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Raman V, Deshpande CP, Khanduja S, Howell LM, Van Dessel N, Forbes NS. Build-a-bug workshop: Using microbial-host interactions and synthetic biology tools to create cancer therapies. Cell Host Microbe 2023; 31:1574-1592. [PMID: 37827116 DOI: 10.1016/j.chom.2023.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/16/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023]
Abstract
Many systemically administered cancer therapies exhibit dose-limiting toxicities that reduce their effectiveness. To increase efficacy, bacterial delivery platforms have been developed that improve safety and prolong treatment. Bacteria are a unique class of therapy that selectively colonizes most solid tumors. As delivery vehicles, bacteria have been genetically modified to express a range of therapies that match multiple cancer indications. In this review, we describe a modular "build-a-bug" method that focuses on five design characteristics: bacterial strain (chassis), therapeutic compound, delivery method, immune-modulating features, and genetic control circuits. We emphasize how fundamental research into gut microbe pathogenesis has created safe bacterial therapies, some of which have entered clinical trials. The genomes of gut microbes are fertile grounds for discovery of components to improve delivery and modulate host immune responses. Future work coupling these delivery vehicles with insights from gut microbes could lead to the next generation of microbial cancer therapy.
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Affiliation(s)
- Vishnu Raman
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA; Ernest Pharmaceuticals, LLC, Hadley, MA, USA
| | - Chinmay P Deshpande
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Shradha Khanduja
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | - Lars M Howell
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA
| | | | - Neil S Forbes
- Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA, USA; Molecular and Cell Biology Program, University of Massachusetts, Amherst, Amherst, MA, USA; Institute for Applied Life Science, University of Massachusetts, Amherst, Amherst, MA, USA.
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Kim JS, Kim H, Lee SY, Han YD, Han K, Min BS, Kim MD, Won JY, Beom SH, Shin SJ, Kim HS, Han DH, Ahn JB. Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol. BMC Cancer 2023; 23:691. [PMID: 37481515 PMCID: PMC10363309 DOI: 10.1186/s12885-023-11085-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 06/16/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis. METHODS This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate. DISCUSSION This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate. TRIAL REGISTRATION ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.
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Affiliation(s)
- Ji Su Kim
- Division of Hepatobiliary and Pancreas Surgery, Incheon St. Mary's Hospital, The Catholic University College of Medicine, Incheon, Korea
| | - Hyunwook Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Seo Young Lee
- Department of Medical Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Dae Han
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kichang Han
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Soh Min
- Department of Colorectal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Man-Deuk Kim
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Yun Won
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Hoon Beom
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Sang Joon Shin
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - Han Sang Kim
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
- Graduate School of Medical Science, Brain Korea 21 Project, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
| | - Dai Hoon Han
- Department of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
| | - Joong Bae Ahn
- Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
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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: 0] [Impact Index Per Article: 0] [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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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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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: 6] [Impact Index Per Article: 1.5] [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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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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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: 89] [Impact Index Per Article: 17.8] [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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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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Bala MM, Riemsma RP, Wolff R, Pedziwiatr M, Mitus JW, Storman D, Swierz MJ, Kleijnen J. 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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11
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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: 20] [Impact Index Per Article: 2.9] [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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12
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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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13
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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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14
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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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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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16
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Kim MS, Kang JK, Cho CK, Choi CW, Seo YS, Hwang DY, Moon SM, Kang HJ, Kim YH, Kim MS, Oh N. Three-Fraction Stereotactic Body Radiation Therapy for Isolated Liver Recurrence from Colorectal Cancer. TUMORI JOURNAL 2018; 95:449-54. [DOI: 10.1177/030089160909500407] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims To determine the feasibility and efficacy of 3-fraction stereotactic body radiation therapy for isolated colorectal cancer liver metastases. Materials and methods Ten patients with isolated inoperable liver metastasis from colorectal cancer with progression after salvage chemotherapy underwent stereotactic body radiation therapy. Follow-up was 7–49 months (median, 12). Six patients had a solitary lesion and 4 patients had 2 lesions. Internal target volumes of metastatic liver tumors ranged from 3.4 to 271 ml. Stereotactic body radiation therapy doses ranged from 36 to 51 Gy and were administered in three fractions. All patients demonstrated disease progression despite chemotherapy prior to stereotactic body radiation therapy. Results Three-year overall survival and local control rates were 40% and 60%, respectively. Tumors with an internal target volume <100 ml showed better local control rate than larger tumors. No severe complication was attributed to the therapy. Conclusion Our study suggests the potential feasibility of stereotactic body radiation therapy for selected patients with colorectal cancer liver metastasis and no treatment option. The study showed that excellent local control was achieved in patients with a total tumor volume of <100 ml but failed to clarify the role of stereotactic body radiation therapy for larger tumors. Further large scale studies are needed to define the indications of such therapy.
