Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132 (original) (raw)
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JAMA Oncology, 2020
IMPORTANCE Adjuvant imatinib is associated with improved recurrence-free survival (RFS) when administered after surgery to patients with operable gastrointestinal stromal tumor (GIST), but its influence on overall survival (OS) has remained uncertain. OBJECTIVE To evaluate the effect of adjuvant imatinib on OS of patients who have a high estimated risk for GIST recurrence after macroscopically complete surgery. DESIGN, SETTING, AND PARTICIPANTS In this open-label, randomized (1:1), multicenter phase 3 clinical trial conducted in Finland, Germany, Norway, and Sweden, 400 patients who had undergone macroscopically complete surgery for GIST with a high estimated risk for recurrence according to the modified National Institutes of Health Consensus Criteria were enrolled between February 2004 and September 2008. Data for this follow-up analysis were analyzed from September to November, 2019. INTERVENTIONS Imatinib 400 mg/d administered orally for either 12 months or 36 months after surgery. MAIN OUTCOMES AND MEASURES The primary end point was RFS; the secondary objectives included OS and treatment safety. RESULTS The intention-to-treat cohort consisted of 397 patients (12-month group, 199; 36-month group, 198; 201 men and 196 women; median [IQR] age, 62 (51-69) years and 60 (51-67) years, during a median follow-up time of 119 months after the date of randomization, 194 RFS events and 96 OS events were recorded in the intention-to-treat population. Five-year and 10-year RFS was 71.4% and 52.5%, respectively, in the 36-month group and 53.0% and 41.8% in the 12-month group (hazard ratio [HR], 0.66; 95% CI, 0.49-0.87; P = .003). In the 36-month group, 5-year OS and 10-year OS rates were 92.0% and 79.0%, respectively, and in the 12-month group 85.5% and 65.3% (HR, 0.55; 95% CI, 0.37-0.83; P = .004). The results were similar in the efficacy population, from which 15 patients who did not have GIST in central pathology review and 24 patients who had intra-abdominal metastases removed at surgery were excluded (36-month group, 10-year OS 81.6%; 12-month group, 66.8%; HR, 0.50; 95% CI, 0.32-0.80; P = .003). No new safety signals were detected. CONCLUSIONS AND RELEVANCE Three years of adjuvant imatinib is superior in efficacy compared with 1 year of imatinib. Approximately 50% of deaths may be avoided during the first 10 years of follow-up after surgery with longer adjuvant imatinib treatment.
2023
Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were retreated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15-0.72; P ¼ 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
European Journal of Cancer, 2005
In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours (GIST) were randomised to receive 400 or 800 mg of imatinib daily. An increase in progression free survival (PFS) was demonstrated for patients randomised to the high-dose arm. Patients randomised to low-dose could cross-over to high-dose upon progression. We evaluated the feasibility, safety and efficacy of this policy. Of the 241 patients available for follow-up, 133 patients (55%) crossed over to high-dose imatinib according to the protocol. Of these patients, 92% had not had a prior dose reduction. The cumulative incidence of subsequent dose reductions after cross-over was 17% after six months with 51% discontinuing therapy without requiring a dose reduction. The extent of anaemia and fatigue increased significantly after cross-over, whilst neutropenia was less severe than during low-dose treatment. Objective responses after cross-over included three patients (2%) with a partial response and 36 (27%) with stable disease. The median PFS after cross-over was 81 days, although 18.1% of patients were still alive and progression free one year after cross-over. We conclude that a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy.
Clinical Cancer Research, 2023
Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were retreated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15-0.72; P ¼ 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
Case Reports in Oncology, 2011
Imatinib mesylate, as treatment for gastrointestinal stromal tumors (GIST), has dramatically changed the prognosis for survival -not only because it is efficacious, but also because it attracted attention to this malignant disease. GIST is now a well-known disease entity and a paradigm for targeted therapies in malignant diseases. A now 74year-old patient presented with recurrence of a primary duodenal GIST (initial diagnosis and primary resection in 1998; diameter 10 cm, KIT exon 11 mutation, PM V559D) and liver metastasis after a second surgical resection was performed in 2000. Conventional chemotherapy with adriamycin and ifosfamide failed to control growth of the relapsed tumor and liver metastasis. In July 2001, compassionate use of imatinib was started. Tumor regression was observed at continuous follow-ups (every 2 months for the first 6 months, and 6 months thereafter) and persisted until now. The patient's physical performance has remained in good condition. Side effects consisted of periorbital edema and sudden muscle cramps of toes and fingers, pain of bones and joints, an intentional tremor, a paler color of the skin, as well as a slight anemia. Imatinib is the first orally administered anticancer drug. Our case shows that a sustained response is possible with continuous therapy over a long time, if the drug is well tolerated. This implies a high compliance of the patient and suggests that resistance to imatinib does not have to develop. Exon 11 (point) mutation might not only represent a positive predictor for imatinib response in general, but especially for imatinib response on long-term. Case
BMC Cancer, 2011
Background The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial. Methods The database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria. Results Fifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients w...
Medical Oncology, 2013
The introduction of imatinib to clinical practice revolutionized therapy of advanced gastrointestinal stromal tumors (GIST), but its long-term results have been only just collected. We have attempted to identify factors related to the long-term survival. We have analyzed the data of 430 inoperable/metastatic/recurrent GIST patients treated with imatinib in reference centers, assessed the factors influencing the long-term overall survival (OS), and compared the outcomes in three periods of initiation of imatinib therapy during one decade (). During analyzed time periods, we have found decrease in median largest tumor size at the start of imatinib therapy: 90.5 mm (2001)(2002)(2003) versus 74 mm (2004)(2005)(2006) versus 58 mm (2007-2010) (p = 0.002). Median progression-free survival (PFS) on 1st line imatinib was 37.5 months, without differences in PFS between three groups. Median OS was 5.8 years, 8-year OS rate was 43 %, and no difference in OS was demonstrated for patients treated in analyzed time periods. Independent good prognostic factors for longer OS were as follows: surgery of residual disease, initial WHO performance status 0/1, normal baseline albumin level, and the presence of exon 11 KIT mutations. Current median OS in advanced GIST reaches 6 years. The long-term survivors were characterized by smaller maximal tumors at imatinib start, better blood tests results, better performance status, and the sur-