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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., (© 2022. Crown.)

Major advances in the medical treatment of gastrointestinal tumors (GISTs) have improved survival for both patients with advanced disease and those diagnosed with high-risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high-risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long-term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third-line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated., (© 2014 Wiley Publishing Asia Pty Ltd.)

Historically, patients with inoperable gastrointestinal stromal tumors (GISTs) had a very poor prognosis because of the highly resistant nature of these tumors to conventional chemotherapy. The rational and progressive development of tyrosine kinase inhibitors (TKIs) since the initial proof-of-concept studies with imatinib mesylate in the late 1990s, all designed to exploit key pathways that lead to GISTs being so oncogenically addicted, have revolutionized the treatment of GIST. Median overall survival has improved from less than a year to at least 5 years in patients with advanced or metastatic disease. Imatinib remains the standard first-line treatment in advanced GIST; however, resistance to imatinib and subsequent other TKIs inevitably develops in most but not all patients. As much as efforts will continue to identify new drugs for patients with disease that becomes refractory to these agents, there has also been a need to focus on optimizing the use of currently available therapies by using a combination of molecular tools to stratify patients more effectively, pharmacodynamic markers and pharmacokinetic modeling to maximize these agents' activity in individual patients, and reappraising the role of surgery in the management of patients with metastatic disease. These all form part of a modern, multidisciplinary approach to the management of GIST patients., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high-dose imatinib or switch to second-line sunitinib in the event of disease progression and appropriately managing treatment-associated side effects. Imatinib is the standard first-line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high-dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high-dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes., (© 2012 Blackwell Publishing Asia Pty Ltd.)

Imatinib is standard first-line treatment for patients with advanced gastrointestinal stromal tumor (GIST). Initial responses are not always accompanied by reductions in tumor size; consequently, other parameters should be considered in response assessments. Conventional size-based criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate responses to imatinib and have poor predictive value for outcome. Imatinib-responding tumors demonstrate decreased metabolic activity on positron emission tomography within the first weeks of treatment, often showing reduced density and greater homogeneity on computed tomography (CT) scans regardless of initial changes in tumor size. New criteria, based on reductions in tumor size or in tumor density on CT, seem more sensitive and specific for detecting early responses to imatinib, and more predictive of time to tumor progression and disease-specific survival. Compared with conventional size-based criteria, new CT-based criteria may potentially offer improved response assessment and be predictive of outcome in GIST. However, such emerging criteria should be further explored and validated in large, multicenter trials with imatinib and other kinase inhibitors in GIST and in other solid tumors., (Copyright © 2011 UICC.)

Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease progression., Experimental Design: Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging and [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography. Where feasible, biopsies were done to document disease progression., Results: A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique "resistant clonal nodule" pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared with 44.6 months for patients whose first progression met Southwest Oncology Group criteria (P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients., Conclusion: The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST.

Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors., Experimental Design: Patients (n=73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC)., Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/microL/d, P=0.03) and smaller decreases in monocyte levels (47% versus 60%, P=0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment., Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

Background: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed., Objective: To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy., Design: Prospective, observational cohort study., Setting: Tertiary care hospital., Patients: 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks)., Measurements: Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction., Results: Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function., Limitations: The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction., Conclusion: Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.

Background: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib., Methods: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218., Findings: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea., Interpretation: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Purpose: While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST., Methods: We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease)., Results: Disease status before surgery was associated with surgical result (P < .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001)., Conclusion: Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.

Purpose: To investigate a new pattern of tumor recurrence observed at imaging in patients with metastatic gastrointestinal stromal tumor (GIST) after initial partial response to imatinib mesylate., Materials and Methods: Ninety-two patients with metastatic GIST who underwent treatment in a clinical trial with oral imatinib mesylate were followed up for 29 months. An institutional review board-approved protocol was used. The study complied with the Health Insurance Portability and Accountability Act, and written informed consent was obtained from all patients. Images of the chest, abdomen, and pelvis, acquired with computed tomography (CT), positron emission tomography (PET), and, in some cases, magnetic resonance imaging, were evaluated for treatment response and disease recurrence. Thirty-nine patients (29 men, 10 women; age range, 18-84 years; mean, 49.2 years) had recurrent disease after an initial variable period of response (range, 2-24 months; median, 14.4 months). Initial response was determined with findings of decreased uptake of fluorine 18 fluorodeoxyglucose at PET, shrinkage of tumor, and decreased attenuation at CT. Images were evaluated for disease recurrence by two experienced radiologists who were blinded to each other's interpretation but not to clinical details. Final reading was performed by consensus., Results: A nodule within a mass was seen in 21 of 39 patients (in intrahepatic tumor [n = 8], extrahepatic tumor [n = 10], or both intra- and extrahepatic tumors [n = 3]) and was the first sign of disease progression in 17 of 21 patients. Other patterns of recurrence included new site of disease (n = 7), regrowth of preexistent lesion (n = 20), and mixed (more than one) pattern (n = 9). Disease progression was verified at needle biopsy (n = 16), follow-up imaging (n = 14), and/or surgical resection (n = 9)., Conclusion: A nodule within a mass is an important sign of recurrent GIST, but measurements of overall tumor size may not enable detection of such nodules., (Copyright RSNA, 2005.)

Major advances in the medical treatment of gastrointestinal tumors ( GISTs) have improved survival for both patients with advanced disease and those diagnosed with high-risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high-risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long-term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third-line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high-dose imatinib or switch to second-line sunitinib in the event of disease progression and appropriately managing treatment-associated side effects. Imatinib is the standard first-line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high-dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high-dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors are rare mesenchymal tumors of the gastrointestinal tract. Progress in diagnosis has led to increased recognition of this disease, and the availability of effective, molecularly targeted therapy has revolutionised its management. Treatment of metastatic gastrointestinal stromal tumors with imatinib has led to unprecedented improvements in progression free and overall survival and there are ongoing investigations into the optimal pre-operative and adjuvant use of imatinib. Second-line sunitinib is now available for patients who develop resistance to imatinib, and third- and fourth-line therapies are being investigated in clinical trials. In this ever-changing environment, evidence from controlled clinical trials and the authors' experience were used to comprehensively outline current best practice management of patients with gastrointestinal stromal tumors. [ABSTRACT FROM AUTHOR]

Sunitinib malate (SU011248, Sutent®[Pfizer]) is an oral multitargeted tyrosine kinase inhibitor with efficacy against renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Sunitinib has been approved by various regulatory authorities for treatment of advanced RCC and unresectable and/or malignant GIST following failure of imatinib mesylate treatment due to resistance or intolerance. Sunitinib is generally well tolerated, with most side-effects being mild to moderate. The most common adverse events are lethargy, diarrhea, stomatitis, hand–foot syndrome and hypertension. Uncommon but important adverse effects are hypothyroidism and hematological toxicity (neutropenia and thrombocytopenia), which require monitoring. Caution is recommended when using concurrent inhibitors or inducers of CYP3A4. The frequency and severity of side-effects often correlates with increased drug exposure. In clinical trials, side-effects seldom led to treatment discontinuation. This paper summarizes the published literature and provides recommendations for patient assessments and management of treatment-related side-effects. [ABSTRACT FROM AUTHOR]