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1
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Abuhelwa AY, Badaoui S, Yuen HY, McKinnon RA, Ruanglertboon W, Shankaran K, Tuteja A, Sorich MJ, Hopkins AM. A clinical scoring tool validated with machine learning for predicting severe hand-foot syndrome from sorafenib in hepatocellular carcinoma. Cancer Chemother Pharmacol 2022; 89:479-485. [PMID: 35226112 PMCID: PMC8956540 DOI: 10.1007/s00280-022-04411-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/15/2022] [Indexed: 12/02/2022]
Abstract
Purpose Sorafenib is an effective therapy for advanced hepatocellular carcinoma (HCC). Hand–foot syndrome (HFS) is a serious adverse effect associated with sorafenib therapy. This study aimed to develop an updated clinical prediction tool that allows personalized prediction of HFS following sorafenib initiation. Methods Individual participant data from Phase III clinical trial NCT00699374 were used in Cox proportional hazard analysis of the association between pre-treatment clinicopathological data and grade ≥ 3 HFS occurring within the first 365 days of sorafenib treatment for advanced HCC. Multivariable prediction models were developed using stepwise forward inclusion and backward deletion and internally validated using a random forest machine learning approach. Results Of 542 patients, 116 (21%) experienced grades ≥ 3 HFS. The prediction tool was optimally defined by sex (male vs female), haemoglobin (< 130 vs ≥ 130 g/L) and bilirubin (< 10 vs 10–20 vs ≥ 20 µmol/L). The prediction tool was able to discriminate subgroups with significantly different risks of grade ≥ 3 HFS (P ≤ 0.001). The high (score = 3 +)-, intermediate (score = 2)- and low (score = 0–1)-risk subgroups had 40%, 27% and 14% probability of developing grade ≥ 3 HFS within the first 365 days of sorafenib treatment, respectively. Conclusion A clinical prediction tool defined by female sex, high haemoglobin and low bilirubin had high discrimination for predicting HFS risk. The tool may enable improved evaluation of personalized risks of HFS for patients with advanced HCC initiating sorafenib. Supplementary Information The online version contains supplementary material available at 10.1007/s00280-022-04411-9.
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Affiliation(s)
- Ahmad Y Abuhelwa
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Sarah Badaoui
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Hoi-Yee Yuen
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Ross A McKinnon
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Warit Ruanglertboon
- Department of Pharmacology, Division of Health and Applied Sceinces, Prince of Songkla University, Songkhla, Thailand
| | - Kiran Shankaran
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Anniepreet Tuteja
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Michael J Sorich
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia
| | - Ashley M Hopkins
- College of Medicine and Public Health, Flinders University, Adelaide, SA, 5042, Australia.
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2
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Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management. Int J Womens Dermatol 2022; 7:615-624. [PMID: 35024416 PMCID: PMC8721134 DOI: 10.1016/j.ijwd.2021.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 01/13/2023] Open
Abstract
Cutaneous toxicities are frequent with targeted therapies. Managing cutaneous toxicities is critical for life-saving treatment continuation. Dermatologists can provide a key input in preventing and managing these toxicities. With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.
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Du J, Yan H, Xu Z, Yang B, He Q, Wang X, Luo P. Cutaneous toxicity of FDA-approved small-molecule kinase inhibitors. Expert Opin Drug Metab Toxicol 2021; 17:1311-1325. [PMID: 34743659 DOI: 10.1080/17425255.2021.2004116] [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] [Indexed: 01/06/2023]
Abstract
INTRODUCTION By 1 January 2021, the FDA has approved a total of 62 small-molecule kinase inhibitors (SMKIs). The increasing clinical use of small-molecule kinase inhibitors has led to some side effects, the most common of which is cutaneous toxicity, as reflected by approximately 90% (57 of 62) of the FDA-approved SMKIs have reported treatment-related cutaneous toxicities. Since these cutaneous toxicities may have a crucial influence on the emotional, physical and psychosocial health of the patients, it is of great importance for doctors, patients, oncologists and interrelated researchers to be aware of the cutaneous side effects of these drugs in order to make the diagnosis accurate and the treatment appropriate. AREAS COVERED This review aims to summarize the potential cutaneous toxicities and the frequency of occurrence of FDA-approved 62 SMKIs, and provide a succinct overview of the potential mechanisms of certain cutaneous toxicities. The literature review was performed based on PubMed database and FDA official website. EXPERT OPINION It is significant to determine the risk factors for SMKI-induced cutaneous toxicity. The mechanisms underlying SMKI-induced cutaneous toxicities remain unclear at present. Future research should focus on the mechanisms of SMKI-induced cutaneous toxicities to find out mechanistically driven therapies.
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Affiliation(s)
- Jiangxia Du
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaohong Wang
- Department of Chemotherapy, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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4
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Naveed H, Reglin C, Schubert T, Gao X, Arold ST, Maitland ML. Identifying Novel Drug Targets by iDTPnd: A Case Study of Kinase Inhibitors. GENOMICS PROTEOMICS & BIOINFORMATICS 2021; 19:986-997. [PMID: 33794377 PMCID: PMC9403029 DOI: 10.1016/j.gpb.2020.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/08/2020] [Accepted: 05/11/2020] [Indexed: 11/16/2022]
Abstract
Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52% and a specificity of 55%. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein–small molecule interactions, when sufficient drug–target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.
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Affiliation(s)
- Hammad Naveed
- Toyota Technological Institute at Chicago, Chicago, IL 60637, USA; Department of Computer Science, National University of Computer and Emerging Sciences, Islamabad 44000, Pakistan.
| | | | | | - Xin Gao
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal 23955, Saudi Arabia
| | - Stefan T Arold
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Biological and Environmental Sciences and Engineering (BESE) Division, Thuwal 23955, Saudi Arabia
| | - Michael L Maitland
- Inova Center for Personalized Health and Schar Cancer Institute, Falls Church, VA 22042 USA,; University of Virginia Cancer Center, Annandale, Virginia 22003, USA
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5
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Tomita Y, Kondo T, Kimura G, Inoue T, Wakumoto Y, Yao M, Sugiyama T, Oya M, Fujii Y, Obara W, Motzer RJ, Uemura H. Nivolumab plus ipilimumab versus sunitinib in previously untreated advanced renal-cell carcinoma: analysis of Japanese patients in CheckMate 214 with extended follow-up. Jpn J Clin Oncol 2020; 50:12-19. [PMID: 31633185 PMCID: PMC6978670 DOI: 10.1093/jjco/hyz132] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/01/2019] [Accepted: 08/02/2019] [Indexed: 12/04/2022] Open
Abstract
Background Nivolumab plus ipilimumab (NIVO+IPI) demonstrated superior efficacy over sunitinib (SUN) for previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214, with a manageable safety profile. We report efficacy and safety with extended follow-up amongst Japanese patients. Methods CheckMate 214 patients received NIVO (3 mg/kg) plus IPI (1 mg/kg) every 3 weeks for four doses, then NIVO (3 mg/kg) every 2 weeks; or SUN (50 mg) once daily for 4 weeks (6-week cycle). This subgroup analysis assessed overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) per investigator in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk and intent-to-treat (ITT) patients and safety (ITT patients). Results Of 550 and 546 patients randomized to NIVO+IPI and SUN, 38 and 34, respectively, were Japanese. Of these, 31 (NIVO+IPI) and 29 (SUN) patients were IMDC intermediate/poor-risk. In IMDC intermediate/poor-risk patients with 30 months’ minimum follow-up, there was a delayed trend in OS benefit with NIVO+IPI (hazard ratio [HR] 0.56; 95% confidence interval [CI]: 0.19–1.59; P = 0.2670), and 24-month OS probability favoured NIVO+IPI (84%) versus SUN (76%). The ORR was 39% with NIVO+IPI and 31% with SUN (P = 0.6968). PFS was similar in both treatment arms (HR 1.17; 95% CI: 0.62–2.20; P = 0.6220). Efficacy in ITT patients was similar to IMDC intermediate/poor-risk patients. Grade 3–4 treatment-related adverse event incidence was lower with NIVO+IPI versus SUN (58 versus 91%). Conclusions Japanese patients with untreated aRCC in the NIVO+IPI arm had a numerically higher ORR and improved safety profile versus patients in the SUN arm. A delayed OS benefit appears to be emerging with NIVO+IPI. Longer follow-up is needed. https://clinicaltrials.gov/ct2/show/NCT02231749?term=NCT02231749&rank=1 identifier: NCT02231749.
