A Retrospective Study of Clinicoepidemiological Aspects of Nasopharyngeal Cancer at NCI-Cairo ( 2000-2010 )

Aim of Work: The aim of this work was to study the clinico-epidemiological characteristics of the patients with nasopharyngeal carcinoma (NPC), analyse the prognostic factors of the disease and to analyse the results of different treatment modalities and their effect on loco-regional, distal metastatic disease control and both overall survival (OS) and disease free survival (DFS) rates. Patients and Methods: This is a retrospective study reviewing all adult nasopharyngeal carcinoma (NPC) patients who presented to the radiotherapy department—National Cancer Institute Cairo University in the period from (2000-2010). Results: In this study, it was found that the mean age was 45 years; most of the patients were of locally advanced stages. Multivariate cox proportional hazards regression identified T-stage, radiotherapy course completion & addition of chemotherapy as independent prognostic factors for local control (LC), DFS, & OS. The 5-year LC, DFS and OS rates for all studied patients were 38.2%, 33.5% & 37.2% respectively. The median DFS was 26 months and median OS was 36.5 months. Conclusion: This study matches the published data that support that radical concurrent chemoradiation is the mainstay of treatment of locally advanced NPC, & that T-stage, M-stage, prescribed dose completion, response to initial treatment are independent prognostic factors for survival. All measures should be taken to improve the local response during primary treatment as this will improve survival rates of patients with NPC.


Introduction
Worldwide, there are 80,000 incident cases of nasopharyngeal carcinoma and 50,000 deaths annually [1].The distinctive racial/ethnic and geographic distribution of NPC worldwide suggests that both environmental factors and genetic traits contribute to its development [2].These unique pathogenic factors are variable such as genetic susceptibility, Epstein-Barr virus (EBV) infection, chemical carcinogens, and environmental factors [3].
The tumor-node-metastasis (TNM) staging system for malignancies is used to evaluate prognosis, aid treatment planning, and facilitate the stratification of treatment.At present, the seventh edition of the American Joint Committee on Cancer (AJCC) staging system is widely used [4].
Nasopharyngeal carcinoma (NPC) commonly demonstrates extensive invasion of adjacent tissues with poorly defined and large tumors in close proximity to critical structures, such as the brain stem, spinal cord, and optic chiasm.These features of NPC can complicate adequate surgical resection [5].
Nasopharyngeal carcinoma is highly sensitive to radiotherapy or chemotherapy [6].Radiotherapy (RT) alone or combined with chemotherapy is the primary treatment depending on the disease stage [7].
Because of the improved treatment outcome and toxicity profile, IMRT (intensity modulated radiotherapy) is now recommended for definitive treatment for all patients with nasopharyngeal cancer [8].

Aim of the Work
This study was conducted to evaluate the clinical and epidemiological characteristics of the patients with NPC who were treated at radiotherapy department, NCI, in the last 10 years.And to study patient management and its outcomes, in addition to analyze potential prognostic factors influencing local control, disease free survival as well as overall survival of the disease

Patients and Methods
This is a retrospective study of adult nasopharyngeal cancer patients who were treated at the radiotherapy department of the National cancer institute of-Cairo university, in the period between 2000 and 2010.
The study included 158 patients; all of them were with pathologically confirmed nasopharyngeal carcinoma, 18 years of age and above, and with complete data files.
Regarding radiotherapy, all patients who were treated by radical radiotherapy were treated in supine position using isocentric technique and all of them had proper fixation by a head and neck mask.Radical radiotherapy dose to the target volume ranged from 66 to 72 Gy with a spinal cord shield after 40 Gy while palliative dose was limited to 30 Gy to the target volume.

Statistical Analysis
Data was analyzed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL).Survival analysis was done using Kaplan-Meier method and comparison between two survival curves was done using log-rank test.All tests were two-tailed.A p-value < 0.05 was considered significant [9].

Results
The study included 158 patients who were properly staged (Table 1).

Treatment Modalities
The most frequently used treatment modality in this study was induction chemotherapy plus concurrent chemo-radiotherapy (34.1%), followed by the treatment modality of concurrent chemo-radiotherapy (32.9%) (Table 2).
Out of the 149 patients who received radical radiotherapy, twenty three patients (15.4%) were treated using 3D conformal radiotherapy (3D CRT) technique, while 2D technique was used for 121patients (81.2%) (Table 3).Eighty four percent of total number of included patients continued there radiotherapy course, course discontinuation was attributed to acute side effects in 37.5% of patients, socioeconomic factors in 12.5% of patients.

