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Lee CK, Chon HJ, Kwon WS, Ban HJ, Kim SC, Kim H, Jeung HC, Chung J, Rha SY. The UGT1A9*22 genotype identifies a high-risk group for irinotecan toxicity among gastric cancer patients. Genomics Inform 2022; 20:e29. [PMID: 36239106 PMCID: PMC9576471 DOI: 10.5808/gi.22051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/08/2022] [Indexed: 11/20/2022] Open
Abstract
Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3 and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III–IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of toxicity such as severe diarrhea or neutropenia.
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Affiliation(s)
- Choong-kun Lee
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hong Jae Chon
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Woo Sun Kwon
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hyo-Jeong Ban
- KM Data Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
| | - Sang Cheol Kim
- Division of Healthcare and AI, Center for Precision Medicine, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul 28159, Korea
| | - Hyunwook Kim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hei-Cheul Jeung
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
| | - Jimyung Chung
- Yonsei University Graduate School, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Korea
- Corresponding author E-mail:
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2
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Boland PM, Fountzilas C, Fakih M, Opyrchal M, Diamond JR, Corr B, Ma WW, Redman M, Chan WK, Wang H, Kramer D, Kwan R, Cutler D, Zhi J, Jimeno A. A dose regimen-finding study to evaluate the safety, tolerability, pharmacokinetics, and activity of oratecan in subjects with advanced malignancies. Cancer Chemother Pharmacol 2022; 90:175-187. [PMID: 35904620 DOI: 10.1007/s00280-022-04453-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/21/2022] [Indexed: 01/09/2023]
Abstract
PURPOSE Irinotecan is a commonly used chemotherapeutic in solid tumor malignancies. Oratecan is an investigational product comprised of encequidar methanesulfonate, a novel minimally absorbed P-glycoprotein pump inhibitor, and irinotecan. This study sought to determine the maximum tolerated dose (MTD) of oratecan in patients with advanced malignancies. METHODS Using a "3 + 3″ dose-escalation design, patients were treated with oratecan on day 1 every 21 days. The irinotecan dose was escalated from 20 to 320 mg/m2. The encequidar methanesulfonate dose was fixed at 15 mg (12.9 mg free base). PK sampling for irinotecan, encequidar and its major metabolites was performed following a single dose of oratecan during cycle 1. Patients were treated until disease progression or unacceptable toxicity. RESULTS Thirty-five patients were treated. The MTD was determined to be 280 mg/m2 every 21 days. Irinotecan and SN-38 plasma concentration-time profile showed that irinotecan exposure increased with dose and followed biexponential decay. Nine of 17 patients at oratecan dose levels 200 mg/m2 and above had SN-38 exposures comparable to those with intravenous irinotecan at standard dosing. None of the 35 patients achieved a radiologic response, ten patients had SD for > 8 weeks; the median progression-free survival for all treated patients was 9 weeks (95% CI 8.6-13.9). CONCLUSIONS The MTD of oratecan was encequidar methanesulfonate 15 mg plus irinotecan 280 mg/m2. Exposure for irinotecan and SN-38 increased with increased dose. Potential antitumor activity was observed at the 280 and 320 mg/m2 dose levels. The safety profile of oratecan was comparable to that of intravenous irinotecan.
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Affiliation(s)
| | - Christos Fountzilas
- Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
| | - Marwan Fakih
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | | | | | - Bradley Corr
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | | | | | - Hui Wang
- Clinical R&D, Athenex Inc., Buffalo, NY, USA
| | - Doug Kramer
- Clinical R&D, Athenex Inc., Buffalo, NY, USA
| | - Rudolf Kwan
- Clinical R&D, Athenex Inc., Buffalo, NY, USA
| | | | - Jay Zhi
- Clinical R&D, Athenex Inc., Buffalo, NY, USA
| | - Antonio Jimeno
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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3
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Milano G, Innocenti F, Minami H. Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs. Cancer Sci 2022; 113:2224-2231. [PMID: 35445479 PMCID: PMC9277406 DOI: 10.1111/cas.15377] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/05/2022] [Accepted: 04/13/2022] [Indexed: 11/30/2022] Open
Abstract
Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.
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Affiliation(s)
- Gérard Milano
- UPR 7497Scientific Valorisation UnitCentre Antoine Lacassagne and Côte d’Azur UniversityNiceFrance
| | | | - Hironobu Minami
- Medical Oncology and HematologyKobe University Graduate School of Medicine and HospitalKobeJapan
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4
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Zhu X, Zhu J, Sun F, Zhen Z, Zhou D, Lu S, Huang J, Que Y, Zhang L, Cai R, Wang J, Zhang Y. Influence of UGT1A1 *6/*28 Polymorphisms on Irinotecan-Related Toxicity and Survival in Pediatric Patients with Relapsed/Refractory Solid Tumors Treated with the VIT Regimen. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:369-377. [PMID: 33790625 PMCID: PMC8001723 DOI: 10.2147/pgpm.s292556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/02/2021] [Indexed: 11/23/2022]
Abstract
Objective The association between UGT1A1*6/*28 polymorphisms and treatment outcomes of irinotecan in children remains unknown. This retrospective study investigated the influence of UGT1A1*6/*28 polymorphisms on irinotecan toxicity and survival of pediatric patients with relapsed/refractory solid tumors. Methods The present study enrolled a total of 44 patients aged younger than 18 years at Sun Yat-sen University Cancer Center between 2014 and 2017. Results There were 26 boys and 18 girls; the median age at first VIT course was six years (range: 1-18 years). The tumor types included neuroblastoma (n = 25), rhabdomyosarcoma (n = 11), Wilm's tumor (n = 4), medulloblastoma (n = 2), and desmoplastic small round cell tumor (n = 2). Overall, 203 courses of VIT regimens were prescribed. Neither UGT1A1*6 nor *28 polymorphisms were associated with the incidence rates of severe (grade III-IV) irinotecan-related toxicities, but tended to reduce the patient overall survival (UGT1A1*6, P = 0.146; UGT1A1*28, P = 0.195). Moreover, patients with mutant UGT1A1*6 genotypes were more likely to develop grade I-IV irinotecan-related diarrhea (P = 0.043) and anemia (P = 0.002). Overall, the UGT1A1*28 polymorphism may play a protective role against irinotecan-related diarrhea and abdominal pain. Conclusion In relapsed/refractory pediatric solid tumors, the UGT1A1*6 polymorphism was a risk factor of irinotecan-related diarrhea and anemia. The UGT1A1*28 polymorphism may serve a protective role in irinotecan-related abdominal pain and diarrhea. Both mutations had a tendency to be risk factors for survival. Nevertheless, prospective studies are required to verify such conclusions.
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Affiliation(s)
- Xiaoqin Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jia Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Feifei Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zijun Zhen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Dalei Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Suying Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Junting Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yi Que
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Lian Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Ruiqing Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Juan Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yizhuo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
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Hindle A, Koneru B, Makena MR, Lopez-Barcons L, Chen WH, Nguyen TH, Reynolds CP. The O6-methyguanine-DNA methyltransferase inhibitor O6-benzylguanine enhanced activity of temozolomide + irinotecan against models of high-risk neuroblastoma. Anticancer Drugs 2021; 32:233-247. [PMID: 33323683 PMCID: PMC9255907 DOI: 10.1097/cad.0000000000001020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
DNA-damaging chemotherapy is a major component of therapy for high-risk neuroblastoma, and patients often relapse with treatment-refractory disease. We hypothesized that DNA repair genes with increased expression in alkylating agent resistant models would provide therapeutic targets for enhancing chemotherapy. In-vitro cytotoxicity of alkylating agents for 12 patient-derived neuroblastoma cell lines was assayed using DIMSCAN, and mRNA expression of 57 DNA repair, three transporter, and two glutathione synthesis genes was assessed by TaqMan low-density array (TLDA) with further validation by qRT-PCR in 26 cell lines. O6-methylguanine-DNA methyltransferase (MGMT) mRNA was upregulated in cell lines with greater melphalan and temozolomide (TMZ) resistance. MGMT expression also correlated significantly with resistance to TMZ+irinotecan (IRN) (in-vitro as the SN38 active metabolite). Forced overexpression of MGMT (lentiviral transduction) in MGMT non-expressing cell lines significantly increased TMZ+SN38 resistance. The MGMT inhibitor O6-benzylguanine (O6BG) enhanced TMZ+SN38 in-vitro cytotoxicity, H2AX phosphorylation, caspase-3 cleavage, and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling. TMZ+IRN+O6BG delayed tumor growth and increased survival relative to TMZ+IRN in two of seven patient-derived xenografts established at time of death from progressive neuroblastoma. We demonstrated that high MGMT expression was associated with resistance to alkylating agents and TMZ+IRN in preclinical neuroblastoma models. The MGMT inhibitor O6BG enhanced the anticancer effect of TMZ+IRN in vitro and in vivo. These results support further preclinical studies exploring MGMT as a therapeutic target and biomarker of TMZ+IRN resistance in high-risk neuroblastoma.
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Affiliation(s)
- Ashly Hindle
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Balakrishna Koneru
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Monish Ram Makena
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD
| | - Lluis Lopez-Barcons
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Wan Hsi Chen
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Thinh H. Nguyen
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
| | - C. Patrick Reynolds
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
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6
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Bernsen EC, Hagleitner MM, Kouwenberg TW, Hanff LM. Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology. Front Pharmacol 2020; 11:1184. [PMID: 32848787 PMCID: PMC7421781 DOI: 10.3389/fphar.2020.01184] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
In the past decades, new cancer treatments have been introduced in pediatric oncology leading to improvement in clinical outcomes and survival rates. However, due to inter-individual differences, some children experience severe chemotherapy-induced toxicities or a poor clinical outcome. An explanation for the diversity in response to chemotherapy is genetic variation, leading to differences in expression and activity of metabolizing and transport enzymes as well as drug targets. Pharmacogenetic testing has emerged as a promising tool to predict and limit acute and long-term adverse effects in patients. However, in pediatric oncology, limited number of patients and a considerable diversity in study results complicate the interpretation of test results and its clinical relevance. With this review, we provide an overview of new developments over the past four years regarding relevant polymorphisms related to toxicity in pediatric oncology. The following chemotherapeutics and associated toxicities are discussed: alkylating agents, anthracyclines, asparaginase, methotrexate, platinum compounds, steroids, thiopurines, topoisomerase inhibitors, and vinca alkaloids. Our review identifies several questions regarding the role of genetic variants in chemotherapy-induced toxicities. Ambiguities in the literature stem from small population sizes, differences in (statistical) interpretation and variations in sequencing technologies as well as different clinical outcome definitions. Standardization of clinical outcome data and toxicity definitions within electronic health records combined with the increased availability of genomic sequence techniques in clinical practice will help to validate these models in upcoming years.
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Affiliation(s)
- Emma C. Bernsen
- Pharmacy, Princess Máxima Centre for Pediatric Oncology, Utrecht, Netherlands
| | - Melanie M. Hagleitner
- Department of Pediatric Hemato-oncology, Princess Máxima Centre for Pediatric Oncology, Utrecht, Netherlands
| | - Theodorus W. Kouwenberg
- Department of Pediatric Hemato-oncology, Princess Máxima Centre for Pediatric Oncology, Utrecht, Netherlands
| | - Lidwien M. Hanff
- Pharmacy, Princess Máxima Centre for Pediatric Oncology, Utrecht, Netherlands
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7
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Kasteel EEJ, Darney K, Kramer NI, Dorne JLCM, Lautz LS. Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors. Arch Toxicol 2020; 94:2637-2661. [PMID: 32415340 PMCID: PMC7395075 DOI: 10.1007/s00204-020-02765-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/22/2020] [Indexed: 01/11/2023]
Abstract
UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro-in vivo extrapolations in chemical risk assessment are discussed.
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Affiliation(s)
- E E J Kasteel
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, 3508 TD, Utrecht, The Netherlands.
| | - K Darney
- Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort, France
| | - N I Kramer
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, 3508 TD, Utrecht, The Netherlands
| | - J L C M Dorne
- European Food Safety Authority, Scientific Committee and Emerging Risks Unit, Via Carlo Magno 1A, 43126, Parma, Italy
| | - L S Lautz
- Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort, France
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8
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Miyachi M, Tsuchiya K, Hosono A, Ogawa A, Koh K, Kikuta A, Hara J, Teramukai S, Hosoi H. Phase II study of vincristine, actinomycin-D, cyclophosphamide and irinotecan for patients with newly diagnosed low-risk subset B rhabdomyosarcoma: A study protocol. Medicine (Baltimore) 2019; 98:e18344. [PMID: 31876708 PMCID: PMC6946342 DOI: 10.1097/md.0000000000018344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Approximately 80% to 90% of patients with low-risk rhabdomyosarcoma can be cured. However, cured patients often face long-term complications associated with the treatment. An important factor in the treatment plan is the dose of cyclophosphamide administered because the dose can have both acute and long-term side effects. It is therefore essential to investigate whether the dose can be reduced without a negative effect on treatment outcome. The ARST0331 trial revealed that drastically reducing the cyclophosphamide dose to 4.8 g/m negatively affected treatment outcomes. The current study aims to determine whether reducing the cyclophosphamide dose to 10.8 g/m while introducing a new drug, irinotecan, can prevent the negative effect on treatment outcome. We also aim to investigate whether the reduced cyclophosphamide dose results in a decrease in infertility, one of the long-term complications of this treatment. METHODS The subjects are patients with stage 1 group III rhabdomyosarcoma (excluding those with orbital group III N0 and NX) or patients with stage 3 group I and II low-risk subset B embryonal rhabdomyosarcoma who will alternately undergo VAC 1.2 treatment (vincristine, actinomycin D, cyclophosphamide 1.2 g/m) and VI treatment (vincristine, irinotecan). The effectiveness and safety of this treatment regimen will be assessed. Data will be presented at international conferences and will be published in peer-reviewed journals. DISCUSSION This study is significant because it aims to establish that the use of irinotecan in patients with low-risk subset B embryonal rhabdomyosarcoma (aged 30 or younger) allows the dose of cyclophosphamide to be reduced and is associated with few short-term adverse effects and long-term complications. The open-label and single-arm design of this study may be a limitation. TRIAL REGISTRATION AND ETHICAL APPROVAL The trial registration number is jRCTs051180200 (Japan Registry of Clinical Trials). The study protocol was approved by the institutional review board at each of the participating centers and the data will be presented at international conferences and published in peer-reviewed journals.
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Affiliation(s)
- Mitsuru Miyachi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto
| | - Kunihiko Tsuchiya
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto
| | - Ako Hosono
- Division of Pediatric Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
| | - Atsushi Ogawa
- Department of Pediatrics, Niigata Cancer Center Hospital, Niigata
| | - Katsuyoshi Koh
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama
| | - Atsushi Kikuta
- Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima
| | - Junichi Hara
- Department of Pediatric Hematology/Oncology, Children's Medical Center, Osaka City General Hospital, Osaka
| | - Satoshi Teramukai
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hajime Hosoi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto
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9
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DuBois SG, Mosse YP, Fox E, Kudgus RA, Reid JM, McGovern R, Groshen S, Bagatell R, Maris JM, Twist CJ, Goldsmith K, Granger MM, Weiss B, Park JR, Macy ME, Cohn SL, Yanik G, Wagner LM, Hawkins R, Courtier J, Lai H, Goodarzian F, Shimada H, Boucher N, Czarnecki S, Luo C, Tsao-Wei D, Matthay KK, Marachelian A. Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 2018; 24:6142-6149. [PMID: 30093449 PMCID: PMC6295246 DOI: 10.1158/1078-0432.ccr-18-1381] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 06/30/2018] [Accepted: 08/06/2018] [Indexed: 01/26/2023]
Abstract
PURPOSE In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. PATIENTS AND METHODS We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. RESULTS Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. CONCLUSIONS This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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Affiliation(s)
- Steven G DuBois
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.
| | - Yael P Mosse
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth Fox
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Rachel A Kudgus
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Joel M Reid
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Renee McGovern
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Susan Groshen
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Rochelle Bagatell
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - John M Maris
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Clare J Twist
- Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York
| | - Kelly Goldsmith
- Department of Pediatrics, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia
| | - M Meaghan Granger
- Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas
| | - Brian Weiss
- Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio
| | - Julie R Park
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, Seattle, Washington
| | - Margaret E Macy
- Department of Pediatrics, Children's Hospital Colorado and University of Colorado, Aurora, Colorado
| | - Susan L Cohn
- Department of Pediatrics, Comer Children's Hospital and University of Chicago, Chicago, Illinois
| | - Greg Yanik
- Department of Pediatrics, CS Mott Children's Hospital and University of Michigan, Ann Arbor, Michigan
| | - Lars M Wagner
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Randall Hawkins
- Department of Radiology, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Jesse Courtier
- Department of Radiology, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Hollie Lai
- Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Fariba Goodarzian
- Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Hiroyuki Shimada
- Department of Pathology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Najee Boucher
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Scarlett Czarnecki
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Chunqiao Luo
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Denice Tsao-Wei
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Katherine K Matthay
- Department of Pediatrics, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Araz Marachelian
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
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10
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Levy EB, Peer C, Sissung TM, Venkatesan A, Pandalai P, Greten T, Hughes MS, Garcia C, Peretti J, Figg W, Lewis A, Wood B. Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization. J Vasc Interv Radiol 2018; 30:19-22. [PMID: 30527657 DOI: 10.1016/j.jvir.2018.06.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 06/22/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022] Open
Abstract
Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.
