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Tsai HJ, Shan YS, Yang CY, Hsiao CF, Tsai CH, Wang CC, Lin MT, Ting CF, Chan DC, Chen TH, Yen CC, Chen YY, Lin HY, Yeh TS, Ho CL, Shieh TY, Bai LY, Hsu JT, Chen IS, Chen LT, Yeh CN. Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study. BMC Cancer 2024; 24:828. [PMID: 38992597 PMCID: PMC11238460 DOI: 10.1186/s12885-024-12567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 06/26/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Chung-Hsin Tsai
- Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
| | - Chuan-Cheng Wang
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Tsan Lin
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Fu Ting
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - De-Chuan Chan
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Te-Hung Chen
- Department of Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chueh-Chuan Yen
- Division of Medical Oncology, Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Clinical Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Yang Chen
- Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsuan-Yu Lin
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ta-Sen Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Liang Ho
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Division of Hematology and Oncology, Medical Department, Taipei Tzu Chi Hospital, Taipei, Taiwan
| | - Tze-Yu Shieh
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Li-Yaun Bai
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jun-Te Hsu
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - I-Shu Chen
- Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital and National Yang Ming Chiao Tung University, Kaohsiung, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Chun-Nan Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
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Dailah HG, Hommdi AA, Koriri MD, Algathlan EM, Mohan S. Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice. Heliyon 2024; 10:e24559. [PMID: 38298714 PMCID: PMC10828696 DOI: 10.1016/j.heliyon.2024.e24559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 02/02/2024] Open
Abstract
Immunotherapy and targeted therapy have emerged as promising therapeutic options for cancer patients. Immunotherapies induce a host immune response that mediates long-lived tumor destruction, while targeted therapies suppress molecular mechanisms that are important for tumor maintenance and growth. In addition, cytotoxic agents and targeted therapies regulate immune responses, which increases the chances that these therapeutic approaches may be efficiently combined with immunotherapy to ameliorate clinical outcomes. Various studies have suggested that combinations of therapies that target different stages of anti-tumor immunity may be synergistic, which can lead to potent and more prolonged responses that can achieve long-lasting tumor destruction. Nurses associated with cancer patients should have a better understanding of the immunotherapies and targeted therapies, such as their efficacy profiles, mechanisms of action, as well as management and prophylaxis of adverse events. Indeed, this knowledge will be important in establishing care for cancer patients receiving immunotherapies and targeted therapies for cancer treatment. Moreover, nurses need a better understanding regarding targeted therapies and immunotherapies to ameliorate outcomes in patients receiving these therapies, as well as management and early detection of possible adverse effects, especially adverse events associated with checkpoint inhibitors and various other therapies that control T-cell activation causing autoimmune toxicity. Nurses practice in numerous settings, such as hospitals, home healthcare agencies, radiation therapy facilities, ambulatory care clinics, and community agencies. Therefore, as compared to other members of the healthcare team, nurses often have better opportunities to develop the essential rapport in providing effective nurse-led patient education, which is important for effective therapeutic outcomes and continuance of therapy. In this article, we have particularly focused on providing a detailed overview on targeted therapies and immunotherapies used in cancer treatment, management of their associated adverse events, and the impact as well as strategies of nurse-led patient education.
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Affiliation(s)
- Hamad Ghaleb Dailah
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Abdullah Abdu Hommdi
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Mahdi Dafer Koriri
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Essa Mohammed Algathlan
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi Arabia
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
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Sasaki K, Kanda T, Matsumoto Y, Ishikawa T, Hirota S, Saijo Y. Sunitinib therapy for imatinib-resistant and/or intolerant gastrointestinal stromal tumors: comparison of safety and efficacy between standard and reduced dosage regimens. Jpn J Clin Oncol 2023; 53:297-303. [PMID: 36644881 DOI: 10.1093/jjco/hyac202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/11/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Sunitinib therapy for patients with imatinib-resistant and/or intolerant gastrointestinal stromal tumors (GISTs) often causes severe adverse events (AEs) that lead to treatment discontinuation. METHODS We retrospectively reviewed the clinical records of imatinib-resistant and/or intolerant GIST patients who underwent sunitinib therapy in our institutions between 2007 and 2020. Forty-one patients were enrolled and divided into two groups on the basis of the starting dosage: the standard dosage group (50 mg/day, 21 patients) and the reduced dosage group (37.5 mg/day, 20 patients). Tolerability, safety and clinical efficacy of the two groups were compared. RESULTS Three patients (14%) in the standard dosage group and another three (15%) in the reduced dosage group (P = 1.000) discontinued sunitinib therapy because of AEs. The incidences of grade 3 or more severe treatment-related AEs were 90 and 75%, respectively (P = 0.238). Two possible treatment-related deaths were noted in the standard dosage group. Clinical efficacy was comparable between the two groups: median time to treatment failure and overall survival were 4.5 months [interquartile range (IQR), 3.6-9.0] and 13.7 months (IQR, 7.5-22.9) in the standard dosage group and 4.6 months (IQR, 2.7-17.0) and 13.4 months (IQR, 9.3-36.8) in the reduced dosage group, respectively. CONCLUSIONS The reduced dosage of 37.5 mg sunitinib tended to decrease toxicity and the incidences of severe AEs and treatment-related deaths. This reduced dosage regimen showed equivalent clinical efficacy including patient survival. The reduced dosage of 37.5 mg sunitinib can be adopted as an alternative therapy for patients with imatinib-resistant and/or intolerant GISTs.
