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1
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Cicala CM, Bauer S, Heinrich MC, Serrano C. Gastrointestinal Stromal Tumor: Current Approaches and Future Directions in the Treatment of Advanced Disease. Hematol Oncol Clin North Am 2025:S0889-8588(25)00044-9. [PMID: 40368739 DOI: 10.1016/j.hoc.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
This review discusses the current and future landscape of advanced gastrointestinal stromal tumor (GIST) treatment. It covers the role of tyrosine kinase inhibitors (TKIs), specifically imatinib, and further treatment options, such as sunitinib, regorafenib, and ripretinib, as well as avapritinib for platelet-derived growth factor receptor alpha D842V mutations. In addition, this review emphasizes individualized treatment strategies within multidisciplinary expert teams, including surgery and other locoregional therapies, together with the importance of mutation-guided approaches, particularly for wild-type GISTs. Finally, it explores the potential of next-generation KIT inhibitors, combination therapies, and other investigational approaches.
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Affiliation(s)
- Carlo M Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Carrer de Natzaret 115-117, 08035 Barcelona, Spain
| | - Sebastian Bauer
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, and DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Hufelandstraße 55, Essen 45122, Germany
| | - Michael C Heinrich
- Division of Hematology and Medical Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, R&D-19 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA
| | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Carrer de Natzaret 115-117, 08035 Barcelona, Spain.
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2
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Beecroft JR, Brar S, Feng X, Hamilton T, Han-Lee C, Henning JW, Josephy PD, Khalili K, Ko YJ, Lemieux C, Liu DM, MacDonald DB, Noujaim J, Pollett A, Salawu A, Saleh R, Smrke A, Warren BE, Zbuk K, Razak AA. Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada. Ther Adv Med Oncol 2024; 16:17588359241266179. [PMID: 39386314 PMCID: PMC11461906 DOI: 10.1177/17588359241266179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/18/2024] [Indexed: 10/12/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.
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Affiliation(s)
- J. Robert Beecroft
- Division of Interventional Radiology, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, ON, Canada
| | - Savtaj Brar
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Xiaolan Feng
- Division of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Trevor Hamilton
- Department of Surgery, BC Cancer, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Cheng Han-Lee
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada
| | - Jan-Willem Henning
- Department of Oncology, Tom Baker Cancer Centre, Cuming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Korosh Khalili
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Department of Medicine, St. Michael’s Hospital, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christopher Lemieux
- Division of Hematology and Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada
| | - David M. Liu
- Department of Radiology, University of British Columbia, School of Biomedical Engineering, Vancouver, BC, Canada
- Department of Interventional Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - D. Blair MacDonald
- Department of Medical Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan Noujaim
- Division of Medical Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Aaron Pollett
- Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Abdulazeez Salawu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Ramy Saleh
- Division of Medical Oncology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alannah Smrke
- Division of Medical Oncology, BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Blair E. Warren
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Kevin Zbuk
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, 610 University Ave., Toronto, ON M2G 2M9, Canada
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De Luca I, Miliziano D, Guerra G, Colombo R, Morosi C, Sposito C, Fiore M, Venturelli E, Sangalli C, Casali PG, Cavalleri A, Fumagalli E. Hemodialysis and imatinib: Plasma levels, efficacy and tolerability in a patient with metastatic GIST - Case report. Heliyon 2024; 10:e28494. [PMID: 38596050 PMCID: PMC11002597 DOI: 10.1016/j.heliyon.2024.e28494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 04/11/2024] Open
Abstract
Purpose To study plasma levels, efficacy and tolerability of imatinib in a patient affected by metastatic GIST treated with oral Imatinib and undergoing hemodialysis. Patients and methods The patient suffered from metastatic GIST to the liver having a mutation of exon 9 of KIT. He was on hemodialysis and received first-line treatment with imatinib 400 mg/day. Results The overall mean plasma level of imatinib was 1875,4 ng/ml pre-dialysis, 1553,0 ng/ml post-dialysis and 1998,1 ng/ml post-24h. In red blood cells the overall mean level of imatinib was 619,5 ng/ml pre-dialysis, 484,9 ng/ml post-dialysis and 663,1 ng/ml post-24h. The plasma level of nor-imatinib/imatinib was 16,2% pre-dialysis, 15,6% post-dialysis and 16,4% post-24h. Comparing our findings regarding levels of imatinib in plasma and RBC, we found a statistically significant difference between pre-dialysis and post-dialysis (respectively p < 0,001 and p = 0,002), post-dialysis and post-24h (both p < 0,001), pre-dialysis and post-24h (respectively p = 0.035 and p = 0,042). Ultimately, regarding nor-imatinib/imatinib in plasma, we did not find any statistically significant difference between pre-dialysis and post-dialysis (p = 0,091), post-dialysis and post-24h (p = 0,091), pre-dialysis and post-24h (p = 0.903). Currently the patient is receiving oral imatinib 400 mg/day with radiological evidence of response. Conclusion In this case, hemodialysis did not affect significantly imatinib plasma levels. The statistically significant difference between pre- and post-dialysis can be explained by the fact that dialysis may likely contribute to a small portion of the normal metabolism of imatinib. The evaluation of imatinib levels in RBC and of its main metabolite in plasma also suggests that hemodialysis did not affect other aspects of the elimination of the drug.
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Affiliation(s)
- Ida De Luca
- Fondazione IRCCS Istituto Nazionale dei Tumori, Oncologia medica 2 Tumori mesenchimali dell'adulto, Milan, Italy
| | - Daniela Miliziano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Oncologia medica 2 Tumori mesenchimali dell'adulto, Milan, Italy
| | - Giulia Guerra
- Fondazione IRCCS Istituto Nazionale dei Tumori, s.c. Epidemiologia e Prevenzione, Milan, Italy
| | | | - Carlo Morosi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Radiologia diagnostica ed interventistica, Milan, Italy
| | - Carlo Sposito
- Fondazione IRCCS Istituto Nazionale dei Tumori, Chirurgia dell'apparato digerente e Trapianto di Fegato, Milan, Italy
| | - Marco Fiore
- Fondazione IRCCS Istituto Nazionale dei Tumori, Dipartimento di Chirurgia, Milan, Italy
| | - Elisabetta Venturelli
- Fondazione IRCCS Istituto Nazionale dei Tumori, s.s.d. Ricerca Nutrizionale e Metabolomica, Milan, Italy
| | - Claudia Sangalli
- Fondazione IRCCS Istituto Nazionale dei Tumori, Radioterapia, Milan, Italy
| | - Paolo G. Casali
- Fondazione IRCCS Istituto Nazionale dei Tumori & University of Milan, Milan, Italy
| | - Adalberto Cavalleri
- Fondazione IRCCS Istituto Nazionale dei Tumori, s.c. Epidemiologia e Prevenzione, Milan, Italy
| | - Elena Fumagalli
- Fondazione IRCCS Istituto Nazionale dei Tumori, Oncologia medica 2 Tumori mesenchimali dell'adulto, Milan, Italy
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, García-del-Muro X, Fernández-Hernández JÁ, Herrero L, López-Pousa A, Poveda A, Martínez-Marín V. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol 2023; 15:17588359231192388. [PMID: 37655207 PMCID: PMC10467260 DOI: 10.1177/17588359231192388] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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Affiliation(s)
- César Serrano
- Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Carrer de Natzaret, 115-117, Barcelona 08035, Spain
| | - Javier Martín-Broto
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- University Hospital General de Villalba, Madrid, Spain Instituto de investigación Sanitaria Fundación Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain
| | - José Manuel Asencio-Pascual
- Department of General Surgery, Gregorio Marañón University Hospital, Madrid, Spain
- Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Jordi Rubió-Casadevall
- Department of Medical Oncology, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Silvia Bagué
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Xavier García-del-Muro
- Department of Medical Oncology, Institut Català d’Oncologia, IDIBELL and University of Barcelona, Barcelona, Spain
| | | | - Luís Herrero
- GIST advocacy group – Colectivo GIST, Valladolid, Spain
| | - Antonio López-Pousa
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Andrés Poveda
- Initia Oncologia, Hospital Quironsalud, Valencia, Spain
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Venkataraman V, George S, Cote GM. Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor. Oncologist 2023:oyad167. [PMID: 37315115 PMCID: PMC10400151 DOI: 10.1093/oncolo/oyad167] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/19/2023] [Indexed: 06/16/2023] Open
Abstract
Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.
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Affiliation(s)
- Vinayak Venkataraman
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
| | - Suzanne George
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
| | - Gregory M Cote
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
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7
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Catalano F, Cremante M, Dalmasso B, Pirrone C, Lagodin D’Amato A, Grassi M, Comandini D. Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives. Cancers (Basel) 2023; 15:cancers15072074. [PMID: 37046734 PMCID: PMC10093725 DOI: 10.3390/cancers15072074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.
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Affiliation(s)
- Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Bruna Dalmasso
- Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Massimiliano Grassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Danila Comandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
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Huang S, Liu X, Guo X, Wu H, Lu H, Pan Z, Cai S, Wu X, Zhang X. Sunitinib versus imatinib dose escalation after failure of imatinib standard dose in patients with advanced Gastrointestinal stromal tumors - a real-world multi-center study. Transl Oncol 2023; 30:101641. [PMID: 36791510 PMCID: PMC9950928 DOI: 10.1016/j.tranon.2023.101641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/28/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Whether to escalate imatinib dosage or directly switch to sunitinib in gastrointestinal stromal tumors (GISTs) failing on standard dose 400 mg/d of imatinib is still controversial. METHODS We evaluated progression-free survival (PFS), overall survival (OS), and time to sunitinib failure (TTSF) of patients selecting imatinib dose escalation or directly switching to sunitinib after the failure of imatinib 400 mg/d therapy from 3 tertery referring centers between January 2008 to December 2016. RESULTS A total of 240 patients receiving sunitinib (37.5 mg continuous daily dose or 50 mg 4 weeks on with 2 weeks off) for at least 8 weeks were examined. After failure on imatinib 400 mg/d, 100 (49.3%) patients had dose escalation to 600 mg or 800 mg per day (IM group, imatinib group), and 103 (50.7%) directly switched to sunitinib (SU group, sunitinib group). The PFS in the SU and IM groups was 12 months and 5.0 months (P < 0.001), respectively. TTSF or OS in both groups was not statistically significantly different. CONCLUSIONS After the progression of imatinib standard-dose treatment in recurrent/metastatic GISTs, the PFS of patients directly switching to sunitinib was significantly longer compared with the PFS of patients with imatinib dose escalation. However, when the patients continued with sunitinib therapy after the failure of IM dose escalation, TTSF and OS in the IM group were similar to those in the SU group. Further exploration of the characteristics of the population benefiting from imatinib dose escalation are warranted.
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Affiliation(s)
- Shaoqing Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xing Liu
- Department of Gastric Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou China
| | - Xiaodan Guo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hui Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huishan Lu
- Department of Colorectal Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou China
| | - Zhizhong Pan
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shirong Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Wu
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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9
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The Application of Virtual Therapeutic Drug Monitoring to Assess the Pharmacokinetics of Imatinib in a Chinese Cancer Population Group. J Pharm Sci 2023; 112:599-609. [PMID: 36202248 DOI: 10.1016/j.xphs.2022.09.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/28/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE Imatinib is used in gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia (CML). Oncology patients demonstrate altered physiology compared to healthy adults, e.g. reduced haematocrit, increased α-1 acid glycoprotein, decreased albumin and reduced glomerular filtration rate (GFR), which may influence imatinib pharmacokinetics. Given that Chinese cancer patients often report raised imatinib plasma concentrations and wider inter-individual variability reported in trough concentration when compared to Caucasian cancer patients, therapeutic drug monitoring (TDM) has been advocated. METHOD This study utilised a previously validated a Chinese cancer population and assessed the impact of imatinib virtual-TDM in Chinese and Caucasian cancer populations across a dosing range from 200-800 mg daily. RESULTS Staged dose titration to 800 mg daily, resulted in recapitulation to within the target therapeutic range for 50 % (Chinese) and 42.1% (Caucasian) subjects possessing plasma concentration < 550 ng/mL when dosed at 400 mg daily. For subjects with plasma concentrations >1500 ng/mL when dosed at 400 mg daily, a dose reduction to 200 mg once daily was able to recover 67 % (Chinese) and 87.4 % (Caucasian) patients to the target therapeutic range. CONCLUSION Virtual TDM highlights the benefit of pharmacokinetic modelling to optimising treatments in challenging oncology population groups.
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10
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von Mehren M, Kane JM, Riedel RF, Sicklick JK, Pollack SM, Agulnik M, Bui MM, Carr-Ascher J, Choy E, Connelly M, Dry S, Ganjoo KN, Gonzalez RJ, Holder A, Homsi J, Keedy V, Kelly CM, Kim E, Liebner D, McCarter M, McGarry SV, Mesko NW, Meyer C, Pappo AS, Parkes AM, Petersen IA, Poppe M, Schuetze S, Shabason J, Spraker MB, Zimel M, Bergman MA, Sundar H, Hang LE. NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022. J Natl Compr Canc Netw 2022; 20:1204-1214. [PMID: 36351335 PMCID: PMC10245542 DOI: 10.6004/jnccn.2022.0058] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.
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Affiliation(s)
| | | | | | | | - Seth M Pollack
- 5Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Edwin Choy
- 9Massachusetts General Hospital Cancer Center
| | - Mary Connelly
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Sarah Dry
- 11UCLA Jonsson Comprehensive Cancer Center
| | | | | | | | - Jade Homsi
- 14UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | - David Liebner
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Nathan W Mesko
- 20Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Christian Meyer
- 21The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Alberto S Pappo
- 22St. Jude Children's Research Hospital/University of Tennessee Health Science Center
| | | | | | - Matthew Poppe
- 25Huntsman Cancer Institute at the University of Utah
| | | | - Jacob Shabason
- 27Abramson Cancer Center at the University of Pennsylvania
| | - Matthew B Spraker
- 28Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Melissa Zimel
- 29UCSF Helen Diller Family Comprehensive Cancer Center; and
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11
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Sun Y, Yue L, Xu P, Hu W. An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol 2022; 12:927587. [PMID: 36119525 PMCID: PMC9471148 DOI: 10.3389/fonc.2022.927587] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10-15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60-70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.
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Affiliation(s)
- Yingchao Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Pengfu Xu
- Department of Gastrointestinal Surgery, Taizhou Hospital, Zhejiang University, Taizhou, China
| | - Weiling Hu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
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12
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Feng M, Yang Y, Liao W, Li Q. Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumor: A Systematic Review. Front Public Health 2022; 9:768765. [PMID: 35083189 PMCID: PMC8784780 DOI: 10.3389/fpubh.2021.768765] [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: 09/01/2021] [Accepted: 12/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved the clinical effectiveness of patients with locally advanced and/or metastatic gastrointestinal stromal tumors (GIST), and this systematic review was conducted aiming at the cost-effectiveness analysis of TKIs in GIST. Methods: A thorough literature search of online databases was performed, using appropriate terms such as “gastrointestinal stromal tumor or GIST,” “cost-effectiveness,” and “economic evaluation.” Data extraction was conducted independently by two authors, and completeness of reporting and quality of the evaluation were assessed. The systematic review was conducted following the PRISMA statement. Results: Published between 2005 and 2020, 15 articles were incorporated into the systematic review. For advanced GIST, imatinib followed by sunitinib was considered cost-effective, and regorafenib was cost-effective compared with imatinib re-challenge therapy in the third-line treatment. For resectable GIST, 3-year adjuvant imatinib therapy represented a cost-effective treatment option. The precision medicine-assisted imatinib treatment was cost-effective compared with empirical treatment. Conclusion: Although identified studies varied in predicted costs and quality-adjusted life years, there was general agreement in study conclusions. More cost-effectiveness analysis should be conducted regarding more TKIs that have been approved for the treatment of GIST. Systematic Review Registration:https://www.crd.york.ac.uk/, PROSPERO: CRD42021225253.
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Affiliation(s)
- Mingyang Feng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Weiting Liao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
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13
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van de Wal D, Elie M, Le Cesne A, Fumagalli E, den Hollander D, Jones RL, Marquina G, Steeghs N, van der Graaf WTA, Husson O. Health-Related Quality of Life and Side Effects in Gastrointestinal Stromal Tumor (GIST) Patients Treated with Tyrosine Kinase Inhibitors: A Systematic Review of the Literature. Cancers (Basel) 2022; 14:cancers14071832. [PMID: 35406604 PMCID: PMC8997462 DOI: 10.3390/cancers14071832] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), resulting in a substantial gain in median overall survival. Subsequently, health-related quality of life (HRQoL) has become more relevant. Here, we systematically review the available literature on HRQoL issues and side effects of different TKIs registered for the treatment of GIST. METHODS A search through five databases was performed. Full reports in English describing HRQoL outcomes and/or side effects in GIST patients on TKI therapy were included. RESULTS A total of 104 papers were included; 13 studies addressed HRQoL, and 96 studies investigated adverse events. HRQoL in patients treated with imatinib, regorafenib, and ripretinib remained stable, whereas most sunitinib-treated patients reported a decrease in HRQoL. Severe fatigue and fear of recurrence or progression were specifically assessed as HRQoL issues and had a negative impact on overall HRQoL as well as psychological and physical well-being. The majority of studies focused on physician-reported side effects. Nearly all GIST patients treated with a TKI experienced at least one adverse event, mostly mild to moderate. CONCLUSIONS Despite the fact that almost all patients treated with a TKI experienced side effects, this did not seem to affect overall HRQoL during TKI therapy. In daily practice, it are the side effects that hamper a patient's HRQoL resulting in treatment adjustments, suggesting that the reported side effects were underestimated by physicians, or the measures used to assess HRQoL do not capture all relevant issues that determine a GIST patient's HRQoL.
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Affiliation(s)
- Deborah van de Wal
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
| | - Mai Elie
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (M.E.); (D.d.H.)
| | - Axel Le Cesne
- Department of Medical Oncology, Gustave Roussy, 94805 Villejuif, France;
| | - Elena Fumagalli
- Department of Medical Oncology, IRCCS Foundation National Cancer Institute, 20133 Milan, Italy;
| | - Dide den Hollander
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (M.E.); (D.d.H.)
| | - Robin L. Jones
- Department of Clinical Oncology, The Royal Marsden Hospital and Institute of Cancer Research, London SM2 5 NG, UK;
| | - Gloria Marquina
- Department of Medical Oncology, Hospital Clinico San Carlos, 28040 Madrid, Spain;
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands
| | - Winette T. A. van der Graaf
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Olga Husson
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Division of Clinical Studies, Institute of Cancer Research, London SM2 5NG, UK
- Correspondence: ; Tel.: +31-614-549-755
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14
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Brinch CM, Aggerholm-Pedersen N, Hogdall E, Krarup-Hansen A. Medical Oncological Treatment for Patients with Gastrointestinal Stromal Tumour (GIST) - a Systematic Review. Crit Rev Oncol Hematol 2022; 172:103650. [PMID: 35283299 DOI: 10.1016/j.critrevonc.2022.103650] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/11/2022] [Accepted: 03/07/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Chemotherapy is ineffective in treating patients with Gastrointestinal Stromal Tumour (GIST). However, several types of tyrosine kinase inhibitors have been investigated since the approval of imatinib in 2001. The purpose of this report was to systematically review studies on the efficacy of neoadjuvant, adjuvant, and lifelong medical oncological treatment of GIST. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout the review process. The protocol was submitted to the International prospective register of systematic reviews database (ID 251724). A systematic literature search was performed, including phase II- and III studies of biological treatment, reporting on treatment effect in patients with GIST. RESULTS Of 308 identified publications, 42 studies were included in this review. CONCLUSION This review gives an overview of the existing evidence for approved lines of oncological treatments and potential alternatives for patients with GIST in the neoadjuvant-, adjuvant- and life-long setting.
