Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial

Background We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy. Methods We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694. Findings From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2.5 years (IQR 2.1-2.9), the estimated 2 year locoregional progression-free interval was 83.7% (95% CI 72.6-94.9), the 2 year distant metastasis-free interval was 90.8% (82.2-99.5), the 2 year progression-free survival was 74.7% (61.8-87.6), and 2 year overall survival was 90.9% (82.3-99.4). Interpretation The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.