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Affiliation(s)
- Kenta Sasaki
- Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.,Department of Internal Medicine, Sanjo General Hospital, Sanjo, Japan
| | - Tatsuo Kanda
- Department of Surgery, Sanjo General Hospital, Sanjo, Japan
| | - Yoshifumi Matsumoto
- Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takashi Ishikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo Medical University School of Medicine, Nishinomiya, Japan
| | - Yasuo Saijo
- Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Wu CE, Chen CP, Huang WK, Pan YR, Aptullahoglu E, Yeh CN, Lunec J. p53 as a biomarker and potential target in gastrointestinal stromal tumors. Front Oncol 2022; 12:872202. [PMID: 35965531 PMCID: PMC9372431 DOI: 10.3389/fonc.2022.872202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/06/2022] [Indexed: 12/07/2022] Open
Abstract
KIT and PDGFRA play a major role in the oncogenic process in gastrointestinal stroma tumors (GIST) and small molecules have been employed with great success to target the KIT and PDGFRA pathways in this cancer. However, approximately 10% of patients with GIST are resistant to current targeted drug therapy. There is a need to explore other potential targets. Although p53 alterations frequently occur in most cancers, studies regarding p53 in GIST have been limited. The CDKN2A/MDM2/p53 axis regulates cell cycle progression and DNA damage responses, which in turn control tumor growth. This axis is the major event required for transformation from low- to high-risk GIST. Generally, p53 mutation is infrequent in GIST, but p53 overexpression has been reported to be associated with high-risk GIST and unfavorable prognosis, implying that p53 should play a critical role in GIST. Also, Wee1 regulates the cell cycle and the antitumor activity of Wee1 inhibition was reported to be p53 mutant dependent. In addition, Wee1 was reported to have potential activity in GIST through the regulation of KIT protein and this mechanism may be dependent on p53 status. In this article, we review previous reports regarding the role of p53 in GIST and propose targeting the p53 pathway as a novel additional treatment strategy for GIST.
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Affiliation(s)
- Chiao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chiao-Ping Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wen-Kuan Huang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yi-Ru Pan
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Erhan Aptullahoglu
- Department of Molecular Biology and Genetics, Bilecik Seyh Edebali University, Bilecik, Turkey
| | - Chun-Nan Yeh
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
- *Correspondence: Chun-Nan Yeh, ; John Lunec,
| | - John Lunec
- Newcastle University Cancer Center, Bioscience Institute, Medical Faculty, Newcastle University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Chun-Nan Yeh, ; John Lunec,
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Hu CH, Yeh CN, Chen JS, Tsai CY, Wang SY, Cheng CT, Yeh TS. Regorafenib treatment outcome for Taiwanese patients with metastatic gastrointestinal stromal tumors after failure of imatinib and sunitinib: A prospective, non-randomized, single-center study. Oncol Lett 2020; 20:2131-2142. [PMID: 32782530 PMCID: PMC7400021 DOI: 10.3892/ol.2020.11756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 04/01/2020] [Indexed: 12/23/2022] Open
Abstract
The present study aimed to conduct a prognosis analysis of Taiwanese patients with metastatic gastrointestinal stromal tumors (GISTs), who are resistant to or were unable to tolerate imatinib or sunitinib, and were subsequently treated with regorafenib. The study considered the survival, potential prognostic factors and safety of these Taiwanese patients. A total of 28 patients with pre-treated metastatic GIST, receiving regorafenib treatment, were analyzed between April 2014 and December 2017. Data were collected prospectively, and patients were followed up for a median of 14.8 months. It was reported that 50% (10/20) of male patients and 50% (4/8) of female patients demonstrated response and clinical benefit to regorafenib. The median progression-free survival (PFS) and overall survival (OS) time in all patients receiving regorafenib were 4.4 and 29.3 months, respectively. Good performance status and disease control mediated by regorafenib were independently associated with a more favorable PFS time. Good performance status, higher pre-treated albumin level, lower neutrophil:lymphocyte ratio (NLR) and lower platelet:lymphocyte ratio (PLR) were independent favorable predictors of OS time. Overall, poor performance status and poor disease control predicted a less favorable PFS time in Taiwanese patients with GISTs, who were pre-treated with regorafenib. Meanwhile poor performance status, high NLR, PLR and low albumin level predicted a less favorable OS time.
