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Impact of intensity-modulated radiotherapy on nasopharyngeal carcinoma: Validation of the 7th edition AJCC staging system
Oral Oncology 51 (2015) 254–259
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Impact of intensity-modulated radiotherapy on nasopharyngeal carcinoma: Validation of the 7th edition AJCC staging system Jingfeng Zong a,b,c, Shaojun Lin a,b,c,1, Jin Lin a,b,c, Linbo Tang a,b,c, Bijuan Chen a,b,c, Mingwei Zhang a,b,c, Yu Zhang a,b,c, Luying Xu a,b,c, Yunbin Chen a,d, Youping Xiao a,d, Yanhong Fang a,d, Jianji Pan a,b,c,⇑ a
Provincial Clinical College of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China Fujian Provincial Key Laboratory of Translational Cancer Medicine (Fujian Provincial Cancer Hospital, Fujian Medical University Union Hospital), Fuzhou, Fujian, People’s Republic of China d Department of Radiology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China b c
a r t i c l e
i n f o
Article history: Received 17 August 2014 Received in revised form 17 October 2014 Accepted 18 October 2014 Available online 6 November 2014 Keywords: Nasopharyngeal cancer Staging system Intensity modulated radiation therapy Prognosis
s u m m a r y Background and purpose: The purpose of this study was to evaluate the 7th edition UICC/AJCC staging system for nasopharyngeal carcinoma (NPC) patients who were treated with intensity modulated radiation therapy (IMRT). Materials and methods: The clinical data of 1241 NPC patients with initial magnetic resonance imaging (MRI) scans were studied retrospectively. All MRIs were independently reevaluated and restaged according to the 7th edition by two radiologists specializing in head and neck cancers. Analysis of prognostic factors in local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were performed. Results: The proportion of patients in Stage I, II, III, IVA and IVB were 4.8%, 26.2%, 45.4%, 18.4%, and 5.2%, respectively. The differences of LRFS between T1 and T2, and between T2 and T3 were not significant (P = 0.055 and 0.605, respectively). Hazard ratios (HRs) for DSS and OS between T2 and T3 or between T3 and T4 differed significantly, but not between T1 and T2. The differences of DMFS between N0 and N1, between N1 and N2 were significant. However no significant difference was found in DMFS between N2 and N3a, or between N2 and N3b. For patients with T1–T3 disease, although skull base infiltration did not impact local failure, it was an independent prognostic factor for both distant failure and cancer death. Conclusion: When treated with IMRT, the difference in the LRFS, DSS, and OS between T1 and T2 patients diminished, indicating that it is rational to merge T2 into T1. The prognostic value of the N classification of the current staging system had not changed much compared to the 6th edition. Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Introduction Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in South China, and it is highly sensitive to radiotherapy or chemotherapy [1]. Radiotherapy alone or combined with chemotherapy is the primary treatment depending on the disease stage [2]. Therefore, the precise stage is crucial in selecting and determining treatment strategies for NPC. ⇑ Corresponding author at: Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China. Tel.: +86 591 83638732; fax: +86 591 83928767. E-mail addresses: [email protected] (S. Lin), [email protected] (J. Pan). 1 Co-corresponding author. Department of Radiation Oncology, Fujian Provincial Cancer Hospital, No. 420, Fuma Road, Fuzhou 350014, People’s Republic of China. Tel.: +86 13860603879; fax: +86 591 83928767.
The 7th AJCC staging system for NPC, which is a revision based on the 5th and 6th editions, is currently universally accepted [3]. With the extensive use of intensity modulated radiation therapy (IMRT), even in locally advanced NPC, the 5-year local control rate has exceeded 90% [4,5]. Therefore, the short comings of the current TNM staging system in predicting the prognosis have been found and proposals for revisions in the next edition have been raised in recent studies [6–8]. However, any change of the staging criterion should be based on sufficient evidences from multiple centers and/or large sample studies which can be applied worldwide [9]. In the present study, the clinical data from 1241 pathologically confirmed NPC patients, who were staged by magnetic resonance imaging (MRI) and treated with radical IMRT, were collected retrospectively and analyzed to assess the validity of the 7th edition AJCC staging system.
http://dx.doi.org/10.1016/j.oraloncology.2014.10.012 1368-8375/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
J. Zong et al. / Oral Oncology 51 (2015) 254–259
Methods and materials Patient characteristics A total of 1241 newly diagnosed NPC patients without distant organ metastasis, who were treated at Fujian Provincial Cancer Hospital between June 1, 2005 and Dec 31, 2010, were collected. The retrospective analysis was approved by Fujian Provincial Cancer Hospital Institutional Review Board. Although consent was not specifically obtained for this retrospective review, all information had been anonymized and de-identified prior to its analysis. The patients included 938 men and 303 women (male: female ratio, 3.1:1), with a median age of 46 yrs (range, 11–84 yrs). The majority of the patients (94.7%; 1175/1241) had World Health Organization (WHO) type III histopathology, 53 patients (4.3%) with WHO type II, and 13 patients (1%) with WHO type I MRI scan All patients underwent MRI with a 1.5-Telsa system (Singa EXCITE III HD, WI, American GE Company). The area from the central temporal lobe to the entrance of thoracic was examined with a head-and-neck combined coil. Seven scanning sequences including axial T1 fast spin-echo (FSE), sagittal T1 FSE, axial proton density fat-suppressed (PD fs), coronal T1 short-tall inversion recovery (STIR), axial T1 enhanced FSE fs, coronal T1 enhanced FSE fs, and diffusion weighted imaging (DWI) were obtained in MRI general scans. Among the above scanning sequences, the coronal orientation was parallel to C3 and axial orientation was perpendiculars to C3. Clinical staging All MRI scans were revaluated separately by two radiologists specializing in head-and-neck cancers. Any disagreement was resolved by consensus. Cranial nerve involvement in T4 disease was evaluated according to physical examination rather than the radiology imaging [10]. Masticator space involvement is defined as extension tumor of beyond the anterior surface of the lateral pterygoid muscle, or lateral extension beyond the posterolateral wall of the maxillary antrum and the pterygomaxillary fissure [11]. The clinical records and MRI results of all patients were collected into a database to be restaged accurately according to the criteria of the 7th edition of AJCC staging system. Treatment All patients were initially treated with definitive IMRT. A detailed description of the IMRT had been published previously [12]. Of the 1181 patients with Stage II–IVB disease, 1,048 (88.7%) patients were given platinum-based chemotherapy. The sequence of chemotherapy used was induction in 263 (22.3%), concurrent in 69 (5.8%), adjuvant in 15 (1.3%), concurrent–adjuvant in 23 (1.9%), induction–concurrent in 216 (18.3%), induction– adjuvant in 301 (25.5%), and induction–concurrent–adjuvant in 161 (13.6%). Whenever possible, salvage treatments (including intracavitary brachytherapy, surgery, and chemotherapy) were provided for patients who developed relapse or persistent disease. Following-up and statistical analysis The median following-up time was 57 months (range, 2–102 months). The following endpoints (measured from the first day of diagnosis to the first defining event) were estimated: local
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relapse-free survival (LRFS), regional relapse-free survival (RRFS), disease-specific survival (DSS) and overall survival (OS). The survival data were analyzed with SPSS software, version 18.0 (SPSS, Inc., Chicago, IL, USA). The host factors, histological types, and treatment characteristics among different subgroups were compared and analyzed using the chi-square test. Survival curves were created with the Kaplan–Meier method and compared with the log-rank test. The Cox proportional hazards model was used to test the hazard ratios of DSS. A two-tailed P value < 0.05 was considered statistically significant. Results Patient distribution According to the 7th edition AJCC TNM stage system, the Stage I, II, III, IVA and IVB disease was 4.8%, 26.2%, 45.4%, 18.4%, and 5.2%, respectively. There were no significant differences in the host factors, histological categories, and chemotherapy among the different T categories. However, significantly more patients with advanced T categories had received additional radiation boost treatment to the nasopharynx than patients with early T categories because of residual disease after IMRT (P = 0.014, Table 1). Patterns of treatment failure and survival At the last following up, 230 (18.5%) patients had succumbed to their disease and 1011 (81.5%) remained alive. The 5-year OS, DSS, DMFS, RRFS and LRFS were 81.1%, 82.6%, 82.6%, 95.4%, and 92.9% respectively. Local recurrences, regional recurrences and distant metastases developed in 81 (6.5%), 52 (4.2%), and 207 (16.7%) patients, whereas 49 patients (3.9%) presented with both locoregional recurrences and distant metastases. T category The 5-year LRFS in T1, T2, T3 and T4 were 97.9%, 93.8%, 94.2%, and 82.9%, respectively (Fig. 1). The difference between T1 and T3, T2 and T4, T3 and T4 were found to be significance (P < 0.05), and was almost statistically significant between T1 and T2 (P = 0.055), however, there was no significant difference between T2 and T3 (P = 0.605). DSS and OS comparisons among the T categories are shown in Table 2. A higher T category was associated with poorer DSS and OS. Hazard ratios (HRs) for DSS and OS between T2 and T3 and between T3 and T4 differed significantly, but not between T1 and T2 (P = 0.070 and 0.235). When the T categories were considered as three groups (T1 + T2, T3, and T4), HRs for both DSS and OS differed significantly between adjacent T categories (Table 2). N category The 5-year DMFS were 94.2%, 84.5%, 75.3%, 70.2%, and 61.7% for N0, N1, N2, N3a, and N3b, respectively (Fig. 2A). The survival differences between N0 and N1, N1 and N2, N2 and N3b were significant. Although there were no significant survival difference found between N2 and N3a (P = 0.498) or N3a and N3b (P = 0.389), there was a significance difference in survival between N2 and combined N3a and N3b (P = 0.046, Fig. 2B). As the N category increased, the DSS and OS became poorer. HR for DSS and OS between the N0 and N1, N1 and N2 differed significantly, but not between N2 and N3a, or N3a and N3b. When combining N3a and N3b, the differences in HRs for both DSS and OS between N3 and N2 were not significant (P = 0.107 and 0.212, Table 2).
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J. Zong et al. / Oral Oncology 51 (2015) 254–259
Table 1 Patient characteristic of different T categories. Characteristic
No. of patients (%) T1
T2
T3
T4
Total
Gender Male Female
226(75.1) 75(24.9)
177(73.4) 64(26.6)
343(74.9) 115(25.1)
192(79.7) 49(20.3)
938(75.6) 303(24.4)
Age (yrs) <50 >50
193(64.1) 108(35.9)
148(61.4) 93(38.6)
299(65.3) 159(34.7)
138(57.3) 103(42.7)
778(62.7) 463(37.3)
Histology WHO grade I WHO grade II WHO grade III
1(0.3) 14(4.7) 286(95.0)
6(2.5) 14(5.8) 221(91.7)
4(0.9) 12(2.6) 442(96.5)
2(0.8) 13(5.4) 226(93.8)
13(1.0) 53(4.3) 1175(94.7)
Chemotherapy in stage III–IV patients No 5(6.5) Yes 72(93.5)
5(6.2) 75(93.8)
35(7.6) 423(92.4)
13(5.4) 228(94.6)
58(6.8) 798(93.2)
Boost treatment No Yes
283(94.0) 18(6.0)
220(91.3) 21(8.7)
407(88.9) 51(11.1)
214(88.8) 27(11.2)
1124(90.6) 117(9.4)
N-stage N0 N1 N2 N3
60(19.9) 164(54.5) 67(22.3) 10(3.3)
28(11.6) 133(55.2) 61(25.3) 19(7.9)
63(13.8) 243(53.0) 129(28.2) 23(5.0)
33(13.7) 147(61.0) 48(19.9) 13(5.4)
184(14.8) 687(55.4) 305(24.6) 65(5.2)
P value 0.402
0.188
0.978
0.725
0.014
0.178
paranasal sinuses involvement. No independent prognostic factor was found for local failure. Skull base infiltration were statistically significant for distant failure, cancer death and death due to any cause, whereas T1–T2 related factors such as nasal fossa extension, oropharynx infiltration, and parapharyngeal involvement failed to show significant positive trends for all endpoints (Table 3).
Discussion
Fig. 1. Local relapse-free survival for different T classifications.
Stage grouping The 5-year DSS was 97.2% for stage I, 90.6% for stage II, 82.9% for stage III, 69.5% for stage IVA, and 68.9% for stage IVB (Fig. 3A). The DSS curves showed fairly good separation among adjacent staging groups. However, the difference between stage IVA and IVB does not reach statistical significance (P = 0.505). Although the OS curves showed no statistically significant difference between stages I and II, and between stages IVA and IVB (P = 0.075 and 0.729 respectively), it still shows a relatively well segregated distribution pattern for all stages (Fig. 3B). Multivariate Cox regression analysis Due to the closed LRFS in T1–3 patients, multivariate Cox regression analysis was performed to evaluate various prognostic factors defined by T-categories. The following covariables were included in the Cox proportion hazards model: age (<50 yrs vs.>50 yrs), gender (male vs. female), chemotherapy (yes vs. no), histology, N category, nasal fossa extension, oropharynx infiltration, parapharyngeal extension, skull base infiltration, and
The AJCC TNM classification of NPC is a universally accepted system to describe the anatomic extent of malignant tumors. To reflect the understanding of the extent of the disease and its role in prognosis, the TNM classification has undergone significant evidence-based revisions [3]. The 7th staging system was revised mainly based on the data from the two-dimensional conventional radiotherapy era [10]. Currently, the IMRT has been confirmed to improve local control and reduce radiation-induced toxicities by providing better tumor target coverage and is significantly better at sparing sensitive normal structures [12]. Despite of the controversy as to whether early or advanced T Stage can benefit from IMRT, it is widely accepted as the standard treatment for NPC [13,14]. Although there are still a certain percentage of patients given conventional radiotherapy instead of IMRT due to limited resources, the vast majority of NPC patients in the world will receive IMRT. Therefore, to revise the TNM staging system and make it applicable to patients treated with IMRT is inevitably the future direction for further refinement of NPC staging [6,7,15]. Lee [6] analyzed the data of 985 NPC patients treated with 3Dconformal radiotherapy or IMRT and found that the difference in the LRFS between T2 and T3 was significant (P = 0.043), but not between T1 and T2 (P = 0.99). The study considered that with modern treatment, the staging system could be further improved and simplified by down-staging the current stage T2 patients to T1. In addition, Chen et al. [7] previously reported a study of 512 NPC patients treated with IMRT, and found that the LRFS between T1 and T2 patients were significantly different, but not between stage T2 and T3 patients. These reports indicated that the differences of local control among T1–3 patients will be diminished when treated with 3DCRT or IMRT. However, how to simplify the
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J. Zong et al. / Oral Oncology 51 (2015) 254–259 Table 2 Disease-specific survival and overall survival in nasopharyngeal carcinoma patients according to the 7th edition of TNM staging system. Category
Comparison
Cancer death 5-yr DSS (%)
T category
N category
T1 T2 T3 T4 T1 + T2
T2 T3 T4 T3
N0 N1 N2 N3a N3b N3
N1 vs. N0 N2 vs. N1 N3a vs. N2 N3b vs. N3a N3 vs. N2
vs. vs. vs. vs.
T1 T2 T3 T1 + T2
92.2 86.6 81.2 69.1 89.7 92 84.5 75.4 69.8 67.6 68.9
Death HR (95% CI)
P value
5-yr OS (%)
HR (95% CI)
P value
1.658(0.960–2.865) 1.544(1.029–2.316) 1.708(1.239–2.355) 1.892(1.344–2.665)
0.070a 0.036a 0.001a <0.001a
90 85.7 80.0 67.6 88.1
1.357(0.82–2.249) 1.566(1.057–2.322) 1.663(1.219–2.268) 1.792(1.295–2.48)
0.235a 0.025a 0.001a <0.001a
1.891(1.149–3.113) 1.689(1.242–2.298) 1.147(0.565–2.331) 1.611(0.649–4.001) 1.493(0.917–2.432)
0.012b 0.001b 0.704b 0.304b 0.107b
90.9 83.2 73.2 69.8 67.6 68.9
1.944(1.177–3.211) 1.710(1.277–2.289) 1.020(0.504–2.064) 1.611(0.649–4.001) 1.359(0.839–2. 201)
0.009b <0.001b 0.957b 0.304b 0.212b
DSS = disease-specific survival; OS = overall survival; HR = hazard ratio; CI = confidence interval. a P value was calculated using Cox proportional hazards model after adjusting for age, gender, histology, chemotherapy and N category. b P value was calculated using Cox proportional hazards model after adjusting for age, gender, histology, chemotherapy and T category.
Fig. 2. Distant metastasis-free survival for different N classifications: (A) N3 was divided into N3a and N3b, (B) N3 was the combination of N3a and N3b.
Fig. 3. Disease-specific survival (A) and overall survival (OS) for different overall stages.
current AJCC staging system of T classification to be more reasonable is still controversial [6,7]. As indicated in this study, stage T4 patients had much worse survival compared to patients in other T categories (T1–3), whereas, the LRFS between stage T1 and T2 patients and between stage T2 and T3 patients was not significantly different. Meanwhile, although the difference in DSS and OS between stage T2 and T3 patients and between T3 and T4
patients was significant, it was not significant between stage T1 and T2 patients (Table 1). Further multivariate analysis were performed in stage T1–T3 patients, which revealed that the skull base infiltration was a statistically significant factor for both distant failure and cancer death. This indicated, that although the LRFS between stage T1 and T2 and between stage T2 and T3 patients was not significantly different,
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J. Zong et al. / Oral Oncology 51 (2015) 254–259 Table 3 Independent prognostic factors by multivariate analyses for patient with T1–T3. Endpoint
Factor
P value
HR (95% CI)
Distant failure
Skull base infiltration Gender Age N category
0.018 0.048 0.002 <0.001
1.559(1.081–2.250) 0.607(0.371–0.995) 1.785(1.236–2.578) 1.811(1.442–2.275)
Cancer death
Skull base infiltration Age N category
0.007 <0.001 <0.001
1.681(1.154–2.448) 2.661(1.830–3.871) 1.897(1.504–2.394)
Death
Skull base infiltration Age N category
0.008 <0.001 <0.001
1.613(1.131–2.3) 3.009(2.105–4.3) 1.807(1.448–2.266)
HR = hazard ratio, CI = confidence interval.
T3 patients had poorer prognosis than patients with stage T1 and T2 disease. Merging the current T2 and T1 stages seems to be more rational than merging stages T2 and T3. In the current study, when the T categories were considered as three groups (T1 + T2, T3, and T4), HRs of DSS and OS differed significantly between adjacent T categories (Table 2). Although the AJCC staging system of NPC had been modified constantly, there has been more updating and improvements of T staging than of N staging [3]. There was no obvious change in N staging after the fourth edition except the clear definition and classification of pharyngeal lymph node involvement [10]. Compared to the previous conventional radiotherapy, the prognosis prediction of N staging has not changed, even in the IMRT era [7,16,17]. The present study demonstrated the N staging is practical and it can predict the prognosis in N1, N2 and N3 patients. Due to the presence of rare NPC patients who are staged N3, there had been several studies trying to challenge the existing N3 staging criteria [17–19]. However, for the lack of a unified endpoint and of a sufficient sample size to study, particularly for the deficiency of unified objective criterion diagnosis of the N3 subgroups, a feasible revision opinion of N staging have not been raised until now [10]. Two studies have reported that the predictive value of the N classification in the Chinese 2008 staging system was superior to the 7th AJCC [15,20]. In the Chinese 2008 staging system, measurement of the lymph nodes was based on MRI images rather than clinical palpation, which may differ among clinicians. In addition, the site, size, laterality and extranodal neoplastic spread to lymph nodes were all enrolled in the criteria of N staging categories [21]. Although it may be objective to evaluate the site, size and laterality of lymph node involvement on MRI, the measurement of the extranodal neoplastic spread is an inevitable ambiguity. Therefore, revising a more sensible and reliable N classification for the current AJCC staging system remains a great challenge. Concurrent chemoradiotherapy has been repeatedly proven to improve survival [22,23]. However, only 39.7% (469/1181) of the stage II–IVB patients received concurrent chemotherapy in the study. Future prospective studies of IMRT combined with concurrent chemotherapy may be needed to evaluate its influence on the staging system. The current AJCC TNM staging system for NPC is based on the anatomical extent of the tumor [24]. Tumor volume has been proposed as an independent prognostic factor besides T classification in patients with NPC [25–27]. Our previous study also demonstrated that the primary tumor volume had a significant impacted on the prognosis of NPC patients treated with IMRT. The 5-year OS was significantly reduced for patients with a large tumor volume (>50 ml), which is almost equal to that of stage T4 patients [28]. To take tumor volume into consideration as an additional stage indicator in the future revision of NPC staging, more studies should
be done to identify a uniform cut-off point of tumor volume. On the other hand, new biomarkers such as miRNA or EBV DNA have been recently reported as having prognostic value. To bring these new molecular factors into the clinical staging system presents a most challenging task [29,30]. In conclusion, regardless of the limitation of this being a single center and retrospective study, our study indicated that the 7th edition AJCC staging system still showed superior prognostic value in NPC patients treated with IMRT. Because patients with T2 disease had similar LRFS to stage T1 patients, the proposal of down stage T2 to T1 seemed to be reasonable. However, how to rationally deal with the stage N3a needs more research. Conflict of interest The authors declare no conflicts of interests. Acknowledgment Grant Sponsored by key Clinical Specialty Discipline Construction Program of Fujian, P.R.C. References [1] Zhang L, Chen QY, Liu H, Tang LQ, Mai HQ. Emerging treatment options for nasopharyngeal carcinoma. Drug Des Dev Ther 2013;7:37–52. [2] Spratt DE, Lee N. Current and emerging treatment options for nasopharyngeal carcinoma. OncoTargets Ther 2012;5:297–308. [3] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009. [4] Lin S, Pan J, Han L, Guo Q, Hu C, Zong J, et al. Update report of nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy and hypothesis of the optimal margin. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2014;110:385–9. [5] Xiao WW, Huang SM, Han F, Wu SX, Lu LX, Lin CG, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer 2011;117:1874–83. [6] Lee AW, Ng WT, Chan LK, Chan OS, Hung WM, Chan CC, et al. The strength/ weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement. Oral Oncol 2012;48:1007–13. [7] Chen L, Mao YP, Xie FY, Liu LZ, Sun Y, Tian L, et al. The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:331–7. [8] Li WF, Sun Y, Mao YP, Chen L, Chen YY, Chen M, et al. Proposed lymph node staging system using the International Consensus Guidelines for lymph node levels is predictive for nasopharyngeal carcinoma patients from endemic areas treated with intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:249–56. [9] Webber C, Gospodarowicz M, Sobin LH, Wittekind C, Greene FL, Mason MD, et al. Improving the TNM classification: findings from a 10-yr continuous literature review. Int J Cancer J Int Du Cancer 2014;135:371–8. [10] O’Sullivan B, Yu E. Staging of nasopharyngeal carcinoma. In: Lu JJ, Cooper JS, Lee AWM, editors. Nasopharyngeal Cancer–Multidisciplinary Management. Berlin Heidelberg: Springer; 2010. p. 309–22.
J. Zong et al. / Oral Oncology 51 (2015) 254–259 [11] 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. [12] 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-yr outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75:1071–8. [13] Peng G, Wang T, Yang KY, Zhang S, Zhang T, Li Q, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma.. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:286–93. [14] Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, et al. How does intensitymodulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80:661–8. [15] OuYang PY, Su Z, Ma XH, Mao YP, Liu MZ, Xie FY. Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. Br J Cancer 2013;109:2987–97. [16] Heng DM, Wee J, Fong KW, Lian LG, Sethi VK, Chua ET, et al. Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma. Cancer 1999;86:1912–20. [17] Lee AW, Au JS, Teo PM, Leung TW, Chua DT, Sze WM, et al. Staging of nasopharyngeal carcinoma: suggestions for improving the current UICC/AJCC Staging System. Clin Oncol 2004;16:269–76. [18] Low JS, Heng DM, Wee JT. The question of T2a and N3a in the UICC/AJCC (1997) staging system for nasopharyngeal carcinoma. Clin Oncol 2004;16:581–3. [19] Liu MZ, Tang LL, Zong JF, Huang Y, Sun Y, Mao YP, et al. Evaluation of sixth edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement. Int J Radiat Oncol Biol Phys 2008;70:1115–23. [20] Pan J, Xu Y, Qiu S, Zong J, Guo Q, Zhang Y, et al. A Comparison between the Chinese 2008 and the 7th edition AJCC staging systems for nasopharyngeal carcinoma. Am J Clin Oncol 2013;23:192–8. [21] Chinese Committee for Staging of Nasopharyngeal Carcinoma. Report on revision of the Chinese staging system for nasopharyngeal carcinoma. J Radiat Oncol 2013;2:233–40.
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[22] Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2011;98:15–22. [23] Chen Y, Sun Y, Liang SB, Zong JF, Li WF, Chen M, et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III–IVB nasopharyngeal carcinoma from endemic regions of China. Cancer 2013;119:2230–8. [24] Ng WT, Yuen KT, Au KH, Chan OS, Lee AW. Staging of nasopharyngeal carcinoma–the past, the present and the future. Oral Oncol 2014;50: 549–54. [25] 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. [26] Sze WM, Lee AW, Yau TK, Yeung RM, Lau KY, Leung SK, et al. Primary tumor volume of nasopharyngeal carcinoma: prognostic significance for local control. Int J Radiat Oncol Biol Phys 2004;59:21–7. [27] Guo R, Sun Y, Yu XL, Yin WJ, Li WF, Chen YY, et al. Is primary tumor volume still a prognostic factor in intensity modulated radiation therapy for nasopharyngeal carcinoma? Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:294–9. [28] Chen C, Fei Z, Pan J, Bai P, Chen L. Significance of primary tumor volume and T-stage on prognosis in nasopharyngeal carcinoma treated with intensitymodulated radiation therapy. Jpn J Clin Oncol 2011;41:537–42. [29] Liu N, Cui RX, Sun Y, Guo R, Mao YP, Tang LL, et al. A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma. Int J Cancer J Int Du Cancer. 2014;134:1359–68. [30] Hsu CL, Chang KP, Lin CY, Chang HK, Wang CH, Lin TL, et al. Plasma Epstein– Barr virus DNA concentration and clearance rate as novel prognostic factors for metastatic nasopharyngeal carcinoma. Head Neck 2012;34:1064–70.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Impact of intensity-modulated radiotherapy on nasopharyngeal carcinoma: Validation of the 7th edition AJCC staging system Jingfeng Zong a,b,c, Shaojun Lin a,b,c,1, Jin Lin a,b,c, Linbo Tang a,b,c, Bijuan Chen a,b,c, Mingwei Zhang a,b,c, Yu Zhang a,b,c, Luying Xu a,b,c, Yunbin Chen a,d, Youping Xiao a,d, Yanhong Fang a,d, Jianji Pan a,b,c,⇑ a
Provincial Clinical College of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China Fujian Provincial Key Laboratory of Translational Cancer Medicine (Fujian Provincial Cancer Hospital, Fujian Medical University Union Hospital), Fuzhou, Fujian, People’s Republic of China d Department of Radiology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China b c
a r t i c l e
i n f o
Article history: Received 17 August 2014 Received in revised form 17 October 2014 Accepted 18 October 2014 Available online 6 November 2014 Keywords: Nasopharyngeal cancer Staging system Intensity modulated radiation therapy Prognosis
s u m m a r y Background and purpose: The purpose of this study was to evaluate the 7th edition UICC/AJCC staging system for nasopharyngeal carcinoma (NPC) patients who were treated with intensity modulated radiation therapy (IMRT). Materials and methods: The clinical data of 1241 NPC patients with initial magnetic resonance imaging (MRI) scans were studied retrospectively. All MRIs were independently reevaluated and restaged according to the 7th edition by two radiologists specializing in head and neck cancers. Analysis of prognostic factors in local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were performed. Results: The proportion of patients in Stage I, II, III, IVA and IVB were 4.8%, 26.2%, 45.4%, 18.4%, and 5.2%, respectively. The differences of LRFS between T1 and T2, and between T2 and T3 were not significant (P = 0.055 and 0.605, respectively). Hazard ratios (HRs) for DSS and OS between T2 and T3 or between T3 and T4 differed significantly, but not between T1 and T2. The differences of DMFS between N0 and N1, between N1 and N2 were significant. However no significant difference was found in DMFS between N2 and N3a, or between N2 and N3b. For patients with T1–T3 disease, although skull base infiltration did not impact local failure, it was an independent prognostic factor for both distant failure and cancer death. Conclusion: When treated with IMRT, the difference in the LRFS, DSS, and OS between T1 and T2 patients diminished, indicating that it is rational to merge T2 into T1. The prognostic value of the N classification of the current staging system had not changed much compared to the 6th edition. Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Introduction Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in South China, and it is highly sensitive to radiotherapy or chemotherapy [1]. Radiotherapy alone or combined with chemotherapy is the primary treatment depending on the disease stage [2]. Therefore, the precise stage is crucial in selecting and determining treatment strategies for NPC. ⇑ Corresponding author at: Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, People’s Republic of China. Tel.: +86 591 83638732; fax: +86 591 83928767. E-mail addresses: [email protected] (S. Lin), [email protected] (J. Pan). 1 Co-corresponding author. Department of Radiation Oncology, Fujian Provincial Cancer Hospital, No. 420, Fuma Road, Fuzhou 350014, People’s Republic of China. Tel.: +86 13860603879; fax: +86 591 83928767.
The 7th AJCC staging system for NPC, which is a revision based on the 5th and 6th editions, is currently universally accepted [3]. With the extensive use of intensity modulated radiation therapy (IMRT), even in locally advanced NPC, the 5-year local control rate has exceeded 90% [4,5]. Therefore, the short comings of the current TNM staging system in predicting the prognosis have been found and proposals for revisions in the next edition have been raised in recent studies [6–8]. However, any change of the staging criterion should be based on sufficient evidences from multiple centers and/or large sample studies which can be applied worldwide [9]. In the present study, the clinical data from 1241 pathologically confirmed NPC patients, who were staged by magnetic resonance imaging (MRI) and treated with radical IMRT, were collected retrospectively and analyzed to assess the validity of the 7th edition AJCC staging system.
http://dx.doi.org/10.1016/j.oraloncology.2014.10.012 1368-8375/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
J. Zong et al. / Oral Oncology 51 (2015) 254–259
Methods and materials Patient characteristics A total of 1241 newly diagnosed NPC patients without distant organ metastasis, who were treated at Fujian Provincial Cancer Hospital between June 1, 2005 and Dec 31, 2010, were collected. The retrospective analysis was approved by Fujian Provincial Cancer Hospital Institutional Review Board. Although consent was not specifically obtained for this retrospective review, all information had been anonymized and de-identified prior to its analysis. The patients included 938 men and 303 women (male: female ratio, 3.1:1), with a median age of 46 yrs (range, 11–84 yrs). The majority of the patients (94.7%; 1175/1241) had World Health Organization (WHO) type III histopathology, 53 patients (4.3%) with WHO type II, and 13 patients (1%) with WHO type I MRI scan All patients underwent MRI with a 1.5-Telsa system (Singa EXCITE III HD, WI, American GE Company). The area from the central temporal lobe to the entrance of thoracic was examined with a head-and-neck combined coil. Seven scanning sequences including axial T1 fast spin-echo (FSE), sagittal T1 FSE, axial proton density fat-suppressed (PD fs), coronal T1 short-tall inversion recovery (STIR), axial T1 enhanced FSE fs, coronal T1 enhanced FSE fs, and diffusion weighted imaging (DWI) were obtained in MRI general scans. Among the above scanning sequences, the coronal orientation was parallel to C3 and axial orientation was perpendiculars to C3. Clinical staging All MRI scans were revaluated separately by two radiologists specializing in head-and-neck cancers. Any disagreement was resolved by consensus. Cranial nerve involvement in T4 disease was evaluated according to physical examination rather than the radiology imaging [10]. Masticator space involvement is defined as extension tumor of beyond the anterior surface of the lateral pterygoid muscle, or lateral extension beyond the posterolateral wall of the maxillary antrum and the pterygomaxillary fissure [11]. The clinical records and MRI results of all patients were collected into a database to be restaged accurately according to the criteria of the 7th edition of AJCC staging system. Treatment All patients were initially treated with definitive IMRT. A detailed description of the IMRT had been published previously [12]. Of the 1181 patients with Stage II–IVB disease, 1,048 (88.7%) patients were given platinum-based chemotherapy. The sequence of chemotherapy used was induction in 263 (22.3%), concurrent in 69 (5.8%), adjuvant in 15 (1.3%), concurrent–adjuvant in 23 (1.9%), induction–concurrent in 216 (18.3%), induction– adjuvant in 301 (25.5%), and induction–concurrent–adjuvant in 161 (13.6%). Whenever possible, salvage treatments (including intracavitary brachytherapy, surgery, and chemotherapy) were provided for patients who developed relapse or persistent disease. Following-up and statistical analysis The median following-up time was 57 months (range, 2–102 months). The following endpoints (measured from the first day of diagnosis to the first defining event) were estimated: local
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relapse-free survival (LRFS), regional relapse-free survival (RRFS), disease-specific survival (DSS) and overall survival (OS). The survival data were analyzed with SPSS software, version 18.0 (SPSS, Inc., Chicago, IL, USA). The host factors, histological types, and treatment characteristics among different subgroups were compared and analyzed using the chi-square test. Survival curves were created with the Kaplan–Meier method and compared with the log-rank test. The Cox proportional hazards model was used to test the hazard ratios of DSS. A two-tailed P value < 0.05 was considered statistically significant. Results Patient distribution According to the 7th edition AJCC TNM stage system, the Stage I, II, III, IVA and IVB disease was 4.8%, 26.2%, 45.4%, 18.4%, and 5.2%, respectively. There were no significant differences in the host factors, histological categories, and chemotherapy among the different T categories. However, significantly more patients with advanced T categories had received additional radiation boost treatment to the nasopharynx than patients with early T categories because of residual disease after IMRT (P = 0.014, Table 1). Patterns of treatment failure and survival At the last following up, 230 (18.5%) patients had succumbed to their disease and 1011 (81.5%) remained alive. The 5-year OS, DSS, DMFS, RRFS and LRFS were 81.1%, 82.6%, 82.6%, 95.4%, and 92.9% respectively. Local recurrences, regional recurrences and distant metastases developed in 81 (6.5%), 52 (4.2%), and 207 (16.7%) patients, whereas 49 patients (3.9%) presented with both locoregional recurrences and distant metastases. T category The 5-year LRFS in T1, T2, T3 and T4 were 97.9%, 93.8%, 94.2%, and 82.9%, respectively (Fig. 1). The difference between T1 and T3, T2 and T4, T3 and T4 were found to be significance (P < 0.05), and was almost statistically significant between T1 and T2 (P = 0.055), however, there was no significant difference between T2 and T3 (P = 0.605). DSS and OS comparisons among the T categories are shown in Table 2. A higher T category was associated with poorer DSS and OS. Hazard ratios (HRs) for DSS and OS between T2 and T3 and between T3 and T4 differed significantly, but not between T1 and T2 (P = 0.070 and 0.235). When the T categories were considered as three groups (T1 + T2, T3, and T4), HRs for both DSS and OS differed significantly between adjacent T categories (Table 2). N category The 5-year DMFS were 94.2%, 84.5%, 75.3%, 70.2%, and 61.7% for N0, N1, N2, N3a, and N3b, respectively (Fig. 2A). The survival differences between N0 and N1, N1 and N2, N2 and N3b were significant. Although there were no significant survival difference found between N2 and N3a (P = 0.498) or N3a and N3b (P = 0.389), there was a significance difference in survival between N2 and combined N3a and N3b (P = 0.046, Fig. 2B). As the N category increased, the DSS and OS became poorer. HR for DSS and OS between the N0 and N1, N1 and N2 differed significantly, but not between N2 and N3a, or N3a and N3b. When combining N3a and N3b, the differences in HRs for both DSS and OS between N3 and N2 were not significant (P = 0.107 and 0.212, Table 2).
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Table 1 Patient characteristic of different T categories. Characteristic
No. of patients (%) T1
T2
T3
T4
Total
Gender Male Female
226(75.1) 75(24.9)
177(73.4) 64(26.6)
343(74.9) 115(25.1)
192(79.7) 49(20.3)
938(75.6) 303(24.4)
Age (yrs) <50 >50
193(64.1) 108(35.9)
148(61.4) 93(38.6)
299(65.3) 159(34.7)
138(57.3) 103(42.7)
778(62.7) 463(37.3)
Histology WHO grade I WHO grade II WHO grade III
1(0.3) 14(4.7) 286(95.0)
6(2.5) 14(5.8) 221(91.7)
4(0.9) 12(2.6) 442(96.5)
2(0.8) 13(5.4) 226(93.8)
13(1.0) 53(4.3) 1175(94.7)
Chemotherapy in stage III–IV patients No 5(6.5) Yes 72(93.5)
5(6.2) 75(93.8)
35(7.6) 423(92.4)
13(5.4) 228(94.6)
58(6.8) 798(93.2)
Boost treatment No Yes
283(94.0) 18(6.0)
220(91.3) 21(8.7)
407(88.9) 51(11.1)
214(88.8) 27(11.2)
1124(90.6) 117(9.4)
N-stage N0 N1 N2 N3
60(19.9) 164(54.5) 67(22.3) 10(3.3)
28(11.6) 133(55.2) 61(25.3) 19(7.9)
63(13.8) 243(53.0) 129(28.2) 23(5.0)
33(13.7) 147(61.0) 48(19.9) 13(5.4)
184(14.8) 687(55.4) 305(24.6) 65(5.2)
P value 0.402
0.188
0.978
0.725
0.014
0.178
paranasal sinuses involvement. No independent prognostic factor was found for local failure. Skull base infiltration were statistically significant for distant failure, cancer death and death due to any cause, whereas T1–T2 related factors such as nasal fossa extension, oropharynx infiltration, and parapharyngeal involvement failed to show significant positive trends for all endpoints (Table 3).
Discussion
Fig. 1. Local relapse-free survival for different T classifications.
Stage grouping The 5-year DSS was 97.2% for stage I, 90.6% for stage II, 82.9% for stage III, 69.5% for stage IVA, and 68.9% for stage IVB (Fig. 3A). The DSS curves showed fairly good separation among adjacent staging groups. However, the difference between stage IVA and IVB does not reach statistical significance (P = 0.505). Although the OS curves showed no statistically significant difference between stages I and II, and between stages IVA and IVB (P = 0.075 and 0.729 respectively), it still shows a relatively well segregated distribution pattern for all stages (Fig. 3B). Multivariate Cox regression analysis Due to the closed LRFS in T1–3 patients, multivariate Cox regression analysis was performed to evaluate various prognostic factors defined by T-categories. The following covariables were included in the Cox proportion hazards model: age (<50 yrs vs.>50 yrs), gender (male vs. female), chemotherapy (yes vs. no), histology, N category, nasal fossa extension, oropharynx infiltration, parapharyngeal extension, skull base infiltration, and
The AJCC TNM classification of NPC is a universally accepted system to describe the anatomic extent of malignant tumors. To reflect the understanding of the extent of the disease and its role in prognosis, the TNM classification has undergone significant evidence-based revisions [3]. The 7th staging system was revised mainly based on the data from the two-dimensional conventional radiotherapy era [10]. Currently, the IMRT has been confirmed to improve local control and reduce radiation-induced toxicities by providing better tumor target coverage and is significantly better at sparing sensitive normal structures [12]. Despite of the controversy as to whether early or advanced T Stage can benefit from IMRT, it is widely accepted as the standard treatment for NPC [13,14]. Although there are still a certain percentage of patients given conventional radiotherapy instead of IMRT due to limited resources, the vast majority of NPC patients in the world will receive IMRT. Therefore, to revise the TNM staging system and make it applicable to patients treated with IMRT is inevitably the future direction for further refinement of NPC staging [6,7,15]. Lee [6] analyzed the data of 985 NPC patients treated with 3Dconformal radiotherapy or IMRT and found that the difference in the LRFS between T2 and T3 was significant (P = 0.043), but not between T1 and T2 (P = 0.99). The study considered that with modern treatment, the staging system could be further improved and simplified by down-staging the current stage T2 patients to T1. In addition, Chen et al. [7] previously reported a study of 512 NPC patients treated with IMRT, and found that the LRFS between T1 and T2 patients were significantly different, but not between stage T2 and T3 patients. These reports indicated that the differences of local control among T1–3 patients will be diminished when treated with 3DCRT or IMRT. However, how to simplify the
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J. Zong et al. / Oral Oncology 51 (2015) 254–259 Table 2 Disease-specific survival and overall survival in nasopharyngeal carcinoma patients according to the 7th edition of TNM staging system. Category
Comparison
Cancer death 5-yr DSS (%)
T category
N category
T1 T2 T3 T4 T1 + T2
T2 T3 T4 T3
N0 N1 N2 N3a N3b N3
N1 vs. N0 N2 vs. N1 N3a vs. N2 N3b vs. N3a N3 vs. N2
vs. vs. vs. vs.
T1 T2 T3 T1 + T2
92.2 86.6 81.2 69.1 89.7 92 84.5 75.4 69.8 67.6 68.9
Death HR (95% CI)
P value
5-yr OS (%)
HR (95% CI)
P value
1.658(0.960–2.865) 1.544(1.029–2.316) 1.708(1.239–2.355) 1.892(1.344–2.665)
0.070a 0.036a 0.001a <0.001a
90 85.7 80.0 67.6 88.1
1.357(0.82–2.249) 1.566(1.057–2.322) 1.663(1.219–2.268) 1.792(1.295–2.48)
0.235a 0.025a 0.001a <0.001a
1.891(1.149–3.113) 1.689(1.242–2.298) 1.147(0.565–2.331) 1.611(0.649–4.001) 1.493(0.917–2.432)
0.012b 0.001b 0.704b 0.304b 0.107b
90.9 83.2 73.2 69.8 67.6 68.9
1.944(1.177–3.211) 1.710(1.277–2.289) 1.020(0.504–2.064) 1.611(0.649–4.001) 1.359(0.839–2. 201)
0.009b <0.001b 0.957b 0.304b 0.212b
DSS = disease-specific survival; OS = overall survival; HR = hazard ratio; CI = confidence interval. a P value was calculated using Cox proportional hazards model after adjusting for age, gender, histology, chemotherapy and N category. b P value was calculated using Cox proportional hazards model after adjusting for age, gender, histology, chemotherapy and T category.
Fig. 2. Distant metastasis-free survival for different N classifications: (A) N3 was divided into N3a and N3b, (B) N3 was the combination of N3a and N3b.
Fig. 3. Disease-specific survival (A) and overall survival (OS) for different overall stages.
current AJCC staging system of T classification to be more reasonable is still controversial [6,7]. As indicated in this study, stage T4 patients had much worse survival compared to patients in other T categories (T1–3), whereas, the LRFS between stage T1 and T2 patients and between stage T2 and T3 patients was not significantly different. Meanwhile, although the difference in DSS and OS between stage T2 and T3 patients and between T3 and T4
patients was significant, it was not significant between stage T1 and T2 patients (Table 1). Further multivariate analysis were performed in stage T1–T3 patients, which revealed that the skull base infiltration was a statistically significant factor for both distant failure and cancer death. This indicated, that although the LRFS between stage T1 and T2 and between stage T2 and T3 patients was not significantly different,
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J. Zong et al. / Oral Oncology 51 (2015) 254–259 Table 3 Independent prognostic factors by multivariate analyses for patient with T1–T3. Endpoint
Factor
P value
HR (95% CI)
Distant failure
Skull base infiltration Gender Age N category
0.018 0.048 0.002 <0.001
1.559(1.081–2.250) 0.607(0.371–0.995) 1.785(1.236–2.578) 1.811(1.442–2.275)
Cancer death
Skull base infiltration Age N category
0.007 <0.001 <0.001
1.681(1.154–2.448) 2.661(1.830–3.871) 1.897(1.504–2.394)
Death
Skull base infiltration Age N category
0.008 <0.001 <0.001
1.613(1.131–2.3) 3.009(2.105–4.3) 1.807(1.448–2.266)
HR = hazard ratio, CI = confidence interval.
T3 patients had poorer prognosis than patients with stage T1 and T2 disease. Merging the current T2 and T1 stages seems to be more rational than merging stages T2 and T3. In the current study, when the T categories were considered as three groups (T1 + T2, T3, and T4), HRs of DSS and OS differed significantly between adjacent T categories (Table 2). Although the AJCC staging system of NPC had been modified constantly, there has been more updating and improvements of T staging than of N staging [3]. There was no obvious change in N staging after the fourth edition except the clear definition and classification of pharyngeal lymph node involvement [10]. Compared to the previous conventional radiotherapy, the prognosis prediction of N staging has not changed, even in the IMRT era [7,16,17]. The present study demonstrated the N staging is practical and it can predict the prognosis in N1, N2 and N3 patients. Due to the presence of rare NPC patients who are staged N3, there had been several studies trying to challenge the existing N3 staging criteria [17–19]. However, for the lack of a unified endpoint and of a sufficient sample size to study, particularly for the deficiency of unified objective criterion diagnosis of the N3 subgroups, a feasible revision opinion of N staging have not been raised until now [10]. Two studies have reported that the predictive value of the N classification in the Chinese 2008 staging system was superior to the 7th AJCC [15,20]. In the Chinese 2008 staging system, measurement of the lymph nodes was based on MRI images rather than clinical palpation, which may differ among clinicians. In addition, the site, size, laterality and extranodal neoplastic spread to lymph nodes were all enrolled in the criteria of N staging categories [21]. Although it may be objective to evaluate the site, size and laterality of lymph node involvement on MRI, the measurement of the extranodal neoplastic spread is an inevitable ambiguity. Therefore, revising a more sensible and reliable N classification for the current AJCC staging system remains a great challenge. Concurrent chemoradiotherapy has been repeatedly proven to improve survival [22,23]. However, only 39.7% (469/1181) of the stage II–IVB patients received concurrent chemotherapy in the study. Future prospective studies of IMRT combined with concurrent chemotherapy may be needed to evaluate its influence on the staging system. The current AJCC TNM staging system for NPC is based on the anatomical extent of the tumor [24]. Tumor volume has been proposed as an independent prognostic factor besides T classification in patients with NPC [25–27]. Our previous study also demonstrated that the primary tumor volume had a significant impacted on the prognosis of NPC patients treated with IMRT. The 5-year OS was significantly reduced for patients with a large tumor volume (>50 ml), which is almost equal to that of stage T4 patients [28]. To take tumor volume into consideration as an additional stage indicator in the future revision of NPC staging, more studies should
be done to identify a uniform cut-off point of tumor volume. On the other hand, new biomarkers such as miRNA or EBV DNA have been recently reported as having prognostic value. To bring these new molecular factors into the clinical staging system presents a most challenging task [29,30]. In conclusion, regardless of the limitation of this being a single center and retrospective study, our study indicated that the 7th edition AJCC staging system still showed superior prognostic value in NPC patients treated with IMRT. Because patients with T2 disease had similar LRFS to stage T1 patients, the proposal of down stage T2 to T1 seemed to be reasonable. However, how to rationally deal with the stage N3a needs more research. Conflict of interest The authors declare no conflicts of interests. Acknowledgment Grant Sponsored by key Clinical Specialty Discipline Construction Program of Fujian, P.R.C. References [1] Zhang L, Chen QY, Liu H, Tang LQ, Mai HQ. Emerging treatment options for nasopharyngeal carcinoma. Drug Des Dev Ther 2013;7:37–52. [2] Spratt DE, Lee N. Current and emerging treatment options for nasopharyngeal carcinoma. OncoTargets Ther 2012;5:297–308. [3] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009. [4] Lin S, Pan J, Han L, Guo Q, Hu C, Zong J, et al. Update report of nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy and hypothesis of the optimal margin. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2014;110:385–9. [5] Xiao WW, Huang SM, Han F, Wu SX, Lu LX, Lin CG, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer 2011;117:1874–83. [6] Lee AW, Ng WT, Chan LK, Chan OS, Hung WM, Chan CC, et al. The strength/ weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement. Oral Oncol 2012;48:1007–13. [7] Chen L, Mao YP, Xie FY, Liu LZ, Sun Y, Tian L, et al. The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:331–7. [8] Li WF, Sun Y, Mao YP, Chen L, Chen YY, Chen M, et al. Proposed lymph node staging system using the International Consensus Guidelines for lymph node levels is predictive for nasopharyngeal carcinoma patients from endemic areas treated with intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:249–56. [9] Webber C, Gospodarowicz M, Sobin LH, Wittekind C, Greene FL, Mason MD, et al. Improving the TNM classification: findings from a 10-yr continuous literature review. Int J Cancer J Int Du Cancer 2014;135:371–8. [10] O’Sullivan B, Yu E. Staging of nasopharyngeal carcinoma. In: Lu JJ, Cooper JS, Lee AWM, editors. Nasopharyngeal Cancer–Multidisciplinary Management. Berlin Heidelberg: Springer; 2010. p. 309–22.
J. Zong et al. / Oral Oncology 51 (2015) 254–259 [11] 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. [12] 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-yr outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75:1071–8. [13] Peng G, Wang T, Yang KY, Zhang S, Zhang T, Li Q, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma.. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:286–93. [14] Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, et al. How does intensitymodulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80:661–8. [15] OuYang PY, Su Z, Ma XH, Mao YP, Liu MZ, Xie FY. Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. Br J Cancer 2013;109:2987–97. [16] Heng DM, Wee J, Fong KW, Lian LG, Sethi VK, Chua ET, et al. Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma. Cancer 1999;86:1912–20. [17] Lee AW, Au JS, Teo PM, Leung TW, Chua DT, Sze WM, et al. Staging of nasopharyngeal carcinoma: suggestions for improving the current UICC/AJCC Staging System. Clin Oncol 2004;16:269–76. [18] Low JS, Heng DM, Wee JT. The question of T2a and N3a in the UICC/AJCC (1997) staging system for nasopharyngeal carcinoma. Clin Oncol 2004;16:581–3. [19] Liu MZ, Tang LL, Zong JF, Huang Y, Sun Y, Mao YP, et al. Evaluation of sixth edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement. Int J Radiat Oncol Biol Phys 2008;70:1115–23. [20] Pan J, Xu Y, Qiu S, Zong J, Guo Q, Zhang Y, et al. A Comparison between the Chinese 2008 and the 7th edition AJCC staging systems for nasopharyngeal carcinoma. Am J Clin Oncol 2013;23:192–8. [21] Chinese Committee for Staging of Nasopharyngeal Carcinoma. Report on revision of the Chinese staging system for nasopharyngeal carcinoma. J Radiat Oncol 2013;2:233–40.
259
[22] Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2011;98:15–22. [23] Chen Y, Sun Y, Liang SB, Zong JF, Li WF, Chen M, et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III–IVB nasopharyngeal carcinoma from endemic regions of China. Cancer 2013;119:2230–8. [24] Ng WT, Yuen KT, Au KH, Chan OS, Lee AW. Staging of nasopharyngeal carcinoma–the past, the present and the future. Oral Oncol 2014;50: 549–54. [25] 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. [26] Sze WM, Lee AW, Yau TK, Yeung RM, Lau KY, Leung SK, et al. Primary tumor volume of nasopharyngeal carcinoma: prognostic significance for local control. Int J Radiat Oncol Biol Phys 2004;59:21–7. [27] Guo R, Sun Y, Yu XL, Yin WJ, Li WF, Chen YY, et al. Is primary tumor volume still a prognostic factor in intensity modulated radiation therapy for nasopharyngeal carcinoma? Radiotherapy Oncol: J Eur Soc Ther Radiology Oncol 2012;104:294–9. [28] Chen C, Fei Z, Pan J, Bai P, Chen L. Significance of primary tumor volume and T-stage on prognosis in nasopharyngeal carcinoma treated with intensitymodulated radiation therapy. Jpn J Clin Oncol 2011;41:537–42. [29] Liu N, Cui RX, Sun Y, Guo R, Mao YP, Tang LL, et al. A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma. Int J Cancer J Int Du Cancer. 2014;134:1359–68. [30] Hsu CL, Chang KP, Lin CY, Chang HK, Wang CH, Lin TL, et al. Plasma Epstein– Barr virus DNA concentration and clearance rate as novel prognostic factors for metastatic nasopharyngeal carcinoma. Head Neck 2012;34:1064–70.