N2-3 Stage Nasopharyngeal Carcinoma Patients With Cervical Node Necrosis And Extracapsular Spread Benet From Capecitabine Maintenance Chemotherapy

Purpose: The purpose of this study was to analyze the ecacy and toxicities of concurrent chemoradiotherapy plus capecitabine maintenance chemotherapy for N2-3 stage nasopharyngeal carcinoma (NPC) with cervical node necrosis (CNN) and extracapsular spread(ECS). Patients and methods: This study included 283 N2-3 stage NPC patients with CNN and extracapsular spread who were treated with concurrent chemoradiotherapy. The prescribed doses delivered to the planning target volumes (PTVs), PTVnx, PTVnd, PTV1, and PTV2, were 68–72, 66–70, 60–64, and 52–56 Gy, respectively, in 30–32 fractions. All patients received induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin alone (80–100 mg/m 2 , day 1, every 21 days is a cycle).Two weeks after completion of concurrent chemoradiotherapy, oral capecitabine (twice daily after meals for 14 consecutive days every 3 weeks) was administered to maintenance chemotherapy patients. Maintenance chemotherapy was administered for 6 months. Results: The 5-year overall survival (OS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 84.8%, 95.4%, and 86.6%, respectively, for all patients. The 5-year OS rates for patients who accepted capecitabine maintenance chemotherapy (group 1) and patients without maintenance chemotherapy (group 2) were 93.8% and 82.1% (P=0.021), respectively. The 5-year LRFS rates for groups 1 and 2 were 96.9% and 95.0% (P=0.467), respectively. The 5-year DMFS rates for groups 1 and 2 were 93.8% and 84.4% (P=0.044), respectively. Hand-Foot syndrome, myelotoxic effects, fatigue, and gastrointestinal symptoms were the common but not severe (grades 1–2) toxicities of the capecitabine maintenance chemotherapy. in N2-3 stage NPC patients with CNN and extracapsular spread. The side effects of treatment were generally tolerated. More clinical trials are required to evaluate the ecacy and toxicity of it.


Introduction
More than 120,000 cases of nasopharyngeal carcinoma (NPC) were newly diagnosed in 2018, with > 70,000 resulting in death. NPC is a unique carcinoma with racial and geographic variation; southwest China has the highest incidence worldwide. 1 Patients with NPC are asymptomatic for a long time, and up to 85% have lymph node metastases at the time of diagnosis. [2][3] Cervical node necrosis (CNN) and extracapsular spread (ECS), the incidence of which is 22.5-42.1% in patients with NPC, have previously been reported as a strong, independent negative prognostic factor for overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS). [4][5] Given the poor prognosis, it is important to nd effective strategies to improve the survival outcomes of this speci c sub-group of NPC patients.
NPC is a radiosensitive malignancy. Radiotherapy forms the basis of all treatment stages, and distant metastases are the main reason for treatment failure. [6][7] Many scholars are of the opinion that chemotherapy intensity should be increased to improve patients' outcomes. [8][9] Nevertheless, the role of maintenance chemotherapy is controversial and increases the complication rate.
In recent years, oral 5-FU has been shown to yield very satisfactory results in multiple solid tumors. [10][11] Stockler 12 and Simkens 13 concluded that oral capecitabine is safe and effective, and maintenance treatments with capecitabine are particularly suitable for the overall management of advanced breast and metastatic colorectal cancers. Capecitabine is an oral anticancer uorouracil derivative that can be converted to 5-FU in vivo. The metronomic use of capecitabine may also be a good choice for NPC, considering its low toxicity and high e cacy.
The aim of the current study was to determine whether N2-3 stage NPC with a CNN and ECS treatment is optimized by concurrent chemoradiotherapy plus capecitabine maintenance chemotherapy.

Material And Methods
Patients Between 1 January 2009 and 30 December 2015, a total of 283 patients with NPC (N2-3) and CNN and ECS were enrolled in the present study.

Pretreatment evaluation
The essential pretreatment assessments included complete medical histories, physical examinations, nasopharyngeal beroptic endoscopies, magnetic resonance imaging (MRI) scans of the head and neck, chest radiographies or CTs, abdominal region ultrasonographies or CTs, bone emission CT scans, hematological and biochemical pro les, and dental evaluations. All of the patients were required to provide written informed consents.

Intensity-modulated radiation therapy
Computed tomography contrast-enhanced scanning was applied from the skull cap to 2 cm below the clavicle, with a layer thickness of 3 mm. Under the guidance of Report 50 and Report 62 of the International Commission on Radiation Units and Measurements, the gross tumor volume (GTV)nx and GTVnd included the entire macroscopic tumor de ned after a correlative analysis by the CT and MRI scans. For the clinical target, the high-risk clinical target volume (CTV1) was de ned as the nasopharynx GTV plus a 5-10 mm margin (2-3 mm posteriorly if adjacent to the brainstem or spinal cord) that can encompass the high-risk sites of microscopic extension and the whole nasopharynx. The low-risk CTV2 was de ned as the nasopharynx GTV plus a 5-10 mm margin (2-3 mm posteriorly if adjacent to the brainstem or spinal cord) that can encompass the low-risk sites of microscopic extension, including the skull base, clivus, sphenoid sinus, parapharyngeal space, pterygoid fossae, posterior parts of the nasal cavity, pterygopalatine fossae, retropharyngeal nodal regions, and cervical node levels II, III, IV, and V. The total doses were prescribed to the median of the target volume, and the 95% isodose was approximately similar to the planning target volume (PTV). PTVnx, PTVnd, PTV1, and PTV2 were generated by adding 5mm margins to GTVnx, GTVnd, CTV1, and CTV2, respectively. The prescribed doses delivered to PTVnx, PTVnd, PTV1, and PTV2 were 68-72,66-70, 60-64, and 52-56 Gy, respectively, in 30-32 fractions.
Magnetic resonance imaging diagnostic criteria On a MRI, the CNN is seen as a focal area of high signal intensity on T2-weighted images and as an area of low signal intensity on contrast material-enhanced T1-weighted images-with or without a surrounding rim of enhancement [14][15][16] (Fig. 1).
ECS is de ned as the presence of indistinct nodal margins, irregular nodal capsular enhancements, or the in ltration of surrounding fats or muscle planes or fusions with adjacent LNs 17 (Fig.1).

Chemotherapy
All patients underwent induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin alone (80-100 mg/m2, day 1, every 21 days is a cycle).
Two weeks after the completion of concurrent chemoradiotherapy, oral capecitabine (twice daily after meals for 14 consecutive days every 3 weeks) was administered to maintenance chemotherapy patients.
The dose of capecitabine was determined on the basis of the body surface area [1250 mg/m 2 twice per day]). Maintenance chemotherapy was administered for 6 months or terminated if there was disease progression or intolerable toxicity. The dose of capecitabine was modi ed according to the toxicity pro le. The chemotherapy was not delayed or paused until the nadir values were >1,500 cells/μL for neutrophils and >100,000 cells/μL for platelets.

Follow-up
During the treatment, all patients underwent weekly examinations. Then, the patients were evaluated for tumor responses through nasopharyngeal beroptic endoscopy and MRI. Toxicities were observed and noted according to the Toxicity Criteria of the Radiation Therapy Oncology Group. E cacy was determined using the RECIST solid tumor e cacy evaluation criteria.
Subsequently, the patients were followed up every 3 months during the rst 2 years, every 6 months for the third year, and every 1 year thereafter. Each follow-up included a physical examination, nasopharyngeal beroptic endoscopy, chest radiography or CT, abdominal region ultrasonography or CT, and a hematological and biochemical pro le. The MRI scan was performed every 6 months.
Additional CT and bone emission CT scans were performed to con rm any suspicious lesions for distant metastasis.

Statistical analysis
The data was processed using SPSS 23.0 software. The OS was calculated from the date of diagnosis until death or the last follow-up using the Kaplan-Meier method, and the difference was analyzed using a two-sided log-rank test. The local relapse-free survival (LRFS) and DMFS were de ned as the time from the day of diagnosis to the locoregional progression and distant metastasis, respectively. The LRFS and DMFS were also calculated and constructed using the Kaplan-Meier method. A comparison between the groups for the frequency of data was carried out using the χ2-test. P-values <0.05 were considered statistically signi cant.

Patient demographics
The male-to-female ratio was 209:74. All patients were WHO II with respect to histologic classi cation. Sixty-ve patients (23.0%) accepted the capecitabine maintenance chemotherapy. The clinical characteristics of the 283 NPC patients are listed in Table 1.
The 5-year OS rates for the patients who accepted capecitabine maintenance chemotherapy (group 1) and patients who did not accept maintenance chemotherapy (group 2) were 93.8% and 82.1% (P=0.021, Figure 2), respectively.
The 5-year DMFS rates for patients who accepted the capecitabine maintenance chemotherapy (group 1) and patients who did not accept the maintenance chemotherapy (group 2) were 93.8% and 84.4%, respectively (P=0.044, Figure 4).

Toxicities of capecitabine maintenance chemotherapy
Hand-Foot syndrome, myelotoxic effects, fatigue, and gastrointestinal symptoms were the common but not severe (grades 1-2) toxicities of the capecitabine maintenance chemotherapy. No grade 4 toxicity or treatment-related deaths occurred during the capecitabine maintenance chemotherapy; detailed information is covered in Table 2.

