
==== Front
J Cancer Res Clin Oncol
J Cancer Res Clin Oncol
Journal of Cancer Research and Clinical Oncology
0171-5216
1432-1335
Springer Berlin Heidelberg Berlin/Heidelberg

5762
10.1007/s00432-024-05762-x
Research
Effects of concurrent chemoradiotherapy with or without Endostar on the regression of retropharyngeal lymph node and prognosis of patients with locally advanced nasopharyngeal carcinoma: a retrospective study
Song Jun-Mei 123
Mo Ning 13
Lv Yu-Qing 13
Huang Lu-Lu 13
Wen Ya-Jing 4
Liu Ting 13
Li Zhi-Ru 13
Wang Ren-Sheng 13807806008@163.com

1
Zhang Ting-Ting ztt8711@163.com

1
1 https://ror.org/030sc3x20 grid.412594.f Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi China
2 grid.452642.3 Oncology Department, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, 637000 Sichuan China
3 grid.256607.0 0000 0004 1798 2653 Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021 China
4 grid.416466.7 0000 0004 1757 959X Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 China
4 5 2024
4 5 2024
2024
150 5 2322 2 2024
23 4 2024
© The Author(s) 2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background and Purpose

To investigate the effect of combining Endostar with concurrent chemoradiotherapy (ECCRT) compared to concurrent chemoradiotherapy (CCRT) on the regression rate of retropharyngeal lymph nodes (RLNs) and the relationship between regression rate of RLNs and prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC).

Methods

A total of 122 LANPC patients with RLNs metastasis were included. Metastatic RLNs were delineated both before and after treatment slice by slice on the magnetic resonance images cross-section. The regression rate of RLNs, adverse effects (AE) were evaluated. The median regression rate of RLNs was taken as the cut-off value, and the patients were furtherly divided into high regression rate (HRR) group and low regression rate (LRR) group, then survival times were evaluated.

Results

The median regression rates of RLNs in the ECCRT and CCRT groups were 81% and 50%, respectively (P < 0.001). There was no statistically significant difference in the incidence of grade 3/4 AEs between the two groups, except for oral mucositis (ECCRT 26.23% vs. CCRT 44.26%, P = 0.037). The 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional failure-free survival (LRFFS) rates in the HRR and LRR groups were 85.48% and 86.67% (P = 0.983), 80.65% and 68.33% (P = 0.037), 83.87% and 85% (P = 0.704), 93.55% and 81.67% (P = 0.033), respectively.

Conclusions

Patients in the ECCRT group had higher regression rates of RLNs and lower incidence of severe oral mucositis. Furthermore, patients in the HRR group had a better 3-year PFS and LRFFS rate than those in the LRR group.

Keywords

Locally advanced nasopharyngeal carcinoma
Endostar
Retropharyngeal lymph nodes
Prognosis
Project of Bureau of Science & Technology Nanchong City20SXQT0257 Song Jun-Mei Major project of Sichuan Science and Technology Departmen2023YFS0473 Song Jun-Mei National Natural Science Foundation of China82060019 Wang Ren-Sheng “Medical Excellence Award” Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University202309 Zhang Ting-Ting issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Nasopharyngeal carcinoma (NPC) has a high prevalence in southern China and is often accompanied by lymph node metastasis. A considerable portion (ranging from 66.2% to 86.3%) of NPC patients were initially diagnosed with metastatic retropharyngeal lymph nodes (RLNs) (Huang et al. 2019; Chen et al. 2022). The RLNs and the level II lymph nodes seem to be the first lymph nodes of nasopharyngeal carcinoma metastasis (Liu et al. 2006; Ho et al. 2012; Wang et al. 2015). The presence of RLNs metastasis in NPC patients was recognized as a main negative prognostic factor (Coskun et al. 2011; Ma et al. 2007). Regional failure has been reported in 6.2–7.7% of patients with NPC after treatment (Kim et al. 2022; Li et al. 2017; Xue et al. 2017). Among NPC patients with local recurrence, 43.8–52.9% of recurrent lesions were located in the retropharyngeal region (Kim et al. 2022; Xue et al. 2017).

According to the guidelines, concurrent chemoradiotherapy (CCRT) is the standard treatment option for stage II-IVa NPC (Chen et al. 2021a, b). However, 28.2% of patients still have residual RLNs after three months of intensity-modulated radiotherapy (IMRT) (Li et al. 2020a, b). Moreover, several researches showed that about 50% of patients with non-metastatic NPC had abnormally enlarged RLNs after radical treatment (Meng et al. 2020; Tan et al. 2023). Meanwhile, residual RLN was an unfavorable prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional failure-free survival (LRFFS) (Li et al. 2020a, b). However, only a few studies reported the prognostic value of regression rate of RLN in locally advanced nasopharyngeal carcinoma (LANPC). Therefore, in-depth exploration of the prognostic value of RLNs in LANPC may have positive clinical significance.

The initiation of angiogenesis is important in the growth and metastasis of the tumor cells (Rankin et al. 2016). It is known that vascular endothelial growth factor (VEGF) is an inducer that promotes angiogenesis and tumor progression (Tan et al. 2017). Endostar (recombinant human endostatin injection), a targeted drug against VEGF receptors, has been found to not only inhibit tumor angiogenesis, but also suppress the generation of tumor lymphatic vessels and lymphatic metastasis (Shang et al. 2014). Previous study had indicated that IMRT combined with Endostar in the treatment of LANPC had better efficacy and fewer serious adverse effects than CCRT (Chen et al. 2021a, b). However, the effect of Endostar on the regression of RLNs remains to be explored, and the evaluation of RLNs was one-dimensional in the past. Here, we compared the regression of RLNs using three-dimensional quantitative measurement in LANPC patients who received Endostar combined with CCRT and CCRT alone.

Materials and methods

Patients

Our study retrospectively analyzed the clinical data of LANPC patients with RLNs metastasis who were treated at the First Affiliated Hospital of Guangxi Medical University from January 1, 2015 to April 30, 2020. Criteria for eligibility are as follows: (1) newly pathologically diagnosed and untreated stage III-IVa (based on the Union for International Cancer Control /American Joint Committee on Cancer 8th edition staging system) NPC patients; (2) aged 18–75 years; (3) RLN metastasis; (4) complete clinical data; (5) magnetic resonance imaging (MRI) of the head and neck performed before and after the radiotherapy; (6) no previous or concurrent malignancies; (7) normal hematologic, liver, renal and heart functions; (8) Eastern Cooperative Oncology Group score 0–1. The present study was approved by the medical ethics committee of the First Affiliated Hospital of Guangxi Medical University.

Treatment

The target delineation followed the international guideline for the delineation of the clinical target volumes (CTV) for NPC (Lee et al. 2018), and radiotherapy process was under the guidance of Report 50 and Report 62 of International Commission on Radiation Units and Measurements. 68–74 Gy was as the prescription dose for PGTVnx; 66–70 Gy was for PGTVnd; 60–66 Gy was for PCTV1; and 50–56 Gy was for PCTV2 (5 fractions per week for 30–33 fractions). Chemotherapy regimens were based on platinum (80–100 mg/m2, every 3 weeks or 40mg/m2, every week). Endostar (7.5 mg/m2/day, day 1–10, every 3 weeks) was continuously pumped intravenously from 5 days before radiotherapy according to the previous study (Yin et al. 2022).

Evaluation and volume measurement of retropharyngeal lymph nodes

Images were acquired using a 1.5-T MRI scanner (GE Healthcare Life Sciences, Little Chalfont, UK). All patients underwent both routine and enhanced scans including nasopharynx and neck. RLNs, which fused with primary tumors, were clearly distinguished by either a contrast-enhancing rim or a disparity in signal intensity when compared to the primary tumor (Liu et al. 2006). The diagnosis of positive RLNs met the criteria proposed by Head and Neck Cancer Radiotherapy Atlas (Luo 2020). And any RLNs with the maximum standardized uptake value (SUVmax) > 4.5 by F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (Matsubara et al. 2012).

The image data from T2 plain-scan weighted axial MRI were imported into the Varian Eclipse radiation treatment planning system in the DICOM format. Then the positive and residual RLNs were delineated slice by slice. The contouring was verified by two medical professionals (a trained radiation oncologist and a radiological expert) following the principle of consensus. If there was disagreement between them, further discussions were held by an expert team composed of two radiation oncology specialists and one chief radiologist. The Eclipse system is used to automatically calculate the RLNs’ volume accurately. The RLNs volume before and after radiotherapy is defined as RNVbefore and RNVafter, respectively. The RNVs regression rate = (RNVbefore -RNVafter) /RNVbefore* 100% (Lee et al. 2016; Li et al. 2023). The median regression rate of RLNs was taken as the cut-off value, and the patients were divided into high regression rate (HRR) and low regression rate (LRR).

Adverse effects (AEs) evaluation

Acute AEs were evaluated from the beginning to 90 days after radiotherapy following the National Cancer Institute Common Terminology Criteria v4.0. Late AEs occurred later than 90 days after radiotherapy. Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer standards were used to assess early and late radiation side effects.

Follow-up

Follow-up duration was determined from the date of pathologically diagnosed until either the date of the last medical encounter date or death. Patients underwent examinations every 3 months for the 0–2 years after treatment; every 6 months within the 3–5 years, and every year beyond 5 years. Post-treatment visits comprised physical examination, fiberoptic nasopharyngoscopy, MRI/CT of the head and neck, hematology and biochemistry examinations, chest CT, and abdominal ultrasound/CT. When patients experienced bone pain, an emission computed tomography for bones should be performed.

