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Abstract
Colorectal cancer (CRC) is one of the most common cancers in the world. About two third of patients with CRC will develop distant recurrence at some point in time. Liver is the most common site where distant metastasis takes place. While the overall survival (OS) of patients with metastatic CRC was poor about 3 decades ago, there has been tremendous improvement in this area in the recent years. With the advent of effective systemic chemotherapy and biologic agents and better understanding of the biological behaviour of the tumour, aggressive treatment strategies such as metastatectomy of the liver metastases (or lung metastases) are now acceptable. More importantly, it has transformed the way how stage IV CRCs are being managed. From predominantly palliative as the primary aim, a comprehensive multidisciplinary approach is now the mainstay of treatment with very successful outcomes. Combination of systemic therapies with liver resection has been shown to be effective in providing promising survival benefits. In addition, other adjunctive modalities in targeting the liver metastases such as ablation, combining resection and ablation, transarterial chemoembolization, stereotactic body radiotherapy (SBRT), hepatic artery perfusion, etc. have also been demonstrated variable outcome in treating colorectal liver metastasis (CRLM). Very recently, transplant oncologists have also explored using liver transplantation as a treatment modality for unresectable CRLM, which has demonstrated very good long-term survival in well selected cases. The new paradigm in the treatment of metastatic CRC has dawned.
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Affiliation(s)
- Alfred Wei Chieh Kow
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System, Singapore, Singapore.,Department of Surgery, National University of Singapore, Singapore, Singapore
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Chakedis J, Squires MH, Beal EW, Hughes T, Lewis H, Paredes A, Al-Mansour M, Sun S, Cloyd JM, Pawlik TM. Update on current problems in colorectal liver metastasis. Curr Probl Surg 2017; 54:554-602. [PMID: 29198365 DOI: 10.1067/j.cpsurg.2017.10.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Jeffrey Chakedis
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Malcolm H Squires
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Eliza W Beal
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Tasha Hughes
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Heather Lewis
- University of Colorado Health System, Fort Collins, CO
| | - Anghela Paredes
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Mazen Al-Mansour
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Steven Sun
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Jordan M Cloyd
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH
| | - Timothy M Pawlik
- The Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH.
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Meng T, Li GQ, Dai MH. Isolated hepatic perfusion for unresectable hepatic malignancies: A systematic review and meta-analysis. World J Meta-Anal 2016; 4:105-117. [DOI: 10.13105/wjma.v4.i5.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/24/2016] [Accepted: 08/16/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the efficacy and safety of isolated hepatic perfusion (IHP) in the management of unresectable liver malignancies.
METHODS Studies were identified manually and on-line by using PubMed and EMBASE database. We formulate the eligibility criteria according to the PICOS elements, and accessed the quality of studies using the MINORS instrument. Data from all included studies were carefully investigated. We calculated the pooled response rate and incidences of mortality reported from all eligible studies by using the Meta-Analyst software, and we computed a pooled relative risk (RR) and 95%CI by using the Comprehensive Meta-Analysis software. Heterogeneity was quantified evaluated using I2 statistic.
RESULTS Eight studies, including 502 patients, were selected. Of these, six studies performed IHP, while the other two studies performed percutaneous IHP. The results showed that the pooled response rate was 60.8% (95%CI: 53.1%-68%), I2 = 37.1%. The median overall survival was 20 mo (range: 12.1 to 25 mo) following IHP or PIHP. The pooled mortality rate was 5.4% (95%CI: 2.5%-11.2%), I2 = 37.5%. Prognostic factors predict the response to IHP or survival, and were reported in six studies. Meta-analysis demonstrated that Gender was not associated with overall survival (RR = 0.877, 95%CI: 0.564-1.365); however, carcino-embryonic antigen ≤ 30 ng/mL was associated with a significant improvement in survival outcomes with colorectal cancer patients (RR = 2.082, 95%CI: 1.371-3.163), and there was no significant heterogeneity.
CONCLUSION The present systemic review and meta-analysis suggest that IHP and PIHP are potentially efficient and safe techniques for unresectable liver primary and secondary malignancies.
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Abstract
Isolated hepatic perfusion uses the unique vascular supply of hepatic malignancies to deliver cytotoxic chemotherapy. The procedure involves vascular isolation of the liver and delivery of chemotherapy via the hepatic artery and extraction from retrohepatic vena cava. Benefits of hepatic perfusion have been observed in hepatic metastases of ocular melanoma and colorectal cancer and primary hepatocellular carcinoma. Percutaneous and prophylactic perfusions are avenues of ongoing research.
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Affiliation(s)
- Rahul Rajeev
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - T Clark Gamblin
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Kiran K Turaga
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
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Reddy SK, Kesmodel SB, Alexander HR. Isolated hepatic perfusion for patients with liver metastases. Ther Adv Med Oncol 2014; 6:180-94. [PMID: 25057304 DOI: 10.1177/1758834014529175] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Up to 80% of colorectal, melanoma, and neuroendocrine liver metastases are unresectable due to excessive tumor burden. Isolated hepatic perfusion (IHP) administers intensive therapy to the liver while limiting systemic toxicity and thus may have an important role in the management of unresectable liver metastases. This review s describes the development of IHP, initial clinical results, open and percutaneous IHP techniques, and contemporary long-term treatment outcomes. IHP with melphalan or tumor necrosis factor α (TNFα) has been shown to achieve hepatic response rates of greater than 50% with progression-free survival of greater than 12 months among patients with refractory ocular melanoma liver metastases. The only series describing outcomes of IHP for neuroendocrine liver metastases notes an overall response rate of 50% and a median actuarial overall survival of 48 months after IHP treatment with melphalan or TNFα. The majority of studies that have evaluated IHP have been performed in patients with colorectal cancer liver metastases (CRCLM). In aggregate, survival results from retrospective studies and phase I/II clinical trials suggest that IHP demonstrated no significant survival benefit compared with systemic chemotherapy alone as first-line therapy. In contrast, IHP does improve outcomes relative to that provided by second-line chemotherapy for CRCLM, with overall response rates of 60% and median duration of liver response of 12 months. Continued evaluation of IHP for unresectable liver metastases is necessary to establish its role in multidisciplinary treatment approaches.
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Affiliation(s)
- Srinevas K Reddy
- Division of General and Oncologic Surgery, Department of Surgery and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Susan B Kesmodel
- Division of General and Oncologic Surgery, Department of Surgery and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - H Richard Alexander
- Division of Surgical Oncology, Department of Surgery, University of Maryland Medical Center, 22 South Greene Street, Baltimore, MD 21201, USA
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Yuan Z, Pastoriza J, Quinn T, Libutti SK. Targeting Tumor Vasculature Using Adeno-Associated Virus Phage Vectors Coding Tumor Necrosis Factor-α. GENE THERAPY OF CANCER 2014:19-33. [DOI: 10.1016/b978-0-12-394295-1.00002-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity. Cancer Gene Ther 2012; 20:46-56. [PMID: 23154431 PMCID: PMC3534156 DOI: 10.1038/cgt.2012.83] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.
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Boone BA, Bartlett DL, Zureikat AH. Isolated Hepatic Perfusion for the Treatment of Liver Metastases. Curr Probl Cancer 2012; 36:27-76. [DOI: 10.1016/j.currproblcancer.2011.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Ortega-Deballon P, Facy O, Consolo D, Magnin G, Tixier H, Simonet M, Rat P, Chauffert B. Hypoxic single-pass isolated hepatic perfusion of hypotonic Cisplatin: safety study in the pig. Ann Surg Oncol 2009; 17:898-906. [PMID: 19859770 DOI: 10.1245/s10434-009-0775-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Indexed: 11/18/2022]
Abstract
BACKGROUND Isolated hepatic perfusion (IHP) of chemotherapy has been proposed to deliver high doses of drug while avoiding systemic toxicity. Hypotonic cisplatin has a high in vitro activity on human colon cancer cells. We studied the safety of a 30-min hypoxic single-pass IHP with hypotonic cisplatin. METHODS A preliminary in vitro assay was performed to compare the cytotoxicity of cisplatin and oxaliplatin, in either a normotonic or hypotonic medium. Cisplatin in hypotonic medium was then chosen for the in vivo IHP. Eleven pigs underwent 30 min of IHP with 0, 50, 75, or 100 mg/L of cisplatin in a hypotonic solution under total vascular exclusion of the liver. Clinical and biological parameters were recorded for 30 days, and liver histology was performed at necropsy. The cytotoxic activity of the effluent against resistant human colon cancer cells was tested in vitro. RESULTS No hepatic failure was recorded after IHP with cisplatin, but limited foci of necrosis were found at necropsy in animals receiving 75 or 100 mg/L of cisplatin. No clinical, biological, macroscopic, or microscopic toxicity was observed after IHP with 50 mg/L of hypotonic cisplatin. The liver effluent showed high in vitro cytotoxic activity against colon cancer cells. CONCLUSIONS A hypoxic single-pass isolated liver perfusion with hypotonic cisplatin is feasible and safe. Effluent from the liver is highly cytotoxic on cancer cells. A clinical study with 50 mg/L of hypotonic cisplatin is warranted in patients with unresectable liver metastases from colon cancer.
