January 22, 2009 (San Francisco, California) —Treatment with imatinib mesylate (Gleevec, Novartis) in the adjuvant setting appears to prolong relapse-free survival in high-risk patients with a primary gastrointestinal stromal tumor (GIST). After potentially curative surgical resection, adjuvant imatinib was well tolerated and extended relapse-free survival for up to 2 years in patients who were at an elevated risk for disease recurrence, researchers report.
The results of the study were presented during a poster session here at the 2009 Gastrointestinal Cancers Symposium. "Our results are promising but still preliminary," lead author Yoon-Koo Kang, MD, from the University of Ulsan College of Medicine, in Korea, told Medscape Oncology. "Right now, the relapse rate is very low, but we need a longer follow-up."
The new study evaluated the efficacy and safety of adjuvant imatinib in patients with primary localized GISTs that are large, have a high mitotic count, and have a c-kit exon 11 mutation.
This patient group was selected because, in a previous study by Dr. Kang and colleagues (Clin Cancer Res. 2004;10:3076-3081), these tumor qualities were independent risk factors for relapse after curative resection of primary localized GIST. Patients who had all 3 risk factors had only a 30% rate of relapse-free survival rate at 2 years.
Imatinib has been used as part of the GIST treatment regimen, and although the majority of GISTs respond well to this agent, some cases are invariably resistant. Tumors with c-kit exon 11 mutations have shown a better response to GIST than wild-type tumors or those with other types of mutations.
Risk Factors Identified
The study was a multicenter open-label nonrandomized phase 2 trial that enrolled 47 patients from August 2005 to June 2007. Eligible participants underwent a complete resection of a primary GIST with a c-kit exon 11 mutation and 10 mitoses/50 high-power fields (HPF), a tumor size of 10 cm, or 5 mitoses/50 HPF and tumor size of 5 cm. Patients received imatinib 400 mg daily until disease recurrence, intolerable toxicities, or for a 2 year period. The primary end point was relapse-free survival, and secondary end points were overall survival and toxicities.
The median patient age was 57.0 years, and the stomach was the most common site of the primary tumor (n = 31; 66%), followed by the small bowel (n = 15; 31.9%) and rectum (n = 1; 2.1%). Median primary tumor size was 7.5 cm, median mitoses index was 11 mitoses/50 HPF, and the average patient follow-up was 27.7 months.
C-Kit Mutations in Cohort
| Type of c-kit Mutation | Number (%) |
| Deletion | 31 (66.0) |
| Deletion 557 or 558 | 17 (38.2) |
| Substitution | 9 (19.1) |
| Others | 4 (8.5) |
High Rate of Relapse Free Survival
The researchers found that 1-year relapse-free survival was 97.9%, and was 93.3% at 2 years. Overall survival and median relapse-free survival have not yet been reached. "Our study is still ongoing," said Dr. Kang, "So we have not reached all of our end points yet. But of the total patient population, there were only 7 relapses, so our preliminary results are very encouraging."
Imatinib therapy was generally well tolerated. The only grade 4 toxicity observed was neutropenia, in 4.3% of patients. Grade 3 toxicities were relatively uncommon, and included neutropenia (23.0%), rash (8.3%), diarrhea (2.1%), and pruritis (2.1%). There were no treatment-related deaths reported.
The researchers concluded that postoperative adjuvant imatinib for 2 years appears safe and well tolerated, and might prolong relapse-free survival in patients with primary GIST who are able to undergo complete resection and remain at a high risk for relapse. But thus far, it remains unknown if the preliminary benefit seen in relapse-free survival can be translated to an overall survival benefit.
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