Gastrointestinal stromal tumors: imatinib and beyond.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Clinicians previously classified GISTs as "benign" or "malignant," but now place resected tumors in risk categories that are based on size and mitotic rate. Historically, GIST patients were managed with surgery alone, as chemotherapy and radiotherapy have minimal activity in this disease. In the pre-imatinib era, patients with recurrent or metastatic disease generally did very poorly. GIST therapy was revolutionized following the discovery of oncogenic mutations in the c-kit gene, as well as in the platelet-derived growth factor receptor. Subsequently, it has been confirmed that the KIT receptor tyrosine kinase is both a diagnostic marker and a useful therapeutic target in GIST. Imatinib, a potent inhibitor of KIT activity, is now standard front-line therapy for advanced GIST. With the introduction of imatinib, there have been dramatic improvements in response rates, time to progression, and survival. Imatinib is now being investigated and shows promise in the neoadjuvant and adjuvant settings. Unfortunately, many patients eventually recur or progress during imatinib therapy. For these patients, imatinib dose escalation and/or surgical evaluation are appropriate. Additionally, a novel tyrosine kinase inhibitor such as SU11248 (sunitinib) is a reasonable option for progressive, imatinib-resistant disease. With the identification of other downstream pathways, several other promising therapies are under current investigation either alone or in combination with imatinib and surgery.
Schnadig
Ian D
ID
Oregon Health Sciences University Cancer Institute, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
Blanke
Charles D
CD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D003131:Combined Modality Therapy; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib