Prognostic nutritional index and serum lactate dehydrogenase predict the prognosis of nasopharyngeal carcinoma patients who received intensity-modulated radiation therapy

Introduction

Nasopharyngeal carcinoma (NPC) has a distinct geographical distribution. According to data published by the International Agency for Research on Cancer (IARC) in 2020, a total of 133,354 new cases of NPC were diagnosed globally in 2018, and it killed 80,008 people. NPC is most prevalent in Southeast Asia, South Asia, and North Africa (Sung et al 2021). In southern China, NPC is one of the most prevalent head and neck cancers, with both incidence and mortality rates higher than the global average. The prognosis of NPC has greatly improved due to the extensive utilization of intensity-modulated radiation therapy (IMRT) and the continuous optimization of chemotherapy strategies (Chen et al 2019). Nevertheless, approximately 10% of individuals still experience local or regional relapse after receiving IMRT or IMRT combined with chemotherapy, while about 15–30% of patients undergo distant metastasis after radical therapy (Co et al 2016; Zhang et al 2015) At present, the prognosis of NPC primarily relies on clinical staging. However, the prognosis of patients in the same stage is not always consistent. This may be because TNM staging primarily relies on anatomical features, such as local invasion and lymph node metastasis of the tumour, and does not account for the heterogeneity of tumour biology or differences in response to radiotherapy between patients (Chen et al 2019). Therefore, it is crucial to actively search for biological markers in clinical settings that can reflect the prognosis of NPC patients, guide personalized treatment, and improve their outcomes.

In recent years, there has been increasing focus on examining how the nutritional and immune status of individuals with cancer affects their prognosis. Derived from the concentration of serum albumin and the lymphocyte count in peripheral blood, the prognostic nutritional index (PNI) has proven valuable to assess the nutritional and immune condition of individuals with cancer (Onodera et al 1984). PNI is closely correlated with the prognosis of various types of malignant tumours, such as oesophageal cancer (Hao et al 2020), colorectal cancer (Luvián-Morales et al 2019), lung cancer (Zhang et al 2021) and gynaecological cancer (Lee et al 2023). Few studies have explored the association between PNI and the prognosis of NPC. The majority of these studies focused on 1–3 occurrences, and their findings were inconsistent (Duan et al 2021; Gundog et al. 2019; Jiang et al 2023; Wei et al 2016; Wu et al 2022).

Cancer cells preferentially metabolize glucose through glycolysis to produce energy (Hsu et al. 2008). After glycolysis, the conversion of pyruvate to lactate is primarily facilitated by lactate dehydrogenase (LDH), the most crucial enzyme for this process. Previous studies have suggested that LDH levels are an independent prognostic factor for various malignant tumours (Chen et al 2018; Namikawa et al 2019). In addition, serum LDH level has been incorporated into the TNM staging system for the prognostic assessment of melanoma (Balch et al 2009). One study linked higher LDH to poorer overall survival (OS) in individuals with NPC, although it did not independently predict progression-free survival (PFS) (Chen et al 2017b). Other research has indicated that elevated LDH can serve as an independent prognostic factor for OS and predict poorer distant metastasis-free survival (DMFS) and PFS (Long et al 2019; Oei et al 2018). Therefore, the impact of LDH on NPC prognosis requires further clarification.

LDH and the albumin and lymphocyte values used to calculate PNI are readily available, inexpensive to test, and routinely measured in clinical practice. Hence, we conducted this retrospective investigation on individuals diagnosed with NPC who underwent IMRT with or without chemotherapy. The objective was to assess the predictive significance of PNI and LDH for various survival outcomes in NPC patients.

Methods

Results

Discussion

As management techniques for NPC have advanced, prognostic prediction has become the focus of research. The assessment of NPC prognosis primarily relies on the TNM staging system, but patients at the same TNM stage have varied prognoses, so it is crucial to identify some biomarkers to distinguish high-risk patients and enhance the precision of the TNM staging system.