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Affiliation(s)
- Charlotte Margareta Brinch
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
| | - Ninna Aggerholm-Pedersen
- Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus, Denmark.
| | - Estrid Hogdall
- Department of Pathology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 73, DK-2730, Herlev, Denmark.
| | - Anders Krarup-Hansen
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
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15
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Foo T, Goldstein D, Segelov E, Shapiro J, Pavlakis N, Desai J, Yip D, Zalcberg J, Price TJ, Nagrial A, Chantrill L, Burge M, Karapetis CS, Tebbutt N, Roy AC. The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours. Target Oncol 2022; 17:95-110. [PMID: 35290591 PMCID: PMC8995292 DOI: 10.1007/s11523-022-00869-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.
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Affiliation(s)
- Tiffany Foo
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, University of NSW, Sydney, NSW, Australia
| | - Eva Segelov
- Department of Medical Oncology, School of Clinical Sciences, Monash University and Monash Health, Melbourne, VIC, Australia
| | - Jeremy Shapiro
- Cabrini Health, Monash University, Melbourne, VIC, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, Canberra, ACT, Australia
| | - John Zalcberg
- Alfred Health, Monash University, Melbourne, VIC, Australia
| | - Timothy J Price
- The Queen Elizabeth Hospital/University of Adelaide, Adelaide, SA, Australia
| | - Adnan Nagrial
- Department of Medical Oncology, Westmead and Blacktown Hospitals, University of Sydney, Sydney, NSW, Australia
| | - Lorraine Chantrill
- Department of Medical Oncology, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Illawarra, NSW, Australia
| | - Matt Burge
- Department of Cancer Care Services, Royal Brisbane Hospital, University of Queensland, Herston, QLD, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Amitesh C Roy
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia.
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16
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Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee JVMG, Boye K, Brodowicz T, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dufresne A, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Frezza AM, Gasperoni S, Gelderblom H, Gouin F, Grignani G, Haas R, Hassan AB, Hindi N, Hohenberger P, Joensuu H, Jones RL, Jungels C, Jutte P, Kasper B, Kawai A, Kopeckova K, Krákorová DA, Le Cesne A, Le Grange F, Legius E, Leithner A, Lopez-Pousa A, Martin-Broto J, Merimsky O, Messiou C, Miah AB, Mir O, Montemurro M, Morosi C, Palmerini E, Pantaleo MA, Piana R, Piperno-Neumann S, Reichardt P, Rutkowski P, Safwat AA, Sangalli C, Sbaraglia M, Scheipl S, Schöffski P, Sleijfer S, Strauss D, Strauss SJ, Hall KS, Trama A, Unk M, van de Sande MAJ, van der Graaf WTA, van Houdt WJ, Frebourg T, Gronchi A, Stacchiotti S. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2022; 33:20-33. [PMID: 34560242 DOI: 10.1016/j.annonc.2021.09.005] [Citation(s) in RCA: 304] [Impact Index Per Article: 101.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/01/2021] [Accepted: 09/04/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- P G Casali
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Oncology and Hemato-oncology University of Milan, Milan, Italy
| | - J Y Blay
- Centre Leon Berard and UCBL1, Lyon, France
| | - N Abecassis
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal
| | - J Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - S Bauer
- Department of Medical Oncology, Interdisciplinary Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany
| | - R Biagini
- Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy
| | - S Bielack
- Klinikum Stuttgart-Olgahospital, Stuttgart, Germany
| | - S Bonvalot
- Department of Surgery, Institut Curie, Paris, France
| | | | - J V M G Bovee
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - K Boye
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - T Brodowicz
- Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria
| | - A Buonadonna
- Centro di Riferimento Oncologico di Aviano, Aviano, Italy
| | - E De Álava
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain; Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain
| | - A P Dei Tos
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - X G Del Muro
- Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain
| | - A Dufresne
- Département d'Oncologie Médicale, Centre Leon Berard, Lyon, France
| | - M Eriksson
- Skane University Hospital-Lund, Lund, Sweden
| | - A Fedenko
- P. A. Herzen Cancer Research Institute, Moscow, Russian Federation
| | - V Ferraresi
- Sarcomas and Rare Tumors Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - A Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - A M Frezza
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - S Gasperoni
- Department of Oncology and Robotic Surgery, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - H Gelderblom
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - F Gouin
- Centre Leon-Berard Lyon, Lyon, France
| | - G Grignani
- Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - R Haas
- Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands
| | - A B Hassan
- Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK
| | - N Hindi
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - P Hohenberger
- Mannheim University Medical Center, Mannheim, Germany
| | - H Joensuu
- Helsinki University Hospital (HUH) and University of Helsinki, Helsinki, Finland
| | - R L Jones
- Sarcoma Unit, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - C Jungels
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - P Jutte
- University Medical Center Groningen, Groningen, The Netherlands
| | - B Kasper
- Mannheim University Medical Center, Mannheim, Germany
| | - A Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - K Kopeckova
- University Hospital Motol, Prague, Czech Republic
| | - D A Krákorová
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - A Le Cesne
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - F Le Grange
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - E Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - A Leithner
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - A Lopez-Pousa
- Medical Oncology Department, Hospital Universitario Santa Creu i Sant Pau, Barcelona, Spain
| | - J Martin-Broto
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - O Merimsky
- Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel
| | - C Messiou
- Department of Radiology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - A B Miah
- Department of Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - O Mir
- Department of Ambulatory Cancer Care, Gustave Roussy, Villejuif, France
| | - M Montemurro
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - C Morosi
- Department of Radiology, IRCCS Foundation National Cancer Institute, Milan, Italy
| | - E Palmerini
- Department of Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - M A Pantaleo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria, di Bologna, Bologna, Italy
| | - R Piana
- Azienda Ospedaliero, Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - P Reichardt
- Helios Klinikum Berlin Buch, Berlin, Germany
| | - P Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - A A Safwat
- Aarhus University Hospital, Aarhus, Denmark
| | - C Sangalli
- Department of Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Sbaraglia
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - S Scheipl
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - P Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - D Strauss
- Department of Surgery, Royal Marsden Hospital, London, UK
| | - S J Strauss
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - K Sundby Hall
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - A Trama
- Department of Research, Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Unk
- Institute of Oncology of Ljubljana, Ljubljana, Slovenia
| | - M A J van de Sande
- Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - W T A van der Graaf
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - W J van Houdt
- Department of Surgical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - T Frebourg
- Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
| | - A Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - S Stacchiotti
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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17
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Blay JY, Hindi N, Bollard J, Aguiar S, Angel M, Araya B, Badilla R, Bernabeu D, Campos F, Caro-Sánchez CHS, Carvajal B, Carvajal Montoya A, Casavilca-Zambrano S, Castro-Oliden V, Chacón M, Clara M, Collini P, Correa Genoroso R, Costa FD, Cuellar M, Dei Tos AP, Dominguez Malagon HR, Donati D, Dufresne A, Eriksson M, Farias-Loza M, Fernandez P, Frezza AM, Frisoni T, Garcia-Ortega DY, Gelderblom H, Gouin F, Gómez-Mateo MC, Gronchi A, Haro J, Huanca L, Jimenez N, Karanian M, Kasper B, Lopes David BB, Lopez-Pousa A, Lutter G, Martinez-Said H, Martinez-Tlahuel J, Mello CA, Morales Pérez JM, Moura David S, Nascimento AG, Ortiz-Cruz EJ, Palmerini E, Patel S, Pfluger Y, Provenzano S, Righi A, Rodriguez A, Salas R, Santos TTG, Scotlandi K, Soule T, Stacchiotti S, Valverde C, Waisberg F, Zamora Estrada E, Martin-Broto J. SELNET clinical practice guidelines for soft tissue sarcoma and GIST. Cancer Treat Rev 2022; 102:102312. [PMID: 34798363 DOI: 10.1016/j.ctrv.2021.102312] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022]
Affiliation(s)
- J Y Blay
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France.
