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San Donato di Ninea, Italy

Bracarda S.,Ospedale San Donato USL8 | Iacovelli R.,Istituto Nazionale Tumori | Boni L.,Clinical Trials Coordinating Center | Rizzo M.,Medical Oncology | And 28 more authors.
Annals of Oncology | Year: 2015

Background: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. Patients and methods: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2→2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. Results: In group 4/2→2/1, the overall incidence of grade ≥3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade =3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2→2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. Conclusions: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Calvo E.,Centro Integral Oncologico Clara Campal | Escudier B.,CNRS Gustave Roussy Institute | Motzer R.J.,Sloan Kettering Cancer Center | Oudard S.,Oncology Translational Research Unit | And 10 more authors.
European Journal of Cancer | Year: 2012

Introduction: In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10 mg once daily (n = 277) or placebo (n = 139). Median progression-free survival (PFS) was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio [HR], 0.33; P <.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. Patients and methods: Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS. Results: All patients (100%) received ≥1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR, 0.32; 95% confidence interval [CI], 0.24-0.43; P <.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0 months with everolimus and 1.8 months with placebo (HR, 0.32; 95% CI, 0.19-0.54; P <.001). The everolimus safety profile was similar for both groups. Conclusions: Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy. © 2011 Elsevier Ltd. All rights reserved.

Bracarda S.,Ospedale San Donato USL8 | Ruggeri E.M.,Ospedale Belcolle | Monti M.,University of Milan | Merlano M.,ASO Santa Croce e Carle | And 4 more authors.
Critical Reviews in Oncology/Hematology | Year: 2012

Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice. © 2011 Elsevier Ireland Ltd.

Porta C.,University of Pavia | Calvo E.,Centro Integral Oncologico Clara Campal | Climent M.A.,Instituto Valenciano Of Oncologia | Vaishampayan U.,Barbara Ann Karmanos Cancer Institute | And 10 more authors.
European Urology | Year: 2012

Background: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. Objective: To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1. Design, setting, and participants: The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416). Intervention: Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. Measurements: Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. Results and limitations: In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. Conclusions: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered. © 2011 European Association of Urology.

Bracarda S.,Ospedale San Donato USL8 | Rottey S.,Ghent University | Bahl A.,British Haematology and Oncology Center | Eichelberg C.,University of Regensburg | And 6 more authors.
Future Oncology | Year: 2015

Aim: RAD001 Expanded Access Clinical Trial (REACT) provided everolimus to patients with metastatic RCC before its commercial availability. This retrospective subgroup analysis evaluated eventual differences, mainly in safety, between the large European population (n = 906; 66.3%) and the overall population (n = 1367). Patients & methods: REACT enrolled patients from 34 countries who received everolimus 10 mg/day until progression/discontinuation or commercial availability. Results: Baseline characteristics, except race/ethnicity, were similar. Incidences of grade 3/4 adverse events were 50.7/11.3% in the European population and 48.8/12.8% in the overall population. A similar percentage of the European and overall populations achieved stable disease (∼51%) and completed treatment (20.6 and 19.7%). Conclusion: These results do not suggest differences for the European population and support everolimus as a worldwide standard of care for VEGFR-refractory metastatic RCC (NCT00655252). © 2015 Future Medicine Ltd.

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