NPC‐0501 trial on the value of changing chemoradiotherapy sequence, replacing 5‐fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma

Background A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5‐fluorouracil (PF). This randomized NPC‐0501 trial evaluated the therapeutic effect of changing to an induction‐concurrent sequence or accelerated‐fractionation sequence, and/or replacing 5‐fluorouracil with capecitabine (X). Methods Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6‐arm full‐randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3‐arm chemotherapy cohort). Results A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction‐concurrent sequence, especially the induction‐PX regimen, achieved significant improvements in progression‐free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated‐fractionation group and the 3‐arm chemotherapy cohort, a comparison of the induction‐concurrent versus concurrent‐adjuvant sequence in the conventional‐fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction‐PX versus the adjuvant‐PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. Conclusions For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent‐adjuvant to an induction‐concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings. The 5‐year results from the NPC‐0501 trial demonstrate that conventional fractionation remains the standard recommendation for patients with locoregionally advanced nasopharyngeal carcinoma who are treated with