Here, we found that both pre-treatment PNI and LDH independently influenced the prognosis of OS, PFS, and DMFS in patients with NPC. Patients exhibiting both low PNI and high LDH experienced significantly poorer OS, PFS, and DMFS than other groups. The AUC values for predicting OS, PFS, and DMFS were higher for LDH-PNI than T category, N category, age, PNI, and LDH. Few studies have explored the association between PNI and the prognosis of NPC, And clinical staging in previous studies was mainly based on the 7th edition of the AJCC/UICC TNM system, a version of the staging system that is largely based on studies using 2D/3D conventional radiotherapy. In the era of IMRT, the survival rate of NPC has improved dramatically. Making it likely that TNM-7 edition is no longer applicable. the recently published 8th edition for NPC was derived primarily from a large study of patients treated with IMRT and incorporates the most recent clinical data(Pan et al. 2016b). The 8th edition of staging can better predict prognosis and guide treatment than the 7th edition (Yang et al 2018). Secondly, most of the previous studies examining the prognostic impact of either PNI or LDH have focused on only 1–3 occurrences. Only three studies have reported the prognostic value of PNI in LRRFS, two of which were from non-endemic areas and had small sample sizes (Gundog et al. 2019; Küçükarda et al 2022). The other was based on 7th edition staging and inconsistent radiotherapy techniques (Du et al 2015). None of the previous studies exploring the prognostic impact of LDH on NPC based on 8th edition included LRRFS as an outcome, and the results on the prognostic value of PFS were inconsistent (Chen et al 2017a; Long et al 2019; Oei et al 2018). Therefore, the prognostic impact of LDH on NPC needs to be further clarified. As far as we are aware, this research is the first investigation into the multiple prognostic implications of PNI-LDH for patients with NPC who received IMRT, accompanied or not by chemotherapy, following the guidelines of the current TNM-8 staging manual.

Studies on the association between PNI and prognosis in NPC can be traced back to 2015, when pre-treatment PNI was found to be an independent predictor of OS, DMFS, and PFS (Du et al 2015). Jiang et al (2023) carried out a retrospective study of 618 patients with locally advanced NPC and showed that the 5-year OS and PFS rates were considerably lower in the PNI ≤ 48.5 group than in the PNI > 48.5 group. He et al (2019) also found that PNI was an independent prognostic predictor for OS and PFS even among middle-aged and elderly patients with NPC. However, their study was based on the TNM-7 edition, while TNM-8 is now widely used. We conducted a retrospective evaluation of 810 patients diagnosed with NPC who underwent IMRT treatment, either with or without chemotherapy, and we restaged all eligible patients following the TNM-8 guidelines. We determined that the PNI cut-off value of 48.5 best distinguished patients by their prognosis. This value is consistent with those reported in previous studies (He et al 2019; Jiang et al 2023). We found a correlation between PNI and OS (P < 0.001), DMFS (P = 0.005), and PFS (P < 0.001) in non-metastatic NPC patients, again consistent with earlier results. Additionally, our analysis confirmed that PNI is not an independent associated factor for LRRFS. However, a study on the impact of PNI dynamics on NPC prognosis revealed that a pre-treatment PNI of ≤ 50.65 not only predicted a shorter OS but also had an independent association with poorer DMFS and LRRFS (Kucukarda et al 2022). Gundog and Basaran (2019) found that with a cut-off value of 45.45 for PNI, low PNI was independently linked to worse OS in patients with NPC, though it was not associated with DMFS or LRRFS. However, both of these studies were conducted in a non-endemic area of Turkey, and the sample size was small, so the findings may not apply to endemic areas.

Several mechanisms may explain why PNI reflects the prognosis of NPC. The PNI calculation formula is serum albumin (g/L) + 5 × lymphocyte count (× 10⁹/L), which takes into account the patient's nutritional status, immune function, and inflammatory response (Onodera et al 1984). A decrease in PNI may reflect a decrease in serum albumin or lymphocyte count. Serum albumin serves as an indicator for both the nutritional condition and systemic inflammation in cancer patients. Low serum albumin has been linked to malnutrition, systemic inflammation, and elevated pro-inflammatory cytokine concentrations (McMillan 2009; Zeng et al 2020).

A decline in PNI may indicate a reduction in serum albumin or lymphocyte count. Serum albumin reflects not only nutritional status in cancer patients but also systemic inflammation. Malnutrition predicts poor prognosis in NPC, as it can exacerbate the adverse effects of radiotherapy and chemotherapy, leading to reduced treatment intensity and even treatment interruption (Lu et al 2021; Mantzorou et al 2017; Shen et al 2013). In patients with malnutrition, impaired immunity affects treatment efficacy, reduces the sensitivity to radiotherapy and chemotherapy, and ultimately shortens survival (Miao et al 2017). Furthermore, inflammation has a significant role in malignant tumours, including causing DNA damage that leads to mutations, promoting tumour cell growth and survival, stimulating angiogenesis, enabling immune evasion, facilitating local and distant metastasis, and increasing tumour cell resistance to anticancer drugs, all of which ultimately contribute to reduced survival rates (Colotta et al 2009; Diakos et al 2014). Lymphocytes are a vital part of the immune response, and they can inhibit cancer cell growth and dissemination by inducing cytotoxic cell death and cytokine production. Various studies have revealed that a reduced lymphocyte count is linked to a worse prognosis in cancer patients (Hanahan et al. 2011). A reduction in lymphocyte numbers is therefore associated with a worse prognosis of cancer patients (Cai et al 2021; Mao et al 2023).

LDH plays a crucial role in glycolysis and could indicate the level of hypoxia in cancerous cells (Muz et al 2015). Increased serum LDH has been proposed as an indicator of immunosuppression in cancer patients. LDH can inhibit and circumvent the immune system by modifying the tumour microenvironment, suggesting that higher LDH is associated with tumour hypoxia, cancer progression and metastasis (Ding et al 2017). Several studies have demonstrated the importance of LDH levels in predicting the prognosis of patients with non-metastatic NPC. These two studies developed a prognostic nomogram showing that elevated LDH was linked to worse OS and PFS (Tang et al 2016; Zhang et al 2020). Oei et al (2018) discovered that high LDH before treatment, with a cut-off value of 168.5, served as an independent predictive indicator for OS (P = 0.001), PFS (P = 0.004), and DMFS (P = 0.001). The results remained consistent even after propensity score matching (Oei et al 2018). A study assessing the prognostic impact of dynamic LDH on NPC found that elevated LDH level, both before and after treatment, was linked to OS, disease-free survival (DFS) and DMFS, but not local recurrence-free survival (LRFS) (Zhou et al 2016). This is consistent with our results. In our study, we reassessed the TNM staging system and conducted a longer follow-up, finding that higher LDH levels were linked to poorer OS (P = 0.000), PFS (P < 0.001), and DMFS (P = 0.021) but had no correlation with LRRFS. It is known that IMRT reduces localized regional recurrence (Chen et al 2019). All patients in our study were treated with IMRT, It may be one of the most important reasons why the effect of LDH on LRRFS is masked. In addition, 29.6% of the patients in our study were in stage I-II, and the 5-year local recurrence rate of early-stage (stage I/II) nasopharyngeal cancer has been reported to be less than 5% (Wang et al 2022). Therefore, we hypothesized that the high percentage of early stage patients may also attenuate the effect of LDH on LRRFS.

According to their different levels of PNI and LDH, we divided the patients into three groups. We also categorized the patients into three groups based on their different levels of PNI and LDH. Individuals exhibiting low PNI and high LDH experienced notably worse OS, PFS, and DMFS than the other groups. Moreover, the AUC of LDH-PNI was higher than that of T category, N category, age, PNI and LDH. This suggests that the union of these two variables can enhance the prognostic prediction for non-metastatic NPC patients. Additionally, we examined alternative variables that could have an effect on the prognosis of patients. Age was a factor affecting OS (p < 0.001), PFS (p < 0.001), and DMFS (p < 0.003) in our analysis. Several studies have demonstrated that age is an independent risk factor for OS and PFS in non-metastatic NPC (He et al 2019; Jiang et al 2023). This may be due to the reduced activation and responsiveness of the immune system as one ages, which increases the risk of developing malignancies and infections (Dorshkind et al 2009; Frasca et al 2011). It is also theoretically possible that the progressive accumulation of cellular damage, reductions in organ function and weakening of immunity with age increase the risk of malnutrition and toxic effects associated with radiotherapy, leading to a poorer prognosis for patients with NPC.

This study has several limitations. Given that our study is a retrospective examination of patients in the same medical centre, there is a risk of selection bias. Prospective studies are needed to validate our results. In addition, EBV DNA is an important prognostic factor in NPC (Gihbid et al 2022; Liu et al 2022), but the Fujian Provincial Cancer Hospital did not start testing plasma EBV DNA in patients with NPC until 2015, so our study was unable to assess data on EBV DNA. Finally, we only studied pre-treatment levels of indicators, whereas the dynamic levels of these indicators may be more meaningful. In the future, prospective studies should gather data from various centres and from dynamic surveillance to confirm the impact of the combination of PNI and LDH in patients with non-metastatic NPC.

Conclusion

Our findings suggest that low pre-treatment PNI or high LDH is linked to significantly lower survival in patients with non-metastatic NPC. The combination of the two predicts prognosis better than PNI or LDH alone. PNI and LDH are cost-effective, simple to evaluate through laboratory tests, and commonly measured in clinical practice. Assessing pre-treatment PNI and LDH and combining them with the TNM staging system can help clinicians better predict patient survival and provide support for individualized treatment.

Author contributions

Conceptualization: ZWZ Data acquisition: YXF and YYR. and ZSD Data analysis: ML and SSY and SXX and YPZ Manuscript drafting: CXZ and ZWZ Manuscript revision, formal analysis: BJC All authors have reviewed and given their approval for the final manuscript.

Funding

This work was sponsored by National Clinical Key Specialty Construction Program and Key Clinical Specialty Discipline Construction Program of Fujian, China. This study was supported by grants from the National Clinical Key Specialty Construction Program; Fujian Provincial Clinical Research Center for Cancer Radiotherapy and Immunotherapy (grant number: 2020Y2012). This research was also supported by grant from the Fujian Provincial Natural Science Foundation of China (Grant No. 2023J011271), Fujian Provincial Health Technology Project (Grant No. 2021NA040) and Startup Fund for scientific research, Fujian Medical University (Grant No. 2022QH1153).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations