Abstract
BackgroundIn this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated.MethodsIn total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra-arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra-arterial infusion of placebo rAd-p53 plus chemotherapy).ResultsThe median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining.ConclusionsIntra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.Trial registrationChiCTR-TRC-09000392 (Date of registration: 2009-05-18).
Highlights
In this study, a combination of recombinant adenoviral p53 gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated
The treatments were administered by intra-arterial infusion into the primary lesion
We propose that the following three criteria are necessary to enhance the efficacy of the treatment: 1) regular and sufficient administration of recombinant adenoviral p53 (rAd-p53); 2) adequate local concentration of rAd-p53; and 3) combination of gene therapy with chemotherapy
Summary
A combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated. Oral cancer is a major global health problem with 300,000 new cases diagnosed each year. Alcohol and tobacco remain prominent etiologic factors in oral cancer [1], but high-risk human papillomavirus (HPV) has emerged as an important etiologic agent [2]. Several potentially curative surgical and non-surgical treatment options exist for patients with oropharyngeal cancer [3,4], but treatment selection (chemoradiotherapy and primary surgery) is complex, reflecting the need for primary tumor and nodal disease control to be balanced against preservation of function and minimizing long-term toxicities. Despite advances in treatment with surgery, radiotherapy, and chemotherapy, this aggressive epithelial malignancy is associated with severe morbidity, and patients have a long-term survival rate of less than 50% [5,6]. New approaches are urgently needed to improve the outcomes of patients with oral cancer
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