Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. Conclusions Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI.
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Affiliation(s)
- J Joshua Smith
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA.,Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA
| | - Walid K Chatila
- Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA.,Center for Molecular Oncology, MSKCC, New York City, New York, USA.,Tri-Institutional Program in Computational Biology & Medicine, New York City, New York, USA
| | - Francisco Sanchez-Vega
- Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA.,Center for Molecular Oncology, MSKCC, New York City, New York, USA
| | - Jashodeep Datta
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA.,Department of Surgery, Hepatopancreatobiliary Service, MSKCC, New York City, New York, USA
| | | | - Bryan C Szeglin
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA
| | - Azfar Basunia
- Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA.,Center for Molecular Oncology, MSKCC, New York City, New York, USA
| | | | - Haley Hauser
- Department of Medicine, MSKCC, New York City, New York, USA
| | - Isaac Wasserman
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA
| | - Chao Wu
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA.,Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA
| | - Andrea Cercek
- Department of Medicine, MSKCC, New York City, New York, USA
| | | | - Chris Madden
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA
| | - William R Jarnagin
- Department of Surgery, Hepatopancreatobiliary Service, MSKCC, New York City, New York, USA
| | - Julio Garcia-Aguilar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, New York, USA
| | - Michael I D'Angelica
- Department of Surgery, Hepatopancreatobiliary Service, MSKCC, New York City, New York, USA
| | - Rona Yaeger
- Department of Medicine, MSKCC, New York City, New York, USA
| | - Nikolaus Schultz
- Human Oncology and Pathogenesis Program, MSKCC, New York City, New York, USA.,Center for Molecular Oncology, MSKCC, New York City, New York, USA.,Department of Epidemiology & Biostatistics, MSKCC, New York City, New York, USA
| | - Nancy E Kemeny
- Department of Medicine, MSKCC, New York City, New York, USA
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24
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Georgakis GV, Goldberg I, Sasson AR. Current Trends in the Surgical Management of Colorectal Cancer Liver Metastases. CURRENT COLORECTAL CANCER REPORTS 2019. [DOI: 10.1007/s11888-019-00440-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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25
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Bala MM, Riemsma RP, Wolff R, Pedziwiatr M, Mitus JW, Storman D, Swierz MJ, Kleijnen J, Cochrane Hepato‐Biliary Group. Cryotherapy for liver metastases. Cochrane Database Syst Rev 2019; 7:CD009058. [PMID: 31291464 PMCID: PMC6620095 DOI: 10.1002/14651858.cd009058.pub3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma. Liver metastases are significantly more common than primary liver cancer and long-term survival rates reported for patients after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients. Cryotherapy is performed with the use of an image-guided cryoprobe which delivers liquid nitrogen or argon gas to the tumour tissue. The subsequent process of freezing is associated with formation of ice crystals, which directly damage exposed tissue, including cancer cells. OBJECTIVES To assess the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and six other databases up to June 2018. SELECTION CRITERIA Randomised clinical trials assessing beneficial and harmful effects of cryotherapy and its comparators for liver metastases, irrespective of the location of the primary tumour. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, and data on the outcomes important for our review, as well as information on the design and methodology of the trials. Two review authors independently assessed risk of bias in each study. One review author performed data extraction and a second review author checked entries. MAIN RESULTS We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision.The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages.We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05). FUNDING the trial did not provide information on funding. AUTHORS' CONCLUSIONS The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.
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Affiliation(s)
- Malgorzata M Bala
- Jagiellonian University Medical CollegeChair of Epidemiology and Preventive Medicine; Department of Hygiene and Dietetics; Systematic Reviews UnitKopernika 7KrakowPoland31‐034
| | - Robert P Riemsma
- Kleijnen Systematic Reviews LtdUnit 6, Escrick Business ParkRiccall Road, EscrickYorkUKYO19 6FD
| | - Robert Wolff
- Kleijnen Systematic Reviews LtdUnit 6, Escrick Business ParkRiccall Road, EscrickYorkUKYO19 6FD
| | - Michal Pedziwiatr
- Jagiellonian University Medical College2nd Department of General SurgeryKopernika Street 21KrakówMalopolskaPoland31‐501
| | - Jerzy W Mitus
- Centre of Oncology, Maria Skłodowska – Curie Memorial Institute, Krakow Branch. Department of Anatomy, Jagiellonian University Medical College Krakow, PolandDepartment of Surgical Oncologyul. Garncarska 11KrakowPoland31‐115
| | - Dawid Storman
- University HospitalDepartment of Hygiene and Dietetics, Systematic Reviews Unit, Jagiellonian University Medical College, Department of Adult PsychiatryKrakowPoland
| | - Mateusz J Swierz
- Jagiellonian University Medical CollegeDepartment of Hygiene and Dietetics, Systematic Reviews UnitKrakowPoland
| | - Jos Kleijnen
- Kleijnen Systematic Reviews LtdUnit 6, Escrick Business ParkRiccall Road, EscrickYorkUKYO19 6FD
- School for Public Health and Primary Care (CAPHRI), Maastricht UniversityMaastrichtNetherlands6200 MD
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Hsiao JH, Chang HT, Tseng YD, Chiang CL, Chen IS, Chen YC, Chang PM, Wang BW. Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Breast Cancer with Liver-predominant Metastatic Disease. In Vivo 2019; 32:1635-1641. [PMID: 30348727 DOI: 10.21873/invivo.11425] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patients with liver metastasis from breast cancer (LMBC) are usually offered systemic therapy. However, for those with progressive liver disease and limited extra-hepatic conditions, local liver management becomes an option. Herein we present our experience with hepatic arterial infusion chemotherapy (HAIC). PATIENTS AND METHODS From 1999 to 2018, 42 patients with LMBC, who had progressive liver metastasis after systemic therapy, were treated with HAIC. A catheter was placed angiographically into the hepatic artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil, folinic acid, and cisplatin. This treatment was repeated at monthly intervals. The medical records were reviewed and analyzed for hepatic tumor response, progression-free survival, overall survival and adverse effects. RESULTS Complete response was observed in two patients (5%), partial response in 18 patients (43%) and stable disease in eight patients (19%). Fourteen patients (33%) had progressive disease after HAIC. The median progression-free survival and overall survival were 8.4 and 19.3 months, respectively. There was no death related to HAIC. The patients with response to the treatment had a significant survival benefit (p<0.005). CONCLUSION HAIC can be an option for those with progressive liver disease who are heavily pretreated while their extra-hepatic conditions are minimal or stable.
