Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian... (original) (raw)
Related papers
Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015
Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial. Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival. A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had l...
Journal of Gastrointestinal Cancer, 2012
Purpose To compare characteristics of patients, the risk of recurrence, and mortality among adult patients with primary resectable gastrointestinal stromal tumor (GIST) receiving short-term (6-12 months) versus long-term (≥24 months) imatinib therapy. Methods Detailed information on primary resectable KITpositive GIST patients initiated on imatinib adjuvant therapy was retrospectively collected for short-and long-term imatinib patients from 318 US oncologists using an online data collection form. Patient characteristics were compared using Wilcoxon and Chi-square tests. Disease recurrence and mortality rates were compared using multivariate Cox proportional hazard models. Results Among the 406 short-term and 406 long-term imatinib patients, the median follow-up was 916 and 970 days, respectively. While patients generally had similar demographic characteristics, the short-term group had a higher prevalence of cardiovascular and ischemic heart diseases and patients in the long-term group had a higher presurgery risk profile. This finding was consistent with the main reason reported by oncologists for prescribing adjuvant imatinib over longer duration, i.e., patient risk profile. Disease recurrence [5.9 versus 1.2 %, (p<.001)] and mortality rates [7.1 % versus 2.0 %, (p<.001)] were higher in short-versus long-term patients. The adjusted risk of recurrence was 5.30 times (p<.001) higher, and mortality risk was 4.02 times (p<.001) higher in short-versus long-term patients. Conclusions Patient risk profile is an important factor in oncologists' decisions to prescribe adjuvant imatinib. Despite the higher risk profile observed in long-term patients, the long-term use of imatinib was associated with a reduction in long-term risk of disease recurrence and mortality. Keywords Gastrointestinal stromal tumors. GIST. KIT. KIT inhibitors. Imatinib. Soft tissue sarcomas. Sarcomas Background A gastrointestinal stromal tumor (GIST) is a type of softtissue sarcoma that usually develops in cells within the wall of the stomach or intestines. GISTs may result from the over-expression or activation of mutation in KIT (CD117) protein or platelet-derived growth factor receptor alpha which provides a stimulus for tumor cell proliferation [1, 2]. The incidence of a GIST is estimated to be approximately 3,000-6,000 cases per year in the US [3, 4]. Most common GISTs sites are stomach (60 %), jejunum and ileum (30 %), duodenum (5 %), and colorectum (<5 %) [5, 6]. Approximately 20 % to 25 % of gastric GISTs and 40 % to
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.
The Oncologist, 2013
Background. The oral tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), most of which harbor oncogenic mutation in genes that encode the receptor tyrosine kinases KIT or PDGFA. Imatinib is the standard of care for patients with advanced GIST and for patients with primary GIST at significant risk of recurrence after surgery. Design. This review discusses data supporting continuous kinase suppression with imatinib and key issues, including response to imatinib reintroduction, effect of treatment interruption on secondary resistance to imatinib, and prognostic factors associated with sustained response to imatinib. Results. Long-term follow-up results of the B2222 study and updated results of the BFR14 trial demonstrate that continuous imatinib treatment in patients with advanced GIST is asso-ciated with reduced risk of progression. For patients progressing on or intolerant of imatinib, continuing therapy with TKIs sunitinib followed by regorafenib is recommended. In the adjuvant setting, final results of the trial by the Scandinavian Sarcoma Group and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie demonstrate that 3 years of adjuvant imatinib, compared with 1 year, significantly reduces the risk of recurrence and improves overall survival of patients with KIT-positive GIST at high risk of recurrence. Conclusions. Maintenance of therapy with TKIs is the key to successful treatment of GIST. Results from recent studies provide a strong rationale for continuous imatinib treatment for 3 years following surgical resection and long-term continuous administration in advanced or metastatic GIST. The Oncologist 2013;18:1192-1199 Implications for Practice: Imatinib interruption in advanced setting results in rapid progression in the vast majority of patients and should not be recommended outside clinical trials unless patients experienced significant toxicity. The results observed in advanced GIST need to be considered also for the use of imatinib in the adjuvant setting where the optimal duration of imatinib is unknown (at least three years) and where reintroduction of imatinib is the standard of care in case of disease recurrence.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017
Purpose To report on the long-term results of a randomized trial comparing a standard dose (400 mg/d) versus a higher dose (800 mg/d) of imatinib in patients with metastatic or locally advanced GI stromal tumors (GISTs). Patients and Methods Eligible patients with advanced CD117-positive GIST from 56 institutions in 13 countries were randomly assigned to receive either imatinib 400 mg or 800 mg daily. Patients on the 400-mg arm were allowed to cross over to 800 mg upon progression. Results Between February 2001 and February 2002, 946 patients were accrued. Median age was 60 years (range, 18 to 91 years). Median follow-up time was 10.9 years. Median progression-free survival times were 1.7 and 2.0 years in the 400- and 800-mg arms, respectively (hazard ratio, 0.91; P = .18), and median overall survival time was 3.9 years in both treatment arms. The estimated 10-year progression-free survival rates were 9.5% and 9.2% for the 400- and 800-mg arms, respectively, and the estimated 10-yea...
Current Oncology, 2020
Background The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Methods Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002-2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Results Of 657 patients diagnosed with gist throughout British Columbia during 1996-2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Conclusions Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.
Oncotarget, 2015
Background: Although treatment with imatinib in advanced gastrointestinal stromal tumor (GIST) patients has led to significant clinical benefits, the disease will eventually progress due to imatinib resistance. Treatment options after failure of first-line imatinib include imatinib dose escalation or shifting to sunitinib. However, there is no large-scale study to compare the efficacy difference between these two treatment strategies or the role of surgery. Results: This study recruited 521 advanced GIST patients including 246, 125, and 150 placed in groups 1, 2, and 3, respectively. Groups 1 and 2 had significantly longer overall survival (OS) as compared with the group 3 (median 37.5 months versus 16.0 months; p < 0.0001). After adjusting for confounding variables, groups 1 and 2 had longer OS than group 3. A favorable survival trend was seen with surgery, although this benefit disappeared after adjusting for confounding factors. Materials and Methods: We conducted a nationwide population-based cohort study using data from the Taiwan National Health Insurance Research Database from July 2004 to December 2010. Advanced GIST patients who no longer responded to first-line imatinib were stratified into three groups: imatinib dose escalation (group 1); imatinib dose escalation and a shift to sunitinib (group 2); a direct shift to sunitinib (group 3). The therapeutic success of the three treatment regimens and the effect of surgery were evaluated by overall survival. Conclusions: For advanced GIST patients who failed first-line imatinib treatment, imatinib dose escalation confers significantly longer OS compared to a direct switch to sunitinib. Surgery does not provide survival benefits.
The Lancet, 2009
Background-Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. The standard treatment of localized, primary GIST has been surgical resection alone. Most GISTs have a mutation in the KIT proto-oncogene, or less commonly in platelet-derived growth factor receptor alpha (PDGFRα). Imatinib mesylate is a small molecule that inhibits activation of the KIT and PDGFRα proteins and is effective in metastatic GIST. We hypothesized that adjuvant treatment with imatinib would result in improved recurrence-free survival (RFS) compared to placebo treatment following resection of localized, primary GIST.
BMC Cancer, 2012
Background: Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. Methods: We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2 nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes.