Sequential vs Induction Plus Concurrent Chemoradiotherapy in Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Abstract

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.