Background: Diffuse-type tenosynovial giant cell tumour (D-TGCT) is a nonmalignant but locally aggressive tumour driven by overexpression of colony-stimulating factor-1 (CSF1). CSF1R inhibitors are... Show moreBackground: Diffuse-type tenosynovial giant cell tumour (D-TGCT) is a nonmalignant but locally aggressive tumour driven by overexpression of colony-stimulating factor-1 (CSF1). CSF1R inhibitors are potential therapeutic strategies for patients not amenable to surgery. We report here the long-term outcome of nilotinib in patients with advanced D-TGCT treated within a phase II prospective international study (ClinicalTrials.gov: NCT01261429). Methods: Patients were enrolled between December 2010-September 2012 at 11 cancer centres. Eligible patients had histologically confirmed D-TGCT, not amenable to surgery. Patients received nilotinib until evidence of progression, toxicity or a maximum of one year. Long-term data were retrospectively collected after the completion of the phase II trial. Patients with nilotinib treatment >= 12 weeks and follow-up >= 12 months were included for long-term analysis. Results: Forty-eight of 56 enrolled patients were included. Median treatment duration was 11 months; 31 (65%) patients completed the treatment protocol. After 102 months of follow-up (median; range 12-129), 25 patients (52%) had progression. The median progression-free survival (PFS) was 77 months. The five-year PFS rate was 53%. Fifteen patients (n=15/46; 33%) experienced clinical worsening after 11 months (median). Twenty-seven patients (58%) received additional treatment, after which eleven patients (n = 11/27; 41%) had a second relapse. Nine patients required a subsequent treatment, primarily other CSF1R inhibitors (n = 6/9; 67%). No unfavourable long-term effects were observed. Conclusion: This long-term analysis of nilotinib for advanced D-TGCT showed that about half of the patients had progression and underwent additional treatment after 8.5 years follow-up. Contrarily, several patients had ongoing disease control after limited treatment duration, demonstrating the mixed effect of nilotinib. Show less
Background: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal... Show moreBackground: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study.Patients and methods: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used.Results: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively.Conclusions: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib. Show less
Frezza, A.M.; Ravi, V.; Vullo, S. lo; Vincenzi, B.; Tolomeo, F.; Chen, T.W.W.; ... ; Stacchiotti, S. 2021
Background This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1... Show moreBackground This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.Methods Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.Results Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-alpha 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.Conclusion Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed. Show less
IMPORTANCE The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood.OBJECTIVE To assess... Show moreIMPORTANCE The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood.OBJECTIVE To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib.DESIGN, SETTING, AND PARTICIPANTS This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July17, 2017, and March 1, 2020.INTERVENTIONS Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately.MAN OUTCOMES AND MEASURES Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors.RESULTS A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR. 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01).CONCLUSIONS AND RELEVANCE The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS. Show less