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Affiliation(s)
- Elliot B Levy
- Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892.
| | - Cody Peer
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - Tristan M Sissung
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - Aradhana Venkatesan
- Department of Diagnostic Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Austin, Texas
| | - Prakash Pandalai
- Kaiser Permanente, Mid-Atlantic Permanente Medical Group, Bethesda, Maryland
| | - Tim Greten
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - Marybeth S Hughes
- Department of Surgical Oncology, Eastern Virginia Medical School, Norfolk, Virginia
| | - Charisse Garcia
- Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - Julie Peretti
- Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - William Figg
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
| | - Andrew Lewis
- Biocompatibles, UK Ltd, A BTG International Group Company, Conshohocken, Pennsylvania
| | - Bradford Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 1C367, Bethesda, MD 20892
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11
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Yu Q, Zhang T, Xie C, Qiu H, Liu B, Huang L, Peng P, Feng J, Chen J, Zang A, Yuan X. UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy. Cancer Chemother Pharmacol 2018; 82:87-98. [PMID: 29728798 DOI: 10.1007/s00280-018-3595-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 04/30/2018] [Indexed: 12/16/2022]
Abstract
PURPOSE To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC). METHODS The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov ). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan-Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome. RESULTS We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217-2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267-3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5-9.6) months compared with 9.8 (95% CI 8.6-10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3-16.2), and 20.8 (95% CI 18.7-23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome. CONCLUSIONS UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.
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Affiliation(s)
- Qianqian Yu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China
| | - Conghua Xie
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430077, Hubei, People's Republic of China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Ping Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Jueping Feng
- Department of Oncology, PuAi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, Hubei, People's Republic of China
| | - Jigui Chen
- Department of Surgery, Wuhan 8th Hospital, Wuhan, 430010, Hubei, People's Republic of China
| | - Aihua Zang
- Hubei Cancer Hospital, Wuhan, 430079, Hubei, People's Republic of China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China.
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12
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Wang Y, Yi C, Wang Y, Li H, Li B, Wang D, Du J, Liu L, Wang X. Distribution of uridine diphosphate glucuronosyltransferase 1A polymorphisms and their role in irinotecan-induced toxicity in patients with cancer. Oncol Lett 2017; 14:5743-5752. [PMID: 29113203 PMCID: PMC5661374 DOI: 10.3892/ol.2017.6933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 04/13/2017] [Indexed: 11/30/2022] Open
Abstract
Uridine diphosphate glucuronosyltransferase 1A (UGT1A1), which affects irinotecan metabolism, has been associated with severe adverse reactions in patients with cancer treated with irinotecan. However, neither large-scale analysis of the distribution of UGT1A1 polymorphisms, nor standardized assessment of how UGT1A1 polymorphisms affect irinotecan treatment has been performed in China. The aim of the present study was to investigate the distribution of UGT1A1 polymorphisms (*28 and *6) in 2,093 Chinese patients with cancer who were treated with irinotecan from more than 15 hospitals in Shandong, to examine how the coexistence of UGT1A1*6 and UGT1A1*28 alleles may be able to predict toxicities induced by irinotecan in 105 of the patients, and to search for other relevant risk factors. The distribution of the genotypes was as follows: TA6/TA6 (1,601, 76.5%), TA6/TA7 (463, 22.1%) and TA7/TA7 (29, 1.4%) for UGT1A1*28 (n=2,093); and G/G (286, 66.4%), G/A (124, 28.8%) and A/A (21, 4.9%) for UGT1A1*6 (n=431). The most frequent severe hematological toxicity was neutropenia, and the predominant non-hematological toxicities were diarrhea and cholinergic syndrome. In toxicity comparisons, grade 3-4 leukopenia and neutropenia were significantly higher in TA6/TA7 compared with TA6/TA6 (P<0.05). The UGT1A1*6 polymorphism was associated with a higher risk of severe diarrhea and total adverse drug reactions (P<0.05). Logistic regression showed that the UGT1A1*6 genotype was an independent predictor of severe diarrhea. These findings suggested that the UGT1A1*28 and UGT1A1*6 genotypes may be associated with irinotecan-induced severe toxicity, and clarified the clinical importance of UGT1A1 polymorphisms, particularly UGT1A1*6, regarding irinotecan therapy in Chinese patients.
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Affiliation(s)
- Yang Wang
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Cuihua Yi
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yawei Wang
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hui Li
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Bei Li
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Dan Wang
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jintong Du
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Lian Liu
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiuwen Wang
- Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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13
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Adiwijaya BS, Kim J, Lang I, Csõszi T, Cubillo A, Chen JS, Wong M, Park JO, Kim JS, Rau KM, Melichar B, Gallego JB, Fitzgerald J, Belanger B, Molnar I, Ma WW. Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer. Clin Pharmacol Ther 2017; 102:997-1005. [PMID: 28445610 PMCID: PMC5697569 DOI: 10.1002/cpt.720] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 03/29/2017] [Accepted: 04/19/2017] [Indexed: 12/18/2022]
Abstract
Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (Cmax) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2 (free‐base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.
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Affiliation(s)
- B S Adiwijaya
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | - J Kim
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | - I Lang
- National Institute of Oncology, Budapest, Hungary
| | - T Csõszi
- JNSZ Megyei Hetényi Géza Kórház Rendelöintézet, Szolnok, Hungary
| | - A Cubillo
- Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - J-S Chen
- Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - M Wong
- Westmead Hospital, Westmead, Australia
| | - J O Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - J S Kim
- Korea University Guro Hospital, Seoul, South Korea
| | - K M Rau
- Chang Gung Memorial Hospital Kaohsiung Branch, Kaohsiung, Taiwan
| | - B Melichar
- Onkologicka Klinika, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic
| | | | - J Fitzgerald
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | - B Belanger
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | - I Molnar
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | - W W Ma
- Mayo Clinic, Rochester, Minnesota, USA
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14
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A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma. Cancer Chemother Pharmacol 2017; 79:603-610. [PMID: 28233053 DOI: 10.1007/s00280-017-3247-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 11/23/2016] [Indexed: 10/20/2022]
Abstract
PURPOSE Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping. METHODS This phase I study stratified patients with recurrent high-grade glioma into 2 groups by UGT1A1 status: homozygous WT ("WT") vs heterozygous WT/*28 ("HT"). Patients who were homozygous *28 were ineligible. The design was a standard 3 + 3 phase I design. WT patients were started at 120 mg/m2 intravenously every 3 weeks with dose increases in 60 mg/m2 increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2 increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days). RESULTS In the WT cohort (n = 16), the MTD was 120 mg/m2. In the HT cohort (n = 18), the MTD was 150 mg/m2. Dose-limiting toxicity in both cohorts included diarrhea, some with associated dehydration and/or fatigue. PK results were comparable to those seen in other PK studies of nal-IRI; UGT1A1*28 genotype (WT vs. HT) did not affect PK parameters. CONCLUSIONS Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.
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15
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Mlakar V, Huezo-Diaz Curtis P, Satyanarayana Uppugunduri CR, Krajinovic M, Ansari M. Pharmacogenomics in Pediatric Oncology: Review of Gene-Drug Associations for Clinical Use. Int J Mol Sci 2016; 17:ijms17091502. [PMID: 27618021 PMCID: PMC5037779 DOI: 10.3390/ijms17091502] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 08/02/2016] [Accepted: 08/15/2016] [Indexed: 02/07/2023] Open
Abstract
During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology. This preliminary evaluation will help steer the committee’s work and should give the reader an idea at which stage researchers and clinicians are, in terms of personalizing medicine for children with cancer. From the evidence presented here, future recommendations to achieve this goal will also be suggested.
