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Milowsky M.I.,University of North Carolina at Chapel Hill | Dittrich C.,Center for Oncology and Haematology | Duran I.,University of San Pablo - CEU | Jagdev S.,St Jamess Institute Of Oncology | And 12 more authors.
European Journal of Cancer | Year: 2014

Background Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib - a broad-targeted inhibitor of tyrosine kinases, including FGFR3 - were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Methods Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3MUT; n = 12), wild-type (FGFR3WT; n = 31), or unknown (n = 1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results Most of the patients were men (75%) and over half of the patients were aged ≥65 years (61%). All patients had received ≥1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3MUT (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3WT (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426. © 2014 Elsevier Ltd. All rights reserved. Source

Aapro M.,IMO Clinique de Genolier | Osterborg A.,Karolinska Institutet | Gascon P.,University of Barcelona | Ludwig H.,Center for Oncology and Haematology | Beguin Y.,University of Liege
Annals of Oncology | Year: 2012

Background: Chronic diseases reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency (ID) and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of ID, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents (ESAs). Design: Clinical trial reports were identified in PubMed and abstracts at relevant major congresses. Results: Reported prevalence of ID in cancer patients ranges from 32 to 60% and most iron-deficient patients are also anaemic. Randomised clinical trials have shown superior efficacy of i.v. iron over oral or no iron in reducing blood transfusions, increasing haemoglobin, and improving quality of life in ESA-treated anaemic cancer patients. Furthermore, i.v. iron without additional ESA should be evaluated as potential treatment in patients with chemotherapy-induced anaemia. At recommended doses, i.v. iron is well tolerated, particularly compared with oral iron. No serious drug-related adverse effects were seen during long-term use in renal disease and no effect on tumour growth has been observed in trials with anaemic cancer patients. Conclusions: Reliable diagnosis and treatment of ID are recommended key steps in modern cancer patient management to minimise impact on quality of life and performance status. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Canon J.-L.,Grand HOpital de Charleroi | Vansteenkiste J.,University Hospital Gasthuisberg | Hedenus M.,Sundsvall Hospital | Gascon P.,Hospital Clinic de Barcelona | And 7 more authors.
Medical Oncology | Year: 2012

Darbepoetin alfa (DA) is an erythropoiesisstimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels <10 g/dL (US) or ≤10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan-Meier percentage (95% CI) of patients achieving Hb ≥10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a C1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≥ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis. Copyright © Springer Science+Business Media, LLC 2011. Source

Beguin Y.,University of Liege | Aapro M.,IMO Clinique de Genolier | Ludwig H.,Center for Oncology and Haematology | Mizzen L.,Vifor Pharma | Osterborg A.,Karolinska Institutet
Critical Reviews in Oncology/Hematology | Year: 2014

The efficacy and tolerability of intravenous (i.v.) iron in managing cancer-related anemia and iron deficiency has been clinically evaluated and reviewed recently. However, long-term data in cancer patients are not available; yet, long-term i.v. iron treatment in hemodialysis patients is not associated with increased cancer risk. This review summarizes epidemiological and nonclinical data on the role of iron in carcinogenesis. In humans, epidemiological data suggest correlations between certain cancers and increased iron exposure or iron overload. Nonclinical models that investigated whether iron can enhance carcinogenesis provide only limited evidence relevant for cancer patients since they were typically based on high iron doses as well as injection routes and iron formulations which are not used in the clinical setting. Nevertheless, in the absence of long-term outcome data from prospectively defined trials in i.v. iron-treated cancer patients, iron supplementation should be limited to periods of concomitant anti-tumor treatment. © 2013 The Authors. Source

Glaspy J.,University of California at Los Angeles | Crawford J.,Duke University | Vansteenkiste J.,University Hospital Gasthuisberg | Henry D.,Pennsylvania Hospital | And 6 more authors.
British Journal of Cancer | Year: 2010

Background: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events. Methods: This meta-analysis included studies from the 2006 Cochrane meta-analysis, studies published/updated since the 2006 Cochrane report, and unpublished trial data from Amgen and Centocor Ortho Biotech. The 60 studies analysed (15 323 patients) were conducted in the settings of chemotherapy/radiochemotherapy, radiotherapy only treatment or anaemia of cancer. Data were summarised using odds ratios (ORs) with 95% confidence intervals (CIs). Results: Results indicated that ESA use did not significantly affect mortality (60 studies: OR1.06; 95% CI: 0.97-1.15) or disease progression (26 studies: OR1.01; 95% CI: 0.90-1.14), but increased the risk for venous-thromoboembolic events (44 studies: OR1.48; 95% CI: 1.28-1.72). Conclusion: Though this meta-analysis showed no significant effect of ESAs on survival or disease progression, prospectively designed, future randomised clinical trials will further examine the safety and efficacy of ESAs when used according to the revised labelling information. © 2010 Cancer Research UK. All rights reserved. Source

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