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

Abstract

Purpose We sought to improve the outcomes for loco-regionally advanced nasopharyngeal carcinoma (NPC) by testing the feasibility/safety of adding bevacizumab to chemoradiation. Patients/Methods Eligible patients with ≥T2b and/or positive node(s) were prescribed 3 cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m2) both given on days 1, 22, and 43 of radiation (70 Gy) using IMRT delivered over 33 days on a daily basis, Monday through Friday. This is followed by 3 cycles of bevacizumab (15 mg/kg), cisplatin (80 mg/m2) both were given on days 64, 85, and 106 and fluorouracil (1000 mg/m2/d) on days 64–67, 85–88, 106–109 after radiation. The primary endpoint was to evaluate the safety of the addition of bevacizumab to chemoradiation, specifically looking at treatment-related Grade 4 hemorrhage and/or any Grade 5 adverse event in the first year. Toxicity during and after treatment were collected along with tumor control endpoints. The analysis was done per protocol. This protocol has completed its target accrual. Results There were a total of 46 patients enrolled in this study of whom 44 patients were eligible for analysis. No grade 3–4 hemorrhage or grade 5 adverse events were observed; 9 patients (20.5%) experienced grade 1–2 hemorrhage. Grade 4 adverse events were experienced by the following numbers of patients: leukopenia NOS – 6; lymphopenia – 5; neutrophil count – 5; pharyngolaryngeal pain – 2; hemoglobin – 1; infection with grade 3–4 neutrophils (blood) – 1; infection with grade 3–4 neutrophils [skin (cellulitis)] – 1; tinnitus – 1; thrombosis – 1; radiation mucositis – 1. The most common grade 3 adverse events were radiation mucositis – 33; dysphagia – 25; and mucositis/stomatitis (clinical exam) (pharynx) – 15. Two patients experienced late grade 3 xerostomia. Other late grade 3 adverse events were: dysphagia – 5; hearing impaired – 3; neuralgia NOS – 2; constitutional symptoms (other) – 1; dehydration – 1; fatigue – 1; hearing disability – 1; infection (other) – 1; muscle weakness NOS – 1; peripheral motor neuropathy – 1; peripheral sensory neuropathy – 1; radiation mucositis – 1.. With a median follow-up of 2.5 years, the estimated 2-year loco-regional progression-free, distant metastasis-free, progression-free and overall survival (OS) rates were 83.7%(95% confidence interval 72.6–94.9), 90.8% (82.2–99.5), 74.7% (61.8–87.6), and 90.9% (82.3–99.4),, respectively. Conclusion It was feasible to add bevacizumab to chemoradiation for NPC treatment. The favorable 2-year OS of 90.9% suggests that bevacizumab might delay progression of subclinical disease.