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Affiliation(s)
- Jui-Hu Hsiao
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Hong-Tai Chang
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Yen-Dun Tseng
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Chia-Ling Chiang
- Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - I-Shu Chen
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Yu-Chia Chen
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Po-Ming Chang
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C
| | - Being-Whey Wang
- Division of Gastroenterologic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.
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Goéré D, Pignon JP, Gelli M, Elias D, Benhaim L, Deschamps F, Caramella C, Boige V, Ducreux M, de Baere T, Malka D. Postoperative hepatic arterial chemotherapy in high-risk patients as adjuvant treatment after resection of colorectal liver metastases - a randomized phase II/III trial - PACHA-01 (NCT02494973). BMC Cancer 2018; 18:787. [PMID: 30081865 PMCID: PMC6080555 DOI: 10.1186/s12885-018-4697-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 07/26/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone. METHODS/DESIGN This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival). DISCUSSION If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients. TRIAL REGISTRATION ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015.
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Affiliation(s)
- Diane Goéré
- Department of Surgical Oncology - Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France.
| | - Jean-Pierre Pignon
- Statistics and Epidemiology Unit - Gustave Roussy, Villejuif, France.,Centre for Research in Epidemiology and Population Health (team 2), INSERM U1018, Paris-Saclay University, Villejuif, France
| | - Maximiliano Gelli
- Department of Surgical Oncology - Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France
| | - Dominique Elias
- Department of Surgical Oncology - Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France
| | - Léonor Benhaim
- Department of Surgical Oncology - Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France
| | - Frédéric Deschamps
- Department of Interventional Radiology - Gustave Roussy, Villejuif, France
| | | | - Valérie Boige
- Department of Cancer Medicine - Gustave Roussy, Villejuif, France
| | - Michel Ducreux
- Department of Cancer Medicine - Gustave Roussy, Villejuif, France
| | - Thierry de Baere
- Department of Interventional Radiology - Gustave Roussy, Villejuif, France
| | - David Malka
- Department of Cancer Medicine - Gustave Roussy, Villejuif, France
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28
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Vaglini M, Cascinelli F, Chiti A, Deraco M, Inglese MG, Rebuffoni G, Rizzi M, Sala B, Santoro N, Santinami M. Isolated Pelvic Perfusion for the Treatment of Unresectable Primary or Recurrent Rectal Cancer. TUMORI JOURNAL 2018; 82:459-62. [PMID: 9063524 DOI: 10.1177/030089169608200510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Between May 1990 and December 1995, 16 patients with primary or recurrent unresectable rectal cancer were treated by isolated pelvic perfusion. All patients had been previously treated and were considered unsuitable for surgery or further systemic chemotherapy or radiotherapy. The treatment was based on a perfusion lasting 90 min at 40.5 C° with 5-fluorouracil, mitomycin-C and mitoxantrone. Whenever technically feasible (10 cases), continuous intraarterial chemotherapy (through a Medtronic device with a catheter in the inferior mesenteric artery) was administered postoperatively. Two complete responses and 2 partial responses were observed; 8 other patients showed stable disease. One patient did not show any response. Finally, 3 patients for various reasons were not assessable. All patients experienced immediate relief of pain. No major side effects directly related to isolated pelvic perfusion were recorded; a transitory bone marrow depletion was observed in all cases. In conclusion, isolated pelvic perfusion is useful in inoperable disease of the pelvis by reliably relieving pain and thereby improving the patients quality of life.
