RESUMO
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
RESUMO
BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.