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Affiliation(s)
- Vid Mlakar
- Cansearch Research Laboratory, Geneva University Medical School, Avenue de la Roseraie 64, 1205 Geneva, Switzerland.
| | - Patricia Huezo-Diaz Curtis
- Cansearch Research Laboratory, Geneva University Medical School, Avenue de la Roseraie 64, 1205 Geneva, Switzerland.
| | | | - Maja Krajinovic
- Charles-Bruneau Cancer Center, Centre hospitalier universitaire Sainte-Justine, 4515 Rue de Rouen, Montreal, QC H1V 1H1, Canada.
- Department of Pediatrics, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, QC H3T 1J4, Canada.
- Department of Pharmacology, Faculty of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montreal, QC H3T 1J4, Canada.
| | - Marc Ansari
- Cansearch Research Laboratory, Geneva University Medical School, Avenue de la Roseraie 64, 1205 Geneva, Switzerland.
- Pediatric Department, Onco-Hematology Unit, Geneva University Hospital, Rue Willy-Donzé 6, 1205 Geneva, Switzerland.
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16
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Yu QQ, Qiu H, Zhang MS, Hu GY, Liu B, Huang L, Liao X, Li QX, Li ZH, Yuan XL. Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy. World J Gastroenterol 2016; 22:4250-4258. [PMID: 27122675 PMCID: PMC4837442 DOI: 10.3748/wjg.v22.i16.4250] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/01/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.
METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer (mCRC) patients treated with irinotecan-based chemotherapy (NCT01282658). Baseline serum bilirubin levels, including total bilirubin (TBil) and unconjugated bilirubin (UBil), were measured, and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve (ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as CoBil, patients were classified into three groups. The classifier’s performance of UGT1A1*28 and CoBil for predicting treatment response was evaluated by ROC analysis. Associations between response and CoBil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models.
RESULTS: Among the 120 mCRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil (P = 0.018) and a higher UBil (P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on CoBil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple (OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple (OR = 16.001; 95%CI: 2.802 -91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28 (TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous (TA)6 genotype in the simple (OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple (OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier’s performance of CoBil and UGT1A1*28 were comparable.
CONCLUSION: CoBil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of mCRC patients to irinotecan-based chemotherapy. After validation, CoBil, an easily determinable index in the clinic, might be helpful in facilitating stratification of mCRC patients for individualized treatment options.
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Wang W, Huang J, Tao Y, Lyu X, Yang L, Wu D, Tian Y. Phase II and UGT1A1 Polymorphism Study of Two Different Irinotecan Dosages Combined with Cisplatin as First-Line Therapy for Advanced Gastric Cancer. Chemotherapy 2016; 61:197-203. [PMID: 26872008 DOI: 10.1159/000442787] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/26/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND We investigated the efficacy and safety of biweekly irinotecan and cisplatin (IP) as first-line treatment in advanced gastric cancer patients. METHODS Irinotecan 125 mg/m2 on day 1 and cisplatin 60 mg/m2 on day 2 were administrated every 14 days. UGT1A1*28/*6 and toxicities were analyzed. RESULTS Forty-one eligible patients were enrolled. Fifteen patients, who were defined as the high-dose group, received starting doses of irinotecan 125 mg/m2. Twenty-six patients, who were defined as the low-dose group, received starting doses of irinotecan 80 mg/m2 and cisplatin 50 mg/m2. The response rate was 53.3% in the irinotecan high-dose group and 53.8% in the irinotecan low-dose group. The most common grade 3/4 toxicity was neutropenia (68.3%). No significant difference in grade 3/4 neutropenia was found between patients with the wild-type genotype and those with variant genotypes for UGT1A1*28 or UGT1A1*6. CONCLUSIONS The combination of biweekly irinotecan 80 mg/m2 and cisplatin 50 mg/m2 was active and tolerable. The role of the UGT1A1 genotype in clinical toxicity of an IP regimen requires further investigation.
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Takano M, Yamamoto K, Tabata T, Minegishi Y, Yokoyama T, Hirata E, Ikeda T, Shimada M, Yamada K, Morita S, Ando Y, Hirata K, Sugihara M, Sugiyama T, Ohashi Y, Sakata Y. Impact of UGT1A1 genotype upon toxicities of combination with low-dose irinotecan plus platinum. Asia Pac J Clin Oncol 2016; 12:115-24. [PMID: 26862009 DOI: 10.1111/ajco.12453] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 12/07/2015] [Accepted: 12/15/2015] [Indexed: 11/26/2022]
Abstract
AIM Irinotecan-induced severe toxicities are possibly related to UGT1A1*6 and *28 genotypes. However, the correlation between UGT1A1 polymorphisms and the risk of toxicities induced by low-dose irinotecan plus platinum combination therapy still remains controversial. This prospective observational study aimed to examine the correlation between UGT1A1 genotypes and clinical outcomes of low-dose irinotecan (median 60 mg/m(2) , range 25-115 mg/m(2) ) plus platinum in Japanese patients with solid tumors. METHODS Toxicity profiles were compared between UGT1A1 SNP heterozygotes (hetero-group) and patients with homozygous SNP profile (*6/*6, *28/*28 and *6/*28). Logistic regression models were used to identify independent risk factors for these toxicities. RESULTS A total of 331 patients were enrolled: 84% with hetero-group and 16% with homo-group. Although the initial irinotecan dose was similar, the dose intensities during the three cycles were significantly lower in the homo-group (P < 0.01). Grade 3/4 hematological toxicities were significantly more frequent in the homo-group. Multivariable analysis identified UGT1A1 genotype (P < 0.01) as an independent factor for grade 4 hematological toxicity in the first treatment cycle. CONCLUSION UGT1A1 genotype has a major impact on the increased risk of severe hematological toxicities, even in low-dose irinotecan regimens. UGT1A1 genotypes are useful biomarkers for predicting severe hematological toxicities in patients treated with irinotecan plus platinum analog.
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Affiliation(s)
- Masashi Takano
- Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan
| | - Kaichiro Yamamoto
- Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Japan
| | - Tsutomu Tabata
- Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yuji Minegishi
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Takuma Yokoyama
- Department of Respiratory Medicine, Kyorin University Hospital, Mitaka, Japan
| | - Eiji Hirata
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Ikeda
- Department of Respiratory Medicine, Naga Municipal Hospital, Kinokawa, Japan
| | - Muneaki Shimada
- Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan
| | - Kouzo Yamada
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Koji Hirata
- Pharmacovigilance Department, Daiichi Sankyo, Tokyo, Japan
| | - Masahiro Sugihara
- Clinical Data and Biostatistics Department, Daiichi Sankyo, Tokyo, Japan
| | - Toru Sugiyama
- Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan
| | - Yasuo Ohashi
- Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan
| | - Yuh Sakata
- CEO, Misawa City Hospital, Misawa, Japan
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Xiao XG, Xia S, Zou M, Mei Q, Zhou L, Wang SJ, Chen Y. The relationship between UGT1A1 gene polymorphism and irinotecan effect on extensive-stage small-cell lung cancer. Onco Targets Ther 2015; 8:3575-83. [PMID: 26664141 PMCID: PMC4671801 DOI: 10.2147/ott.s95149] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aims To analyze the distribution of uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms in Chinese patients with extensive-stage small-cell lung cancer (E-SCLC), and to evaluate correlations between the UGT1A1 gene polymorphisms and toxicity, and efficacy of irinotecan (CPT-11) based regimen in the patients with E-SCLC. Methods The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The analysis of UGT1A1*28 and UGT1A1*6 gene polymorphisms was performed in 67 patients with E-SCLC admitted to the clinic in the Department of Oncology from June 2011 to January 2013. A total of 67 cases with E-SCLC treated with irinotecan (CPT-11)-based regimen were enrolled to observe the adverse events and efficacy during the chemotherapy, including objective response rate, progression-free survival (PFS) and overall survival (OS). The correlation between UGT1A1 gene polymorphisms and severe adverse events was analyzed. The influences of UGT1A1*6/*28 polymorphisms on objective response rate, PFS, and OS were also analyzed. Results The distribution of UGT1A1 genotypes among 67 patients was as follows: UGT1A1*28 wild-type (WT) genotype TA6/6 (56, 83.6%), heterozygous mutant genotype TA6/7 (11, 16.4%); UGT1A1*6 WT genotype G/G (45, 67.2%), heterozygous mutant genotype G/A (22, 32.8%); no significant difference of PFS and OS was observed between different genotypes. The incidence of grade 3 and 4 delayed diarrhea and neutropenia in the patients carrying UGT1A1*6 G/A mutation was higher than that in the WT genotype (36.4% vs 6.6% P=0.034; 27.2% vs 4.4% P=0.026, respectively). The incidence of grade 3 and 4 thrombocytopenia in the patients carrying UGT1A1*28 TA6/7 mutation was higher than that in the WT genotype (27.2% vs 1.8% P=0.017). The patients simultaneously carrying UGT1A1*28 TA6/7 and UGT1A1*6 G/A mutations were prone to suffering grade 3 and 4 delayed diarrhea and neutropenia. Conclusion For irinotecan-based regimens in E-SCLC, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for severe adverse events. We also found that neither clinical response nor prognosis was significantly associated with the UGT1A1 gene polymorphisms.
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Affiliation(s)
- Xiao-Guang Xiao
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Man Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Lei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu-Jing Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Fujita KI, Kubota Y, Ishida H, Sasaki Y. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol 2015; 21:12234-12248. [PMID: 26604633 PMCID: PMC4649109 DOI: 10.3748/wjg.v21.i43.12234] [Citation(s) in RCA: 213] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/05/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.
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Wagner LM. Fifteen years of irinotecan therapy for pediatric sarcoma: where to next? Clin Sarcoma Res 2015; 5:20. [PMID: 26322224 PMCID: PMC4552408 DOI: 10.1186/s13569-015-0035-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 08/22/2015] [Indexed: 12/31/2022] Open
Abstract
Over the past 15 years, irinotecan has emerged as an important agent for treating pediatric sarcoma patients. This review summarizes the activity noted in previous studies, and outlines current issues regarding scheduling, route of administration, and amelioration of side effects. Also discussed are new pegylated and nanoliposomal formulations of irinotecan and its active metabolite, SN-38, as well as future plans for how irinotecan may be used in combination with other conventional cytotoxic as well as targeted agents.
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Affiliation(s)
- Lars M Wagner
- Division of Pediatric Hematology/Oncology, Kentucky Clinic Suite, University of Kentucky, J-457, Lexington, KY 40536 USA
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Xiao X, Wang S, Xia S, Zou M, Li Y, Wei Y, Mei Q, Chen Y. Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer. Onco Targets Ther 2015; 8:2209-14. [PMID: 26345293 PMCID: PMC4551306 DOI: 10.2147/ott.s89606] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Much research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC. Methods Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. Results Median overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy. Conclusion There were no statistically significant differences in between the two sequences of IP and EP in the treatment of E-SCLC. Except EP regimen, IP may be another reserved regimen in the first-line treatment of E-SCLC.
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Affiliation(s)
- Xiaoguang Xiao
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shujing Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Man Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yang Li
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yao Wei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Etienne-Grimaldi MC, Boyer JC, Thomas F, Quaranta S, Picard N, Loriot MA, Narjoz C, Poncet D, Gagnieu MC, Ged C, Broly F, Le Morvan V, Bouquié R, Gaub MP, Philibert L, Ghiringhelli F, Le Guellec C. UGT1A1genotype and irinotecan therapy: general review and implementation in routine practice. Fundam Clin Pharmacol 2015; 29:219-37. [DOI: 10.1111/fcp.12117] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 02/05/2015] [Accepted: 02/24/2015] [Indexed: 12/19/2022]
Affiliation(s)
| | - Jean-Christophe Boyer
- Unité de Toxicologie; Laboratoire de Biochimie; CHU Carémeau, Place du Pr Debré; 30029 Nîmes Cedex France
| | - Fabienne Thomas
- Institut Claudius Regaud; 1, avenue Irène Joliot-Curie 31059 Toulouse France
| | - Sylvie Quaranta
- Service de Pharmacocinétique et Toxicologie; Laboratoire de Biologie Médicale; Hôpital de la Timone; Bât F; 264 rue Saint Pierre 13385 Marseille Cedex 05 France
| | - Nicolas Picard
- Service Pharmacologie; Toxicologie et Pharmacovigilance; CHU Limoges, Bâtiment CBRS; 2 avenue Martin Luther King 87042 Limoges France
| | - Marie-Anne Loriot
- Hôpital Européen Georges Pompidou; SERVICE BIOCHIMIE; 20 Rue Leblanc 75015 Paris France
| | - Céline Narjoz
- Hôpital Européen Georges Pompidou; SERVICE BIOCHIMIE; 20 Rue Leblanc 75015 Paris France
| | - Delphine Poncet
- Equipe Signalisation Métabolisme et Progression Tumorale; UMR 1052-5286; Centre Léon Bérard; 28 rue Laennec 69373 Lyon Cedex 08 69008 Lyon France
| | - Marie-Claude Gagnieu
- Fédération de Biochimie; UF Pharmacologie Spécialisée; Hôpital E. Herriot; 5 place d'Arsonval 69437 Lyon Cedex 03 France
| | - Cécile Ged
- Plateau Technique de Biologie Moléculaire; Pôle de Biologie et Pathologie; CHU de Bordeaux; 1, place A Raba Leon 33 000 Bordeaux France
| | - Franck Broly
- Service de Toxicologie et Génopathies; Centre de Biologie Pathologie Génétique; Centre Hospitalier Régional et Universitaire de Lille; 59037 Lille Cedex France
| | - Valérie Le Morvan
- Institut Bergonié; Unité Inserm VINCO; 229 cours de l'Argonne 33076 Bordeaux Cedex France
| | - Régis Bouquié
- Laboratoire de Pharmacologie clinique; Institut de Biologie - CHU Nantes; 9, quai Moncousu 44093 Nantes Cedex 1 France
| | - Marie-Pierre Gaub
- EA3430; FMTS Université de Strasbourg; Laboratoire de Biochimie- Biologie Moléculaire; Hôpital de hautepierre; Avenue Molière 67098 Strasbourg France
| | - Laurent Philibert
- Unité de Biopathologie et pharmacogénétique; Laboratoire d'oncopharmacologie; Institut régional du Cancer Montpellier - Val d'Aurelle; 208 Avenue des Apothicaires 34298 Montpellier Cedex 5 France
| | - François Ghiringhelli
- Département de biopathologie; Centre Georges Francois Leclerc; 1 rue du professeur Marion 21000 Dijon France
| | - Chantal Le Guellec
- Unité de pharmacogénétique; Laboratoire de biochimie et biologie moléculaire; CHU Bretonneau; 2 bis boulevard Tonnellé 37044 Tours France
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Phase I/II study of (131)I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma. Br J Cancer 2015; 112:644-9. [PMID: 25602966 PMCID: PMC4333502 DOI: 10.1038/bjc.2015.12] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 12/16/2014] [Accepted: 12/21/2014] [Indexed: 11/08/2022] Open
Abstract
Background: 131I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan. Methods: Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m−2 per dose IV) on days 0–4, vincristine (2 mg m−2) on day 0, MIBG (555 or 666 MBq kg−1) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients. Results: Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg−1. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients. Conclusions: MIBG (666 MBq kg−1) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.
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Intérêt du génotypage de l’UGT1A1 dans le cadre du traitement des cancers digestifs par irinotécan. Bull Cancer 2014; 101:533-53. [DOI: 10.1684/bdc.2014.1933] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Moriya H, Saito K, Helsby N, Sugino S, Yamakage M, Sawaguchi T, Takasaki M, Kato H, Kurosawa N. Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers. Oncol Lett 2014; 7:2035-2040. [PMID: 24932285 PMCID: PMC4049750 DOI: 10.3892/ol.2014.2046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.
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Affiliation(s)
- Hiroyuki Moriya
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
| | - Katsuhiko Saito
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
| | - Nuala Helsby
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Shigekazu Sugino
- Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Michiaki Yamakage
- Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takeru Sawaguchi
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Masahiko Takasaki
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Hidenori Kato
- Department of Gynecology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Nahoko Kurosawa
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
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Biswas T, Sharma N, Machtay M. Controversies in the management of stage III non-small-cell lung cancer. Expert Rev Anticancer Ther 2014; 14:333-47. [PMID: 24397773 DOI: 10.1586/14737140.2014.867809] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Lung cancer remains the leading cause of death in the USA and is the most common cancer both in incidence and in mortality globally (1.35 million deaths annually). Non-small-cell lung cancer accounts for >80% of all lung cancers [1] . About 35-45% of non-small-cell lung cancer patients present with locally advanced non-metastatic stage III disease. However, confirmed stage III disease represents a very heterogeneous group ranging from borderline surgical candidate with minimal mediastinal involvement to bulky mediastinal nodes or contralateral nodal involvement with significant controversy regarding optimal management in these various situations. This article specifically addresses the role of surgery, radiotherapy and chemotherapy in multimodal approach to treat stage III patients with N2/N3 involvement and controversies surrounding these recommendations.
