Induction vs Adjuvant Chemoradiotherapy in Patients With High-Risk N2 to N3 Nasopharyngeal Carcinoma

Importance: It remains uncertain which chemotherapy sequence is more effective for locoregionally advanced nasopharyngeal carcinoma. Objective: To compare the efficacy and safety of induction-concurrent with concurrent-adjuvant chemotherapy in high-risk N2 to N3 nasopharyngeal carcinoma. Design, Setting, and Participants: In this open-label, randomized, phase 3 clinical trial conducted at Sun Yat-sen University Cancer Center (China) from November 20, 2017, to March 19, 2021, patients aged 18 to 65 years with stage T1-4N2-3M0 and a pretreatment Epstein-Barr virus DNA level of 1500 or more copies/mL were enrolled. The data were analyzed from December 2024 to March 2025. Intervention: The patients were randomly assigned to receive 3 cycles of paclitaxel-cisplatin-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy followed by 3 cycles of cisplatin-fluorouracil adjuvant chemotherapy. Main Outcome and Measure: The primary end point was 3-year progression-free survival, assessed locally by the investigator and defined as the time from random assignment to documented local or regional relapse, distant metastasis, or death of any cause, whichever occurred first. Results: A total of 162 patients (median [IQR] age, 44 [34-53] years; 40 female individuals [24.7%]) were assigned to the induction-concurrent group and 162 (median [IQR] age, 45 [37-52] years; 36 female individuals [22.2%]) to the concurrent-adjuvant group. Regarding the data cutoff (October 8, 2024), the median (IQR) follow-up period was 60.4 (58.2-62.6) months. The 3-year progression-free survival rates were 73.5% (95% CI, 65.9%-79.6%) in the induction-concurrent group and 70.4% (95% CI, 62.7%-76.8%) in the concurrent-adjuvant group (stratified hazard ratio, 0.86; 95% CI, 0.58-1.27; P = .45). The most common short-term grade 3 or worse adverse events were leukopenia (53 of 160 [33.1%] in the induction-concurrent group vs 47 of 142 [33.1%] in the concurrent-adjuvant group), neutropenia (52 [32.5%] vs 32 [22.5%], respectively), and mucositis (47 [29.4%] vs 42 [29.6%], respectively). The most common grade 3 or worse late adverse event was auditory or hearing loss (10 [6.3%] vs 12 [8.5%], respectively). Two patients in the induction-concurrent group died of treatment-related toxic effects. No treatment-related death occurred in the concurrent-adjuvant group. Conclusions and Relevance: This randomized clinical trial found that induction-concurrent chemotherapy did not significantly improve progression-free survival compared with concurrent-adjuvant chemotherapy in high-risk N2 to N3 nasopharyngeal carcinoma. Both treatment strategies were effective, and clinicians should discuss with the patients about the potential risks and benefits of the induction chemotherapy or adjuvant chemotherapy to provide the most appropriate treatment for patients with high-risk features. Trial Registration: ClinicalTrials.gov Identifier: NCT03306121.