Imatinib-refractory gastrointestinal stromal tumors: The clinical problem and therapeutic strategies

Abstract

Treatment of gastrointestinal stromal tumor (GIST) is a paradigm for targeted therapy. These mesenchymal tumors are refractory to standard chemotherapy and radiation therapy. Targeted therapy has successfully exploited the oncologic drivers of GIST--the tyrosine kinases, KIT, and the platelet-derived growth factor receptor. Therapy with imatinib has dramatically altered the natural history of patients with advanced GIST. However, patients are developing resistance to imatinib and thus presenting with a major clinical challenge. Alternative approaches to imatinib-refractory disease are needed. Newer approaches using biologic data regarding the mechanisms of resistance are being tested alone or in combination with imatinib and are the focus of this review. Effective novel agents for imatinib-refractory GIST used as single agents or in combination with imatinib will likely become future regimens to be tested in first-line metastatic disease and in the adjuvant setting.

Multidisciplinary Treatment of Gastrointestinal Stromal Tumors

“…GIST are considered radiation-resistant tumors, and there are no prospective trials of the effect of radiation therapy. 50 The only role for radiation therapy is for palliative treatment or possibly with rectal GIST. Radiofrequency ablation (RFA) is a technique that is now being used more frequently with metastatic GIST in the liver.…”

The insulin-like growth factor system as a potential therapeutic target in gastrointestinal stromal tumors

“…Alternate targets may prove to have a greater impact on the management of advanced GIST (see review in ref. 61). …”

FDG-PET and PET/CT in the clinical management of gastrointestinal stromal tumor

“…With the increasing use of imatinib, acquired resistance to imatinib owing to secondary point mutations has become a frequent occurrence in GIST and poses a major clinical challenge [26,27]. As seen in the case example 7, the metabolic 'switch-on' in FDG-PET may prove valuable for early detection and study of imatinib resistance and thereby help in adopting alternative approaches early in imatinib-refractory disease.…”