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Affiliation(s)
- Mi-Sook Kim
- Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Jin-Kyu Kang
- Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Chul Koo Cho
- Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Chul Won Choi
- Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Young Seok Seo
- Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Dae Yong Hwang
- Department of General Sugery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Sun Mi Moon
- Department of General Sugery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Hae Jin Kang
- Department of Hematooncology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Young Han Kim
- Department of Radiology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Min Suk Kim
- Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Korea
| | - Nahmgun Oh
- Department of Surgery, Pusan National University School of Medicine, Korea
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17
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Arru M, Aldrighetti L, Gremmo F, Ronzoni M, Angeli E, Caterini R, Ferla G. Arterial Devices for Regional Hepatic Chemotherapy: Transaxillary versus Laparotomic Access. J Vasc Access 2018; 1:93-9. [PMID: 17638234 DOI: 10.1177/112972980000100305] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Introduction Intra-Arterial Hepatic Chemotherapy (IAHC) based on floxuridine (FUdR) infusion is an effective treatment for hepatic metastases from colorectal cancer. A percutaneously implanted intra-arterial device may overcome the surgical stress of the laparotomic placement allowing an increase in the number of patients treated by IAHC. The aim of the present study is the comparative analysis of surgical and percutaneous transaxillary approaches to implant the catheter into the hepatic artery (HA) for IAHC. Materials and Methods Between September 1993 and February 1999, 56 patients received an implantable infusion system [SynchroMed® (Medtronic, USA) or Port-a-cath® (Deltec, USA) connected to an external infusion pump (CADD®, Deltec, USA)] for IAHC. Twenty-eight patients (LPT group) underwent laparotomy to implant the catheter into the HA, the other 28 patients (PCT group) received a percutaneous catheter into the HA through a transaxillary percutaneous access. Indications for the laparotomic placement were: 1) synchronous metastases not suitable [technically unresectable or large (>40% of liver parenchyma) or multiple (> 3) metastases] for hepatic resection during colorectal surgery; 2) metachronous metastases treated by radical hepatic resection and subsequent adjuvant IAHC. Indications for percutaneous placement were: 1) metachronous metastases not suitable [see above] for hepatic resection; 2) metachronous metastases suitable for hepatic resection after neoadjuvant IAHC for tumor downstaging. All patients received IAHC based on continuous infusion of FUdR (dose escalation 0.15–0.30 mg/kg/day for 14 days every 28 days) plus dexamethasone 28 mg. For the purpose of the study, the LPT group and the PCT group were comparatively analyzed in terms of age, gender, primary diagnosis, vascular anatomy of HA, ligation/embolization of aberrant HA, previous intestinal or hepatic surgery, contextual systemic chemotherapy, concomitant diseases. Safety and efficacy of surgical and percutaneous transaxillary approaches were then comparatively analyzed in terms of number of IAHC cycles administered, device-related complications causing temporary or definitive suppression of IAHC, biological costs of the procedures (procedure-related complications, postoperative pain and hospitalization). LPT cases without concomitant surgical procedure other than catheter placement (Cath-LPT group - 10 cases) were also compared with the PCT group for the same end points of the study. Results LPT group and PCT group were comparable (p=n.s.) when evaluated for all the above listed variables. As for the end points of the study, mean postoperative hospitalization was 8.2±2.2 days in the LPT group and 1.8±0.7 days in the PCT group (p<0.0001), while mean analgesic requirements were 9.7±3.2 doses in the LPT group and 2±0.9 doses in the PCT group (p<0.0001). Mean number of IAHC cycles administered was 6.5±4.2 in the LPT group and 4.3±3.4 in the PCT group (p=0.038). Device-related complications causing temporary or definitive suppression of IAHC included catheter displacement in 10 cases (35.7%), HA thrombosis in 1 case (3.5%) and catheter occlusion in 1 case (3.5%) in the PCT group, while in the LPT group 1 case (3.5%) of catheter occlusion and 1 case (3.5%) of HA thrombosis occurred. The overall incidence of device-related complications causing temporary or definitive suppression of IAHC was 42.7% in the PCT group and 7.1% in the LPT group (p=0.005). Comparison of Cath-LPT group and the PCT group showed mean postoperative hospitalization of 5.5±0.7 days in the Cath-LPT group and 1.8±0.7 days in the PCT group (p<0.0001), and mean analgesic requirements of 8±3.1 doses in the Cath-LPT group and 2±0.9 in the PCT group (p<0.0001). Conclusions Surgically implanted indwelling catheters for IAHC present lower incidence of device-related complications than percutaneous transaxillary implanted catheters. In spite of its irreversibility and significant biological costs, surgical implant is still advised when laparotomy has to be performed for other contextual procedures, such as colorectal or hepatic resection, while percutaneous transaxillary catheter placement is indicated for palliative or neoadjuvant IAHC.
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Affiliation(s)
- M Arru
- Department of Surgery, Scientific Institute San Raffaele Hospital, Milan - Italy
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Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections. Eur J Clin Microbiol Infect Dis 2017; 37:141-148. [DOI: 10.1007/s10096-017-3114-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/27/2017] [Indexed: 12/22/2022]
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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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Kallini JR, Gabr A, Abouchaleh N, Ali R, Riaz A, Lewandowski RJ, Salem R. New Developments in Interventional Oncology: Liver Metastases From Colorectal Cancer. Cancer J 2017; 22:373-380. [PMID: 27870679 DOI: 10.1097/ppo.0000000000000226] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Colorectal cancer is the third leading cause of cancer death in the United States. Although hepatic excision is the first-line treatment for colorectal liver metastasis (CRLM), few patients are candidates. Locoregional therapy (LRT) encompasses minimally invasive techniques practiced by interventional radiology. These include ablative treatments (radiofrequency ablation, microwave ablation, and cryosurgical ablation) and transcatheter intra-arterial therapy (hepatic arterial infusion chemotherapy, transarterial "bland" embolization, transarterial chemoembolization, and radioembolization with yttrium 90). The National Comprehensive Cancer Network recommends LRT for unresectable CRLM refractory to chemotherapy. The following is a review of LRT in CRLM, including salient features, advantages, limitations, current roles, and future considerations.
