Adjuvant therapy for high-risk gastrointestinal stromal tumour: considerations for optimal management

One randomized trial has found that adjuvant treatment with imatinib for gastrointestinal stromal tumour (GIST) 3 cm or larger in diameter prolongs recurrence-free survival, and another trial has reported that 3 years of adjuvant imatinib improves both recurrence-free and overall survival compared with 1 year of imatinib in high-risk GIST. The US National Comprehensive Cancer Network now recommends consideration of adjuvant imatinib for at least 3 years for patients with a high risk of GIST recurrence. Estimation of the risk of GIST recurrence is mandatory when considering adjuvant therapy. The risk varies greatly from negligible risk (tumours smaller than 1 cm) to 90% or greater risk (large tumours with frequent mitoses). The risk of recurrence can be estimated using one of the three validated risk stratification schemes, the National Institutes of Health (NIH) consensus risk criteria, the Armed Forces Institute of Pathology criteria or the modified NIH criteria, which have roughly similar prognostic accuracy, or with nomograms or prognostic contour maps. Patients with an intermediate risk may pose a problem when considering adjuvant therapy because few research data are available. The decision about whether or not to treat these patients with adjuvant imatinib can be solved using the modified NIH risk stratification criteria, since, with these criteria, patients with intermediate risk have similar outcomes to those with low risk, leaving only patients with high risk for consideration of adjuvant therapy. Analysis of tumour tissue for KIT and PDGFRA mutations is recommended to exclude patients with imatinib-insensitive mutations from adjuvant therapy (notably patients with PDGFRA substitution mutation D842V), and those with neurofibromatosis-1-associated wild-type GIST. The standard daily dose of adjuvant imatinib is 400 mg, but it is unknown whether this dose is optimal. Some patients, such as those with KIT exon 9 mutation, might benefit from a higher dose. While the optimal duration of adjuvant therapy is also unknown, 3 years of adjuvant imatinib is currently a reasonable choice. Early detection and management of imatinib side effects is likely important for achieving high compliance. Repeat imaging of the abdomen with CT or MRI during adjuvant imatinib and after its completion is also likely to be beneficial, since most patients whose GIST recurs after adjuvant treatment respond to reinstitution of imatinib, and the presence of a small tumour burden when imatinib is reinstituted may reduce the likelihood of rapid emergence of a second mutation that confers imatinib resistance.