The findings in this study indicate that PNI and weight loss are associated with tumor progression, metastasis and long-term mortality in patients with NPC. Moreover, higher pre-therapy BMI, white blood cell count, serum globulin level, female gender, chemotherapy, and advanced stage disease were predictive of greater weight loss during treatment.
PNI is calculated from albumin concentration and lymphocyte count. Serum albumin is known to correlate with systemic inflammation through high levels of pro-inflammatory cytokines. Albumin may help to stabilize cell growth and DNA replication, buffer a variety of biochemical changes, and maintain sex hormone homeostasis to protect against cancers . Growing numbers of studies have demonstrated associations between a low serum albumin level and an increased severity of disease, a high risk of disease progression and poor survival in cancer patients . Lymphocytes are crucial components of adaptive immune system, which is always suppressed in tumours through several pathways, including inhibition of dendritic cell differentiation and activation, infiltration of regulatory T cells and tumour-associated macrophages [7, 8, 29]. Infiltrating lymphocytes have been reported to represent an effective antitumour cellular immune response. A low peripheral lymphocyte level may indicate a poor lymphocyte-mediated immune response to tumour and suggest a poor prognosis . Previous studies have shown that a high lymphocyte count was associated with improved clinical outcome in rectal cancer  and pancreatic ductal adenocarcinoma . High peripheral lymphocyte percentage was also demonstrated to be associated with a long survival of patients with NPC .
Consistent with our results for NPC, the prognostic value of PNI has been validated in other tumors in several published studies, including pancreatic cancer , gastric carcinoma, esophageal carcinoma , malignant pleural mesothelioma , hepatocellular carcinoma [15, 16], colorectal cancer , and renal cell cancer . To the best of our knowledge, this is the first study to specifically focus on the predictive value of PNI in NPC. In the present study, it would appear that PNI is superior to other systemic inflammation-based factors, in particular, the white blood cell count, NLR and PLR, in predicting survival in NPC.
Another prognostic factor for metastasis and mortality in NPC that we identified in this study is serum globulin. High levels of globulins are attributable to increased accumulation of acute-phase proteins and immunoglobulins, as well as other serum proteins, and all these changes are reflective of an inflammatory state. Besides, elevated levels of serum alkaline phosphatase have been reported to predict disease progression and poor outcome in some malignancies, including NPC . It was considered as an indicator of distant micrometastases in other organs such as bone .
Another factor that this study examined was weight loss, which has been shown to affect the clinical outcome in NPC patients. Ng et al. reported that the mean percentage weight loss during radiotherapy in 38 patients with NPC from Hong Kong was 10.8 %, and that 55 % of the patients experienced ≥10 % weight loss by the end of the treatment . Qiu et al. conducted a prospective study of 159 patients with NPC and observed a median weight loss of 6.9 kg (range 2.1–12.6 kg) . Oates et al. reported that the median weight loss during concurrent chemoradiotherapy in 14 patients with NPC was 8.2 kg (range 2.3–13.9 kg), which represented a percentage weight loss range of 4–17 % . Further, Shen et al. conducted a retrospective study in 2433 NPC patients and reported that high weight loss during radiotherapy (weight loss ≥5 %) was indepentently associated with poor survival . In the present study, we evaluated weight loss during the entire treatment procedure and found that high weight loss (weight loss ≥10 %) was still a predictor of metastasis and survival.
We speculate that there are three possible reasons why weight loss significantly associates with mortality. First, percentage weight loss is a commonly used tool in assessment of recently developed malnutrition. Malnutrition can weaken a number of human defense mechanisms, including anatomic barriers, cellular and humoral immunity, and phagocyte function [5–7], thus promoting susceptibility to infection and further compromising the response to malignancy. Second, weight loss may cause treatment interruption and decrease treatment tolerance, thus affecting therapeutic efficacy . Additionally, weight loss is also an indicator of systemic inflammatory response, that encompasses a variety of physiologic alterations facilitating tumour development, invasion, and metastasis [5, 8].
Weight loss during NPC treatment is partially due to oral mucositis induced by radiotherapy and chemotherapy. Oral mucositis is considered to be the most important acute side effect in almost all patients undergoing radiotherapy of the head and neck . The oral lesions may cause dysphagia with solid and liquid food, dysarthria and odynophagia, and thus directly reduce food intake. Effective management of oral mucositis may minimize the symptoms, improve the nutritional status, allow for more effective cancer treatment and improve patient survival .
Many factors affect weight loss in cancer patients. Consistent with the findings of Qiu et al. , we observed that high weight loss was associated with heavier tumor burden and chemotherapy. Patients treated with chemotherapy are more likely to have advanced stage disease. Despite the encouraging results achieved by multimodal therapy in terms of tumor control, aggressive chemoradiotherapy can lead to more serious acute toxicities, which directly impact the ability to eat . We also found that female patients were more likely to experience high weight loss than males. Similar findings have been reported in head and neck cancer . Further, a recent study showed that female patients with NPC tended to experience anxiety before treatment, lacked a positive coping mode, and experienced poor quality of life after radiotherapy . We speculated that poorer treatment compliance and tolerance among female patients may account for their greater weight loss. In the present study, higher pre-therapy BMI was associated with higher weight loss in NPC, which has also been reported by Qiu et al. . A patient with a higher pre-therapy BMI might have more weight to lose and show strong resistance to malnutrition. Furthermore, a high white blood cell count and high serum globulin concentration were shown to be predictors of high weight loss. In keeping with our results, there is good consistent evidence that the presence of systemic inflammatory response is associated with increased weight loss, elevated resting energy expenditure, loss of lean tissue and functional decline . These findings may suggest the effectiveness of anti-inflammatory therapy in weight loss in cancer patients.
There are some limitations to the current study. First, the data were retrospectively analyzed. Second, PNI was only assessed at a single time point before the treatment. Thus, the relationship between the kinetics of PNI and its prognostic effect in NPC would be of considerable interest. Third, there were no standard criteria for nutritional support in patients undergoing oncotherapy during the time period of the study. Therefore, insufficient information on food intake and nutritional status during the treatment is available for further analysis of weight loss.