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Radiotherapy-induced dysphagia and its impact on quality of life in patients with nasopharyngeal carcinoma

  • Honghong Li
  • Liting Li
  • Xiaolong Huang
  • Yi Li
  • Tangjie Zou
  • Xiaohuang Zhuo
  • Yan Chen
  • Yimin LiuEmail author
  • Yamei TangEmail author
Original Article
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Abstract

Purpose

To investigate the swallowing status and its impact on quality of life (QOL) in patients who underwent radiotherapy for nasopharyngeal carcinoma (NPC).

Methods

In this study, 334 patients with NPC who underwent radiotherapy were reviewed. Clinical characteristics, videofluoroscopic swallowing studies (VFSSs), and scores of the World Health Organization quality of life-BREF (WHOQOL-BREF) were retrospectively analyzed for all patients.

Results

In this study, 143 of 334 (42.8%) patients showed dysphagia. The nodular stage N3 of NPC, neoadjuvant and concurrent chemotherapy were clinical predictors for dysphagia. VFSS of patients with dysphagia showed a high incidence of vallecular residue (100%), apraxia (99%), premature bolus loss (98%), bolus formation (98%), pyriform sinus residue (95%), and mastication (94%). Moreover, WHOQOL-BREF scores for the physical health, psychological, and environment domains were lower of the dysphagia group than those of the control group (P < 0.01). Videofluoroscopic dysphagia scale scores showed significant negative correlations with scores for the physical health (R = −0.66, P < 0.01), psychological (R = −0.70, P < 0.01), social relationships (R = −0.56, P < 0.01), and environment (R = −0.61, P < 0.01) domains of WHOQOL-BREF.

Conclusions

Radiotherapy-induced dysphagia is common in NPC patients and is correlated with poor quality of life. Patients, caregivers, and clinical physicians should be aware of these adverse effects and provide timely treatment for radiotherapy-induced dysphagia in collaboration with cross-disciplinary colleagues.

Keywords

Radiotherapy Dysphagia NPC Videofluoroscopic swallowing study Quality of life 

Strahlentherapieinduzierte Dysphagie und ihr Einfluss auf die Lebensqualität von Menschen mit Nasopharynxkarzinom

Zusammenfassung

Zielsetzung

Untersuchung der Schluckfunktion und ihre Auswirkungen auf die Lebensqualität (QOL) bei Patienten, die eine Strahlentherapie aufgrund eines Nasopharynxkarzinoms (NPC) erhalten haben.

Methoden

In dieser Studie wurden 334 Patienten mit NPC, die eine Strahlentherapie erhielten, überprüft. Klinische Parameter, videofluoroskopische Schluckstudien (VFSS) und Ergebnisse aus dem World Health Organization Quality of Life Bref (WHOQOL-BREF), der die Lebensqualität von Patienten einschätzt, wurden retrospektiv für alle Patienten analysiert.

Ergebnisse

In dieser Studie zeigten 143 von 334 (42,8%) Patienten eine Dysphagie. Das noduläre Stadium N3 von NPC, neoadjuvante und gleichzeitige Chemotherapie waren klinische Prädiktoren für Dysphagie. Die VFSS von Patienten mit Dysphagie zeigten eine hohe Inzidenz von vallekulären Rückständen (100%), Apraxie (99%), vorzeitigem Bolusverlust (98%), Bolusbildung (98%), Resten des Sinus piriformis (95%) und Mastikation (94%). Darüber hinaus waren die Ergebnisse des WHOQOL-BREF für psychische Gesundheit, physische und Umwelt-Domäne bei der Dysphagie-Gruppe niedriger als bei der Kontrollgruppe (P < 0,01). Die videofluoroskopischen Dysphagie-Skalenwerte der WHOQOL-BREF für die Bereiche körperliche Gesundheit (R = −0,66; P < 0,01), psychologische (R = −0,70; P < 0,01) und soziale Beziehungen (R = −0,56; P < 0,01) und Umwelt (R = −0,61; P < 0,01) zeigten signifikante negative Korrelationen.

