Long Term Outcomes and Prognostic Factors of N 0 Stage Nasopharyngeal Carcinoma : a Single Institutional Experience with 610 Patients

Nasopharyngeal carcinoma (NPC) is a malignancy normally happening in head and neck, with unique histological features, epidemiology, natural progression behaviors, management approaches, and high prevalence in Southeast Asia and Southern China. It is believed that, because of a rich lymphatic network in the nasopharynx, the incidence rate of cervical lymphatic metastasis in NPC patients is substantially high. The clinically evident cervical lymphadenopathy was reported to occur in more than 85 % of the patients with NPC (Ng et al., 2007; Tang et al., 2009), which was near the rate of approximately 86% in a total of 4,342 NPC patients admitted in our hospital from May 1989 to Oct. 2009. However, some patients with extensive primary tumors in the nasopharynx did not present detectable neck lymph adenopathy, representing a specific clinical


Introduction
Nasopharyngeal carcinoma (NPC) is a malignancy normally happening in head and neck, with unique histological features, epidemiology, natural progression behaviors, management approaches, and high prevalence in Southeast Asia and Southern China.It is believed that, because of a rich lymphatic network in the nasopharynx, the incidence rate of cervical lymphatic metastasis in NPC patients is substantially high.The clinically evident cervical lymphadenopathy was reported to occur in more than 85 % of the patients with NPC (Ng et al., 2007;Tang et al., 2009), which was near the rate of approximately 86% in a total of 4,342 NPC patients admitted in our hospital from May 1989 to Oct. 2009.
However, some patients with extensive primary tumors in the nasopharynx did not present detectable neck lymph adenopathy, representing a specific clinical

RESEARCH COMMUNICATION
Long Term Outcomes and Prognostic Factors of N 0 Stage Nasopharyngeal Carcinoma: a Single Institutional Experience with 610 Patients Jian-Da Sun, Chuang-Zhen Chen, Jian-Zhou Chen, Dong-Sheng Li, Zhi-Jian Chen, Ming-Zhen Zhou, De-Rui Li* pattern.These N 0 (neck node negative) NPC might differ from NPC with cervical lymph node metastasis in terms of biological characteristics.However, its underlining biological mechanism in tumor progression had yet to be determined.
Although much had been known regarding to the treatment and prognostic factors of this cancer as a whole, there had not been a systematic study on the N 0 NPC, perhaps due to the fact that it only represented a relatively small subgroup in the NPC patient population.For example, it's still remained unclear whether a combination of chemotherapy with radiotherapy could bring any survival benefits for NPC patients with stages T 3-4 /N 0 tumors.
Our study was designed to evaluate the therapeutic outcomes of N 0 NPC patients treated primarily with external-beam radiation for improving the current N 0 NPC treatment strategies.

Patients and pretreatment evaluation
From May 1989 to Oct. 2009, 610 patients with N 0 NPC were treated with definite radiotherapy (RT) in the Cancer Hospital of Shantou University Medical College.The pretreatment evaluation included history reviews, physical examination, nasopharyngoscopy with biopsy, chest radiography, abdominal ultrasonography, computed tomography (CT) scan of the nasopharynx and skull base, bone marrow function and biochemistry profiles.Bone scan and thoracic CT were performed if indicated.All patients were staged according to 1992 Fuzhou Chinese staging system (Min et al., 1994).Patients with no palpable lymph nodes in the neck were defined as N 0 stage.The case distribution profile in this study was T 1 , 9.3%; T 2 , 44.6%; T 3 , 20.7%; and T 4 , 25.4%, and the detailed characteristics of all patients were listed in Table 1.Anemia was defined as hemoglobin lower than 120 g/L and 110 g/L in male and female patients, respectively.

Radiation therapy
Patients initially underwent conventional external beam radiotherapy (EBRT) 5 times a week at 2 Gy/d using a two-dimensional (2D) technique RT.All patients were treated firstly with two block-shielding lateral opposing faciocervical fields which covered the primary tumor and upper neck to a total dose of 36 to 40 Gy, followed by two lateral preauricular fields with matching anterior cervical fields (covered upper neck).An additional boost of 8~10 Gy was given in case of evident skull-base erosion and/or carotid space (CS) involvement.Since January 2002, CT simulation and three-dimensional conformal radiotherapy (3D CRT) were routinely performed.At the same time, some patients were treated with intensity modulated radiation therapy (IMRT) by simultaneous modulated accelerated radiation therapy (SMART) boost technique.The prescribe dose of IMRT was 70.4 Gy to nasopharynx, 60 to upper neck (including level II, III, Va) in 32 fractions.Of the 610 patients, 322 were treated with 2D EBRT, 281 with 3DCRT, and 7 with IMRT.542 patients (88.9%) received prophylactic radiation to upper neck, while the rest to entire neck as recommended by the attending physicians.The total dose delivered to the primary lesion was 34-91 Gy (median, 70 Gy) and 34-70 Gy (median, 50 Gy) to upper neck and regions which might harbor subclinical lesion.Radiotherapy was terminated prematurely in two cases, one due to lung infection and the other to death after receiving a total dose of 34 Gy and 52 Gy, respectively.

Residual disease and boost radiotherapy
After the completion of 70-72 Gy of EBRT, patients with primary residual disease were treated with a boost RT using either 192Ir intracavitary brachytherapy (6-24 Gy in 1-3 fractions, once a week) or 3DCRT depending on the size and location of the residual lesion.99 patients were found with nasopharyngeal residual lesion in this study.Of them, 3 were treated with 3D CRT, 50 with intracavitary brachytherapy, 2 with 3D CRT plus brachytherapy, and 8 without any further treatment.

Chemotherapy
65 patients (10.7%) received cisplatin alone or cisplatin-based combined chemotherapeutic agents, and 57 of them being concurrent with or without sequential (neoadjuvant/adjuvant) chemotherapy, and 8 with sequential chemotherapy.

Follow-up
The follow-up duration was calculated from the day of treatment commencement to either the day of death or the day of the latest clinic visit.After the completion of treatment, patients were followed every 3 months during the first 2 years, then every 6 months for the subsequent 3 years, and then once every year thereafter.Complete physical and fiberoptic nasopharyngoscopy or indirect nasopharyngeal speculum examinations were also performed.Biochemistry profiles, chest radiography and abdominal ultrasonography were routine elements of the follow-up assessment.CT of the nasopharynx and cervical region was performed at least once a year.Further investigations included enhanced CT of chest or abdomen and bone scan were arranged as indicated.The last followup date was Dec. 31 st , 2010 and the median follow-up duration was 85 months (3-254), with the 5-and 10-year follow-up rates being 91.8% and 84.5%, respectively.

Statistical analysis
The endpoints of this study included overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), local failure-free survival (L-FFS), regional failure-free survival (R-FFS) and distant metastasis-free survival (DMFS) rates calculated with the Kaplan-Meier method.As few patients received IMRT in this study, they were added into those patients treated with 3D CRT during the univariate analysis.The Statistical Package for Social Sciences, version 18.0 (SPSS, Chicago, III) was used.Potential outcome differences were compared using the log-rank test.Multivariate analysis with Cox proportional hazards model was performed to identify prognostic factors.All P values were based on a 2-sided test, and the differences were regarded as statistically significant when P <0.05.

Local control
A total of 119 patients (19.5%) had local recurrence with a median time of 29 months (10-121), and 84.9% of them happened within 5 years.The 5-year and 10-year actuarial L-FFS rates for the entire group were 81.2% and 72.5%, respectively.The corresponding 5-year L-FFS rates for T 1 , T 2 , T 3 and T 4 disease were 86.6%, 86.2%, 79.6%, and 70.7%, respectively, and these rates were significantly correlated with the T stages (P = 0.000; Figure 1a).

Regional control
31 cases (5.1%) of this cohort developed regional recurrence at a median time of 38.5 months (18-53).Of them, 15 patients (2.5%) had regional recurrence as a first event of treatment failure, and the rest had local recurrence    and/or distant metastasis simultaneously.Of these regional recurrence, 16 (2.7%)occurred within the elective irradiated area, while 13 (2.1%)out of the area, and 2 (6.5%) both in and out of the areas.The 5-year and 10-year actuarial R-FFS rates for the entire group were 95.8% and 91.8%, respectively.The corresponding 5-year R-FFS rates for T 1 , T 2 , T 3 and T 4 disease were 97.9%, 95.4%, 96.0%, and 95.5%, respectively.There were no significant differences among them (P=0.768; Figure 1b).The 5-year R-FFS rates in patients with or without local treatment failures were 93.6% and 96.2%, respectively (P=0.006).

Distant metastases
71 patients (11.6%) developed distant metastases with a median time of 29 months (8-48).Of them, 52 were found with isolated distant metastases, the other 19 patients with simultaneous local and/or regional failure.The sites of distant metastasis were depicted in Table 2.

Other survival endpoints
During the analysis, 156 patients (25.6%) died, and 139 of them died of the disease (Table 3).The patterns of treatment failure were shown in Table 4.The 5-year and 10-year OS, DFS and DSS rates for the entire group were 78.7% and 66.8%, 68.8% and 55.8%, 79.9% and 70.4%, respectively.Table 4 depicted the 5-year survival rates according to T stage, and the overall survival curves according to T classification were shown in Figure 1d.

Failure patterns and prognostic factors
There were 192 failure (32.0%) after initial treatment.Out of them, 100 patients (16.7%) experienced isolated local failure, and 52 distant metastases as the first event (8.7%).The patterns of treatment failure were shown in Table 5.
The values of various potential prognostic factors, including age, gender, T stage, cranial nerve paralysis, radiation doses to the nasopharynx, radiation doses to the neck, radiotherapy technique, chemotherapy, residual disease, boost, CS invasion, parapharyngeal space (PPS) involvement, skull base erosion, and pre-radiation hemoglobin (Hb) level on predicting different endpoints  6 and 7, respectively.Multivariate analysis showed that T stage was the only independent prognostic factor associated with OS.While T stage, male gender and anemia were unfavorable prognostic factors for DFS.

Discussion
Over the past decade, the treatment results of NPC have been substantially improved with a 5-year OS rate in the range of 59-76.1% (Palazzi et al., 2004;Lee et al., 2005;Leung et al., 2005;Yeh et al., 2005;Yi et al., 2006), with even better treatment outcome in the patients with N 0 NPC.The 5-year OS rate in our series was 78.7%, similar to that of other reports (Gao et al., 2010;Xie et al., 2010).
Local recurrences and distant metastases were reported to be the main causes of treatment failures in NPC.With the advances in imaging technology and the advent of modern radiation techniques, local control has been substantially improved, and distant metastases has become the predominant pattern of treatment failure (Lee et al., 2005;Leung et al., 2005;Yi et al., 2006).However, patients with N 0 NPC demonstrated different patterns of treatment failures.In the current analysis, 100 patients failed with local recurrence alone, and 52 patients failed with distant metastases as the main events.The corresponding 5-year local recurrence and distant metastasis rates were 18.8% and 11.5%, respectively.Therefore, local recurrence could be identified as the dominant form of treatment failure in N 0 NPC.It was hoped that an even better survival outcome could be achieved by improving the local control.
Nasopharyngeal carcinoma is a highly radiosensitive tumor.Some reports (Teo et al., 2000;Teo et al., 2006) showed that a significant radiation dose-tumor control relationship was present above the conventional tumoricidal dose level.Dose-escalation significantly improved local control in NPC at early and advanced stages.Similar in the current study, the radiation dose delivered to the nasopharynx was a significant prognostic factor affecting the L-FFS and DSS rates, suggesting that escalating radiation dose to the primary tumor could improve the overall survival of patients.Yi et al. (2006) found that a boost after 70-72 Gy EBRT to the residual primary lesion improved the treatment outcome in terms of OS rates, locoregional control rates, and DFS rates.In our study, 99 patients had nasopharyngeal residual disease after 70-72 Gy EBRT.82 of them received a boost.Our results showed that boost irradiation significantly improved OS and DFS.However, the survival difference in other clinical endpoints did not indicate statistical significance.It suggested that boost irradiation delivered higher dose to the primary lesion, in turn improved local control and the treatment outcome.
IMRT represents a technical innovation in NPC management.IMRT could produce customized conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal structures.Hence, it enables the delivery of high radiation dose to the targets without jeopardizing the radiosensitive organs, thereby reducing treatment complications and improving the quality of life.A serial of studies were conducted to investigate the potential benefits of IMRT, using simultaneous integrated multi-target treatment technique (SIMT-IMRT) over highly optimized conventional 3D CRT combined with intracavitary brachytherapy for the treatment of NPC, and came to the same conclusion that a good therapeutic ratio could be achieved with the use of IMRT (Kam et al., 2004;Wolden et al., 2006;Taheri-Kadkhoda et al., 2008;Tham et al., 2009;Han et al., 2010;Wong et al., 2010).Moreover, the severity of xerostomia, neck fibrosis and trismus, and the incidences of xerostomia at 6 months and 1, 2, 3, 4 years after treatment were significantly reduced in IMRT group than in CRT group (Lai et al., 2011).Therefore, it has been proven that IMRT was an effective approach to enhance the local control in NPC.As only limited number of patients who received IMRT (7/610) was included in the current analysis, and the follow-up time was not long enough, it was difficult to come to conclusion whether IMRT could provide a survival benefit to patients with N 0 NPC.
In the present study, most patients (542, 88.9%) received prophylactic radiation to the upper neck, and an excellent 5-year R-FFS rate was achieved, even for advanced T stage NPC.Moreover, few patients experienced regional recurrence out of the irradiation level, with an occurrence rate as low as 2.1%.Our retrospective study also indicated that, compared with upper neck elective irradiation, whole neck irradiation did not result in any additional benefit for N 0 NPC patients in terms of regional control.N 0 NPC was defined as NPC with no palpable lymph nodes in neck, but it was unreasonable to ignore the existence of some impalpable cervical lymph nodes evidenced by imaging studies, as it was obviously not enough to irradiate just the upper neck lymph nodes without elective treatment to the lower neck.During the study, 288 patients received enhanced CT or MRI scans of the head and neck to exclude the existence of some occult lymph node metastases in the cervical region.However, the treatment outcomes of these patients were not significantly different when compared with the rest of patients.The 5-year OS, DFS, L-FFS and DMFS rates in these two subgroups were 77.7%, 68.4%, 81.0%, 88.0% and 79.2%, 68.9%, 81.2%, 88.9%, respectively.Gao once reported an excellent 5-year L-FFS rate of 88.6% in their N 0 NPC series, better than that obtained in our analysis (Gao et al., 2010).One of the possible explanations for this difference was that a considerable proportion of patients It was still remained controversial for the value of combined chemoradiotherapy used in N 0 NPC patients.Lee reported their treatment results of 189 patients with T 3-4 N 0-1 M 0 NPC between 1999 and 2004 (Lee et al., 2006), finding that significant improvement only in failure-free survival was achieved in the concurrent chemoradiotherapy arm, when compared with the radiotherapy arm.The results of other studies also demonstrated that chemotherapy was not the significant prognostic factor for patients with N 0 NPC (Gao et al., 2010;Xie et al., 2010).In the present analysis, combined chemoradiotherapy did neither reduce the risk of local treatment failures and distant metastases nor improve OS, when compared with radiotherapy alone.To date, no consensus has been reached regarding to the magnitude of the effects of chemotherapy on the survival of patients with T 3-4 N 0 .This still warrants additional investigations.
Different researchers reported a 5-year DMFS rate in the range of 75.9-80% for stage Ⅲ patients, and 56.2-67% for stage Ⅳ patients.Though most patients received radiotherapy without chemotherapy, an excellent 5-year DMFS rate of 85.3% in stage Ⅲ patients, and 81.5% in stage Ⅳ patients, respectively, were achieved in our analysis.The risk of distant metastasis was significantly increased for NPC of advanced T stage.Based on our assessment of the DMFS rate in our patient cohort, the T stage was the significant factor on the univariate analysis (P=0.003).
Anemia was indicated to be associated with the low local control rate and survival rate in the head and neck malignancies (Chua et al., 2004;Rades et al., 2008;Gao et al., 2010).Low Hb levels led to tumor hypoxia, which was a well known factor contributing to decreased radiosensitivity and poor treatment outcomes.Our results revealed that low Hb level was an independent factor adversely affecting DFS, suggesting that treating anemia might lead to better survival of N 0 NPC patients.Further investigations were now being conducted.
Ng proved that with better tumor delineation in the help of MRI and improved coverage using modern radiotherapy techniques, neither PPS involvements nor CS invasions predicted for local treatment failure, distant failures and OS (Ng et al., 2008).Similarly, Xie found that prestyloid space involvement was not an independent prognostic factor for N 0 NPC patients (Xie et al, 2010).In the present analysis, PPS involvement showed no statistical significance for any clinical endpoint.
On univariate analysis, the CS invasion was an independent prognostic factor affecting the OS, DFS and DMFS rates.However, the prognostic value of CS invasion was lost for OS and DFS on multivariate analysis, and it only reached statistical significance in predicting DMFS for N 0 NPC patients.The CS invasion was found to be associated with a lower 5-year DMFS rate, suggesting that the tumor invaded the blood vessels in the carotid sheath directly, and then disseminated through blood stream to the distant sites.