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Affiliation(s)
- Joseph R Kallini
- From the *Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center; †Department of Surgery, Division of Transplantation, Comprehensive Transplant Center; and ‡Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
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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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Wu ZB, Si ZM, Qian S, Liu LX, Qu XD, Zhou B, Zhang W, Wang GZ, Liu R, Wang JH. Percutaneous microwave ablation combined with synchronous transcatheter arterial chemoembolization for the treatment of colorectal liver metastases: results from a follow-up cohort. Onco Targets Ther 2016; 9:3783-9. [PMID: 27382314 PMCID: PMC4922761 DOI: 10.2147/ott.s105192] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The purpose of this study was to retrospectively evaluate the therapeutic efficacy and safety of ultrasound-guided percutaneous microwave ablation (MWA) combined with synchronous transcatheter arterial chemoembolization (TACE) in patients with colorectal liver metastases (CRLM). PATIENTS AND METHODS A retrospective analysis was performed in 30 patients who were treated with ultrasound-guided percutaneous MWA combined with synchronous TACE for colorectal cancer liver metastases from November 2011 to December 2014 in Zhongshan Hospital, Fudan University. The response of the tumor to treatment was evaluated by follow-up computed tomography and/or magnetic resonance imaging. Local tumor control, procedure-related complications, and long-term survival data were analyzed. RESULTS A total of 30 patients with 43 tumors ranging in size from 1.4 cm to 10.0 cm were analyzed. The patients' mean age was 61.6±10.3 years (range, 44.0-78.0 years). The median follow-up time was 26.5±10.4 months (range, 13.3-50.6 months). The complete ablation rate was 81.4% (35/43 lesions) for CRLM. Complete response was achieved in eight cases (26.7%), and partial response was achieved in 17 cases (56.7%) 1 month after the procedure. The objective response rate (complete response + partial response) was 83.4%. Progression-free survival and overall survival were 5.0 months and 11.0 months, respectively. The 12-month and 24-month survival rates were 46.7% and 25.4%, respectively. A total of 22 patients succumbed during follow-up due to tumor progression. No major complications or perioperative mortalities were recorded. CONCLUSION Ultrasound-guided percutaneous MWA combined with synchronous TACE therapy is a safe and effective modality for patients with CRLM.
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Affiliation(s)
- Zeng-Bao Wu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zeng-Mei Si
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Sheng Qian
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ling-Xiao Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xu-Dong Qu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Bo Zhou
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wei Zhang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Guang-Zhi Wang
- Department of Intervention Radiology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jian-Hua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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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; 27:118-26. [PMID: 26566233 DOI: 10.1097/cad.0000000000000290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [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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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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Comito T, Clerici E, Tozzi A, D’Agostino G. Liver metastases and SBRT: A new paradigm? Rep Pract Oncol Radiother 2015; 20:464-71. [PMID: 26696787 PMCID: PMC4661346 DOI: 10.1016/j.rpor.2014.10.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 09/03/2014] [Accepted: 10/10/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The outstanding innovations made by early diagnosis, novel surgical techniques, effective chemotherapy regimens and conformal radiotherapy, have significantly improved patients overall survival and quality of life. Multidisciplinary approach to cancer has also led to an increased prevalence of patients with few, organ-confined metastases, who can experience long-term survival even if their disease is no longer localized. Liver is one of the most common site for metastatic disease from several cancers, and when metastatic disease is confined to liver, given the ability of this organ to regenerate almost to its optimal volume, surgical resection represents the standard of care because is associated with a better prognosis. Approximately 70-90% of liver metastases, however, are unresectable and a safe, effective alternative therapeutic option is necessary for these patients. MATERIALS AND METHODS A review of the current literature was performed to analyze the role of SBRT in treating liver metastases from different cancers. A literature search using the terms "SBRT" and "liver metastases" was carried out in PUBMED. RESULTS Stereotactic body radiation therapy has shown to provide promising results in the treatment of liver metastases, thanks to the ability of this procedure to deliver a conformal high dose of radiation to the target lesion and a minimal dose to surrounding critical tissues. CONCLUSION Stereotactic body radiation therapy is a non-invasive, well-tolerated and effective treatment for patients with liver metastases not suitable for surgical resection.
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Affiliation(s)
- Tiziana Comito
- Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, Rozzano, Milano, Italy
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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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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: 50] [Impact Index Per Article: 5.0] [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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30
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Abstract
The benefits of applying comparative effectiveness research (CER) strategies to the management of cancer are important. As the incidence of cancer increases both in the United States and worldwide, accurate analysis of which tests and treatments should be applied in which situations is critical, both in terms of measurable and meaningful clinical outcomes and health care costs. In the last 20 years alone, multiple controversies have arisen in the diagnosis and treatment of primary and metastatic tumors of the liver, making the management of liver malignancies a prime example of CER. Contributing factors to the development of these controversies include improvements in molecular characterization of these diseases and technological advances in surgery and radiology. The relative speed of these advances has outpaced data from clinical trials, in turn making robust data to inform clinical practice lacking. Indeed, many of the current treatment recommendations for the management of liver malignancies are based primarily on retrospective data. We herein review select CER issues concerning select decision-making topics in the management of liver malignancies.