Statistical methods

SPSS 25.0 statistical software (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.0 were used. Non-normal continuous variables were described using median and interquartile range, while categorical variables were described in percentages. Statistical comparisons between groups were conducted using the rank-sum test, and chi-square test/Fisher precision method. The OS, PFS, DMFS, and LRFFS were calculated with the Kaplan–Meier method. Then the log-rank test was employed for comparison. The Cox proportional hazards model was employed to analyze the hazard ratio (HR), and to determine the corresponding 95% confidence intervals (CIs). Gender, clinical stage, age, pathological types, ECOG score, smoking, drinking, laterality, necrosis, ENS, T stage, N stage and regression rate of RLNs were included in the univariate analysis. Covariates with P ≤ 0.20 in univariable analysis were included as covariates in multivariable analysis. All statistical tests were bilateral with a significance level set to P < 0.05.

Results

Patient characteristics

A total of 122 LANPC patients were enrolled with 61 patients in each group. The detailed characteristics of patients are shown in Table 1. All 122 patients completed the entire radiation therapy process and all the patients in the ECCRT group completed 3 cycles of Endostar. In the ECCRT group, 6 patients (9.84%) experienced a 25% reduction of chemotherapy drug dosage due to serious AEs; while in the CCRT group, 4 patients (6.56%) also underwent a reduction. Table 1 Clinical characteristics in the ECCRT and CCRT group

Characteristics	ECCRT
n = 61	CCRT
n = 61	P	
Age			0.769	
 ≥ 60	7 (11.48%)	6 (9.84%)		
 < 60	54 (88.52%)	55 (90.16%)		
Gender			0.410	
Male	43 (70.49%)	47 (77.05%)		
Female	18 (29.51%)	14 (22.95%)		
Clinical stage*			0.587	
III	31 (50.82%)	28 (45.90%)		
IVa	30 (49.18%)	33 (54.10%)		
Pathological types			1.000	
WHO II	4 (6.56%)	5 (8.20%)		
WHO III	57 (93.44%)	56 (91.80%)		
ECOG score			0.364	
0	35 (57.38%)	30 (49.18%)		
1	26 (42.62%)	31 (50.82%)		
Smoking			0.258	
Yes	19 (31.15%)	25 (40.98%)		
No	42 (68.85%)	36 (59.02%)		
Drinking			0.533	
Yes	14 (22.95%)	17 (27.87%)		
No	47 (77.05%)	44 (72.13%)		
Chemotherapy cycles			1.000	
 ≥ 2	58 (95.08%)	57 (93.44%)		
1	3 (4.92%)	4 (6.56%)		
T stage			0.481	
T1-2	2 (3.28%)	7 (11.48%)		
T3	35 (57.38%)	31 (50.82%)		
T4	24 (39.34%)	23 (37.70%)		
N stage			0.094	
N0-1	19 (31.15%)	12 (19.67%)		
N2	34 (55.74%)	36 (59.02%)		
N3	8 (13.12%)	13 (21.31%)		
*TNM staging followed the 8th edition of the American Joint Commission on Cancer (AJCC) staging system

WHO, World Health Organization; ECOG, Eastern Cooperative Oncology Group

RLNs

The comparable baseline features of the RLNs before radiotherapy were presented in Table 2 (P > 0.05). The median volume of RLNs in the ECCRT and CCRT groups before treatment were 3.90 cm3 and 4.81 cm3, respectively. There was no statistically significant difference between them (P = 0.158). However, the median volume of residual RLNs after treatment in the ECCRT group was smaller than that in the CCRT group (0.58 cm3 vs. 2.59 cm3, P < 0.001). In addition, the median regression rate of RLNs was 81% in the ECCRT group, which was higher than 50% in the CCRT group (P < 0.001). (Table 3). And the median regression rate of RLNs was 66% in all patients. Table 2 Baseline characteristics of the RLNs before radiotherapy

RLNs	ECCRT (n = 61)	CCRT (n = 61)	P	
Laterality			1.000	
Unilateral	37 (60.66%)	37 (60.66%)		
Bilateral	24 (39.34%)	24 (39.34%)		
Necrosis			0.091	
Yes	27 (44.26%)	18 (29.51%)		
No	34 (55.74%)	43 (70.49%)		
ENS			0.361	
Yes	29 (47.54%)	24 (39.34%)		
No	32 (52.46%)	37 (60.66%)		
ENS Extranodal neoplastic spread

Table 3 Regression rates of RLNs

	ECCRT Median (IQR)	CCRT Median (IQR)	P	
RLN				
RNVbefore (cm3)	3.90 (2.01,6.61)	4.81 (3.11,7.31)	0.158	
RNVafter (cm3)	0.58 (0.32,0.96)	2.59 (1.34,3.75)	 < 0.001*	
Regression rates of RLNs (%)	81 (71.5,89)	50 (36.5,61)	 < 0.001*	
IQR interquartile range

*Statistically significant

AEs

Neither cardiac dysfunction nor treatment-related bleeding occurred in either group. The acute AEs observed in both groups were myelosuppression, oral mucositis, skin reaction, nausea/vomiting, liver dysfunction, and renal dysfunction. The occurrence of grade 3/4 oral mucositis in the ECCRT group was 26.23%, which was lower than that (44.26%) in the CCRT group (P = 0.037). Meanwhile, there was no statistically significant difference in other AEs between the two groups. There was no patient discontinuing treatment due to AEs and none died from acute AEs.

The late toxicities included limitation of mouth opening, dysphagia, decreased vision, hearing loss, radiation-induced brain injury, and xerostomia. One grade 5 late AE was observed in the ECCRT group. The incidences of late AEs were similar between the two groups (P > 0.05) (Table 4). Table 4 Treatment-related Aes

Toxicity	ECCRT group (n = 61)	CCRT group (n = 61)	P*	
Acute AEs	Grade 0	Grade 1/2	Grade 3/4	Grade 0	Grade 1/2	Grade 3/4		
Leukopenia	22 (36.07%)	29 (47.54%)	10 (16.39%)	15 (24.59%)	37 (60.66%)	9 (14.75%)	0.803	
Hemoglobin decrease	6 (9.84%)	48 (78.69%)	7 (11.48%)	12 (19.67%)	45 (73.77%)	4 (6.56%)	0.343	
Liver dysfunction	53 (86.89%)	6 (9.84%)	2 (3.28%)	52 (85.25%)	8 (13.11%)	1 (1.64%)	1.000	
Renal dysfunction	52 (85.25%)	9 (14.75%)	0 (0)	51 (83.61%)	10 (16.39%)	0(0)	-	
Thrombocytopenia	32 (52.46%)	27 (44.26%)	2 (3.28%)	43 (70.49%)	17 (27.87%)	1 (1.64%)	1.000	
Nausea/vomiting	30 (49.18%)	25 (40.98%)	6 (9.84%)	29 (47.54%)	29 (47.54%)	3 (4.92%)	0.491	
Oral mucositis	5 (8.20%)	40 (65.57%)	16 (26.23%)	4 (6.56%)	30 (49.18%)	27 (44.26%)	0.037*	
Skin reaction	16 (26.23%)	42 (68.85%)	3 (4.92%)	17 (27.87%)	39 (63.93%)	5 (8.20%)	0.717	
Late AEs	Grade 0	Grade 1/2	Grade 3/4/5	Grade 0	Grade 1/2	Grade 3/4	P	
Limitation of mouth opening	60 (98.36%)	1 (1.64%)	0 (0)	60 (98.36%)	1 (1.64%)	0 (0)	1.000	
Dysphagia	60 (98.36%)	0 (0)	1 (1.64%)	59 (96.72%)	2 (3.28%)	0 (0)	0.573	
Decreased vision	60 (98.36%)	1 (1.64%)	0 (0)	58 (95.08%)	3 (4.92%)	0 (0)	0.619	
Hearing loss	55 (90.16%)	6 (9.84%)	0 (0)	53 (86.89%)	8 (13.11%)	0 (0)	0.570	
Radiation-induced brain injury	59 (96.72%)	2 (3.28%)	0 (0)	60 (98.36%)	1 (1.64%)	0 (0)	1.000	
Xerostomia	45 (73.77%)	16 (26.23%)	0 (0)	42 (68.85%)	19 (31.15%)	0 (0)	0.548	
P* values showed the comparison results of grade 3/4 acute toxicity between the two groups

*Statistically significant

Survival and prognosis analysis

Patients were classified into two groups based on the median regression rate of RLNs: HRR (≥ 66%) and LRR (< 66%); The final follow-up time is May 15, 2023, with a median follow-up time of 65 months (range: 11–96 months). The 3-year OS, PFS, DMFS and LRFFS in the HRR and LRR group were 85.48% and 86.67% (HR 1.009, 95% CI 0.445–2.287, log-rank P = 0.983), 80.65% and 68.33% (HR 0.503, 95% CI 0.260–0.974, log-rank P = 0.037), 83.87% and 85% (HR 0.854, 95% CI 0.376–1.935, log-rank P = 0.704), 93.55% and 81.67% (HR 0.368, 95% CI 0.141–0.958, log-rank P = 0.033), respectively (Fig. 1). We also conducted univariable and multivariate analyses and found that regression rate of RLNs was an independent prognostic factor for PFS and LRFFS (Table 5). 12 patients (20%) died in the LRR group, of which 11 patients died of disease progression, 1 case died due to a car accident. In the HRR group, 14 patients (22.58%) died, of which 12 deaths were caused by disease progression, 1 patient died of second primary lung cancer, and 1 patient died due to dysphagia after radiotherapy. Disease progression occurred in 14 patients (22.58%) in the HRR group and 24 patients (40%) in the LRR group. Distant metastases were observed in 11 patients (17.74%) in the HRR group and 12 patients (20%) in the LRR group. In the HRR group, 6 patients (9.68%) had locoregional recurrence, while in the LRR group, 14 patients (23.33%) had locoregional recurrence.Fig. 1 Kaplan -Meier survival curve of the different ratios of patients with LANPC in the HRR group and the LRR group. The 3-year overall survival rates (A), progression-free survival rates (B), distant metastasis-free survival rates (C), locoregional failure-free survival rates (D). HR hazard ratio, CI confidence interval

