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Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies.

ABSTRACT: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Before the advent of tyrosine kinase inhibitors (TKIs) there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis was dismal. With the advent of imatinib and second-line TKIs the prognosis of metastatic GIST has improved dramatically; however, there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents are under investigation and may have promise. This article discusses the current standard of care in terms of standard and investigational pharmacotherapy in the management of metastatic GIST.

SUBMITTER: Vadakara J

PROVIDER: S-EPMC3792495 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies.

Vadakara Joseph J von Mehren Margaret M

Hematology/oncology clinics of North America 20131001 5

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Before the advent of tyrosine kinase inhibitors (TKIs) there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis was dismal. With the advent of imatinib and second-line TKIs the prognosis of metastatic GIST has improved dramatically; however, there is still a need for therapies for patients with disease refractory ...[more]

PMID: 24093167

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Project description:UnlabelledSummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype.SignificanceGastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.

Project description:Simple Summary Gastrointestinal stromal tumors are considered to be insensitive to radiotherapy. However, with the development of radiation techniques and the accumulation of cases, some studies have indicated that radiotherapy could help achieve objective response in advanced or metastatic gastrointestinal stromal tumors. Therefore, it is necessary to conduct a systematic review to reassess the role of radiotherapy in gastrointestinal stromal tumors. The purpose of this study was to draw the attention of scholars and clinicians to radiotherapy and promote further research on radiotherapy in gastrointestinal stromal tumors. Abstract Gastrointestinal stromal tumors (GISTs) are considered insensitive to radiotherapy. However, a growing number of case reports and case series have shown that some lesions treated by radiotherapy achieved an objective response. The aim of the study was to perform a systematic review of all reported cases, case series, and clinical studies of GISTs treated with radiotherapy to reevaluate the role of radiotherapy in GISTs. A systematic search of the English-written literature was conducted using PubMed, Web of Science, and Embase databases. Overall, 41 articles describing 112 patients were retrieved. The included articles were of low to moderate quality. Bone was the most common site treated by radiotherapy, followed by the abdomen. In order to exclude the influence of effective tyrosine kinase inhibitors (TKIs), a subgroup analysis was conducted on whether and which TKIs were concurrently applied with radiotherapy. Results showed that radiotherapy alone or combined with resistant TKIs could help achieve objective response in selected patients with advanced or metastatic GISTs; however, survival benefits were not observed in the included studies. Pain was the most common symptom in symptomatic GISTs, followed by neurological dysfunction and bleeding. The symptom palliation rate was 78.6% after excluding the influence of effective TKIs. The adverse reactions were mainly graded 1–2. Radiotherapy was generally well-tolerated. Overall, radiotherapy may relieve symptoms for GIST patients with advanced or metastatic lesions and even help achieve objective response in selected patients without significantly reducing the quality of life. In addition to bone metastases, fixed abdominal lesions may be treated by radiotherapy. Publication bias and insufficient quality of included studies were the main limitations in this review. Further clinical studies are needed and justified.

Dataset Information

Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies.

Publications

Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies.

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