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Affiliation(s)
- Tithi Biswas
- University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Wong A, Ma BBY. Personalizing therapy for colorectal cancer. Clin Gastroenterol Hepatol 2014; 12:139-44. [PMID: 24025538 DOI: 10.1016/j.cgh.2013.08.040] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 08/26/2013] [Accepted: 08/26/2013] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Several important scientific discoveries in the molecular biology of CRC have changed clinical practice in oncology. These included the comprehensive genome-wide profiling of CRC by the Cancer Genome Atlas Network, the discovery of mutations along the RAS-RAF signaling pathway as major determinants of response to antibodies against the epidermal growth factor receptor, the elucidation of new molecular subsets of CRC or gene signatures that may predict clinical outcome after adjuvant chemotherapy, and the innovative targeting of the family of vascular endothelial growth factor and receptors. These new data have allowed oncologists to individualize drug therapy on the basis of a patient's tumor's unique molecular profile, especially in the management of metastatic CRC. This review article will discuss the progress of personalized medicine in the contemporary management of CRC.
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Affiliation(s)
- Ashley Wong
- Sir Y. K. Pao Centre for Cancer, Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Brigette B Y Ma
- Sir Y. K. Pao Centre for Cancer, Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR, China.
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Goy A. Mantle cell lymphoma: continuously improving the odds! Expert Opin Orphan Drugs 2013. [DOI: 10.1517/21678707.2013.854700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmöller J. Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review. Pharmacol Ther 2013; 141:92-116. [PMID: 24076267 DOI: 10.1016/j.pharmthera.2013.09.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 09/10/2013] [Indexed: 01/01/2023]
Abstract
UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.
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Affiliation(s)
- J C Stingl
- Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Translational Pharmacology, University of Bonn Medical Faculty, Germany.
| | - H Bartels
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany
| | - R Viviani
- Department of Psychiatry and Psychotherapy III, University of Ulm, Germany
| | - M L Lehmann
- Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - J Brockmöller
- Institute of Clinical Pharmacology, University of Göttingen, Germany
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Mochizuki Y, Ohashi N, Kojima H, Ishigure K, Kinoshita T, Eguchi T, Fujitake S, Ito S, Fujiwara M, Kodera Y. CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702). Cancer Chemother Pharmacol 2013; 72:629-35. [PMID: 23881212 DOI: 10.1007/s00280-013-2235-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 07/13/2013] [Indexed: 01/01/2023]
Abstract
BACKGROUND In Japan, CPT-11 is often used to treat unresectable gastric cancer in the second-line setting. However, evidence regarding benefit of second-line chemotherapy remains sparse, especially after failing S-1. METHODS A phase II study to evaluate the efficacy and safety of weekly administration of CPT-11 at a dose of 100 mg/m(2) after failing a S-1-containing first-line treatment was planned with response rate as a primary end point. UGT1A1*6, *27, and *28 genotyping were performed in all cases, and those found to have either homozygous for *28, homozygous for *6, heterozygous for both *6 and *28, and heterozygous for *27 were rendered ineligible for the phase II trial. RESULTS Two patients of homozygous for *28, two patients of homozygous for *6, and one patient of heterozygous for *27 were found among 39 recruited patients. The median number of courses delivered was 3 courses. The overall response rate was 15.4 % and disease control rate was 65.4 %. The median time to treatment failure was 87.5 days and median overall survival was 268 days. Twenty-two (73 %) of 30 valuable patients experienced protocol-specified skip of treatment and 8 (30 %) of patients could continue treatment with dose reduction. ≥G3 neutropenia was found in 30 % and ≥G3 anorexia and diarrhea were found in 23 and 17 %, respectively. CONCLUSION Weekly CPT-11 at 100 mg/m(2) showed moderate response among gastric cancer patients who were refractory to S-1, but the disease control rate seemed meaningful. Even after selection of patients by UGT1A1 polymorphism of *6, *27, and *28, severe toxic events could not be prevented completely.
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Affiliation(s)
- Yoshinari Mochizuki
- Department of Surgery, Komaki City Hospital, 1-20 Jobushi, Komaki, Aichi, Japan.
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Xu JM, Wang Y, Ge FJ, Lin L, Liu ZY, Sharma MR. Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World J Gastroenterol 2013; 19:3899-3903. [PMID: 23840132 PMCID: PMC3699040 DOI: 10.3748/wjg.v19.i24.3899] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 04/24/2013] [Accepted: 05/10/2013] [Indexed: 02/06/2023] Open
Abstract
Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UGT1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.
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Gao J, Zhou J, Li Y, Lu M, Jia R, Shen L. UGT1A1 6/28 polymorphisms could predict irinotecan-induced severe neutropenia not diarrhea in Chinese colorectal cancer patients. Med Oncol 2013; 30:604. [PMID: 23686699 DOI: 10.1007/s12032-013-0604-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 05/09/2013] [Indexed: 01/29/2023]
Abstract
The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced colorectal cancer patients. The genotypes of UGT1A1 6 and UGT1A1 28 were analyzed by PCR amplification and Sanger sequencing in 276 advanced colorectal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1 6/28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1 6 and UGT1A1 28 variants was 35.5 % (GA: 28.6 %; AA: 6.9 %) and 21.0 % (TA6/TA7: 19.9 %; TA7/TA7: 1.1 %) in our cohort, respectively. A total of 16 patients (5.8 %, 16/276) had severe diarrhea and 56 patients (20.3 %, 56/276) had severe neutropenia. Neither UGT1A1 6 nor UGT1A1 28 variants were associated with severe diarrhea; however, either UGT1A1 6 (P = 0.001) or UGT1A1 28 (P = 0.029) variants were significantly associated with severe neutropenia. No differences were found between severe toxicities and clinical response in this study. Compared to western countries, Chinese patients had a distinct frequency of UGT1A1 6 or UGT1A1 28 genotypes. Both UGT1A1 6 and UGT1A1 28 variants were closely associated with irinotecan-induced severe neutropenia, but not diarrhea.
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Affiliation(s)
- Jing Gao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University, Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
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35
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Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. J Hum Genet 2013; 58:346-52. [PMID: 23677053 DOI: 10.1038/jhg.2013.42] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cancer treatment is complicated because of a multitude of treatment options and little patient-specific information to help clinicians choose appropriate therapy. There are two genomes relevant in cancer treatment: the tumor (somatic) and the patient (germline). Together, these two genomes dictate treatment outcome through four processes: the somatic genome primarily determines tumor prognosis and response while the germline genome modulates treatment exposure and toxicity. In this review, we describe the influence of these genomes on treatment outcomes by highlighting examples of genetic variation that are predictors of each of these four factors, prognosis, response, toxicity and exposure, and discuss the translation and clinical implementation of each. Use of pre-treatment pharmacogenetic testing will someday enable clinicians to make individualized therapy decisions about aggressiveness, drug selection and dose, improving treatment outcomes for cancer patients.
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Kobayashi M, Hazama S, Takahashi K, Oba K, Okayama N, Nishioka M, Hinoda Y, Oka M, Okamoto K, Maeda H, Nakamura D, Sakamoto J, Mishima H. Is there diversity among UGT1A1 polymorphism in Japan. World J Gastrointest Oncol 2012; 4:170-5. [PMID: 22848786 PMCID: PMC3406281 DOI: 10.4251/wjgo.v4.i7.170] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 05/22/2012] [Accepted: 05/27/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan.
METHODS: We enrolled 50 healthy volunteers from each of the Yamaguchi (western part of Japan), Kochi (southern part of Japan) and Akita (northern part of Japan) prefectures. Blood samples (7 mL) were collected from each participant and stored in EDTA for subsequent genotyping by fragment size analysis, direct sequencing and TaqMan assay of UGT1A1*28, UGT1A7*3/UGT1A9*22 and UGT1A1*93/UGT1A1*6/UGT1A1*27/UGT1A1*60/UGT1A7 (-57), respectively.
RESULTS: The only statistically significant differences in allele polymorphisms among the group examined were for UGT1A1*6. The Akita population showed more UGT1A1*6 heterozygosity (P = 0.0496).
CONCLUSION: Our study revealed no regional diversity among UGT1A1, UGT1A7 or UGT1A9 polymorphisms in Japan.
