Sequential chemoradiotherapy versus induction chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: A multicentre, open-label, non-inferiority, randomised, phase 3 trial.

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6075 Background: Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable disease control. Now, distant metastasis was the main cause of failure. However, concurrent cisplatin is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and chemotherapy before or after radiotherapy decreases the risk of distant failure, it is worth exploring whether sequential chemoradiotherapy (SCRT) regimen could replace IC+CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from January 2018 to September 2021 in 6 centers in China. Patients aged 18–65 years with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive 2 cycles of IC with GP regimen (gemcitabine 1000mg/m2 d1,8 + cisplatin 25 mg/m2 d1-3, q21d) plus IMRT, followed by 2 cycles of adjuvant chemotherapy (AC) with the same regimen or IC with GP regimen for 2 cycles followed by IMRT plus concomitant weekly cisplatin (30 mg/m²). The primary endpoint was 3-year failure-free survival (FFS) with non-inferiority margin of 10% (HR<1.6) and the incidence of grade ≥3 acute mucositis during radiotherapy. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 420 patients were randomly assigned to SCRT group (n = 210) or IC+CCRT group (n = 210). With a median follow-up of 47.0 months (IQR: 35.0-57.8), the 3-year FFS was 84.0% in SCRT group versus 79.8% in IC+CCRT group (log rank P=0.344), with an HR of 0.804 (95% CI, 0.510 to 1.266) and absolute difference of 4.2% (95% CI, -3.2 to 11.6). No significant differences were observed between groups in 3-year overall survival (97.4% vs. 94.5%; HR 0.413; 95% CI, 0.159 to 1.076; log rank P=0.061), locoregional control (91.7% vs. 88.8%; HR 0.767; 95% CI, 0.420 to 1.401; log rank P=0.386), or distant metastasis-free survival (93.6% vs. 91.5%; HR 0.756; 95% CI, 0.376 to 1.520; log rank P=0.430). Compared with IC+CCRT group, the SCRT group had significantly lower incidences of grade ≥3 acute nonhematological AEs due to the omission of concurrent chemotherapy (including acute mucositis 29.0% vs. 41.9%, P<0.001; nausea 9.5% vs. 18.1%, P=0.011; and vomiting 3.8% vs. 9.5%, P=0.019), and higher incidences of grade ≥3 acute hematological AEs (including thrombocytopenia and leukopenia) due to the additional AC. Conclusions: For LA-NPC, SCRT was not inferior in 3-year FFS to IC+CCRT. It might be an alternative treatment for LA-NPC patients with fewer sever nonhematological AEs during IMRT. Clinical trial information: NCT03366415 .