Schlussfolgerung

Strahlentherapieinduzierte Dysphagie ist bei NPC-Patienten häufig und korreliert mit schlechter Lebensqualität. Patienten, Pflegepersonal und klinische Ärzte sollten sich dieser Nebenwirkungen bewusst sein und eine zeitnahe Behandlung von strahlentherapieinduzierter Dysphagie in Zusammenarbeit mit interdisziplinären Kollegen anbieten.

Schlüsselwörter

Strahlentherapie Dysphagie NPC Videofluoroskopische Schluckstudie Lebensqualität 

Introduction

Nasopharyngeal carcinoma (NPC) is known as a geographical disease with a high incidence in Southern China and Southeast Asia [1]. Radiotherapy is the major and widely used treatment for NPC [2, 3]. Although it has led to increased survival rates, it frequently causes burdensome symptoms, such as mucositis, dysphagia, disturbance of taste, and xerostomia. Dysphagia is one of the most prevalent and challenging late adverse effects of radiotherapy in patients with NPC [4, 5]. Swallowing abnormalities are long-term or even permanent sequelae which will negatively influence the patient’s quality of life (QOL) and social function [6, 7]. Radiotherapy-induced dysphagia refers to difficulty in swallowing as a result of chronic effects of radiotherapy, including lower cranial neuropathy and rigidity and loss of function of the swallowing apparatus due to tissue fibrosis [6], and it could be associated with several problems, including poor QOL and significant morbidities such as poor nutritional status, enteral feeding tube dependence, and aspiration pneumonia. The condition becomes life-threatening if aspiration pneumonia and sepsis occur [8]. Approximately one third of patients with dysphagia develop aspiration pneumonia, with mortality rates of 20–65% [9]. However, radiotherapy-induced dysphagia in patients with NPC has often been underdiagnosed and improperly treated. Moreover, patients usually ignore dysphagia, and only those with significant swallowing problems may seek medical help. Therefore, an understanding of the influence of radiotherapy on swallowing function and the impact of radiotherapy-induced dysphagia on QOL is crucial to determine the long-term care needs of patients with NPC.

Accordingly, we designed this retrospective study to assess the incidence of radiotherapy-induced dysphagia and its effects on QOL in patients with NPC. Swallowing function after radiotherapy in our patients was assessed using the videofluoroscopic swallowing study (VFSS), a gold standard method for detecting and evaluating swallowing abnormalities.

Materials and methods

Patients

This retrospective study included patients with NPC who received radiotherapy ≥1 year [10] prior to admission at hospital, between February 2011 and February 2016. The patients’ baseline characteristics were retrospectively collected through chart reviews. All patients underwent the screening for dysphagia according to a detailed history including indirect aspiration symptoms like coughing or choking during eating [11], and the findings of the Kubota water drinking test [12]. Kubota water drinking test was performed when patients come to our hospital the first time because of clinical difficulty in eating and swallowing. Moreover, a complete physical examination, including a reduced gag reflex, vocal cord palsy, or reduced laryngeal elevation, was also performed. The inclusion criteria were as follows: history of radiotherapy for NPC; evidence of dysphagia (Kubota water drinking test grade >2); performance of magnetic resonance imaging to rule out dysphagia resulting from brainstem injury; age ≥18 years; and the absence of tumor relapse, metastases, other malignant diseases, infection of the nervous system, neurovascular disease, and demyelinating disease. Among patients with a history of aspiration pneumonia, those with evidence of dysphagia before radiotherapy, or with posterior pharyngeal wall or post-cricoid disease were excluded. In all, 155 dysphagic patients with NPC who received radiotherapy were screened, and 12 patients were excluded including 2 with NPC relapse, 5 with brain ischemic disease, 2 with dysphagia before radiotherapy, and 3 with infection tuberculous meningoencephalitis. Thus, a total of 143 dysphagic patients were included in our analysis. In addition, 191 irradiated NPC patients without radiotherapy-induced dysphagia during the same period were recruited as controls from the same department.

All patients were treated according to the principles of the National Comprehensive Cancer Network (NCCN) guidelines for NPC. For conventional radiotherapy, irradiation volume were chosen according to the extension of the tumor. The target volume included the entire tumor with a 2-cm margin in all directions. For intensity-modulated radiation therapy (IMRT), the primary nasopharyngeal gross tumor volume (GTVnx) and the involved cervical lymph nodes (GTVnd) were delineated slice by slice on the treatment planning computed tomography scan, with the determination from imaging, clinical, and endoscopic findings. In the conventional radiotherapy (RT) group, the nasopharyngeal (NP) dose was 69.98 ± 2.00 Gray (Gy) and the neck dose was 63.50 ± 10.00 Gy. In the IMRT group, the NP dose was 70.00 ± 2.00 Gy and the neck dose was 60.00 ± 4.00 Gy.