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Affiliation(s)
- Michiya Kobayashi
- Michiya Kobayashi, Ken Okamoto, Hiromichi Maeda, Department of Human Health and Medical Sciences, Kochi Medical School, Nankoku 783-8505, Japan
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Phan VH, Tan C, Rittau A, Xu H, McLachlan AJ, Clarke SJ. An update on ethnic differences in drug metabolism and toxicity from anti-cancer drugs. Expert Opin Drug Metab Toxicol 2011; 7:1395-410. [PMID: 21950349 DOI: 10.1517/17425255.2011.624513] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Based on recent emerging evidence of inter-ethnic differences in drug response and toxicity, ethnic diversity in pharmacokinetics, pharmacogenomics and clinical outcomes are being increasingly investigated. Ultimately, this will promote improved understanding of inter-individual differences in the pharmacokinetics and tolerance of cytotoxic drugs. AREAS COVERED This article reviews potential explanations for the observed ethnic differences in treatment outcomes and provides clinical data to support this concept. A literature search was implemented on PubMed and PharmGKB to investigate the areas of ethnic differences in pharmacogenomics, pharmacogenetics and clinical outcomes of cancer therapies. EXPERT OPINION There has been a relative paucity of clinical evidence linking genetic polymorphisms of genes encoding drug-metabolizing enzymes to the pharmacokinetics, pharmacodynamics and tolerance of anti-cancer drugs. Future research should focus on studies using large sample sizes, in the hope that they will provide results of high clinical significance. Due to the potential for ethnic differences to impact on both toxicities and benefits of systemic cancer therapies, the development of new therapeutic agents should include patients from diverse geographical ancestries in each phase of drug development.
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Affiliation(s)
- Viet Hong Phan
- The University of Sydney, Concord Repatriation General Hospital, Sydney Cancer Centre, Concord, NSW, Sydney, Australia
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38
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Aranda E, Abad A, Carrato A, Cervantes A, García-Foncillas J, García Alfonso P, García Carbonero R, Gómez España A, Tabernero JM, Díaz-Rubio E. Treatment recommendations for metastatic colorectal cancer. Clin Transl Oncol 2011; 13:162-78. [PMID: 21421461 DOI: 10.1007/s12094-011-0636-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metastatic colorectal cancer (CRC) represents an important health problem in which several biological predictive and prognostic factors have been identified, including clinical features and molecular markers that might influence the response to treatment. Actually, certain prognostic factors are considered key elements, along with disease extent, for deciding the therapeutic approach. However, a distinction between resectable/potentially resectable and unresectable patients must be made in order to establish an adequate therapeutic strategy. Different drugs and chemotherapy regimens are currently available, and their administration depends on patient characteristics, disease-related factors and the treatment objective. Moreover, special situations such as peritoneal carcinomatosis and local treatment of CRC in the setting of metastatic disease should be considered when deciding the most appropriate treatment strategy. This article reviews all the previously mentioned issues involved in the management of metastatic CRC and suggests some general recommendations for its treatment.
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Affiliation(s)
- Enrique Aranda
- Medical Oncology Department, Hospital Universitario Reina Sofía, Córdoba, Spain.
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39
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Deenen MJ, Cats A, Beijnen JH, Schellens JHM. Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist 2011; 16:992-1005. [PMID: 21659608 DOI: 10.1634/theoncologist.2010-0260] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.
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Affiliation(s)
- Maarten J Deenen
- The Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands
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Crews KR, Cross SJ, McCormick JN, Baker DK, Molinelli AR, Mullins R, Relling MV, Hoffman JM. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm 2011; 68:143-50. [PMID: 21200062 DOI: 10.2146/ajhp100113] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
PURPOSE The development and implementation of a pharmacist-managed clinical pharmacogenetics service are described. SUMMARY A pharmacist-managed clinical pharmacogenetics service was designed and implemented at an academic specialty hospital to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in the hospital's patients. A series of accredited educational seminars were conducted for our pharmacists to establish competencies in providing pharmacogenetic consults for the genes to be tested by the clinical pharmacogenetics service. The service was modeled after and integrated with an already-established clinical pharmacokinetics service. A steering committee was formed to evaluate the use of available tests, new evidence for implementation of additional tests, and other service quality metrics. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consultation. The consultation includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed. The service has been met with positive clinician feedback. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care. CONCLUSION The development of and experience with a pharmacist-managed clinical pharmacogenetics service are described. The program's success has depended on collaboration between the clinical laboratory and pharmacists, and pharmacists' pharmacogenetic recommendations have been well accepted by prescribers.
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Affiliation(s)
- Kristine R Crews
- Pharmaceutical Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
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Wagner L. Camptothecin-based regimens for treatment of ewing sarcoma: past studies and future directions. Sarcoma 2011; 2011:957957. [PMID: 21512587 PMCID: PMC3075817 DOI: 10.1155/2011/957957] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 01/17/2011] [Indexed: 01/01/2023] Open
Abstract
New therapies are needed to improve survival for patients with Ewing sarcoma. Over the past decade, camptothecin agents such as topotecan and irinotecan have demonstrated activity against Ewing sarcoma, especially in combination with alkylating agents. Previous studies have shown camptothecin-based combinations to be tolerable outpatient strategies that are attractive for salvage therapy. This paper highlights important issues related to drug dosing, schedule of administration, pharmacokinetics, toxicity, and activity of commonly used camptothecin-based regimens. Also discussed are strategies for incorporating these regimens into therapy for newly diagnosed patients, including several potential possibilities for combination with targeted agents.
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Affiliation(s)
- Lars Wagner
- Division of Pediatric Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, MLC 7015, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
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Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol 2010; 24:555-71. [PMID: 20955959 DOI: 10.1016/j.bpg.2010.07.007] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Revised: 07/17/2010] [Accepted: 07/22/2010] [Indexed: 02/06/2023]
Abstract
Hyperbilirubinemia is an important clinical sign that often indicates severe hepatobiliary disease of different etiologies. Inherited non-haemolytichyperbilirubinemic conditions include Dubin-Johnson, Rotor, and Gilbert-Meulengracht syndromes, which are important differential diagnoses indicating benign disease that require no immediate treatment. Dubin-Johnson and Rotor syndromes are rare, exhibit mixed direct and indirect hyperbilirubinemia as well as typical profiles or urinary coproporphyrin excretion. Gilbert-Meulengracht disease leads to unconjugated hyperbilirubinemia because of impaired glucuronidation activity, and is part of a spectrum of genetic variants also encompassing fatal Crigler-Najjar syndrome. Gilbert-Meulengracht syndrome can be diagnosed by clinical presentation, biochemistry and genotyping, and carries significance regarding the disposition towards drug-associated toxicity. In addition, the precise diagnosis of these inherited hyperbilirubinemic syndromes avoids unnecessary invasive procedures for suspected more severe hepatobiliary disease.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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43
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Hu ZY, Yu Q, Pei Q, Guo C. Dose-dependent association between UGT1A1*28 genotype and irinotecan-induced neutropenia: low doses also increase risk. Clin Cancer Res 2010; 16:3832-42. [PMID: 20562211 DOI: 10.1158/1078-0432.ccr-10-1122] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE A previous meta-analysis showed that the association between the UGT1A1*28 genotype and irinotecan-induced neutropenia was influenced by irinotecan dose and that the risk of neutropenia was similar at low doses for patients with all genotypes. However, the sample sizes for the low- and high-dose groups were small. Because additional studies have now been reported, an updated and refined meta-analysis is needed. EXPERIMENTAL DESIGN Meta-analyses were done to assess the relationship between UGT1A1*28 and neutropenia. The association between UGT1A1*28 and the relative extent of glucuronidation (REG) of SN-38 was also examined. The studies included were stratified into different dose groups. RESULTS A total of 1,998 patients were included for the analysis of neutropenia and 581 patients were included for REG. The risk of neutropenia at low doses was significantly higher among patients with a UGT1A1*28/*28 genotype than among those carrying the UGT1A1*1 allele(s) [relative risk (RR), 2.43; 95% confidence interval, 1.34-4.39; P = 0.003]. In addition, the RR of neutropenia at low doses was comparable with that at medium doses (2.43 versus 2.00). The RR of neutropenia at high doses was significantly higher than that at low and medium doses (7.22 versus 2.04). We found the weighted mean difference of REG (UGT1A1*1/*1 or UGT1A1*1/*28 versus UGT1A1*28/*28) increased with increasing dose of irinotecan. CONCLUSIONS In conclusion, the UGT1A1*28/*28 genotype was associated with an increased risk of neutropenia not only at medium or high doses of irinotecan but also at low doses. The dose-dependent manner of SN-38 glucuronidation explained why the association between UGT1A1*28 and neutropenia was dose dependent.
