Abstract
Aim:
Intensity-modulated radiotherapy (IMRT) is a widely accepted therapy for nasopharyngeal carcinoma (NPC), but it inevitably brings out radiation-related complications and seriously affects the quality of life (QoL). Endoscopic nasopharyngectomy (ENPG) has been successfully conducted in locally recurred NPC, but few studies evaluated its application in early NPC. This study aims to assess the feasibility and safety of ENPG combined with low-dose radiotherapy (LDRT) in T1-2 NPC.
Patients and Methods:
We recruited 37 newly diagnosed localized T1-2 NPC patients who voluntarily accepted ENPG +LDRT from June 2013 to September 2016. Meanwhile, the data of 132 T1-2 NPC patients treated with IMRT were collected and used as control group. The survival outcomes, QoL score and late RT-related sequelaes were compared between the 2 groups.
Results:
After a median follow-up of 54 months, only 1 patient in ENPG+LDRT group died along with hepatic metastases. The 5-year overall survival, distant metastasis-free survival, local relapse-free survival and regional relapse-free survival in ENPG+LDRT group were 97.3%, 97.3%, 100% and 100%, which were not statistically different from the control group (97.7%, 90.2%, 95. 5%, 97.0%, respectively, all P > 0.05). In comparison with IMRT group, ENPG+LDRT exhibited better QoL and less rate of late RT-related sequlaes including hearing loss (53.8% vs 27.0%, P = 0.005), xerostomia (46.2% vs 24.3%, P = 0.023) and dysphagia (25.8% vs 8.1%, P = 0.024).
Conclusions:
ENPG+LDRT provided satisfactory survival outcomes, and improved the QoL and reduced the incidence of sequelae for T1-2 NPC patients.
Keywords: nasopharyngeal carcinoma, endoscopic nasopharyngectomy, intensity-modulated radiotherapy, low-dose radiotherapy, quality of life
Introduction
Nasopharyngeal carcinoma (NPC) is highly prevalent in southeastern China and other Asian countries, where the incidence even reaches to 50/100,000 people per year.1 According to the World Health Organization (WHO) standards, the histopathologic type of NPC is divided into keratinized and non-keratinized types, grade of which is classified into differentiated and undifferentiated types, and more than 90% them are undifferentiated non-keratinizing.2 Because of the special anatomical location of the nasopharynx, early local NPC is hard to detected, and most cases are in the advanced stage when they are diagnosed.3 These clinical and biological characteristics of NPC and its high sensitivity to radiotherapy limit the application of surgery and make radiotherapy (RT) an unassailable track record as the backbone of NPC therapy.
Up to date, intensity-modulated RT (IMRT) is the standard RT modality, it provides a high dose of radiation to the tumor bed to achieve local control and protects surrounding structures form high-dose radiation damage. However, NPC patients continue to suffer from a high rate of severe RT-related complications because of high doses of radiation.4 Recently, several studies reported that low-dose radiotherapy (LDRT) can achieve long-term tumor control with mild late toxicities for T1-2 NPC patients, but the rate of reoccurrence is relatively high.5,6 With the popularity of health education and the development of early cancer screening methods such as narrow band imaging technique, plasma Epstein-Barr virus (EBV) DNA screening and nasopharyngeal brushing samples detection, the detection rate of early-stage NPC in high-risk groups has been greatly improved, making it possible to perform endoscopic nasopharyngectomy (ENPG) for these NPC patients.7,8 Previous publications have observed that salvage ENPG were successfully conducted in recurrent NPC patients and resulted in better survival outcomes and less occurrence of complications than IMRT.9 Therefore, it is theoretically feasible to apply ENPG to resect localized early-stage NPC and avoid RT-related sequlae. In a recent study, Liu et al 10 treated 10 localized stage I NPC patients with single ENPG, and these patients all got good long-term survival outcomes with zero recurrence and satisfactory QoL. However, the number of patients in that study was small and the risk of tumor recurrence is uncertain, which limits its wide applications. In the present study, we reported the application of ENPG+LDRT in patients with newly diagnosed localized T1-2 NPC, and evaluated the long-term survival outcomes, QoL and late treatment-related sequelae of this regimen and assessed whether it may become an alternative regimen for conventional treatment.