Table 5 Multivariate analysis of factors associated with OS, PFS, DMFS, and LRRFS

Endpoint	Factors	HR	95% CI	P	
OS	Gender (female vs male)	0.358	0.106–1.207	0.098	
	Clinical stage (IVa vs III)	1.886	0.716–4.971	0.199	
	Necrosis (yes vs no）	1.934	0.846–4.417	0.118	
	N stage (N2 vs N0+1)	7.577	1.004–57.186	0.050	
	N stage (N3 vs N0+1)	5.960	0.689–51.534	0.105	
PFS	Group (HRR vs LRR)	0.482	0.245–0.947	0.034*	
	Age (<60 vs ≥60)	0.392	0.168–0.910	0.029*	
	N stage (N2 vs N0+1)	2.112	0.800–5.576	0.131	
	N stage (N3 vs N0+1)	3.174	1.080–9.326	0.036*	
DMFS	Laterality (bilateral vs unilateral)	1.758	0.762–4.054	0.186	
	N stage (N2 vs N0+1)	7.505	0.983–57.279	0.052	
	N stage (N3 vs N0+1)	9.704	1.165–80.812	0.036*	
	Gender (female vs male)	0.361	0.107–1.217	0.100	
LRRFS	Group (HRR vs LRR)	0.321	0.121–0.846	0.022*	
	Laterality (bilateral vs unilateral)	0.280	0.092–0.851	0.025*	
	N stage (N2 vs N0 + 1)	1.288	0.401–4.138	0.671	
	N stage (N3 vs N0 + 1)	2.486	0.697–8.863	0.160	
*Statistically significant

Discussion

So far, numerous studies have focused on the treatment of cervical lymph nodes, but there is little research on RLNs. It has been reported that the incomplete regression of the primary tumor and/or metastatic lymph node at the end of radiotherapy was a predictor of poor outcomes in NPC patients (Liang et al. 2019). Bartelink’s study showed that tumors with a slow regression rate in head and neck squamous cell carcinoma had a high probability of recurrence (Bartelink et al. 1983). Moreover, previous research showed that the 5-year PFS, 5-year local recurrence-free survival (LRFS) rate in NPC patients with or without residual tumors after radiotherapy were 67.9% and 84.7% (P = 0.006), 80.4% and 93.4% (P = 0.002) (Lv et al. 2017). Li et al. reported that the 3-year PFS rates of patients with or without residual RLNs after treatment were 78.4% and 90.4% (P < 0.001), and the 3-year LRRFS rates were 93.3% and 96.9%, respectively (P < 0.001) (Li et al. 2020a, b). He et al. reported that the 3-year PFS rates of patients with or without residual tumors after treatment were 67% and 82% (P = 0.001), and the 3-year LRFS rates were 89% and 97%, respectively (P = 0.002) (He et al. 2015). Lee et al. pointed out that the regression rate of tumor is considered to have greater prognostic value than absolute tumor volume, and found that the tumor regression rate in patients without recurrence is higher than that in patients with recurrence (44.3% and 34.0%, p = 0.004), and patients with tumor regression rate greater than 35% have higher 5-year PFS than patients with tumor regression rate less than 35% (79.2% and 53.2%, P < 0.001) (Lee et al. 2016). Similarly in our study, patients in the HRR group have higher survival rates than those in the LRR group. The 3-year PFS rates in the HRR and LRR groups were 80.65% and 68.33% respectively (P = 0.037), and 3-year LRFFS rates were 93.55% and 81.67%, respectively (P = 0.033). Multivariate analyses found that regression rate of RLNs was an independent prognostic factor for PFS and LRFFS of LANPC patients. The 3-year PFS and LRFFS in our study were lower than those in the study of Li WZ, considering that our study only included patients with LANPC, while the study of Li WZ also included stage II patients, and the study of Li WZ was qualitative in RLNs, while our study was quantitative.

Due to the deep location and difficult dissection of RLNs in NPC, it is a difficult challenge to treat residual or recurrent RLNs. More than 50% of cases with secondary radiation therapy experienced severe radiation toxicity (Han et al. 2012). Therefore, how to improve the regression rate of RLNs is significant. In recent years, targeted therapy has become a promising anti-tumor treatment method. Researches have demonstrated that anti-angiogenic drugs and chemoradiotherapy have a synergistic effect on NPC (Lee et al. 2012; Zhang et al. 2018). Currently, the application of Endostar in NPC mainly focused on recurrent and metastatic patients (Guan et al. 2015; Jin et al. 2013), and had improved the complete remission rate of CLNs metastasis (Li et al. 2020a, b). However, it is unclear whether Endostar has an impact on the regression of RLNs, as both primary nasopharyngeal lesions and RLNs were previously unified as GTVnx in the radiotherapy target area. This is the first study to explore the role of Endostar in the regression of RLNs using accurate three-dimensional measurement of RLNs’ volume, which can provide some reference and new idea for the treatment of LANPC patients with RLNs metastasis. In this study, we separately outlined RLNs and found that the regression rate of RLNs in the ECCRT group was higher than that in the CCRT group (81% vs. 50%, P < 0.001).

