Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours

Gastro-intestinal stromal tumours (GISTs) are rare connective tissue tumours that show a differentiation profile similar to the interstitial cells of Cajal. They represent less than 1% of the tumours arising in the gastro-intestinal (GI) tract. Although GISTs can occur along the length of the GI tract, the majority arise in the stomach (60% to 70%), small bowel (25% to 35%), colon and rectum (5%) and, to a lesser extent, the oesophagus. Presenting features of these tumours depend on the size and location of the tumour and include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. However, many people with GISTs are asymptomatic during early stages of the disease until tumours reach a large size, at which time the tumours rupture and bleed or obstruct the GI tract.

Most GISTs express the tyrosine kinase growth factor receptor c-KIT, which is detected by immunostaining with the antibody for the cell-surface marker CD117. Under normal conditions, this receptor is activated by stem-cell factor, which stimulates signal transduction pathways such as cell growth, differentiation and apoptosis (cell death). Most GISTs express a form of the tyrosine kinase receptor that is permanently 'switched on' (constitutively activated), leading to unregulated cell proliferation.

Until recently, there has been no appropriate test for the diagnosis of GIST. An immunohistochemical test for the presence of the cell-surface marker CD117 (present in 80% to 100% of GISTs) is now considered to be an appropriate diagnostic marker for the diagnosis of GIST. A diagnosis of GIST is made on the basis of histological characteristics of the tumour biopsy, clinical presentation and immunohistochemical profile, including a positive test for the CD117 marker.

As a result of difficulties in the diagnosis of GIST, estimates of its incidence vary widely, from 4 to 40 cases per million population, which corresponds to between 200 and 2,000 new cases per year in England and Wales. Recent epidemiological data from Sweden suggest that the incidence of GIST is in the region of 15 per million per year. Approximately half of new cases of GIST are likely to be metastatic and/or unresectable on first presentation. Although GIST can occur at any age, the mean age of presentation is between 50 and 70 years.

The prognosis of people with GIST depends primarily on whether the tumour is resectable, although the size and location of the tumour and the stage of the tumour at initial diagnosis are also important prognostic indicators. A recent study suggested that the prognosis for unresectable and/or metastatic GIST is poor with few, if any, people surviving beyond 5 years.

Complete surgical resection is the treatment of choice for people presenting with GISTs amenable to surgery, but there is currently no effective treatment for people with unresectable and/or metastatic tumours. As GISTs are particularly resistant to conventional cytotoxic chemotherapy and radiotherapy, current treatment normally comprises symptom relief and best supportive care. This includes palliative care for the management of pain, fever, GI obstruction, and anaemia caused by GI haemorrhage.