Data collection

Age; sex; the interval between radiotherapy completion and dysphagia onset; glucose (Glu), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and albumin tests were administered and the values were documented when dysphagia or other conditions related to radiotherapy were diagnosed for the first time in our hospital; the TNM classification of the tumor, the radiation dose, the radiation volume, the duration between radiotherapy and assessment (DRA), the radiotherapy and chemotherapy technique were recorded for all patients (Table 1). All the patients were restaged according to the seventh American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM staging manual [13].
Table 1

Demographic, clinical, tumor-related, and radiotherapy-related characteristics of patients who received radiotherapy for nasopharyngeal carcinoma (NPC)

 

All

Type of radiotherapy

P value

Conventional (n = 252)

IMRT

(n = 82)

Clinical characteristics

Age, years

51.07 (10.07)

52.01 (15.00)

49.51 (11.75)

0.18

Men

244 (73%)

181 (72%)

63 (77%)

0.46

Dysphagia

143 (43%)

114 (45%)

29 (35%)

0.15

Glu, mmol/l

5.31 (2.35)

5.61 (2.30)

4.86 (2.15)

0.02

TC, mmol/l

5.36 (1.22)

5.24 (1.53)

5.31 (1.54)

0.40

TG, mmol/l

0.92 (0.67)

0.82 (0.61)

1.09 (0.80)

<0.01

HDL-C, mmol/l

1.43 (0.39)

1.44 (0.56)

1.29 (0.38)

<0.01

LDL-C, mmol/l

3.39 (1.00)

3.25 (1.17)

3.42 (1.20)

0.14

ApolA1, g/l

1.20 (0.24)

1.19 (0.32)

1.14 (0.24)

0.13

ApolB, g/l

0.94 (0.25)

0.91 (0.29)

1.00 (0.33)

<0.01

Albumin, g/l

40.24 (4.34)

40.41 (6.03)

40.11 (5.45)

0.29

DRA, months

54.43 (51.64)

63.13 (60.00)

38.17 (30.24)

<0.01

Tumor and treatment characteristics

T

<0.01

 T1

17 (5%)

17 (7%)

0 (0%)

 T2

67 (20%)

60 (24%)

7 (9%)

 T3

138 (41%)

99 (39%)

39 (48%)

 T4

112 (34%)

76 (30%)

36 (44%)

N

0.86

 N0

79 (24%)

61 (24%)

18 (22%)

 N1

149 (45%)

114 (45%)

35 (43%)

 N2

90 (27%)

65 (26%)

25 (30%)

 N3

16 (5%)

12 (5%)

4 (5%)

Clinical stage

<0.01

 1

5 (1.5%)

5 (2%)

0 (0%)

 2

49 (15%)

44 (17%)

4 (5%)

 3

163 (49%)

119 (47%)

40 (49%)

 4

117 (35%)

84 (33%)

38 (46%)

Neoadjuvant chemotherapy

141 (42%)

103 (41%)

38 (46%)

0.46

Concurrent chemotherapy

179 (54%)

106 (42%)

73 (89%)

<0.01

The normal range for lab values: Glu, 3.9–5.6 mmol/l; TC, 2.9–6.0 mmol/l; TG, 0.31–2.3 mmol/l; HDL-C, 0.8–1.96 mmol/l; LDL-C, 1.3–3.6 mmol/l; ApolA1, 1.0–1.6 g/l; ApolB, 0.5–1.10 g/l; Albumin, 40–55 g/l

Data are presented as mean (standard deviation), median (interquartile range), or n (%)

Glu glucose, TC total cholesterol, TG triglyceride, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, ApolA1 apolipoprotein A1, ApolB apolipoprotein B, DRA duration between RT and assessment, Gy Gray, IMRT intensity-modulated radiation therapy

VFSS

VFSS has been adopted as the gold standard for the evaluation and management of swallowing function [14, 15]. Since February 2014, the VFSS was performed for every patient when dysphagia was diagnosed for the first time in our hospital. For this test, 40 ml of 76% meglumine diatrizoate was added to 40 ml of 10% glucose solution to achieve a mixed solution. Then, 5 g of thickening powder (Resource Thicken Up, Nestle Health Science ) [16] was added to 20 ml of the mixed solution to achieve a paste-like consistency, while 2.5 g of thickening powder was added to 20 ml of the mixed solution to prepare thick food. The remaining 40 ml of the mixed solution was used as thin food. The patients were instructed to consume 3‑, 5‑, and 10-ml boli of the thin food, thick food, and paste, respectively, while undergoing frontal and lateral imaging for observation of swallowing function. The patient began to swallow when the clinician gave them a signal, and the swallowing movements were recorded at 30 frames/s and evaluated after the test. The entire swallowing movement was recorded and each phase (oral, pharyngeal, and esophageal) was analyzed and timed. All test procedures were recorded in a digital video file and analyzed by two physiatrists. For objective assessment of the findings of VFSS, the videofluoroscopic dysphagia scale (VDS; total score, 100) was created on the basis of the odds ratios for various prognostic factors ([17]; Table 2). VDS measures the following 14 parameters: lip closure, mastication, tongue-to-palate contact, premature bolus loss, pyriform sinus residue, apraxia, vallecular residue, bolus formation, aspiration, coating of the pharyngeal wall, laryngeal elevation, pharyngeal transit time, triggering of pharyngeal swallow, and oral transit time. It has been validated as a reliable, objective, and quantifiable predictor of long-term persistent dysphagia, with a sensitivity and specificity of 0.91 and 0.92, respectively [18].The two physiatrists who performed VFSS and assigned VDS scores had undergone standard training in these procedures for at least 1 year and had received the qualification certificate. All patients were informed of the purpose and potential risks of VFSS and subsequently asked to sign informed consent forms before the actual examination.
Table 2

Analyses of the clinical predictors for dysphagia for IMRT groups and conventional radiotherapy groups

 

Conventional

IMRT

Univariate analysis

Multivariate analysis

Univariate analysis

Multivariate analysis

OR

P-value

OR

P-value

OR

P-value

OR

P-value

Demographic characteristics

Age, years

0.990

0.666

1.025

0.055

Women

1.087

0.878

0.915

0.753

DRA

0.984

0.140

0.978

0.065

1.004

0.079

Tumor and treatment characteristics

T

 T1

Ref

 T2

Ref

0.545

0.297

 T3

3.750

0.242

0.513

0.222

 T4

3.391

0.282

0.267

0.019

N

 N0

Ref

Ref

Ref

 N1

0.820

0.741

0.659

0.191

1.506

0.337

 N2

0.739

0.640

0.604

0.162

2.074

0.164

 N3

1.571

0.684

1.813

0.370

8.096

0.010

Neoadjuvant chemotherapy

1.734

0.237

2.141

0.146

0.456

0.003

0.380

0.001

Concurrent chemotherapy

2.054

0.390

0.631

0.075

0.559

0.040

Radiation dose for the nasopharyngeal region, Gy

0.706

0.090

0.550

0.018

0.922

0.480

Radiation dose for the neck, Gy

1.013

0.398

0.959

0.060

0.941

0.058

Univariate and multivariate logistic regression analyses were performed to identify the clinical predictors for dysphagia. The final multivariate logistic regression model selection was performed by backward stepwise regression with Akaike Information Criterion (AIC)

IMRT intensity-modulated radiation therapy, DRA duration between RT and assessment, Gy Gray, OR odds ratio, T Tumor, N Lymp Node.

QOL assessment

QOL was assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) in its validated Chinese version, which is widely used in clinical studies, including oncological disease studies [19, 20]. The questionnaire comprises 26 items and measures the following broad domains: physical health (7 items), psychological health (6 items), social relationships (4 items), and environment (9 items) [21]. Each item was scored from 1 to 5 points, and a higher score indicates a better QOL. The 4–20 scale was used to transform domain scores for each domain in this study. The domain scores were calculated by multiplying the average scores of all items in the domain by a factor of 4. Therefore, each domain score would have the same range (from 4 to 20). This questionnaire was conducted on every patient when dysphagia was diagnosed for the first time in our hospital.

Statistical analysis

Statistical analyses were performed using R for Windows (version 3.4.2, http://www.r-project.org/). The data are presented as mean (standard deviation), median (interquartile range), or number (%). Categorical variables were compared by Chi-square/Fisher’s exact tests. Normally distributed variables were compared by Student’s t test. Non-parametric data were compared by Mann–Whitney U test. Because of better normal tissue sparing of IMRT, we divided the patients into IMRT groups and conventional radiotherapy groups. To identify the clinical predictors for dysphagia, univariate and multivariate logistic regression analyses was performed for IMRT groups and conventional radiotherapy groups, respectively. Univariate logistic regression model was used for the analyses of age, sex, DRA, tumor/nodes stages of TNM staging system, neoadjuvant chemotherapy, concurrent chemotherapy, radiation dose for the nasopharyngeal region and neck. The final multivariate logistic regression model selection was performed by backward stepwise regression with Akaike Information Criterion (AIC). Pearson’s correlation test was used to assess the linear dependence between VDS and four domain scores of WHOQOL-BREF. All statistical tests were two-sided, and P values of less than 0.05 were considered to be statistically significant.

Results

Clinical factors and outcomes of patients

In total, 334 patients, including 143 with dysphagia and 191 controls, with a mean age of 51.07 ± 10.07 years were included in the study. Of these patients, 252 (75.45%) and 82 (24.55%) were treated with conventional radiotherapy or IMRT, respectively. The median time of DRA for dysphagic patients and controls were 55.53 ± 69.07 months and 54.03 ± 45.68 months, respectively. There was no significant difference in DRA between these two groups (P = 0.615). The demographic data of all patients are summarized in Table 1. The incidence of dysphagia after radiotherapy for NPC was 42.8% (143/334). Because of better normal tissue sparing of IMRT, we divided the patients into IMRT group and conventional radiotherapy group. We compared the proportion of IMRT in the dysphagic groups and non-dysphagic groups, and we found no significant difference between the two groups (P = 0.118). The Glu, TG, HDL-C, apolipoprotein B (ApolB), DRA, T stage, clinical stage, and concurrent chemotherapy were different between conventional RT group and IMRT group. Thus, we investigate the risk factor of dysphagia respectively in these two groups. The predictors in the multivariate logistic regression model of dysphagia are shown in Table 2. This result indicated that for patients who received conventional radiotherapy, radiation dose for the nasopharyngeal region was a predictor for dysphagia; for patients who received IMRT, the N3 stage, neoadjuvant and concurrent chemotherapy were clinical predictors for dysphagia. Furthermore, total cholesterol (5.21 ± 1.16 mmol/l vs. 5.48 ± 1.26 mmol/l), LDL-C (3.27 ± 0.91 mmol/l vs. 3.48 ± 1.05 mmol/l), and albumin (39.42 ± 4.52g/l vs. 40.58 ± 4.112 g/l) levels were significantly lower in the dysphagia group than in the control group (Table 3).
Table 3

Serum markers of patients with or without dysphagia

 

Control (n = 191)

Dysphagia (n = 143)

P-value

Glu, mmol/l

5.11(2.30)

5.61(2.30)

0.641w

TC, mmol/l

5.48(1.26)

5.21(1.16)

0.048t

TG, mmol/l

0.95(0.69)

0.78(0.62)

0.061w

HDL-C, mmol/l

1.44(0.38)

1.41(0.41)

0.601t

LDL-C, mmol/l

3.48(1.05)

3.27(0.91)

0.046t

ApolA1, g/l

1.22(0.23)

1.17(0.26)

0.121t

ApolB, g/l

0.96(0.27)

0.92(0.22)

0.222t

Albumin, g/l

40.85(4.12)

39.42(4.52)

0.003t

The normal range for lab values: Glu, 3.9–5.6 mmol/l; TC, 2.9–6.0 mmol/l; TG, 0.31–2.3 mmol/l; HDL-C, 0.8–1.96 mmol/l; LDL-C, 1.3–3.6 mmol/l; ApolA1, 1.0–1.6 g/l; ApolB, 0.5–1.10 g/l; Albumin, 40–55 g/l.

Data are presented as mean (standard deviation), median (interquartile range [IQR]), or n (%)

Glu glucose, TC total cholesterol, TG triglyceride, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, ApolA1 apolipoprotein A1, ApolB apolipoprotein B, t Independent t‑test, w Nonparametric statistics (median, IQR, Mann–Whitney test)

VDS scores

Between February 2014 and February 2016, 89 (62.24%) patients with dysphagia underwent VFSS. The VDS scores for these patients are presented in Fig. 1. The patients showed a high incidence of vallecular residue (100%), apraxia (99%), premature bolus loss (98%), bolus formation (98%), pyriform sinus residue (95%), and mastication (94%). The oral transit time (78%), triggering of pharyngeal swallow (66%), pharyngeal transit time (57%), laryngeal elevation (55%), and coating of the pharyngeal wall (54%) were the most seriously affected parameters.
Fig. 1

Videofluoroscopic dysphagia scale (VDS) scores for patients with dysphagia induced by radiotherapy. A high incidence of vallecular residue (100%), apraxia (99%), premature bolus loss (98%), bolus formation (98%), pyriform sinus residue (95%), and mastication (94%) was observed. The oral transit time (78%), triggering of pharyngeal swallow (66%), pharyngeal transit time (57%), laryngeal elevation (55%), and coating of the pharyngeal wall (54%) were the most seriously affected parameters

Correlation between QOL and swallowing function after radiotherapy

With regard to QOL, scores of the physical health (P = 0.004), psychological (P = 0.0003), and environment (P = 0.024) domains of WHOQOL-BREF were significantly lower in the dysphagia group than in the control group (Fig. 2). VDS scores showed significant negative correlations with scores of the physical health (R = −0.66, P < 0.001), psychological (R = −0.70, P < 0.001), social relationships (R = −0.56, P < 0.001), and environment (R = −0.61, P < 0.001) domains of WHOQOL-BREF (Fig. 3).
Fig. 2

Quality of life for patients with or without (controls) dysphagia after radiotherapy. Quality of life was assessed by the World Health Organization Quality of Life instrument (WHOQOL-BREF). abc, and d show the scores for the physical health, psychological health, social relationships, and environment domains of WHOQOL-BREF for patients with dysphagia and control patients (a P = 0.004, b P = 0.0003, c P = 0.111, d P = 0.024)

Fig. 3

Correlations between videofluoroscopic dysphagia scale (VDS) scores and four domains of WHOQOL-BREF in patients with dysphagia. a Correlation between the VDS score and the score for the physical health domain of WHOQOL-BREF (R = −0.66, P < 0.01). b Correlation between the VDS score and the score for the psychological health domain of WHOQOL-BREF (R = −0.70, P < 0.01). c Correlation between the VDS score and the score for the social relationships domain of WHOQOL-BREF (R = −0.56, P < 0.01). d Correlation between the VDS score and the score for the environment domain of WHOQOL-BREF (R = −0.61, P < 0.01)

Discussion

In the present study, we found that radiotherapy-induced dysphagia occurred in 42.8% patients with NPC and resulted in a poor QOL in this patient population. The incidence of radiotherapy-induced dysphagia in our study was consistent with previous studies, which showed that swallowing difficulty occurred in 48.4% of irradiated patients with NPC [10]. Furthermore, our study demonstrated that radiation dose for the nasopharyngeal region, the N3 stage, neoadjuvant and concurrent chemotherapy were predictors for dysphagia.

In patients treated with radiotherapy, dysphagia occurs secondary to conditions characterized by damage to neural and soft tissues [22], such as soft tissue fibrosis, lymphedema, scar tissue formation, and neurological impairment [23]. Specifically, dysphagia is caused by poor synchronization between pharyngeal contractions, opening of the upper esophageal sphincter (UES), and larynx closure [24]. In addition, radiotherapy often alters the sensitivity of the swallowing structures, which may result in a deficient cough reflex and silent aspiration. Therefore, clear identification of the swallowing status is of great importance to ensure the selection of optimal treatment strategies.

