It is well-established that over 80% of newly diagnosed NPCs are non-metastatic [11]. The number of older patients with non-metastatic NPCs is increasing with the growing older population. Therefore, NPC therapy has attracted the attention of clinicians. The definition of age in older patients with NPC varies among studies. The definition of the older population in developed countries is 65 years of age or older. Older patients are classified into three categories: “young old” (65–74 years old), “older old” (75–84 years old), and “oldest old” (≥ 85 years old) following the consensus of the National Institute of Aging in the United States [12]. Given the strict inclusion criteria in clinical studies, older patients with NPC over 65 are typically excluded. However, clinical treatment standards are mainly derived from evidence-based data, and whether the existing standard treatment models can be applied to patients with NPC over 65 years remains controversial. Therefore, we included patients with NPC over 65 years (the cutoff point) to assess the older population retrospectively and explore critical prognostic factors for NPC in older adults, providing a reference for clinical diagnosis and treatment.
In this study, additional chemotherapy during RT did not improve the OS. Chemotherapy was not an independent risk factor affecting survival outcomes in older patients with NPC. Notably, several studies have shown that concurrent chemoradiotherapy (CCRT) can improve the survival of older NPC patients. However, RT is mainly two-dimensional RT [13-15]. However, given the widespread use of IMRT, whether chemotherapy benefits older patients with NPC remains uncertain. Mi et al. have shown that the efficacy of IMRT-only and CCRT was similar in older patients with NPC aged > 65 years; however, the IMRT-only group had low rates of grade 3 or higher adverse events [16]. Sommat et al. [17] have shown no benefit of CCRT in patients with locally advanced NPC. Furthermore, Su et al. [18] have reported that CCRT had similar survival results to IMRT-only in locally advanced NPC. Notably, several studies have suggested that older patients with NPC who receive concurrent chemotherapy have no survival advantage. This can be attributed to the improved local control afforded by IMRT without increasing adverse reactions in patients, thereby limiting the effect of chemotherapy. In addition, older patients with NPC (over 65 years of age) might have poor tolerance to chemotherapy and limited organ function. Chemotherapy aggravates adverse reactions during RT, resulting in a shortened chemotherapy cycle and reduced dose. Therefore, chemotherapy efficacy is reduced.
Herein, we found that age was an independent predictor of OS after the Cox regression analyses. We divided patients into two groups (≤ 70 years old and > 70 years old). According to this categorization, the older the patient, the worse the prognosis; this finding is consistent with that previously reported [19]. Advanced age affects the survival prognosis of older patients and contributes to delayed seeking of medical treatment, often at later stages. Our results revealed that the common symptoms in older patients with NPC were mainly nasal congestion, bloody discharge, tinnitus, and hearing loss, which were atypical and were easily overlooked. With disease progression, the patients were only treated when the mass size increased, and local invasion symptoms or lymph node compressions appeared; however, this resulted in their presentation at a late stage. Our study showed that 91.4% of patients had locally advanced NPC (stage III-IV), indicating a significant delay in NPC diagnosis, substantially higher than that in the adult age group [20]. Therefore, strengthening disease awareness, protection, and regular screening may facilitate early NPC diagnosis.
In addition, older patients with NPC have more comorbidities, and their prognosis is typically related to these comorbidities [21]. Comorbidities are crucial in determining cancer treatment options and survival assessment [22]. Notably, several scoring tools, including the ACCI and adult comorbidity evaluation-27 (ACE-27) scores, have been used to measure the burden of complex comorbidities. The ACCI score is simple and clear and has been used to score comorbidities. Our results revealed that an ACCI score of 2–3 was an independent predictor of good OS. The presence, type, and severity of comorbidities have been shown to influence treatment choices and survival of older patients with head and neck cancer [23,24]. On assessing 103 older patients with NPC, Sze et al. reported that overall mortality and cancer-specific mortality were high in patients with more comorbidities who received radiation therapy [25]. Notably, two recent clinical studies involving the use of IMRT have indicated that concurrent chemoradiotherapy achieves similar survival outcomes of older patients with NPC experiencing severe comorbidities (ACE-27 score ≥ 2) when compared with RT-only [26, 27]. Our results are consistent with this finding. We also found an association between the severity of comorbidities and the prognosis of older patients with NPC.
