This study is first to examine the clinical effectiveness of ICT + CCRT followed by ACT in LANC patients. We discovered that ACT following ICT + CCRT had no significant effect on improving the survival of LANC patients. Furthermore, we observed that patients with N2-3-positive LANC in the ICT + CCRT + ACT group had better 5-yesr OS, DFS, and DMFS than those in the ICT + CCRT group. Based on this study, we suggest that patients with N2-3-positive LANC should be treated with the ICT + CCRT + ACT regimen to further reduce the incidence of distant metastasis.
CCRT is the cornerstone of the treatment of LANC[5, 20]. With the wide application of IMRT, the incidence of local control of NPC has been significantly improved; however, the occurrence of distant metastasis has become the main cause of treatment failure[21, 22]. In recent years, the combination of ICT or ACT with CCRT has minimized the incidence of distant metastases in LANC patients . Compared with CCRT alone, CCRT following ICT was found to improve 5-year OS in an IPD pooled analysis (HR = 0.75, 95% CI 0.57 ~ 0.99) by improving DMFS (HR = 0.68, 95% CI 0.90 ~ 0.51) . Since then, IC + CCRT has become the standard treatment regimen for LANC according to 2018 NCCN guidelines . Although the addition of ICT to CCRT can improve the survival of patients with LANC, a small number of patients with a high risk of metastasis still have a residual primary tumor and lymph node metastasis after treatment. ACT is administered to reduce residual tumor cells, prevent relapse, and eliminate micrometastases . We found that the ICT + CCRT and CCRT + ACT regimens had the same level of evidence, both of which were 2A . Therefore, whether ACT following ICT plus CCRT can further improve survival in patients with high-risk LANC is worth further exploration.
ACT remains controversial because a previous study failed to demonstrate clinical effectiveness [25–27]. Chen et al showed that there were no significant differences between the CCRT group and the CCRT + ACT group in 5-year FFS (75% vs. 71%; P = 0.45), OS (83% vs. 80%; P = 0.35), DMFS (85% vs. 80%; P = 0.30) and LRFS (91% vs. 90%; P = 0.73). The main reason for this was that most patients with poor tolerance after CCRT exhibited decreased compliance. Approximately 40% of patients did not complete three cycles of ACT, and 44 of them refused ACT [25, 26]. In this study, all the patients in the ICT + CCRT + ACT group received two or more courses of ACT, providing more reliable results.
Additionally, not all patients are suitable for ACT, and patients who are more likely to benefit from ACT are still uncertain at present. Many N0-1-positive patients were included in Chen et al.’s study. Similarly, Anthony et al.  explored the connection between ACT and plasma Epstein-Barr virus DNA. This study suggested that ACT with cisplatin and gemcitabine (GP) did not improve 5-year DMFS. Therefore, using biomarkers cannot screen patients who can benefit from ACT. As per our findings, the ICT + CCRT + ACT regimen could further improve the OS, DFS, and DMFS in N2-3-positive LANC patients. The 5-year OS, DFS and DMFS rates in the ICT + CCRT group were 78.9%, 73.4% and 76.0%, respectively, which were significantly lower than those in the ICT + CCRT + ACT group (85.0%, 81.7% and 84.9%, respectively) (all P < 0.05). Therefore, according to the results of this study, we believe that the addition of ACT based on the IC + CCRT regimen is suitable for those with N2-3-positive LANC.
Generally, cisplatin plus fluorouracil (PF) is the most common ACT regimen and is the preferred treatment recommended by the guidelines. However, ACT with the PF regimen may not be the most effective, and some new chemotherapy agents (such as capecitabine, docetaxel, and capecitabine) may further improve the clinical value of ACT. A recent study  found that ACT with capecitabine could improve the 3-year FFS in LANC patients. Zhang et al. reported that ACT with the TP regimen is an effective strategy for treating LANC. Likewise, our study demonstrates the clinical value and feasibility of ACT with the TP regimen.
Docetaxel is widely used in head and neck squamous cell carcinoma because it impairs mitosis and induces apoptosis. Meanwhile, docetaxel has demonstrated a lower rate of grade 3 and 4 nausea/vomiting than fluorouracil. A retrospective study revealed that compared with TP regimen, ICT with 5-fluorouracil-based regimens significantly increased the incidence of mucositis/vomiting toxicity . Zhang et al.  discovered that ACT with the TP regimen is a successful treatment for LANC, with no patients experiencing grade 3/4 nausea or vomiting. Therefore, LANC patients tolerate the TP regimen better than the PF regimen, and 75% of the patients in the current study completed three cycles of ACT.
According to Zou et al., the rate of grade 3/4 leukocytopenia and neutropenia was significantly elevated, and the incidence was 67.5% and 55.8%, respectively, which was similar to the result of our study. We found that grade 3/4 leukocytopenia/neutropenia in the ICT + CCRT + ACT group was significantly greater than that in the ICT + CCRT group (all P < 0.001). Additionally, our study showed no notable differences in 3/4 nausea/vomiting and oral mucositis between the two groups, which was in line with previous research .
There are some limitations to the current study. First, this is a retrospective study using data from a single center. Another caveat is that some biases were inevitable since it was retrospective. PSM and multivariable regression can help us minimize confounding effects, but other unmeasured potential confounding factors may still exist. Meanwhile, some outpatient information was not fully documented. Therefore, large prospective clinical studies will be required to confirm our results.