Our results showed that in patients with IMRT, N3 stage, neoadjuvant and concurrent chemotherapy were predictors for dysphagia. Radiotherapy has been the standard treatment for NPC, and the application of IMRT with a better normal tissue sparing, together with the administration of chemotherapy may improves patients’ survival and minimizes the risks of radiation-induced long-term adverse effects [25, 26]. Chen J et al. analyzed the clinical and prognostic factors for pediatric NPC and found that the N stage was a significant factor for survival [27]. In this study we further demonstrated that N3 stage was an adverse factor of dysphagia. Consistent with our study, Wang W et al. also suggested that the N stage and chemotherapy were the main prognostic factor for the overall survival in NPC patients with IMRT. In the present study, total cholesterol, LDL-C, and albumin levels were significantly lower in the dysphagia group than in the control group (Table 3). The lower albumin levels may be related to malnutrition caused by dysphagia. Swallowing abnormalities was reported to result in dietary adaptations that may cause nutritional deficiencies, including lower albumin in head and neck cancer patients [28]. Silvia Carrion et al. also suggested that patients with oropharyngeal dysphagia presented lower albumin [29]. The cholesterol metabolism is complex with many determinants including hereditary conditions. Prospective studies will be required for the interaction between cholesterol and dysphagia.

VFSS is the gold standard for the evaluation and management of swallowing function. In the present study, 89 of the 143 patients with dysphagia underwent VFSS. A higher VDS score indicates more severe dysphagia [17]. In our study, vallecular residue, apraxia, premature bolus loss, bolus formation, pyriform sinus residue, and mastication were observed in the majority of patients. Oral and pharyngeal phase dysphagia is prevalent in patients with NPC, and we found that the oral transit time, triggering of pharyngeal swallow, pharyngeal transit time, laryngeal elevation, and coating of the pharyngeal wall were the most seriously affected parameters in our patients. Food residue is associated with a decreased tongue driving pressure [30]. Kapur et al. described that the muscle tissue contained deposits of collagen and remained damaged and swollen after radiotherapy [31]. Moreover, the muscle cells were replaced by fibrillar collagen bundles combined with hyaline in the irradiated area. These changes resulted in the loss of normal muscle cells, weakening of the muscle power, and stiffening of the soft tissue. The characteristics of dysphagia in the present study differ from those in previous studies. Chang et al. [10] performed VFSS and found that aspiration was a major problem at 10 years after radiotherapy in patients with NPC. Hughes et al. [31] also performed VFSS and documented a high incidence of laryngeal penetration and aspiration in the chronic phase following radiotherapy for NPC. Wu et al. identified that as many as 83.9% patients had laryngeal penetration or aspiration by using fiberoptic endoscopic evaluation of swallowing [32]. However, in the present study, aspiration was observed in 56% patients, presumably because of the short follow-up time. Furthermore, in our study, pharyngeal function was impaired in the majority of patients. Consistent with our findings, Patterson et al. suggested that pharyngeal function was the most commonly impaired parameter after radiotherapy for NPC [33].The upper and middle pharyngeal constrictor muscles allow elevation of the larynx and contraction of the pharynx to generate bolus propulsion [34]. Therefore, a radiotherapy volume that avoids these muscles is very important for the preservation of swallowing function, but it must be carefully considered. Meanwhile, patients should be educated about the signs and symptoms of aspiration and be instructed to report them immediately to their healthcare providers. Clinicians should investigate the signs and symptoms that would herald dysphagia or aspiration after radiotherapy [35]. In order to increase the range of movement of the tongue, lips, and jaw, indirect (exercise to strengthen the swallowing muscles) and direct (postural exercises while swallowing) exercises should be suggested for patients with dysphagia [36, 37].

In the present study, we found that VDS scores were significantly and negatively correlated with the scores for all four WHOQOL-BREF domains (Fig. 3). Patients with dysphagia have a significant dysphagia-related burden, experience difficulty in finding foods they can both eat and enjoy, and require much effort to finish a meal [12]. These factors may limit their desire to eat. Dysphagia-related burden and extended mealtimes significantly affect the physical and psychological health of patients. The aim of care is to maximize QOL and minimize symptom. VDS and QOL evaluation may inform the clinician of the impact of dysphagia on QOL of each patient, and be used to guide the clinical management and rehabilitation strategies for swallowing difficulties, particularly late radiotherapy-induced toxicity. The management of radiotherapy-induced dysphagia should be implemented in collaboration with cross-disciplinary colleagues (including neurology, speech therapy, and physiotherapy specialists) in order to address the effects of dysphagia on physical and psychosocial health.

We used both objective assessments and patient reports to assess the clinical outcomes of radiotherapy-induced dysphagia and investigated the correlation between subjective and objective measurements of swallowing status in our patients with NPC. The findings support the fact that dysphagia is a long-term consequence of radiotherapy for NPC, although the underlying mechanism in this particular patient population remains unclear and is an area for future investigation. These findings may facilitate future targeted clinical trials on the treatment of dysphagia in patient with NPC treated by radiotherapy.

Limitations

This study has some limitations. First, certain factors such as the implementation of swallowing exercises immediately after radiotherapy were not considered and may have limited the applicability of our findings. Second, the relatively small sample size limited our capacity to identify more information concerning dysphagia after radiotherapy for NPC. Next, we did not use a swallowing-related questionnaire (SWAL-QOL) to focus on the effects of swallowing impairment on QOL. Finally, the study used a cross-sectional design, which may be inadequate to collect the data of the cholesterol, albumin, body mass index (BMI) and other nutritional status prior to radiotherapy. However, we suppose that this would not affect our results. Nevertheless, larger prospective studies will be required to clarify our findings.

Conclusions

Our findings suggest that dysphagia is common after radiotherapy in patients with NPC. Radiotherapy combined the chemotherapy might reduce the incidence of dysphagia. VDS scores showed significant negative correlations with scores for the physical health and psychological, social relationships, and environment domains of WHOQOL-BREF. This highlights the importance of clinical swallowing exercises and suggests potential therapeutic targets for radiotherapy-induced dysphagia. The aim of care is to maximize QOL and minimize symptom burden. Therefore, collaboration with cross-disciplinary colleagues (including neurologists, physical therapists, oncologists, and respiratory specialists, among others) is necessary in order to address the effects of radiotherapy-induced dysphagia on physical and psychosocial health. Such targeted therapies will prevent patient from fatigue and improve the curative effects. We believe that our study will contribute to further development of the definition of radiotherapy-induced dysphagia and treatment strategies for patients with NPC in daily clinical practice.

Notes

Author Contributions

H. Li, L. Li and X. Huang, Yimin Liu and Yamei Tang contributed equally to the study. Honghong Li, data acquisition and evaluation, manuscript writing. Liting Li, data collection, analysis and interpretation. Xiaolong Huang, data analysis, drafting and manuscript revision. Yi Li, data collection and analysis. Tangjie Zou, data collection. Xiaohuang Zhuo, data interpretation, manuscript revision. Yan Chen, data collection. Yimin Liu, manuscript revision. Yamei Tang, study conception and design, manuscript revision, and approval of the version to be published.

Funding

This study was funded by National Natural Science Foundation of China (No. 81471249, 81622041), Major Program of Collaborative Innovation Specialized in Livehood Science Topics (201604020097), Science and Technology Planning Project of Guangdong Province (2016A050502016), and Tip-top Scientific and Technical Innovative Youth Talents of the Guangdong special support program (No. 2016TQ03R559) to Yamei Tang. Science and Technology Planning Project of Guangzhou (201704030033), and Young Teacher Training Program of Sun Yat-sen University (17ykpy38) to Yi Li.

Compliance with ethical guidelines

Conflict of interest

H. Li, L. Li, X. Huang, Y. Li, T. Zou, X. Zhuo, Y. Chen, Y. Liu and Y. Tang declare that they have no competing interests.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Honghong Li
    • 1
  • Liting Li
    • 2
  • Xiaolong Huang
    • 3
  • Yi Li
    • 1
  • Tangjie Zou
    • 1
  • Xiaohuang Zhuo
    • 1
  • Yan Chen
    • 1
  • Yimin Liu
    • 2
    Email author
  • Yamei Tang
    • 1
    • 4
    • 5
    Email author
  1. 1.Department of Neurology, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou, Guangdong ProvinceChina
  2. 2.Department of Radiation Oncology, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.Department of Intensive Care MedicineThe First Affiliated Hospital of Xiamen UniversityXiamen cityChina
  4. 4.Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  5. 5.Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhouChina

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