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Jones A, Alexander HR. Development of Isolated Hepatic Perfusion for Patients Who Have Unresectable Hepatic Malignancies. Surg Oncol Clin N Am 2008; 17:857-76, x. [DOI: 10.1016/j.soc.2008.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Nowis D, McConnell EJ, Dierlam L, Palamarchuk A, Lass A, Wójcik C. TNF potentiates anticancer activity of bortezomib (Velcade) through reduced expression of proteasome subunits and dysregulation of unfolded protein response. Int J Cancer 2007; 121:431-41. [PMID: 17373661 DOI: 10.1002/ijc.22695] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Bortezomib (Velcade) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2 alpha and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies.
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Affiliation(s)
- Dominika Nowis
- Department of Anatomy and Cell Biology, Indiana University School of Medicine-Evansville, 8600 University Boulevard, Evansville, IN 47712, USA
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Mocellin S, Pilati P, Da Pian P, Forlin M, Corazzina S, Rossi CR, Innocente F, Ori C, Casara D, Ujka F, Nitti D, Lise M. Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease. Ann Surg Oncol 2006; 14:802-9. [PMID: 17103263 DOI: 10.1245/s10434-006-9108-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2006] [Revised: 05/23/2006] [Accepted: 05/23/2006] [Indexed: 12/16/2022]
Abstract
BACKGROUND In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement <or=50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). RESULTS Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). CONCLUSIONS Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.
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Affiliation(s)
- Simone Mocellin
- Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, via Giustiniani 2, 35128, Padova, Italy
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Kresse M, Latta M, Künstle G, Riehle HM, van Rooijen N, Hentze H, Tiegs G, Biburger M, Lucas R, Wendel A. Kupffer Cell-Expressed Membrane-Bound TNF Mediates Melphalan Hepatotoxicity via Activation of Both TNF Receptors. THE JOURNAL OF IMMUNOLOGY 2005; 175:4076-83. [PMID: 16148157 DOI: 10.4049/jimmunol.175.6.4076] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Isolated hepatic perfusion of nonresectable liver cancer using the combination of TNF and melphalan can be associated with a treatment-related hepatotoxicity. We investigated whether, apart from TNF, also melphalan is cytotoxic in primary murine liver cells in vitro and investigated mediators, mode of cell death, and cell types involved. Melphalan induced a caspase-dependent apoptosis in hepatocytes, which was not seen in liver cell preparations depleted of Kupffer cells. Neutralization of TNF prevented melphalan-induced apoptosis and liver cells derived from mice genetically deficient in either TNFR 1 or 2, but not from lpr mice lacking a functional CD95 receptor, were completely resistant. Cell-cell contact between hepatocytes and Kupffer cells was required for apoptosis to occur. Melphalan increased membrane-bound but not secreted TNF in Kupffer cells and inhibited recombinant TNF-alpha converting enzyme in vitro. Melphalan induced also severe hepatotoxicity in the isolated recirculating perfused mouse liver from wild-type mice but not from TNFR 1 or 2 knockout mice. In conclusion, this study shows that melphalan elicits membrane TNF on Kupffer cells due to inhibition of TNF processing and thereby initiates apoptosis of hepatocytes via obligatory activation of both TNFRs. The identification of this novel mechanism allows a causal understanding of melphalan-induced hepatotoxicity.