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Affiliation(s)
- M Vaglini
- Istituto Nazionale per lo Studio e.la Cura dei Tumori, Milan, Italy
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29
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Colleoni M, Nelli P, Manente P. Clinical Development of new Fluoropyrimidines: A Major Improvement in Colorectal Cancer Treatment? TUMORI JOURNAL 2018; 81:303-7. [PMID: 8804444 DOI: 10.1177/030089169508100501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Colorectal cancer represents an increasing problem and is responsible for about 16,000 deaths per year in Italy. Fluorouracil represents the most widely used agent, but therapeutic responses have remained consistently discouraging. The overall response rates for fluorouracil as a single agent range from 5% to 15%, and the addition of biochemical modulators, although able to improve response rate, has not been shown conclusively to prolong survival. Methods In recent years, several new compounds characterized by a high therapeutic index, optimal absorption through the gastrointestinal tract when administered orally and selective hepatic metabolization have been synthesised. In this review we analyzed published data on new fluoropyrimidines in an attempt to better define their role and to evaluate any significant improvement over fluorouracil. Results Athough no sure advantage over fluorouracil has been detected, interesting results have been reported for fluorouracil analogs with alternative routes of administration such as oral or intra-arterial chemotherapy. Conclusions Further studies, possibly randomized, should also measure quality of life and treatment-related costs in order to define their real advantage over fluorouracil in the palliation of advanced colorectal cancer.
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Affiliation(s)
- M Colleoni
- Division of Medical Oncology, City Hospital, Castelfranco Veneto, Italy
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Abstract
Current information on the medical treatment of colorectal cancer was reviewed after a search of the literature through Medline. Publications from 1984 to present were surveyed. Appropriate adjuvant therapy increases overall survival and disease-free intervals. The treatment modalities of unresectable or metastatic tumors are disappointing, with at best 40% of patients experiencing short-lasting responses. Whenever possible, patients with advanced colorectal cancer should be enrolled in clinical trials.
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Affiliation(s)
- C F Verschraegen
- Division of Medicine, University of Texas, M.D. Anderson Cancer Center, Houston 77030
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31
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Bertuccelli M, Falcone A, Campoccia S, Conti M, Brunetti I, Caramella D, Giulianotti PC, Mosca F, Bartolozzi C, Conte PF. Intrahepatic Chemotherapy with Floxuridine, Leucovorin and Dexamethasone in Continuous Infusion and Mitomycin-c Bolus in Unresectable Hepatic Metastases from Colorectal Cancer: A Phase II Study. TUMORI JOURNAL 2018; 85:473-7. [PMID: 10774568 DOI: 10.1177/030089169908500609] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Intrahepatic continuous infusion FUDR induces a 50% response rate in patients with hepatic metastases from colorectal cancer. Lower rates have been observed in pretreated patients. The combination of floxuridine plus leucovorin has obtained over 70% responses, with high hepatic toxicity. The use of dexamethasone can decrease hepatic toxicity. A randomized study reported an increase in response rate and a decrease in hepatic toxicity in a group of patients treated with floxuridine plus dexamethasone compared to a group receiving only floxuridine. Moreover, the combination of mitomycin C, carmustine and floxuridine is also effective in pretreated patients. Methods On such premises, since July 1993 we have treated 39 patients affected by unresectable hepatic metastases from colon carcinoma (26 patients) and rectal carcinoma (13 patients) with the combination continuous infusion of floxuridine (0.20 mg/kg per day) + leucovorin (7.5 mg/m2/day) + dexamethasone (20 mg on days 1 to 14) and bolus mitomycin C (10 mg/m2 on day 1) via the hepatic artery. Cycles were administered every four weeks. There were as 28 males and 11 females, with a median age of 64 years (range, 39-75) and a median PS = 0. Twenty-two patients were pretreated with systemic chemotherapy including 5-fluorouracil plus leucovorin. Total number of cycles was 189, with a median of 6 cycles per patient (range, 1-12). Results Of 39 patients 37 were assessable for response (2 patients were not assessable because they stopped chemotherapy for occlusion of the catheter after the first cycle). There were 3 complete responses (1 in a naive patient and 2 in pretreated patients), 16 partial responses (11 in pretreated patients and 5 in chemonaive patients), 4 minor responses, 4 stable disease and 10 progressive disease. The overall response rate was 51.3% (95 CI, 51.3-86.7%). Median time to progression was 6 months (range, 1-34+). Overall survival was 18 months (range, 1-34+). Of 39 patients, 36 were assessable for toxicity (WHO) (3 patients died after the first cycle for progression of disease): diarrhea and nausea-vomiting grade 3-4 occurred respectively in 15 (41%) and 3 patients (8%); hepatic toxicity was mild. Conclusions The treatment we used showed an elevated activity in liver metastases from colorectal cancer even in patients pretreated and resistant to systemic chemotherapy, although toxicity grade 3-4 diarrhea occurred in approximately 40% of the patients.
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Affiliation(s)
- M Bertuccelli
- Sezione di Oncologia Medica, Ospedale di Livorno, Italy
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32
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A Comparison of Yttrium-90 Microsphere Radioembolization to Hepatic Arterial Infusional Chemotherapy for Patients with Chemo-refractory Hepatic Colorectal Metastases. Curr Treat Options Oncol 2018; 18:42. [PMID: 28608276 DOI: 10.1007/s11864-017-0481-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OPINION STATEMENT Patients with unresectable hepatic colorectal metastases who become chemo-refractory have limited treatment options. Systemic chemotherapies such as TAS102 and regorafenib have been used in the refractory setting, but with only modest improvement in overall survival compared to best supportive care. In patients with liver-only or liver-dominant disease, direct chemotherapy to the liver such as hepatic artery infusional (HAI) chemotherapy and radioembolization (yttrium-90 (Y90)) should be considered. Due to the difficulty of HAI therapy post Y90 for technical reasons, we recommend HAI therapy prior to Y90.
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Tewes M, Peis MW, Bogner S, Theysohn JM, Reinboldt MP, Schuler M, Welt A. Hepatic arterial infusion chemotherapy for extensive liver metastases of breast cancer: efficacy, safety and prognostic parameters. J Cancer Res Clin Oncol 2017; 143:2131-2141. [PMID: 28646261 DOI: 10.1007/s00432-017-2462-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 06/16/2017] [Indexed: 01/22/2023]
Abstract
PURPOSE Hepatic arterial infusion chemotherapy (HAIC) is an option for patients with liver-predominant metastatic breast cancer (LMBC), when no further systemic treatment is available. But systematic reports are limited. Here we conducted a retrospective analysis of LMBC patients treated at an expert center. METHODS Individual patient data were retrieved from the clinical data base of the West German Cancer Center. Primary endpoints included hepatic response (RECIST), progression-free survival (PFS), overall survival (OS), and toxicity. A score based on LDH, AST, ALT and bilirubine was developed to estimate the hepatic metastasis load. RESULTS Data from 70 consecutive patients were included. All patients were heavily pretreated (median 7 treatment lines for LMBC). HAIC protocols included mitomycin/5-FU (70%), mitomycin (14.3%), melphalan (12.9%) and 5-FU (7.1%), with selection based on patient characteristics. Partial hepatic remission was obtained as best response in 14 patients (20.0%), stable disease in 27 patients (38.6%), and progressive disease in 29 patients (41.4%). Median PFS and OS from initiation of HAIC were 2 (range 0-10) and 7 months (range 1-37). Mainly hepatic and hematopoietic HAIC-related toxicities were observed; there was no treatment-related death. The hepatic metastasis score effectively separated two prognostic groups: Patients with a score <3 had significantly superior PFS (15 vs 7 weeks, p = 0.017) and OS (12 vs 5 months, p = 0.002). CONCLUSION HAIC offers a safe and effective salvage treatment strategy in heavily pretreated patients with LMBC and no further treatment options. The hepatic metastasis score may help to identify patients with sustained clinical benefit.
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Affiliation(s)
- Mitra Tewes
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany.
| | - Michael Wilhelm Peis
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
| | - Simon Bogner
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
| | - Jens M Theysohn
- Department of Radiology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
| | - Marcus Paul Reinboldt
- Department of Radiology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122, Essen, Germany
| | - Anja Welt
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg Essen, 45122, Essen, Germany
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34
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Beckwith MC, Mullin S. This CE is published through an unrestricted educational grant from Bristol-Myers Squibb. Hosp Pharm 2017. [DOI: 10.1177/001857870103600109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Credit This lesson is good for 0.2 CE units, with a passing grade of 70%. Goal The goal of this program is to inform the participant of costeffective ways to prevent, identify, and manage nausea and vomiting induced by antineoplastic agents. Objectives At the completion of this program the participant will be able to: 1. List antineoplastic agents associated with a high incidence of nausea and vomiting. 2. Identify patient-specific risk factors for developing chemotherapyinduced nausea and vomiting (CINV) and how these factors may influence treatment of this syndrome. 3. Compare the three major types of CINV, including the pathophysiologic mechanism, time of onset, and symptom duration of each type. 4. Explain the mechanism of action and appropriate place in therapy for each type of antiemetic agent. 5. Differentiate between pharmacologic regimens for the prevention and treatment of CINV in adults. 6. Identify drug-specific factors that must be considered in developing a formulary management strategy for the antiemetic agents. 7. Describe specific information that the pharmacist can share with patients to help them understand and manage CINV.
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Affiliation(s)
- M. Christina Beckwith
- Clinical Drug Information Specialist, University Hospitals and Clinics, Department of Pharmacy Services, 50 North Medical Drive A-050, Salt Lake City, UT 84132
| | - Shantei Mullin
- †Clinical Drug Information Specialist, University Hospitals and Clinics, Department of Pharmacy Services, 50 North Medical Drive A-050, Salt Lake City, UT 84132
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35
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Zarour LR, Anand S, Billingsley KG, Bisson WH, Cercek A, Clarke MF, Coussens LM, Gast CE, Geltzeiler CB, Hansen L, Kelley KA, Lopez CD, Rana SR, Ruhl R, Tsikitis VL, Vaccaro GM, Wong MH, Mayo SC. Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions. Cell Mol Gastroenterol Hepatol 2017; 3:163-173. [PMID: 28275683 PMCID: PMC5331831 DOI: 10.1016/j.jcmgh.2017.01.006] [Citation(s) in RCA: 203] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 01/11/2017] [Indexed: 02/08/2023]
Abstract
In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.
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Key Words
- 5-FU, fluorouracil
- Biomarkers
- CDX2, caudal-type homeobox transcription factor 2
- CEA, carcinoembryonic antigen
- CK, cytokeratin
- CRC, colorectal cancer
- CRLM, colorectal cancer liver metastasis
- CTC, circulating tumor cells
- Colorectal Cancer Liver Metastasis
- DFS, disease-free survival
- EGFR, epidermal growth factor receptor
- EpCAM, epithelial cell adhesion molecule
- HAI, hepatic arterial infusion
- Hepatic Arterial Infusion
- High-Risk Colorectal Cancer
- IL, interleukin
- LV, leucovorin
- MSI, microsatellite instability
- OS, overall survival
- PD, programmed death
- Recurrence
- TH, T-helper
- cfDNA, cell-free DNA
- dMMR, deficient mismatch repair
- miRNA, microRNA
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Affiliation(s)
- Luai R. Zarour
- Division of Surgical Oncology, Department of Surgery, Oregon Heath and Science University, Portland, Oregon
| | - Sudarshan Anand
- Department of Cell Developmental and Cancer Biology, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon
| | - Kevin G. Billingsley
- Division of Surgical Oncology, Department of Surgery, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon
| | - William H. Bisson
- The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon,Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon
| | - Andrea Cercek
- Department of Gastrointestinal Medical Oncology, Solid Tumor Division, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Michael F. Clarke
- Stanford Institute for Stem Cell and Regenerative Medicine, Stanford University, Stanford, California,Division of Oncology, Department of Medicine, Stanford University, Stanford, California
| | - Lisa M. Coussens
- Department of Cell Developmental and Cancer Biology, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon
| | - Charles E. Gast
- Department of Cell Developmental and Cancer Biology, Oregon Heath and Science University, Portland, Oregon
| | - Cristina B. Geltzeiler
- Division of Colorectal Surgery, Department of Surgery, Oregon Heath and Science University, Portland, Oregon
| | - Lissi Hansen
- The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon,School of Nursing, Oregon Heath and Science University, Portland, Oregon
| | - Katherine A. Kelley
- Division of Colorectal Surgery, Department of Surgery, Oregon Heath and Science University, Portland, Oregon
| | - Charles D. Lopez
- The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon,Division of Hematology and Medical Oncology, Department of Medicine, Oregon Heath and Science University, Portland, Oregon
| | - Shushan R. Rana
- Department of Radiation Medicine, Oregon Heath and Science University, Portland, Oregon
| | - Rebecca Ruhl
- Department of Cell Developmental and Cancer Biology, Oregon Heath and Science University, Portland, Oregon
| | - V. Liana Tsikitis
- Division of Colorectal Surgery, Department of Surgery, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon
| | - Gina M. Vaccaro
- The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon,Division of Hematology and Medical Oncology, Department of Medicine, Oregon Heath and Science University, Portland, Oregon
| | - Melissa H. Wong
- Department of Cell Developmental and Cancer Biology, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon
| | - Skye C. Mayo
- Division of Surgical Oncology, Department of Surgery, Oregon Heath and Science University, Portland, Oregon,The Knight Cancer Institute, Oregon Heath and Science University, Portland, Oregon,Correspondence Address correspondence to: Skye C. Mayo, MD, Department of Surgery, Oregon Heath and Science University, 3181 SW Sam Jackson Park Road, Mailcode L223, Portland, Oregon 97239. fax: (503) 494–8884.Department of SurgeryOregon Heath and Science University3181 SW Sam Jackson Park Road, Mailcode L223PortlandOregon 97239
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Cloyd JM, Aloia TA. Hammer versus Swiss Army knife: Developing a strategy for the management of bilobar colorectal liver metastases. Surgery 2017; 162:12-17. [PMID: 28109616 DOI: 10.1016/j.surg.2016.11.035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 11/23/2016] [Accepted: 11/28/2016] [Indexed: 01/01/2023]
Abstract
For patients with bilobar colorectal liver metastases, the recent increase in surgical approaches has resulted in more opportunities to extend the benefits of surgery to patients who were previously deemed unresectable. Surgical options now include anatomic hepatectomy, 1-stage parenchymal sparing hepatectomy, traditional 2-stage hepatectomy with or without portal vein embolization, associated liver partition and portal vein ligation for staged hepatectomy, local ablative techniques, and hepatic arterial infusion therapy. As the diversity of options has increased, controversy has arisen as to the optimal operative management of patients with complex bilateral disease. Moreover, there has been a tendency for various surgeons and groups to champion a single strategy. In contrast to this trend, this article introduces a novel "tailored approach" that takes advantage of all available tools and individually applies them based on an algorithmic assessment of the extent and distribution of metastatic disease.
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Affiliation(s)
- Jordan M Cloyd
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Thomas A Aloia
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
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37
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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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Abstract
Objective. Colorectal cancer is the second largest cause of death from malignant disease in Western countries. Although surgical resection is the preferred treatment in early disease, chemotherapy has an important role to play both as an adjunct to surgery and in the palliation of advanced disease. For many years 5-fluorouracil (5-FU) has been the only cyto toxic drug with significant activity in this condition and, recently, considerable effort has been directed toward enhancing its activity and finding better, alternative agents. Recently, raltitrexed (Tomudex; Zeneca Pharmaceuticals), the first of a new class of cytotoxic drugs, the selective, direct, thymidylate synthase inhibitors, received its first regulatory ap proval for the first-line treatment of advanced colo rectal cancer. The purpose of this review is to con sider the efficacy, toxicity, and resource implications of using this new antineoplastic agent, alongside developments that have been made in the more effective use of fluoropyrimidines, and the place of drug treatment in the management of colorectal cancer. Data Sources. A variety of sources were used, including manual and on-line (Medline and Pharm- line) literature searching. Approved and other drug names were used as primary search terms, linked with colorectal cancer where limitation was required. The medical information department of Zeneca Pharma ceuticals also was used where appropriate. Study Selection. Particular attention was di rected to randomized clinical trials, but nonrandom ized and preclinical studies were considered where appropriate. Conclusions. Although colorectal cancer is in herently resistant to cytotoxic chemotherapy, such treatment now has an established role as an adjunct to surgery and in the palliation of advanced disease. The optimum 5-FU- based regimen has yet to be estab lished with certainty, although in advanced disease a four-times-weekly, 5-day regimen of 5-FU and low- dose folinic acid is probably the best of those fully evaluated to date. Raltitrexed seems to be as effective as this combination while having definite advantages in terms of toxicity and the resources required for its preparation and administration, although it remains to be seen to what extent these and other resource benefits will be offset by its higher cost and how its efficacy and tolerability will compare with other 5-FU- based regimens in ongoing clinical trials.
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Chen H, Zhang J, Cao G, Liu P, Xu H, Wang X, Zhu X, Gao S, Guo J, Zhu L, Zhang P. Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy. Anticancer Drugs 2016; 27:118-126. [PMID: 26566233 DOI: 10.1097/cad.0000000000000290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials.
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Affiliation(s)
- Hui Chen
- aKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy bDepartment of Gastrointestinal Surgery, Peking University Cancer Hospital, Beijing, China
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40
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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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McAuliffe JC, Qadan M, D'Angelica MI. Hepatic resection, hepatic arterial infusion pump therapy, and genetic biomarkers in the management of hepatic metastases from colorectal cancer. J Gastrointest Oncol 2015; 6:699-708. [PMID: 26697204 DOI: 10.3978/j.issn.2078-6891.2015.081] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The liver is the most common site of colorectal cancer metastasis. Fortunately, improvements have been made in the care of patients with colorectal liver metastasis (CRLM). Effective management of CRLM requires a multidisciplinary approach that is tailored to individuals in order to achieve long-term survival, and cure. Resection and systemic chemotherapy provides benefit in selected individuals. An adjunct to resection and/or systemic chemotherapy is the use of hepatic arterial infusion pump (HAIP) therapy. Many studies show HAIP provides benefit for select patients with CRLM. Added to the crucible of a multidisciplinary approach to managing CRLM is the ever growing understanding of tumor biology and genetic profiling. In this review, we discuss the outcomes of resection, systemic therapies and HAIP therapy for CRLM. We also discuss the impact of recent advances in genetic profiling and mutational analysis, namely mutation of KRAS and BRAF, for this disease.
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Affiliation(s)
- John C McAuliffe
- Hepatopancreatobiliary Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Motaz Qadan
- Hepatopancreatobiliary Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Michael I D'Angelica
- Hepatopancreatobiliary Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
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Byrne JD, Jajja MRN, O'Neill AT, Bickford LR, Keeler AW, Hyder N, Wagner K, Deal A, Little RE, Moffitt RA, Stack C, Nelson M, Brooks CR, Lee W, Luft JC, Napier ME, Darr D, Anders CK, Stack R, Tepper JE, Wang AZ, Zamboni WC, Yeh JJ, DeSimone JM. Local iontophoretic administration of cytotoxic therapies to solid tumors. Sci Transl Med 2015; 7:273ra14. [PMID: 25653220 DOI: 10.1126/scitranslmed.3009951] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of -0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.
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Affiliation(s)
- James D Byrne
- Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mohammad R N Jajja
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Adrian T O'Neill
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lissett R Bickford
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Amanda W Keeler
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Nabeel Hyder
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kyle Wagner
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Allison Deal
- Lineberger Comprehensive Cancer Center Biostatistics and Clinical Data Management Core, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ryan E Little
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Richard A Moffitt
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Colleen Stack
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. School of Medicine, Duke University, Durham, NC 27708, USA. Synecor LLC, Chapel Hill, NC 27517, USA
| | - Meredith Nelson
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Christopher R Brooks
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William Lee
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - J Chris Luft
- Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mary E Napier
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - David Darr
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Carey K Anders
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Richard Stack
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Synecor LLC, Chapel Hill, NC 27517, USA. Division of Cardiology, Department of Medicine, Duke University, Durham, NC 27708, USA
| | - Joel E Tepper
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Andrew Z Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jen Jen Yeh
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Joseph M DeSimone
- Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.
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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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Vincenzi B, Imperatori M, Picardi A, Vespasiani Gentilucci U, Gallo P, Fausti V, Spalato Ceruso M, Santini D, Tonini G. Liver toxicity in colorectal cancer patients treated with first-line FOLFIRI-containing regimen: a single institution experience. Expert Rev Anticancer Ther 2015; 15:971-976. [PMID: 26112080 DOI: 10.1586/14737140.2015.1061937] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Chemotherapy-induced toxic liver injury is a relevant issue in the clinical management of patients affected with metastatic colorectal cancer (mCRC). This retrospective study evaluated patterns of liver toxicity in patients treated with FOLinic acid, Fluorouracil, IRInotecan (FOLFIRI)-based regimens. METHODS One hundred and fifty-six mCRC patients treated at the University Campus Bio-Medico between January 2003 and January 2013 were included in this retrospective analysis. All patients received a FOLFIRI backbone-based chemotherapy. Basal liver enzymes levels were assessed before starting the treatment and before every therapy course. R ratio and the aspartate aminotransferase/alanine aminotransferase ratio were calculated. RESULTS Ninety-one patients were male versus 55 female, and the median age of the population was 62 years (range: 38-83). Most patients had liver involvement at the beginning of first-line regimen (101 patients, 64.74%) and 59 patients had received a previous 5-FU based therapy in the adjuvant setting (37.82%). Aspartate aminotransferase level (167.87 vs 41.05 U/l; p < 0.001), Alanine aminotransferase level (94.48 vs 39.80 U/l; p = 0.004) and alkaline phosphatase (289.0 vs 172.44 U/l; p = 0.02) were significantly increased during the first 3 months of treatment. In the entire population, the calculated R ratio was 3.96 (95% CI: 3.25-4.51). In all three regimens, the calculated R ratio was between 2 and 5, without any statistical differences. CONCLUSIONS FOLFIRI-based hepatotoxicity has been indirectly defined as a mixed pattern injury in all three regimens evaluated.
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Affiliation(s)
- Bruno Vincenzi
- Medical Oncology, University Campus Bio-Medico, via Alvaro del portillo 200, Roma 00128, Italy
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Transarterial chemoembolization (TACE) for colorectal liver metastases--current status and critical review. Langenbecks Arch Surg 2015; 400:641-59. [PMID: 26088872 DOI: 10.1007/s00423-015-1308-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 05/24/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Transarterial liver-directed therapies are currently not recommended as a standard treatment for colorectal liver metastases. Transarterial chemoembolization (TACE), however, is increasingly used for patients with liver-dominant colorectal metastases after failure of surgery or systemic chemotherapy. The limited available data potentially reveals TACE as a valuable option for pre- and post-operative downsizing, minimizing time-to-surgery, and prolongation of overall survival after surgery in patients with colorectal liver only metastases. PURPOSE In this overview, the current status of TACE for the treatment of liver-dominant colorectal liver metastases is presented. Critical comments on its rationale, technical success, complications, toxicity, and side effects as well as oncologic outcomes are discussed. The role of TACE as a valuable adjunct to surgery is addressed regarding pre- and post-operative downsizing, conversion to resectability as well as improvement of the recurrence rate after potentially curative liver resection. Additionally, the concept of TACE for liver-dominant metastatic disease with a focus on new embolization technologies is outlined. CONCLUSIONS There is encouraging data with regard to technical success, safety, and oncologic efficacy of TACE for colorectal liver metastases. The majority of studies are non-randomized single-center series mostly after failure of systemic therapies in the 2nd line and beyond. Emerging techniques including embolization with calibrated microspheres, with or without additional cytotoxic drugs, degradable starch microspheres, and technical innovations, e.g., cone-beam computed tomography (CT) allow a new highly standardized TACE procedure. The real efficacy of TACE for colorectal liver metastases in a neoadjuvant, adjuvant, and palliative setting has now to be evaluated in prospective randomized controlled trials.
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Abstract
Transarterial therapies in the setting of primary and secondary liver malignancies are becoming an essential part of the oncology landscape. Most patients with hepatic malignancies are not candidates for curative surgical intervention, thereby warranting exploration of alternative means of treatment that preserves quality of life while providing clinical benefit. Herein, the data for intra-arterial chemoinfusion, transarterial chemoembolization, drug-eluting beads, and radioembolization are discussed in the setting of malignancies within the liver; outcome data relating to survival, time-to-progression, time-to-recurrence, and adverse events are presented. Further data regarding different treatment paradigms for hepatocellular carcinoma, metastatic colorectal carcinoma, neuroendocrine tumours, and intrahepatic cholangiocarcinoma are also provided. In light of these and forthcoming data, transarterial therapies seem to offer a viable treatment pathway for select populations of patients.