Discussion
NPC is a unique carcinoma with racial and geographical variations; southwest China has the highest incidence of NPC worldwide. 1 NPC is a radiosensitive malignancy. Radiotherapy forms the basis for all treatments in patients with NPC. Intensity-modulated radiation therapy (IMRT) has replaced conventional two-dimensional radiotherapy as the pivotal radiotherapy technique, and it has improved the local control rate to > 90%. Distant metastases are the main treatment failure pattern in patients with NPC. [18][19] Therefore, it is crucial to choose a proper therapeutic modality to maximally reduce distant metastases.
It is unknown if increasing the intensity of chemotherapy will improve the outcome of patients with NPC Multiple studies have failed to demonstrate a signi cant advantage in the entire population without risk strati cation. Several randomized studies have attempted to elucidate this matter, but they failed to get the expected result. [20][21] In our opinion, the major goal of maintenance chemotherapy in patients with NPC is to reduce the occurrence of distant failure; however, not all NPC patients require maintenance chemotherapy. Of note, none of the studies focused on the ECS and CNN sub-groups. Due to a lack of strati cation, we were intent on identifying the speci c sub-group that would bene t from maintenance chemotherapy.
CNN and ECS is a late biological event in the evolution of tumor metastases in lymph nodes, and it often occurs at the interface between necrotic areas and well-aerated cells. An increase in the radioresistance of hypoxic tumor cells has been well-documented in previous studies, [22][23] therefore, CNN may serve as a marker for hypoxia. ECS may serve as a marker for an increase in the number of metastases. The presence of CNN and ECS in tumors induces relatively poor sensitivity to radiotherapy or chemotherapy. Moreover, it can lead to gene ampli cation with a resistance that can increase tumor aggressiveness and accelerate progression. [24][25][26][27] CNN and ECS proved to be an independent negative prognostic factor for OS, DFS, and DMFS. [28][29][30] It has been reported that an increase in chemotherapy intensity provides survival bene ts for high-risk patients. [31][32] Therefore, identifying patients as being high risk is signi cant for selecting an individualized therapy strategy. Assuming that the last fraction of IMRT is completed, the tumor does not often completely regress, especially in patients with CNN and ECS. 33 Thus, maintenance chemotherapy is an effective method to improve treatment outcomes.
Capecitabine is an oral pro-drug of 5-uorouracil (5-FU), and it is frequently used for treating cancer.
Capecitabine proved to have very satisfactory results in multiple solid tumors. [11][12][13] It is completely and rapidly absorbed after oral administration. [34][35] It has been concluded that oral capecitabine is safe and effective, and maintenance treatment with capecitabine is particularly suitable for the overall management of advanced breast cancer. [36][37] In our study, the 5-year OS, LRFS, and DMFS rates were 84.8%, 95.4%, and 86.6%, respectively. The data is similar to other studies. [28][29] Our data reveals the pattern of treatment failure is distant metastasis. The most common site of metastasis includes the lungs, brain, liver and bones. The 5-year DMFS rates for groups 1 and 2 were 93.8% and 84.4% (P = 0.044), respectively. Thus, capecitabine maintenance chemotherapy may improve DMFS rates in N2-3 NPC patients with CNN and ECS. The role of adjuvant chemotherapy is controversial. Our study demonstrates a different conclusion compared to the previous studies. Because the shortcoming was a lack of strati cation in the previous studies, 20-21 we were intent on identifying the speci c sub-group that would bene t from maintenance chemotherapy.
Based on our sub-group analysis, 166 patients had MRI scans of the head and neck immediately when concurrent chemoradiotherapy was completed. There were only 38 patients who had complete responses; the remaining patients had partial responses. We will choose to observe and evaluate these 3 months later. With time, the residual tumors became disintegrated and fully disappeared by 3 months' time. Our studies failed to demonstrate a signi cant relationship between the patients with PR and CR. The number of cases was too small to analyze statistically, a larger sample size is needed to verify this.
We proposed a new idea for selecting a better individualized therapy to maximally reduce distant metastases. Nevertheless, there were some limitations in this study. Speci cally, the study had a retrospective design and some existent biases. Additional studies with a larger sample size and unit participation are imperative.

Conclusion
In this study we showed that capecitabine maintenance chemotherapy can improve the outcomes of and reduce the occurrence of distant failures in N2-3 stage NPC patients with CNN and ECS.

Availability of data and materials
All data generated or analyzed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.

Funding
None.

Authors' contributions
Tingliu and Siwen liu conceived and designed the study. Yuting Gu and Xuehua Wen collected, analyzed, and interpreted the data, prepared the draft and gave nal approval of the version to be submitted. Tingliu and Siwen liu undertook data analysis and interpretation, and performed the statistical analysis. All authors approved the nal manuscript. Kaplan-Meier estimate of overall survival for patients who accepted capecitabine maintenance chemotherapy group 1 and patients who did not accept maintenance chemotherapy group 2 .

Figure 3
Kaplan-Meier estimate of LRFS for patients who accepted capecitabine maintenance chemotherapy group 1 and patients who did not accept maintenance chemotherapy group 2 .

Figure 4
Kaplan-Meier estimate of DMFS for patients who accepted capecitabine maintenance chemotherapy group 1 and patients who did not accept maintenance chemotherapy group 2 .