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Affiliation(s)
- Matthias Kresse
- Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
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Canter RJ, Kesmodel SB, Heitjan DF, Veeramachaneni NK, Mokadam NA, Drebin JA, Fraker DL. Suppression of beta-catenin by antisense oligomers augments tumor response to isolated limb perfusion in a rodent model of adenomatous polyposis coli-mutant colon cancer. Ann Surg Oncol 2005; 12:733-42. [PMID: 16132380 DOI: 10.1245/aso.2005.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2004] [Accepted: 05/08/2005] [Indexed: 02/06/2023]
Abstract
BACKGROUND Isolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of beta-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC. METHODS Adenomatous polyposis coli-mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for beta-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus beta-catenin-specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated. RESULTS The maximal decrease (mean +/- SE) in tumor volume was 0% +/- 10% for no treatment, 19% +/- 14% for control ILP, 58% +/- 3% for melphalan ILP, 58% +/- 9% for beta-catenin-specific ILP, 13% +/- 19% for nonspecific antisense ILP, and 73% +/- 6% for melphalan plus beta-catenin-specific ILP (P < .05 for melphalan ILP, beta-catenin-specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after beta-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus beta-catenin-specific ILP (P < .05 for melphalan plus beta-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of beta-catenin expression after beta-catenin-specific ILP. CONCLUSIONS Short-term beta-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC.
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Affiliation(s)
- Robert J Canter
- Department of Surgery, University of Pennsylvania School of Medicine, 3400 Spruce Street, 4 Silverstein, Philadelphia, Pennsylvania, 19104, USA
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Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist 2005; 10:112-22. [PMID: 15709213 DOI: 10.1634/theoncologist.10-2-112] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
A new strategy currently under evaluation in patients with peritoneal carcinomatosis from gastrointestinal and gynecologic cancers is perioperative intraperitoneal chemotherapy. Although results to date show benefit to carefully selected groups of patients, continued local-regional failure is seen in many treated patients. Continued clinical and laboratory research efforts to improve local-regional effects are desired. The chemotherapeutic agents that have been used in the past or are currently being tested were reviewed. Their pharmacologic properties and clinical features were collected from the medical literature and are reviewed in the text. An organized presentation of available data concerning the drugs available for perioperative intraperitoneal chemotherapy for peritoneal surface malignancy was made. From this review, new possibilities for improved doses, schedules, and drug combinations for perioperative intraperitoneal chemotherapy may become important in future clinical studies. Continued optimal utilization of intraperitoneal chemotherapy treatments in the operating room with hyperthermia or normothermic treatment in the early postoperative period is desirable. Innovative treatment strategies can improve the outcome of patients with peritoneal surface malignancy.
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Affiliation(s)
- Paul H Sugarbaker
- Program in Peritoneal Surface Malignancy, Washington Cancer Institute, 110 Irving St., NW Washington, DC 20010, USA.
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Abstract
Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors, or primary colangio- or hepatocellular carcinomas. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not enjoyed consistent or widespread evaluation. In light of the antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers.
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Affiliation(s)
- Amelia Grover
- Surgical Metabolism Section, National Cancer Institute/NIH, 10 Center Drive, Building 10, Room 2B07, Bethesda, Maryland 20892-1502, USA
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Elaraj DM, Alexander HR. Current Role of Hepatic Artery Infusion and Isolated Liver Perfusion for the Treatment of Colorectal Cancer Liver Metastases. Cancer J 2004; 10:128-38. [PMID: 15130272 DOI: 10.1097/00130404-200403000-00008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
There are many treatment options for patients with metastatic colorectal carcinoma confined to the liver. Surgical resection alone can result in significant prolongation of survival in patients with favorable prognostic factors. Randomized studies of hepatic artery infusion therapy after complete resection of liver metastases have demonstrated improvements in hepatic recurrence-free survival but no impact on overall survival. Randomized trials evaluating the treatment of unresectable disease with hepatic artery infusion therapy have demonstrated higher response rates (31%-50%) than those seen with systemic chemotherapy (8%-20%) but no survival benefit. Vascular isolation and perfusion of the liver with chemotherapy with or without biologic agents under hyperthermic conditions is another regional modality that has been explored for the treatment of unresectable colorectal cancer liver metastases. Large series report high partial response rates (68%-77%), with responses being achieved in patients with advanced tumor burden and in those who have disease progression through prior treatment of hepatic metastases.
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Affiliation(s)
- Dina M Elaraj
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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