Sequential vs Induction Plus Concurrent Chemoradiotherapy in Nasopharyngeal Carcinoma

Importance: Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been a standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but with high acute toxic effects in CCRT phase. Whether CCRT can be safely replaced by radiation therapy with adjuvant chemotherapy (AC) is unknown. Objective: To assess if sequential chemoradiotherapy (SCRT; IC, followed by radiotherapy alone, followed by AC) is noninferior to IC plus CCRT for LA-NPC in terms of efficacy, with less acute toxic effects. Design, Setting, and Participants: This multicenter, open-label, phase 3 noninferiority randomized clinical trial was conducted from January 2018 to September 2021 in 6 centers in China. Patients aged 18 to 65 years with newly diagnosed stage III/IVA NPC were enrolled. The data cutoff date was June 30, 2024. Interventions: Patients were randomly assigned 1:1 to receive 2 cycles of IC with a gemcitabine and cisplatin (GP) regimen (gemcitabine, 1000 mg/m2, on days 1 and 8 plus cisplatin, 25 mg/m2, on days 1, 2, and 3, repeated every 3 weeks) plus radiotherapy alone, followed by 2 cycles of AC with a GP regimen (SCRT group) or 2 cycles IC (GP regimen) followed by radiotherapy concurrent with weekly cisplatin, 30 mg/m2 (IC plus CCRT group). Main Outcomes and Measures: The primary end points were 3-year failure-free survival (FFS) with a noninferiority margin of 10% (hazard ratio [HR] less than 1.6) and the incidence of grade 3 or higher acute mucositis during radiotherapy. The secondary end points included overall survival, locoregional FFS, distant FFS, response rate, and toxic effects. Results: Of 420 enrolled patients, 107 (25.5%) were women, and the median (IQR) age was 48 (41-54) years. A total of 210 patients were randomized to the SCRT group and 210 to the IC plus CCRT group. The median (IQR) follow-up time was 50 (40-61) months. In the intention-to-treat population, 3-year FFS was 83.7% (95% CI, 78.6-88.8) vs 79.5% (95% CI, 74.0-85.0) in the SCRT group vs the IC plus CCRT group, respectively (HR, 0.77; 95% CI, 0.50-1.19; P = .24), with the upper bound of the 95% CI less than 1.6. Identical outcomes were reported in the per-protocol population. Compared with the IC plus CCRT group, the SCRT group had significantly lower incidences of grade 3 or higher acute nonhematological toxic effects (acute mucositis, 61 [29.0%] vs 88 [41.9%], respectively; P < .001; nausea, 20 [9.5%] vs 38[18.1%], respectively; P = .01; vomiting, 8 [3.8%] vs 20 [9.5%], respectively; P = .02). No differences were observed in late toxic effects. Conclusions and Relevance: Results from this noninferiority randomized clinical trial suggest that SCRT is noninferior to IC plus CCRT in terms of 3-year FFS in LA-NPC, with less severe acute nonhematological toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT03366415.