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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: 145] [Impact Index Per Article: 14.5] [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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Page AJ, Cosgrove DC, Herman JM, Pawlik TM. Advances in understanding of colorectal liver metastasis and implications for the clinic. Expert Rev Gastroenterol Hepatol 2015; 9:245-59. [PMID: 25033964 DOI: 10.1586/17474124.2014.940897] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Colorectal cancer is one of the most common cancers in both the USA and Europe. Over the course of diagnosis, treatment and surveillance, up to 50% of these patients will develop metastases to their liver. In the past 20 years alone, there have been multiple advances in the management of these colorectal metastases to the liver. These advances have been made in characterization of these tumors, diagnosis and in treatment, both locally and systemically. Because of this progress, there are subsets of patients with this stage IV disease who are cured of their disease. While significant progress has been made, there still exist limitations in the management of metastatic colorectal cancer to the liver. This review outlines current strategies and highlights recent advances in the management of colorectal liver metastases.
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Affiliation(s)
- Andrew J Page
- Department of Surgery, Johns Hopkins Hospital, Blalock 688, 600 N. Wolfe Street, Baltimore, MD 21287, USA
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33
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Terashima T, Yamashita T, Arai K, Sunagozaka H, Kitahara M, Nakagawa H, Kagaya T, Mizukoshi E, Honda M, Kaneko S. Feasibility and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma after sorafenib. Hepatol Res 2014; 44:1179-85. [PMID: 24171787 DOI: 10.1111/hepr.12266] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 10/22/2013] [Accepted: 10/23/2013] [Indexed: 12/13/2022]
Abstract
AIM Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no proven therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy. METHODS We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m(2) per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5-fluorouracil (330 mg/m(2) per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon α-2b (1 μg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest. RESULTS The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatment-related deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively. CONCLUSIONS Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib.
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Affiliation(s)
- Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
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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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35
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Budker VG, Monahan SD, Subbotin VM. Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) of therapeutic agents as the future direction. Drug Discov Today 2014; 19:1855-70. [PMID: 25173702 DOI: 10.1016/j.drudis.2014.08.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 07/10/2014] [Accepted: 08/21/2014] [Indexed: 01/01/2023]
Abstract
Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities. One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity. Although loco-regional delivery has been most prominent in cancers of the liver, soft tissues and serosal peritoneal malignancies, survival benefits are very far from desirable. This review discusses the evolution of loco-regional treatments, the present approaches and offers rapidly reversible hydrophobization of drugs as the new future direction.
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Perez DR, Kemeny NE, Brown KT, Gewirtz AN, Paty PB, Jarnagin WR, D'Angelica MI. Angiographic identification of extrahepatic perfusion after hepatic arterial pump placement: implications for surgical prevention. HPB (Oxford) 2014; 16:744-8. [PMID: 24345007 PMCID: PMC4113257 DOI: 10.1111/hpb.12208] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 11/06/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic arterial infusion (HAI) chemotherapy is an effective treatment for patients with liver malignancy. Extrahepatic perfusion (EHP) after HAI pump placement requires correction prior to starting chemotherapy. The aim of this study was to define the origin of arterial branches causing EHP in order to determine if alterations in surgical technique during pump placement might prevent EHP. METHODS A prospectively maintained, single-centre HAI database was reviewed for all patients (2008-2011) with EHP. The origin of arterial branches causing EHP was classified anatomically and patient outcomes were analysed. RESULTS Of the 327 patients with pumps implanted, 24 evidenced EHP. The arterial branch responsible for EHP perfused the duodenum, pancreas and/or stomach. The branch responsible for EHP arose from the proper hepatic artery (PHA), 1(st) , 2(nd) , or 3(rd) order hepatic artery branches in 7, 10, 5 and 2 patients, respectively. The majority of branches beyond the PHA causing EHP (13/17) originated from the right hepatic artery. In 18 patients, aberrant branches were successfully treated with embolization. CONCLUSION These findings provide the anatomic basis for prevention of up to one-third of the cases of EHP intra-operatively, decreasing the number of patients who will require additional procedures for correction of EHP post-operatively.