Endostar has been shown to normalize blood vessels, thereby enhancing the blood supply to necrotic tissues and promoting tumor regression. Besides, it stimulates endogenous anti-angiogenic activity and inhibits VEGF activity, which results in a decrease in the number of microvessels, the oxygen consumption of immature blood vessels, and inflammatory exudation (Ling et al. 2007; Peng et al. 2012). According to the previous researches, Endostar can reduce radiation-induced tissue damage. It is reported that Endostar plus radiochemotherapy reduced the incidence of grade 3/4 oral mucositis compared to the group without Endostar (29.3% vs. 54.8%, P = 0.019) (Xu et al. 2022). Furthermore, Endostar reduced the occurrence of radiation-induced lung injury (Zhang et al. 2012), and the progression of early brain edema after radiation-induced brain injury (Ma et al. 2019). Analogously, Our study results indicated that patients in the ECCRT group exhibited a lower incidence of grade 3/4 oral mucositis compared to those in the CCRT group (26.23% vs. 44.26%, P = 0.037), which may be related to the radiological protective effect of Endostar on normal tissues.

Conclusion

Our findings demonstrated that Endostar combined with CCRT is expected to become an effective and low-toxicity treatment method for LANPC patients with RLNs. Moreover, the high or low RLNs regression rate can help clinical doctors develop personalized treatment strategies and provide intensive treatment for patients with poor RLNs regression. However, there are some limitations to our study. Firstly, this is a retrospective cohort study. We cannot completely alleviate selection bias. Secondly, positive RLNs diagnosis relied on MRI due to the difficulty in obtaining pathological tissue. Thirdly, this is a single-center study that lacks external validation from other centers.

Author contributions

TTZ and RSW conceived and designed the research, made the final revisions. JMS and NM prepared the manuscript writing and manuscript editing. JMS, NM, YQL, TL, ZRL collected the data. JMS and LLH analyzed the data. YQL and JMS checked the data. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the “Medical Excellence Award” Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University (2023), the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2024GXNSFBA010244), the Basic Ability Enhancement Project of Young Teachers in Guangxi Zhuang Autonomous Region (2023KY0120), the Project of Bureau of Science & Technology Nanchong City (20SXQT0257), and the Major project of Sichuan Science and Technology Department (2023YFS0473).

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare no conflict of interest.

Ethics approval

This study was approved by the Institutional Review Committee of the First Affiliated Hospital of Guangxi Medical University (approval number: 2023-E529-01, approval date: September 27, 2023).

Informed consent

All participants in the study received informed consent.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jun-Mei Song and Ning Mo contributed equally to this work.
==== Refs
References

Bartelink H Prognostic value of the regression rate of neck node metastases during radiotherapy Int J Radiat Oncol Biol Phys 1983 9 7 993 996 10.1016/0360-3016(83)90386-3 6408042
Chen YP Ismaila N Chua MLK Colevas AD Haddad R Huang SH Wee JTS Whitley AC Yi JL Yom SS Chan ATC Hu CS Lang JY Le QT Lee AWM Lee N Lin JC Ma B Morgan TJ Shah J Sun Y Ma J Chemotherapy in combination with radiotherapy for definitive-intent treatment of stage II-IVA nasopharyngeal carcinoma: CSCO and ASCO Guideline J Clin Oncol 2021 39 7 840 859 10.1200/JCO.20.03237 33405943
Chen B Zhan Z Pan J Xiao Y Tang L Guo Q Xu Y Zong J Zhang R Xu H Lin S Re-evaluation of the prognostic significance of retropharyngeal node metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy Asia Pac J Clin Oncol 2022 18 2 e173 e181 10.1111/ajco.13589 34541812
Chen W, Wang F, Yang Z, Zhang T, Shen M, Wang R, Kang M (2021a) Long-term efficacy and adverse reactions of IMRT combined with Endostar versus IMRT combined with chemotherapy for locally advanced nasopharyngeal carcinoma: a retrospective study. Ann Palliat Med 10(11):11891–11900. 10.21037/apm-21-3018
Coskun HH Ferlito A Medina JE Robbins KT Rodrigo JP Strojan P Suárez C Takes RP Woolgar JA Shaha AR de Bree R Rinaldo A Silver CE Retropharyngeal lymph node metastases in head and neck malignancies Head Neck 2011 33 10 1520 1529 10.1002/hed.21526 20737485
Guan Y, Li A, Xiao W, Liu S, Chen B, Lu T, Zhao C, Han F (2015) The efficacy and safety of Endostar combined with chemoradiotherapy for patients with advanced, locally recurrent nasopharyngeal carcinoma. Oncotarget 6 (32):33926–33934. 10.18632/oncotarget.5271
Han F Zhao C Huang SM Lu LX Huang Y Deng XW Mai WY Teh BS Butler EB Lu TX Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy Clin Oncol (R Coll Radiol) 2012 24 8 569 576 10.1016/j.clon.2011.11.010 22209574
He Y Zhou Q Shen L Zhao Y Lei M Wei R Shen L Cao S A retrospective study of the prognostic value of MRI-derived residual tumors at the end of intensity-modulated radiotherapy in 358 patients with locally-advanced nasopharyngeal carcinoma Radiat Oncol 2015 10 89 10.1186/s13014-015-0401-0 25881159
Ho FC Tham IW Earnest A Lee KM Lu JJ Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence BMC Cancer 2012 12 98 10.1186/1471-2407-12-98 22433671
Huang L Zhang Y Liu Y Li H Wang S Liang S Zhou J Cui C Sun Y Chen M Xu S Li J Liu L Prognostic value of retropharyngeal lymph node metastasis laterality in nasopharyngeal carcinoma and a proposed modification to the UICC/AJCC N staging system Radiother Oncol 2019 140 90 97 10.1016/j.radonc.2019.04.024 31195216
Jin T Li B Chen XZ A phase II trial of Endostar combined with gemcitabine and cisplatin chemotherapy in patients with metastatic nasopharyngeal carcinoma (NCT01612286) Oncol Res 2013 21 6 317 323 10.3727/096504014X13983417587401 25198661
Kim D Keam B Ahn SH Choi CH Wu HG Feasibility and safety of neck level IB-sparing radiotherapy in nasopharyngeal cancer: a long-term single institution analysis Radiat Oncol J 2022 40 4 260 269 10.3857/roj.2022.00346 36606303
Lee NY Zhang Q Pfister DG Kim J Garden AS Mechalakos J Hu K Le QT Colevas AD Glisson BS Chan AT Ang KK Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial Lancet Oncol 2012 13 2 172 180 10.1016/S1470-2045(11)70303-5 22178121
Lee H Ahn YC Oh D Nam H Noh JM Park SY Tumor Volume reduction rate during adaptive radiation therapy as a prognosticator for nasopharyngeal cancer Cancer Res Treat 2016 48 2 537 545 10.4143/crt.2015.081 26194371
Lee AW Ng WT Pan JJ Poh SS Ahn YC AlHussain H Corry J Grau C Grégoire V Harrington KJ Hu CS Kwong DL Langendijk JA Le QT Lee NY Lin JC Lu TX Mendenhall WM O’Sullivan B Ozyar E Peters LJ Rosenthal DI Soong YL Tao Y Yom SS Wee JT International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma Radiother Oncol 2018 126 1 25 36 10.1016/j.radonc.2017.10.032 29153464
Li JG Venigalla P Leeman JE LaPlant Q Setton J Sherman E Tsai J McBride S Riaz N Lee N Patterns of nodal failure after intensity modulated radiotherapy for nasopharyngeal carcinoma Laryngoscope 2017 127 2 377 382 10.1002/lary.26139 27438558
Li WZ Liu GY Lin LF Lv SH Qiang MY Lv X Wu YS Liang H Ke LR Wang DL Yu YH Qiu WZ Liu KY Guo X Li JP Zou YJ Xiang YQ Xia WX MRI-detected residual retropharyngeal lymph node after intensity-modulated radiotherapy in nasopharyngeal carcinoma: Prognostic value and a nomogram for the pretherapy prediction of it Radiother Oncol 2020 145 101 108 10.1016/j.radonc.2019.12.018 31931288
Li Y Tian Y Jin F Wu W Long J Ouyang J Zhou Y A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update Curr Probl Cancer 2020 44 1 100492 10.1016/j.currproblcancer.2019.06.007 32035692
Li Y Bi J Pi G He H Li Y Zheng D Wei Z Han G Optimizing induction chemotherapy regimens for radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma Cancer Med 2023 12 8 9449 9457 10.1002/cam4.5707 36872566
