Results from several randomized, placebo-controlled clinical trials for patients with primary gastrointestinal stromal tumor (GIST), a type of tumor usually found in the stomach or small intestine, showed that patients who received imatinib mesylate (Gleevec ®) after complete removal of their tumor were significantly less likely to have a recurrence of their cancer compared to those who did not receive imatinib. For example, ACOSOG Z9001 trial was stopped early when planned interim analysis disclosed that significantly fewer patients in the treated group recurred. At a median follow-up of 20 months, 30 patients in the imatinib group recurred or died, versus 70 in the placebo group (8 versus 20 percent). The one-year RFS rate was 98 versus 83 percent favoring imatinib, with a hazard ratio for RFS of 0.35, 95% CI 0.22 to 0.53. On farther followup, no overall survival differences have emerged in favor of imatinib in the ACOSOG Z9001 trial. It is not clear why this is so. Among the possible reasons are the short duration of follow-up, the limited number of relapses, and the high degree of efficacy of imatinib in relapsed disease. Furthermore, after the study was unblinded, all patients randomized to placebo were allowed to crossover to active treatment, thus obscuring any potential differences in overall survival between the groups. The role of KIT and PDGFR overexpression must be clarified because some patients who lack detectable KIT or PDGFRA mutations or who have specific mutations that are known to be insensitive to imatinib (eg, PDGFRA exon 18 D842V) may not benefit.
Imatinib was given accelerated approval in the US in 2008 for adjuvant treatment of completely resected GISTs ≥3 cm in size, without definitive guidance as to the optimal duration of treatment or which patients are most likely to benefit.
The Scandinavian Sarcoma Group (SSG) XVIII trial compared 36 versus 12 months of adjuvant therapy. Data from the SSGXVIII trial provide compelling evidence that at least three years of adjuvant imatinib therapy is both safe and effective in reducing GIST recurrence and that it improves overall survival as well. Whether longer duration of therapy than three years will provide additional benefit and the optimal selection of patients for adjuvant therapy remains unclear.
In 2008, the FDA granted accelerated approved for imatinib in the adjuvant setting for completely resected primary GIST ≥3 cm without indicating the optimal length of therapy; labeling was updated in January 2012 to include the significantly prolonged survival seen with three years of therapy as compared to one year of adjuvant imatinib. However, whether all patients in this broad category have a high enough risk of recurrence to warrant adjuvant therapy is not established. The EMA (European Medicines Agency) has extended the licensed indications of imatinib to include adjuvant treatment of adult patients who are at “significant risk of relapse” after resection of a KIT-positive GIST, but does not define these subsets further.
Clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) suggest adjuvant imatinib for at least 36 months for patients with high risk GIST (tumor >5 cm in size with high mitotic rate [>5 mitoses/50 HPF] or a risk of recurrence that is >50 percent). The European Society of Medical Oncology (ESMO) does not give a strong recommendation for the use of adjuvant imatinib, stating that its use can be “proposed as an option for those patients with a substantial risk of relapse for shared decision-making”; however, these recommendations were written prior to the publication of results from the SSGXVIII trial, which established a survival benefit from the use of three as compared to one year of adjuvant imatinib.
Adjuvant and neoadjuvant imtinib for GIST
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AUCasali PG, Blay JY, Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up., ESMO/CONTICANET/EUROBONET Consensus Panel of ExpertsSOAnn Oncol. 2010 May;21 Suppl 5:v98-102.
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nccn, GIST(Sarcoma) 2012