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Affiliation(s)
- Daniel R Perez
- Department of Surgery, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
| | - Nancy E Kemeny
- Department of Medical Oncology, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
| | - Karen T Brown
- Department of Interventional Radiology, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
| | - Alexandra N Gewirtz
- Department of Medical Oncology, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
| | - Philip B Paty
- Department of Surgery, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan-Kettering Cancer CenterNew York, NY, USA
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Inoue Y, Kusunoki M. Advances and directions in chemotherapy using implantable port systems for colorectal cancer: a historical review. Surg Today 2014; 44:1406-14. [PMID: 23893159 PMCID: PMC4097209 DOI: 10.1007/s00595-013-0672-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 07/03/2013] [Indexed: 01/08/2023]
Abstract
With the recent advances in chemotherapy for colorectal cancer, the prognosis for patients with metastatic colorectal cancer has been significantly improved. The development of the implantable port system has also enabled patients to receive multiagent chemotherapy with a more satisfactory quality of life. Historically, chemotherapy using implantable port systems was begun to obtain an oncological benefit in the treatment of locoregional cancer. In the 1950s, there was an increasing interest in perfusion techniques for the application of chemotherapeutic agents, such as nitrogen mustard, in the locoregional treatment of metastatic cancer. Among them, the treatment of liver metastasis has interested oncologists for many years. On the other hand, implantable devices were developed during the intervening decades that have enabled patients with colorectal cancer with liver metastases to be treated effectively using hepatic arterial infusion; which became more common in the 1980s. The treatment of metastatic colorectal cancer increasingly requires a multimodal approach and multiple treatment options based not on convenience, but in terms of personalization and efficacy. Therefore, it is important to optimize the pharmacokinetics of chemotherapeutic agents. Implantable port systems for colorectal cancer patients have been essential for oncological practice, and the importance of these systems will remain unchanged in the near future.
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Affiliation(s)
- Yasuhiro Inoue
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan,
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Scorsetti M, Clerici E, Comito T. Stereotactic body radiation therapy for liver metastases. J Gastrointest Oncol 2014; 5:190-7. [PMID: 24982767 DOI: 10.3978/j.issn.2078-6891.2014.039] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/19/2014] [Indexed: 12/18/2022] Open
Abstract
Over the years, early diagnosis of metastatic disease has improved and the prevalence of oligometastatic patients is increasing. Liver is a most common site of progression from gastrointestinal, lung and breast cancer and in the setting of oligometastatic patients, surgical resection is associated with increased survival. Approximately 70-90% of liver metastases, however, are unresectable and an effective and safe alternative therapeutic option is necessary for these patients. The role of stereotactic body radiation therapy (SBRT) was investigated in the treatment of oligometastatic patients with promising results, thanks to the ability of this procedure to deliver a conformal high dose of radiation to the target lesion and a minimal dose to surrounding critical tissues. This paper was performed to review the current literature and to provide the practice guidelines on the use of stereotactic body radiotherapy in the treatment of liver metastases. We performed a literature search using Medical Subject Heading terms "SBRT" and "liver metastases", considering a period of ten years.
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Affiliation(s)
- Marta Scorsetti
- Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, Rozzano (Mi), Italy
| | - Elena Clerici
- Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, Rozzano (Mi), Italy
| | - Tiziana Comito
- Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center, Rozzano (Mi), Italy
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Grigorian A, O'Brien CB. Hepatotoxicity Secondary to Chemotherapy. J Clin Transl Hepatol 2014; 2:95-102. [PMID: 26357620 PMCID: PMC4521265 DOI: 10.14218/jcth.2014.00011] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 05/06/2014] [Accepted: 05/22/2014] [Indexed: 12/20/2022] Open
Abstract
The difficult problem faced by multiple generation of practicing physicians is determining the cause of abnormal liver function tests in cancer patients on chemotherapy. Hepatotoxicity from chemotherapy occurs frequently from an unpredictable or idiosyncratic reaction. Despite remarkable advances in our understanding of the mechanisms of action, pharmacodynamics, and interrelationships between the liver and chemotherapy, the underlying etiology of hepatic toxicity for various agents remains unexplained. Here, we present a concise review of the broad differential diagnosis for abnormal liver function tests (LFTs) in oncology patients.
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Affiliation(s)
- Alla Grigorian
- Divisions of Liver and GI Transplantation, University of Miami School of Medicine, Miami, FL, USA
| | - Christopher B O'Brien
- Divisions of Liver and GI Transplantation, University of Miami School of Medicine, Miami, FL, USA
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Liu W, Yan XL, Wang K, Bao Q, Sun Y, Xing BC. The outcome of liver resection and lymphadenectomy for hilar lymph node involvement in colorectal cancer liver metastases. Int J Colorectal Dis 2014; 29:737-45. [PMID: 24743847 DOI: 10.1007/s00384-014-1863-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/02/2014] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Hepatic hilar lymph node (HLN) involvement is considered as a poor prognostic factor during liver resection in colorectal liver metastases (CLM). The purpose of this study is to identify the clinical factors that distinguish HLN-positive patients from those who are hilar lymph node negative and to evaluate the frequency of macroscopic involvement of hepatic HLN, to investigate the impact of HLN involvement on survival after resection for CLM with lymphadenectomy and adjuvant chemotherapy. PATIENTS AND METHODS Between January 2000 and August 2012, 73 selected CLM patients underwent liver resections with lymphadenectomy in the Hepatopancreatobiliary Surgery Department I of Beijing Cancer Hospital. Clinical data, surgical outcome, and prognosis after operation of patients with HLN involvement were compared with that of patients without HLN involvement. RESULTS Of the 73 patients who underwent liver resections with lymphadenectomy, 12 (16.4 %) patients had HLN involvement identified by pathology. Compared with patients without HLN involvement, the frequency of lymph nodes metastasis for primary tumor was significantly higher in HLN-positive patients (p = 0.023). For CLM patients with and without HLN involvement, 5-year overall survival (OS) was 16.2 and 37.1 %, respectively (p = 0.04). Five-year disease-free survival (DFS) rates were 0 and 32.9 % (p = 0.034). Multivariate analysis showed that involved resected HLN was an independent risk factor for overall survival. CONCLUSION We should suspect HLN involvement in patients with colorectal cancer liver metastases when they have regional lymph nodes of primary tumor metastasis. Liver resection with HLN dissection might offer a unique curative opportunity for CLM patients with HLN involvement.