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Affiliation(s)
- Chia-Hsiang Hu
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Chun-Nan Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Jen-Shi Chen
- Department of Medical Oncology, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Chun-Yi Tsai
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Shang-Yu Wang
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Chi-Tung Cheng
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan
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Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View. Cancers (Basel) 2019; 11:cancers11050679. [PMID: 31100836 PMCID: PMC6563074 DOI: 10.3390/cancers11050679] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/15/2019] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal are mesenchymal tumors of the gastrointestinal tract and have been found to harbor c-KIT mutations and KIT (CD117) expression since 1998. Later, PDGFRA mutations, SDH alterations, and other drive mutations were identified in GISTs. In addition, more and more protein markers such as DOG1, PKCθ were found to be expressed in GISTs which might help clinicians diagnose CD117-negative GISTs. Therefore, we plan to comprehensively review the molecular markers and genetics of GISTs and provide clinicians useful information in diagnostic and therapeutic strategies of GISTs. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs became much more accurate by using immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. The accurately molecular diagnosis of GISTs guides clinicians to precision medicine and provides optimal treatment for the patients with GISTs. Successful treatment in GISTs prolongs the survival of GIST patients and causes GISTs to become a chronic disease. In the future, the development of effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be the challenge for GISTs.
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Affiliation(s)
- Chiao-En Wu
- GIST Team, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chin-Yuan Tzen
- Forlab Clinic, F2, No 14, Sec 2, Zhongxiao East Rd, Taipei 100, Taiwan.
| | - Shang-Yu Wang
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chun-Nan Yeh
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
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Xie F, Xiao W, Jiang Y, Xia X, Wang Y. Relationship between efficacy of sunitinib and KIT mutation of patients with advanced gastrointestinal stromal tumors after failure of imatinib: A systematic review. Medicine (Baltimore) 2019; 98:e15478. [PMID: 31083182 PMCID: PMC6531104 DOI: 10.1097/md.0000000000015478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND A large number of studies have shown that KIT mutations are closely related to the prognosis of gastrointestinal stromal tumors (GISTs). At the same time, sunitinib (SU) has become the second-line recommended drug for GISTs because of its efficacy. We initiated a systematic review to compare the efficacy of SU after failure of Imatinib (IM) in different KIT mutations. METHODS We searched for SU-treated patients with advanced GISTs after failed IM treatment by using databases such as PubMed, EMBASE, and the Cochrane Library, up to March 2018. We conducted statistical analyses to calculate the odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) using fixed-effects and random-effects models by Review Manager 5.3 software. RESULTS We included a total of 474 patients from 3 retrospective studies and 2 cohort studies. Patients with exon 9 mutations had higher clinical benefit (OR = 2.61, 95% CIs = 1.32-5.18, P = .006) rates and longer progression-free survival (progressive disease, HR = 0.51, 95% CIs = 0.36-0.72, P = .0001) compared with exon 11, but there was no statistically significant difference in overall survival (OS, HR = 0.93, 95% CIs = 0.34-2.55, P = .89) and there was greater heterogeneity (Tau = 0.72, Chi = 21.45, df = 3, P < .001, I = 86%). Subgroup analysis suggests that race may be one of the sources of heterogeneity. CONCLUSION The results show that efficacy of SU is closely associated with KIT genotypes in GISTs. Moreover, racial factor also directly affects the prognosis of different KIT mutational status, so GISTs patients of different genotypes might also consider the use of targeted drugs in consideration of ethnic differences.
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Affiliation(s)
- Fuming Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, P. R. China
| | - Yahui Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University
| | - Xiao Xia
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University
| | - Yaxu Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University
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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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Nie Y, Sun W, Xiao Z, Ye S. Complete response to sunitinib for more than three years in a patient with a jejunum gastrointestinal stromal tumor: A case report. Medicine (Baltimore) 2019; 98:e14060. [PMID: 30653116 PMCID: PMC6370167 DOI: 10.1097/md.0000000000014060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
RATIONALE Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is characterized by KIT mutations. Patientsresistant to 1st-line imatinib therapy are usually given sunitinib assecond-line treatment, which provides a median progression-free survival of 8 to 12 months. We report the 1st case of metastatic jejunum GIST with a KIT exon 11 deletion that showed complete response (CR) to sunitinib for more than 3 years. PATIENT CONCERNS A 34-year-old man with advanced jejunum GIST was surgically treated upon initial diagnosis, and was histologically found to carry a high recurrence risk. Genetic testing revealed a KIT exon 11 deletion, and adjuvant therapy with imatinib was administered. The imatinib dose was escalated following recurrence in the abdomen, but the mass continued to grow. DIAGNOSIS He was diagnosed with abdominal recurrence of GIST based on his medical history and histopathological results. INTERVENTION Second-line sunitinib therapy was given. OUTCOMES The mass disappeared, and CR was seen following 7 months of sunitinib therapy; this CR was sustained for more than 45 months. LESSONS In cases of metastatic jejunum GIST with a KIT exon 11 deletion, sunitinib as second-line therapy can be used to achieve CR for more than 3 years.
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Affiliation(s)
- Yanli Nie
- Department of Gastrointestinal Medical Oncology, The Hubei Cancer Hospital, Huazhong University of Science and Technology
| | - Wenjia Sun
- Department of Pathology, The Hubei Cancer Hospital, Huazhong University of Science and Technology
| | - Zhihua Xiao
- Department of Gastrointestinal Medical Oncology, The Hubei Cancer Hospital, Huazhong University of Science and Technology
| | - Shengwei Ye
- Department of Gastrointestinal Surgical Oncology, The Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China
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Tan S, Chen P, Ji J, Guo S, Yu D, Asakawa T, Zhou Y, Abe M, Zong L. Genomic Subtypes of GISTs for Stratifying Patient Response to Sunitinib following Imatinib Resistance: A Pooled Analysis and Systematic Review. DISEASE MARKERS 2018; 2018:1368617. [PMID: 30224936 PMCID: PMC6129330 DOI: 10.1155/2018/1368617] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 06/20/2018] [Accepted: 06/28/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Sunitinib (a second-line chemotherapeutic agent that inhibits multiple kinases, including KIT and PDGFR) is widely used in imatinib-resistant patients with gastrointestinal stromal tumors (GISTs). However, diverse responses to sunitinib have been observed in the clinic. We aimed to evaluate whether the different GIST genotypes could be used to stratify patient response to sunitinib. METHODS We searched the PubMed, Embase, and Cochrane databases and included English-language literature published up to August 31, 2017. Inclusion criteria were GIST patients with KIT exon 9, KIT exon 11, or PDGFRA mutations and those without KIT/PDGFRA mutations (termed the wild-type genotype) who were receiving sunitinib within a clinical trial, and the efficacy evaluation was clinical benefit rate (CBR), median progression-free survival (PFS), and overall survival (OS). Odds ratios (ORs) for CBR and hazard ratios (HRs) for PFS and OS with 95% confidence intervals (CIs) in sunitinib-treated GIST patients with different genotypes were compared. RESULTS Seven studies totaling 531 patients were included. Patients with KIT mutations showed an improved CBR to sunitinib compared to those with PDGFRA mutations. In particular, those with the KIT exon 9 or 11 mutation showed improved CBR over those with PDGFRA mutation. Moreover, GIST patients with the KIT exon 9 mutation showed improved CBR over those with the KIT exon 11 mutation. Patients without KIT/PDGFRA mutations (wild-type genotype) showed better CBR than those with PDGFRA mutations. CONCLUSION GIST genotypes may be useful for stratifying patient response to sunitinib after imatinib resistance.
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Affiliation(s)
- Siyuan Tan
- Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Ping Chen
- Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Shanshan Guo
- Department of Oncology, Graduate School of Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Dapeng Yu
- Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Tetsuya Asakawa
- Department of Neurosurgery, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Shizuoka, Japan
| | - Yu Zhou
- Department of General Surgery, Suzhou Municipal Hospital (North Campus), Suzhou, Jiangsu, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Liang Zong
- Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17. Oncotarget 2018; 8:44121-44130. [PMID: 28487491 PMCID: PMC5546467 DOI: 10.18632/oncotarget.17310] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 03/31/2017] [Indexed: 12/26/2022] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%–90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2–3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. Patients and Methods Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1–21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. Results Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). Conclusion Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. Trial registration This trial is registered atClinicalTrials.gov in November 2015, number NCT02606097. Key message This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.
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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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Shirakawa T, Hirata T, Maemura K, Goto T, Shimao Y, Marutsuka K, Ueda Y, Kikuchi I. Complete response to second-line chemotherapy with sunitinib of a gastrointestinal stromal tumor: A case report. Mol Clin Oncol 2017; 7:93-97. [PMID: 28685083 DOI: 10.3892/mco.2017.1268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/19/2017] [Indexed: 12/25/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are a type of sarcoma, and the most common mesenchymal tumor of the gastrointestinal tract. Systemic chemotherapy is recommended for unresectable or metastatic GISTs. Imatinib is an oral multitargeted receptor tyrosine kinase inhibitor that is effective as adjuvant chemotherapy for primary high-risk cases, and as palliative chemotherapy for unresectable or metastatic cases. For imatinib-resistant cases, second-line chemotherapy with sunitinib is recommended due to significantly longer median progression-free survival and higher response rates compared with a placebo. A 54-year-old woman presented with persistent upper abdominal pain and anorexia. An upper gastrointestinal endoscopy and computed tomography revealed a submucosal tumor of the stomach with no apparent metastases. The patient underwent total radical gastrectomy, and was diagnosed histologically with high-risk GIST for recurrence, therefore, the patient received adjuvant chemotherapy with imatinib. However, multiple liver and lymph node metastases were detected, and the patient received sunitinib therapy. After four cycles of sunitinib, the liver and lymph node metastases disappeared, and a complete response (CR) was achieved. To date, there have been no cases of CR in the prospective clinical trials examining the effects of sunitinib, or in case reports worldwide. Therefore, this is a very rare case report of a patient with metastatic GISTs who achieved CR with sunitinib as second-line chemotherapy.