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Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg 2015; 261:353-60. [PMID: 24646562 DOI: 10.1097/sla.0000000000000614] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE Evaluate conversion rate of patients with unresectable colorectal-liver metastasis to complete resection with hepatic-arterial infusion plus systemic chemotherapy including bevacizumab (Bev). PATIENTS AND METHODS Forty-nine patients with unresectable colorectal liver metastases (CRLM) were included in a single-institution phase II trial. Conversion to resection was the primary outcome. Secondary outcomes included overall survival (OS), progression-free survival, and response rates. Multivariate and landmark analyses were performed to evaluate survival differences between resected and nonresected patients. RESULTS Median number of tumors was 14 and 65% were previously treated patients. A high biliary toxicity rate was found in the first 24 patients whose treatment included Bev. The remaining 25 patients were treated without Bev. Overall response rates were 76% (4 complete responses). Twenty-three patients (47%) achieved conversion to resection at a median of 6 months from treatment initiation. Median OS and progression-free survival for all patients were 38 (95% confidence interval: 28 to not reached) and 13 months (95% confidence interval: 7-16). Bev administration did not impact outcome. Conversion was the only factor associated with prolonged OS and progression-free survival in multivariate analysis. On landmark analysis, patients who had undergone resection had longer OS than those who did not undergo resection (3-year OS: 80% vs 26%). Currently, 10 of 49 (20%) patients have no evidence of disease (NED) at a median follow-up of 39 months (32-65 months). CONCLUSIONS In patients with extensive unresectable CRLM, the majority of whom were previously treated, 47% were able to undergo complete resection after combined HAI and systemic therapy. Conversion to resection is associated with prolonged survival.
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Saxena A, Meteling B, Kapoor J, Golani S, Morris DL, Bester L. Is yttrium-90 radioembolization a viable treatment option for unresectable, chemorefractory colorectal cancer liver metastases? A large single-center experience of 302 patients. Ann Surg Oncol 2015; 22:794-802. [PMID: 25323474 DOI: 10.1245/s10434-014-4164-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Indexed: 05/01/2025]
Abstract
INTRODUCTION We report the largest series to date on the safety and efficacy of yttrium-90 (90Y) radioembolization for the treatment of unresectable, chemorefractory colorectal cancer liver metastases (CRCLM). METHODS A total of 302 patients underwent resin-based 90Y radioembolization for unresectable, chemorefractory CRCLM between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the response criteria in solid tumors criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method, and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS Median follow-up in the complete cohort was 7.2 months (range 0.2-72.8), and the median survival after 90Y radioembolization was 10.5 months with a 24-month survival of 21%. On imaging follow-up of 293 patients who were followed up beyond 2 months, complete response to treatment was observed in 2 patients (1%), partial response in 111 (38%), stable disease in 96 (33%), and progressive disease in 84 (29%). Four factors were independently associated with a poorer prognosis: extensive tumor volume, number of previous lines of chemotherapy, poor radiological response to treatment, and low preoperative hemoglobin. One hundred fifteen (38%) developed clinical toxicity after treatment; most complications were minor (grade I/II) and resolved without active intervention. CONCLUSIONS 90Y radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM.
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Affiliation(s)
- Akshat Saxena
- Department of Interventional Radiology, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia,
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Abstract
To date, hepatic artery infusion (HAI) chemotherapy has primarily been investigated in the setting of colorectal cancer liver metastases (CRLM). Few studies have been conducted in North America regarding HAI chemotherapy for primary liver cancers (PLC) or noncolorectal liver metastases (non-CRLM). Despite decades of evaluation, controversy surrounding the use of HAI chemotherapy still exists. In this article the methods of HAI chemotherapy delivery, technical aspects of catheter and pump insertion, and specific complications of HAI chemotherapy are discussed. Outcomes of clinical trials and reviews of HAI chemotherapy in the setting of CRLM, PLC, and non-CRLM are evaluated.
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Affiliation(s)
- Julie N Leal
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - T Peter Kingham
- Department of Surgery, Division of Hepatopancreatobiliary Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Paul SB, Sharma H. Role of Transcatheter Intra-arterial Therapies for Hepatocellular Carcinoma. J Clin Exp Hepatol 2014; 4:S112-21. [PMID: 25755602 PMCID: PMC4284218 DOI: 10.1016/j.jceh.2014.03.048] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 03/03/2014] [Indexed: 02/07/2023] Open
Abstract
Transcatheter intra-arterial therapies play a vital role in treatment of HCC due to the unique tumor vasculature. Evolution of techniques and newer efficacious modalities of tumor destruction have made these techniques popular. Various types of intra-arterial therapeutic options are currently available. These constitute: bland embolization, trans-arterial chemotherapy, trans-arterial chemo embolization with or without drug-eluting beads and trans-arterial radio embolization, which are elaborated in this review.
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Key Words
- AFP, alpha feto protein
- CR, complete response
- HAIC, hepatic artery infusion chemotherapy
- HCC, hepatocellular carcinoma
- LA, laser ablation
- OLT, orthotopic liver transplant
- PD, progressive disease
- PEI, percutaneous ethanol injection
- PR, partial response
- PVT, portal vein thrombosis
- RFA, ablation
- SD, stable disease
- TACE, trans-arterial chemoembolization
- TAE, Trans-arterial embolization
- TART, trans-arterial radiotherapy
- drug eluting bead (DEB)
- hepatocellular carcinoma (HCC)
- trans-arterial chemoembolization (TACE)
- trans-arterial embolization (TAE)
- trans-arterial radiotherapy (TART)
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Affiliation(s)
- Shashi B. Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Hanish Sharma
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
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