Therapy with postoperative adjuvant imatinib for GIST patients with completely resected localized disease is under investigation. This is a very heterogeneous population in terms of risk of relapse and death after surgical resection (see Table 1). Depending on mitotic count, tumor size, and tumor site, the risk of relapse after complete gross resection may be considerable. Results from two trials suggest that adjuvant imatinib reduces recurrence after complete resection of localized, primary GIST.[3,4] However, it is not clear whether improvements in recurrence with adjuvant therapy will translate into improved survival. In addition, the optimal duration of adjuvant imatinib is unknown.
In a single-arm, open-label, phase II multicenter study (ACOSOG-Z9000), patients underwent complete gross resection of KIT-expressing primary GIST that were at high risk of recurrence (tumor size >10 cm, tumor rupture, or <5 peritoneal metastases) and received a daily dose of imatinib for 1 year. One hundred and seven patients with gastric (50%) and intestinal (42%) GIST and a median tumor size of 13 cm were evaluable with a median follow-up of 4 years. The 1-, 2- and 3-year rates for overall survival (OS) were 99%, 97%, and 97%, respectively, while the 1-, 2- and 3-year recurrence-free survival (RFS) rates were 94%, 73%, and 61%, respectively.[Level of evidence: 3iiiDiii]
In one randomized, double-blinded phase III trial (ACOSOG-Z9001), 713 patients who underwent complete gross resection of a primary GIST measuring at least 3 cm and expressing KIT were treated with 1 year of imatinib (400 mg daily) or placebo. The original primary endpoint of the trial was OS. However, when it became clear that the overall death rate from GIST would be low as a result of the efficacy of imatinib for advanced or recurrent disease, the investigators changed the endpoint to RFS. The trial was subsequently stopped early as a result of an interim analysis showing that patients assigned to the imatinib arm experienced a 1-year RFS of 98%, whereas those assigned to the placebo arm had a 1-year RFS of 83% (overall HR = 0.35; 95% confidence interval (CI), 0.22-0.53; P < .0001). Since quality of life (QoL) was not measured in the study, it is not clear whether delayed RFS translated into improved patient QoL. No difference in OS was observed between the two arms, possibly because of the fairly short follow-up time and the crossover design of the study.[Level of evidence: 1iDii] At 48 months, there had been 5 deaths of the original 359 patients in the imatinib arm (about 1%) and 8 deaths of the original 354 patients in the placebo arm (about 2%) ( P = .47). It is possible that imatinib is simply delaying recurrences that can be treated equally well at relapse in those patients that have a recurrence of their tumors. In fact, the RFS curves appear to be converging after about 30 months of follow-up. The question of whether RFS will translate into improved OS may be answered by an ongoing Intergroup trial (EORTC-62024) in which patients are randomly assigned to 2 years of adjuvant imatinib versus observation, with OS as the primary endpoint.
Given the current uncertainties about the overall impact of adjuvant imatinib, shared decision making with the patient is important. Since the cost of administration of imatinib for a year or more may be high, knowledge about what the patient may have to pay out of pocket may help inform the discussion.