A total of 490 patients who were newly diagnosed with stage I NPC were identified from an inpatient database at the Sun Yat-sen University Cancer Center (Guangzhou, China) from June 2007 to September 2017.
Our NPC research team, consisting of head and neck surgeons, radiation oncologists, medical oncologists, pathologists, radiologists, and nuclear medicine physicians, established the indication, relative contraindication, and absolute contraindication criteria for applying ENPG in the localized stage I NPC.
The indication criteria for ENPG were: (1) had a maximum diameter of the primary tumor ≤ 1.5 cm; (2) distance of the tumor margin to the internal carotid artery was ≥ 0.5 cm; (3) the minimal axial diameter in magnetic resonance imaging (MRI) was no more than 0.4 cm for retropharyngeal lymph nodes (RPLN) and 0.6 cm for cervical lymph node (CLN). Relative contraindications criteria for ENPG were: (1) exogenous tumor diameter > 1.5 cm but tumor basis ≤ 1.5 cm; (2) RPLN and CLN ranged 0.4–0.5 cm and 0.6–1.0 cm, respectively, for minimal diameter but was proved negative by 18F-fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) or pathology. Absolute contraindications criteria for ENPG were: (1) tumor basis diameter > 1.5 cm, or occupied the entire nasopharyngeal cavity; (2) T2–T4 primary tumor, i.e. tumor involving to or beyond the pharyngobasilar fascia; (3) N1–N3 regional lymph node metastasis. i.e. LN with central necrosis or annular enhancement, or groups of two or more lymph nodes (the minimal diameter ≥ 8 mm for CLN), or minimal diameter ≥ 0.5 cm for RPLN, or minimal diameter ≥ 1.0 cm for CLN; (4) had distant metastasis, i.e. bone, liver, or lung metastasis; (5) was physiologically unsuitable for surgery.
In the present study, the inclusion and exclusion criteria for applying ENPG were as follows:
Inclusion criteria: (1) all patients were previously untreated, pathologically diagnosed with undifferentiated or differentiated, keratinizing or nonkeratinizing NPC; (2) staged as T1N0M0 classification; stage I according to the 8th edition staging system of the American Joint Committee on Cancer [AJCC], referring to primary tumors confined in the nasopharyngeal cavity, and the RPLN and CLN were no more than 0.5 cm and 1.0 cm respectively. Of note, the inclusion criteria also comprised of patients with relative contraindications. Exclusion criteria: (1) in accordance with the absolute contraindications criteria; (2) without intention to surgery.
All patients provided preoperative written informed consent. The study was approved by the ethical committee of Sun Yat-Sen University Cancer Center.
The detailed procedures for administrating ENPG were performed as previously reported [9, 10]. All operations were performed under systemic anesthesia with an electrotome guided by a 4-mm rigid endoscope (0° and 30°, Karl-Storz, Tuttlingen, Germany).
Before the operation, our NPC research team first defined the tumor invasion regions and surgical margins for high-risk microinvasion regions, such as gross tumor volume (GTV) and high risk clinical target volume (CTV1) in radiotherapy, respectively . In principle, surgical margins were defined as the tumor invasion regions plus an additional 0.5–1.0 cm peripheral mucosal margin and a 2–3 mm basal margin on the surface of the sphenoid bone and the clivus in the skull base (Fig. 2a–c). The surgeons were required to strictly follow this planned surgical boundary to remove the tumor during the dissection.
Commonly, the posterior column of the nasal septum was first removed, then the mucoperiosteum in the roof wall of the nasopharynx was separated from the surface of the sphenoid to the clivus. After excising the bilateral eustachian cartilage from the pharyngeal recess under the mucous membrane and foramen lacerum, we separated the posterior nasopharyngeal mucoperiosteum along the clivus. After that, the mucoperiosteum at the level of the soft palate from the surface of the prevertebral muscle was isolated and subsequently turned upward to meet the other resection margins. Thus, the whole nasopharyngeal cavity mucosa including the swelling around the tumor was removed en bloc. To recover the defect, the nasal septum and floor mucosa were separated from the surface of the bone, and only a narrow posterior pedicle above the posterior naris remained to contain the posterior septal artery. The flap was then gently rotated backward and unrolled to cover the nasopharyngeal defect.
Radiotherapy was administered with IMRT techniques. Target volumes definition were as previously reported . The prescribed dose was 66–70 Gy, 60–62 Gy, and 54–56 Gy, in 28–33 fractions, for the planning target volumes (PTVs) derived from GTV, CTV1, and the low-risk clinical target volume (CTV2), respectively. GTV was determined by physical examination, imaging (including MRI and PET/CT, if available) and endoscopic findings. CTV1 was defined as the GTV region plus an additional anterior, superior, inferior and lateral margin of 5 mm to 1 cm and an additional posterior margin of 2 mm to 3 mm (the range of extension was determined by adjacent structural characteristics), the CTV1 volume also included the entire mucosal stratum and 5 mm of submucosal stratum of the nasopharynx. The CTV2 was defined as the CTV1 region plus an additional anterior, superior, inferior, and lateral margin of 5 mm to 10 mm and an additional posterior margin of 2 mm to 3 mm, and bilateral upper neck lymph node groups that were at risk of potential microscopic spread of disease . Simultaneously integrated boost, with 5 fractions per week, was adopted.
The success of the operation was evaluated by the NPC research team, based on the following three conditions: (1) the intraoperative macroscopic observation showed no tumor-like tissues residue (Fig. 2d, h); (2) had negative margins on pathology; and (3) underwent total resection of the planned resection volume, judged by comparison of preoperative magnetic resonance imaging (MRI) to postoperative, within 1 week after the surgery (Fig. 2a–c, e, f, g).
Quality of life and cost effectiveness
All patients were asked to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 general (EORTC QLQ-C30, version 3) and head and neck-specific (EORTC QLQ-H&N35) questionnaires in the latest follow-up . Medical cost data were provided by the financial department of our cancer center, which included examination expenses, hospital bed cost, nursing care, anesthesia, medicine, radiotherapy, operation, blood transfusion, and other treatments related costs ($1.00 = ¥6.72 [11th March 2019]).
The last follow-up date was on May 17, 2019. During the follow-up, the patients usually underwent endoscopies to assess the wound reconstruction every 2 weeks until the wound was completely re-epithelialized. Subsequent follow-up assessments were performed every 3 months during the first year and every 6 months thereafter until the fifth year. Nasopharyngoscopy, MRI of the head and neck, chest radiography, and abdominal sonography were performed at each assessment. Whenever possible, salvage treatments, including radiotherapy, chemotherapy, and surgery were administered to patients after tumor relapse.
Categorical variables were analyzed using the χ2 test, Fisher’s exact test and continuous variables were analyzed using the Mann–Whitney U test. The events for OS, distant metastasis-free survival (DMFS), local relapse-free survival (LRFS) and regional relapse-free survival (RRFS) were death from any cause, distant metastasis, local and regional relapse, respectively. The duration was calculated from the date of diagnosis for NPC to the date of each event or the last follow-up. Survival results were calculated using the Kaplan–Meier method, and differences were compared by log-rank test. All analyses were performed using Statistical Product and Service Solutions (SPSS) software (version 22.0, SPSS Inc., Chicago, USA), and a 2-tailed P < 0.05 was considered as statistically significant.