Gastrointestinal Stromal Tumours – 20th Century Management
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumour of the intestinal tract. Historically, these tumours were labelled leiomyosarcomas, leiomyomas or leiomyoblastomas. In 1983, Mazur and Clark reclassified these tumours as GIST because they contained both smooth muscle and neural features.1 Later studies found these tumours also expressed CD34 and KIT, further aiding in their classification.2,3 The most common site of primary tumours is the stomach (39–70%), followed by the small intestine (31–45%), colon, rectum and anus (10–16%), mesentery and peritoneum (8%), with rare cases arising in the oesophagus.4-8 Metastatic disease is most commonly found in the liver, as well as the peritoneum and omentum, with less common sites of spread involving the lung and bone.
In 2000, patients with metastatic GIST had only one viable treatment option – surgical resection. This was an appropriate option for a subset of patients; however, despite surgery, some patients were destined to relapse.6 Systemic therapy for GIST with standard chemotherapy was largely ineffective. Patients with metastatic disease had rapid progression of disease, with an average survival of 12–18 months.9 There was clearly a need for effective therapeutic options.
The discovery of KIT as the biologic driver of GIST provided the rationale for the testing of imatinib, a tyrosine kinase inhibitor with specificity against ABL, KIT, platelet-derived growth factor receptor (PDGFR) and TEL.10,11 Imatinib had been shown to have efficacy against chronic myelogenous leukaemia with the Philadelphia chromosone, the BCR-ABL translocation.12,13 The identification of PDGFR as an alternative oncologic driver provided further rationale for the use of imatinib in GIST.
The US – Finland Trial
The US-Finland trial was the first multiinstitutional study of imatinib in metastatic GIST. It was designed to evaluate two doses of imatinib – 400mg and 600mg daily – based on safety data from an on-going phase I trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC).14 The number of patients included in the trial was initially planned to be 36. However, this was increased once the initial benefits had been observed. The sample size of the study, however, was not sufficient to determine whether one dose level was superior to the other. The initial trial planned to monitor patients for three years. Patients at the lower dose level were allowed to cross over to the higher dose level at the time of tumour progression. With the completion of the phase I trial demonstrating the safety of imatinib at 400mg twice daily, the trial was amended to allow patients to have their dose increased to a maximum dose of 800mg daily.
Imatinib – Response and Tolerability
The early period of the trial was positive as patients experienced rapid symptomatic relief. With longer follow-up, the symptomatic benefit translated into radiographic responses using bi-dimensional tumour (see Table 1). The majority of patients achieved a partial response (66.7%) with only two patients (1.4%) achieving a complete response. An additional 15.6% of the patients attained stable disease, for an overall clinical benefit of 83.4%.
The rate of progression was 11.6% with an additional 4.8% of patients who were removed from study prior to disease response evaluation. Responses evolved over time, with a median time to response of 12 weeks. However, the maximum time to response was 171 weeks. In addition, not only were patients responding to therapy, but they were tolerating imatinib with very acceptable safety profiles. Grade III and IV adverse events included fluid retention (6.8%, 12.2%), abdominal pain (12.3, 5.4%), haemorrhage (5.5, 10.8%) liver toxicity (5.5, 8.1%), diarrhoea (2.7, 6.8%), and nausea (5.5, 4.1%), respectively, in the 400 and 600mg cohorts. No cases of congestive heart failure were observed in this group.