Combined pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts survival and prognosis in patients with non-metastatic nasopharyngeal carcinoma: a retrospective, multicenter clinical study

doi:10.21203/rs.3.rs-2946728/v1

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Research Article

Combined pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts survival and prognosis in patients with non-metastatic nasopharyngeal carcinoma: a retrospective, multicenter clinical study

https://doi.org/10.21203/rs.3.rs-2946728/v1

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published 30 Apr, 2024

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Background

Local recurrence and distant metastasis is the main cause of treatment failure in nasopharyngeal carcinoma (NPC). It is necessary to find a reliable, economical and convenient prognostic indicator to accurately predict the prognosis of NPC. The clinical significance of the combination of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) is unclear. This study investigated the predictive value of pretreatment NLR (pre-NLR) combined with pretreatment PLR (pre-PLR) for the survival and prognosis of NPC.

Methods

We retrospectively analyzed 765 patients with non-metastatic NPC. The NLR and PLR before treatment were examined. The pre-NLR-PLR scoring criteria and grouping were as follows: HRG, score of 2, high pre-NLR and high pre-PLR. MRG, score of 1, either high pre-NLR or high pre-PLR. LRG, score of 0, neither high pre-NLR nor high pre-PLR. We compared survival rates and factors affecting the prognosis among different groups. Receiver operating characteristic (ROC) curves were used to identify the cutoff-value and discriminant performance of the model.

Results

The ROC curve indicated a cut-off value of 3.29 for pre-NLR and 196.74 for pre-PLR. The 5-year overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of NPC patients in HRG were significantly poorer than those in MRG and LRG. The pre-NLR-PLR score was positively correlated with T stage, clinical stage, ECOG score and pathological classification. Multivariate cox regression analysis showed that pre-NLR-PLR scoring system, ECOG score and pre-ALB were independent risk factors affecting 5-year OS, 5-year LRFS and 5-year DMFS in NPC patients. Age, T stage, smoking history were independent risk factors for 5-year OS. Age, pathological type, smoking history were independent risk factors for 5-year LRFS. T stage and N stage were independent risk factors for 5-year DMFS. The ROC curve showed that area under the curve (AUC) values of pre-NLR-PLR of 5-year OS, LRFS and DMFS in NPC were higher than those of pre-NLR and pre-PLR.

Conclusions

pre-NLR-PLR is an independent risk factor for the prognosis of NPC. The pre-NLR-PLR scoring system can be used as an individualized clinical assessment tool to predict the prognosis of patients with non-metastatic NPC more accurately and easily.

Neutrophil-lymphocyte ratio

Platelet-lymphocyte ratio

survival

Prognosis

Non-metastatic nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) occurs all over the world, but there is an obvious regional high incidence phenomenon. Worldwide, NPC has a high incidence in China and Southeast Asian countries, followed by North Africa, while the incidence of NPC is extremely low in Europe, the United States, and Oceania [1]. In China, the incidence of NPC shows a trend of higher in the south and lower in the north, the provinces with high incidence are in the south and southwest of China, such as Guangdong, Guangxi, Hainan, Hong Kong, Macao and Jiangxi. The male to female incidence ratio of NPC is 2.5:1, and the peak age of incidence is 40–59 years old [2]. In recent years, with the development of intensity modulated radiotherapy (IMRT), and the improvement of comprehensive treatment level, the local control rate and survival rate of NPC have been significantly improved, the 5-year survival rate is more than 80% [3]. However, the distant metastasis control rate is still not very ideal, local recurrence and distant metastasis are the main causes of treatment failure in NPC. At present, TNM staging is widely used in the treatment decision and prognosis evaluation of NPC, but there are cases with the same clinical stage but different prognosis, which suggests that there may be tumor biological heterogeneity in NPC patients [4]. Therefore, it is of great significance to use scientific and reasonable means to find reliable and economical prognostic indicators or systems for more accurate prognostic evaluation of NPC.

Recent studies have found that inflammation plays an important role in the occurrence, proliferation, invasion and metastasis of tumors by regulating immunity and promoting angiogenesis, high expression of inflammatory factors is associated with poor prognosis [5]. Systemic inflammation, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and C-reactive protein (CRP), can be used as an independent prognostic biomarker for a variety of tumors [6–8]. Some studies have shown that NLR and PLR have an impact on the prognosis of NPC [9], but the results are still controversial. Consequently, based on the data of 765 patients with non-metastatic NPC, the aim of this study was to investigate the predictive value of pretreatment NLR (pre-NLR) combined with pretreatment PLR (pre-PLR) for the survival and prognosis of NPC.

Patients

We retrospectively analyzed 765 patients with non-distant metastatic NPC treated with IMRT in two hospitals from December 2014 to December 2017 (the First Affiliated Hospital of Guangxi Medical University, 748 patients; the First Affiliated Hospital of University of South China, 17 patients). All patients met the following inclusion criteria: (1) confirmed by histopathology as NPC; (2) there was no distant metastasis before and during treatment; (3) had not received any antitumor therapy before; (4) denied the history related to other malignancies; (5) Eastern Cooperative Oncology Group(ECOG) score 0 ~ 1; (6) received radiotherapy or concurrent chemoradiotherapy with / without induction or adjuvant chemotherapy, and completed the entire treatment as planned; (7) complete clinical data, examination data and follow-up data were available. Our exclusion criteria included: (1) distant metastasis was found or could not be ruled out before and during treatment; (2) complicated with severe infection, underlying diseases; (3) previous or concurrent history of other malignant tumors; (4) unable to complete the treatment.

The data of all NPC patients’ serum biomarkers and clinical characteristics were measured and collected within the two weeks before initiating treatment, including age, gender, pathological type, treatment regimen, smoking history, drinking history, ECOG score, radiotherapy technique and dose, chemotherapy regimen and dose, pretreatment (pre-) blood cell count (lymphocytes, neutrophils, monocytes, platelets, and white blood cells), pre-hemoglobin (pre-HGB), and pre-albumin (pre-ALB). We restaged all patients by the eighth edition of the AJCC/UICC TNM staging system. NLR was determined by dividing the absolute neutrophil count by the absolute lymphocyte count. PLR was determined by the absolute platelet count divided by the absolute lymphocyte count. The Ethics Committee at the First Affiliated Hospital of Guangxi Medical University approved the study, which analyzed anonymous information as well as waived the demand for informed consent (Approval Number: 2023-E207-01).

Therapeutic Schedule

In accordance with National Comprehensive Cancer Network (NCCN) guidelines, a standardized treatment plan was established according to the TNM stage of the patients. Stage Ⅰ patients received radical radiotherapy. Stage Ⅱ patients received radiotherapy or concurrent chemoradiotherapy combined with platinum drugs. Stage III-IVa patients received concurrent with induction chemotherapy or adjuvant chemotherapy. The patients were all treated with IMRT. The radiotherapy target areas of NPC include gross tumor volume of nasopharynx (GTVnx), metastatic cervical lymph node volume (GTVnd), Two clinical target volumes (CTV1 is high risk clinical target volume, CTV2 is low risk clinical target volume), GTV or CTV expansion of 3 to 5mm is the planned target volume (PTV). According to the nasopharyngeal primary focus, nasopharyngeal subclinical focus, cervical lymph node and cervical lymph drainage area, different prescription doses were given respectively. Prescription dosage of nasopharyngeal primary focus, PTV-GTVnx: DT68 ~ 76Gy/30 ~ 33f, PTV-CTV1: DT60 ~ 64Gy/30 ~ 33f, PTV-CTV2: DT50 ~ 54Gy/30 ~ 33f, Fractional dose: 2.00 ~ 2.33Gy/ time. The prescription dosage of cervical lymph node, PTV-GTVnd: DT66 ~ 70Gy/30 ~ 33f, PTV-CTV2: DT50 ~ 54Gy/30 ~ 33f. For tissue and organ limit dose, refer to QUANTEC (2012 standard). Induction or adjuvant chemotherapy mainly included GP regimen (gemcitabine 1000 mg/m² on days 1 and 8 + cisplatin 80 mg/m² on day 1), PF regimen (cisplatin 80 mg/m² on day 1 + 5-fluorouracil 800 ~ 1000 mg/m², continuous intravenous drip from day 1 to day 5), TPF regimen (docetaxel 60 mg/m² on day 1 + cisplatin 60 mg/m² on day 1 + 5-fluorouracil 600 mg/m², continuous intravenous drip from day 1 to day 5), and TP regimen (docetaxel 75 mg/m² on day 1 + cisplatin75 mg/m² on day 1), once every 3 weeks, for a total of 2 ~ 3 cycles. Concurrent chemotherapy regimen used cisplatin (80 ~ 100mg/m2) once every 3 weeks for 2 ~ 3 cycles, or cisplatin (30 ~ 40mg/m2) once a week for 5 ~ 6 cycles. For patients who were not suitable for cisplatin during chemotherapy, other platinum-based drugs were used instead.

Endpoint and Follow-Up

The primary endpoint of the study was overall survival (OS, defined as calculated from the start of treatment to the date of death from any cause). The secondary endpoints were locoregional relapse-free survival (LRFS, defined as calculated from the start of treatment to the date of recorded relapse in the local area) and distant metastasis free survival (DMFS, defined as calculated from the start of the first treatment to the date of recorded distant metastasis). Patients were followed up at least every 3 months for the first 2 years after completion of treatment and at least every 6 months for 2 to 5 years after completion of treatment, or until death. Efficacy evaluation was performed according to RECIST Version 1.1 of the Efficacy Evaluation Criteria for solid tumors. The follow-up period ended on August 30, 2022.

Statistical Analysis

SPSS version 26.0 (IBM Corporation, Armonk, NY, USA) and MedCalc 20.1 (MedCalc Software Ltd, Ostend, Belgium) were used for all statistical analyses. P < 0.05 was considered statistically significant.

We transformed continuous variables into categorical variables. The age was grouped into < 47, and ≥ 60 years old. According to the standard of anemia, pre-HGB was divided into < 120 g/L and ≥ 120 g/L[10]. According to previous studies, pre-ALB was divided into < 43g/L and ≥ 43g/L [11]. The general characteristics of patients were compared with frequency and descriptive statistics. A chi-square test or Fisher's exact test was used to compare the characteristics of patients in different groups. To determine the cut-off value of the research indicators based on 5-year OS, receiver operating characteristic (ROC) curves were used. Then, the research indicators were divided into high or low according to the cut-off value. The area under the curve (AUC) > 0.5 is considered to be a predictive value. To plot survival curves and compare survival among groups, Kaplan-Meier and Log rank tests were used. The factors with P < 0.1 were selected for multivariate analysis based on univariate cox regression analysis. The multivariate cox regression analysis showed independent risk factors for NPC with P < 0.05. A ROC analysis was performed to assess whether NPC prognosis could be accurately predicted by pre-NLR combined with pre-PLR.

General clinical features of patients and their correlation with NLR and PLR

A total of 765 patients were enrolled in this study, including 573 males and 192 females, with a median age of 47 years (12–81 years). Detailed general clinical characteristics were shown in Table 1.

Table 1

765 NPC patients with general clinical features and the correlation between pre-NLR and pre-PLR groups
Characteristics	Total (%)	pre-NLR (%)		p-Value	pre-PLR (%)		p-Value
Characteristics	Total (%)	Low(n = 484)	High(n = 281)	p-Value	Low(n = 446)	High(n = 319)	p-Value
Gender				0.548			0.007*
Male	573(74.9)	366(75.6)	207(73.7)		350(78.5)	223(69.9)
Female	192(25.1)	118(24.4)	74(26.3)		96(21.5)	96(30.1)
Age (years old)				0.870			0.325
< 47	370(48.4)	233(48.1)	137(48.8)		209(46.9)	161(50.5)
≥ 47	395(51.6)	251(51.9)	144(51.2)		237(53.1)	158(49.5)
8th T stage				0.002*			<0.001*
T1-2	133(17.4)	101(20.9)	32(11.4)		96(21.5)	37(11.6)
T3	308(40.2)	191(39.5)	117(41.6)		185(41.5)	123(38.6)
T4	324(42.4)	192(39.6)	132(47.0)		165(37.0)	159(49.8)
8th N stage				0.778			0.192
N0-N1	213(27.8)	139(28.7)	74(26.3)		126(28.3)	87(27.3)
N2	432(56.5)	270(55.8)	162(57.7)		259(58.1)	173(54.2)
N3	120(15.7)	75(15.5)	45(16.0)		61(13.6)	59(18.5)
8th Clinical stage				0.043*			<0.001*
I-II	37(4.8)	29(6.0)	8(2.8)		29(6.5)	8(2.5)
III	323(42.3)	212(43.8)	111(39.5)		210(47.1)	113(35.4)
IVa	405(52.9)	243(50.2)	162(57.7)		207(46.4)	198(62.1)
ECOG				0.004*			0.004*
0	566(74.0)	375(77.5)	191(68.0)		347(77.8)	219(68.7)
1	199(26.0)	109(22.5)	90(32.0)		99(22.2)	100(31.3)
Pathological type				<0.001*			0.008*
NKUC	743(97.1)	478(98.8)	265(94.3)		440(98.6)	303(95.0)
NKDC	14(1.8)	2(0.4)	12(4.3)		3(0.7)	11(3.4)
KSCC	8(1.1)	4(0.8)	4(1.4)		3(0.7)	5(1.6)
Smoking				0.232			0.124
No	516(67.5)	319(65.9)	197(70.1)		291(65.2)	225(70.5)
Yes	249(32.5)	165(34.1)	84(29.9)		155(34.8)	94(29.5)
Drinking				0.899			0.388
No	638(85.6)	415(85.7)	240(85.4)		386(86.5)	269(84.3)
Yes	110(14.4)	69(14.3)	41(14.6)		60(13.5)	50(15.7)
Treatment				0.812			0.105
IMRT	43(5.6)	29(6.0)	14(5.0)		28(6.3)	15(4.7)
CCRT	220(28.8)	137(28.3)	83(29.5)		139(31.2)	81(25.4)
CCRT + IC/AC	502(65.6)	318(65.7)	184(65.5)		279(62.5)	223(69.8)
pre-HGB				<0.001*			<0.001*
< 120g/L	212(27.7)	97(20.0)	115(40.9)		67(15.0)	145(45.5)
≥ 120g/L	553(72.3)	387(80.0)	166(59.1)		379(85.0)	174(54.5)
pre-ALB				0.002*			0.004*
< 43g/L	354(46.3)	203(41.9)	151(53.7)		187(41.9)	167(52.4)
≥ 43g/L	411(53.7)	281(58.1)	130(46.3)		259(58.1)	152(47.6)
* indicates a significant difference among groups with p < 0.05.
NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; ECOG, Eastern Cooperative Oncology Group; IMRT, intensity modulated radiotherapy; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; AC, adjuvant chemotherapy; NKUC, undifferentiated non-keratinizing carcinomas; NKDC, differentiated non-keratinizing carcinomas; KSCC, keratinizing squamous cell carcinoma; HGB, hemoglobin; ALB, albumin; pre, pretreatment.

The maximum approximate entry index was calculated according to the ROC curve (with patient death as the state variable), and the cut-off value was as follows: pre-NLR 3.29 (AUC 0.661, P < 0.001), pre-PLR 196.74 (AUC 0.651, P < 0.001), pre-NLR and pre-PLR were divided into high and low groups according to the cut-off value. 63.3% (484/765) of patients had pre-NLR < 3.29 (low grade group) and 36.7% (281/765) had pre-NLR ≥ 3.29 (high grade group). 58.3% (446/765) of patients had pre-PLR < 196.74 (low grade group) and 41.7% (319/765) had pre-PLR ≥ 196.74 (high grade group). T stage, clinical stage, ECOG score, pathological classification, pre-HGB, pre-ALB were correlated with the level of pre-NLR, and the difference was statistically significant. Gender, T stage, clinical stage, ECOG score, pathological classification, pre-HGB and pre-ALB were correlated with the level of pre-PLR, and the differences were statistically significant (Table 1).

