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Ray-Coquard I.,Leon Berard | Ray-Coquard I.,Center Leon Berard | Rizzo E.,European Organisation for Research and Treatment of Cancer Headquarters | Blay J.Y.,Leon Berard | And 12 more authors.
Gynecologic Oncology | Year: 2016

Objective UtS are a group of uncommon tumors representing 1% of malignant neoplasms of the female genital tract, and 7% of sarcomas. The objective of this study was to evaluate the factors associated with the clinical behavior UtS. Methods Information on 269 patients with advanced or metastatic first line UtS treated by chemotherapy was available in a database containing information on 3270 patients with advanced soft tissue sarcomas (STS) entered in EORTC-STBSG clinical trials between 1977 and 2010. The chemotherapy was aggregated in 4 categories: anthracyclines alone, ifosfamide alone, the combination of doxorubicin and ifosfamide, and CYVADIC. Results Among the 269 UtS pts, there were 231 deaths (median OS 10.4 months, 95% CI: 9.1-11.9) and 257 progressions and/or deaths (median PFS 4.1 months, 95% CI: 3.5-4.9). Multivariate analyses reported PS (p < 0.001) only to be a statistically significant prognostic factor for OS in UtS; for PFS, LMS histology (p = 0.025) is associated with a better outcome. There was no relationship between the 4 groups of chemotherapy regimens and impact on clinical outcomes. Histological subtype was significantly correlated with response to chemotherapy (RR: LMS 19% vs other 33%, p = 0.026). Ifosfamide single agent yielded only 5% of RR. Conclusions Clearly, UtS are very aggressive neoplasms with poor outcome when treated with chemotherapy consisting of anthracyclines with or without ifosfamide or cyclophosphamide. New strategies are urgently needed. © 2016 Elsevier Inc.

Basset-Seguin N.,Hopital Saint Louis | Hauschild A.,University of Kiel | Grob J.-J.,Aix - Marseille University | Kunstfeld R.,Medical University of Vienna | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. Methods: In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. Findings: Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). Interpretation: This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. © 2015 Elsevier Ltd.

Saloura V.,University of Chicago | Cohen E.E.W.,University of California at San Diego | Licitra L.,Fondazione IRCCS Instituto Nazionale dei Tumori | Billan S.,Oncology Institute | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: Treatment options for patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) are limited. The purpose of this study was to assess the efficacy and safety of zalutumumab in platinum-refractory R/M SCCHN. Methods: Patients with platinum-refractory R/M SCCHN were enrolled if they had performance status of 0-2, age ≥18 years and adequate organ function. Patients received weekly infusions of zalutumumab individually titrated to a grade 2 skin rash. Primary objective was overall survival (OS), and secondary objectives were efficacy and safety. A subgroup analysis of OS and progression-free survival (PFS) was conducted for various demographic, disease-related and molecular factors. Results: Ninety patients were enrolled. Twenty-three percent of patients had performance status (PS) 2 and 74 % had distant metastases. Median OS was 5.3 months (95 % CI [4.1, 7.1]), and median PFS was 2.1 months (95 % CI [2.0, 2.6]). Subgroup analysis by ECOG PS revealed median OS of 6.3 months for PS = 0-1 and 2.5 months for PS = 2. Objective response rate was 5.7 %, and disease control rate was 39.8 %. Grade 3-4 adverse events related to zalutumumab were observed in 19 % of patients and included skin rash (5 %), hypomagnesemia (4 %) and pneumonitis (1 %). The frequency of all-cause grade 3-4 AEs was 62 % and included infections (14 %), gastrointestinal disorders (12 %) and hypokalemia (6 %). Two deaths were deemed related to zalutumumab [ClinicalTrials.gov Identifier: NCT00542308]. Conclusions: Zalutumumab showed reasonable efficacy in platinum-refractory R/M SCCHN patients, and dose titration based on skin rash evaluation was feasible. © 2014 Springer-Verlag.

Ose J.,German Cancer Research Center | Fortner R.T.,German Cancer Research Center | Schock H.,German Cancer Research Center | Peeters P.H.,University Utrecht | And 47 more authors.
British Journal of Cancer | Year: 2015

Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk. © 2015 Cancer Research UK.

Mossoba M.E.,U.S. National Institutes of Health | Halverson D.C.,U.S. National Institutes of Health | Kurlander R.,U.S. National Institutes of Health | Schuver B.B.,U.S. National Institutes of Health | And 22 more authors.
Clinical Cancer Research | Year: 2015

Purpose: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD. Experimental Design: Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m2/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤200 mg/d) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T-cell-replete peripheral blood stem cell allografts, and high-dose sirolimus (serum trough target, 20-30 ng/mL). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered (days 0, 14, and 45 posttransplant), and sirolimus was discontinued early (day 60 posttransplant). Results: PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10 of 10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No antitumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed. Conclusions: Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer. © 2015 American Association for Cancer Research.

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