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Affiliation(s)
- Tsuyoshi Shirakawa
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan.,Department of Oncology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Tomoya Hirata
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Kosuke Maemura
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Toshiyuki Goto
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Yoshiya Shimao
- Department of Pathology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Kosuke Marutsuka
- Department of Pathology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Yuji Ueda
- Department of Surgery, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
| | - Ikuo Kikuchi
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan
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Giner F, Machado I, Lopez-Guerrero JA, Mayordomo-Aranda E, Llombart-Bosch A. High-risk gastrointestinal stromal tumour (GIST) and synovial sarcoma display similar angiogenic profiles: a nude mice xenograft study. Ecancermedicalscience 2017; 11:726. [PMID: 28386296 PMCID: PMC5365342 DOI: 10.3332/ecancer.2017.726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Indexed: 12/20/2022] Open
Abstract
Background Gastrointestinal stromal tumour (GIST) is the most common primary mesenchymal tumour of the gastrointestinal tract. Spindle cell monophasic synovial sarcoma (SS) can be morphologically similar. Angiogenesis is a major factor for tumour growth and metastasis. Our aim was to compare the angiogenic expression profiles of high-risk GIST and spindle cell monophasic SS by histological, immunohistochemical and molecular characterisation of the neovascularisation established between xenotransplanted tumours and the host during the initial phases of growth in nude mice. Methods The angiogenic profile of two xenotransplanted human soft-tissue tumours were evaluated in 15 passages in nude mice using tissue microarrays (TMA). Tumour pieces were also implanted subcutaneously on the backs of 14 athymic Balb-c nude mice. The animals were sacrificed at 24, 48, and 96 h; and 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularisation experiments). Results Morphological similarities were apparent in the early stages of neoplastic growth of these two soft-tissue tumours throughout the passages in nude mice and in the two neovascularisation experiments. Immunohistochemistry demonstrated overexpression of pro-angiogenic factors between 24 h and 96 h after xenotransplantation in both tumours. Additionally, neoplastic cells coexpressed chemokines (CXCL9, CXCL10, GRO, and CXCL12) and their receptors in both tumours. Molecular studies showed two expression profiles, revealing an early and a late phase in the angiogenic process. Conclusion This model could provide information on the early stages of the angiogenic process in monophasic spindle cell SS and high-risk GIST and offers an excellent way to study possible tumour response to antiangiogenic drugs.
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Affiliation(s)
- Francisco Giner
- Department of Pathology, Universitat de València Estudi General (UVEG), València 46010, Spain
| | - Isidro Machado
- Department of Pathology, Fundación Instituto Valenciano de Oncología (FIVO), Valencia 46009, Spain
| | | | - Empar Mayordomo-Aranda
- Department of Pathology, Universitat de València Estudi General (UVEG), València 46010, Spain
| | - Antonio Llombart-Bosch
- Department of Pathology, Universitat de València Estudi General (UVEG), València 46010, Spain
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Mulet-Margalef N, Garcia-Del-Muro X. Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives. Onco Targets Ther 2016; 9:7573-7582. [PMID: 28008275 PMCID: PMC5171199 DOI: 10.2147/ott.s101385] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multi-targeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with 18F-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor.
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Affiliation(s)
- Nuria Mulet-Margalef
- Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Català d'Oncologia Hospitalet, IDIBELL, Barcelona, Spain
| | - Xavier Garcia-Del-Muro
- Sarcoma Multidisciplinary Unit and Medical Oncology Department, Institut Català d'Oncologia Hospitalet, IDIBELL, Barcelona, Spain
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Shinagare AB, Barysauskas CM, Braschi-Amirfarzan M, O'Neill AC, Catalano PJ, George S, Ramaiya NH. Comparison of performance of various tumor response criteria in assessment of sunitinib activity in advanced gastrointestinal stromal tumors. Clin Imaging 2016; 40:880-4. [PMID: 27179958 DOI: 10.1016/j.clinimag.2016.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 03/30/2016] [Accepted: 04/21/2016] [Indexed: 11/30/2022]
Abstract
PURPOSE To compare the performance of various tumor response criteria (TRC) in the assessment of patients with advanced gastrointestinal stromal tumor (GIST) treated with sunitinib after failure of imatinib. METHODS Sixty-two participants with advanced GIST in two clinical trials received oral sunitinib after prior failure of imatinib (median duration 24 weeks; interquartile range 14-56) and were followed with contrast-enhanced computed tomography at baseline and thereafter at median intervals of 6 weeks (IRQ 6-9). Tumor response was prospectively determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0, and retrospectively reassessed for comparison using RECIST 1.1, Choi criteria, and modified Choi (mChoi) criteria using the original target lesions. For mChoi criteria, progressive disease was defined as 20% increase in sum of the longest dimension, similar to RECIST 1.1. Clinical benefit rate (CBR; complete response, partial response, or stable disease ≥12 weeks) and progression-free survival were compared between various TRCs using kappa statistics. RESULTS While partial response as the best response was more frequent by Choi and mChoi criteria (50% each) than RECIST 1.1 (15%) and RECIST 1.0 (13%), CBR was similar between various TRCs (overall CBR 60%-77%, 77%-94% agreement between all TRC pairs). Time to best response was shorter for Choi and mChoi criteria (median 11 weeks each) compared to RECIST 1.1 and RECIST 1.0 (median 25 and 24 weeks, respectively). PFS was similar for RECIST 1.1, RECIST 1.0, and mChoi (median 35 weeks each), and shortest for Choi criteria (median 23 weeks). CONCLUSIONS CBR was similar among the various TRCs, although Choi criteria led to earlier determination of disease progression. Therefore, RECIST 1.1 and mChoi criteria may be preferred for response assessment in patients with advanced GIST.