Acute Side Effects
Acute side effects of radiotherapy were properly reported for 104 patients.Mucositis was by far the most frequently encountered acute side effect in 98.1% of cases, followed by xerostomia in 93.3% of cases with grade 2 being the most frequent.
Patients who received radiotherapy by 2D technique exhibited higher incidence of acute toxicities compared to their counterparts who received 3DCRT, this was highly statistically significant for xerostomia with a p-value > 0.001.

Late Side Effects and Quality of Life
The most frequently encountered late side effects were xerostomia & dysphagia in 80% & 44% of cases respectively.
The incidence of xerostomia, dysphagia, visual affection, hearing affection & neck fibrosis was higher in patients treated with the 2D technique, with xerostomia being significantly lower in patients treated with 3D CRT.

Local Control
The local response was evaluated in 125 patients who completed the radiotherapy course; evaluation was done 2 -4 months after treatment by either local imaging or nasopharyngeal endoscopy or both (Table 4).
The local control among all 149 patients was 48.3% at 3 years and 38.2% at 5 years (Figure 1).Among all prognostic factors studied, only T-stage (T1-2 vs T3-4), RTH alone vs. RTH + CTH, and RTH course completion had statistically significant difference on both univariate & multivariate analyses.

Disease Free Survival (DFS)
The DFS among all 149 patients was 42% at 3 years and 33.5% at 5 years.The performance status, T-Stage, the addition of chemotherapy, patients who succeeded to achieve a complete remission and radiotherapy course completion significantly influenced the DFS rates.Multivariate analysis showed them as independent indicators of DFS (Figure 2).

Overall Survival (OS)
The OS among all 158 patients was 50.9% at 3 years and 37.2% at 5 years (Figure 3).
Patients who were 50 years of age or younger, with performance status I, T1-2 tumor, non-metastatic disease, with stage groups I-III, and those who received chemotherapy in addition to radiotherapy, and those who completed radiotherapy course, and patients who succeeded to achieve a complete remission, had more favorable 3-year & 5-year OS & achieved significantly higher 3-year and 5-year OS rates on univariate analysis .onmultivariate analysis performance status and stage group were not persistently significant.

Discussion
In this retrospective study, 158 patients with nasopharyngeal carcinoma presenting to the radiotherapy department at NCI Cairo from the year 2000 to 2010 were reviewed.
While nasopharyngeal carcinoma can occur in any age, Ferlay et al. 2010 [1] reported a bimodal age distribution, the first peak incidence arises between 15 to 25 years of age, with the second peak at 50 to 59 years of age.This was affirmed in our study, where the highest incidence was observed in the fifth (26.6%), & second (13.3%) decades respectively.The incidence of NPC is higher in males than that in females, and the ratio is 2 -3:1 [1].Similarly, in our study, male patients represented about 70% of patients.
Most of the patients in our study presented with WHO type III which constituted about 76.6% of all histological type.This came close to the study by Chee et al. (2013) [11] in which about 70.5% of the patient presented with WHO type III.
The vast majority of patients in our study presented at an advanced stage, as 86% of patients were diagnosed at stage III & IV.Recently, a study from Malaysia analyzing the five-year survival of 134 NPC patients, reported similar findings, where 80% of patients presented at stage III & IV [12], which was also supported by Chee et al. (2013) [11].
With regards to clinical presentation, it was found that 71% of cases presented with a neck swelling.This was entirely consistent with what was reported by Skinner et al. 1991 [13], and T. Dhaneshor et al., 2011 [14].
Acute toxicities were recorded during radiotherapy sessions.In the current study, we found that mucositis & xerostomia are the most frequently encountered acute side effects, occurring in 98% & 93.3% respectively.This was nearly similar to what was reported by Lee et al. 2002 [15].As regards the late toxicities, xerostomia & dysphagia were the commonest late side effects.There was a significant reduction in xerostomia in patients who received 3D conformal radiotherapy.Similarly, in a study comparing the quality of life for NPC patients treated with different RT technologies, it was found that there was a significant difference in the incidence of xerostomia between patients treated using the 2D technique & those receiving 3DCRT or IMRT [16].
Most of the studies analyzing the prognostic impact of age in NPC indicate that younger patients have a higher overall survival [17]- [20].Some studies also showed that disease-related survival, local control and distant metastasis were affected by age [21].In the current study, the overall survival rate in patients older than 50 years of age was significantly lower than in patients younger than 50 years of age (p = 0.001) by both univariate & multivariate analyses, however, there was no significant difference in DFS between the two age groups (p = 0.105), This was consistent with what was recently reported by Dou et al. 2014 [20].
Previous studies have reported slightly better, though not significant, long-term survival rates in women with NPC than in men [5] [22].The same as we had reported in our study.
Xiao et al. 2013 [23] Found that male patients were more likely to have distant metastases than female patients and exhibited inferior overall survival and disease progression-free survival rates.
In a study, retrospectively, reviewed clinical outcome of 905 NPC patients treated by radiation alone during 1990 to 1999 from Mainland China, Karnofsky performance status showed no significant effect on overall and disease-free survival by multivariate analysis [24].In the current study patients with ECOG PS I achieved significantly higher DFS & OS by univariate analysis and on DFS only on multivariate analysis.This may be attributed to the fact that many of the patients with poor general condition received radiotherapy only despite being locally advanced as chemotherapy couldn't be tolerated.
Many studies have confirmed a clear association between long-term survival and NPC clinical stage [22] [25] [26].Results of the current study also demonstrated that, as the disease stage increased, the 5-year OS rates significantly decreased (p = 0.01) on univariate analysis, however the clinical stage didn't prove to be an independent prognostic factor of OS on multivariate analysis.Further analysis demonstrated that T stage and distant metastases (M) are decisive independent factors for OS, the T stage also significantly influenced the local control & DFS on both univariate & multivariate analyses.Similarly, Dou et al. 2014 reported that T-stage, & M-stage are independent predictors of OS [20].
The efficacy of primary treatment was also found to be an independent prognostic factor affecting long-term survival by univariate & multivariate analyses.The 5-year OS and DFS rates were significantly higher in patients with CR than those with PR (p < 0.001).This was consistent with what was reported by Dou et al. 2014 that the initial treatment modality and its therapeutic efficacy are the major factors affecting the prognosis of patients in all stages of NPC [20].
Many studies have shown that adding chemotherapy to radiotherapy can improve treatment efficacy and prolong OS in patients with intermediate or advanced stage NPC [27]- [30].Two large meta-analysis studies showed superiority of concurrent chemo-radiotherapy (CCRT) compared to radio-therapy alone [31] [32].
In a meta-analysis by Langendijk et al. 2004, it was shown that the most efficacious way to introduce chemotherapy was concurrently with radiotherapy and this approach resulted in an absolute 5-year survival benefit of 20% [33].Similarly, in the current study, patients who received chemotherapy in addition to radiotherapy achieved significantly higher local control, DFS, & OS rates by both univariate & multivariate analyses.
Several randomized controlled trials compared induction chemotherapy followed by concurrent chemoradiation versus chemoradiation with or without adjuvant chemotherapy in advanced NPC; [34]- [39], but none of them were large enough to show a statistically significant effect.Recently, Zhong-Guo et al. 2013 [40] conducted a meta-analysis of 1096 patients from 11 randomized controlled trials comparing efficacy of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy with or without adjuvant chemotherapy.The study concluded that induction chemotherapy followed by concurrent chemo-radiotherapy couldn't improve OS, LFFS, and DMFS significantly.The authors recommended that larger and multicenteric randomized controlled trials are required to assess whether induction chemotherapy followed by CCRT is superior to CCRT with or without adjuvant chemotherapy for locoregionally advanced NPC.Similarly, in the current study induction chemotherapy didn't produce any statistically significant survival benefit.
In the treatment of nasopharyngeal carcinoma with radiotherapy, completed planned prescription dose and regular radiotherapy are vital [41].In a recent study by Fei et al. 2013 [42], it was found that completion of the prescribed dose and radiotherapy regularity are related to the prognosis of nasopharyngeal carcinoma, multivariate analysis results revealed that treatment course completion and radiotherapy regularity are independent risk factors influencing survival with p values (p = 0.003) and (p = 0.002) respectively.In the current study, we concluded that radiotherapy course completion is an independent prognostic factor influencing local control, as well as DFS & OS rates.
The LC as well as the DFS & OS rates in this study were very poor.This may be attributed to a number of reasons.First, over 86% of patients were locally advanced.Second, the 2D technique was used for the vast majority of patients in this study, which may have led to higher acute toxicities that would result in treatment interruptions & radiotherapy course discontinuation [43].

Conclusion and Recommendations
This study matches the published data that support that radical concurrent chemoradiation is the mainstay of treatment of locally advanced NPC, & that T-stage, M-stage, prescribed dose completion, response to initial treatment are independent prognostic factors for survival.
All measures should be taken to improve the local response during primary treatment as this will improve survival rates of patients with NPC.
Large and multicenteric randomized controlled trials are required to assess whether induction chemotherapy followed by concurrent chemoradiotherapy is superior to chemoradiotherapy for locoregionally advanced NPC.
New techniques like IMRT should be the standard of care for treatment of NPC.

Figure 3 .
Figure 3. OS for all NPC patients.
* Including 2 patients who received Adjuvant CTH after the CCRT.