Patients and Methods
Patient Population
One hundred sixty-nine newly diagnosed localized T1-2 NPC patients from June 2013 to September 2016 in the inpatient system of People’s Hospital of Guangxi Zhuang Autonomous Region were recruited. All patients met the following inclusion criteria: (1) newly diagnosed early-stage (T1-2N0-1) NPC according to the 2007 NPC staging of the Union for International Cancer Control (UICC); (2) no previous treatment for NPC; (3) age ranges from 18 to 70 years old; (4) patients with Karnofsky performance status score ≥ 80; (5) patients voluntarily participated and signed informed consents. We exclude the following patients: (1) T2 patients with oropharynx or posterior parapharyngeal space, or patients with parapharyngeal lymph node enlargement; (2) tumor basis diameter > 1.5 cm, or occupied the entire nasopharyngeal cavity; (3) with bone, liver, lung or other distant metastasis; (4) with severe heart, liver and kidney damage and related diseases; (5) history of another malignant tumor. Before onset of treatment, all patients received essential clinical and laboratory examinations, including magnetic resonance imaging (MRI), B ultrasound, chest X-ray, and hematologic and biochemistry profiles, and etc. The present study was approved by the ethical committee of People’s Hospital of Guangxi Zhuang Autonomous Region (No: KY-SY-2013-1), and all patients provided preoperative written informed consent.
Treatment Protocols
All patients were divided into ENPG+LDRT group and IMRT group based on the treatment protocols. In the ENPG+LDRT group, the detailed procedures of ENPG were performed as previous publications described.10,11 Surgical instruments adopt the German KARL STORZ endoscopic system, and preoperative gross tumor volume (GTV) and high-risk clinical target volume (CTV) in radiotherapy were used to determine the tumor infiltration area and surgical margin.12 Surgical margin was defined as the tumor invasion regions plus at least 5 mm of normal peripheral mucosa and 3 mm basal margin on the posterior bone surface and the clivus in the skull base. Intraoperative biopsies were performed at peripheral and basal incision lines to ensure safety of the surgical margins (Figure 1A-C). First, we removed the posterior part of the nasal septum and separated the mucous membrane of the posterior nasopharyngeal wall from the sphenoid bone surface to the clivus the resection of bilateral cartilaginous tube auditive. The vascular pedicle above the posterior nostril was left to repair the nasopharyngeal defect. All patients received IMRT in the radiation regimen, the target area was sketched according to the tumor image form MRI. The radiotherapy dose in the ENPG+LDRT group was 56.63 ± 13.36 Gy, and 70.69 ± 1.85 Gy in the IMRT group. Clinical stage II Patients were administrated with 3 cycles chemotherapy, including cisplatin (40 mg/m2), carboplatin (500 mg/m2), and flurouracil (2000 mg/m2), with intervals of 21 days between cycles.
Figure 1.
Comparisons of preoperative magnetic resonance imaging and endoscopic images to postoperative results. (A-C) T1-weighted magnetic resonance imaging in horizontal, coronal and sagittal planes showed tumor infiltration area (red line) and scope of operation (yellow line) before surgery. (D) Preoperative endoscopic image showed the tumor was in the right superior wall of the nasopharynx, which infiltrated into the bilateral pharyngeal recesses and eustachian tubes. (E-G) T1-weighted magnetic resonance imaging in horizontal, coronal and sagittal planes showed extent of surgical depletion, at 3 days after surgery. The scope of the excision is consistent with the plan (yellow line). (H) Intraoperative endoscopic image (I-K) T1-weighted magnetic resonance imaging in horizontal, coronal and sagittal planes found no signs of tumor recurrence, at 6 years after surgery. (L) Contemporaneous endoscopic image showed well epithelized nasopharyngal mucous membrane and no signs of tumor recurrence.
