There are situations where resection of a primary GIST might be aided with the downsizing of the tumor. For example, large GIST arising low in the rectum might require sphincter-sacrificing surgical procedures (i.e., abdominoperitoneal resection); however, if the tumor shrank and pulled away from the sphincter, local resection with sphincter preservation might be possible. In this way, neoadjuvant imatinib may provide several advantages: it will provide valuable in vivo evidence of the tumor’s sensitivity to imatinib, potentially downsize the tumor, and “reduce” the surgical procedure necessary (or facilitate complete tumor extirpation). It may also work as conversion therapy for initially unresectable GIST. On the other hand, a potential downfall of the use of neoadjuvant imatinib may be that it precludes the accurate assessment of risk recurrence using any of the risk-classification models, as none of the current prognostic systems account for neoadjuvant therapy.

The largest retrospective study (to date) of neoadjuvant imatinib therapy published evaluated 126 patients who all received neoadjuvant imatinib for initially unresectable GIST; 17 patients subsequently had surgical resection. These patients received imatinib for a median of 10 months. The radiographic overall response rate was 76 % (1 CR, 12 PR). Two patients were found to have no viable tumor at the time of surgical resection [37]. In a different study, neoadjuvant imatinib improved resectability and reduced surgical morbidity in patients with locally advanced or unresectable primary GIST. The median tumor size reduction was 34 %, and the estimated PFS at 3 years was 77 % [38]. Currently, the NCCN guidelines recommend considering preoperative imatinib on an individual basis for patients in whom surgical morbidity may be improved by reducing the size of the tumor [18].

Despite successful primary tumor resection, GIST have a high risk for recurrence. Stemming from the initial success of imatinib therapy for metastatic disease, several trials were designed to determine the efficacy of adjuvant imatinib in patients with primary GIST after complete surgical resection.

The ACOSOG Z-9001, an intergroup randomized, double-blind, placebo-controlled trial compared imatinib (at a dose of 400 mg daily for 1 year) versus placebo in 713 patients. The study reported a recurrence-free survival (RFS) of 98 % (95 % CI 96–100) in the imatinib group versus 83 % (CI 78–88) in the placebo group (hazard ratio [HR] 0.35 [0.22–0.53], p < 0.0001), but did not reveal an overall survival (OS) benefit [39]. Interestingly, the slopes of the disease-free survival curves become parallel after cessation of imatinib therapy. This suggests that imatinib might provide “growth suppression” of radiographically occult, micrometastatic disease. The similar OS between the study groups was likely an effect of the crossover design of the study that permitted patients assigned to the placebo group to get imatinib on tumor recurrence. This trial clearly showed, however, that the risk of recurrent disease is directly linked to TKI therapy, and suggested that the duration of therapy might play an important role.

Accordingly, the SSG XVIII/AIO study, a randomized, open-label Phase III trial, compared the administration of imatinib (400 mg daily) for 1 year versus 3 years as adjuvant therapy. Four hundred KIT-positive, high-risk patients were recruited. The results clearly demonstrated that adjuvant imatinib given for 3 years improved RFS compared to that for 1 year only (hazard ratio [HR], 0.46; 95 % CI, 0.32–0.65; p = 0.001; 5-year RFS, 65.6 % vs. 47.9 %, respectively) [40]. Moreover, the 3 years of imatinib arm had a better overall survival (HR, 0.45; 95 % CI, 0.22–0.89; p = 0.02; 5-year survival, 92.0 % vs. 81.7 %) [40]. Based on these findings, 3 years of adjuvant therapy is currently the recommended duration of therapy for patients deemed at high risk for recurrence in the United States [18].