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Affiliation(s)
- Atul B Shinagare
- Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
| | - Constance M Barysauskas
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA
| | - Marta Braschi-Amirfarzan
- Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Ailbhe C O'Neill
- Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Paul J Catalano
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115, USA
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA
| | - Nikhil H Ramaiya
- Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
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Takaki H, Litchman T, Covey A, Cornelis F, Maybody M, Getrajdman GI, Sofocleous CT, Brown KT, Solomon SB, Alago W, Erinjeri JP. Hepatic artery embolization for liver metastasis of gastrointestinal stromal tumor following imatinib and sunitinib therapy. J Gastrointest Cancer 2015; 45:494-9. [PMID: 25358551 DOI: 10.1007/s12029-014-9663-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE The purpose of the study is to determine the efficacy of hepatic artery embolization (HAE) as a therapy for gastrointestinal stromal tumor (GIST) in patients who are refractory to imatinib and sunitinib. METHODS After institutional review board approval, a retrospective review revealed 11 patients with GIST metastatic to the liver who underwent 15 HAEs between February 2002 and May 2013. These patients were stratified into two groups according to the previous treatment: (a) those treated with HAE as second-line treatment after failing first-line imatinib (n = 3) and (b) those treated with HAE as third-line therapy after failing first-line imatinib and second-line sunitinib (n = 8). Initial therapeutic response, overall survival (OS), progression-free survival (PFS), and safety were evaluated. RESULTS Initial therapeutic response rates at 3 months after HAE were 27.3 % (95 % confidence interval (CI), 6.0-61.0 %) by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.0 and 45.5 % (95 % CI, 16.7-76.6 %) by modified RECIST (mRECIST). The median OS and PFS after HAE were 14.9 and 3.9 months in group A and 23.8 and 3.4 months in group B, respectively. No procedure-related mortality or major complication was observed. CONCLUSIONS HAE is an effective and well-tolerated therapeutic option for GIST liver metastases. Although larger studies are necessary, HAE should be considered as an alternative or adjuvant to third-line or even second-line systemic treatment.
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Affiliation(s)
- Haruyuki Takaki
- Interventional Radiology Service, Memorial Sloan-Kettering Cancer Center, Howard-118, 1275 York Avenue, New York, NY, USA,
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Kitayama H, Hirayama M, Sugiyama J, Kondo T, Oyamada Y, Takahashi S, Tsuji Y. Complete response of gastrointestinal stromal tumor liver metastases to regorafenib. Int Cancer Conf J 2015. [DOI: 10.1007/s13691-014-0192-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Basilio-de-Oliveira RP, Nunes Pannain VL. Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World J Gastroenterol 2015; 21:6924-6930. [PMID: 26078569 PMCID: PMC4462733 DOI: 10.3748/wjg.v21.i22.6924] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the correlation between the immunoexpression of angiogenic markers [CD31, CD105 and vascular endothelial growth factor (VEGF)], proliferative index (Ki67), and prognosis of patients with gastrointestinal stromal tumors (GIST).
METHODS: This is a retrospective study of 54 GIST cases. Medical records were searched to obtain the GIST patients’ demographic and clinical data, and paraffin-embedded blocks of tumor samples were retrieved from the hospital archives to conduct a new immunohistochemical evaluation. The tumor samples of GIST patients were subject to immunohistochemical evaluation for endoglin (CD105), CD31, VEGF, and Ki67 expression. The CD105 and CD31 intratumoral microvascular density (IMVD) was measured using automated analysis. We determined the correlation between the immunoexpression of CD105, CD31, VEGF, Ki67 and prognosis. In addition, we conducted a cutoff analysis using the receiver-operating characteristic curve. VEGF positivity was classified as either null/weak or strong. Ki67 was evaluated using a cutoff of 5% positive cells. The prognosis was classified as good (patient alive without recurrence) or poor (patient with recurrence/death).
RESULTS: The distribution of tumor sites among the 54 analyzed samples was as follows: 27 (50%) in the stomach, 20 (37.1%) in the small intestine, 6 (11.1%) in the colon, and 1 (1.8%) in the esophagus. The size of the tumors ranged from 2 to 33 cm (median: 8 cm); in 12 cases (22.2%), the tumor was below 5 cm at the largest diameter, but in 42 cases (77.7%), the tumor was larger than 5 cm. The means of CD105 and CD31 were significantly higher in the group with poor prognosis (P < 0.001). The cut-off values of CD105 (> 1.2%) and CD31 (> 2.5%) in the receiver-operating characteristic curve were related to a poorer prognosis. Cases with a better prognosis showed significantly null/weak staining for VEGF (P < 0.001). Ki-67 expression of ≥ 5% was strongly correlated with a worse prognosis (P < 0.001). In the multivariate analysis, CD105 was the variable that most strongly correlated with prognosis.
CONCLUSION: The IMVD cutoff values for the angiogenic markers CD105 and CD31, may be prognostic factors for GIST, in addition to VEGF and Ki67.