Correlation analysis between general clinical features and pre-NLR-PLR score system

In order to analyze the prognostic value of pre-NLR combined with pre-PLR, the pre-NLR-PLR scoring system was established in this study. Patients were divided into low-risk group (LRG), medium-risk group (MRG) and high-risk group (HRG), pre-NLR-PLR scoring criteria and grouping were as follows: HRG (n = 224, 29.3%), score of 2, high pre-NLR (≥ 3.29) and high pre-PLR (≥ 196.74). MRG (n = 152, 19.9%), score of 1, either high pre-NLR or high pre-PLR. LRG (n = 389,50.8%), score of 0, neither high pre-NLR nor high pre-PLR. The correlation between different risk groups and the general clinical characteristics of patients was shown in Table 2. LRG and MRG had significant differences in T stage (P = 0.001), clinical stage (P < 0.001), and pre-HGB (P < 0.001). There were significant differences between LRG and HRG in T stage (P < 0.001), clinical stage (P = 0.002), ECOG score (P = 0.001), pathological classification (P = 0.001), pre-HGB (P < 0.001) and pre-ALB(P = 0.001). There was significant difference between MRG and HRG in pre-HGB (P < 0.001). There were no significant differences in LRG, MRG and HRG among different genders, ages, N stages, treatment methods, smoking and drinking history.

Table 2

Correlation between general clinical features and pre-NLR-PLR groups
Characteristics	LRG (%) (n = 389)	MRG (%) (n = 152)	HRG (%) (n = 224)	p-Value
Characteristics	LRG (%) (n = 389)	MRG (%) (n = 152)	HRG (%) (n = 224)	LRG vs. MRG	LRG vs. HRG	MRG vs. HRG
Gender				0.174	0.073	0.842
Male	303(77.9)	110(72.4)	160(71.4)
Female	86(22.1)	42(27.6)	64(28.6)
Age(years old)				0.712	0.463	0.357
< 47	186(47.8)	70(46.1)	114(50.9)
≥ 47	203(52.2)	82(53.9)	110(49.1)
8th T stage				0.001*	< 0.001*	0.504
T1-2	89(22.9)	19(12.5)	25(11.2)
T3	161(41.4)	54(35.5)	93(41.5)
T4	139(35.7)	79(52.0)	106(47.3)
8th N stage				0.035*	0.585	0.132
N0-N1	109(28.0)	47(30.9)	57(25.4)
N2	228(58.6)	73(48.0)	131(58.5)
N3	52(13.4)	32(21.1)	36(16.1)
8th Clinical stage				< 0.001*	0.002*	0.231
I-II	26(6.7)	6(3.9)	5(2.2)
III	187(48.1)	48(31.6)	88(39.3)
IVa	176(45.2)	98(64.5)	131(58.5)
ECOG				0.432	0.001*	0.065
0	304(78.1)	114(75.0)	148(66.1)
1	85(21.9)	38(25.0)	76(33.9)
Pathological type				1.000	0.001*	0.023*
NKUC	384(98.7)	150(98.6)	209(93.3)
NKDC	2(0.5)	1(0.7)	11(4.9)
KSCC	3(0.8)	1(0.7)	4(1.8)
Smoking				0.690	0.118	0.370
No	254(65.3)	102(67.1)	160(71.4)
Yes	135(34.7)	50(32.9)	64(28.6)
Drinking				0.357	0.638	0.651
No	337(86.6)	127(83.6)	191(85.3)
Yes	52(13.4)	25(16.4)	33(14.7)
Treatment				0.155	0.578	0.584
IMRT	26(6.7)	5(3.3)	12(5.4)
CCRT	118(30.3)	40(26.3)	62(27.7)
CCRT + IC/AC	245(63.0)	107(70.4)	150(66.9)
pre-HGB				< 0.001*	< 0.001*	< 0.001*
< 120g/L	60(15.4)	44(28.9)	108(48.2)
≥ 120g/L	329(84.6)	108(71.1)	116(51.8)
pre-ALB				0.042*	0.001*	0.444
< 43g/L	157(40.4)	76(50.0)	121(54.0)
≥ 43g/L	232(59.6)	76(50.0)	103(46.0)
* indicates a significant difference among groups with p < 0.05.
HRG, high risk group; MRG, medium risk group; LRG, low risk group.

Spearman rank correlation was used to analyze the correlation between patients' general characteristics and pre-NLR-PLR score. pre-NLR-PLR score was positively correlated with T stage, clinical stage, ECOG score and pathological classification (P < 0.001, P < 0.001, P = 0.002, P < 0.001, respectively). pre-NLR-PLR score was negatively correlated with pre-HGB and pre-ALB. The higher the pre-NLR-PLR score, the lower the pre-HGB and pre-ALB (P < 0.001, P = 0.001, respectively). There was no significant correlation between pre-NLR-PLR score and N stage (Table 3).

Table 3

Correlation analysis between clinical characteristics and pre-NLR-PLR
characteristics	pre-NLR-PLR
characteristics	r	p-Value
8th T stage	0.150	< 0.001*
8th N stage	0.036	0.316
8th Clinical stage	0.145	< 0.001*
ECOG	0.114	0.002*
Pathological type	0.127	< 0.001*
pre-HGB	-0.312	< 0.001*
pre-ALB	-0.123	0.001*
* indicates a significant difference among groups with p < 0.05.

Survival of Different Groups in pre-NLR-PLR scoring system

At a median follow-up of 75 months (IQR 1–96 months), a total of 20.4% (156/765) patients died during follow-up period, including 77.6% (121/156) of tumor-related death, and 22.4% (35/156) of other cause. Locoregional recurrence occurred in 79 patients (10.3%), distant metastasis occurred in 122 patients (15.9%), and both locoregional recurrence and distant metastasis occurred in 23 patients. Among the pre-NLR < 3.29 and pre-NLR ≥ 3.29 groups, five-year OS were 88.0% and 70.8%, LRRFS were 94.4% and 83.6%, DMFS were 89.0% and 78.6%, respectively. Among the pre-PLR < 196.74 and pre-PLR ≥ 196.74 groups, five-year OS were 88.1% and 72.7%, LRRFS were 94.32% and 85.3%, DMFS were 89.2% and 79.6%, respectively. Among the LRG, MRG and HRG groups, five-year OS were 88.4%, 86.2% and 67.0%, LRRFS were 94.6%, 92.8% and 81.7%, DMFS were 88.9%, 90.1% and 75.4%, respectively. The K-M survival curves of those groups were show in Figs. 1 and 2.

Univariate and Multivariate Analysis of Prognostic Factors for NPC

As shown in Table 4, according to univariate cox regression analysis, a number of variables associated with 5-year OS, including age, T stage, N stage, clinical stage, ECOG, pathological type, smoking history, pre-HGB, pre-ALB and pre-NLR-PLR. Variables associated with 5-year LRFS included age, N stage, ECOG, pathological type, smoking history, pre-ALB and pre-NLR-PLR. Age, T stage, N stage, clinical stage, ECOG, pathological type, pre-HGB, pre-ALB and pre-NLR-PLR were the variables associated with 5-year DMFS.

Table 4

Univariate analysis of prognostic factors in NPC patients
Characteristics	5-year OS		5-year LRFS			5-year DMFS
Characteristics	HR (95%CI)	p-Value	HR (95%CI)	p-Value		HR (95%CI)		p-Value
Gender
Male	Reference		Reference			Reference
Female	1.319(0.877–1.986)	0.184	0.737(0.410–1.325)		0.308	0.703(0.441–1.120)	0.138
Age(years old)
< 47	Reference		Reference			Reference
≥ 47	2.201(1.541–3.146)	< 0.001*	2.153(1.297–3.572)		0.003*	1.405(0.966–2.042)	0.075*
8th T stage
T1-2	Reference		Reference			Reference
T3	2.514(1.322–4.781)	0.005*	1.555(0.707–3.424)		0.273	2.975(1.412–6.270)	0.004*
T4	2.800(1.482–5.291)	0.002*	1.898 (0.879-4.100)		0.103	3.050(1.451–6.408)	0.003*
8th N stage
N0-N1	Reference		Reference			Reference
N2	1.626(1.047–2.524)	0.030*	1.434(0.780–2.636)		0.246	1.264(0.787–2.029)	0.332
N3	2.165(1.280–3.660)	0.004*	2.003(0.967–4.149)		0.062*	2.287(1.331–3.928)	0.003*
8th Clinical stage
I-II	Reference		Reference			Reference
III	1.899(0.592–6.098)	0.281	1.367(0.322–5.799)		0.671	2.282(0.551–9.459)	0.255
IVa	2.935(0.929–9.273)	0.067*	2.184(0.530–9.011)		0.280	3.670(0.901–14.954)	0.070*
ECOG
0	Reference		Reference			Reference
1	11.692(7.964–17.165)	< 0.001*	7.944(4.803–13.140)		< 0.001*	7.785(5.258–11.525)	< 0.001*
Pathological type
NKUC	Reference		Reference			Reference
NKDC	3.514(1.641–7.524)	0.001*	3.113(0.977–9.924)		0.055*	3.766(1.653–8.582)	0.002*
KSCC	3.597(1.329–9.736)	0.012*	5.375(1.686–17.132)		0.004*	3.108 (0.986–9.799)	0.053*
Smoking
No	Reference		Reference			Reference
Yes	1.515(1.083–2.121)	0.015*	1.560 (0.967–2.515)		0.068*	1.156(0.786-1.700)	0.461
Drinking
No	Reference		Reference			Reference
Yes	1.283(0.827–1.991)	0.267	1.293(0.694–2.410)		0.418	1.236(0.755–2.024)	0.400
Treatment
IMRT	Reference		Reference			Reference
CCRT	0.620(0.324–1.183)	0.147	1.454(0.436–4.842)		0.542	0.640(0.305–1.344)	0.239
CCRT + IC/AC	0.633(0.347–1.157)	0.138	1.204(0.374–3.882)		0.756	0.676(0.338–1.351)	0.268
pre-HGB
< 120g/L	Reference		Reference			Reference
≥ 120g/L	0.701(0.495–0.994)	0.046*	0.892(0.530–1.501)		0.668	0.691(0.469–1.018)	0.062*
pre-ALB
< 43g/L	Reference		Reference			Reference
≥ 43g/L	0.488(0.347–0.686)	< 0.001*	0.397(0.240–0.654)		< 0.001*	0.530(0.364–0.773)	0.001*
pre-NLR-PLR
LRG (0 point)	Reference		Reference			Reference
MRG (1 point)	1.196(0.712–2.007)	0.499	1.489(0.709–3.129)		0.294	0.895(0.497–1.611)	0.711
HRG (2 point)	3.203(2.211–4.640)	< 0.001*	4.073(2.353–7.052)		< 0.001*	2.544(1.706–3.792)	< 0.001*
* indicates statistically significant with p < 0.1.
HR, hazard ratio; CI, confidence interval.

Subsequently, multivariate cox regression analysis was conducted for the above variables. Variables for inclusion were carefully chosen, given the number of events available, to ensure parsimony of the final model. For example, because the clinical stage was determined by stage T and stage N, we did not include it in the multivariate analysis. Analysis showed that pre-NLR-PLR scoring system, ECOG and pre-ALB were independent risk factors affecting 5-year OS, 5-year LRFS and 5-year DMFS in NPC patients. Among them, Patients with pre-NLR-PLR score of 2 (HRG) were 2.208 times more likely to die within 5 years than those with score of 0 (LRG) (p < 0.001), the risk of local recurrence was 3.106 times more likely than those with LRG (p < 0.001), and the risk of distant metastasis was 1.727 times greater than that of LRG (p = 0.012). In addition, age, T stage, and smoking history were independent risk factors for 5-year OS in NPC patients. Age, pathological type, and smoking history were independent risk factors for 5-year LRFS. T stage and N stage were independent risk factors for DMFS at 5 years (Table 5).

Table 5

Multivariable analysis of prognostic factors in NPC patients
Characteristics	5-year OS		5-year LRFS		5-year DMFS
Characteristics	HR (95%CI)	p-Value	HR (95%CI)	p-Value	HR (95%CI)	p-Value
Age (years old)
< 47	Reference		Reference		Reference
≥ 47	1.757(1.222–2.527)	0.002*	1.772(1.061–2.959)	0.029*	1.115(0.760–1.637)	0.578
8th T stage
T1-2	Reference		Reference		Reference
T3	1.769(0.914–3.425)	0.090	1.067(0.473–2.407)	0.876	2.574(1.203–5.509)	0.015*
T4	1.961(1.023–3.759)	0.042*	1.256 (0.570–2.763)	0.572	2.610(1.220–5.581)	0.013*
8th N stage
N0-N1	Reference		Reference		Reference
N2	1.328(0.840–2.100)	0.225	1.212(0.642–2.287)	0.553	1.102(0.679–1.789)	0.693
N3	1.680(0.973–2.901)	0.063	1.495(0.701–3.187)	0.298	1.967(1.126–3.435)	0.017*
ECOG
0	Reference		Reference		Reference
1	9.847(6.645–14.572)	< 0.001*	6.916(4.126–11.591)	< 0.001*	6.854(4.589–10.237)	< 0.001*
Pathological type
NKUC	Reference		Reference		Reference
NKDC	1.540(0.692–3.425)	0.290	1.169(0.352–3.881)	0.798	1.850(0.772–4.435)	0.168
KSCC	2.763(0.999–7.641)	0.050	3.925(1.197–12.871)	0.024*	2.525 (0.788–8.091)	0.119
Smoking
No	Reference		Reference		-	-
Yes	1.568(1.109–2.216)	0.011*	1.644 (1.006–2.687)	0.047*	-	-
pre-HGB
< 120g/L	Reference		-	-	Reference
≥ 120g/L	1.096 (0.747–1.610)	0.638	-	-	1.123(0.730–1.726)	0.597
pre-ALB
< 43g/L	Reference		Reference		Reference
≥ 43g/L	0.570(0.394–0.823)	0.003*	0.484(0.289–0.811)	0.006*	0.613(0.409–0.920)	0.018*
pre-NLR-PLR
LRG (0 point)	Reference		Reference		Reference
MRG (1 point)	0.959(0.567–1.622)	0.875	1.198(0.563–2.552)	0.639	0.690(0.381–1.251)	0.222
HRG (2 point)	2.208(1.493–3.266)	< 0.001*	3.106(1.763–5.473)	< 0.001*	1.727(1.128–2.642)	0.012*
* indicates a significant difference among groups with p < 0.05.

Prognostic performance of pre-NLR-PLR scoring system

According to ROC curve analysis, it was concluded that the AUC values of pre-NLR-PLR of 5-year OS, LRFS and DMFS in NPC patients were higher than those of pre-NLR and pre-PLR. Among them, the difference of the AUC values of pre-NLR-PLR and pre-PLR in 5-year OS and 5-year LRFS was statistically significant, but not in 5-year DMFS. There was no statistical significance in the AUC values of 5-year OS, LRFS and DMFS between pre-NLR-PLR and pre-NLR (Table 6).

Table 6

Comparison of ROC curves of pre-NLR-PLR, pre-NLR and pre-PLR
Prognostic factors	5-year OS		5-year LRFS		5-year DMFS
Prognostic factors	AUC	p-Value	AUC	p-Value	AUC	p-Value
pre-NLR-PLR	0.652	N/A	0.664	N/A	0.609	N/A
pre-NLR	0.634	0.089 ^a	0.649	0.272 ^a	0.596	0.253 ^a
pre-PLR	0.625	0.008^b*	0.629	0.013^b*	0.593	0.121 ^b
^a Comparison between pre-NLR-PLR and pre-NLR.
^b Comparison between pre-NLR-PLR and pre-PLR.
* indicates a significant difference among groups with p < 0.05.

With the wide application of IMRT and the introduction of comprehensive treatment modalities such as chemoradiotherapy combined with immunotherapy and targeted therapy, the local control rate of NPC patients has been significantly improved, and the 5-year overall survival rate has reached more than 80% [2, 12–13]. In spite of this, local recurrence and distant metastasis still remain the leading cause of NPC treatment failure, accounting for about 70% of NPC specific deaths [14]. At present, the prognosis of NPC patients still depends on TNM staging system [15]. Nevertheless, although patients have the same clinical stage and receive the same treatment, there are still different treatment effects, which may be due to tumor heterogeneity, immune and inflammatory responses. TNM staging system is based on imaging and anatomy, and does not take into account the biological diversity of the tumor, so the stratified prognosis cannot be satisfactorily evaluated. Some scholars [16] proposed to use molecular genetic biomarkers, such as mRNA, as new prognostic predictors. However, the detection process of these markers is complicated and the detection cost is high. Many technologies are limited to the laboratory and cannot be promoted clinically.

Inflammation and immune response are involved in the occurrence and development of tumor, including initiation, promotion and metastasis [17], Since the first reported by Virchow in 1863 [18], There is growing evidence that inflammatory responses play a key role in tumor development and show independent prognostic value, Some examples include NLR[5, 17, 19], LMR[20], PLR[21], etc. Studies have shown that malignant tumors induce a systemic inflammatory response through the release of cytokines and chemokines, which can be manifested by elevated neutrophils and platelet counts and decreased lymphocytes [22]. CHEN CJ et al. [23] found in their study on the prognosis of 299 patients with limits-stage small cell lung cancer after surgery that the high levels of preoperative NLR and PLR indicated poor prognosis of patients with limits-stage small cell lung cancer after surgery, and the detection was simple, fast, and low-cost, which could be used as a reference for initial screening of patients who would benefit from immunotherapy. Previous studies have shown that NLR and PLR are associated with the prognosis of NPC [24–25]. However, no comprehensive evaluation of the relationship between the combination of NLR and PLR and the prognosis of NPC patients has been reported. Therefore, based on the current research results that both NLR and PLR have an impact on the prognosis of NPC, our study combined these two hematological parameters and established pre-NLR-PLR scoring system, divided the NPC patients into groups according to different scores, investigated the correlation between hematological parameters and clinical characteristics, survival and prognosis of patients with NPC. In addition, in this study, NLR, PLR and other indicators closely related to OS, LRFS, and DMFS were detected only by peripheral blood of patients with NPC, the method was simple, effective, reproducible, and practical.

The level of NLR is closely related to the occurrence and development of tumor. It is speculated that the mechanism may be as follows: (1) neutrophils affect tumor microenvironment by releasing matrix metalloproteinase-9, vascular endothelial growth factor and other factors, promoting tumor neovascularization, and promoting tumor occurrence and development [26]; (2) neutrophils promote tumor movement and migration by releasing enzymes, and promote tumor invasion and metastasis; (3) the rise of neutrophils can inhibit the immune cell activity of lymphocytes, natural killer cells and activated T cells, thus reducing the immunity of the body; (4) as the main members of tumor immunity, lymphocytes are involved in cell destruction and apoptosis. Lymphocytes such as CD4 + and CD8 + T cells can induce tumor cell apoptosis and inhibit tumor progression through immune-mediated cytotoxic activity [27]. In this study, pre-NLR was related to T stage, clinical stage, ECOG, pathological type, pre-HGB and pre-ALB of patients with NPC, which was similar to the conclusions of previous studies [28–29]. In addition, in this study, 5-year OS, LRFS and DMFS of NPC patients with pre-NLR ≥ 3.29 were significantly lower than those with pre-PLR < 3.29, indicating that pre-NLR is a risk factor for survival and prognosis of NPC, high pre-PLR indicates poor prognosis.

Tumor growth requires abundant blood supply, platelets can promote angiogenesis and release growth factors, tumor cells mediate platelet aggregation, leading to the body in a hypercoagulable state. Platelet aggregation around tumor cells can protect them from NK cell killing, regulate the process of tumor micrometastasis by activating TGF-β signal transduction pathway, and promote tumor cell exosmosis [30–31]. Studies have shown that PLR, as an indicator of the combination of platelet count and lymphocyte count in the body, can reflect not only the tumor-promoting state and inflammatory response in the body, but also the anti-tumor immune state. SUN et al. [32] found that PLR is a prognostic factor affecting PFS and OS in non-metastatic NPC, while some studies [33–36] believed that PLR is not significantly correlated with survival and prognosis of NPC, which may be attributed to tumor heterogeneity. In this study, pre-PLR was related to the gender, T stage, clinical stage, ECOG, pathological type, pre-HGB and pre-ALB of patients with NPC, which was consistent with the conclusion of JIANG et al. [31] who studied 247 patients with NPC who received IMRT. In addition, 5-year OS, LRFS and DMFS of NPC patients with pre-PLR ≥ 196.74 were significantly lower than those with pre-PLR < 196.74, indicating that pre-PLR is a risk factor for survival and prognosis of NPC, high pre-PLR indicates poor prognosis.

