Comparison of the seventh and eighth editions of the UICC/AJCC staging system for nasopharyngeal carcinoma: analysis of 1317 patients treated with intensity-modulated radiotherapy at two centers

Comparison of the seventh and eighth editions of the UICC/AJCC staging system for nasopharyngeal... Background: In the intensity-modulated radiotherapy (IMRT) era, great improvement has been made in survival of nasopharyngeal carcinoma (NPC). The 7th edition of the International Union against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system seems “outdated ” as it mainly based on the study in 2D/3D era, and thus the 8th edition has made some amendments according to recent studies. We aimed to compare and evaluate these two editions of staging system for NPC in patients treated with intensity-modulated radiotherapy. Methods: A total of 1317 patients with biopsy-proven, non-metastatic NPC treated with IMRT between 2009 and 2014 at two institutions were retrospectively assessed. All patients were assessed by magnetic resonance imaging and restaged according to the 7th and 8th editions. Prognostic factors for local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were assessed and compared using the Kaplan-Meier method and log-rank test. The Cox proportional hazards model was also used to calculate the hazard ratio (HR). Results: In both 7th and 8th edition, insignificant difference could be observed between T2 and T3 disease, T2 and T4 disease (all P > 0.05) for LRFS, while the difference of LRFS between T3 and T4 disease was significant in the previous edition (P = 0.001) but insignificant (P = 0.279) after revision. For OS, highly similar survival curve could be seen between T2 and T3 disease in both edition (all P > 0.1). DMFS and OS were not significantly different between N3a and N1-3b categories of the 7th edition (all P > 0.05). In contrast, obvious segregation was observed between N3 and the other N categories after the revision and combination in the 8th edition (all P < 0.05). DFS and OS were not significantly different between stage IVA and IVB of the 7th edition (P = 0.057 and P = 0.365, respectively); therefore, combining these stages in the 8th edition was reasonable. (Continued on next page) * Correspondence: lulx@sysucc.org.cn; chenyong@mail.sysu.edu.cn Xing-Li Yang, Yan Wang and Shao-Bo Liang contributed equally to this work. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, Guangdong, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. BMC Cancer (2018) 18:606 Page 2 of 11 (Continued from previous page) Conclusion: The overall stages and N categories of the 8th edition of the UICC/AJCC staging system provide better segregation of survival outcomes than the 7th edition. The 8th edition is also more clinically applicable as it has reduced ambiguity and revised out-of-date definitions. However, the T categories need further optimizing as the 8th edition failed to solve the problem of similar survival between adjacent T-classification, which has been exited since 7th edition. Keywords: Nasopharyngeal cancer, Staging system, Intensity-modulated radiation therapy, Prognostication Background as T3. In the N category classification, N3a and N3b in Nasopharyngeal carcinoma (NPC) is mysterious malig- the 7th edition were merged to N3. For clinical stage, nancy with marked racial and geographical differences stages IVA and IVB of the 7th edition were merged into which was prevalent in Southern China, Southeast Asia stage IVA; Correspondingly, previous stage IVC was and North Africa [1]. Crude incident in China had reached upgraded to stage IVB in the new edition [15]. up to 3.09/100,000 in 2012 and the age-standardized inci- Although the revisions incorporated into the 8th edition dence rates by world standard population (ASIRW) in were based on a large-sample study from two centers and south China is 9.69/100,000 [2]. The extensive use of mag- supported byevidencefrom multiple centers [15], the prog- th netic resonance imaging (MRI) and intensity-modulated nostic value of the 8 edition needs to be validated using radiation therapy (IMRT) have markedly improved 5-year data from other centers. In this analysis, 1317 patients with survival rates in NPC, especially local relapse-free survival NPC without distant metastasis at diagnosis who received (LRFS), which now exceeds 90% [3, 4]. IMRT with or without chemotherapy at two institutions The TNM staging system developed by the International were assessed to compare the prognostic performance of Union against Cancer (UICC) and American Joint Com- the 7th and 8th editions of the UICC/AJCC staging system. mittee on Cancer (AJCC) is considered the authoritative system for assessing disease progression, predicting prog- Methods nosis and assisting treatment selection [5–7]. Therefore, The study protocol was designed in accordance with the the importance of accurate staging in terms of selecting guidelines outlined in the Declaration of Helsinki and and determining treatment strategies cannot be overem- was approved by the Ethics Committee of the First phasized. Since the 7th edition of the UICC/AJCC staging Hospital of Foshan and Sun Yat-Sen University Cancer system had been internationally recommended, numerous Center (South China). The requirement for informed con- studies confirmed its ability to predict prognosis [8–10]. sent was waived due to the retrospective nature of the However, the use of ambiguous or out-of-date definitions study. limited the clinical relevance of the 7th edition [11–13]. Fortunately, there is improvement of this aspect in the 8th edition. Firstly, the ambiguous definition-infratemporal fossa (ITF)/masticatory space (MS), which was regarded Patient characteristics as T4 in the 7th edition, has been replaced by a more spe- A total of 1317 eligible patients (1014 males and 303 cific description in the 8th edition—the MP, LP and pre- females; median age, 47.3 years; range, 13–83) with vertebral muscles are included as T2, and the parotid NPC treated at the First Hospital of Foshan (776 patients, gland and lateral surface of the LP muscle as T4 [14]. Sec- 58.8%) or Sun Yat-Sen University Cancer Center (541 pa- ondly, widespread use of MRI in diagnosis and IMRT in tients, 41.2%) between October, 2009 and March, 2014 treatment calls for a cross-sectional imaging method to re- were retrospectively enrolled using the same inclusion cri- place supraclavicular fossa (SCF), which was primarily teria: (i) patients with pathological evidence of NPC; (ii) based on clinical examination and treated as the boundary with complete baseline clinical information and laboratory for N3b to other N stage disease in the previous edition. data; (iii) who received IMRT; and (iv) with complete In the 8th staging edition, such demoded term was re- follow-up data. Patients with distant metastasis at presen- placed by lower level (LL), which is defined as the area tation were excluded. below the caudal border of the cricoid cartilage. Moreover, According to the 2003 World Health Organization there are other revisions incorporated into the 8th edition (WHO) classification, 99.8% of all patients had non- of the UICC/AJCC staging system for NPC. In the T keratinizing carcinoma and the remainder (0.2%) had category classification, EBV-positive cervical nodes were basaloid squamous cell carcinoma. The tumor, node and added as T0 disease, the prevertebral muscle invasion was stage distributions of the 1317 patients according to the th added as T2, and the cervical vertebra invasion was added 7 and 8th editions are presented in Tables 2, 3 and 4. Yang et al. BMC Cancer (2018) 18:606 Page 3 of 11 Treatment Results All patients were treated with IMRT at a median total As a result of the revisions in the 8th edition (Table. 1), dose of 70 Gy (range, 63–76 Gy) in 31 fractions (range, 8/1317 (0.6%) patients in this cohort were up-staged 28–36 fractions) at 2.26 per fraction to the planning tar- from T1 to T2, 19/1317 (1.4%) were down-staged from get volume (PTV) of the gross primary tumor volume T4 to T2, 116/1317 (8.8%)were down-staged from T4 to and 68 Gy (range, 50–75 Gy) in 31 fractions (range, T3, and 12/1317 (0.9%) and 26/1317 (2.0%) patients 20–35 fractions) to the PTV of the gross nodal tumor were upstaged to N3 from N1 and N2, respectively. In volume (GTV-N), 60 Gy in 31 fractions to the PTV of terms of overall stage, 2/1317 (2%) patients were up- the high-risk clinical target volume (CTV1), and 54 Gy staged from stage I to II, 9/1317 (0.7%) from II to IVA in 31 fractions to the PTV of the low-risk clinical target and 17/1317 (1.3%) from III to IVA, and 10/1317 (0.8%) volume (CTV2). All patients received one fraction daily, and 113/1317 (8.6%) patients were down-staged from 5 days per week. Overall, 88 (6.7%) patients received IVA to II and III, respectively (Tables 2, 3 and 4). additional intracavitary irradiation for tumor persistence. According to institutional guidelines, chemotherapy was Patterns of failure and survival outcomes recommended for patients with stage II-IVB NPC In total, 75/1317 (5.7%) and 171/1317 (13.0%) patients (7th edition). Overall, 87.4% (1151/1317) of patients re- developed local recurrence and metastasis, and 198 ceived chemotherapy. Concomitant chemotherapy was (15.0%) died. The median time to local and distant delivered to 918 patients: 211 with stage II and 703 with failure was 26.17 (range: 7.00–69.37) and 21.96 (range: stage III to IVB NPC (7th edition); 505 patients with stage 1.9–69.13) months, respectively. The 4-year LRFS, II to IVB disease received both induction and concomitant DMFS, DFS, and OS rates were 94.4%, 87.3%, 82.1%, chemotherapy; no patients received adjuvant chemother- and 87.6%, respectively. apy. In total, 92.0% (451/490) of patients with stage III NPC and 93.2% (419/440) of patients with stage IVA and T classification IVB NPC received chemotherapy. Neoadjuvant chemo- Cox multivariate regression analysis showed the T cat- therapy consisted of cisplatin (80 mg/m ) and fluorouracil egory classifications of both editions were independent 2 2 (1000 mg/m daily for 4 days); docetaxel (75 mg/m )and prognostic factors for LRFS and OS (P < 0.001). For the 2 2 cisplatin (75 mg/m ); or a triplet of docetaxel (60 mg/m ), 7th edition, LRFS and OS were not significantly different 2 2 cisplatin (60 mg/m ) and fluorouracil (800 mg/m daily between T2 and T3 (P = 0.515 and P = 0.418, respect- for 4 days) every 3 weeks for 2–3 cycles. Concurrent ively, Fig. 1), while LRFS was borderline significantly dif- chemotherapy was cisplatin given every 3 weeks (100 mg/ ferent between T2 and T4 (P = 0.084, Fig. 1), with a clear 2 2 2 m or 80 mg/m ) or weekly (40 mg/m )during RT. distinction in OS between T2 and T4 (P = 0.002, Fig. 1). However, no significant differences in LRFS were ob- served between T2 and T3, T2 and T4, and T3 and T4 Follow-up and statistical analysis of the 8th edition (P = 0.825, P = 0.332 and P = 0.279, re- After treatment, all patients were assessed every 3 to spectively, Fig. 1), and the OS curves for T2 and T3 of 6 months in the first 3 years, then every 6 to 12 months. the 8th edition even overlapped (P = 0.900, Fig. 1). In Follow-up was calculated from the first day of treatment summary, the T categories of the 8th edition seems failed until death or last examination visit. June 27th, 2017 was to raise obviously superior prognostic value compared to the last follow-up date. Median follow-up was 55.62 months the 7th edition. (range; 1.47–90.17 months). Subgroup analysis was conducted to explore the prog- Statistical Package for the Social Sciences (SPSS) soft- nostic significance of MP and LP involvement. 19 patients ware, version 20.0 (SPSS, Chicago, IL USA) was used to with MP/LP invasion who did not fulfill the criteria for T3 perform analysis. Actuarial rates were estimated using the or T4 in the 7th edition, and who were restaged as Tx1 in Kaplan-Meier method [16], and survival curves were com- the 8th edition, did not have significantly different LRFS pared using the log-rank test [17]. All endpoints: local compared to T2, T3 or T4 of the 7th edition (P = 0.388, relapse-free survival (LRFS), distant metastasis-free survival P = 0.465 and P = 0.756, respectively, Fig. 2). The 116 (DMFS), disease-free survival (DFS) and overall survival patients with T3 tumors with anatomical MP/LP in- (OS), were defined as the interval to the first defining event. volvement, who were staged as T4 in the 7th edition Multivariate analyses with the Cox proportional hazards butas T3inthe 8thedition,had similarsurvivaltoT4and model were used to test the independent significance of dif- significantly different survival to T3 without anatomical ferent parameters by forward elimination of insignificant MP/LP involvement for the 7th edition (P < 0.001, Fig. 2). explanatory variables. The Cox proportional hazards model Due to the lack of differences in LRFS between the T was also used to calculate the hazard ratio (HR). A two- categories of the 8th edition, multivariate Cox regression tailed P-value < 0.05 was considered statistically significant. analysis was performed to evaluate the various prognostic Yang et al. BMC Cancer (2018) 18:606 Page 4 of 11 Table 1 Classification criteria of the 7th and 8th editions of the UICC/AJCC staging system for nasopharyngeal carcinoma th th 7 edition 8 edition T category T0 No tumor identified, but EBV-positive cervical node involvement T1 Nasopharynx, oropharynx or nasal cavity Nasopharynx, oropharynx, nasal cavity without parapharyngeal involvement T2 Parapharyngeal extension Parapharyngeal space and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles) T3 Bony structures and/or paranasal sinuses Bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses T4 Intracranial extension and/or cranial nerves, hypopharynx, Intracranial extension, involvement of cranial nerves, hypopharynx, orbit or infratemporal fossa/masticatory space* orbit, parotid gland and/or extensive soft tissue infiltration beyond lateral surface of lateral pterygoid N category N0 None None N1 Unilateral cervical and/or unilateral or bilateral retropharyngeal Unilateral cervical and/or unilateral or bilateral retropharyngeal node(s), node(s), ≤ 6 cm in greatest dimension, above supraclavicular fossa ≤ 6 cm in greatest dimension, above caudal border of cricoid cartilage N2 Bilateral cervical node(s), ≤ 6 cm in greatest dimension, above Bilateral cervical node(s), ≤ 6 cm in greatest dimension, above caudal supraclavicular fossa border of cricoid cartilage N3 N3a > 6 cm in greatest dimension, above supraclavicular fossa Unilateral or bilateral cervical node(s), > 6 cm in greatest dimension, below caudal border of cricoid cartilage N3b in supraclavicular fossa Clinical stage I T1N0M0 T1N0M0 II T1N1M0, T2N0-1M0 T1N1M0, T2N0-1M0 III T1-2N2M0, T3N0-2M0 T1-2N2M0, T3N0-2M0 IV IVA: T4N0-2M0 T4N0-2M0, T0-4N3M0 IVB: any T1-4N3M0 infratemporal fossa/masticatory space: the superficial layer of the deep cervical fascia splits to enclose the four masticatory muscles, including the medial pterygoid (MP), lateral pterygoid (LP), temporalis and masseter muscles, to enclose this space factors used to define the T categories (Table 5). The follow- significantly associated with disease failure. Notably, male ing covariables were included in the Cox proportional and advanced N category may more likely to develop dis- hazards model with backward conditional: age (≤ 50 vs. ease failure. Male, aged (> 50 years old), prevertebral muscle > 50 years), gender (female vs. male), paranasal sinus, skull extension, skull base infiltration, cranial nerve invasion and base infiltration, medial pterygoid muscle, lateral pterygoid more advanced N category of 8th edition were found to be muscle, prevertebral muscle, 8th edition N category, and the independent factors for OS (Table. 5). chemotherapy (no vs. yes). Multivariate Cox regression ana- lyses showed that prevertebral muscle extension and medial N classification pterygoid muscle extension were the independent factors Cox multivariate regression analysis showed that the N for local failure. Gender, prevertebral muscle extension, cra- category classifications of both editions were independ- nial nerve invasion and N category of 8th edition were ent prognostic factors for local recurrence free survival Table 2 Distribution of T categories as defined by the 7th and 8th editions 8th edition T1 T2 T3 T4 Total 7th edition T1 324 (24.6%) 8 (0.6%) 332 (25.2%) T2 166 (12.6%) 166 (12.6%) T3 420 (31.8%) 420 (31.8%) T4 19 (1.4%) 116 (8.8%) 264 (20.0%) 399 (30.3%) Total 324 (24.6%) 193 (14.6%) 536 (40.7%) 264 (20.0%) 1317 Yang et al. BMC Cancer (2018) 18:606 Page 5 of 11 Table 3 Distribution of N categories as defined by the 7th and 8th editions 8th edition N0 N1 N2 N3 Total 7th edition N0 250 (19.0%) 250 (19.0%) N1 719 (54.6%) 12 (0.9%) 731 (55.4%) N2 252 (19.1%) 26 (2.0%) 278 (21.1%) N3a 16 (1.2%) 16 (1.2%) N3B 42 (3.2%) 42 (3.2%) Total 250 (19.0%) 719 (54.6%) 252 (19.1%) 96 (7.3%) 1317 and overall survival (P < 0.001, Fig. 3). For example, sig- respectively, Fig. 5); therefore, it was reasonable to merge nificant separations in distant metastasis-free survival T4 and N3 disease. Compared to the 7th edition, the 8th (DMFS) were observed between adjacent N categories of edition provided better segregation of long-term DFS and the 8th edition (Fig. 3), but the differences between N3a OS between adjacent clinical stages (Fig. 5). and N1, N2, N3b of the 7th edition were insignificant (P =0.286, P = 0.915, P = 0.288, respectively, Fig. 3). The Discussion small number of patients with N3a (n = 16) disease may The UICC/AJCC TMN staging system is the authoritative have reduced statistical power. Moreover, the differences method of assessing the extent of local invasion, regional in OS between N0 and N1, and N2 and N3 (including lymphatic spread and distant metastasis, and is considered N3a and N3b in the 7th edition) were not significant (all the most valuable prognostic factor in NPC. Although the th P > 0.05, Fig. 3), though the difference between N0 and N1 8 edition was only published one year ago, several studies was slightly larger for the 8th edition than 7th edition. have attempted to validate its clinical applicability. Pan et Subgroup analysis was conducted to assess the value of al. reported clear separation was not observed between altering SCF to the lower neck in the 8th edition. Patients stage I and II (P =0.07 and P =0.10, respectively) of the upstaged from N1 and N2 in the 7th edition to N3 in the 7th and 8th editions. Tang et al. [18] and Xu et al. [19] 8th edition were staged as NX (lymph nodes above SCF found no significant differences between stage II and III but below the caudal border of the cricoid cartilage) in the (all P > 0.05) of either edition. However, overlapping subgroup analysis; the other criteria were the same as the between these cohorts was inevitable, as the patients 7th N categories, apart from the lower neck alteration. No were from the same center and treated during the same statistically significant differences in 4-year DMFS and OS period [21, 22]. OuYang et al. [20] compared the proposed were detected between Nx and N3a or N3b (P = 0.288, Guangzhou, Hong Kong, Guangxi staging system with P = 0.991, respectively, Fig. 4). the 7th and 8th editions of the AJCC/UICC staging system using a cohort of 899 patients. They found the Overall stage N classification of the 8th edition had better prognostic The overall stage classifications of both editions were inde- performance than the 7th, while the T category classification pendent prognostic factors for death, disease failure, local still required further optimization. In this study, a total failureand diseasefailure in Cox multivariate regression of 1317 patients treated with IMRT at two different analysis (P < 0.001, Fig. 5). For DFS and OS, the differences hospitals were assessed to compare the prognostic between stage IVA (T4 N0–2) and IVB (T1-3 N3) of the value of the 7th and 8th editions of the UICC/AJCC 7th edition were not significant (P = 0.057, P = 0.365, staging system. Table 4 Distribution of overall stage as defined by the 7th and 8th editions 8th edition I II III IVA Total 7th edition I 93 (7.1%) 2 (0.2%) 95 (7.3%) II 283 (21.5%) 9 (0.7%) 292 (22.2%) III 473 (35.9%) 17 (1.3%) 490 (37.2%) IVA 10 (0.8%) 113 (8.6%) 259 (19.7%) 382 (29.0%) IVB 58 (4.4%) 58 (4.4%) Total 93 (7.1%) 295 (22.4%) 586 (44.5%) 343 (26.0%) 1317 Yang et al. BMC Cancer (2018) 18:606 Page 6 of 11 Fig. 1 Survival analyses for the T category classifications of the 7th and 8th edition staging systems. a and c: Local relapse-free survival and overall survival for T categories defined by the 7th edition; b and d: local relapse-free survival and overall survival for T categories defined by the 8th edition Study limitations same center showed c-index in the previous edition was Firstly, this study was a retrospective study of 1317 patients slightly higher than the latest one [18]. from two centers in Guangdong Province of China. In In this study, the 8th edition failed to solve the prob- some subgroups, especially the subgroups with PSI and lem of similar survival between adjacent T-classification, MSI, a small number of patients limited the reliability of which has been exited since 7th edition; indeed, the lack our conclusions. Larger-scale analyses are needed to con- of significance between T categories was more obvious firm this study. Secondly, only 372 (28.2%) patients received for the 8th edition, which mainly own to the alteration PET-CT before treatment. Thirdly, other factors such as of ITF/MS. In fact, IFT/MS involvement has long been EBV DNA [21]and primarytumor volume [22], which included in the UICC/AJCC staging system as a T4 cri- have been found to have a profound influence on progno- terion, though the exact anatomical boundaries for these sis, were not considered in this study. structures have varied between editions [23, 24]. In the 5th and 6th editions, the ITF/MS did not involve the medial pterygoid (MP) or lateral pterygoid (LP) [25], T classification while the 7th edition definition of the MS included all In a study which compared different staging systems in- four masticatory muscles: MP, LP, temporalis and mas- cluding the 7th, 8th edition of AJCC/UICC staging system seter [14]. It was laudable that descriptions in the latest and Guangzhou, Hongkong, Guangxi staging system, edition were more specific. However, the best classifica- Guangzhou staging system led to the highest c-index in T tion of IFT /MS had not reach a consensus. Pan et al. classification and the 8th edition ranked the second [20]. found patients without T3 or T4 criteria but MP/LP in- Minor difference was found between these two systems, volvement achieved much better 5-year OS than patients which was extension of Oropharynx or nasal cavity was with T4 disease with other criteria except for MP/LP in- staged as T1 disease in the 8th edition but T2 in volvement (93% vs. 71%, respectively, P = 0.003) [15]. A Guangzhou system. Nevertheless, validation between 7th similar result was reported by Tang et al. [26], though and 8th edition of AJCC/UICC staging system from the different degrees of MS invasion did not significantly Yang et al. BMC Cancer (2018) 18:606 Page 7 of 11 Fig. 2 Survival analyses for the masticatory space subset compared with other subsets using the 7th edition of the staging system. a and b: Local relapse-free survival and overall survival for MSI without other T3/T4 criteria; c and d: Local relapse-free survival and overall survival for MSI without other T4 criteria affect LRFS or OS (P = 0.34 and P = 0.54, respectively). In another study of 816 patients, including 283 (36.4%) patients with MS invasion, MS involvement was an inde- pendent prognostic factor for local control (P = 0.007) and OS (P = 0.024) in multivariate analyses, and patients Table 5 Independent prognostic survival factors for local relapse, with MP involvement had similar survival rates as T2 or disease failure and death in multivariate Cox regression analyses T3 disease (all P > 0.1), though the outcomes for patients End-point Factor Value HR 95% HR with LP involvement were similar to T4 disease (P > 0.1) [27]. In this study, limited number of patients in the Local failure Prevertebral muscle 0.048 1.319 1.003–1.734 subgroup showed that MS involvement with T3 criteria Medial pterygoid muscle 0.011 1.607 1.116–2.315 had similar survival outcomes to T4 disease in this study Disease failure Gender (female vs. male) 0.012 1.539 1.100–2.154 (P = 0.134 for LRFS, P = 0.292 for OS). Such discrepan- Prevertebral muscle < 0.001 1.339 1.171–1.532 cies may be due to the varied demographics, inclusion Cranial nerve < 0.001 1.675 1.291–2.171 criteria, treatment strategies and follow-up times in each 8th edition N category < 0.001 1.692 1.461–1.960 study, and the a larger-scale, multicenter study is wanted to figure the staging of MS. Death Gender 0.007 1.715 1.162–2.530 Involvement of the prevertebral muscles, mentioned Age (≤ 50 vs. > 50) 0.031 1.365 1.028–1.817 for the first time in the 8th edition as a T2 criterion, has Prevertebral muscle 0.001 1.308 1.111–1.541 been shown to increase the risk of local and distance Skull base infiltration 0.011 1.582 1.113–2.248 failure. In a study of 506 patients, prevertebral space in- Cranial nerve < 0.001 1.860 1.454–2.379 vasion (PSI) was associated with similar survival to T4 8th edition N category < 0.001 1.615 1.362–1.191 disease, but not T3 [28]. However, due to the lack of a HR hazard ratio, CI confidence interval significant difference in OS between PSI and MS Yang et al. BMC Cancer (2018) 18:606 Page 8 of 11 Fig. 3 Survival analyses for the N category classifications of the 7th and 8th editions of the UICC/AJCC staging system. a and c: Distant metastasis-free survival and overall survival for the N categories of the 7th edition; Panels b and d: Distant metastasis-free survival and overall survival for the N categories of the 8th edition Fig. 4 Survival analyses for the lower neck subset compared with other subsets using the 7th edition of the UICC/AJCC staging system. a and b: Distant metastasis-free survival and overall survival for the change from the supraclavicular fossa in the 7th edition to the lower neck in the 8th edition Yang et al. BMC Cancer (2018) 18:606 Page 9 of 11 Fig. 5 Survival analyses for the overall stages of the 7th and 8th editions of the UICC/AJCC staging system. a and c: Disease-free survival and overall survival for the T categories of the 7th edition; b and d: Disease-free survival and overall survival for the T categories of the 8th edition invasion reported by Pan et al. [15], single PSI was N classification classified as T2 in the 8th edition. Unfortunately, only In Ouyang’s study, which compared five staging systems, eight patients had PSI without T2, T3 or T4 criteria N-classification in the 8th edition of AJCC/UICC staging in this study; this sample size was too small conduct system owned higher C-index for OS, DMFS and RRFS subgroup analysis. However, multivariate analysis than the previous edition [20]. Another validation of showed PSI was independent prognostic factor for the 8th edition also supported that the new prognos- LRFS, DFS and OS. More detailed studies of a lager tic model of N-classification predicted outcomes fairly cohort are required. well [18]. The marginal differences in prognosis between adjacent Compared to the N category classification of the 7th T categories of the 7th and 8th editions (Fig. 1) reflect de- edition, the 8th edition became consistent with the con- velopments in diagnosis and treatment. On the one hand, sensus guidelines used for other head-and-neck cancers the widespread use of MRI makes skull base erosion easier [33], making the staging system more convenient in clin- to detect [3, 29]. Although MRI can more precisely detect ical practice, and also resulting in better segregation of deep tumor infiltration and has improved LRFS by around both DMFS and OS (Fig. 2). 20% [30], some early micro-migration—which can only be The 8th edition uses the caudal border of the cricoid detected by MRI—may have a better prognosis than the cartilage to differentiate N1–2 and N3 [15], in other obvious invasion easily observed on CT scans in other pa- words, the LL is a demarcating criterion for N3. The tients with the same T category. Compared to the erosion data supporting the proposal of the 8th edition did not easily detected on CT, skull-base erosion detectable on show this replacement improved prognostic value, MRI but undetectable on CT may have a more favorable though there was little controversy about the alternation. prognosis [30, 31]. On the other hand, the popularity of SCF, defined by the superior margin of the sternal end of IMRT and addition of chemotherapy have also reduced the clavicle, the superior margin of the lateral end of the local failure [32]. Distant metastasis remains the main fail- clavicle and the point where the neck meets the shoulder ure pattern in NPC, further emphasizing the importance [34], is not a reliable radiological landmark in this IMRT of accurate N category classification. era when MRI is widely used for diagnosis while the new Yang et al. BMC Cancer (2018) 18:606 Page 10 of 11 boundary - lower level (LL), defined as the area below Abbreviations AJCC: American Joint Committee on Cancer; DFS: disease-free survival; the caudal border of the cricoid cartilage -is an anatomical DMFS: distant metastasis-free survival; IMRT: intensity-modulated landmark that can be reliably defined on physical examin- radiotherapy; ITF: Infratemporal fossa; LL: Lower level; LP: Lateral pterygoid; ation and also accurately located in cross-sectional images. LRFS: Local relapse-free survival; MAD: Maximal axial diameter; MP: Medial pterygoid; MRI: Magnetic resonance imaging; MS: Masticatory space; Replacing the SCF with the LL is sensible and practicable NPC: Nasopharyngeal carcinoma; OS: Overall survival; PSI: Prevertebral space as the LL corresponds to the entire area of levels IVa, IVb, invasion; SCF: Supraclavicular fossa; UICC: International Union against Cancer Vb and Vc as defined by the 2013 International Consensus Acknowledgements Guidelines [33]. Yue et al. found that, compared to Ho’s The authors acknowledge the department of medical records for permission SCF, the LL provided more distinct separation of DMFS, to access the linked databases. DFS and OS between adjacent N categories [11]. A similar result was obtained in this study. Moreover, 38 patients Funding This work was supported by the Natural Science Foundation of Guangdong (about 3%) in our cohort were upstaged from 7th edition Province, China [grant number 2016A020215083]; Medical Science and N1 or N2 to 8th edition N3 because of this change, and Technology Research Foundation of Guangdong Province, China [grant these patients achieved closer survival outcomes to N3 number A02016031]. The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the than N1 or N2 (Fig. 4). Therefore, it is reasonable to as- manuscript. This work was supported by a grant from the Medical Research sign lymph node(s) metastasis in the LL as a new N3 Foundation of Sun Yat-sen University of Guangdong Province, China. criterion. Although Lee et al. [35] found maximal axial diameter Availability of data and materials The datasets used and analyzed during the current study were