Integration of antiangiogenic therapy with cisplatin and gemcitabine chemotherapy in patients with nasopharyngeal carcinoma.

Abstract

PURPOSE: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced NPC. Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of 2 doses of either sunitinib or bevacizumab with chemotherapy in NPC. EXPERIMENTAL DESIGN: Patients with treatment naïve locally advanced NPC were treated with 3 cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: Arm A patients received 7 days of 12.5mg/day sunitinib; Arm B 7 days of 25mg/day sunitinib; Arm C bevacizumab 7.5mg/kg infusion; Arm D bevacizumab 2.5mg/kg infusion. Patients with metastatic NPC were treated with up to 6 cycles of similar treatment without concurrent chemoradiation. RESULTS: Complete metabolic response (mCR) by whole body 18fluorodeoxyglucose PET was highest in Arm C (significant difference in 4 groups Fisher's exact test p=0.001; type 1 error=0.05), with 42% mCR (95% CI 18 - 67) and 3-year relapse free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in post treatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in Arm C where hypertension was the most significant toxicity. CONCLUSION: Bevacizumab 7.5mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumour response was observed and supported mechanistically by positive effects on tumour perfusion and immune cell trafficking into the tumour.