Currently, there are several ongoing trials that aim to clarify the role and duration of imatinib as an adjuvant treatment for GIST. The EORTC 62024 is a Phase III, randomized, open-label study, which aims to compare the effect of adjuvant imatinib mesylate (400 mg daily) for 2 years versus observation on the prognosis of patients with completely resected localized GIST at intermediate/high risk of relapse and to compare overall survival among patients in both arms [41]. Preliminary results of the first interim analysis were reported at the 2013 ASCO Annual Meeting. Five-year imatinib failure-free survival (IFS) was 87 % in the imatinib arm compared to 84 % in the control arm (HR 0.80, 95 % CI 0.51–1.26); 3-year RFS was 84 % versus 66 %; and 5-year overall survival was 100 % versus 99 % [42]. Finally, the PERSIST 5 trial is a Phase II, nonrandomized, open-label multicenter study of 5-year adjuvant imatinib in patients at significant risk for recurrence following complete resection of primary GIST. This study is ongoing but not recruiting patients at this time [43].

The RTOG S0132/ACRIN (American College of Radiology Imaging Network) 6665 trial enrolled patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) who received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years [44]. Thirty patients had locally advanced primaries and 22 had locally recurrent or metastatic disease. In the localized primary disease group, 7 % (2 patients) had an objective response to preoperative imatinib, but stable disease was achieved in 83 % (25 patients). In patients with recurrent or metastatic GIST, partial response and stable disease were observed in 4.5 % and 91 % of patients, respectively [44]. The most recent update at a median follow-up of 5.1 years demonstrated that the estimated 5-year progression-free survival was 57 % in group A versus 30 % in group B, and overall survival was 77 % in group A versus 68 % in group B. Median time to progression has not been reached for group A, and was 4.4 years for group B [45]. Long-term analysis suggested that a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. For that reason, they concluded that longer treatment duration should be studied in intermediate- to high-risk GIST patients [45]. These results added further evidence in support of longer treatment times. Similarly, the phase III BFR14 trial conducted by the French Sarcoma Group explored the effect of interrupting therapy after 1, 3, and 5 years of treatment with 400 mg/daily of imatinib in patients with advanced GIST. A subgroup analysis of patients with locally advanced primary GIST was associated with a 60 % partial response rate, and 36 % of patients underwent surgical resection after a median of 7.3 months of therapy. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival and overall survival for patients who underwent surgical resection versus those who did not (median not reached vs. 23.6 months, p = 0.0318 for PFS and median not reached vs. 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by imatinib, the 3-year PFS and OS rates were 67 % and 89 %, respectively [46]. These data clearly demonstrate that adjuvant therapy with imatinib provides both disease-free and overall survival benefit to patients who have high-risk GIST.

Imatinib is the primary systemic therapy for patients with advanced/metastatic GIST [18]. The standard dose of imatinib was established in an EORTC phase I trial led by Van Oosterom and associates [47]. Utilizing a dose escalation schema, they concluded that a dose of 400 mg/day had the most favorable clinical benefit–side effect profile, including edema, nausea, diarrhea, malaise, and fatigue. Other rare side effects included myelosuppression, hemorrhage, and elevated transaminases, which required interruption or discontinuation in treatment [47]. Several phase II and III clinical trials were designed to assess the efficacy of imatinib in the metastatic setting. These studies reported an imatinib response ranging from 48 to 71 % and disease stabilization in 70–85 % of patients. The median progression-free survival ranges from 20 to 24 months [13, 48–50]. The B2222 trial reported an overall survival of 35 % at 9 years, and 38 % for those with complete response or partial response [51]. These data demonstrated the possibility of durable survival benefit for those patients who responded to imatinib.

Two large international studies randomized patients with metastatic GIST to standard dose or high-dose imatinib (400 versus 800 mg/daily, respectively) [13, 48]. The EORTC 62005 reported that after 760 days of follow-up, 56 % of the patients in the 400 mg daily dose had progression compared to 50 % in the 800 mg daily dose [13]. As one might expect, the lower dose cohort had fewer side effects. The North American Sarcoma Intergroup study, S0033, was an open-label phase III trial on patients with unresectable or metastatic GIST. Patients were randomized to receive the 400 mg daily dose (standard dose) versus 400 mg twice daily (high dose). At a median follow-up of 4.5 years, the median progression-free survival was nearly identical between the two dosing regimens. Similarly, the median overall survival was essentially identical. Interestingly, after progression on standard dose imatinib, 33 % of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease [48]. These data were hypothesis-generating, including raising the possibility that some GIST require higher dosing to achieve therapeutic benefit.

One important concept regarding imatinib dosing is that different mutations in the KIT gene require different doses. The EORTC designed a phase III trial in which patients with GIST were randomized to receive imatinib at a dose of either 400 mg daily or 800 mg daily. The presence of KIT exon 9 mutations increased the relative risk of progression by 171 % and the relative risk of death by 190 % when compared with KIT exon 11 mutants [52]. Interestingly, patients whose tumors expressed an exon 9 KIT mutation did better with the higher dosing scheme [52]. It was concluded that tumor genotype is of major prognostic significance for patients treated with imatinib for advanced GIST. Interestingly, the relative risk of progression was also increased by 108 % and the relative risk of death by 76 % in patients without detectable KIT or PDGFRA mutations [52]. Typically, patients are started on 400 mg/day of imatinib, and after a short period, the dose is gradually escalated up to 800 mg/day. This seems to minimize some of the side effects when compared to starting out de novo with the 800 mg/day dosing.

A correlation study of the kinase genotype and clinical outcomes done along with the CALGB 150105 trial reported that patients with KIT exon 9 mutations treated with 800 mg daily dose of imatinib had better response rates compared to that with 400 mg daily dose (67 % vs. 17 %) [53]. Nevertheless, the survival outcomes for patients with exon 9-mutant, exon 11-mutant, or wild-type GIST were not affected by the imatinib dose. Furthermore, CD117-negative GIST patients had a similar time to tumor progression but inferior overall survival compared to CD117-positive patients. Those outcomes suggest that CD 117-negative GIST patients may also benefit from imatinib therapy [53]. The Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) reviewed the data of two doses of imatinib (400 mg daily versus twice daily) in 1640 patients with advanced GIST. Patients with wild-type, KIT exon 9 mutations, and patients with other mutations had worse progression-free survival and overall survival than patients with KIT exon 11 mutations [54]. In addition to proper dosing, interruption of therapy seems to impact outcome. Patients who continuously take their imatinib seem to have a more durable response, while patients whose therapy is interrupted develop progression sooner [55]. Reinstitution of therapy for patients who experience progression can result in control of the tumor in most patients. In one study, nearly one-half of patients who had achieved an initial response and subsequently progressed following discontinuation of imatinib were able to respond to restarting therapy [56]. Thus, interruption of imatinib causes rapid progression in most patients with advanced GIST and cannot be recommended unless there is significant toxicity.

For some patients, resistance to imatinib develops during therapy. Several mechanisms of resistance had been proposed, including inadequate imatinib plasma levels, specific types of mutations (BRAF mutation, PDGFRA D842V mutation, NF-1, SDH complex loss), accumulation of secondary mutations, KIT gene amplification, or loss of the wild-type allele. Some patients will develop clones that become resistant, while other tumor nodules remain sensitive. In practice, imatinib resistance is divided into primary and secondary.

Multiple authors have reported the presence of heterogeneity of resistance within the different lesions but also within the same tumor [63–66]. Liegl et al. studied KIT and PDGFRA mutations in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. Primary KIT oncogenic mutations were found in 11/14 patients (79 %). Of these, 9/11 (83 %) had secondary drug-resistant KIT mutations, including six (67 %) with two to five different secondary mutations in separate metastases, and three (34 %) with two secondary KIT mutations in the same metastasis. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intralesional and interlesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST [65]. Other mechanisms of survival of imatinib-resistant GIST cells like PI3k/AKT pathway activation and AXL or IGF1R overexpression are being studied at this time. The mechanisms of development of additional genetic mutations is poorly understood.