At present, the addition of IC to the CCRT has been demonstrated as an attractive multidisciplinary approach for the treatment of LANPC [3,4,5]. Accordingly, few prognostic factors in LANPC patients treated with IC have been investigated. The tumor response to IC was shown to be an independent prognostic factor for LANPC patients underwent IMRT [7, 8]. In addition, the SUA level was confirmed to be elevated because of the radiochemotherapy that led to tumor trauma or lysis [13]. However, the prognostic value of SUA after IC or the SUA levels combined with the tumor response to IC in LANPC patients remains unclear. The current study represents the first report to explore the combined prognostic value of the SUA levels and the tumor response to IC in LANPC patients. In this study, it was shown that a high SUA level after two cycles of IC was involved in significantly improved OS, while PFS and DMFS in LANPC patients exhibited borderline significance. Furthermore, the satisfactory tumor response to IC was correlated with significantly improved OS, PFS, and DMFS in LANPC patients. Moreover, the combination of the SUA level with tumor response to IC represented an optimal predictor of OS, PFS, and DMFS, respectively, in patients with a high SUA level and satisfactory tumor response to IC. These results provided a clinical reference for further guiding the risk stratification and early treatment modification for LANPC.
In this study, both univariate and multivariable analyses revealed that the high SUA level after two cycles of IC (> 327 μmol/L) was a positive prognostic factor for NPC as a comparison to the SUA level ≤ 327 μmol/L with a 2.385-fold increased risk of death. Additionally, borderline significant differences were discovered between the high and low SUA levels with respect to the risk of disease failure and distant failure. However, the SUA level was not correlated with the risk of locoregional failure. Uric acid is considered as an antioxidant, which has the effects of eliminating reactive oxygen free radicals, protecting DNA damage, reducing the cell migration ability, and regulating tumor cell death [11, 19]. Chemotherapy is always associated with increased damage to DNA and reduced tumor burden of the patients, which might finally elevate the SUA levels [20]. In addition, uric acid mediates the cytotoxicity of natural killer and T cells by inducing vital stress-inducing ligands’ expression on cancer cells [21]. Thus, it can be hypothesized that uric acid may exert a preventive effect against the development of cancer. Hence, the SUA levels after chemotherapy reflect the efficacy of chemotherapy in patients with NPC, which leads us to propose that the level of SUA after chemotherapy might be closely related to the prognosis. The level of SUA at the pretreatment and the completion of the definitive IMRT has been reported to be closely tied up with the prognosis in NPC [14, 15]. Nevertheless, additional studies are essential to elucidate the mechanisms associated with high SUA levels after IC and improved survival in LANPC patients treated by IC plus CCRT.
According to the current findings, LANPC patients with SD/PD to IC presented an unfavorable OS, PFS, and DMFS than those with CR/PR to IC. Moreover, the tumor response to IC was identified to be an independent prognostic factor for OS, PFS, and DMFS, respectively. To our knowledge, the prognostic significance of tumor response to chemotherapy in various malignancies has been confirmed [22, 23]. Subsequently, the tumor response to IC was demonstrated to be an independent prognostic factor for LANPC patients with IMRT [7, 8], which was similar to our results. Intriguingly, the tumor response to chemotherapy basically represented the changes in gross tumor volume. Typically, patients with CR/PR to IC implied that the tumor volume shrank dramatically or disappeared completely. In contrast, patients with SD/PD to IC showed that the tumor volume shrank insignificantly or rather increased. Several studies demonstrated the prognostic value of changes in the tumor volume in different types of cancers [24, 25]. Therefore, the prognostic value of tumor response to IC in LANPC patients can be elucidated. Taken together, it can be deduced that the SUA level and tumor response to IC were closely involved in IC, and hence, the combined predictive value of the SUA level and tumor response to IC needs deeper investigation.
To explore the prognostic value of combining SUA levels with tumor response to IC, LANPC patients were divided into three subgroups. The outcomes of recent study showed that the subgroup of patients with a high SUA level and CR/PR exhibited improved OS, PFS, and DMFS; this was defined as the low-risk group. The subgroup of patients with a low SUA level and SD/PD showed poor prognosis and was classified as the high-risk group. These phenomena demonstrated that the combination of SUA levels and tumor response to IC had significant prognostic value in LANPC, which might help in differentiating the risk stratification and improving the prognosis after IC. The high-risk group seemed insensitive to IC, needing more aggressive treatment strategies after IC: (1) an increased dose of RT, (2) the administration of an additional target agent during CCRT, like cetuximab that reported to be a feasible strategy against LANPC [26], (3) the inclusion of adjuvant chemotherapy, or (4) the addition of immunotherapy [27, 28]. For the low-risk group, the radiation dose could be decreased to decrease the side effects of radiotherapy. Furthermore, it is feasible for the treating physicians to decide whether to continue or change the IC regimen based on the SUA level and tumor response after two cycles of IC, which could lower the expenses of the treatment and the complications of chemotherapy.
The current study showed that both the N stage and age were independent prognostic factors for OS by multivariable analyses. In addition, the N stage was also verified to be an independent prognostic factor for DMFS. At present, the N stage is the most crucial risk factor for death and distant metastasis [29]. Furthermore, elderly patients are more likely to develop disease failure and die [30], which is in agreement with the outcome of this study.
Nevertheless, our study has several limitations. First, the tumor response was assessed by the radiologists according to RECIST 1.1 [18]; however, it is hard to evaluate the tumor response in LANPC patients with skull base invasion. In this study, the abnormal MRI signal of the skull base was observed after soft tumor regression, which made it difficult to identify whether the skull base was actually infiltrated. Under such circumstances, the skull base was not included in the measurement of tumor length that may lead to an inaccurate evaluation of the tumor response. Second, the median follow-up duration was only 41 months; thus, it is of great importance to prolong the follow-up time to assess the long-term outcomes of patients with LANPC. Third, other biomedical biomarkers, including plasma EBV-DNA, ALP, and LDH, were not evaluated in our study. Therefore, developing a predictive nomogram model to investigate the array of prognostic factors is imperative.