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Fas/Fas Ligand Mediates Keratinocyte Death in Sunitinib-Induced Hand-Foot Skin Reaction. J Invest Dermatol 2014; 134:2768-2775. [DOI: 10.1038/jid.2014.218] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 03/24/2014] [Accepted: 04/07/2014] [Indexed: 01/27/2023]
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Kim S, Ding W, Zhang L, Tian W, Chen S. Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials. Onco Targets Ther 2014; 7:719-28. [PMID: 24872713 PMCID: PMC4026584 DOI: 10.2147/ott.s61388] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Angiogenesis is an integral process in carcinogenesis, and molecular inhibitors of angiogenic factors are currently being tested as treatments for cancer. Sunitinib is an oral multitargeted tyrosine-kinase inhibitor that blocks activation through the stem cell-factor receptor (Kit) and platelet-derived growth-factor receptor. Sunitinib has shown potent antitumor activity against several solid tumors, including renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine tumors in several Phase II/III trials. Recently, sunitinib has been used to treat other solid cancers, such as lung cancer, pancreatic cancer, chondrosarcoma, esophageal cancer, bladder cancer, glioma, and aggressive fibromatosis, and also showed potential efficacy in progression-free survival and overall survival. In this review, we examine the efficacy of sunitinib as a molecular-targeted therapy in patients with different types of solid cancers.
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Affiliation(s)
- Sungkyoung Kim
- Department of Oncology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Wenping Ding
- Department of Oncology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Lian Zhang
- Department of Oncology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Wei Tian
- Department of Oncology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
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Sodergren SC, White A, Efficace F, Sprangers M, Fitzsimmons D, Bottomley A, Johnson CD. Systematic review of the side effects associated with tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumours on behalf of the EORTC Quality of Life Group. Crit Rev Oncol Hematol 2014; 91:35-46. [PMID: 24495942 DOI: 10.1016/j.critrevonc.2014.01.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 12/16/2013] [Accepted: 01/10/2014] [Indexed: 02/07/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have revolutionised the treatment of advanced gastrointestinal stromal tumours (GISTs). Imatinib is approved as first line therapy and sunitinib is used in cases of imatinib resistance or intolerance. Compared with conventional treatments, TKIs are delivered over longer periods of time and are more specific in their targets (i.e., molecularly targeted), thus presenting different side effect profiles. We review the safety profiles of imatinib and sunitinib, documenting a total of 95 side effects including patient based as well as medically defined outcomes. Gastrointestinal complaints, particularly diarrhoea and nausea, oedema, fatigue and haematological disorders, notably anaemia, are amongst the most prevalent side effects. While there is overlap between the side effect profiles of imatinib and sunitinib, important differences emerge in the frequencies of oedema, hypertension, thyroid functioning, muscle and joint pains, as well as skin and oral conditions. Awareness of potential side effects is informative to both clinician and patient in terms of treatment decision making and can have important implications for treatment adherence and clinical outcome.
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Affiliation(s)
| | - Alice White
- Cancer Sciences, University of Southampton, Southampton SO16 6YD, UK
| | - Fabio Efficace
- Health Outcomes Research Unit, Gimema, 00161 Rome, Italy
| | - Mirjam Sprangers
- Department of Medical Psychology, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Deborah Fitzsimmons
- Swansea Centre for Health Economics, Swansea University, Swansea SA2 8PP, UK
| | - Andrew Bottomley
- European Organisation for Research and Treatment of Cancer Quality of Life Department, 1200 Brussels, Belgium
| | - Colin D Johnson
- Cancer Sciences, University of Southampton, Southampton SO16 6YD, UK
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23
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Kefeli U, Benekli M, Sevinc A, Yildiz R, Kaplan MA, Ciltas A, Balakan O, Isikdogan A, Coskun U, Dane F, Harputluoglu H, Karaca H, Yazilitas D, Durnali A, Kaya AO, Demirci U, Gumus M, Buyukberber S. Efficacy of sorafenib in patients with gastrointestinal stromal tumors in the third- or fourth-line treatment: A retrospective multicenter experience. Oncol Lett 2013; 6:605-611. [PMID: 24137379 PMCID: PMC3789037 DOI: 10.3892/ol.2013.1408] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 06/05/2013] [Indexed: 01/14/2023] Open
Abstract
Sorafenib is a multi-targeted tyrosine kinase receptor inhibitor used to treat patients with advanced gastrointestinal stromal tumors (GISTs). The present study evaluated the efficacy and tolerability of sorafenib therapy for patients with GISTs. Between January 2001 and November 2012, 25 patients, from multiple centers, who had received sorafenib as the third- or fourth-line treatment for GISTs were investigated retrospectively. In total, 17 patients were male and eight were female. The median age was 54.0 years (range, 16–82 years). From the patients, 21 received imatinib for longer than six months and four received it for less than six months. The clinical benefit rate of sorafenib was 40.0%. Treatment-related adverse events were reported in 72% of patients. These adverse events were generally mild to moderate in intensity. The median progression-free survival (PFS) and overall survival (OS) times of the patients who received sorafenib were 7.2 and 15.2 months, respectively. The duration of imatinib usage was an independent prognostic factor for PFS and OS. Sorafenib is an effective treatment in patients with GISTs showing a clinical benefit rate of 40.0% and an acceptable tolerability.
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Affiliation(s)
- Umut Kefeli
- Department of Medical Oncology, Medeniyet University Goztepe Training and Research Hospital, Istanbul
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24
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Liu Y, Zhang HL, Zhang Y, Mei JZ, Lin HW, Guo YW, Li RJ, Meng XR, Liu GJ, Li M, Xiao P, Bai H. Digestive tract hemorrhage due to complications with gastrointestinal stromal tumor treated with sunitinib: A case report. Oncol Lett 2012; 5:699-701. [PMID: 23420084 PMCID: PMC3572955 DOI: 10.3892/ol.2012.1050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 10/11/2012] [Indexed: 01/13/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are rare, and account for 1% of all gastrointestinal neoplasms. GISTs are the most frequent mesenchymal tumors of the gastrointestinal tract. However, the clinical and pathological characteristics of these neoplasms are not adequately understood. The best treatment approach for GISTs remains unclear. In the present study, we report a case of a GIST originating from the stomach. A digestive tract hemorrhage occurred as a complication of sunitinib treatment. This is the first report of a digestive tract hemorrhage due to sunitinib treatment.
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Affiliation(s)
- Yan Liu
- Department of Oncology, Zhengzhou People's Hospital, Southern Medical University, Zhengzhou, Henan 450003
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25
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Yeh CN, Hwang TL, Huang CS, Lee PH, Wu CW, Chen-Guo K, Jan YY, Chen MF. Clinical practice guidelines for patients with gastrointestinal stromal tumor in Taiwan. World J Surg Oncol 2012; 10:246. [PMID: 23153013 PMCID: PMC3523083 DOI: 10.1186/1477-7819-10-246] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 10/15/2012] [Indexed: 12/07/2022] Open
Abstract
For many years, the understanding of gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, has been very limited. However, it is now possible to provide a more precise definition through the use of pathology classification and molecular techniques. Coupled with the advancement of clinical practice, especially the development of targeted therapy, there is now a much better insight into its treatment. At present, organizations such as the National Comprehensive Cancer Network in the USA and the European Society for Medical Oncology in Europe have established a consensus and drawn up guidelines for the diagnosis, treatment, and follow-up of GISTs.With experts coming from various districts in Taiwan and combining the most recent clinical data and experiences, the Taiwan Surgical Society of Gastroenterology drafted the first national GIST treatment guidelines after a consensus meeting in 2007. Following subsequent advances in GIST diagnosis and treatment, further revisions and modifications have been made to the original guidelines. We present here the updated consensus and recommendations of the Taiwan Surgical Society of Gastroenterology for the diagnosis and treatment of GIST. We hope these guidelines can help enhance the quality of diagnosis, treatment, and care of patients with GIST in Taiwan.
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Affiliation(s)
- Chun-Nan Yeh
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, #5, Fu-Hsing Street Kwei-Shan, Taoyuan, Taiwan
| | - Tsann-Long Hwang
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, #5, Fu-Hsing Street Kwei-Shan, Taoyuan, Taiwan
| | - Ching-Shui Huang
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, #5, Fu-Hsing Street Kwei-Shan, Taoyuan, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Chew-Wun Wu
- Department of Surgery, Taipei Veteran General Hospital, Taipei, 100, Taiwan
| | - Ker Chen-Guo
- Department of Surgery, Yuan’s General Hospital, Kaohsiung City, Taiwan
| | - Yi-Yin Jan
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, #5, Fu-Hsing Street Kwei-Shan, Taoyuan, Taiwan
| | - Miin-Fu Chen
- Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, #5, Fu-Hsing Street Kwei-Shan, Taoyuan, Taiwan
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26
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Imatinib Mesylate for Patients with Recurrent or Metastatic Gastrointestinal Stromal Tumors Expressing KIT: A Decade Experience from Taiwan. Transl Oncol 2011; 4:328-35. [PMID: 22190996 DOI: 10.1593/tlo.11253] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Revised: 08/23/2011] [Accepted: 09/23/2011] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Our preliminary report of imatinib mesylate (IM) in gastrointestinal stromal tumor (GIST) patients detailed a high response rate; however, the long-term result is still unknown. We conducted an analysis of Taiwan advanced inoperable/metastatic GIST patients treated on IM regarding survival, pattern of failure, potential prognostic factors, and mutational status. PATIENTS AND METHODS From 2001 to 2010, patients with pathologically proven advanced inoperable/metastatic GIST receiving IM were enrolled onto this study. Data on KIT mutational status, measurable tumor size, and other potential prognostic factors were prospectively collected. Patients were followed up for a median of 33.6 months. RESULTS There were 171 patients (106 men and 65 women) with response rate, and their clinical benefit for IM was 57.3% and 87.1%, respectively. Median progression-free survival (PFS) and overall survival (OS) for these 171 patients are 37.6 and 71.0 months, respectively. Of 171 patients, 120 (70.2%) remained on long-term IM use. Poor performance status, tumor larger than 11.5 cm, primary resistance, and the presence of an exon 9 mutation were independently associated with unfavorable PFS. Regarding OS, poor performance status, primary resistance, and tumor larger than 11.5 cm were three independently unfavorable predictors. CONCLUSIONS The median PFS and OS of 171 GIST patients are 37.6 and 71.0 months, respectively. Poor performance status, tumor size larger than 11.5 cm, primary resistance, and an exon 9 mutation were independently associated with unfavorable PFS. Regarding OS, poor performance status, primary resistance, and tumor size larger than 11.5 cm were three independent unfavorable predictors.
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