Operation Effectiveness Evaluations
In the ENPG+LDRT group, the success of the operation was assessed by our NPC team. Evaluation of compliance with the conditions of radical resection: (1) no residual tumor under the endoscope during the operation (Figure 1D, H); (2) pathological examination of the incisional mucosa was negative; (3) comparison of pre- and post-operative MRI changes to determine whether it matched the planned excision extension on 1 week following surgery (Figure 1 A-C, E-G).
Follow-Up
The last follow-up date was on 15 August, 2019. During post-operation follow-up, nasal endoscopy was performed every 2-3weeks to evaluate the wound reconstruction until mucosal epithelialization. Subsequent follow-up evaluations were conducted every 3-6 months. The auxiliary examinations including nasopharyngoscopy, MRI of neck, chest radiography and ultrasonography were performed at each follow-up visit.
Patients’ Health-Related Quality of Life
Assistant nurses asked all follow-up cases to fill out the questionnaires, including The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, version 3.0 (EORTC QLQ-C30) and The EORTC Quality of Life Questionnaire–Head and Neck Module (EORTC QLQ-H&N35).13 Ten common RT-related complications were recorded simultaneously, and then the differences between the 2 groups were compared.
Statistical Analysis
Chi-square test and Mann–Whitney U test were used to analyze categorical variables and continuous variables, respectively. The survival results were calculated by the Kaplan-Meier method, and the log-rank test was performed to compare the differences. All analyses were performed by SPSS software (version 23.0). Double-tailed P < 0.05 was considered statistically significant.
Results
Patient Characteristics
A total of 169 newly diagnosed localized T1-2 NPC patients were recruited in the study. Among these patients, 39 patients were included in the ENPG+LDRT group and 132 patients in the IMRT group. In the ENPG+LDRT group, the average RT dose was 58.6 ± 0.9 Gy, which was significantly lower than in the IMRT group (70.7 ± 1.9 Gy, P < 0.001). There is no statistic difference in age, gender, BMI, smoking history, Karnofsky performance status score, T stage, N stage, clinical stage and chemotherapy between 2 groups (Table 1).
Table 1.
Characteristics of NPC Patients According to Their Therapeutic Regimen.
| Variable | IMRT (n = 132) |
ENPG+LDRT (n = 37) |
P value |
|---|---|---|---|
| Age (years) | 47.6 ± 10.8 | 46.1 ± 10.6 | 0.454 |
| Gender | 0.841 | ||
| Male | 92 (69.7) | 25 (67.6) | |
| Female | 40 (30.3) | 12 (32.4) | |
| BMI (kg/m2) | 23.6 ± 2.6 | 24.1 ± 2.9 | 0.315 |
| Smoking history | 0.542 | ||
| No | 96 (72.7) | 25 (67.6) | |
| Yes | 36 (27.3) | 12 (32.4) | |
| Karnofsky performance status score | 85.2 ± 4.7 | 86.4 ± 5.6 | 0.191 |
| T stage | 0.161 | ||
| 1 | 37 (28.0) | 15 (40.5) | |
| 2 | 95 (72.0) | 22 (59.5) | |
| N stage | 0.338 | ||
| 0 | 80 (60.6) | 26 (70.3) | |
| 1 | 52 (39.4) | 11 (29.7) | |
| Clinical stage | 0.296 | ||
| Ⅰ | 33 (25.0) | 13 (35.1) | |
| Ⅱ | 99 (75.0) | 24 (64.9) | |
| Radiotheapy dose (Gy) | 70.7 ± 1.9 | 58.6 ± 0.9 | <0.001 |
| Chemotherapy | 0.296 | ||
| No | 33 (27.3) | 13 (37.8) | |
| Yes | 99 (72.7) | 24 (62.2) |
IMRT, intensity-modulated radiotherapy; ENPG, endoscopic nasopharyngectomy; LDRT, low-dose radiotherapy; BMI, body mass index.
