Randomized clinical trials in gastrointestinal stromal tumors.
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ABSTRACT:
SUBMITTER: Learn PA
PROVIDER: S-EPMC3164338 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
Publications
Randomized clinical trials in gastrointestinal stromal tumors.
Learn Peter A PA Sicklick Jason K JK DeMatteo Ronald P RP
Surgical oncology clinics of North America 20100101 1
Gastrointestinal (GI) stromal tumor (GIST) is the most common mesenchymal tumor of the GI tract, constituting 80% of all GI mesenchymal tumors and approximately 20% of all small bowel malignancies, excluding lymphomas. This article provides a summary of recent randomized clinical trials of these tumors. ...[more]
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Project description:Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.
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Project description:Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with high-risk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.
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Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors located in the alimentary tract. Its usual manifestation is gastrointestinal bleeding. However, small asymptomatic lesions are frequently detected as incidental finding. Characteristically, most GISTs (> 95%) are positive for the KIT protein (CD117) by IHC staining and approximately 80%-90% of GISTs carry a mutation in the c-KIT or PDGFRA genes. Mutational analysis should be performed when planning adjuvant and neoadjuvant therapy, due to its possible resistance to conventional treatment. The arise of tyrosine kinase inhibitor has supposed a revolution in GISTs treatment being useful as adjuvant, neoadjuvant or recurrence disease treatment. That is why a multidisciplinary approach to this disease is required. The correct characterization of the tumor at diagnosis (the diagnosis of recurrences and the evaluation of the response to treatment with tyrosine kinase inhibitors) is fundamental for facing these tumors and requires specialized Endoscopist, Radiologists and Nuclear Medicine Physician. Surgery is the only potentially curative treatment for suspected resectable GIST. In the case of high risk GISTs, surgery plus adjuvant Imatinib-Mesylate for 3 years is the standard treatment. Neoadjuvant imatinib-mesylate should be considered to shrink the tumor in case of locally advanced primary or recurrence disease, unresectable or potentially resectable metastasic tumors, and potentially resectable disease in complex anatomic locations to decrease the related morbidity. In the case of Metastatic GIST under Neoadjuvant treatment, when there are complete response, stable disease or limited disease progression, complete cytoreductive surgery could be a therapeutic option if feasible.
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Project description:GIST (gastrointestinal stromal tumors) represent 20% of sarcomatous tumors and 1-2% of primary gastrointestinal cancers. They have an excellent prognosis when localized and resectable, though their prognosis is poor in the metastatic setting, with limited options after the second line until recently. Four lines are now standard in KIT-mutated GIST and one in PDGFRA-mutated GIST. An exponential growth of new treatments is expected in this era of molecular diagnostic techniques and systematic sequencing. Currently, the main challenge remains the emergence of resistance linked to secondary mutations caused by selective pressure induced by TKIs. Repeating biopsies to tailor treatments might be a step in the right direction, and liquid biopsies at progression may offer a non-invasive alternative. New molecules with wider KIT inhibition are under investigation and could change the catalog and the sequence of existing treatments. Combination therapies may also be an approach to overcome current resistance mechanisms. Here, we review the current epidemiology and biology of GIST and discuss future management options, with an emphasis on genome-oriented therapies.
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Project description:Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.
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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.
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Project description:Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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