Two-cycle versus three-cycle induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A phase III randomized noninferiority trial.

6003 Background: Although two- and three-cycle induction chemotherapy are both widely utilized and confer significant survival benefits in locoregionally advanced nasopharyngeal carcinoma, direct comparative evidence remains lacking. Furthermore, given the cumulative treatment-related toxicity, economic burden, and potential delays in the initiation of radiotherapy, the optimal number of induction chemotherapy cycles remains undefined. Methods: We conducted a phase 3, open-label, multicenter, randomized controlled noninferiority trial in an endemic area. Patients with previously untreated, stage III-IVB (except T3-4N0, AJCC 8 th edition) nasopharyngeal carcinoma, aged 18-70 years without severe comorbidities were enrolled. Eligible patients were randomly assigned to receive two cycles or three cycles induction chemotherapy followed by concurrent chemoradiotherapy in a 1:1 ratio. The primary endpoint was failure-free survival (FFS) and the noninferiority margin was defined as an 8% absolute between-group difference, with an 80% statistical power and a one-sided α of 0.025. The secondary endpoints included overall survival, distant metastasis-free survival, locoregional relapse-free survival, and toxicity, , among others. Results: Among 654 eligible patients, 327 were allocated to each group (two-cycle vs three-cycle). Two groups were well-balanced in all prognostic factors. After a median follow-up of 34.3 months, intention-to-treat analysis showed that estimated 3-year FFS was 85.4% (95% CI 80.9-89.9) in the two-cycle group and 86.7% (95% CI 82.4-91.0) in the three-cycle group, with a difference of -1.3% (95% CI, -7.54% to 4.94%; hazard ratio 1.11, 95% CI 0.72-1.71; P = 0.0031 for noninferiority). Similar result was found in the per-protocol analysis: estimated 3-year FFS for two-cycle group and three-cycle group was 86.5% (95% CI 82.0-91.0) and 87.0% (95% CI 82.7-91.3), respectively, with a difference of -0.5% (95% CI, -6.74% to 5.74%; hazard ratio 1.10, 95% CI 0.69-1.75; P = 0.0014 for noninferiority). No differences were observed between groups in terms of overall survival and the cumulative incidences of locoregional relapse and distant metastasis. Patients in the three-cycle group developed significantly more grade 3-4 adverse events such as neutropenia (three-cycle group 34.3% vs two-cycle group 24.8%), leukopenia (32.7% vs 24.5%) and vomiting (15.9% vs 10.4%). No patients died from treatment-related causes. Conclusions: Two-cycle induction chemotherapy followed by concurrent chemoradiotherapy provides comparable disease control and survival, with less toxicity, compared to three-cycle counterpart in locoregionally advanced nasopharyngeal carcinoma. Clinical trial information: ChiCTR1800018417 .