| | - N Hindi
- Research Health Institute Fundacion Jimenez Diaz (IIS/FJD), 28015 Madrid, Spain; Hospital Fundación Jimenez Diaz University Hospital, 28040 Madrid, Spain; General de Villalba University Hospital, 28400 Madrid, Spain
| | - J Bollard
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - S Aguiar
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - M Angel
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - B Araya
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - R Badilla
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - D Bernabeu
- Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain
| | - F Campos
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - C H S Caro-Sánchez
- Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico
| | - B Carvajal
- Fundación GIST México, Altadena 59, Nápoles, Benito Juárez, 03810 Ciudad de Mexico, CDMX, Mexico
| | - A Carvajal Montoya
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - S Casavilca-Zambrano
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru
| | - V Castro-Oliden
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru
| | - M Chacón
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - M Clara
- Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico
| | - P Collini
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - R Correa Genoroso
- Hospital Clínico Universitario Virgen de la Victoria, Campus Universitario de Teatinos s/n, 29010 Malaga, Spain
| | - F D Costa
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - M Cuellar
- Fundación GIST México, Altadena 59, Nápoles, Benito Juárez, 03810 Ciudad de Mexico, CDMX, Mexico
| | - A P Dei Tos
- Treviso General Hospital Treviso, University of Padua, Padova, Italy
| | - H R Dominguez Malagon
- Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico
| | - D Donati
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy
| | - A Dufresne
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - M Eriksson
- Skane University Hospital and Lund University, Lund, Sweden
| | - M Farias-Loza
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru
| | | | - A M Frezza
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - T Frisoni
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy
| | - D Y Garcia-Ortega
- Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico
| | - H Gelderblom
- Leiden University Medical Center, Leiden, the Netherlands
| | - F Gouin
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - M C Gómez-Mateo
- Hospital Universitario Miguel Servet, Paseo Isabel la Católica, 1-3, 50009 Zaragoza, Spain
| | - A Gronchi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - J Haro
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru
| | - L Huanca
- Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru
| | - N Jimenez
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - M Karanian
- Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France
| | - B Kasper
- University of Heidelberg, Mannheim Cancer Center, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - B B Lopes David
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - A Lopez-Pousa
- Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041 Barcelona, Espagne
| | - G Lutter
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - H Martinez-Said
- Centro Oncologico Integral, Hospital Medica Sur, Planta Baja Torre III - Cons. 305, Col. Toriello Guerra, Deleg. Tlalpan. C.P. 14050, Mexico, D.F
| | - J Martinez-Tlahuel
- Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico
| | - C A Mello
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - J M Morales Pérez
- Hospital Universitario Virgen del Rocio, Av Manuel Siurot s/n, 41013 Sevilla, Spain
| | - S Moura David
- Hospital Universitario Virgen del Rocio, Av Manuel Siurot s/n, 41013 Sevilla, Spain
| | - A G Nascimento
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - E J Ortiz-Cruz
- Hospital Universitario La Paz, MD Anderson Cancer Center, Calle de Arturo Soria, 270 28033 Madrid, Spain
| | - E Palmerini
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy
| | - S Patel
- UT MD Anderson Cancer Center, Houston, TX, USA
| | - Y Pfluger
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - S Provenzano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - A Righi
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy
| | - A Rodriguez
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - R Salas
- Fundación GIST México, Altadena 59, Nápoles, Benito Juárez, 03810 Ciudad de Mexico, CDMX, Mexico
| | - T T G Santos
- A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil
| | - K Scotlandi
- IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy
| | - T Soule
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - S Stacchiotti
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy
| | - C Valverde
- Vall d́Hebrón University Hospital, Passeig de la Vall d'Hebron, 119, 08035 Barcelona, Spain
| | - F Waisberg
- Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina
| | - E Zamora Estrada
- Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica
| | - J Martin-Broto
- Research Health Institute Fundacion Jimenez Diaz (IIS/FJD), 28015 Madrid, Spain; Hospital Fundación Jimenez Diaz University Hospital, 28040 Madrid, Spain; General de Villalba University Hospital, 28400 Madrid, Spain
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18
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George S, Chi P, Heinrich MC, von Mehren M, Jones RL, Ganjoo K, Trent J, Gelderblom H, Razak AA, Gordon MS, Somaiah N, Jennings J, Meade J, Shi K, Su Y, Ruiz-Soto R, Janku F. Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour. Eur J Cancer 2021; 155:236-244. [PMID: 34391056 PMCID: PMC9362852 DOI: 10.1016/j.ejca.2021.07.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/10/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. METHODS Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. RESULTS Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third- and ≥fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. CONCLUSION Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen.
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Affiliation(s)
- Suzanne George
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
| | - Ping Chi
- Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill Cornell Medical College, New York, NY, United States.
| | - Michael C Heinrich
- Hematology/Medical Oncology, VA Health Care System and OHSU Knight Cancer Institute, Portland, OR, United States.
| | - Margaret von Mehren
- Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States.
| | - Robin L Jones
- Royal Marsden and Institute of Cancer Research, London, United Kingdom.
| | - Kristen Ganjoo
- Medical Oncology, Stanford University, Stanford, CA, United States.
| | - Jonathan Trent
- Medical Oncology, Sylvester Comprehensive Cancer Center/University of Miami, Miami, FL, United States.
| | - Hans Gelderblom
- Medical Oncology, Leiden University Medical Center, Leiden, Netherlands.
| | - Albiruni A Razak
- Toronto Sarcoma Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
| | | | - Neeta Somaiah
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| | - Julia Jennings
- Deciphera Pharmaceuticals, LLC, Waltham, MA, United States.
| | - Julie Meade
- Deciphera Pharmaceuticals, LLC, Waltham, MA, United States.
| | - Kelvin Shi
- Deciphera Pharmaceuticals, LLC, Waltham, MA, United States.
| | - Ying Su
- Deciphera Pharmaceuticals, LLC, Waltham, MA, United States.
| | | | - Filip Janku
- Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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19
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Zalcberg JR, Heinrich MC, George S, Bauer S, Schöffski P, Serrano C, Gelderblom H, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Somaiah N, Meade J, Reichert V, Shi K, Sherman ML, Ruiz-Soto R, von Mehren M, Blay JY. Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study. Oncologist 2021; 26:e2053-e2060. [PMID: 34313371 PMCID: PMC8571742 DOI: 10.1002/onco.13917] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/20/2021] [Indexed: 12/16/2022] Open
Abstract
Background Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth‐line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods Tumor imaging was performed every 28‐day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. period. Among the ripretinib IPDE patients, progression‐free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. Results Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7–6.4) and median PFS2 was 3.7 months (95% CI, 3.1–5.3). Median overall survival was 18.4 months (95% CI, 14.5–not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3–4 treatment‐emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. Conclusion Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth‐line GISTs. Implications for Practice Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression‐free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist. This article presents further results from the INVICTUS study, focusing on patients who received ripretinib 150 mg QD who received intrapatient dose escalation to 150 mg b.i.d. after progressive disease.
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Affiliation(s)
- John R Zalcberg
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.,Department of Medical Oncology, The Alfred Hospital, Melbourne, Australia
| | - Michael C Heinrich
- Portland VA Healthcare System and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sebastian Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, Essen, Germany
| | - Patrick Schöffski
- University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - César Serrano
- Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | | | - Robin L Jones
- Royal Marsden and Institute of Cancer Research, London, United Kingdom
| | | | - Gina D'Amato
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA
| | - Ping Chi
- Memorial Sloan Kettering Cancer Center & Weill Cornell Medicine, New York, New York, USA
| | - Peter Reichardt
- Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany
| | - Neeta Somaiah
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Julie Meade
- Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts, USA
| | | | - Kelvin Shi
- Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts, USA
| | | | | | | | - Jean-Yves Blay
- Centre Léon Bérard & Université Claude Bernard, Lyon, France
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20
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Patel SR, Reichardt P. An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer 2021; 127:2187-2195. [PMID: 33974733 PMCID: PMC8252111 DOI: 10.1002/cncr.33630] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 12/21/2022]
Abstract
Before the introduction of tyrosine kinase inhibitors (TKIs), the overall survival of patients with advanced or metastatic gastrointestinal stromal tumors (GISTs) was 10 to 20 months because of the lack of approved therapies. In the last 20 years, a treatment algorithm for patients with advanced GISTs, which includes imatinib, sunitinib, and regorafenib as first‐, second‐, and third‐line therapies, respectively, has been established. Recently, 2 new TKIs have been approved: ripretinib for fourth‐line therapy and avapritinib as first‐line therapy in patients harboring platelet‐derived growth factor receptor α (PDGFRA) exon 18 D842V mutations. Additionally, there are several experimental therapies under investigation that could advance individualized patient care. All of these therapies have varying efficacies and safety profiles that warrant an updated treatment landscape review. This review article summarizes the efficacy and safety data currently available for conventional TKIs along with recently approved and experimental therapies. With evolving treatment options and effective toxicity management, patients with advanced gastrointestinal stromal tumors are living longer than ever before. Recently approved targeted therapies and the investigation of experimental treatment options have the potential to alter the current treatment algorithm and encourage personalized patient care.
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Affiliation(s)
- Shreyaskumar R Patel
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peter Reichardt
- Oncology and Palliative Care, Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany
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21
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Italiano A. New insights into the clinical management of advanced gastrointestinal stromal tumors. Expert Opin Pharmacother 2020; 22:439-447. [PMID: 33307872 DOI: 10.1080/14656566.2020.1828346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION 90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity. AREAS COVERED The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter. EXPERT OPINION Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.
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22
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Kimura T, Togawa T, Onishi K, Iida A, Sato Y, Goi T. Efficacy of Long-Term Adjuvant Therapy With Imatinib Mesylate After Extensive Surgical Treatment for Ruptured Gastrointestinal Stromal Tumors of the Small Intestine With Peritoneal Metastases: A Case Report. J Investig Med High Impact Case Rep 2020; 8:2324709620970736. [PMID: 33228387 PMCID: PMC7691891 DOI: 10.1177/2324709620970736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal
neoplasms of the gastrointestinal tract. Although most patients with
advanced GISTs benefit from imatinib mesylate (IM) as standard
targeted therapy, the optimal duration of adjuvant IM for GIST
patients with high risk of recurrence who underwent surgical resection
remains unknown. In this article, we present a case of a ruptured GIST
of the small intestine accompanied by peritoneal metastases, which was
effectively treated by surgical procedure followed by long-term
adjuvant therapy with IM. Surgical resection was performed for the
ruptured small intestinal GIST, and multitude of peritoneal metastases
were cauterized. The patient received adjuvant therapy with IM (400
mg/day) for 12 years without an interruption or a dose change.
Peritoneal metastatic recurrence was observed by the follow-up
computed tomography scan obtained 12 years after surgery, and surgical
resection of the recurrent GIST was performed. The molecular
examination indicated a KIT exon 11 deletion mutation in both the
primary GIST and recurrent GIST. An additional point mutation was
observed in the recurrent GIST in exon 17 that caused resistance to
IM. The present case might indicate that extensive removal of the
tumor cells through surgery and long-term administration of IM without
an interruption or a dose change were important for achieving improved
recurrence-free survival in patients with ruptured GISTs of the small
intestine with peritoneal metastases.
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Affiliation(s)
- Toshihisa Kimura
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Tamotsu Togawa
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Kenji Onishi
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
| | - Atsushi Iida
- National Hospital Organization Tsuruga Medical Center, Tsuruga, Fukui, Japan
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23
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Schöffski P, Mir O, Kasper B, Papai Z, Blay JY, Italiano A, Benson C, Kopeckova K, Ali N, Dileo P, LeCesne A, Menge F, Cousin S, Wardelmann E, Wozniak A, Marreaud S, Litiere S, Zaffaroni F, Nzokirantevye A, Vanden Bempt I, Gelderblom H. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 'CaboGIST'. Eur J Cancer 2020; 134:62-74. [PMID: 32470848 DOI: 10.1016/j.ejca.2020.04.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/30/2020] [Accepted: 04/06/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS EORTC 1317, NCT02216578, EudraCT 2014-000501-13.
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Affiliation(s)
- Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium.
| | - Olivier Mir
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Bernd Kasper
- Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim, Germany
| | | | - Jean-Yves Blay
- Department of Medical Oncology, Centre Léon Bérard, NETSARC+, LYRICAN, and Université Claude Bernard Lyon I, Lyon, France
| | | | | | | | - Nasim Ali
- Clatterbridge Cancer Centre, Wirral, United Kingdom
| | - Palma Dileo
- Sarcoma Unit, University College London, United Kingdom
| | - Axel LeCesne
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Franka Menge
- Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim, Germany
| | | | | | - Agnieszka Wozniak
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium
| | - Sandrine Marreaud
- European Organization for Research and Treatment of Cancer, Brussels, Belgium
| | - Saskia Litiere
- European Organization for Research and Treatment of Cancer, Brussels, Belgium
| | - Facundo Zaffaroni
- European Organization for Research and Treatment of Cancer, Brussels, Belgium
| | | | - Isabelle Vanden Bempt
- Department of Human Genetics, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
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24
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Liu P, Tan F, Liu H, Li B, Lei T, Zhao X. The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther 2020; 13:2433-2447. [PMID: 32273716 PMCID: PMC7102917 DOI: 10.2147/ott.s241331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor in the digestive tract. Tyrosine kinase inhibitors (TKIs), represented by imatinib, sunitinib, and regorafenib, have become the main treatment for recurrent and metastatic GISTs. With the wide application of mutation analysis and the precision medicine, molecular characteristics have been determined that not only predict the prognosis of patients with recurrent and metastatic GISTs, but also are closely related to the efficacy of first-, second- and third-line TKIs for GISTs, as well as other TKIs. Despite the significant effects of TKIs, the emergence of primary and secondary resistance ultimately leads to treatment failure and tumor progression. Currently, due to the signal transmission of KIT/PDGFRA during onset and tumor progression, strategies to counteract drug resistance include the replacement of TKIs and the development of new drugs that are directed towards carcinogenic mutations. In addition, it is also the embodiment of precision medicine for GISTs to explore new carcinogenic mechanisms and develop new drugs relying on new biotechnology. Surgery can benefit specific patients but its major purpose is to diminish the resistant clones. However, the prognosis of recurrent and metastatic patients is still unsatisfactory. Therefore, it is worth paying attention to how to maximize the benefits for patients.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha410008, Hunan, People’s Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
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Rare Tumors GI Group, Farhat F, Farsi AA, Mohieldin A, Bahrani BA, Sbaity E, Jaffar H, Kattan J, Rasul K, Saad K, Assi T, Morsi WE, Abood RA. Comprehensive review into the challenges of gastrointestinal tumors in the Gulf and Levant countries. World J Clin Cases 2020; 8:487-503. [PMID: 32110658 PMCID: PMC7031830 DOI: 10.12998/wjcc.v8.i3.487] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/13/2019] [Accepted: 01/01/2020] [Indexed: 02/05/2023] Open
Abstract
Although gastrointestinal stromal tumors (GISTs) are rare, with an incidence of 1/100000 per year, they are the most common sarcomas in the peritoneal cavity. Despite considerable progress in the diagnosis and treatment of GIST, about half of all patients are estimated to experience recurrence. With only two drugs, sunitinib and regorafenib, approved by the Food and Drug Administration, selecting treatment options after imatinib failure and coordinating multidisciplinary care remain challenging. In addition, physicians across the Middle East face some additional and unique challenges such as lack of published local data from clinical trials, national disease registries and regional scientific research, limited access to treatment, lack of standardization of care, and limited access to mutational analysis. Although global guidelines set a framework for the management of GIST, there are no standard local guidelines to guide clinical practice in a resource-limited environment. Therefore, a group of 11 experienced medical oncologists from across the Gulf and Levant region, part of the Rare Tumors Gastrointestinal Group, met over a period of one year to conduct a narrative review of the management of GIST and to describe regional challenges and gaps in patient management as an essential step to proposing local clinical practice recommendations.
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Affiliation(s)
| | - Fadi Farhat
- Hammoud Hospital UMC, Saida PO Box 652, Lebanon
| | | | - Ahmed Mohieldin
- Medical Oncology Department, Kuwait Cancer Control Center, Kuwait PO Box 42262, Kuwait
| | - Bassim Al Bahrani
- Medical Oncology Department, Royal Hospital, Muscat PO Box 1331, Oman
| | - Eman Sbaity
- Division of General Surgery, American University of Beirut, Beirut 1107 2180, Lebanon
| | - Hassan Jaffar
- Oncology Department, Tawam Hospital, Al Ain PO Box 15258, United Arab Emirates
| | - Joseph Kattan
- Hemato-oncology Department, Hotel Dieu de France, Beirut, Lebanon
| | - Kakil Rasul
- Hemato-oncology Department, National Center for Cancer Care and Research, Doha, Qatar
| | - Khairallah Saad
- Pathology Department, Institute National de Pathologic, Beirut, Lebanon
| | - Tarek Assi
- Oncology Department, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon
| | - Waleed El Morsi
- Pfizer Oncology-Emerging Markets, Dubai Media City, Dubai, United Arab Emirates
| | - Rafid A Abood
- Oncology Department, Basra College of Medicine, Basra, Iraq
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Cho H, Ryu MH, Lee Y, Park YS, Kim KH, Kim JH, Park Y, Lee SM, Kim CW, Kim BS, Yoo MW, Kang YK. Role of Resection Following Focal Progression with Standard Doses of Imatinib in Patients with Advanced Gastrointestinal Stromal Tumors: Results of Propensity Score Analyses. Oncologist 2019; 24:e1443-e1449. [PMID: 31315961 PMCID: PMC6975948 DOI: 10.1634/theoncologist.2019-0009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 06/12/2019] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND There are limited data on the clinical benefits of adding surgical resection in patients with focally progressive gastrointestinal stromal tumor (GIST). This study aims to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced GIST following focal progression (FP) with standard doses of imatinib. MATERIALS AND METHODS A total of 90 patients with advanced GISTs who experienced FP with standard doses of imatinib were included in this retrospective analysis. The primary endpoints were time to imatinib treatment failure (TTF) and overall survival (OS). RESULTS Compared with the NS group (n = 52), patients in the S group (n = 38) had a higher proportion of primary tumor site involvement and lower tumor burden at FP. With a median follow-up duration of 31.0 months, patients in the S group had significantly better TTF and OS than patients in the NS group (median TTF: 24.2 vs. 6.5 months, p < .01; median OS: 53.2 vs. 35.1 months, p = .009). Multivariate analysis showed that S group independently demonstrated better TTF (hazard ratio [HR], 0.29; p < .01) and OS (HR, 0.47; p = .01). Even after applying inverse probability of treatment-weighting adjustments, S group demonstrated significantly better TTF (HR, 0.36; p < .01) and OS (HR, 0.58; p = .049). CONCLUSION Our results suggested that resection following FP with standard doses of imatinib in patients with advanced GIST provides additional benefits over imatinib dose escalation alone. IMPLICATIONS FOR PRACTICE This is the first study to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced gastrointestinal stromal tumor (GIST) following focal progression (FP) with standard doses of imatinib. These findings suggest that resection can be safely performed following FP, and the addition of surgical resection provides further clinical benefit over imatinib dose escalation alone. Based on these results, the authors recommend resection following FP in patients with advanced GIST provided that an experienced multidisciplinary team is involved in the patient's treatment.
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Affiliation(s)
- Hyungwoo Cho
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yongjune Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ki-Hun Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jwa Hoon Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yangsoon Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sun Mi Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chan Wook Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Beom Soo Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Moon-Won Yoo
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Reichardt P, Schlemmer M, Delgado Perez JR, Papai Z, Prausova J, Melichar B, Fumagalli E, Barone C, Bauer S, Pustowka A, Crippa S, Castellana R, Quiering C, Le Cesne A. Safety of Imatinib Mesylate in a Multicenter Expanded Access Program in Adult Patients with Gastrointestinal Stromal Tumors in the Adjuvant Setting. Oncol Res Treat 2019; 42:629-635. [PMID: 31550719 DOI: 10.1159/000502749] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 08/14/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors most often caused by activating mutations of the KIT gene. KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection. This is a report of the safety of imatinib in patients with GIST in the adjuvant setting in an expanded access program. METHODS In this multicenter, open-label, single-arm trial, safety was assessed based on the frequency of adverse events (AEs). RESULTS Three hundred patients were treated and analyzed; 40 patients discontinued treatment. Median overall exposure during the program was 181 days (range 9-420); most patients (260/300 treated) completed the study. Six patients had disease recurrence, 4 of whom discontinued. In line with previously published reports, the most frequent AEs were nausea, diarrhea, and periorbital edema. The AEs were mild to moderate in most cases (76%). CONCLUSIONS These findings are in agreement with the known safety profile of imatinib and confirm the safety of imatinib at 400 mg/day in the adjuvant setting. The incidence of severe AEs was low.
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Affiliation(s)
- Peter Reichardt
- Department of Oncology and Palliative Care, Sarcoma Center Berlin-Brandenburg, Helios Klinikum Berlin-Buch, Berlin, Germany
| | - Marcus Schlemmer
- Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany,
| | - Juan R Delgado Perez
- Department of Medical Oncology, University Hospital Virgen de las Nieves, Granada, Spain
| | - Zsuzsanna Papai
- Department of Oncology, Medical Centre, Hungarian Defense Forces, Budapest, Hungary
| | - Jana Prausova
- Department of Oncology, University Hospital Motol, 2nd Faculty of Medicine, Charles University, Prague, Czechia
| | - Bohuslav Melichar
- Department of Oncology, Palacky University Medical School and Teaching Hospital Olomouc, Olomouc, Czechia
| | - Elena Fumagalli
- Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlo Barone
- Division of Medical Oncology, University Hospital A. Gemelli, Rome, Italy
| | - Sebastian Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Hospital, University of Duisburg-Essen, Essen, Germany
| | | | | | | | | | - Axel Le Cesne
- Department of Medical Oncology, Gustave Roussy Institute of Oncology, Villejuif, France
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Wu Y, Wang B, Wang J, Qi S, Zou F, Qi Z, Liu F, Liu Q, Chen C, Hu C, Hu Z, Wang A, Wang L, Wang W, Ren T, Cai Y, Bai M, Liu Q, Liu J. Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors. J Med Chem 2019; 62:6083-6101. [DOI: 10.1021/acs.jmedchem.9b00280] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Yun Wu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
| | - Beilei Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
| | - Junjie Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
| | - Shuang Qi
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
| | - Fengming Zou
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Ziping Qi
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Feiyang Liu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Qingwang Liu
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Cheng Chen
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
| | - Chen Hu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
| | - Zhenquan Hu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
| | - Aoli Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Li Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
| | - Wenchao Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
| | - Tao Ren
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
- Precedo Pharmaceuticals Inc, Hefei, Anhui 230088, P. R. China
| | - Yujiao Cai
- Department of General Surgery, Second Hospital Affiliated to Army Medical University, Xinqiao Road, Chongqing 400037, P. R. China
| | - Mingfeng Bai
- Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, United States
| | - Qingsong Liu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, P. R. China
| | - Jing Liu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, China
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China
- Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
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Mutua SN, Anderson F, Nyakale NE, Mody KG. Gastrointestinal stromal tumours at Inkosi Albert Luthuli Central Hospital from 2005 to 2015. SOUTH AFRICAN JOURNAL OF ONCOLOGY 2019. [DOI: 10.4102/sajo.v3i0.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Mazzocca A, Napolitano A, Silletta M, Spalato Ceruso M, Santini D, Tonini G, Vincenzi B. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol 2019; 11:1758835919841946. [PMID: 31205499 PMCID: PMC6535752 DOI: 10.1177/1758835919841946] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/13/2019] [Indexed: 12/11/2022] Open
Abstract
The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.
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Affiliation(s)
| | | | | | | | | | | | - Bruno Vincenzi
- Medical Oncology, Università Campus Bio-Medico, Via Alvaro del Portillo 200, Rome, Italy
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31
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Yang W, Li K, Yu J, Shou C, Zhang Q, Hong Y, Sun J, Yu H, Gao Y, Shen Q, Zhao Z, Zheng S. Clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure gastrointestinal stromal tumour. Scand J Gastroenterol 2019; 53:1328-1334. [PMID: 30346846 DOI: 10.1080/00365521.2018.1518484] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
AIM The majority of available data on the clinical efficacy of sunitinib in patients with imatinib-resistant or -intolerant gastrointestinal stromal tumours (GISTs) are from studies of western populations. We investigated the clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure Asian GIST patients to further guide clinical treatment. METHODS Patients received imatinib dose escalation and a shift to sunitinib (Group A) or a direct shift to sunitinib (Group B). The objective tumour response was assessed according to Choi's criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. The relationship between genetic mutation and survival was analysed. RESULTS In total, 40 patients who fulfilled the inclusion criteria were recruited. The differences in survival between Group A and Group B were not significant for PFS (p = .776) or OS (p = .219). For patients with KIT exon 11 mutation, a trend towards a better PFS was found in Group B (p = .122), OS of Group B was better than Group A (p = .013). The median PFS and OS of sunitinib treatment were 8 and 24 months, respectively, and a clinical benefit was observed in 80%. Patients with KIT exon 11 mutations had better PFS compared to those with KIT exon 9 mutations or wild-type GISTs (p = .017, p = .040, respectively). CONCLUSIONS Both imatinib dose escalation and sunitinib were optional in Asian patients after failure of first-line imatinib, and patients with KIT exon 11 mutation benefited more from a direct shift to sunitinib.
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Affiliation(s)
- Weili Yang
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Kai Li
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Jiren Yu
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Chunhui Shou
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Qing Zhang
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Yanyun Hong
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Jianyi Sun
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Hang Yu
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Yuan Gao
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Qianyun Shen
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Zhicheng Zhao
- a Department of gastrointestinal surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
| | - Shusen Zheng
- b Department of hepatopancreatobiliary surgery, The First Affiliated Hospital , Zhejiang University School of Medicine , Hangzhou , China
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32
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Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects. Front Med 2019; 13:427-437. [PMID: 30798508 DOI: 10.1007/s11684-018-0672-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 09/27/2018] [Indexed: 12/17/2022]
Abstract
Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.
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Kim JH, Ryu MH, Yoo C, Chae H, Na H, Beck M, Kim BS, Yoo MW, Yook JH, Kim BS, Kim KH, Kim CW, Kang YK. Long-term survival outcome with tyrosine kinase inhibitors and surgical intervention in patients with metastatic or recurrent gastrointestinal stromal tumors: A 14-year, single-center experience. Cancer Med 2019; 8:1034-1043. [PMID: 30693663 PMCID: PMC6434201 DOI: 10.1002/cam4.1994] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/11/2018] [Accepted: 01/08/2019] [Indexed: 12/17/2022] Open
Abstract
The long‐term effects of tyrosine kinase inhibitors (TKIs), including imatinib, and surgical intervention on advanced gastrointestinal stromal tumor (GIST) were evaluated. All 379 patients had metastatic or recurrent GIST and started 400 mg/d imatinib at the Asan Medical Center in periods 1 and 2 [2001‐2007 (33.2%) and 2008‐2014 (66.8%), respectively]. Men constituted 60.4%; median patient age and tumor size at the initiation of imatinib were 58.6 (14.6‐85.5) years and 51 (0‐324) mm, respectively, without differences between periods except for older age and less preimatinib surgery in period 2. Response and disease control rates with imatinib in measurable GIST were 63.1% and 94.3%, respectively, without differences between periods. More patients in period 2 underwent surgical resection for TKI‐responsive diseases within the first 2 years (24.9%, P = 0.006). With a median follow‐up of 6.1 years (2.5‐16.0) in survivors, median progression‐free survival (PFS) was 5.4 years [95% confidence interval (CI), 4.0‐6.9]. Subsequent sunitinib (P = 0.066) and regorafenib (P = 0.003) were more commonly administered in period 2. Median overall survival (OS) was 8.8 years (95% CI, 7.8‐9.7). PFS with imatinib (P = 0.002) and OS (P = 0.019) were significantly longer in period 2. Young age, smaller tumor size at the initiation of imatinib, KIT exon 11 mutation, surgical intervention, and period 2 were favorable factors for PFS and OS. Patients with advanced GIST showed better prognosis with the optimal use of imatinib, along with active surgical intervention and more common use of subsequent TKIs in period 2.
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Affiliation(s)
- Jwa Hoon Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Heejung Chae
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hana Na
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moyoul Beck
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Beom Su Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moon-Won Yoo
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Byung Sik Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan Wook Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, Xu H, Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, Pan J, Cao H. Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors. World J Gastroenterol 2018; 24:5189-5202. [PMID: 30581268 PMCID: PMC6295840 DOI: 10.3748/wjg.v24.i46.5189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/04/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.
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Affiliation(s)
- Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wu
- Department of General Surgery, the General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Tian-Long Lin
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Xiu-Feng Liu
- Department of Oncology, The Chinese People’s Liberation Army 81st Hospital, Nanjing 210031, Jiangsu Province, China
| | - Ye Zhou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Xin-Hua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 320100, Jiangsu Province, China
| | - Li-Jing Shen
- Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Jing Zou
- Department of Respirology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Ping Lu
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Dong Zhang
- Department of Nephrology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Wei-Jun Gu
- Department of Endocrinology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Mei-Xia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
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Abstract
OPINION STATEMENT Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and 177Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life.
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Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.,Department of Medical Oncology, Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.,Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.
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36
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Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee JVMG, Brodowicz T, Broto JM, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dileo P, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Ferrari S, Frezza AM, Gasperoni S, Gelderblom H, Gil T, Grignani G, Gronchi A, Haas RL, Hassan B, Hohenberger P, Issels R, Joensuu H, Jones RL, Judson I, Jutte P, Kaal S, Kasper B, Kopeckova K, Krákorová DA, Le Cesne A, Lugowska I, Merimsky O, Montemurro M, Pantaleo MA, Piana R, Picci P, Piperno-Neumann S, Pousa AL, Reichardt P, Robinson MH, Rutkowski P, Safwat AA, Schöffski P, Sleijfer S, Stacchiotti S, Sundby Hall K, Unk M, Van Coevorden F, van der Graaf WTA, Whelan J, Wardelmann E, Zaikova O, Blay JY. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29:iv68-iv78. [PMID: 29846513 DOI: 10.1093/annonc/mdy095] [Citation(s) in RCA: 285] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023] Open
Affiliation(s)
- P G Casali
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - N Abecassis
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal
| | - H T Aro
- Turku University Hospital (Turun Yliopistollinen Keskussairaala), Turlu, Finland
| | - S Bauer
- University Hospital Essen, Essen Germany
| | - R Biagini
- Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy
| | - S Bielack
- Klinikum Stuttgart-Olgahospital, Stuttgart, Germany
| | | | | | - J V M G Bovee
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - T Brodowicz
- Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria
| | - J M Broto
- Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain
| | - A Buonadonna
- Centro di Riferimento Oncologico di Aviano, Aviano
| | - E De Álava
- Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain
| | - A P Dei Tos
- Ospedale Regionale di Treviso 'S.Maria di Cà Foncello', Treviso, Italy
| | - X G Del Muro
- Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain
| | - P Dileo
- Sarcoma Unit, University College London Hospitals, London, UK
| | - M Eriksson
- Skane University Hospital-Lund, Lund, Sweden
| | - A Fedenko
- N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation
| | - V Ferraresi
- Institute of Scientific Hospital Care (IRCCS), Regina Elena National Cancer Institute, Rome
| | - A Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
| | - S Ferrari
- Istituto Ortopedico Rizzoli, Bologna
| | - A M Frezza
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - S Gasperoni
- Azienda Ospedaliera Universitaria Careggi Firenze, Florence, Italy
| | - H Gelderblom
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - T Gil
- Institut Jules Bordet, Brussels, Belgium
| | - G Grignani
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
| | - A Gronchi
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - R L Haas
- Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam and Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands
| | - B Hassan
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - R Issels
- Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - H Joensuu
- Helsinki University Central Hospital (HUCH), Helsinki, Finland
| | | | - I Judson
- The Institute of Cancer Research, London, UK
| | - P Jutte
- University Medical Center Groningen, Groningen
| | - S Kaal
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - B Kasper
- Mannheim University Medical Center, Mannheim
| | | | - D A Krákorová
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - A Le Cesne
- Gustave Roussy Cancer Campus, Villejuif, France
| | - I Lugowska
- Maria Sklodowska Curie Institute, Oncology Centre, Warsaw, Poland
| | - O Merimsky
- Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel
| | - M Montemurro
- Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - M A Pantaleo
- Azienda Ospedaliera, Universitaria, Policlinico S Orsola-Malpighi Università di Bologna, Bologna
| | - R Piana
- Azienda Ospedaliero, Universitaria Cita della Salute e della Scienza di Torino, Turin, Italy
| | - P Picci
- Istituto Ortopedico Rizzoli, Bologna
| | | | - A L Pousa
- Fundacio de Gestio Sanitaria de L'hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - P Reichardt
- Helios Klinikum Berlin Buch, Berlin, Germany
| | - M H Robinson
- YCRC Department of Clinical Oncology, Weston Park Hospital NHS Trust, Sheffield, UK
| | - P Rutkowski
- Maria Sklodowska Curie Institute, Oncology Centre, Warsaw, Poland
| | - A A Safwat
- Aarhus University Hospital, Aarhus, Finland
| | | | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - S Stacchiotti
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - K Sundby Hall
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - M Unk
- Institute of Oncology of Ljubljana, Ljubljana, Slovenia
| | - F Van Coevorden
- Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | | | - J Whelan
- University College Hospital, London, UK
| | - E Wardelmann
- Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany
| | - O Zaikova
- Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway
| | - J Y Blay
- Centre Leon Bernard and UCBL1, Lyon, France
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37
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Tu L, Hohenberger P, Allgayer H, Cao H. Standard Approach to Gastrointestinal Stromal Tumors - Differences between China and Europe. Visc Med 2018; 34:353-358. [PMID: 30498702 PMCID: PMC6257205 DOI: 10.1159/000494347] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. With the considerable research and application of molecular-targeted therapy for GISTs in the last two decades, GISTs have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those by the European Society of Medical Oncology (ESMO), the clinical situations in China are different from those in European countries. There are distinct differences between the clinical practice, diagnostic methods, surgical approach, and availability of new targeted agents in China and those in Europe. This review summarizes the Chinese GIST consensus guidelines compared to the European ones, which may provide an optimal approach to the diagnosis and management of GIST patients.
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Affiliation(s)
- Lin Tu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Peter Hohenberger
- Division of Surgical Oncology, Mannheim University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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38
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Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy CJ, Hunt T, Jones RDO, Li X, Moleva O, Ogg D, Overman RC, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith JM, Stead D, Stokes S, Tucker M, Ye Y. Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors. J Med Chem 2018; 61:8797-8810. [PMID: 30204441 DOI: 10.1021/acs.jmedchem.8b00938] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.
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Affiliation(s)
- Jason G Kettle
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Rana Anjum
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Evan Barry
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Deepa Bhavsar
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Crystal Brown
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Scott Boyd
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Andrew Campbell
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Kristin Goldberg
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Michael Grondine
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Sylvie Guichard
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Christopher J Hardy
- Discovery Sciences, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Tom Hunt
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Rhys D O Jones
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Xiuwei Li
- Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P. R. China
| | - Olga Moleva
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Derek Ogg
- Discovery Sciences, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Ross C Overman
- Discovery Sciences, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Martin J Packer
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Stuart Pearson
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Marianne Schimpl
- Discovery Sciences, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Wenlin Shao
- Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Park , Waltham , Massachusetts 02451 , United States
| | - Aaron Smith
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - James M Smith
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Darren Stead
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Steve Stokes
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Michael Tucker
- Oncology, IMED Biotech Unit , AstraZeneca , Unit 310, Darwin Building, Cambridge Science Park, Milton Road , Cambridge CB4 0WG , United Kingdom
| | - Yang Ye
- Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P. R. China
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Schrage Y, Hartgrink H, Smith M, Fiore M, Rutkowski P, Tzanis D, Messiou C, Servois V, Bonvalot S, van der Hage J. Surgical management of metastatic gastrointestinal stromal tumour. Eur J Surg Oncol 2018; 44:1295-1300. [DOI: 10.1016/j.ejso.2018.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022] Open
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40
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Wu X, Li J, Xu W, Gao J, Li Y, Shen L. Postoperative imatinib in patients with intermediate risk gastrointestinal stromal tumor. Future Oncol 2018; 14:1721-1729. [PMID: 29969914 DOI: 10.2217/fon-2017-0691] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Aim: To determine whether imatinib adjuvant treatment improved recurrence-free survival (RFS) in gastrointestinal stromal tumor (GIST) with intermediate risk. Materials & methods: Patients who had undergone complete tumor resection with intermediate risk were enrolled. Results: A total of 99 patients received imatinib adjuvant therapy and 93 patients only received observation. The RFS in patients who received adjuvant therapy was superior to RFS in control group (p = 0.004). GIST with location of intestine or rectum and GIST with exon 11 deletion mutation had longer RFS. Conclusion: Adjuvant imatinib improves RFS of GIST with intermediate risk of recurrence, particularly in GIST with intestinal and rectal location or c-kit gene exon 11 deletion mutation.
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Affiliation(s)
- Xin Wu
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, PR China
| | - Jian Li
- Department of GI Oncology, Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, PR China
| | - Wentong Xu
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, PR China
| | - Jing Gao
- Department of GI Oncology, Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, PR China
| | - Yanyan Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, PR China
| | - Lin Shen
- Department of GI Oncology, Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, PR China
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41
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Szucs Z, Jones RL. Perspectives on the evolving state of the art management of gastrointestinal stromal tumours. Transl Gastroenterol Hepatol 2018; 3:21. [PMID: 29780899 DOI: 10.21037/tgh.2018.04.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 03/30/2018] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumours (GISTs) represent a very exciting tumour entity for the medical oncologist. There has been extensive clinical and preclinical research dissecting the natural behaviour, molecular landscape and therapeutic responsiveness of this rare mesenchymal tumour. Various molecular subtypes of GIST have a differing prognostic and predictive relevance in the state of the art management of the disease. Emerging mature clinical trial data gathered over the last one and half decade provided substantial molecular profiling information in understanding the success and eventual failure of treatment. In our review of the most relevant literature we aim to guide the clinician in tailoring neoadjuvant, adjuvant and palliative treatment of GIST alongside the different, now well established molecular subgroups of GISTs.
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Affiliation(s)
- Zoltan Szucs
- Consultant Medical Oncologist, Ipswich Hospital NHS Trust, UK
| | - Robin L Jones
- Consultant Medical Oncologist, Head of Sarcoma Unit, The Royal Marsden Hospital NHS Foundation Trust/Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK
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42
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Taylor SJ, Duyvestyn JM, Dagger SA, Dishington EJ, Rinaldi CA, Dovey OM, Vassiliou GS, Grove CS, Langdon WY. Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib. Sci Transl Med 2018; 9:9/402/eaam8060. [PMID: 28794285 DOI: 10.1126/scitranslmed.aam8060] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/19/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023]
Abstract
We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.
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Affiliation(s)
- Samuel J Taylor
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Johanna M Duyvestyn
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Samantha A Dagger
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Emma J Dishington
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Catherine A Rinaldi
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Oliver M Dovey
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
| | - George S Vassiliou
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.,Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Carolyn S Grove
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.,PathWest Department of Haematology, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia.,Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia
| | - Wallace Y Langdon
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.
