# Questions Considered
Does treatment with imatinib mesylate (Gleevec TM have palliative benefit, in terms of tumour response, disease progression, survival or quality of life, for patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing the KIT tyrosine kinase receptor (identified by CD117 immunohistochemical staining)?

# Literature Search and New Evidence
The new search (2006 to March 2011) yielded six relevant new publications from one meta-analysis and four randomized controlled trials (RCTs). One RCT was already included in the existing guideline. Brief results of these publications are shown in the Document Assessment and Review Tool at the end of this report.

# Impact on Guidelines and Its Recommendations
The new data supports existing recommendations for EBS 11-7 (imatinib mesylate in adult patients with unresectable or metastatic GIST). Hence, the Sarcoma DSG ENDORSED the 2006 recommendations on imatinib mesylate in adult patients with unresectable or metastatic GIST. 
Does treatment with imatinib mesylate (Gleevec TM have palliative benefit, in terms of tumour response, disease progression, survival or quality of life, for patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing the KIT tyrosine kinase receptor (identified by CD117 immunohistochemical staining)?

# Target Population
These recommendations apply to adult patients with unresectable or metastatic GIST expressing KIT (CD117+).
- In patients with KIT-expressing (CD117+) unresectable or metastatic GIST, treatment with imatinib is a recommended therapy.  Until additional data become available, the initial dose of imatinib should be prescribed at a dose of 400 mg daily. A dose of 400 mg twice daily may be considered in patients who demonstrate progression on the lower dose.
- The optimal duration of therapy in responding patients or in those patients who achieve a complete clinical and/or radiologic remission has not yet been defined. Phase III trials have demonstrated benefit for up to two years of continued therapy.  Eligible patients with GIST who do not respond adequately to optimum doses of imatinib should be considered for entry into a clinical trial. Qualifying Statements  It is acknowledged that there are no randomized controlled trials (RCTs) comparing imatinib to no treatment or best supportive care thereby making it difficult to statistically quantify the benefits for progression free survival and overall survival conferred by imatinib. The Sarcoma DSG has concluded that such trials will never be performed in the future in patients with unresectable or metastatic GISTs. In framing its recommendations, the DSG has also borne in mind the fact that treatment with imatinib in such patients has already gained wide acceptance among oncologists internationally.  The recommendations for an initial dose of 400 mg daily is based on analyses of two randomized phase III trials that have compared two doses (400 mg versus 800 mg/day) of imatinib. A higher dose has not been shown to increase overall survival. There is a discrepancy in two-year progression-free survival, with one trial reporting a significant advantage in progression-free survival with the higher dose and one trial finding no significant difference.  The treatment duration in responding patients, particularly those who achieve a clinical complete response is as yet undefined. For practical purposes, until further studies are done:  Patients with stable disease should be treated until disease progression. Phase III data beyond two years of continued therapy are not available.  Treatment should be discontinued if serious toxicity develops. The dose may be reduced or interrupted to allow side effects to resolve, then may be re-started.  For patients who achieve a complete clinical response and radiologic remission with imatinib, treatment should be continued indefinitely until further data is available regarding the optimum duration of therapy in such patients. This is based on the observation that the majority of patients relapse following cessation of therapy with imatinib.  At present, there is insufficient evidence to support the use of imatinib as an adjuvant therapy in patients who have undergone initial complete resection of disease.  Surgery may be considered for patients whose disease is rendered resectable following imatinib therapy or to remove residual disease in selected patients.  At present, the use of neoadjuvant imatinib is not recommended.

# Key Evidence
- Evidence was available from two parallel phase III randomized trials (one in abstract form) that compared two doses of imatinib. None of the trials compared imatinib with a control.  Across trials, response rates ranged from 41 to 65%, with an additional 32 to 36% of patients achieving stable disease.  No quality-of-life data were reported from clinical trials of imatinib.  Phase III trials comparing 400 mg and 800 mg of imatinib daily detected no survival advantage with the higher dose but a significant increase in side effects. Data on progression-free survival are mixed, with one trial reporting a significant improvement with the higher dose and a second trial finding no significant difference.