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Affiliation(s)
- Yoshihiko Tomita
- Department of Urology, Niigata University, Niigata, Japan
- Department of Urology, Yamagata University Hospital, Yamagata, Japan
- For reprints and all correspondence: Yoshihiko Tomita, Department of Urology, Niigata University, Asahimachi 1-757, Niigata 951-8510, Japan. E-mail:
| | - Tsunenori Kondo
- Department of Urology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
| | - Go Kimura
- Department of Urology, Nippon Medical School Hospital, Tokyo, Japan
| | - Takamitsu Inoue
- Department of Urology, Akita University Hospital, Akita, Japan
| | | | - Masahiro Yao
- Department of Urology, Yokohama City University Hospital, Yokohama, Japan
| | - Takayuki Sugiyama
- Department of Urology, Hamamatsu University Hospital, Hamamatsu, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University Hospital, Tokyo, Japan
| | - Yasuhisa Fujii
- Department of Surgery, Urology, Tokyo Medical and Dental University Hospital, University Hospital of Medicine, Tokyo, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University Hospital, Morioka, Japan
| | - Robert J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer, New York, NY, USA
| | - Hirotsugu Uemura
- Department of Urology, Kinki University Hospital, Faculty of Medicine, Osakasayama, Japan
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6
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Ferreira MN, Ramseier JY, Leventhal JS. Dermatologic conditions in women receiving systemic cancer therapy. Int J Womens Dermatol 2019; 5:285-307. [PMID: 31909148 PMCID: PMC6938835 DOI: 10.1016/j.ijwd.2019.10.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 12/24/2022] Open
Abstract
As advances in cancer therapies have improved cancer-related survival, novel therapeutics have also introduced a variety of dermatologic toxicities, and an increased number of patients are living with these sequalae. Women with cancer in particular experience a spectrum of dermatologic conditions that affect their skin, hair, nail, and mucosal surfaces. Studies have shown that these toxic effects can significantly affect quality of life and alter a woman's self-image, cultural identity, femininity, sexuality, and mental health. In severe instances, dermatologic toxicities may even disrupt cancer therapy and can therefore affect overall survival and treatment response. In this article, we review the dermatologic adverse effects from traditional chemotherapy, targeted therapy, immune checkpoint inhibitors, and endocrine therapy that disproportionately affect women. The timely diagnosis and management of these dermatologic conditions is crucial in the multidisciplinary care of women with cancer.
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7
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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8
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Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the Phase III CheckMate 025 study. Jpn J Clin Oncol 2019; 49:506-514. [PMID: 30941424 DOI: 10.1093/jjco/hyz026] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/04/2019] [Accepted: 03/20/2019] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups. METHODS Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life. RESULTS Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval [CI]: 0.63-0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50-2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio [OR] 6.19; 95% CI: 3.82-10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60-28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%). CONCLUSIONS At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.
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Affiliation(s)
- Yoshihiko Tomita
- Current affiliation: Department of Urology, Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata.,Department of Urology, Yamagata University Hospital, Yamagata
| | - Satoshi Fukasawa
- Prostate Center and Division of Urology, Chiba Cancer Center, Chiba
| | | | - Hiroshi Kitamura
- Current affiliation: Department of Urology, University of Toyama, Toyama.,Department of Urology, Sapporo Medical University Hospital, Sapporo
| | - Mototsugu Oya
- Department of Urology, Keio University Hospital, Tokyo
| | - Masatoshi Eto
- Current affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka.,Department of Urology, Kumamoto University, Kumamoto
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University Hospital, Tokyo
| | - Mitsuru Saito
- Department of Urology, Akita University Hospital, Akita
| | - Go Kimura
- Department of Urology, Nippon Medical School Hospital, Tokyo
| | - Junji Yonese
- Department of Urology, Cancer Institute Hospital, Tokyo
| | - Masahiro Yao
- Department of Urology, Yokohama City University Hospital, Yokohama
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
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10
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Wang L, Min Z, Wang X, Hu M, Song D, Ren Z, Cheng Y, Wang Y. Arsenic trioxide and sorafenib combination therapy for human hepatocellular carcinoma functions via up-regulation of TNF-related apoptosis-inducing ligand. Oncol Lett 2018; 16:3341-3350. [PMID: 30127933 DOI: 10.3892/ol.2018.8981] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 04/27/2018] [Indexed: 12/18/2022] Open
Abstract
The survival benefits of sorafenib treatment for patients with hepatocellular carcinoma (HCC) are limited due to drug resistance and side effects. Therefore, combinations of sorafenib with other low toxicity drugs, including arsenic trioxide (As2O3) require investigation. The present study aimed to evaluate the potency of apoptosis-induction by As2O3/sorafenib treatment in HCC cell lines, Huh7, 97H and freshly-isolated HCC cells, and also to elucidate the underlying mechanism. A total of 10 patients with HCC were enrolled in the present study. Freshly-isolated HCC cells were purified from HCC tissues collected at surgery. HCC-cell apoptosis was measured by flow cytometry using proprium iodide/Annexin-V staining. The impacts of As2O3 and/or sorafenib on Huh7, 97H and fresh-isolated HCC-cell proliferation were evaluated by Cell Counting Kit-8 assay. The expression of TNF-related apoptosis-inducing ligand (TRAIL) was determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The downregulation of TRAIL protein expression was achieved using small interfering RNA. The combination of As2O3 and sorafenib had anti-proliferative and pro-apoptotic effects in the liver cancer cell line, Huh7, via increased expression of TRAIL, but not in 97H cells. TRAIL-knockdown increased the drug-resistance of Huh7 cells. Freshly-isolated HCC cells were more sensitive to the As2O3 and sorafenib combination than the single drug treatments. Overall, the combination of As2O3 and sorafenib demonstrated potent anti-tumor activity in Huh7 and freshly-isolated HCC cells via a TRAIL-dependent pathway. This may be a potential therapeutic approach for advanced HCC treatment.