Bold values indicate statistically significant, P < 0.05.
Survival Outcomes
After a median follow-up of 54 months, only 1 case in the ENPG+LDRT group died along with hepatic metastases, and no patient developed tumor recurrence. In the IMRT group 3 cases died, 13 cases developed distant metastasis, and 6 cases developed local recurrence and 4 cases regional recurrence. The 5-year overall survival (OS), distant metastasis-free survival (DMFS), local relapse-free survival (LRFS) and regional relapse-free survival (RRFS) of patients in ENPG+LDRT group was 97.3%, 97.3%, 100% and 100%, which were not statistically different from the IMRT group, 97.7%, 90.2%, 95.5% and 97.0%, respectively (all P > 0.05) (Figure 2).
Figure 2.
Kaplan–meier survival curves for NPC patients according to their therapeutic regimen. (A) Overall survival, (B) distant metastasis-free survival, (C) local relapse-free survival, and (D) regional relapse-free survival.
Life of Quality Outcomes and Late RT-Related Sequelaes
All participants completed the questionnaires of EORTC QLQ-C30 and EORTC QLQ-H&N35. Patients in the ENPG+LDRT exhibited significantly better QoL outcomes than IMRT group, particularly in items of cognitive functioning (97.6 ± 2.7 vs 95.6 ± 4.2, P = 0.007), social functioning (98.4 ± 4.1 vs 96.2 ± 3.0, P < 0.001), Pain (12.8 ± 4.7 vs 16.2 ± 5.6, P = 0.001), dyspnea (12.6 ± 5.7 vs 23.5 ± 7.3, P < 0.001), swallowing (11.3 ± 6.0 vs 23.9 ± 7.9, P < 0.001), social eating (12.5 ± 5.4 vs 16.7 ± 6.9, P < 0.001), social contacts (5.3 ± 3.0 vs 8.4 ± 4.6, P < 0.001) and dry mouth (20.1 ± 13.9 vs 31.7 ± 17.6, P < 0.001) (Table 2). Compared to IMRT group, patients in the ENPG+LDRT suffered less late RT-related sequlaes including hearing loss (53.8% vs 27.0%, P = 0.005), xerostomia (46.2% vs 24.3%, P = 0.023) and dysphagia (25.8% vs 8.1%, P = 0.024) (Table 3).
Table 2.
Inquiry of Quality of Life Using the QLQ-C30 and QLQH&N35 Scales.
| Observational items | IMRT (n = 132) | ENPG+LDRT (n = 37) | P value |
|---|---|---|---|
| QLQ-C30 | |||
| Global health status | 91.7 ± 3.2 | 93.4 ± 8.5 | 0.062 |
| Functional scales | |||
| Physical functioning | 96.3 ± 3.1 | 97.3 ± 4.2 | 0.112 |
| Role functioning | 96.4 ± 3.8 | 97.1 ± 3.5 | 0.316 |
| Emotional functioning | 97.9 ± 2.6 | 98.7 ± 2.8 | 0.106 |
| Cognitive functioning | 95.6 ± 4.2 | 97.6 ± 2.7 | 0.007 |
| Social functioning | 96.2 ± 3.0 | 98.4 ± 4.1 | <0.001 |
| Symptom scales | |||
| Fatigue | 24.3 ± 7.0 | 25.2 ± 3.0 | 0.448 |
| Nausea/vomiting | 4.2 ± 3.1 | 3.7 ± 3.0 | 0.384 |
| Pain | 16.2 ± 5.6 | 12.8 ± 4.7 | 0.001 |
| Dyspnea | 23.5 ± 7.3 | 12.6 ± 5.7 | <0.001 |
| Insomnia | 19.6 ± 6.2 | 17.8 ± 4.6 | 0.102 |
| Appetite loss | 16.4 ± 8.6 | 13.7 ± 6.4 | 0.078 |
| Constipation | 11.0 ± 3.5 | 9.9 ± 4.1 | 0.106 |
| Diarrhea | 5.2 ± 2.5 | 4.5 ± 2.0 | 0.119 |
| Financial difficulties | 10.2 ± 3.6 | 9.4 ± 2.4 | 0.205 |
| QLQ-H&N35 score | |||
| Pain | 10.5 ± 7.4 | 9.8 ± 4.7 | 0.586 |
| Swallowing | 23.9 ± 7.9 | 11.3 ± 6.0 | <0.001 |
| Senses | 20.2 ± 10.7 | 18.9 ± 9.5 | 0.505 |
| Speech | 11.0 ± 4.5 | 9. 6 ± 3.2 | 0.079 |
| Social eating | 16.7 ± 6. 9 | 12.5 ± 5.4 | 0.001 |
| Social contacts | 8.4 ± 4.6 | 5.3 ± 3.0 | <0.001 |
| Sexuality | 27.5 ± 11.6 | 25.1 ± 10.2 | 0.256 |
| Teeth | 11.5 ± 10.0 | 10.4 ± 7.8 | 0.537 |
| Opening mouth | 13.2 ± 10.5 | 10.67 ± 7.8 | 0.175 |
| Dry mouth | 31.7 ± 17.6 | 20.1 ± 13.9 | <0.001 |
| Sticky saliva | 17.2 ± 10.3 | 15.8 ± 11.7 | 0.479 |
| Coughing | 22.5 ± 17.6 | 19.9 ± 16.3 | 0.421 |
| Feeling ill | 11.3 ± 8.4 | 9.8 ± 7.3 | 0.324 |
| Pain killers | 11.7 ± 7.6 | 9.7 ± 4.8 | 0.131 |
| Nutritional supplement | 20.4 ± 14.3 | 18.9 ± 16.2 | 0.585 |
| Feeding tube | 6.4 ± 3.1 | 5.7 ± 2.7 | 0.214 |
| Weight loss | 14.3 ± 7.4 | 12.8 ± 6.9 | 0.271 |
| Weight gain | 11.5 ± 5.6 | 10.3 ± 4.8 | 0.237 |
IMRT, intensity-modulated radiotherapy; ENPG, endoscopic nasopharyngectomy; LDRT, low-dose radiotherapy.
Bold values indicate statistically significant, P < 0.05.
Table 3.
Late Treatment-Related Sequlae (n, %).
| Sequelae | IMRT n = 132 |
ENPG+LDRT n = 37 |
P value |
|---|---|---|---|
| Hearing loss | 71 (53.8) | 10 (27.0) | 0.005 |
| Xerostomia | 61 (46.2) | 9 (24.3) | 0.023 |
| Neck fibrosis | 26 (19.7) | 6 (16.2) | 0.813 |
| Radiation encephalopathy | 12 (9.1) | 2 (5.4) | 0.737 |
| Cranial nerve palsy | 11 (8.3) | 2 (5.4) | 0.736 |
| Stomatitis | 21 (15.9) | 7 (18.9) | 0.626 |
| Dysphagia | 34 (25.8) | 3 (8.1) | 0.024 |
| Trismus | 18 (13.6) | 3 (8.1) | 0.573 |
| Dermatitis | 31 (23.5) | 12 (32.4) | 0.290 |
| Temporal bone necrosis | 6 (4.5) | 1 (2.7) | 1.000 |
IMRT, intensity-modulated radiotherapy; ENPG, endoscopic nasopharyngectomy; LDRT, low-dose radiotherapy.
Bold values indicate statistically significant, P < 0.05.
Discussion
To the best of our knowledge, the present study was the first one to evaluate the efficacy and safety of ENPG+LDRT in the treatment of localized T1-2 NPC patients compared to IMRT alone. We found similar survival outcomes, including 5-year overall survival, distant metastasis-free survival, local relapse-free survival and regional relapse-free survival, between ENPG+LDRT group and IMRT group. Moreover, ENPG+LDRT exhibited better QoL and less rate of late RT-related sequlaes.
Currently, IMRT is the standard RT modality for NPC patients and it provides satisfactory disease control.14 However, it does not significantly improve the QoL of patients and continues to induce a high rate of RT-related complications after exposing to high dose of radiation.15 Therefore, more and more researchers try to explore innovative strategies to decrease the radiation dose and improve the QoL, especially in early-stage NPC patients. Miao and colleagues treated NPC patients with LDRT, and found this treatment could achieve long-term tumor control with mild late toxicities, but the rate of recurrence and metastasis was relatively high.5 With the development of the endoscopic technique, ENPG was widely used in the recurrent NPC patients, and it showed fewer invasions, better treatment effect and QoL than re-radiotherapy.16 In a recent study, researchers tried to utilize single ENPG to treat localized stage I NPC patients and found ENPG exhibited encouraging survival results, better QoL and less medical cost.10 However, Huang et al doubted the safety and feasibility of this innovative surgery for its uncertain tumor recurrence rate. In the present study, we combined ENPG and LDRT to treat the localized T1-2 NPC patients and observed that ENPG+LDRT presented with similar survival outcomes in comparison with IMRT. This suggests that ENPG+ LDRT could be technically feasible for primary localized T1-2 NPC patients.
Nowadays, effective disease control is relatively easily achieved with a variety of available treatments, NPC patients come to pursue individualize treatments to achieve the best possible results, better QoL and lower risk of late complications. Although IMRT is classic treatment for NPC patients and the survival time of patients is significantly prolonged, the late toxicity of IMRT is increasingly affecting the QoL of patients, including xerostomia, pharyngitis sicca, neck dermatitis, hearing loss, radiation-induced cranial neuropathy, encephalopathy, pneumonitis and osteoradionecrosis.14,17 In general, severe radiotherapy toxicity is directly related to the dose and volume absorbed by the normal tissue.17 In the present study, the average radiotherapy dose was 58.6 ± 0.9 Gy, which was significantly lower than conventional RT and IMRT. Patients in the ENPG+LDRT exhibited significantly better QoL outcomes, particularly in items of cognitive functioning, social functioning, pain, dyspnea, swallowing, social eating, social contacts and dry mouth. We also found that patients in the ENPG+LDRT suffered less late RT-related sequlaes including hearing loss, xerostomia and dysphagia in comparison with IMRT group. With this de-intensification technique, the treatment time was shortened and the health care resources were utilized more efficiently.
The present study has several limitations. First, this study is a retrospective analysis of collected clinical data which inevitably suffers the risk of selection bias. Second, the sample in this study was relatively small. All above problems may decrease the reliability of conclusion.
Conclusion
In primary localized T1-2 NPC, ENPG + LDRT provides survival outcome comparable to that with IMRT, and significantly improves the QoL and reduces late RT-related sequlaes.
Well-designed large randomized clinical trials are needed to confirm our findings and to help formulate individualized therapies for these patients.
Footnotes
Author Contributions: Benjian Zhang and Yiliang Li contributed equally to this work.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Guangxi Zhuang Automomous Region Key Research an Development Program (No. AB19259002 and No. 14124003-3), Guangxi Zhuang Automomous Region Health Commission Self-funded Research Project (No. Z20190741 and No. Z20190704), and a grant of Guangxi Science and Technology Base and Talent Project (Guangxi Nasopharygeal Carcinoma Clinical Medicine Research Center).
ORCID iD: Yongfeng Si, MD 
https://orcid.org/0000-0003-4046-2480
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