available (MAD) was a significant independent predictor of sur- from the corresponding author on reasonable request. vival, other relevant studies such as Teo et al. [36] and Heng et al. [37] deemed the prognostic value of MAD Authors’ contributions was mainly due to the fact large lymph nodes are more YXL, WY and LSB contributed to the conception and design of the study, data acquisition, data analysis, data interpretation and the draft of the frequent at lower nodal levels. Only 25 (1.9%) patients manuscript. HSS, and CHY carried out the acquisition and interpretation of had lymph node(s) with a MAD larger than 6 cm, of data. CDM performed the data analysis and data interpretation. LLX and CY whom eight had lymph node involvement extending to contributed with the conception and design of the study, data acquisition, data interpretation and critical edit of the manuscript. All authors read and the SCF (7th edition N3b). Similar overlaps have also approved the final manuscript. been reported in other studies [10, 15]. Furthermore, the similar DMFS and DFS rates for N3a and N3b indicate Ethics approval and consent to participate The study protocol was designed in accordance with the guidelines outlined that this sub-category separation is unnecessary. in the Declaration of Helsinki and was approved by the Ethics Committee of the First Hospital of Foshan and Sun Yat-Sen University Cancer Center (South China). The requirement for informed consent was waived due to Clinical stage the retrospective nature of the study. Stages IVA and IVB of the 7th edition were merged into Competing interests stage IVA in the 8th edition, and naturally, previous The authors declare that they have no competing interests. stage IVC was upgraded to IVB. The differences in DFS and OS between IVA and IVB of the 7th edition were in- Publisher’sNote significant, whereas the overall stages of the 8th edition Springer Nature remains neutral with regard to jurisdictional claims in resulted in better separation of the DFS and OS curves. published maps and institutional affiliations. Although no significant difference in OS was observed Author details between stage I and II in either the 7th and 8th editions Department of Radiation Oncology, The First Affiliated Hospital of Sun (P = 0.157 and P = 0.171, respectively), the distinction be- Yat-sen University, Guangzhou 510060, Guangdong, People’s Republic of China. Department of Radiation Oncology, Sun Yat-sen University Cancer tween stage I and II is necessary as chemotherapy may Center, Guangzhou, China. State Key Laboratory of Oncology in South benefit patients with stage II. China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Department of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan Affiliated to Sun Yat-sen University, Foshan, China. The Sixth Affiliated Hospital of Sun Conclusion Yat-sen University, Guangzhou, China. Department of Radiation Oncology, The 8th edition of the UICC/AJCC staging system for Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou NPC has superior prognostic value compared to the 7th 510060, Guangdong, People’s Republic of China. edition, especially as the 8th edition N categories and overall stages. 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Validation and comparison of the 7th and 8th edition of AJCC staging systems for non- metastatic nasopharyngeal carcinoma, and proposed staging systems from Hong Kong, Guangzhou, and Guangxi. Oral Oncol. 2017;72:65–72. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Comparison of the seventh and eighth editions of the UICC/AJCC staging system for nasopharyngeal carcinoma: analysis of 1317 patients treated with intensity-modulated radiotherapy at two centers

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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
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Abstract

Background: In the intensity-modulated radiotherapy (IMRT) era, great improvement has been made in survival of nasopharyngeal carcinoma (NPC). The 7th edition of the International Union against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system seems “outdated ” as it mainly based on the study in 2D/3D era, and thus the 8th edition has made some amendments according to recent studies. We aimed to compare and evaluate these two editions of staging system for NPC in patients treated with intensity-modulated radiotherapy. Methods: A total of 1317 patients with biopsy-proven, non-metastatic NPC treated with IMRT between 2009 and 2014 at two institutions were retrospectively assessed. All patients were assessed by magnetic resonance imaging and restaged according to the 7th and 8th editions. Prognostic factors for local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were assessed and compared using the Kaplan-Meier method and log-rank test. The Cox proportional hazards model was also used to calculate the hazard ratio (HR). Results: In both 7th and 8th edition, insignificant difference could be observed between T2 and T3 disease, T2 and T4 disease (all P > 0.05) for LRFS, while the difference of LRFS between T3 and T4 disease was significant in the previous edition (P = 0.001) but insignificant (P = 0.279) after revision. For OS, highly similar survival curve could be seen between T2 and T3 disease in both edition (all P > 0.1). DMFS and OS were not significantly different between N3a and N1-3b categories of the 7th edition (all P > 0.05). In contrast, obvious segregation was observed between N3 and the other N categories after the revision and combination in the 8th edition (all P < 0.05). DFS and OS were not significantly different between stage IVA and IVB of the 7th edition (P = 0.057 and P = 0.365, respectively); therefore, combining these stages in the 8th edition was reasonable. (Continued on next page) * Correspondence: lulx@sysucc.org.cn; chenyong@mail.sysu.edu.cn Xing-Li Yang, Yan Wang and Shao-Bo Liang contributed equally to this work. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, Guangdong, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. BMC Cancer (2018) 18:606 Page 2 of 11 (Continued from previous page) Conclusion: The overall stages and N categories of the 8th edition of the UICC/AJCC staging system provide better segregation of survival outcomes than the 7th edition. The 8th edition is also more clinically applicable as it has reduced ambiguity and revised out-of-date definitions. However, the T categories need further optimizing as the 8th edition failed to solve the problem of similar survival between adjacent T-classification, which has been exited since 7th edition. Keywords: Nasopharyngeal cancer, Staging system, Intensity-modulated radiation therapy, Prognostication Background as T3. In the N category classification, N3a and N3b in Nasopharyngeal carcinoma (NPC) is mysterious malig- the 7th edition were merged to N3. For clinical stage, nancy with marked racial and geographical differences stages IVA and IVB of the 7th edition were merged into which was prevalent in Southern China, Southeast Asia stage IVA; Correspondingly, previous stage IVC was and North Africa [1]. Crude incident in China had reached upgraded to stage IVB in the new edition [15]. up to 3.09/100,000 in 2012 and the age-standardized inci- Although the revisions incorporated into the 8th edition dence rates by world standard population (ASIRW) in were based on a large-sample study from two centers and south China is 9.69/100,000 [2]. The extensive use of mag- supported byevidencefrom multiple centers [15], the prog- th netic resonance imaging (MRI) and intensity-modulated nostic value of the 8 edition needs to be validated using radiation therapy (IMRT) have markedly improved 5-year data from other centers. In this analysis, 1317 patients with survival rates in NPC, especially local relapse-free survival NPC without distant metastasis at diagnosis who received (LRFS), which now exceeds 90% [3, 4]. IMRT with or without chemotherapy at two institutions The TNM staging system developed by the International were assessed to compare the prognostic performance of Union against Cancer (UICC) and American Joint Com- the 7th and 8th editions of the UICC/AJCC staging system. mittee on Cancer (AJCC) is considered the authoritative system for assessing disease progression, predicting prog- Methods nosis and assisting treatment selection [5–7]. Therefore, The study protocol was designed in accordance with the the importance of accurate staging in terms of selecting guidelines outlined in the Declaration of Helsinki and and determining treatment strategies cannot be overem- was approved by the Ethics Committee of the First phasized. Since the 7th edition of the UICC/AJCC staging Hospital of Foshan and Sun Yat-Sen University Cancer system had been internationally recommended, numerous Center (South China). The requirement for informed con- studies confirmed its ability to predict prognosis [8–10]. sent was waived due to the retrospective nature of the However, the use of ambiguous or out-of-date definitions study. limited the clinical relevance of the 7th edition [11–13]. Fortunately, there is improvement of this aspect in the 8th edition. Firstly, the ambiguous definition-infratemporal fossa (ITF)/masticatory space (MS), which was regarded Patient characteristics as T4 in the 7th edition, has been replaced by a more spe- A total of 1317 eligible patients (1014 males and 303 cific description in the 8th edition—the MP, LP and pre- females; median age, 47.3 years; range, 13–83) with vertebral muscles are included as T2, and the parotid NPC treated at the First Hospital of Foshan (776 patients, gland and lateral surface of the LP muscle as T4 [14]. Sec- 58.8%) or Sun Yat-Sen University Cancer Center (541 pa- ondly, widespread use of MRI in diagnosis and IMRT in tients, 41.2%) between October, 2009 and March, 2014 treatment calls for a cross-sectional imaging method to re- were retrospectively enrolled using the same inclusion cri- place supraclavicular fossa (SCF), which was primarily teria: (i) patients with pathological evidence of NPC; (ii) based on clinical examination and treated as the boundary with complete baseline clinical information and laboratory for N3b to other N stage disease in the previous edition. data; (iii) who received IMRT; and (iv) with complete In the 8th staging edition, such demoded term was re- follow-up data. Patients with distant metastasis at presen- placed by lower level (LL), which is defined as the area tation were excluded. below the caudal border of the cricoid cartilage. Moreover, According to the 2003 World Health Organization there are other revisions incorporated into the 8th edition (WHO) classification, 99.8% of all patients had non- of the UICC/AJCC staging system for NPC. In the T keratinizing carcinoma and the remainder (0.2%) had category classification, EBV-positive cervical nodes were basaloid squamous cell carcinoma. The tumor, node and added as T0 disease, the prevertebral muscle invasion was stage distributions of the 1317 patients according to the th added as T2, and the cervical vertebra invasion was added 7 and 8th editions are presented in Tables 2, 3 and 4. Yang et al. BMC Cancer (2018) 18:606 Page 3 of 11 Treatment Results All patients were treated with IMRT at a median total As a result of the revisions in the 8th edition (Table. 1), dose of 70 Gy (range, 63–76 Gy) in 31 fractions (range, 8/1317 (0.6%) patients in this cohort were up-staged 28–36 fractions) at 2.26 per fraction to the planning tar- from T1 to T2, 19/1317 (1.4%) were down-staged from get volume (PTV) of the gross primary tumor volume T4 to T2, 116/1317 (8.8%)were down-staged from T4 to and 68 Gy (range, 50–75 Gy) in 31 fractions (range, T3, and 12/1317 (0.9%) and 26/1317 (2.0%) patients 20–35 fractions) to the PTV of the gross nodal tumor were upstaged to N3 from N1 and N2, respectively. In volume (GTV-N), 60 Gy in 31 fractions to the PTV of terms of overall stage, 2/1317 (2%) patients were up- the high-risk clinical target volume (CTV1), and 54 Gy staged from stage I to II, 9/1317 (0.7%) from II to IVA in 31 fractions to the PTV of the low-risk clinical target and 17/1317 (1.3%) from III to IVA, and 10/1317 (0.8%) volume (CTV2). All patients received one fraction daily, and 113/1317 (8.6%) patients were down-staged from 5 days per week. Overall, 88 (6.7%) patients received IVA to II and III, respectively (Tables 2, 3 and 4). additional intracavitary irradiation for tumor persistence. According to institutional guidelines, chemotherapy was Patterns of failure and survival