J Cancer 2017; 8(8):1417-1424. doi:10.7150/jca.18339

Research Paper

Temozolomide and Bevacizumab Induction before Chemoradiotherapy in Patients with Bulky Glioblastoma and/or with Severe Neurological Impairment

Ilan Darmon1, Mony Chenda Morisse2, Alexandre Coutte1, Marie Blonski3, Emilie Le Rhun4, Luc Taillandier3, Diana Bello Roufai2, Christine Desenclos5, Stéphanie Trudel6, Jean-Christophe Faivre7, 8, Nicolas Blanchard9, Bruno Chauffert2, Mathieu Boone2✉

1. Department of Radiotherapy, University Hospital, Amiens, France;
2. Department of Medical Oncology, University Hospital, Amiens, France;
3. Department of Neuro-Oncology, University Hospital, Nancy, France;
4. Department of Neuro-Oncology, University Hospital, Lille, France; Department of Neurology, General Hospital, Valenciennes, France; Neurology, Breast Unit, Oscar Lambret, Lille, France; INSERM UMR 1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Lille University, Villeneuve d'Ascq, France;
5. Department of Neurosurgery, University Hospital, Amiens, France;
6. Laboratory of Molecular Oncology, University Hospital, Amiens, France;
7. Department of Radiotherapy, Centre Alexis Vautrin, Nancy, France;
8. Department of Radiotherapy, Hospital of Metz-Thionville, France;
9. Department of Radiotherapy, Clinique des Dentellières, Valenciennes, France.

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Darmon I, Morisse MC, Coutte A, Blonski M, Le Rhun E, Taillandier L, Roufai DB, Desenclos C, Trudel S, Faivre JC, Blanchard N, Chauffert B, Boone M. Temozolomide and Bevacizumab Induction before Chemoradiotherapy in Patients with Bulky Glioblastoma and/or with Severe Neurological Impairment. J Cancer 2017; 8(8):1417-1424. doi:10.7150/jca.18339. Available from https://www.jcancer.org/v08p1417.htm

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Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor-related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy.

Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE.

Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)], respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients. Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis.

Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose.

Keywords: bulky glioblastoma, multifocal glioblastoma, bevacizumab, temozolomide, radiotherapy.