It is one-sided to rely solely on TNM staging and NLR or PLR to assess the prognosis. Therefore, this study combined these two hematological indicators to establish the pre-NLR-PLR scoring system innovatively. When comparing the baseline characteristics of patients, significant differences were found in T stage, N stage, clinical stage, ECOG, pathological type, pre-HGB and pre-ALB among different groups of patients. Survival analysis showed that 5-year OS, LRFS, and DMFS in HRG patients were significantly worse than those in MRG and LRG. Multivariate analysis showed that pre-NLR-PLR scoring system was an independent prognostic factor for NPC patients. Patients with pre-NLR-PLR score of 2 (HRG) were 2.208 times more likely to die within 5 years than those with score of 0 (LRG) (HR: 2.208, 95% CI: 1.493–3.266, p < 0.001), the risk of local recurrence was 3.106 times more likely than those with LRG (HR: 3.106, 95% CI: 1.763–5.473, p < 0.001), and the risk of distant metastasis was 1.727 times greater than that of LRG (HR: 1.727, 95% CI: 1.128–2.642, p = 0.012). However, there was no significant difference in prognosis between MRG and LRG. This result seems to be inconsistent with previous studies, which may suggest that high pre-NLR or high pre-PLR alone is inferior to high pre-NLR and high pre-PLR in predicting the prognosis of patients with NPC. In ROC curve analysis, the AUC values of pre-NLR-PLR scoring system on OS, LRFS and DMFS in 5 years were higher than those of pre-NLR and pre-PLR, which also indicated that pre-NLR-PLR scoring system had certain advantages in predicting the prognosis of patients with NPC.

These results may suggest that the pre-NLR-PLR scoring system can discriminate patients with better prognosis after treatment from all patients, compared with pre-NLR or pre-PLR alone, and the pre-NLR-PLR scoring system is a potentially useful prognostic predictor that can be assessed before treatment. Those would be the greatest advantage of the pre-NLR-PLR score. In addition, the pre-NLR-PLR score can be easily determined by calculating the NLR and PLR with a small volume of blood (only 2 ml). Thus, assessment of the pre-NLR-PLR score is inexpensive.

To be honest, our study also has some limitations. This study is a retrospective study, and all eligible patients have different treatment methods according to the choice of the doctors in charge, including chemotherapy regimen, chemotherapy cycle and drug dosage, which may affect the results of the study. In addition, some sample sizes are small, such as NKDC and KSCC, which may also affect the results of the study. In the future, it is necessary to expand the sample size, further improve the classification of various clinical factors, control other factors that may affect the results, find and include more factors that may affect the outcome and prognosis, and explore a more perfect scoring system for better application in clinical diagnosis and treatment.

In summary, we established the pre-NLR-PLR scoring system innovatively, which is an independent risk factor for the prognosis of NPC. NPC patients with high pre-PLR and high pre-NLR have poor prognosis. The pre-NLR-PLR scoring system can be used as an individualized clinical assessment tool to predict the prognosis of patients with non-metastatic NPC more accurately and easily.

NPC, nasopharyngeal carcinoma; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; IMRT, intensity modulated radiotherapy; OS, overall survival; LRFS, local recurrence-free survival; DMFS, distant metastasis-free survival; ROC, receiver operating characteristic; AUC, area under the curve; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; AC, adjuvant chemotherapy; HRG, high risk group; MRG, medium risk group; LRG, low risk group; NKUC, undifferentiated non-keratinizing carcinomas; NKDC, differentiated non-keratinizing carcinomas; KSCC, keratinizing squamous cell carcinoma; HGB, hemoglobin; ALB, albumin; HR, hazard ratio; CI, confidence interval.

Ethics approval and consent to participate

This study was conducted in accordance with the Helsinki Declaration and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. Participant information is confidential. The need for informed consent was waived by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. (Approval Number: 2023-E207-01)

Consent for publication

Not applicable.

Availability of data and materials

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

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82272736,81460460,81760542)，the Research Foundation of the Science and Technology Department of Guangxi Province, China (grant No. 2022JJD140115, 2016GXNSFAA380252, 2018AB61001 and 2014GXNSFBA118114), the Research Foundation of the Health Department of Guangxi Province, China (No.S2018087), the Scientific Research Project of Hunan Provincial Health Commission (No. 202215014474), the Teaching Reform Research Project of the University of South China (No. 2020YB-XJG94), Guangxi Medical University Training Program for Distinguished Young Scholars (2017), Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University(2016).Guangxi Medical High-level Talents Training Program. The central government guide local science and technology development projects (ZY18057006).

Authors' contributions

D.Y. conceived the original idea and wrote the proposal. M.K. and D.Y. designed the study. M.K., D.Y., Y.L., P.L., Z.M., X.H., Z.H., H.H., H.D., Y.Q., C.C., X.C., Z.L., Z.Z. organized the data collection and analyzed the data. M.K., D.Y. and Y.L. performed the statistical analysis and wrote the manuscript for publication. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Authors' information

¹Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China. ² Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. ³ Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning 530021, Guangxi, China. ⁴ Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi, China. ⁵ Department of Obstetrics and Gynecology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. ⁶ Department of Oncology, Langdong Hospital of Guangxi Medical University, Nanning 530028, Guangxi, China. ⁷ Department of Clinical Laboratory Medicine, Institution of microbiology and infectious diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang421001, Hunan, China.

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Combined pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts survival and prognosis in patients with non-metastatic nasopharyngeal carcinoma: a retrospective, multicenter clinical study

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