**9. Follow-up**

Further analysis of data from EU-AUS and S0033 trials reported that tumor genotype has a significant prognostic impact on PFS and OS, with tumors with mutation of KIT exon 9 having a worse prognosis when compared to tumors with mutation of KIT exon 11 [96, 97]. A subsequent meta-analysis combining S0033 and EU-AUS trials [98] reported a minor albeit significant PFS advantage for a higher imatinib dose of 400 mg twice daily for patients with advanced GIST. The PFS benefit was only evident in patients with KIT exon 9 mutations treated with a high-dose imatinib without difference in OS between the two groups, while patients with KIT exon 11 had a more favorable prognosis. Thus, genotype is required for the

The findings of the results of the previous studies [94, 95, 98] designated imatinib dosage of 400mg/ day to be the standard treatment for patients with advanced GISTs, and patients with advanced GISTs with KIT exon 9 mutations to be started on the higher imatinib dose (400 mg twice daily), keeping in mind that the toxicity of imatinib is dose-dependent [99]. Imatinib treatment should be life long as interruption of treatment has a higher rate of disease progression as proven by the phase III randomized trial [100–102]. Indications of surgery in advanced GISTs are still debatable. Multiple retrospective studies have shown that debulking surgery may be beneficial in patients with a stable disease without generalized progression as surgery may improve the prognosis. However, patients should be treated with imatinib first before attempting surgery [103–108].

**8.3. Alternatives of imatinib in case of resistance or progression of disease with** 

in KIT exons 13, 14, and 17 and a D842V mutation in PDGFRA exon 18 [111–113].

second-line therapy like sunitinib may be recommended.

Most patients with advanced GISTs will show improvement with imatinib therapy, although a subgroup of patients will fail to show a response. Resistance to imatinib may be primary or secondary. Primary resistance is defined as continuous growth or growth within 6 months of therapy, and occurs in 15–20% of patients with advanced GIST [109] and occurs frequently in patients with wild-type (WT) GIST or KIT exon 9 mutations or D842V mutation in PDGFRA exon 18 [110]. Unfortunately, most patients develop secondary resistance, which is defined as patients who received treatment with imatinib for longer than 6 months and had an initial response and then developed progressive disease. Secondary KIT mutations occur frequently

If a patient develops resistance, escalating imatinib dosage to 800 mg daily or shifting to a

Sunitinib is considered a second-line therapy for patients with advanced GIST refractory to imatinib therapy. Outcomes of a randomized phase III trial versus placebo reported a prolongation of the time to progression from 1.5 to 6.3 months in patients with GIST who progressed on imatinib treatment [114]. It is approved by the EMA and the FDA for the treatment of patients with GIST resistant to imatinib therapy and for patients who are not tolerant to ima-

In case of progression on imatinib and sunitinib, regorafenib is considered a third-line therapy [4]. It was recently approved by EMA and FDA for the treatment of patients with unresectable or metastatic GISTs who are resistant or intolerant to imatinib and sunitinib, and

treatment of advanced or metastatic GISTs.

**imatinib therapy**

80 Gastric Cancer - An Update

tinib therapy.

There are no studies assessing the efficacy of different follow-up modules. Nevertheless, follow-up strategies were created based on the fact that most recurrences occur within the first 5 years after surgery.

A follow-up schedule frequency is based on the risk of aggressiveness and recurrence of GISTs [4]. CT is favored over other imagings, such as MRI and FDG-PET scan, because it is more readily obtainable, although other modalities can be used in case CT is inconclusive.

## **9.1. Follow-up for localized resectable GISTs**

Very low-risk patients with surgically removed tumor do not require a follow-up. Low-risk patients require an annual CT. Intermediate- and high-risk patients require CT every 4 months for the first 1–2 years, every 6 months for 3–5 years, and then CT every year thereafter [4].

#### **9.2. Follow-up for unresectable/metastatic GISTs**

Follow-up should be done at the start of every 3 months and can be delayed to every 6 months if there is response to the treatment.