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Affiliation(s)
- Lingyan Wang
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhihui Min
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Xiangdong Wang
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Mushuang Hu
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Dongli Song
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Yunfeng Cheng
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.,Department of Hematology, Zhongshan Hospital Qingpu Branch, Shanghai 201700, P.R. China
| | - Yanhong Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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11
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Liu F, Wang G, Wang X, Che Z, Dong W, Guo X, Wang Z, Chen P, Hou D, Zhang Q, Zhang W, Pan Y, Yang D, Liu H. Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma. Oncotarget 2018; 8:27953-27965. [PMID: 28427193 PMCID: PMC5438621 DOI: 10.18632/oncotarget.15853] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/20/2017] [Indexed: 12/16/2022] Open
Abstract
The Aurora kinases A and B control tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, however, it remains unknown whether Aurora A and B overexpressed concomitantly and its clinical significance in hepatocellular carcinoma (HCC). Here, we obsearved Aurora A and B tended to overexpress parallelly on protein level (r = 0.8679, P < 0.0001) and their co-overexpression (Aurora AHBH), associated with the worst prognosis, was an independent predictor for the survival. Importantly, with the lower IC50 and stronger anti-tumor effect than selective inhibitors, SNS-314, the pan-inhibitor of Aurora kinases, which induced YAP (Yes-associated protein) reduction and resulted in P21 accumulation, significantly promoted the polyploidy (> 4N) formation and apoptosis in HCC. High YAP expression (YAPH) was associated with Aurora AHBH, and appeared to be an independent predictor for survival, but P21 not. Moreover, silencing YAP also induced P21 accumulation, and knockdown P21, which enhanced YAP accumulation and weakened the SNS-314-induced YAP reduction, impaired SNS-314-induced apoptosis. Therefore, P21 enhanced the apoptotic effect of SNS-314 in HCC. Taken together, our findings indicated Aurora kinases/YAP/P21 was an oncogenic signaling axis in HCC, and revealed targeting Aurora AHBH induced apoptosis by YAP suppression. Our results also provided a solid evidence for SNS-314 as a potential targeted therapy, and a proof-of-concept evidence for a possible combined therapy of SNS-314 plus Hippo pathway inhibitors on HCC.
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Affiliation(s)
- Fuchen Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.,Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Guangyong Wang
- Department of Gastroenterology, 411 Hospital of PLA, Shanghai 200081, China
| | - Xiaoqiang Wang
- Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhihui Che
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Wei Dong
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Xinggang Guo
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Zhenguang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Ping Chen
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Daisen Hou
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Qi Zhang
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Wenli Zhang
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Yida Pan
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Dongqin Yang
- Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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12
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Yamamoto K, Yano I. Genetic polymorphisms associated with adverse reactions of molecular-targeted therapies in renal cell carcinoma. Med Oncol 2018; 35:16. [PMID: 29302760 DOI: 10.1007/s12032-017-1077-0] [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: 11/22/2017] [Accepted: 12/27/2017] [Indexed: 12/28/2022]
Abstract
The prognosis of patients with metastatic renal cell carcinoma has drastically improved due to the development of molecular-targeted drugs and their use in clinical practice. However, these drugs cause some diverse adverse reactions in patients and sometimes affect clinical outcomes of cancer therapy. Therefore, predictive markers are necessary to avoid severe adverse reactions, to establish novel and effective prevention methods, and to improve treatment outcomes. Some genetic factors involved in these adverse reactions have been reported; however, perspectives on each adverse response have not been integrated yet. In this review, genetic polymorphisms relating to molecular-targeted therapy-induced adverse reactions in patients with renal cell carcinoma are summarized in the points of pharmacokinetic and pharmacodynamic mechanisms. We also discuss about the relationship between systemic drug exposure and adverse drug reactions.