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Affiliation(s)
- Wei Liu
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, No. 52, Fu-Cheng-Lu Street, Beijing, 100142, People's Republic of China
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Magge D, Choudry HA, Zeh HJ, Cunningham DE, Steel J, Holtzman MP, Jones HL, Pingpank JF, Bartlett DL, Zureikat AH. Outcome analysis of a decade-long experience of isolated hepatic perfusion for unresectable liver metastases at a single institution. Ann Surg 2014; 259:953-9. [PMID: 24169176 DOI: 10.1097/sla.0000000000000261] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To evaluate outcomes of isolated hepatic perfusion (IHP) on isolated liver metastases (LMs). BACKGROUND Isolated unresectable LMs are often the main determinant of overall survival (OS) for colorectal cancer (CRC) and other solid malignancies. We hypothesized that IHP can be performed safely and yield impressive responses for a variety of solid tumor pathology, using different perfusion agents. METHODS Retrospective review of a prospectively collected database of patients undergoing IHP for unresectable solid tumor LM. RESULTS Between 2003 and 2012, IHP was completed in 91 patients. Primary tumor pathology was CRC = 54, non-CRC = 37 (ocular/cutaneous melanoma = 32, cholangiocarcinoma = 3, appendiceal = 1, and breast = 1). IHP employed Melphalan (n = 69) (CRC = 32, non-CRC = 37), Oxaliplatin (n = 10) (CRC), or Oxaliplatin + 5FU (n = 12) (CRC). Hepatic arterial infusion (HAI) pumps were placed in all CRC patients. There were 3(3.3%) perioperative deaths. Response rates for CRC, melanoma, and cholangiocarcinoma were 68.2%, 57.1%, and 100% respectively. Response rates for CRC patients using 5FU + Oxaliplatin, Oxaliplatin, or Melphalan were 83.3%, 66.7%, and 60.9%, respectively. Median OS for the CRC patients (from IHP date) was 23 months (95% confidence interval: 15-28 months). On univariate analysis, receipt of HAI-FUDR (floxuridine) within 1 year of IHP was the only factor associated with improved OS (P = 0.043) in CRC patients. CONCLUSIONS IHP results in excellent response rates for patients with unresectable liver metastasis from solid tumors. Improved local control for CRC patients undergoing IHP-HAI may improve survival.
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Affiliation(s)
- Deepa Magge
- *Division of Surgical Oncology, Koch Regional Perfusion Center and †Department of Psychiatry, University of Pittsburgh Medical Center ‡Biostatistics Facility, University of Pittsburgh Cancer Institute, PA
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Xing M, Kooby DA, El-Rayes BF, Kokabi N, Camacho JC, Kim HS. Locoregional therapies for metastatic colorectal carcinoma to the liver--an evidence-based review. J Surg Oncol 2014; 110:182-96. [PMID: 24760444 DOI: 10.1002/jso.23619] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 03/18/2014] [Indexed: 12/17/2022]
Abstract
The liver is the most common visceral site of colorectal cancer metastasis and recurrence. Given that only 25% of patients with colorectal liver metastases are amenable to curative surgical resection at initial diagnosis, locoregional intra-arterial therapies including hepatic arterial infusion chemotherapy, conventional transarterial chemoembolization, drug-eluting-bead transarterial chemoembolization, and radioembolization have increasingly developed as viable treatment options. The rationale, efficacy, safety, and toxicity of each of these therapies are reviewed and stratified based on current evidence.
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Affiliation(s)
- Minzhi Xing
- Division of Interventional Radiology, Department of Radiology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia
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Allard MA, Malka D. Place of hepatic intra-arterial chemotherapy in the treatment of colorectal liver metastases. J Visc Surg 2014; 151 Suppl 1:S21-4. [PMID: 24636278 DOI: 10.1016/j.jviscsurg.2013.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The rationale for hepatic intra-arterial chemotherapy (HACT) is based on the predominantly arterial vascularization of liver metastases (HM). The intra-arterial route of administration thus increases the exposure of tumor cells to cytotoxic agents while limiting systemic toxicity. Chemotherapy is administered through a catheter placed in the gastroduodenal artery by either a surgical or percutaneous approach. Several anticancer agents can be administered to hepatic metastases from colorectal cancer (HMCRC) by HACT. Fluorodeoxyuridine (FUDR), used mainly in the United States, has a high intrahepatic extraction rate but also has intrinsic hepatobiliary toxicity. The HACT route is less suitable for irinotecan, since its active metabolite requires first-pass metabolism. In France, oxaliplatin is the most commonly used agent administered by HACT in combination with intravenous chemotherapy according to a 5-FU-Leucovorin protocol. The three main indications for HACT are: (1) potentially resectable HMCRC, (2) adjuvant treatment after resection of HMCRC in patients at high risk of intrahepatic recurrence, (3) palliative treatment of patients with primarily intra-hepatic disease that is definitely unresectable. In the setting of potentially resectable HMCRC, HACT can increase the chemotherapeutic response rate and improve the rate of secondary resectability. In the adjuvant setting, HACT seems to improve disease-free survival after complete resection of HMCRC in patients at high risk of intrahepatic recurrence. Finally, in the palliative setting, HACT prolongs progression-free survival, even in patients whose disease has progressed with intravenously administered oxaliplatin.