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Mocellin S, Pasquali S, Campana L, Yuan Y, Gronchi A, Griffiths E, Vohra R. Tyrosine kinase inhibitor therapies for gastrointestinal stromal tumours. Hippokratia 2018. [DOI: 10.1002/14651858.cd012951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Simone Mocellin
- University of Padova; Department of Surgery, Oncology and Gastroenterology; Via Giustiniani 2 Padova Veneto Italy 35128
| | - Sandro Pasquali
- Fondazione IRCCS ‘Istituto Nazionale dei Tumori’; Sarcoma Service; Via G. Venezian 1 Milano Italy 20133
| | - Luca Campana
- Istituto Oncologico Veneto IOV - IRCCS; Padova Italy
| | - Yuhong Yuan
- McMaster University; Department of Medicine, Division of Gastroenterology; 1280 Main Street West Room HSC 3N51 Hamilton ON Canada L8S 4K1
| | - Alessandro Gronchi
- Fondazione IRCCS Istituto Nazionale dei Tumori; Department of Surgery; Via Venezian 1 Milan Italy 20133
| | | | - Ravinder Vohra
- Nottingham University Hospitals; Trent OesophagoGastric Unit; Hucknall Road Nottingham UK NG5 1PB
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Qiu HB, Zhou ZG, Feng XY, Liu XC, Guo J, Ma MZ, Chen YB, Sun XW, Zhou ZW. Advanced gastrointestinal stromal tumor patients benefit from palliative surgery after tyrosine kinase inhibitors therapy. Medicine (Baltimore) 2018; 97:e9097. [PMID: 29480823 PMCID: PMC5943843 DOI: 10.1097/md.0000000000009097] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/11/2017] [Accepted: 11/14/2017] [Indexed: 01/17/2023] Open
Abstract
The role of palliative surgery is controversial in advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitors (TKIs) therapy.We evaluated safety and clinical outcomes in a single institution series of advanced GIST patients from January 2002 to December 2008.One hundred and fifty-six patients had been recruited, including 87 patients underwent surgical resection and 69 patients kept on TKIs treatment. Four patients had major surgical complications. Median follow-up was 38.3 months, the overall survival (OS) and progression-free survival (PFS) of the patients in surgical group were longer than the nonsurgical group, PFS: 46.1 versus 33.8 months (P < .01), OS: 54.8 versus 40.4 months. In the subgroup analysis for the patients received surgery, the median PFS for patients with progression disease, stable disease, and partial response was 33.3, 51.5, and 83.0 months, respectively (P < .01). Median OS was 68.0 months in those with only liver or peritoneal metastases, and 45.3 months in those with both metastases. Median PFS of patients underwent R0/R1 resection was 73.6 months compared with 35.8 months in R2 resection patients (P < .01).Patients with advanced GISTs have prolonged OS after debulking procedures. Surgery for patients who have responsive disease after TKIs treatment should be considered.
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Affiliation(s)
- Hai-Bo Qiu
- Department of Gastric and Pancreatic Surgery
| | - Zhong-Guo Zhou
- State Key Laboratory of Southern China, Department of Hepatobilliary Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine
| | - Xing-Yu Feng
- Department of General Surgery, Guangdong General Hospital, Guangzhou, Guangdong, China
| | | | - Jing Guo
- Department of Gastric and Pancreatic Surgery
| | - Ming-Zhe Ma
- Department of Gastric and Pancreatic Surgery
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Rutkowski P, Magnan H, Chou AJ, Benson C. Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series. BMC Cancer 2017; 17:717. [PMID: 29110655 PMCID: PMC5674814 DOI: 10.1186/s12885-017-3727-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 10/30/2017] [Indexed: 01/24/2023] Open
Abstract
Background Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1–2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. Methods Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. Results We identified 9 paediatric/young adult patients (aged 11–21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to >73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. Conclusion The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment.
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Affiliation(s)
- Piotr Rutkowski
- Maria Skłodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland.
| | - Heather Magnan
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Dong Z, Gao J, Gong J, Li J, Li Y, Shen L, Li J. Clinical benefit of sunitinib in gastrointestinal stromal tumors with different exon 11 mutation genotypes. Future Oncol 2017; 13:2035-2043. [PMID: 28685593 DOI: 10.2217/fon-2017-0252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To assess the efficacy of second-line sunitinib therapy in gastrointestinal stromal tumor patients with different exon 11 mutation genotypes. Patients & methods: Thirty eight of the 75 patients received imatinib (IM) dose escalation followed by sunitinib (IM escalation group), while 37 were switched to sunitinib directly after the failure of first-line IM treatment (sunitinib group). Progression-free survival and overall survival were compared. Results: The median progression-free survival in the sunitinib group was significantly longer than in the IM escalation group (14 vs 4 months; p < 0.001), so was in patients with exon 11 deletions (16 vs 3 months; p < 0.001). Conclusion: Patients who have an exon 11 deletion mutation are more likely to benefit from switching to sunitinib directly than from IM dose escalation.
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Affiliation(s)
- Zhi Dong
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Jing Gao
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Jifang Gong
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Jie Li
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Yanyan Li
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Lin Shen
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
| | - Jian Li
- Laboratory of Carcinogenesis & Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142 China
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Phase IV Study of Sunitinib in Chinese Patients with Imatinib-Resistant or Imatinib-Intolerant Gastrointestinal Stromal Tumors. Oncol Ther 2017. [DOI: 10.1007/s40487-017-0052-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Abstract
Introduction
Sunitinib is approved in China for treatment of gastrointestinal stromal tumors (GIST), after disease progression on, or intolerance to, imatinib. However, available data from prospective clinical trials on its efficacy and safety in Chinese patients is limited. Our objective is to determine the efficacy and safety of sunitinib in Chinese patients with imatinib-resistant/intolerant GIST.
Methods
An open-label, single-arm, multicenter, phase IV study was performed in Chinese patients with imatinib-resistant/intolerant GIST. Sunitinib was administered orally in 6-week cycles of 4 weeks on-treatment (50 mg once daily) and 2 weeks off-treatment. The primary endpoint was progression-free survival (PFS). Tumors were assessed every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Responses were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.
Results
A total of 60 patients were enrolled, of whom 59 were treated with sunitinib. All patients were Asian, and mean age was 55.1 years. Median PFS was 46.4 weeks (95% CI 33.6–53.1). An objective response (complete or partial) was observed in 11/58 (19%) patients. Median overall survival was 111.3 weeks (95% CI 75.4–167.1), median time to tumor progression was 47.3 weeks (95% CI 34.1–59.3), and median time to tumor response was 22.6 weeks (95% CI 10.4–57.3). The most common adverse events included leukopenia, fatigue, hand-foot syndrome, and neutropenia. No new safety concerns were identified.
Conclusions
This study confirms that sunitinib is active and well tolerated in Chinese patients with imatinib-resistant/intolerant GIST.
ClinicalTrials.gov identifier
NCT00793871.
Funding
Pfizer Inc, USA.
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Abstract
This review explores the current standard of care for the surgical management of gastrointestinal stromal tumors, highlights important studies in the medical management of gastrointestinal stromal tumors, and provides guidance in how these studies changed the standard of care in clinical practice.
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Hsu JT, Le PH, Kuo CF, Chiou MJ, Kuo CJ, Chen TH, Lin CJ, Chen JS, Yu HP, Yeh CN, Jan YY, Yeh TS. Imatinib dose escalation versus sunitinib as a second-line treatment against advanced gastrointestinal stromal tumors: A nationwide population-based cohort study. Oncotarget 2017; 8:71128-71137. [PMID: 29050348 PMCID: PMC5642623 DOI: 10.18632/oncotarget.16795] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 03/22/2017] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Although treatment with imatinib in advanced gastrointestinal stromal tumor (GIST) patients has led to significant clinical benefits, the disease will eventually progress due to imatinib resistance. Treatment options after failure of first-line imatinib include imatinib dose escalation or shifting to sunitinib. However, there is no large-scale study to compare the efficacy difference between these two treatment strategies or the role of surgery. RESULTS This study recruited 521 advanced GIST patients including 246, 125, and 150 placed in groups 1, 2, and 3, respectively. Groups 1 and 2 had significantly longer overall survival (OS) as compared with the group 3 (median 37.5 months versus 16.0 months; p < 0.0001). After adjusting for confounding variables, groups 1 and 2 had longer OS than group 3. A favorable survival trend was seen with surgery, although this benefit disappeared after adjusting for confounding factors. MATERIALS AND METHODS We conducted a nationwide population-based cohort study using data from the Taiwan National Health Insurance Research Database from July 2004 to December 2010. Advanced GIST patients who no longer responded to first-line imatinib were stratified into three groups: imatinib dose escalation (group 1); imatinib dose escalation and a shift to sunitinib (group 2); a direct shift to sunitinib (group 3). The therapeutic success of the three treatment regimens and the effect of surgery were evaluated by overall survival. CONCLUSIONS For advanced GIST patients who failed first-line imatinib treatment, imatinib dose escalation confers significantly longer OS compared to a direct switch to sunitinib. Surgery does not provide survival benefits.
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Affiliation(s)
- Jun-Te Hsu
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chang-Fu Kuo
- Division of Rheumatology, Allergy, and Immunology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Meng-Jiun Chiou
- Office for Big Data Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Hsing Chen
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chun-Jung Lin
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Jen-Shi Chen
- Department of Hemato-Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Huang-Pin Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yi-Yin Jan
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Abstract
Constitutive activating mutations in KIT and platelet-derived growth factor receptor α ( PDGFRα) are heavily involved in the pathobiology of gastrointestinal stromal tumors (GISTs). This disease has served as an effective "proof-of-concept" model for targeting gain-of-function kinase mutations in cancer. This review discusses the current standard of care in terms of pharmacotherapy in the management of localized and metastatic GISTs.
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Affiliation(s)
- Florence Duffaud
- Service d'Oncologie Médicale, CHU La Timone, Marseille, France.,UMR S910 INSERM, Marseille, France.,Aix-Marseille Université, Marseille, France
| | - Axel Le Cesne
- Département d'Oncologie Médicale, Gustave Roussy Institut, Villejuif, France
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