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Affiliation(s)
- Kazuhiro Yamamoto
- Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Ikuko Yano
- Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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13
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Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Kimura G, Yonese J, Yao M, Motzer RJ, Uemura H, McHenry MB, Berghorn E, Ozono S. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study. Jpn J Clin Oncol 2017; 47:639-646. [PMID: 28419248 PMCID: PMC5896687 DOI: 10.1093/jjco/hyx049] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/03/2017] [Indexed: 12/21/2022] Open
Abstract
Background Nivolumab improved overall survival (OS) and objective response rate (ORR) versus everolimus in previously treated patients with advanced renal cell carcinoma in the phase III CheckMate 025 study (minimum follow-up: 14 months). We report efficacy and safety in the global and Japanese populations (minimum follow-up: 26 months). Methods Patients were randomized 1:1 to receive nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10-mg tablet orally once daily. Primary endpoint: OS, key secondary endpoints: ORR, progression-free survival and safety. Results Of 410 (nivolumab) and 411 (everolimus) patients, 37 (9%) and 26 (6%), respectively, were Japanese. Median OS for the global population was 26.0 months (nivolumab) and 19.7 months (everolimus; hazard ratio 0.73 [95% confidence interval [CI]: 0.61-0.88]; P = 0.0006), with medians not reached for Japanese patients. ORR for the global population was 26% (nivolumab) versus 5% (everolimus; odds ratio 6.13; 95% CI: 3.77-9.95); ORR for Japanese patients: 43% versus 8% (odds ratio 9.14; 95% CI: 1.76-88.33). In Japanese patients, any-grade treatment-related adverse events (AEs) occurred in 78% (Grade 3-4, 19%; most common, anemia [5%]) treated with nivolumab and 100% (Grade 3-4, 58%; most common, hypertriglyceridemia [12%]) treated with everolimus; the most common with nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of life was stable in the nivolumab arm. Conclusions With >2 years of follow-up, Japanese patients had a higher response rate with nivolumab versus everolimus that was more pronounced yet consistent with the global population, with median OS not reached, and a favorable safety profile.
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Affiliation(s)
- Yoshihiko Tomita
- Department of Urology, Yamagata University Hospital, Yamagata.,Department of Urology, Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Satoshi Fukasawa
- Prostate Center and Division of Urology, Chiba Cancer Center, Chiba
| | | | - Hiroshi Kitamura
- Department of Urology, Sapporo Medical University Hospital, Sapporo.,Department of Urology, University of Toyama, Toyama, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University Hospital, Tokyo
| | - Masatoshi Eto
- Department of Urology, Kumamoto University, Kumamoto.,Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University Hospital, Tokyo
| | - Go Kimura
- Department of Urology, Nippon Medical School Hospital, Tokyo
| | - Junji Yonese
- Department of Urology, Cancer Institute Hospital, Tokyo
| | - Masahiro Yao
- Department of Urology, Yokohama City University Hospital, Yokohama, Japan
| | - Robert J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - M Brent McHenry
- Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Elmer Berghorn
- Global Clinical Research, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Seiichiro Ozono
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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14
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Abstract
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
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Affiliation(s)
- Anton Ivanyuk
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland.
| | - Françoise Livio
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
| | - Jérôme Biollaz
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
| | - Thierry Buclin
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
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15
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Numakura K, Tsuchiya N, Kagaya H, Takahashi M, Tsuruta H, Inoue T, Narita S, Huang M, Satoh S, Niioka T, Miura M, Habuchi T. Clinical effects of single nucleotide polymorphisms on drug-related genes in Japanese metastatic renal cell carcinoma patients treated with sunitinib. Anticancer Drugs 2017; 28:97-103. [DOI: 10.1097/cad.0000000000000425] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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16
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Tomita Y, Fukasawa S, Oya M, Uemura H, Shinohara N, Habuchi T, Rini BI, Chen Y, Bair AH, Ozono S, Naito S, Akaza H. Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a randomized, double-blind phase II study. Jpn J Clin Oncol 2016; 46:1031-1041. [PMID: 27572087 PMCID: PMC5091032 DOI: 10.1093/jjco/hyw103] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 06/03/2016] [Accepted: 07/03/2016] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. METHODS The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. RESULTS The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. CONCLUSIONS Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation.
