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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 6  |  Page : 179-184

Long-term outcomes and failure patterns of patients with nasopharyngeal carcinoma staged by magnetic resonance imaging in intensity-modulated radiotherapy era: The Zhejiang Cancer Hospital's experience


Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, People's Republic of, China

Date of Web Publication26-Oct-2015

Correspondence Address:
Xiao-Zhong Chen
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.168181

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 > Abstract 

Purpose: To study and report the clinical outcomes and patterns of failure in the patients with nasopharyngeal carcinoma (NPC) staged by magnetic resonance imaging (MRI) and treated with intensity-modulated radiotherapy (IMRT).
Materials and Methods: From January 2007 to December 2011, 720 NPC patients without metastasis staged by MRI were treated with definitive IMRT at Zhejiang Cancer Hospital. The IMRT prescribed dose was 69 Gy to planning target volume (PTV) of gross disease in nasopharynx and 67.5 Gy to PTV of positive lymph nodes in 30 fractions, high risk, and low risk region PTV was 60 and 54 Gy in 30 fractions, respectively. The treatment outcomes and patterns of failure were observed.
Results: Using the 7th edition of the American Joint Committee on Cancer staging system for NPC, the proportions of the 720 patients with Stages I, II, III, and IVa-b disease were 2.1% (15/720), 17.8% (128/720), 51.7% (372/720), and 28.5% (205/720), respectively. After the median follow-up period of 48 months (range: 3–89 months), a total of 146/720 (20.3%) patients had experienced failure: 37 (5.1%) at primary sites, 17 (2.4%) at regional sites, 79 (11.0%) at distant sites, and 13 (1.8%) at multiple sites. The 5-year overall survival, cancer-specific survival, disease-free survival, local relapse-free survival (LRFS), regional relapse-free survival, and distant metastasis (DM) free survival were 86.1%, 88.1%, 76.6%, 90.8%, 93.6%, and 87.2%, respectively. LRFS of T1 to T3 was all >90% and has no significant difference. In addition to N stage, T category, and neoadjuvant chemotherapy were independent predictors for DM in multivariate analysis.
Conclusion: Our long-term outcome of large NPC series supports the effectiveness of IMRT for excellent local-regional control though up to 20% patients would develop DM, which becomes the main pattern of failure. T4 disease remained difficult to be cured not only for local recurrence but distant failure. A taxane-based combination chemotherapy might be useful to reduce DM in the induction setting and worth further studying.

Keywords: Failure patterns, intensity-modulated radiotherapy, nasopharyngeal carcinoma, outcomes


How to cite this article:
Jiang F, Jin T, Feng XL, Jin QF, Chen XZ. Long-term outcomes and failure patterns of patients with nasopharyngeal carcinoma staged by magnetic resonance imaging in intensity-modulated radiotherapy era: The Zhejiang Cancer Hospital's experience. J Can Res Ther 2015;11, Suppl S2:179-84

How to cite this URL:
Jiang F, Jin T, Feng XL, Jin QF, Chen XZ. Long-term outcomes and failure patterns of patients with nasopharyngeal carcinoma staged by magnetic resonance imaging in intensity-modulated radiotherapy era: The Zhejiang Cancer Hospital's experience. J Can Res Ther [serial online] 2015 [cited 2021 Feb 27];11:179-84. Available from: https://www.cancerjournal.net/text.asp?2015/11/6/179/168181


 > Introduction Top


Nasopharyngeal carcinoma (NPC) is an epithelial malignancy distinct to other head and neck cancers with respect to its epidemiology, histopathology, clinical characteristics, therapeutic regimen, and outcome.[1] NPC is endemic in the Southeast Asia, the Mediterranean basin, and the Southern China; the annual average incidence is 20/100,000 among the Hong Kong Chinese population and around 5/100,000 in the Taiwanese population.[2]

Intensity-modulated radiotherapy (IMRT) is a major breakthrough in the treatment of NPC. It is capable of producing highly conformal dose distributions with steep dose gradients and complex isodose surfaces. Its technical advantages over two-dimensional and three-dimensional conformal radiotherapy have been shown clearly in a number of dosimetric studies.[3],[4],[5] Encouraging results with IMRT studies have been reported, and more than 85% locoregional control has been consistently shown.[6],[7],[8],[9],[10],[11],[12] And other studies had proved that magnetic resonance imaging (MRI) was superior to computed tomography (CT) in demonstrating the soft-tissue tumor extent, especially in bone marrow infiltration at the skull base.[13],[14],[15]

Here, we report the clinical outcomes and patterns of failure of NPC patients staged by MRI and treated with IMRT with or without chemotherapy at the Zhejiang cancer Hospital to assess the efficacy and the overall quality of the treatment technique. It also provides information on the weakness of current treatment and opportunity for improvement.


 > Materials and Methods Top


Patient characteristics

After obtaining approval from the Institutional Review Board, we retrospectively reviewed the medical records of all the patients with NPC treated at our hospital between January 2007 and December 2011. In total, 795 patients were identified; of whom 53 patients were excluded due to the presence of metastatic disease at diagnosis, 15 patients, who received palliative treatment only; and 7 patients, whose treatment deviated from the standard IMRT treatment protocol. The remaining 720 patients were included in this study. Of those, 497 were male and 223 were female, with a male/female ratio of 2.2:1. The median age was 48 years old (range: 14nd years). Histologically, 92.4% of the patients were the World Health Organization (WHO) type II or III disease, and 7.6% of the patients were WHO type I disease [Table 1].
Table 1: Characteristics of the patients

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Clinical staging

All patients were evaluated by the following methods before treatment: Complete patient history, physical examination, hematology, and biochemistry profiles, MRI of the nasopharynx and neck, CT scan of the chest and liver, and acquisition of whole body bone scans by the single photon emission CT.

Treatment

Patients were immobilized in the supine treatment position by a thermoplastic head and shoulder device. Contrast-enhanced planning CT scans with a 3 mm slide thickness were then obtained, with coverage from the skull vertex to 2 cm below the clavicles. Registration of diagnostic MRI with planning CT images was performed for the patients with T3-4 disease for an accurate delineation of tumor volumes and critical structures.

All patients were treated with definitive IMRT. Target volumes were delineated according to the institutional treatment protocol, which is in agreement with the International Commission on Radiation Units and Measurements Reports 50 and 62. The prescribed radiation dose was defined as follows: A total dose of 69 Gy in 30 fractions to the planning target volume (PTV) of the gross tumor volume of the primary and retropharyngeal lymph nodes, 67.5 Gy in 30 fractions to the PTV of the nodal gross tumor volume, 60 Gy in 30 fractions to the PTV of clinical target volume (CTV)-1 (i.e., high risk regions of primary and positive node regions) and 54 Gy in 30 fractions to PTV of CTV-2 (other node regions). All the patients were treated with one fraction daily over 5 days/week.



According to the institutional guidelines, there was no chemotherapy for patients with Stage I disease, concomitant and adjuvant chemotherapy for patients with Stage II disease, and both neoadjuvant or adjuvant chemotherapy and concomitant chemotherapy for patients with Stages III to IV disease. In patients with Stages III to IV disease, neoadjuvant chemotherapy was administered if the waiting time for radiotherapy was considered to be longer than acceptable or when it was considered advantageous to downsize bulky tumors. Neoadjuvant or adjuvant chemotherapy consisted of cisplatin with 5-fluorouracil or cisplatin with docetaxel and 5-fluorouracil every 3 weeks for three cycles. Concomitant chemotherapy consisted of cisplatin 80 mg/m 2 given on days 1 and 22 of radiotherapy. Deviations from the chemotherapy guidelines were allowed for patients aged over 70-year-old and/or patients with organ dysfunction suggesting intolerance to chemotherapy.

Follow-up

Patients attended an outpatient clinic for endoscopy, CT or MRI scans of the head and neck every 3 months during the first 3 years, every 6 months in years 3–5, and annually thereafter or until death. Additional examinations such as chest CT scans, bone scans, or abdominal CT scans were performed annually or if the distant failure was suspected. Patients with residual or recurrent disease underwent a biopsy to confirm malignancy.

The follow-up period was measured from the 1st day of therapy until death or last follow-up. The median follow-up period for the study was 48 months (range: 3–89 months).

Statistical analysis

All analyzes were performed using Statistical Package for the Social Sciences (SPSS) version 17.0 (SPSS, Chicago, IL, USA). Clinicopathological factors were compared between groups using the Student's t- test or Mann–Whitney U-test for continuous variables and Pearson's Chi-squared test or Fisher's exact test for categorical variables. Actuarial survival rates were estimated by the Kaplan–Meier method and survival curves were compared using the log-rank test. All events were measured from the start of treatment. The following endpoints (interval to the first defining event) were estimated: The following endpoints (interval to the first defining event) were estimated: Overall survival (OS), in which the event was death from any cause; cancer specific survival (CSS) in which the event was death of cancer progression or unknown causes; disease-free survival (DFS), in which event was local, regional, or distant failure or death of unknown causes; local relapse-free survival (LRFS), in which the event was local failure; regional relapse-free survival (RRFS), in which the event was regional lymph node failure; distant metastasis free survival (DMFS), in which the event was distant failure. Multivariate analyzed using the Cox proportional hazards model were used to test for independent significance. Two-tailed P < 0.05 was considered statistically significant.

Multivariate analyzed using the Cox proportional hazards model were used to test for independent significance. Two-tailed P < 0.05 was considered statistically significant.


 > Results Top


Using the 7th edition of the American Joint Committee on Cancer (AJCC) staging system for NPC, the proportions of the 720 patients with Stages I, II, III, and IVa-b disease were 2.1% (15/720), 17.8% (128/720), 51.7% (372/720), and 28.5% (205/720), respectively.

After the median follow-up period of 48 months (range: 3–89 months), a total of 146/720 (20.3%) patients had experienced failure: 37 (5.1%) at primary sites, 17 (2.4%) at regional sites, 79 (11.0%) at distant sites, and 13 (1.8%) at multiple sites. In total, 84/720 (11.7%) patients died during follow-up: 67 (9.3%) of disease progression, 8 (1.1%) of treatment-related complications, 6 (0.8%) of secondary cancer, 4 (0.6%) of other diseases and 2 (0.3%) of unknown causes. The 5-year OS, CSS, DFS, LRFS, RRFS, and DMFS were 86.1%, 88.1%, 76.6%, 90.8%, 93.6%, and 87.2%, respectively. [Table 2] listed the 5 years treatment results according to the stage, T and N category.
Table 2: The 5 years estimated endpoints of patients treated with IMRT

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[Figure 1] shows the OS and DFS of patients with a different stage of the disease. The 5-year OS for Stages I, II, III, and IVa-b disease were 100%, 94.1%, 85.0%, and 82.0%, but the difference in OS between Stages III and IVa-b disease was not statistically significant (P = 0.17). The 5-year PFS for Stages I, II, III and IVa-b disease were 100%, 87.1%, 76.5%, and 68.2%. The curves separated well and the differences between groups were all significant. It seemed that the 7th AJCC/Union for the International Cancer Control stage were a better predictor of disease failure than OS.
Figure 1: The overall survival and disease-free survival curves of the nasopharyngeal carcinoma patients with different stages. The overall survival curves separated well-except Stages III and IV whose difference was not significant. While the curves of disease-free survival revealed better separation and significant differences between adjacent stages

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[Figure 2] shows the LRFS and DMFS of patients with different T category. The 5-year LRFS were 93.7%, 90.1%, 92.8%, and 86.1% and DMFS was 95.1%, 91.3%, 86.7%, and 81.0% for T1, T2, T3, and T4 disease, respectively. The differences of LRFS of different T stages had no significance except T4 disease, whose local control was significantly worse than other groups. While the curves of DMFS for different T stages were separated well except T2 and T3 disease, which had a similar distribution (P = 0.629).
Figure 2: The local relapse-free survival and distant metastasis-free survival curves of the nasopharyngeal carcinoma patients with different T stages. Only the curve of local relapse-free survival for T4 separated well with the other curves. While the distribution of distant metastasis-free survival curves for T2 and T3 was quite similar but separated well with T1 and T4 group

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[Figure 3] shows the RRFS and DMFS of the patients with different N stages. The N0 and N1 disease had a similar 5-year RRFS (97.3% and 96.3%, P = 0.750), but was significantly better than N2 (89.4%) and N3 (87.1%) disease, whose difference was insignificant.
Figure 3: The regional relapse-free survival and distant metastasis-free survival curves of the nasopharyngeal carcinoma patients with different N stages. The distribution of regional relapse-free survival curves could group in two sets: Group 1 for N0 and N1 and Group 2 for N2 and N3. The two groups differed well, but not among the group. While the distribution of distant metastasis-free survival curves for N stage separated well with each other

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The curves of DMFS for different N stage separated well and the difference were significant except N0 and N1 disease, whose distribution was quite similar and had no significantly difference.

Multivariate Cox regression analyzes to identify the variables associated with DMFS were summarized in [Table 3]. Neoadjuvant chemotherapy (Yes vs. No, hazard ratio [HR] 0.54, 95% confidence interval [95% CI] 0.33–0.087, P = 0.012), T stage (HR 1.70, 95% CI 1.30–2.23, P < 0.001) and N stage (HR 1.98, 95% CI 1.49–2.61, P < 0.001) were independent predictors of DMFS. Compared to T1 disease (as reference), the HR of DM for T2, T3, and T4 disease was 1.91 (95% CI 0.62–5.79) 2.57 (95% CI 0.91–7.29), and 5.24 (95% CI 1.82–15.05), respectively. While the risk of distant failure increase to 1.61 (95% CI 0.56–4.61), 3.66 (95% CI 1.29–10.38), and 6.07 (95% CI 1.96–18.82) compared to N0 disease (as reference).
Table 3: Multivariate Cox proportional hazards model analyzes of associations with DMFS

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 > Discussion Top


There is a little controversy that IMRT is the treatment of choice for NPC because dosimetric studies show clear advantages by improving dose conformity for complex tumor targets and better protection of the adjacent organs. It has been well-established that MRI is superior to CT in demonstrating the soft-tissue tumor extent and marrow infiltration at the skull base. Lee et al.[6] reported excellent results from a single center with 4-year estimates of local progression-free, locoregional progression-free, and DM free rates at 97%, 98%, and 66%, respectively. Wolden et al.[7] reported a 3-year actuarial rate of local control of 91%, regional control of 93%, and freedom from DM rate of 78%. Kam et al.[8] reported the Hong Kong experience with the 3-year actuarial local relapse-free survival, nodal relapse-free survival, and DM free survival at 92%, 98%, and 79%, respectively. The short-term outcomes of NPC treated with IMRT from different centers are excellent and comparable, but data on long-term disease control is still lacked, especially staged by MRI.

Here we report our long-term results of 720 NPC patients staged by MRI and treated with IMRT. The 5-year OS, CSS, DFS, LRFS, RRFS, and DMFS were 86.1%, 88.1%, 76.6%, 90.8%, 93.6%, and 87.2%. It is quite comparable to the short-term results reported from other centers. With >90% 5-year local and regional disease control and >85% 5-year OS despite around 80% of the patients having Stages III and IVa-b disease, this outcomes validates IMRT as the first choice of NPC treatment.

Local control

As 5-year local recurrence-free rates are > 90%, there were only 54 patients developed local relapse, 5 with T1 disease, 13 with T2 disease, 16 with T3 disease and 20 with the T4 disease. The 5-year LRFS for T1, T2, T3, and T4 disease were 93.7%, 90.1%, 92.8%, and 86.1%. One interesting observation in our series is that the current T classification is becoming less powerful in segregating patients into various at-risk groups of local relapse. LRFS of T1, T2, and T3 was all > 90% and has no significant difference. This mainly attributes to IMRT technology which enables coverage of irregularly shaped tumor while limiting the dose to critical organs. Other factors such as MRI implication for better tumor delineation, the addition of chemotherapy, and better supportive care, may also contribute to the significant improvement in local control. However, even with the most sophisticated treatment technique and intensive use of chemotherapy, the advanced T4 disease remained difficult to treat and had a significantly worse local disease control. These patients usually had a large volume, close to critical structures such as the brainstem and optical chiasm. Tumor dose or margins were thus compromised in these difficult clinical situations. The addition of concurrent chemotherapy was also not sufficient to sterilize the tumor.

In a study with 290 NPC patients,[16] PTV > 60 cc were associated with significantly poorer local control (P < 0.001). In the early 1980s, Fletcher has proposed that a certain tumor volume requires a certain radiation dose so as to get a radical cure. Tumors about 3 cm 3 should not be irradiated <75 Gy, and the larger ones even need more than 100 Gy.[17] Therefore, larger tumors require higher doses for their control. As expected, the locoregional failure correlates with the minimum dose to the target volumes. One possible strategy is to lessen the dose constraint criteria of selected neurologic structures (e.g., to sacrifice one side of the optic nerve or temporal lobe). However, the therapeutic gain remains questionable at this situation and may not be justifiable considering the potential consequences. Then increasing the dose discriminately at the target by the functional imaging guiding such as 18 F-FMISO,18 F-FAZA, or 62 Cu-ATSM PET might reduce local failure while without increasing in complication risks.

Another strategy is to implicate image-guide radiotherapy (IGRT) in those locally very advanced NPC patients. Given the very steep dose gradient with IMRT proximal to the critical neurologic structures, marginal miss may be reduced by increasing the treatment precision by IGRT with adequate but very tight dose coverage to the target volumes. Den et al.[18] found that daily Cone Beam CT improved treatment accuracy, allowing a 50% reduction in the PTV expansion margin overall. Thus we could reduce the margins of targets for set-up uncertainty technically to fulfill the good dose coverage to tumor targets while still keep critical organs at risk at safe dose constrains.

Distant failure

In our series, 79 patients developed DM, with a 5-year DMFS of 87.2%. Less than 5% patients would develop distant failure with early stage disease (5-year DMFS 100% for Stage I and 95% for Stage II), while up to 20% would suffer distant failure in patients with advanced stage (5-year DMFS 87.7% for Stage III and 81.3% for Stage IVa-b). Because IMRT with or without chemotherapy achieved superb local-regional control, the development of DM has become the main pattern of relapse. This resulted in 5-year PFS and OS of 76.5% and 85.0% for Stage III patients, 68.2% and 82% for Stage IVa-b.

In addition to N stage, T category was an independent predictor for DM In multivariate Cox proportional hazards model analysis. Compared to T1 disease, the DM risk was 1.91, 2.57, and 5.24 times for T2, T3, and T4 disease.

Another interesting finding in out series was that neoadjuvant chemotherapy was a protective factor for DM. The DM risk of patients who received neoadjuvant chemotherapy was only half (0.54, 95% CI 0.33–0.087, P = 0.012) of those without, even other known prognostic factors (age, gender, T and N stage) had been adjusted. One reason might be 47.8% (228/447) patient's received docetaxel-based regimen. A Phase III trial on patients with advanced unresectable head and neck cancers [19] showed that significant survival benefit can be achieved by changing the induction regimen from cisplatin-fluorouracil to cisplatin, fluorouracil, and docetaxel. It is worth studying the use of a taxane-based combination in the induction setting. Preliminary efficacy has been shown with this strategy in NPC,[20] but randomized Phase III study was warranted.


 > Conclusion Top


Our long-term outcomes of large NPC series supports the effectiveness of IMRT for excellent local-regional control, though up to 20% patients would develop DM, which results in DM as the main pattern of failure for the patients with locally advanced disease. The current T classification is becoming less powerful in segregating patients into various at-risk groups of local relapse. T4 disease remained difficult to be cured not only for local recurrence but distant failure. A taxane-based combination chemotherapy might be useful to reduce DM in the induction setting and worthy further studying.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;365:2041-54.  Back to cited text no. 1
    
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Xia P, Fu KK, Wong GW, Akazawa C, Verhey LJ. Comparison of treatment plans involving intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000;48:329-37.  Back to cited text no. 3
    
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Kam MK, Chau RM, Suen J, Choi PH, Teo PM. Intensity-modulated radiotherapy in nasopharyngeal carcinoma: Dosimetric advantage over conventional plans and feasibility of dose escalation. Int J Radiat Oncol Biol Phys 2003;56:145-57.  Back to cited text no. 4
    
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Cheng JC, Chao KS, Low D. Comparison of intensity modulated radiation therapy (IMRT) treatment techniques for nasopharyngeal carcinoma. Int J Cancer 2001;96:126-31.  Back to cited text no. 5
    
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Wolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: Update of the Memorial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 2006;64:57-62.  Back to cited text no. 7
    
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Kam MK, Teo PM, Chau RM, Cheung KY, Choi PH, Kwan WH, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60:1440-50.  Back to cited text no. 8
    
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Kwong DL, Pow EH, Sham JS, McMillan AS, Leung LH, Leung WK, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: A prospective study on disease control and preservation of salivary function. Cancer 2004;101:1584-93.  Back to cited text no. 9
    
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Kwong DL, Sham JS, Leung LH, Cheng AC, Ng WM, Kwong PW, et al. Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;64:374-81.  Back to cited text no. 10
    
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Lin S, Pan J, Han L, Zhang X, Liao X, Lu JJ. Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: Report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75:1071-8.  Back to cited text no. 11
    
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Tham IW, Hee SW, Yeo RM, Salleh PB, Lee J, Tan TW, et al. Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the national cancer centre Singapore experience. Int J Radiat Oncol Biol Phys 2009;75:1481-6.  Back to cited text no. 12
    
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Ng SH, Chang TC, Ko SF, Yen PS, Wan YL, Tang LM, et al. Nasopharyngeal carcinoma: MRI and CT assessment. Neuroradiology 1997;39:741-6.  Back to cited text no. 13
    
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Chong VF, Mukherji SK, Ng SH, Ginsberg LE, Wee JT, Sham JS, et al. Nasopharyngeal carcinoma: Review of how imaging affects staging. J Comput Assist Tomogr 1999;23:984-93.  Back to cited text no. 14
    
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Chong VF, Fan YF. Skull base erosion in nasopharyngeal carcinoma: Detection by CT and MRI. Clin Radiol 1996;51:625-31.  Back to cited text no. 15
    
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Chua DT, Sham JS, Kwong DL, Tai KS, Wu PM, Lo M, et al. Volumetric analysis of tumor extent in nasopharyngeal carcinoma and correlation with treatment outcome. Int J Radiat\Oncol Biol Phys 1997;39:711-9.  Back to cited text no. 16
    
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Fletcher GH, Million RR. Nasopharynx. In: Fletcher GH, editor. Textbook of Radiotherapy. 3rd ed. Philadelphia: Lea and Febiger Press; 1980. p. 364-83.  Back to cited text no. 17
    
18.
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.  Back to cited text no. 18
    
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Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 2009;27:242-9.  Back to cited text no. 19
    
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Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 2009;27:242-9  Back to cited text no. 20
    


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