Nomograms have a wide application perspective for tumor prognosis prediction, providing a graphical depiction of a statistical model that combines independent prognostic factors to calculate the probability of survival [28]. Nomograms were found to be a better predictive method for prognostic assessment than the current AJCC staging system [29]. As a multivariate visualization tool, nomograms can simplify interpretation and aid clinicians in more effective individualized clinical decision-making. Furthermore, nomograms aim to overcome heterogeneity, as the same stage often has different clinical prognoses. We developed a 5-year OS nomogram for older patients with NPC. Comparing the AUC values of our nomogram with AJCC stages, we found that our nomogram was superior to AJCC for OS prediction. The calibration curves also obtained good results. These findings suggest the broad applicability of our nomogram.
Regarding toxicity, the RT-only group had a reduced incidence of neutropenia, anemia, vomiting, and nausea compared with the CRT group. Wen et al. [26] have highlighted that the IMRT group had lower treatment-related toxicity and no serious neutropenia or vomiting than the CRT group. Mi et al. have suggested that IMRT alone might provide lower toxicity, including severe neutropenia, nausea, and vomiting [16]. In the present study, IMRT significantly increased patient tolerability and reduced the severity of acute toxicity. The most common acute toxicity in both groups was mucositis, with a low dermatitis incidence consistent with recently reported results [30,31]. Due to their metabolic changes, older patients with NPC have more comorbidities and experience more severe treatment-related toxicity [27]. In addition, impaired organ function may affect the pharmacokinetics of chemotherapeutic drugs, hindering the prediction of related toxicity [32]. Vercelli et al. [33] have reported that increased toxicity was closely associated with poorer prognosis in older patients with cancer. For older patients with NPC over 65 years, especially those with poor physical conditions or multiple comorbidities, an IMRT-only regimen may be an alternative treatment option.
Furthermore, we analyzed the routine blood markers Hb and ALB as prognostic factors associated with OS in older patients with NPC receiving IMRT. Our study found no evidence that anemia or low ALB levels before treatment are independent factors impacting the OS of older patients with NPC. Anemia can reportedly lead to hypoxia in tumor tissues, which increases tumor tissue resistance to RT and is an independent predictor of poor overall survival for head and neck squamous cell carcinoma (HNSCC) during RT [34]. ALB is a vital nutritional index, and most patients with sarcopenia have hypoalbuminemia. Chargi et al. reported that approximately half of older patients with HNSCC exhibited sarcopenia, substantially influencing survival [35]. In addition, Alexander et al. have suggested that the baseline ALB concentration is a vital prognostic indicator for older patients with HNSCC undergoing chemoradiotherapy [36]. However, none of our studies suggested an impact on the prognosis of the older NPC. This inconsistency might be a result of a small sample size. The focus of the future is to identify potential biomarkers for prognosis in older NPC patients and to help select patients for treatment.
Some limitations of this study should be addressed. First, this study was based on retrospective data with some selection bias. However, we utilized real-world data and represented real-world conditions. Second, due to incomplete data on Epstein-Barr virus DNA concentration, a prognostic factor [37], our study did not address its prognostic relationship with survival. Third, the nomogram was not externally validated due to insufficient cases. In addition, our sample size was small, which may be attributed to the low incidence of NPC among older individuals and the fact that older patients with malignancies discontinued treatment owing to age. The survival of older patients with NPC could be further improved by utilizing tumor-targeted and immunotherapeutic drugs. Therefore, in the context of IMRT, the therapeutic modalities and prognostic factors for older patients with NPC warrant further investigation.