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Affiliation(s)
- Yoshihiko Tomita
- Department of Urology, Yamagata University Faculty of Medicine, Yamagata
| | - Satoshi Fukasawa
- Prostate Center and Division of Urology, Chiba Cancer Center, Chiba
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo
| | - Hirotsugu Uemura
- Department of Urology, Kinki University School of Medicine, Osaka
| | - Nobuo Shinohara
- Department of Urology, Hokkaido University Graduate School of Medicine, Hokkaido
| | - Tomonori Habuchi
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Brian I. Rini
- Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | | | | | - Seiichiro Ozono
- Department of Urology, Hamamatsu University School of Medicine, Shizuoka
| | - Seiji Naito
- Department of Urology, Kyushu University, Graduate School of Medical Sciences, Fukuoka
| | - Hideyuki Akaza
- Strategic Investigation on Comprehensive Cancer Network, Interfaculty Initiative in Information Studies/Graduate School of Interdisciplinary Information Studies, The University of Tokyo, Tokyo, Japan
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17
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Neul C, Schaeffeler E, Sparreboom A, Laufer S, Schwab M, Nies AT. Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol Sci 2016; 37:904-932. [PMID: 27659854 DOI: 10.1016/j.tips.2016.08.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/18/2016] [Accepted: 08/19/2016] [Indexed: 12/21/2022]
Abstract
Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.
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Affiliation(s)
- Claudia Neul
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
| | - Alex Sparreboom
- Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH, USA
| | - Stefan Laufer
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
| | - Anne T Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
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18
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Bins S, Lenting A, El Bouazzaoui S, van Doorn L, Oomen-de Hoop E, Eskens FA, van Schaik RH, Mathijssen RH. Polymorphisms in SLCO1B1 and UGT1A1 are associated with sorafenib-induced toxicity. Pharmacogenomics 2016; 17:1483-90. [PMID: 27533851 DOI: 10.2217/pgs-2016-0063] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIM Sorafenib-treated patients display a substantial variation in the incidence of toxicity. We aimed to investigate the association of genetic polymorphisms with observed toxicity on sorafenib. PATIENTS & METHODS We genotyped 114 patients that were treated with sorafenib at the Erasmus MC Cancer Institute, the Netherlands, for SLCO1B1, SLCO1B3, ABCC2, ABCG2, UGT1A1 and UGT1A9. RESULTS The UGT1A1 (rs8175347) polymorphism was associated with hyperbilirubinemia and treatment interruption. Polymorphisms in SLCO1B1 (rs2306283, rs4149056) were associated with diarrhea and thrombocytopenia, respectively. None of the investigated polymorphisms was associated with overall or progression-free survival in hepatocellular cancer patients. CONCLUSION Polymorphisms in SLCO1B1 and UGT1A1 are associated with several different sorafenib side effects.
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Affiliation(s)
- Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Anne Lenting
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Samira El Bouazzaoui
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Leni van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ferry Alm Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ron Hn van Schaik
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ron Hj Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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Chanprapaph K, Rutnin S, Vachiramon V. Multikinase Inhibitor-Induced Hand-Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management. Am J Clin Dermatol 2016; 17:387-402. [PMID: 27221667 DOI: 10.1007/s40257-016-0197-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Multikinase inhibitors (MKIs) are targeted cancer therapies designed to inhibit multiple tyrosine kinase pathways responsible for tumor proliferation, growth, and survival. These agents are more able to target cancer cells and possess better safety profiles than conventional chemotherapies. However, MKIs can produce significant cutaneous adverse events, hand-foot skin reaction (HFSR) being the most clinically significant. Although not life threatening, HFSR can lead to MKI dose modification, interruption, or termination, potentially limiting the anti-tumor effect. This article summarizes the current knowledge concerning the epidemiology, clinical presentation, pathogenesis, histopathology, prognostic implication, and current evidence-based prophylactic and reactive treatment options for MKI-induced HFSR. Its high incidence and significant impact on the quality of life emphasizes the great need to understand the pathogenesis and improve management of this condition.
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Affiliation(s)
- Kumutnart Chanprapaph
- Division of Dermatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok, 10400, Thailand.
| | - Suthinee Rutnin
- Division of Dermatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok, 10400, Thailand
| | - Vasanop Vachiramon
- Division of Dermatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok, 10400, Thailand
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20
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Diekstra MHM, Swen JJ, Gelderblom H, Guchelaar HJ. A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review. Expert Rev Mol Diagn 2016; 16:605-18. [PMID: 26837796 DOI: 10.1586/14737159.2016.1148601] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The individual response to targeted tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell cancer (mRCC) is highly variable. Outlined in this article are findings on potential biomarkers for TKI treatment outcome in mRCC and an evaluation of the status of clinical implementation. METHODS Articles were selected by two independent reviewers using a systematic search in five medical databases on renal cell carcinoma, TKIs, and pharmacogenetics. RESULTS Many researchers have focused on predictive biomarkers for treatment outcome of targeted therapies in mRCC patients. Attempts to explain differences in efficacy and toxicity of TKIs by use of genetic variants in genes related to the pharmacokinetics and pharmacodynamics of the drug have been successful. CONCLUSION Most findings on potential biomarkers have not been validated and therefore biomarker testing to guide choice of therapy and dose in mRCC is not yet feasible.
