This multicenter randomized clinical study compared IC + CCRT with CCRT + AC for treating LA-NPC. After a median follow-up of 39 months, we found that the 3-year PFS was similar between the two groups (79.0% vs 74.5%, HR = 0.83[95% CI:0.520 − 0.1.34]; P = 0.454). Both groups had similar compliance rates for radiotherapy and chemotherapy, but the IC group experienced fewer toxic effects during CCRT such as nausea, dermatitis, mucositis, swallowing, and dryness. These findings provide further evidence in support of previous studies indicating that the survival outcomes after IC + CCRT are consistent with those after CCRT + AC23,24,30, while toxic side effects were increased during CCRT19,20,31–33.
The pairing of IMRT with advanced chemotherapy modalities (whether induction, concurrent, or adjuvant) has been shown to lead to improved survival outcomes in NPC patients34–37. However, a significant proportion of the research focusing on the integration of CCRT with IC was conducted in regions where NPC is endemic19,38–41. The Intergroup study 0099 and NCT00677118 Trial solidified the PF protocol’s role as the standard in AC for LA-NPC16,17. To date, the lack of definitive evidence from direct comparison trials assessing the two methods (IC followed by CCRT versus CCRT with subsequent AC) has hindered the determination of a superior sequence of therapies. Although both the NCCN and Chinese Society of Clinical Oncology(CSCO) have updated their recommendations to endorse the approach of IC (with an emphasis on TPF or gemcitabine combined with cisplatin(GP)42 ) followed by CCRT for LA-NPC13,25,43,44, there has been no previously reported head-to-head RCT contrasting these two methodologies. Therefore, our study addresses this knowledge gap.
The 3-year PFS in the IC group of our trial was approximately 79.0% (95% CI:50.62–57.78), which is lower than the rate of 90% reported by Sun et al19 and the rates of other studies18,23,31,32. One reason may be that our IC group had more patients with stage IVa NPC. In the AC group, the 3-year PFS was similar to that in previous studies16,45,46. This trial demonstrates that the combination of IC + CCRT produces comparable outcomes in terms of overall response rates, OS, LRFS, and DMFS to CCRT + AC in the intention-to-treat population. Subgroup analyses also yielded similar results. Interestingly, a meta-analysis showed a benefit for OS and DMFS from the IC regimens. The results of our RCT did not reveal this result. Our results are similar to those of two large meta-analyses of IC plus CCRT for LA-NPC47,48. Moreover, Chan et al.49studied NPC patients deemed at high risk and observed a 3-year OS rate of 70.8% specifically in the AC cohort. Notably, the 3-year OS outcome in our study was superior to that reported in the Intergroup Study 009916 and other studies46,49, which applied a dual approach of CCRT combined with AC. Studies have reported that IC increases the waiting time for radiotherapy and interrupts the radiation treatment, resulting in accelerated tumor growth and reduced treatment efficacy50–53. However, another reason may be that our IC group has increased the interrupts the radiation and the low completion rate of 3-cycle CC for radiotherapy due to the lack of PFS and other outcomes benefits.
Previous research has demonstrated that the cumulative cisplatin dose given during CCRT plays a pivotal role in controlling the disease locally and influencing OS. Specifically, patients treated with a minimum of 200 mg/m2 cisplatin concurrently were found to have superior survival outcome54,55. A radiation dose of 70 Gy is considered to be the standard dose for NPC43,44. Interestingly, in this study, over 97% of patients in both treatment groups received the precise cumulative dose of cisplatin as specified, and the median radiation dosage exceeded 70Gy ( eTable 2 and eTable3 in Supplement 2).
Among all acute toxicities, neutropenia, leukopenia, nausea/vomiting, and mucositis were universally observed among all participants. Compared with the findings of Sun et al19 and other studies39,41,56, the prevalence of these hematological effects was higher observed in our study. A possible explanation for this difference is that the dose we selected for the treatment regimen was an international dose, which was 20% higher than the domestic dose(docetaxel at a dose of 60 mg/m2, cisplatin at a dose of 60 mg/m2, and fluorouracil at a dose of 600 mg/m2/d). The international dose used in the docetaxel-cisplatin-fluorouracil IC regimen around the world is mainly derived from TAX323 and TAX324 trials in head and neck cancer57,58. The standard dosages for this regimen are 75 mg/m2 docetaxel, 75 mg/m2 cisplatin, and 750 mg/m2/d, fluorouracil, and this regimen is efficacious for head and neck cancer in trial settings59–63. However, these dosages are reported to cause serious toxic and side effects41,45. Relevant studies have reported that this dosage is also safe and well-tolerated for LA-NPC, with improved therapeutic efficacy45. Therefore, we chose the full dosages for treatment. Notwithstanding these findings, it is encouraging that the severity of certain adverse effects, such as nausea, vomiting, dermatitis, mucositis, dysphagia, and xerostomia, was less intense among patients who received IC in conjunction with CCRT. This stands in contrast to the adverse effects reported among those who received CCRT and subsequent AC. This advantageous trend may be related to the premise that IC has the potential to reduce tumor volume and thus improve the sensitivity of the cancer to subsequent radiotherapy. This may also be related to the overall good health status and resilience of the patients in our study47,64.
The present study has several strengths. First, this phase 3 trial was conducted across multiple centers, employing a randomized controlled design to directly compare two treatment strategies. Furthermore, this study provides evidence that the combination of IC with CCRT did not significantly improve PFS, OS, LRFS, and DMFS compared with CCRT followed by AC. The study also has some limitations that should be considered. We included some low-risk cases, specifically those with T3N0 classification. Fortunately, the ongoing anyTN2-3M0 high-risk nasopharyngeal carcinoma NCT03306121 study may address this deficiency. Additionally, the standardized chemotherapy dosage was associated with worse hematological side effects.
In conclusion, in this RCT, the combination of IC and CCRT demonstrated a similar PFS rate compared to CCRT followed by AC. Additionally, the study revealed a tolerable toxicity profile for IC and CCRT.