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Affiliation(s)
- M-A Allard
- Department of general surgery, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France
| | - D Malka
- Unité de gastro-entérologie, department of medical oncology, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France.
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Intravital microscopic research of microembolization with degradable starch microspheres. JOURNAL OF DRUG DELIVERY 2013; 2013:242060. [PMID: 24324891 PMCID: PMC3845399 DOI: 10.1155/2013/242060] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 09/10/2013] [Accepted: 10/02/2013] [Indexed: 11/18/2022]
Abstract
Treatment efficacy in cancer patients using systemically applied cytostatic drugs is decreased by cytotoxic side effects, which limits the use of efficient dosages. Degradable starch microspheres (DSM) are used to apply drugs into blood vessels which supply the target organ leading to drug accumulation in the target organ by reduction of the blood flow. The present investigations show that DSM is a very effective embolization material leading to effective and enhanced accumulation of 5-FU within the liver tumor tissue of experimental induced liver cancer in rats. By using intravital microscopy, a rapid deceleration of the blood flow into the target organ is observed immediately after application of DSM. The microspheres are stepwise degraded in the direction of the systemic blood flow and are totally dissolved after 25 minutes. These stepwise processes leave the degraded material during the degradation process within the vessels leading to temporally reciprocal blood flow via some of the side-arms of the major blood vessels. By using DMS in transarterial chemoembolization (TACE), severe adverse side effects like postembolization syndrome are rarely observed when compared to other embolization materials. The complete degradation of DSM causes only a short-lasting temporary vascular occlusion, which allows a repeat application of DSM in TACE.
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Abstract
Most hepatotoxicity secondary to chemotherapy is idiosyncratic and, therefore, neither dose dependent nor predictable. Some chemotherapy is cleared by the liver and requires dose adjustment in the face of significant liver dysfunction. In addition, preexisting abnormal liver function has been shown to increase the risk of hepatotoxicity. In addition to typical hepatocellular injury, other presentations, including cholestasis and hepatic sinusoidal obstruction syndrome, also commonly occur. The outcomes can range from asymptomatic liver function test abnormalities, which resolve spontaneously, to cirrhosis, which occurs despite discontinuation of the chemotherapeutic agent.
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Affiliation(s)
- Ameet V Thatishetty
- Department of Medicine, Memorial Health, University Medical Center, 4700 Waters Avenue, Savannah, GA 31403, USA
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Hickey R, Vouche M, Sze D, Hohlastos E, Collins J, Schirmang T, Memon K, Ryu RK, Sato K, Chen R, Gupta R, Resnick S, Carr J, Chrisman H, Nemcek A, Vogelzang R, Lewandowski RJ, Salem R. Cancer concepts and principles: primer for the interventional oncologist-part II. J Vasc Interv Radiol 2013; 24:1167-88. [PMID: 23810312 PMCID: PMC3800031 DOI: 10.1016/j.jvir.2013.04.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 04/20/2013] [Accepted: 04/20/2013] [Indexed: 02/07/2023] Open
Abstract
This is the second of a two-part overview of the fundamentals of oncology for interventional radiologists. The first part focused on clinical trials, basic statistics, assessment of response, and overall concepts in oncology. This second part aims to review the methods of tumor characterization; principles of the oncology specialties, including medical, surgical, radiation, and interventional oncology; and current treatment paradigms for the most common cancers encountered in interventional oncology, along with the levels of evidence that guide these treatments.
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Affiliation(s)
- Ryan Hickey
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Michael Vouche
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Daniel Sze
- Department of Radiology, Stanford University, Palo Alto, CA
| | - Elias Hohlastos
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Jeremy Collins
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Todd Schirmang
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Khairuddin Memon
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Robert K Ryu
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Kent Sato
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Richard Chen
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Ramona Gupta
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Scott Resnick
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - James Carr
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Howard Chrisman
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Al Nemcek
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Robert Vogelzang
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Robert J Lewandowski
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
| | - Riad Salem
- Department of Radiology, Division of Interventional Oncology, Northwestern University, Chicago IL
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Ammori JB, Kemeny NE, Fong Y, Cercek A, Dematteo RP, Allen PJ, Kingham TP, Gonen M, Paty PB, Jarnagin WR, D'Angelica MI. Conversion to complete resection and/or ablation using hepatic artery infusional chemotherapy in patients with unresectable liver metastases from colorectal cancer: a decade of experience at a single institution. Ann Surg Oncol 2013; 20:2901-7. [PMID: 23771246 DOI: 10.1245/s10434-013-3009-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND When feasible, surgical treatment of colorectal liver metastases (CRLM) is the treatment of choice. Regional hepatic artery infusional (HAI) chemotherapy effectively treats CRLM. The combination of HAI and systemic chemotherapy may downsize tumors and allow for complete resection and/or ablation (R/A). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on conversion to complete R/A. METHODS All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert. Survival was compared using a landmark analysis to account for bias. RESULTS A total of 373 patients were included; 93 patients (25%) subsequently underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16% during 2000-2003 to 30% during 2004-2009. Factors associated with conversion on multivariate analysis were more recent treatment (2004-2009), no prior chemotherapy, clinical risk score<3, treatment on clinical protocol, and younger age. Median and predicted 5-year survival from the time of HAI pump placement was 59 months and 47%, respectively, in the patients who converted to complete R/A, compared with 16 months and 6%, respectively in those who did not (p<0.001). CONCLUSIONS Despite extensive disease, 25% of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Combination HAI and systemic chemotherapy is an effective strategy to convert patients to complete resection with an associated excellent long-term survival.