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Affiliation(s)
- Zhe-Yi Hu
- Shanghai Institute of Materia Medica and Graduate School, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, PR China.
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Fujiwara Y, Minami H. An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 2010; 11:391-406. [PMID: 20235794 DOI: 10.2217/pgs.10.19] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Recent developments in a number of molecular profiling technologies, including genomic/genetic testing, proteomic profiling and metabolomic analysis have allowed the development of 'personalized medicine'. Irinotecan is one of the models for personalized medicine based on pharmacogenetics, and a number of clinical studies have revealed significant associations between UGT1A1*28 and irinotecan toxicity. Based on this cumulative evidence, the US FDA and pharmaceutical companies revised the irinotecan label in June 2005. However, a recommended strategy for irinotecan-dose adjustments based on individual genetic factors has not yet been fully established. This article provides an overview of recent progress in irinotecan pharmacogenetics and discusses the clinical significance of the UGT1A1 genotype/haplotype with regard to severe irinotecan toxicity.
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Affiliation(s)
- Yutaka Fujiwara
- Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital & Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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De Pas T, Raimondi S, Pelosi G, Spaggiari L, De Braud F, Veronesi G, Maisonneuve P. A critical appraisal of the adjuvant chemotherapy guidelines for patients with completely resected T3N0 non-small-cell lung cancer. Acta Oncol 2010; 49:480-4. [PMID: 20105088 DOI: 10.3109/02841860903490077] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND A Joint Expert Panel recently published guidelines for adjuvant cisplatin-based chemotherapy, recommending routine use in patients with completely resected stage II (T1-2N1 and T3N0) non-small-cell lung cancer (NSCLC). However, these two tumor subgroups should be considered as different entities. While the efficacy of adjuvant chemotherapy has been established in patients with T1-2N1 NSCLC, its benefit in patients with T3N0 tumor remains questionable. MATERIAL AND METHODS We performed an extensive review of the literature using the Joint Expert Panel guidelines as a start point. Altogether, we identified 76 potentially relevant articles. Basing on inclusion and exclusion criteria, 23 of the 76 articles were eventually included in this review. RESULTS After careful evaluation of the selected articles, we found no information on the effect of adjuvant chemotherapy in patients with T3N0 NSCLC. DISCUSSION In the absence of evidence-based data, we recommend that the lack of information on the efficacy of adjuvant chemotherapy for T3N0 tumors be discussed with patients and propose chemotherapy as an individual option. While the efficacy of adjuvant chemotherapy will be difficult to assess prospectively through a large randomized clinical trial, a pooled-analysis of the existing data would quickly and with a limited effort provide a preliminary answer.
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Affiliation(s)
- Tommaso De Pas
- New Drugs Development and Clinical Pharmacology Unit, Department of Medicine, European Institute of Oncology, Milan, Italy.
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Wagner LM, Perentesis JP, Reid JM, Ames MM, Safgren SL, Nelson MD, Ingle AM, Blaney SM, Adamson PC. Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Pediatr Blood Cancer 2010; 54:538-45. [PMID: 20049936 PMCID: PMC3074342 DOI: 10.1002/pbc.22407] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. METHODS Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m(2) administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. RESULTS On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m(2)/day combined with temozolomide 100 mg/m(2)/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m(2)/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m(2)/day, temozolomide 150 mg/m(2)/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m(2)/day, the mean SN-38 AUC(inf) was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received >or=6 courses. CONCLUSIONS The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.
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Affiliation(s)
- Lars M Wagner
- Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
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Piccirillo MC, Daniele G, Di Maio M, Bryce J, De Feo G, Del Giudice A, Perrone F, Morabito A. Vinorelbine for non-small cell lung cancer. Expert Opin Drug Saf 2010; 9:493-510. [DOI: 10.1517/14740331003774078] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
| | - Gennaro Daniele
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Massimo Di Maio
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Jane Bryce
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Gianfranco De Feo
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Antonia Del Giudice
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Francesco Perrone
- Clinical Trials Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy ;
| | - Alessandro Morabito
- Thoraco-Pulmonary Medical Oncology Unit, National Cancer Institute, Via M Semmola, 80131 Napoli, Italy
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Hu ZY, Yu Q, Zhao YS. Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis. Eur J Cancer 2010; 46:1856-65. [PMID: 20335017 DOI: 10.1016/j.ejca.2010.02.049] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Accepted: 02/25/2010] [Indexed: 12/26/2022]
Abstract
Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1*28 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1*28 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1*28 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1*28 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 genotype (OR=3.69, 95% confidence interval [CI]=2.00-6.83; P<0.001). Considering the patients with a UGT1A1*1/*28 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR=1.92, 95% CI=1.31-2.82; P=0.001). No association was observed between UGT1A1*28 and severe diarrhoea at low doses (<125 mg/m(2)). In conclusion, patients carrying UGT1A1*28 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.
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Affiliation(s)
- Zhe-Yi Hu
- Shanghai Institute of Materia Medica and Graduate School, Chinese Academy of Sciences, Shanghai 201203, PR China
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Ruggiero A, Coccia P, Scalzone M, Attinà G, Riccardi R. Treatment of childhood sarcoma with irinotecan: bilirubin level as a predictor of gastrointestinal toxicity. J Chemother 2010; 21:693-7. [PMID: 20071295 DOI: 10.1179/joc.2009.21.6.693] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Irinotecan is a promising anticancer agent for the treatment of childhood cancer unresponsive to conventional chemotherapy. Its active metabolite, 7-ethyl-10 hydroxycamptothecin (SN-38) is glucuronidated by a uridine-diphosphoglucuronosyltransferase (UGT1A1) to form an inactive metabolite. It was supposed that patients with the UGT1A1*28 polymorphism would have a greater prevalence of elevated pretreatment serum bilirubin levels and higher toxicity. The aim of our study was to investigate the predictive value of pre-treatment bilirubin levels in the development of severe diarrhea in solid tumor patients treated with irinotecan. The survey included 14 pediatric patients with refractory sarcomas treated with irinotecan (CPT-11). Patients were grouped based on the development of mild (G0-2) or severe (G3) gastrointestinal toxicity. The simple linear regression model and the non-parametric paired wilcoxon test were adopted for the analysis. p <0.05 was judged to indicate a significant difference. The results showed a significant increase in severity of diarrhea with increasing total pre-treatment bilirubin. therefore, we propose that pre-treatment bilirubin levels can predict gastrointestinal toxicity in pediatric cancer.
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Affiliation(s)
- A Ruggiero
- Division of Pediatric Oncology, Catholic University, Rome, Italy.
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Hazama S, Nagashima A, Kondo H, Yoshida S, Shimizu R, Araki A, Yoshino S, Okayama N, Hinoda Y, Oka M. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Sci 2010; 101:722-7. [PMID: 20028383 PMCID: PMC11159193 DOI: 10.1111/j.1349-7006.2009.01428.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Although individuals carrying the UGT1A1 allele *28 have an increased risk of severe toxicities associated with irinotecan, no phase I study has been conducted based on the polymorphism. This report presents the recommended doses of irinotecan for patients with the respective genotypes. Twenty-seven patients with advanced colorectal cancer were enrolled in this study, and the UGT1A1*28 polymorphism was genotyped before chemotherapy. One course of chemotherapy consisted of irinotecan infused once every 2 weeks at 70, 100, 120, and 150 mg/m(2) at dose levels 1, 2, 3, and 4, respectively, and doxifluridine was administered orally. This treatment continued for at least 12 weeks. The dose-limiting toxicity was determined as grade 3 hematological and non-hematological toxicities for the TA(6)/TA(6) (6/6) and TA(6)/TA(7) (6/7) genotypes. The pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide, was assessed at dose level 2. Eighteen and nine patients had the 6/6 and 6/7 genotypes, respectively. The maximum tolerated dose (MTD) was not observed up to dose level 4 in patients with the 6/6 genotype. In contrast, MTD was observed at dose level 2 (100 mg/m(2)) in patients with the 6/7 genotype. Patients with the 6/7 genotype had a significantly higher area under the plasma time-concentration curve (0-infinity) SN-38 (P = 0.022) and biliary index (P = 0.030) than those with 6/6. The recommended starting doses of biweekly irinotecan for phase II/III were 150 mg/m(2) for patients with the UGT1A1 6/6 genotype and 70 mg/m(2) for those with the 6/7 genotype, respectively. The gene polymorphism should be considered when determining the precise recommended doses to be administered in phase I studies.
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Affiliation(s)
- Shoichi Hazama
- Department of Digestive Surgery and Surgical Oncology (Surgery II), Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
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