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Affiliation(s)
- Meta H M Diekstra
- a Department of Clinical Pharmacy and Toxicology , Leiden University Medical Center , Leiden , Netherlands
| | - Jesse J Swen
- a Department of Clinical Pharmacy and Toxicology , Leiden University Medical Center , Leiden , Netherlands
| | - Hans Gelderblom
- b Department of Medical Oncology , Leiden University Medical Center , Leiden , Netherlands
| | - Henk-Jan Guchelaar
- a Department of Clinical Pharmacy and Toxicology , Leiden University Medical Center , Leiden , Netherlands
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Zheng Y, Wang F, Wu G, Zhang L, Wang Y, Wang Z, Chen P, Wang Q, Lu J, Wang Y, Li P, Wang J, Lu X, Yuan J. The Relationship Between the Adverse Events and Efficacy of Sorafenib in Patients With Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Study from Northwest China. Medicine (Baltimore) 2015; 94:e2222. [PMID: 26656362 PMCID: PMC5008507 DOI: 10.1097/md.0000000000002222] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
The aim of the study is to evaluate the relationship between the adverse events and efficacy of sorafenib in patients with metastatic renal cell carcinoma (mRCC), with a purpose to guide the judgment of efficacy in sorafenib treatment.Eighty-three mRCC patients who received sorafenib therapy at northwest China were studied retrospectively. Univariate and multivariate analyses were performed to correlate tumor response, progression-free survival (PFS), and overall survival (OS) with adverse event types and grades.Among 83 patients who underwent sorafenib therapy, 2 cases (2.4%) had completed response (CR), 14 cases (16.9%) had partial response (PR), 57 cases (68.7%) had stable disease (SD), and 10 cases (12.0%) developed progressive disease (PD). The median PFS and OS were 15.0 and 29.0 months, respectively. The most frequent grade 1 or 2 adverse events included hand-foot syndrome (68.7%), diarrhea (54.2%), and alopecia (51.8%). The most common grade 3 or 4 adverse events were hand-foot syndrome (6.0%), hypertension (4.8%), and diarrhea (3.6%). The frequency and severity of adverse events correlated with tumor response rate (both with P < 0.05). Multivariate analysis showed the independent predictors of better PFS included rash (OR 0.307, 95%CI 0.148-0.636, P = 0.001) and diarrhea (OR 0.391, 95%CI 0.169-0.783, P = 0.008). Elevated transaminase was the independent predictor of poor PFS (OR 2.606, 95%CI 1.299-5.532, P = 0.012). For OS, rash (OR 0.473, 95%CI 0.253-0.886, P = 0.019) and diarrhea (OR 0.321, 95%CI 0.171-0.605, P = 0.000) correlated with better OS.Sorafenib-related adverse events are associated with efficacy in patients with mRCC from northwest China. Rash and diarrhea are independent protective factors of both PFS and OS, and elevated transaminase is an independent risk factor of PFS. A large prospective study is warranted.
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Affiliation(s)
- Yu Zheng
- From the Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province (YZ, FW, GW, LZ, JY); Department of Urology, General Hospital of Lanzhou Military Area Command of Chinese PLA (YW); Department of Urology, The Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu Province (ZW); Department of Urology, Affiliated Tumor Hospital of Xinjang Medical University (PC); Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi (QW); Department of Urology, Xinjiang karamay Central Hospital, Karamay (JL); Department of Urology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region (YW); Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region (PL); Department of Urology, Qinghai University Affiliated Hospital, Xining, QingHai Province (JW); and Department of Urology, First People's Hospital of Shizuishan, Shizuishan, Ningxia Hui Autonomous Region, China (XL)
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Yamamoto K, Shinomiya K, Ioroi T, Hirata S, Harada K, Suno M, Nishioka T, Kume M, Makimoto H, Nakagawa T, Hirano T, Bito T, Nishigori C, Miyake H, Fujisawa M, Hirai M. Association of Single Nucleotide Polymorphisms in STAT3 with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors: A Retrospective Analysis in Japanese Patients. Target Oncol 2015; 11:93-9. [DOI: 10.1007/s11523-015-0382-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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McLellan B, Ciardiello F, Lacouture ME, Segaert S, Van Cutsem E. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol 2015; 26:2017-26. [PMID: 26034039 PMCID: PMC4576906 DOI: 10.1093/annonc/mdv244] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/12/2015] [Indexed: 12/13/2022] Open
Abstract
Regorafenib is an oral multikinase inhibitor licensed for use in gastrointestinal cancers. In clinical trials, regorafenib showed a consistent toxicity profile, including clinically significant hand–foot skin reaction (HFSR). Treatment modifications and symptomatic measures, as recommended in this review, can be used to manage HFSR and help patients to continue treatment at an optimal dose. Background Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand–foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. Design This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. Results Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand–foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical experience with other multikinase inhibitors and cytotoxic chemotherapies. Conclusions As recommended in this review, treatment modifications and supportive measures to prevent, reduce, and manage HFSR can allow patients to continue regorafenib at the optimal dose to derive benefit from treatment.