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Affiliation(s)
- John B Ammori
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Adjuvant chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence: a comparative study between hepatic arterial infusion of oxaliplatin and modern systemic chemotherapy. Ann Surg 2013; 257:114-20. [PMID: 23235397 DOI: 10.1097/sla.0b013e31827b9005] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION After curatively intended surgery for colorectal liver metastases, liver recurrences occur in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The aim of this study was to assess the benefit of combined adjuvant hepatic arterial infusion (HAI) and intravenous (IV) 5-FU compared with standard modern adjuvant IV chemotherapy in patients at high risk of hepatic recurrence. PATIENTS AND METHODS From January 2000 to December 2009, 98 patients, who had undergone curative resection of at least 4 colorectal liver metastases, were selected from a prospective database. Among them, 44 (45%) had received postoperative HAI combined with systemic 5-FU (HAI group) and 54 (55%) had received "modern" systemic chemotherapy (IV group). RESULTS The 2 groups were similar in terms of age, sex, the stage of the primary, and the administration of preoperative chemotherapy. The median number of HAI cycles received per patient was 7 [range, 1-12]. Twenty-nine patients (66%) had received at least 6 cycles of HAI oxaliplatin, and 22 patients (50%) had received the full planned treatment. For the remaining 22 patients (50%), HAI chemotherapy had been discontinued because of toxicity (n = 8), HAI catheter dysfunction (n = 6), an early recurrence (n = 6), and patient's refusal (n = 2). After a median follow-up of 60 months (51-81 months), 3-year overall survival was slightly higher in the HAI group (75% vs 62%, P = 0.17). Three-year disease-free survival was significantly longer in patients in the HAI group than those in the IV group (33% vs 5%, P < 0.0001). In the multivariate analysis, adjuvant HAI chemotherapy and an R0 resection margin status were the only independent predictive factors for prolonged disease-free survival. CONCLUSIONS Postoperative HAI oxaliplatin combined with systemic chemotherapy after curatively intended surgery of colorectal liver metastases is feasible and may significantly improve disease-free survival of patients at high risk of hepatic recurrence compared with adjuvant modern systemic chemotherapy alone. These results should be confirmed in a randomized study.
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Magge D, Zureikat AH, Bartlett DL, Holtzman MP, Choudry HA, Beumer JH, Pingpank JF, Holleran JL, Strychor S, Cunningham DE, Jones HL, Zeh HJ. A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer. Ann Surg Oncol 2013; 20:2180-7. [PMID: 23575907 DOI: 10.1245/s10434-013-2960-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.
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Affiliation(s)
- D Magge
- University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
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Tsimberidou AM, Leick MB, Lim J, Fu S, Wheler J, Piha-Paul SA, Hong D, Falchook GS, Naing A, Subbiah IM, Fortier A, Avritscher R, Kurzrock R. Dose-finding study of hepatic arterial infusion of oxaliplatin-based treatment in patients with advanced solid tumors metastatic to the liver. Cancer Chemother Pharmacol 2013; 71:389-97. [PMID: 23143207 DOI: 10.1007/s00280-012-2014-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 10/16/2012] [Indexed: 02/03/2023]
Abstract
BACKGROUND Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients. PATIENTS AND METHODS Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab. Patients were divided into two treatment arms according to KRAS mutational status and physician choice. A "3 + 3" design was used. RESULTS Among 76 patients (median age 61 years; 34 women; median number of prior therapies 4), the most common cancer was colorectal (CRC) (n = 58). Overall, the only dose-limiting toxicity was Grade 3 diarrhea (n = 2). The most common treatment-related toxicities were hypertension (n = 40), nausea (n = 29), fatigue (n = 28), and transaminitis (n = 26). Of 76 patients, one (1 %) had a complete response (CR), 12 (16 %) had a partial response (PR), and 12 (16 %) had SD for ≥ 6 months (total CR/PR/SD ≥ 6 months 25/76 = 33 %). In CRC (n = 58), total CR/PR/SD ≥ 6 months was 31 % (n = 18). Both patients with pancreatic neuroendocrine tumors achieved a PR (24+ months) and a CR (6+ months). Time to treatment failure (TTF) on the current regimen was 3.5 versus 2.8 months on patients' prior systemic treatment (p = 0.37). CONCLUSIONS HAI oxaliplatin combination therapy with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab was well tolerated and had antitumor activity in selected heavily pretreated patients with predominant liver disease.
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Affiliation(s)
- Apostolia M Tsimberidou
- Phase I Program, Department of Investigational Cancer Therapeutics, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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