Liang SB Zhang N Chen DM Yang XL Chen BH Zhao H Lu RL Chen Y Fu LW Prognostic value of gross tumor regression and plasma Epstein Barr Virus DNA levels at the end of intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma Radiother Oncol 2019 132 223 229 10.1016/j.radonc.2018.10.010 30366725
Ling Y Yang Y Lu N You QD Wang S Gao Y Chen Y Guo QL Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells Biochem Biophys Res Commun 2007 361 1 79 84 10.1016/j.bbrc.2007.06.155 17644065
Liu LZ Zhang GY Xie CM Liu XW Cui CY Li L Magnetic resonance imaging of retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: patterns of spread Int J Radiat Oncol Biol Phys 2006 66 3 721 730 10.1016/j.ijrobp.2006.05.054 17011448
Luo JW Head and Neck Cancer Radiotherapy Atlas 2020 China People’s Medical Publishing House
Lv JW Zhou GQ Li JX Tang LL Mao YP Lin AH Ma J Sun Y Magnetic resonance imaging-detected tumor residue after intensity-modulated radiation therapy and its association with post-radiation plasma Epstein-Barr Virus deoxyribonucleic acid in nasopharyngeal carcinoma J Cancer 2017 8 5 861 869 10.7150/jca.17957 28382149
Ma J Liu L Tang L Zong J Lin A Lu T Cui N Cui C Li L Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: prognostic value and staging categories Clin Cancer Res 2007 13 5 1445 1452 10.1158/1078-0432.CCR-06-2059 17332287
Ma C, Zhou J, Xu X, Wang L, Qin S, Hu C, Nie L, Tu Y (2019) The construction of a radiation-induced brain injury model and preliminary study on the effect of human recombinant endostatin in treating radiation-induced brain injury. Med Sci Monit 25:9392–9401. 10.12659/MSM.917537
Matsubara R Kawano S Chikui T Kiyosue T Goto Y Hirano M Jinno T Nagata T Oobu K Abe K Nakamura S Clinical significance of combined assessment of the maximum standardized uptake value of F-18 FDG PET with nodal size in the diagnosis of cervical lymph node metastasis of oral squamous cell carcinoma Acad Radiol 2012 19 6 708 717 10.1016/j.acra.2012.02.009 22484437
Meng K Tey J Ho FCH Asim H Cheo T Utility of magnetic resonance imaging in determining treatment response and local recurrence in nasopharyngeal carcinoma treated curatively BMC Cancer 2020 20 1 193 10.1186/s12885-020-6664-3 32143592
Peng F Xu Z Wang J Chen Y Li Q Zuo Y Chen J Hu X Zhou Q Wang Y Ma H Bao Y Chen M Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models PLoS ONE 2012 7 4 e34646 10.1371/journal.pone.0034646 22496834
Rankin EB Giaccia AJ Hypoxic control of metastasis Science 2016 352 6282 175 180 10.1126/science.aaf4405 27124451
Shang L Zhao J Wang W Xiao W Li J Li X Song W Liu J Wen F Yue C Inhibitory effect of endostar on lymphangiogenesis in non-small cell lung cancer and its effect on circulating tumor cells Zhongguo Fei Ai Za Zhi 2014 17 10 722 729 10.3779/j.issn.1009-3419.2014.10.03 25342038
Tan J Jiang L Cheng X Wang C Chen J Huang X Xie P Xia D Wang R Zhang Y Association between VEGF-460T/C gene polymorphism and clinical outcomes of nasopharyngeal carcinoma treated with intensity-modulated radiation therapy Onco Targets Ther 2017 10 909 918 10.2147/OTT.S126159 28243126
Tan W Mao M He H Chen M Deng Q Yang Y Li Y Sheng H He L Li J Endonasopharyngeal ultrasound and magnetic resonance imaging features of recurrent retropharyngeal nodes in nasopharyngeal carcinoma patients: a radiologic-histopathologic study Radiother Oncol 2023 183 109579 10.1016/j.radonc.2023.109579 36842662
Wang X Hu C Ying H He X Zhu G Kong L Ding J Patterns of lymph node metastasis from nasopharyngeal carcinoma based on the 2013 updated consensus guidelines for neck node levels Radiother Oncol 2015 115 1 41 45 10.1016/j.radonc.2015.02.017 25748143
Xu L Li D Ji J Chen Z Tang X Chen D Li X Bao D Yan F Pang Y Liu S Zhou Y Xu X Recombinant human endostatin injection (Endostar) combined with PF chemotherapy and sequential intensity-modulated radiotherapy is tolerable and improves prognosis of locally advanced nasopharyngeal carcinoma: a randomized, open, multicenter phase II clinical study Am J Cancer Res 2022 12 10 4622 4636 36381335
Xue F Hu C He X Long-term patterns of regional failure for nasopharyngeal carcinoma following intensity-modulated radiation therapy J Cancer 2017 8 6 993 999 10.7150/jca.17858 28529611
Yin Y Zhou Z Li Z Shen M Qin Y Yang C Wang R Kang M Efficacy of concurrent chemoradiotherapy plus Endostar compared with concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma: a retrospective study Radiat Oncol 2022 17 1 135 10.1186/s13014-022-02104-4 35906636
Zhang K Yang S Zhu Y Mo A Zhang D Liu L Protection against acute radiation-induced lung injury: a novel role for the anti-angiogenic agent Endostar Mol Med Rep 2012 6 2 309 315 10.3892/mmr.2012.903 22562140
Zhang HJ Yuan GL Liang QL Peng XX Cheng SA Jiang L Addition of bevacizumab to systemic therapy for locally advanced and metastatic nasopharyngeal carcinoma Oncol Lett 2018 15 5 7799 7805 10.3892/ol.2018.8284 29740494