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Affiliation(s)
- B McLellan
- Albert Einstein College of Medicine and Jacobi Medical Center, Bronx, USA
| | - F Ciardiello
- Seconda Università degli Studi di Napoli, Napoli, Italy
| | - M E Lacouture
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - S Segaert
- University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - E Van Cutsem
- University Hospitals Leuven and KU Leuven, Leuven, Belgium
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25
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Ye D, Eto M, Chung JS, Kimura G, Chang WC, Chang YH, Pang ST, Lee JL, Niu Y, Gurney H, Uemura H. Use of targeted therapies for advanced renal cell carcinoma in the Asia-Pacific region: opinion statement from China, Japan, Taiwan, Korea, and Australia. Clin Genitourin Cancer 2014; 12:225-33. [PMID: 24630778 DOI: 10.1016/j.clgc.2014.01.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/17/2014] [Accepted: 01/23/2014] [Indexed: 01/20/2023]
Abstract
Rates of renal cell carcinoma (RCC) morbidity and mortality vary widely by geography, with increasing incidence in most countries. Interestingly, RCC incidence is significantly lower in Asian countries relative to other regions, which is attributed to environmental and genetic influences. Additionally, it has been demonstrated that different ethnic groups differ in their RCC characteristics which might lead to varied responses to therapy. In this review, physicians drawn from countries across the Asia-Pacific region--China, Japan, Taiwan, Republic of Korea, and Australia--take all available data into consideration to develop the first opinion statement on treatment of advanced RCC in the region. We have sought to determine what factors influence treatment patterns and availability of therapeutic agents in our respective countries, discussed whether these factors are fully justified or should be modified, and considered what additional efforts should be undertaken to optimize treatment outcomes in RCC. Additionally, we have addressed the limitations on treatment of RCC in the region, capturing the restrictive situations of targeted therapy use in the Asia-Pacific region, mainly because of drug availability and treatment reimbursement. Often this illustrates the gap between Western and regional or even among local guidelines, the opinions of leading physicians regarding the treatment, and the realistic access to agents for most patients. Proposals made in this document are based on clinical experience and data from clinical trials of RCC therapies in which Asian patients have been included.
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Affiliation(s)
- Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
| | - Masatoshi Eto
- Department of Urology, Kumamoto University, Kumamoto, Japan
| | - Jin Soo Chung
- National Cancer Center, Goyang-si Gyeonggi-do, Republic of Korea
| | - Go Kimura
- Department of Urology, Nippon Medical School Hospital, Tokyo, Japan
| | - Wen-Cheng Chang
- Department of Hematology-Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yen-Hwa Chang
- Department of Surgery, Division of Urology, Taipei-Veterans General Hospital, Taipei, Taiwan
| | - See-Tong Pang
- Department of Surgery, Division of Urology, Chang Gung Memorial Hospital, TaoYuan, Taiwan
| | - Jae Lyun Lee
- Department of Oncology, Urologic Oncology Section, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Yuanjie Niu
- The Second Hospital of Tianjin Medical Hospital, Tianjin, China
| | - Howard Gurney
- Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia
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26
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Ikeda M, Fujita T, Amoh Y, Mii S, Matsumoto K, Iwamura M. Stevens-Johnson syndrome induced by sorafenib for metastatic renal cell carcinoma. Urol Int 2013; 91:482-3. [PMID: 23969404 DOI: 10.1159/000351918] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 04/22/2013] [Indexed: 11/19/2022]
Abstract
Sorafenib is an orally administered active multikinase inhibitor for metastatic renal cell carcinoma that is now considered a standard agent. Skin toxicity, such as hand-foot skin reaction, is one of the frequent adverse effects of sorafenib. On the other hand, sorafenib-induced erythema multiforme is very rare, and Stevens-Johnson syndrome and toxic epidermal necrolysis induced by sorafenib have not been reported. We report the first case of Stevens-Johnson syndrome caused by sorafenib for metastatic renal cell carcinoma.
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Affiliation(s)
- Masaomi Ikeda
- Departments of Urology and Dermatology, Kitasato University School of Medicine, Sagamihara, Japan
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