Surgical interventions for focal progression of gastrointestinal stromal tumors under imatinib therapy

9548 Background: Although Imatinib has shown high activity oin advanced gastrointestinal stromal tumors (GIST), secondary resistance appears as focal or systemic progressions during chronic therapy. At present, there are limited therapeutic options for Imatinib-resistant GIST. This retrospective study examines the safety and short-term outcomes of surgical interventions for focal progressions under Imatinib. Patients and Methods: Between Jan. 2002 and May 2005, 16 patients (pts) with focal progressions of secondarily-resistant GIST (Male:Female, 12:4; median age, 61 years) underwent surgical interventions including resection (N=13), radiofrequency ablation (RFA) (n=2), and their combination (n=1). Doses of Imatinib were 400 (n=10) or 600 (n=6) mg/day. Results: Postoperative complications including liver abscess (n=1), minor bile leak (n=1), wound infection (n=1) and transient ileus (n=1) were occurred to 4 patients, who recovered from them within a few weeks. There was no in-hospital deaths. Median time to progression (TTP) was 5.5 months. Only one patient died of the of disease, 16 months after the resection, and the remaining 15 pts are alive, with a median follow-up of 13 months. Pts with total eradication of resistant lesions (n=7) had longer TTP than those with incomplete (n=9) (p<0.05). Total eradication could be performed in patients with a smaller number (P=0.014) and size (P=0.018) of resistant lesions. Overall survival after Imatinib therapy was 100% at 1 year and 93% at 3 years, with a median follow-up of 39 months. Conclusions: These data suggest that surgical interventions for focal progressions of secondarily-resistant GIST under Imatinib may be safe and that total eradication of resistant lesions may result in a survival benefits under conditions of limited treatment modality. No significant financial relationships to disclose.

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Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.2265 ◽

2006 ◽

Vol 24 (29) ◽

pp. 4764-4774 ◽

Cited By ~ 528

Author(s):

Michael C. Heinrich ◽

Christopher L. Corless ◽

Charles D. Blanke ◽

George D. Demetri ◽

Heikki Joensuu ◽

...

Keyword(s):

Gastrointestinal Stromal Tumors ◽

Molecular Mechanisms ◽

Clonal Evolution ◽

Clinical Problem ◽

Primary Resistance ◽

Imatinib Resistance ◽

Secondary Resistance ◽

Stromal Tumors ◽

Rnai Technology ◽

Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

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Prospective Observational Study of Imatinib Therapy in Japanese Patients with Advanced Gastrointestinal Stromal Tumors: Long-term Follow-up and Second Malignancy

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hys056 ◽

2012 ◽

Vol 42 (7) ◽

pp. 578-585 ◽

Cited By ~ 11

Author(s):

Tatsuo Kanda ◽

Takashi Ishikawa ◽

Seiichi Hirota ◽

Kazuhito Yajima ◽

Shin-ichi Kosugi ◽

...

Keyword(s):

Observational Study ◽

Gastrointestinal Stromal Tumors ◽

Prospective Observational Study ◽

Japanese Patients ◽

Imatinib Therapy ◽

Long Term Results ◽

Second Malignancies ◽

Stromal Tumors

Abstract Objective Limited data are available concerning long-term results of imatinib therapy in patients with advanced gastrointestinal stromal tumors. We aimed to clarify the long-term outcomes of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors. Methods A prospective, observational study of imatinib therapy for unresectable and metastatic gastrointestinal stromal tumors was conducted in our institution. Imatinib was initiated at a dose of 400 mg daily and continued until disease progression. Safety, efficacy and long-term tolerability and survival were evaluated in an intent-to-treat population. The median follow-up period in this study was 68 months. Results Seventy patients were enrolled between December 2001 and December 2009. Treatment-related Grade 3/4 adverse events occurred in 49 patients (70.0%). Although 14 patients required adverse effect management with hospitalization, only 5 patients (7.1%) withdrew from the treatment owing to imatinib intolerance. The tumor response and clinical benefit rates were 61.4 and 85.7%, respectively. Thirty-seven patients (52.9%) maintained the treatment at 400 mg daily imatinib, whereas 33 patients (47.1%) had their dose reduced to 300 mg daily or less. The overall survival rate at 5 years was 60.9% and the median survival time was 70 months. The median progression-free survival time of all the 70 enrolled patients was 30 months. Seven patients (10.0%) suffered from second malignancies, including three patients with genitourinary carcinomas. Conclusions Despite the need for dose reduction, the long-term results of imatinib therapy for advanced gastrointestinal stromal tumors were good in Japanese patients. Physicians should pay attention to the occurrence of second malignancies during imatinib therapy for gastrointestinal stromal tumor patients.

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Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919849757 ◽

2019 ◽

Vol 11 ◽

pp. 175883591984975

Author(s):

Feiyang Liu ◽

Fengming Zou ◽

Cheng Chen ◽

Kailin Yu ◽

Xiaochuan Liu ◽

...

Keyword(s):

Gastrointestinal Stromal Tumors ◽

Binding Modes ◽

Primary Cells ◽

Resistance Mutations ◽

Preclinical Models ◽

Gain Of Function ◽

Secondary Resistance ◽

Stromal Tumors ◽

Imatinib Resistant

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

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Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy

International Journal of Clinical Oncology ◽

10.1007/s10147-007-0657-y ◽

2007 ◽

Vol 12 (3) ◽

pp. 212-217 ◽

Cited By ~ 39

Author(s):

Junichi Hasegawa ◽

Tatsuo Kanda ◽

Seiichi Hirota ◽

Masafumi Fukuda ◽

Akiko Nishitani ◽

...

Keyword(s):

Gastrointestinal Stromal Tumors ◽

Imatinib Therapy ◽

Surgical Interventions ◽

Stromal Tumors

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Initial experiences utilizing perfusion CT in the follow-up of patients with gastrointestinal stromal tumors under imatinib mesylate treatment

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/s-0028-1085909 ◽

2008 ◽

Vol 180 (09) ◽

Author(s):

F Berger ◽

M Hittinger ◽

M Schlemmer ◽

T Saam ◽

K Nikolaou ◽

...

Keyword(s):

Imatinib Mesylate ◽

Gastrointestinal Stromal Tumors ◽

Perfusion Ct ◽

Stromal Tumors

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Multislice imaging of gastrointestinal stromal tumors

10.32512/jmr.1.1.2018/3.14 ◽

2018 ◽

pp. 3-14

Keyword(s):

Computed Tomography ◽

Key Words ◽

Gold Standard ◽

Gastrointestinal Stromal Tumors ◽

Mesenchymal Tumors ◽

Stromal Tumors ◽

Preferential Localization ◽

Multislice Imaging ◽

Computed Tomography Diagnosis

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract (1%). These tumors express the CD 117 in 95% of cases. The stomach is the preferential localization (70%). Diagnosis is difficult and sometimes late. Progress of imaging has greatly improved the management and the prognosis. Computed tomography (CT) is the gold standard for diagnosis, staging, and treatment follow-up. The increasing recognition of GIST’s histopathology and the prolonged survival revealed some suggestive imaging aspects. Key words: gastro-intestinal stromal tumors; computed tomography; diagnosis

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