Effects of induction taxotere, platinum, and fluorouracil (TPF) chemotherapy in patients with stage III and IVA/B nasopharyngeal cancer treated with concurrent chemoradiation therapy: final results of two parallel phase 2 clinical trials

Abstract Background Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced nasopharyngeal cancer. The effect of induction chemotherapy plus CCRT in patients with this stage of disease is unclear. We therefore examined the long-term outcomes of the addition of induction chemotherapy (consisting of docetaxel, cisplatin, and fluorouracil [TPF]) to CCRT in patients with stage III and IVA/B nasopharyngeal cancer. Methods Between January, 2007, and July, 2011, we synchronously undertook two parallel phase 2 single-arm trials to evaluate the efficacy and toxicity of TPF-based induction chemotherapy. One trial was for patients with stage III nasopharyngeal cancer, and the other was for patients with stage IVA/B disease. Treatment regimens used in both trials were identical. The induction chemotherapy consisted of three cycles of docetaxel 75 mg/m 2 (day 1), cisplatin 75 mg/m 2 (day 1), and a continuous fluorouracil infusion at 500 mg/m 2 per day (days 1–5) every 4 weeks. Radiotherapy was given mainly with intensity-modulated technique (IMRT) at 2·0 Gy per fraction with five daily fractions per week to a total dose of 70 Gy to the primary tumour and neck adenopathy, and 54–60 Gy to the uninvolved neck region. The concurrent chemotherapy consisted of weekly cisplatin at 40 mg/m 2 . Our primary endpoint for both trials was 5-year overall survival, based on intention-to-treat analysis. Both studies were designed to detect a 20% improvement in 5-year overall survival from historical controls. Comparison of results between the two trials was planned. The protocol was conducted with approval from the institutional review board of the Shanghai Proton and Heavy Ion Center. The trials are registered with ClinicalTrials.gov, numbers NCT00816855 and NCT00816816. Findings 52 eligible patients with stage III nasopharyngeal cancer and 64 eligible patients with non-metastatic stage IV disease were accrued to the two trials. With a median follow-up of 66·8 months (range 15·9–105·4), 5-year overall survival was 91·6% (95% CI 83·6–99·6) for stage III patients and 83·1% (72·9–93·3) for stage IVA/B patients (p=0·059), which approximated to a 20% improvement compared with historical controls. 5-year progression-free survival was 80·1% (95% CI 69·1–91·1) versus 66·8% (54·1–79·5; p=0·072), distant metastasis free survival was 93·0% (85·4–100·0) versus 93·1% (86·6–99·6; p=0·387), and local progression-free survival was 92·0% (84·6–99·4) versus 87·2% (77·6–96·8; p=0·276), for patients with stage III versus stage IVA/IVB nasopharyngeal cancer. Multivariate analyses indicated that T-classification (T1/2 vs T3/4) and N-classification (N3 vs N0–2) were the only two significant prognosticators for overall survival (hazard ratio [HR] 2·52, 95% CI 1·178–5·394, p=0·017; HR 1·808, 95% CI 1·002–3·264, p=0·045, respectively), whereas age, gender, number of induction chemotherapy cycles (two vs three), number of concurrent chemotherapy cycles (four or more vs five or less), RT technique, and the presence of residual primary or neck disease were not significant in predicting overall survival. Interpretation TPF-based induction chemotherapy significantly improved overall and progression-free survival when given before CCRT in locoregionally advanced nasopharyngeal cancer. T-classification and N-classification were the only two significant prognostic factors in predicting overall survival. A phase 3 trial is ongoing to confirm such benefit. Funding None.