Biology driven multimodality treatment of gastrointestinal stromal tumour (GIST)

Abstract

The management of GIST is multidisciplinary, involving surgery, systemic therapy with tyrosine kinase inhibitors (TKIs) in the pre-surgical, post-surgical adjuvant and metastatic settings, other local therapies to treat specific metastatic sites, such as the liver, using radiofrequency or cryoablation and radiotherapy. Surgery remains the primary treatment modality and the only curative one. Since the advent of TKIs with the introduction of imatinib in the year 2000 the outlook for patients with GIST has steadily improved and even those with metastatic disease now have a median survival in excess of 5 years. Adjuvant therapy with 3 years of imatinib is standard therapy for patients at high risk of recurrence. Although most tumours are driven by activating mutations in exon 11 of KIT, and are responsive to imatinib, at least initially, those in which the D842V mutation in exon 18 of PDGFRA is the driver show little sensitivity to imatinib, sunitinib or regorafenib. These latter 2 drugs are licensed to treat GIST with acquired resistance to imatinib and have extended the period of control and improved overall survival. Tumours lacking activating mutations may be driven by succinate dehydrogenase (SDH) deficiency, including paediatric GIST.. New agents have recently been approved, including avapritinib which is effective against tumours with the PDGFRA D842V mutation. This will expand the numbers of patients who may be treated effectively and further improvements in outcome will no doubt result.