Four cycles of docetaxel plus cisplatin as neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in stage N2-3 nasopharyngeal carcinoma: phase 3 multicentre randomised controlled trial

Dear Editor

Xie et al. 2025 present a well-structured phase 3, multicentre, randomised controlled trial (RCT) investigating four cycles of docetaxel plus cisplatin as neoadjuvant chemotherapy prior to concurrent chemoradiotherapy in stage N2-3 nasopharyngeal carcinoma. This study’s robust RCT design remains the gold standard for evaluating treatment efficacy and minimising bias. The multicentre approach boosts the external validity of the outcomes across diverse patient populations [1]. Importantly, focusing on N2-3 disease addresses a clinically urgent need, as these stages are associated with higher rates of distant metastases and poorer outcomes. Moreover, the trial appropriately selected clinically meaningful endpoints, such as progression-free survival (PFS) and overall survival (OS), providing direct relevance to patient care.

Nonetheless, there are notable concerns. The intensive chemotherapy regimen of four cycles before chemoradiotherapy raises concerns about cumulative toxicity. This upbuild of toxins could limit real-world applicability, especially in lower-resource settings or among frailer patients [2]. The study, while demonstrating improved PFS, would have benefited from longer term follow-up to assess OS, late toxicity, and quality of life, given the known delayed toxicities of cisplatin-based therapies [3].

Additionally, there was no stratification or subgroup analysis based on EBV-DNA levels, which is an important prognostic biomarker in nasopharyngeal carcinoma and could guide more personalised approaches [4]. The trial also failed to show translational endpoints or molecular correlates, which are increasingly essential in modern oncology research for identifying responders versus non-responders.

In conclusion, while the study represents a significant advancement in the management of advanced nasopharyngeal carcinoma, future studies should aim for biomarker integration, toxicity mitigation strategies, and more comprehensive longitudinal outcomes.

References
[1] Xie WH, Xiao WW, Chang H, Xu MJ, Hu YH, Zhou TC, et al. Four cycles of docetaxel plus cisplatin as neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in stage N2-3 nasopharyngeal carcinoma: phase 3 multicentre randomised controlled trial. BMJ. 2025 Apr 15;e081557–7.
[2] Shah BA, Qureshi MM, Logue JM, Cooley TP, Zaner KS, Scharukh Jalisi, et al. Assessing cumulative acute toxicity of chemoradiotherapy in head and neck cancer with or without induction chemotherapy. American Journal of Otolaryngology. 2017 Apr 12;38(4):456–61.
[3] Minerva, Bhat A, Verma S, Chander G, Jamwal RS, Sharma B, et al. Cisplatin-based combination therapy for cancer. Journal of Cancer Research and Therapeutics [Internet]. 2023 Apr 1 [cited 2023 Nov 15];19(3):530. Available from: https://journals.lww.com/cancerjournal/fulltext/2023/19030/cisplatin_bas...
[4] Leung SF, Chan KCA, Ma BB, Hui EP, Mo F, Chow KCK, et al. Plasma Epstein–Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Annals of Oncology. 2014 Jun;25(6):1204–8.