Recombinant adenoviral human p53 gene combined with radio- and chemotherapy in treatment of advanced nasopharyngeal carcinoma: A randomized clinical study.

Abstract

5558 Background: Studies showed p53 gene therapy could enhance the anti-tumor effect of both chemo- and radiotherapy. The anti-tumor function of p53 gene is associated with up-regulated expression of p21 and Bax. Here, we investigate the beneficial role of recombinant adenoviral human p53 gene (rAd-p53) combined with chemoradiotherapy in treatment of advanced nasopharyngeal carcinoma (NPC), and p21 and Bax protein expression in pre- and post-treatment tumor tissues. Methods: Sixty-three patients with historically-diagnosed advanced NPC, with ECOG performance status less than 2, life expectancy greater than 3 months and adequate organ function tests, were randomly assigned into two groups: 32 in experimental group (EG) and 31 in control group (CG). EG received intratumoral injection of 1×1012 rAd-p53 viral particles (VP) per 3 days for 6-8 times, carboplatin 300 mg/m2 on day1 and continuous infusion of a total dose of 2000 mg/m2 of 5-Fu on day1-5 for 3 cycles, and radiotherapy at a dose of 2Gy/fraction for a total dose of 70-76 Gy/35-38f. CG received the same chemo- and radiotherapy. Pre- and post-treatment tissue samples were analyzed for Bax and p21 protein levels. Results: The median follow-up time was 28 months. EG achieved a complete response rate (CR) of 62.5% and overall response rate (RR) of 90.6%, both rates being statistically significantly higher than that of CG (CR=35.5%, RR=74.2%). One-year of overall survival (OS) was 100.0% for EG and 90.3% for CG, and one year of progress free survival (PFS) was 96.7% and 77.4% for EG and CG, respectively. Two-year OS was 95.7% and 86.4% for EG and CG, respectively, and two-year of PFS was 79.6% and 73.5% for EG and CG, respectively. After treatment, both Bax and p21 protein levels in EG increased significantly. In CG, both proteins levels also increased after treatment but not significantly. The main side effects of rAd-p53 were self-limited fever, occurring in all of EG patients. Conclusions: RAd-p53 as a component of the comprehensive therapy for advanced NPC contributes significant beneficial effects. Increased levels of Bax and p21proteins after treatment represent two mechanisms of p53 anti-tumor activities.