C Lévy1, D Allouache2, J Lacroix3, A E Dugué4, S Supiot2, M Campone2, M Mahe5, S Kichou6, M Leheurteur2, C Hanzen7, V Dieras2, Y Kirova8, F Campana8, E Le Rhun2, L Gras9, T Bachelot2, M-P Sunyach10, I Hrab2, J Geffrelot11, K Gunzer12, J-M Constans13, J-M Grellard4, B Clarisse4, X Paoletti14. 1. Department of Oncology c.levy@baclesse.unicancer.fr. 2. Department of Oncology. 3. Department of Radiology, Centre François Baclesse, Caen Department of GIP Cyceron, Caen. 4. Department of Clinical Research, Centre François Baclesse, Caen. 5. Department of Radiotherapy, Institut de Cancérologie de l'Ouest René Gauducheau, Nantes-Saint Herblain, Caen. 6. Department of Radiology, Centre François Baclesse, Caen. 7. Department of Radiotherapy, Centre Henri Becquerel, Rouen. 8. Department of Radiotherapy, Institut Curie, Paris. 9. Department of Radiotherapy, Centre Oscar Lambret, Lille. 10. Department of Radiotherapy, Centre Léon Bérard, Lyon. 11. Department of Radiotherapy, Centre François Baclesse, Caen. 12. Department of Oncology Department of Clinical Research, Centre François Baclesse, Caen. 13. Department of GIP Cyceron, Caen Department of Radiology, Centre Hospitalier Universitaire, Caen. 14. Department of Biostatistics, Institut Curie/Inserm U900, Paris, France.
Abstract
BACKGROUND: Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. PATIENTS AND METHODS: In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. RESULTS: Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1-2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. CONCLUSION: Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929.
BACKGROUND: Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. PATIENTS AND METHODS: In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. RESULTS: Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1-2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. CONCLUSION:Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929.
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