outcomes recommended for patients with stage II-IVB NPC In total, 75/1317 (5.7%) and 171/1317 (13.0%) patients (7th edition). Overall, 87.4% (1151/1317) of patients re- developed local recurrence and metastasis, and 198 ceived chemotherapy. Concomitant chemotherapy was (15.0%) died. The median time to local and distant delivered to 918 patients: 211 with stage II and 703 with failure was 26.17 (range: 7.00–69.37) and 21.96 (range: stage III to IVB NPC (7th edition); 505 patients with stage 1.9–69.13) months, respectively. The 4-year LRFS, II to IVB disease received both induction and concomitant DMFS, DFS, and OS rates were 94.4%, 87.3%, 82.1%, chemotherapy; no patients received adjuvant chemother- and 87.6%, respectively. apy. In total, 92.0% (451/490) of patients with stage III NPC and 93.2% (419/440) of patients with stage IVA and T classification IVB NPC received chemotherapy. Neoadjuvant chemo- Cox multivariate regression analysis showed the T cat- therapy consisted of cisplatin (80 mg/m ) and fluorouracil egory classifications of both editions were independent 2 2 (1000 mg/m daily for 4 days); docetaxel (75 mg/m )and prognostic factors for LRFS and OS (P < 0.001). For the 2 2 cisplatin (75 mg/m ); or a triplet of docetaxel (60 mg/m ), 7th edition, LRFS and OS were not significantly different 2 2 cisplatin (60 mg/m ) and fluorouracil (800 mg/m daily between T2 and T3 (P = 0.515 and P = 0.418, respect- for 4 days) every 3 weeks for 2–3 cycles. Concurrent ively, Fig. 1), while LRFS was borderline significantly dif- chemotherapy was cisplatin given every 3 weeks (100 mg/ ferent between T2 and T4 (P = 0.084, Fig. 1), with a clear 2 2 2 m or 80 mg/m ) or weekly (40 mg/m )during RT. distinction in OS between T2 and T4 (P = 0.002, Fig. 1). However, no significant differences in LRFS were ob- served between T2 and T3, T2 and T4, and T3 and T4 Follow-up and statistical analysis of the 8th edition (P = 0.825, P = 0.332 and P = 0.279, re- After treatment, all patients were assessed every 3 to spectively, Fig. 1), and the OS curves for T2 and T3 of 6 months in the first 3 years, then every 6 to 12 months. the 8th edition even overlapped (P = 0.900, Fig. 1). In Follow-up was calculated from the first day of treatment summary, the T categories of the 8th edition seems failed until death or last examination visit. June 27th, 2017 was to raise obviously superior prognostic value compared to the last follow-up date. Median follow-up was 55.62 months the 7th edition. (range; 1.47–90.17 months). Subgroup analysis was conducted to explore the prog- Statistical Package for the Social Sciences (SPSS) soft- nostic significance of MP and LP involvement. 19 patients ware, version 20.0 (SPSS, Chicago, IL USA) was used to with MP/LP invasion who did not fulfill the criteria for T3 perform analysis. Actuarial rates were estimated using the or T4 in the 7th edition, and who were restaged as Tx1 in Kaplan-Meier method [16], and survival curves were com- the 8th edition, did not have significantly different LRFS pared using the log-rank test [17]. All endpoints: local compared to T2, T3 or T4 of the 7th edition (P = 0.388, relapse-free survival (LRFS), distant metastasis-free survival P = 0.465 and P = 0.756, respectively, Fig. 2). The 116 (DMFS), disease-free survival (DFS) and overall survival patients with T3 tumors with anatomical MP/LP in- (OS), were defined as the interval to the first defining event. volvement, who were staged as T4 in the 7th edition Multivariate analyses with the Cox proportional hazards butas T3inthe 8thedition,had similarsurvivaltoT4and model were used to test the independent significance of dif- significantly different survival to T3 without anatomical ferent parameters by forward elimination of insignificant MP/LP involvement for the 7th edition (P < 0.001, Fig. 2). explanatory variables. The Cox proportional hazards model Due to the lack of differences in LRFS between the T was also used to calculate the hazard ratio (HR). A two- categories of the 8th edition, multivariate Cox regression tailed P-value < 0.05 was considered statistically significant. analysis was performed to evaluate the various prognostic Yang et al. BMC Cancer (2018) 18:606 Page 4 of 11 Table 1 Classification criteria of the 7th and 8th editions of the UICC/AJCC staging system for nasopharyngeal carcinoma th th 7 edition 8 edition T category T0 No tumor identified, but EBV-positive cervical node involvement T1 Nasopharynx, oropharynx or nasal cavity Nasopharynx, oropharynx, nasal cavity without parapharyngeal involvement T2 Parapharyngeal extension Parapharyngeal space and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles) T3 Bony structures and/or paranasal sinuses Bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses T4 Intracranial extension and/or cranial nerves, hypopharynx, Intracranial extension, involvement of cranial nerves, hypopharynx, orbit or infratemporal fossa/masticatory space* orbit, parotid gland and/or extensive soft tissue infiltration beyond lateral surface of lateral pterygoid N category N0 None None N1 Unilateral cervical and/or unilateral or bilateral retropharyngeal Unilateral cervical and/or unilateral or bilateral retropharyngeal node(s), node(s), ≤ 6 cm in greatest dimension, above supraclavicular fossa ≤ 6 cm in greatest dimension, above caudal border of cricoid cartilage N2 Bilateral cervical node(s), ≤ 6 cm in greatest dimension, above Bilateral cervical node(s), ≤ 6 cm in greatest dimension, above caudal supraclavicular fossa border of cricoid cartilage N3 N3a > 6 cm in greatest dimension, above supraclavicular fossa Unilateral or bilateral cervical node(s), > 6 cm in greatest dimension, below caudal border of cricoid cartilage N3b in supraclavicular fossa Clinical stage I T1N0M0 T1N0M0 II T1N1M0, T2N0-1M0 T1N1M0, T2N0-1M0 III T1-2N2M0, T3N0-2M0 T1-2N2M0, T3N0-2M0 IV IVA: T4N0-2M0 T4N0-2M0, T0-4N3M0 IVB: any T1-4N3M0 infratemporal fossa/masticatory space: the superficial layer of the deep cervical fascia splits to enclose the four masticatory muscles, including the medial pterygoid (MP), lateral pterygoid (LP), temporalis and masseter muscles, to enclose this space factors used to define the T categories (Table 5). The follow- significantly associated with disease failure. Notably, male ing covariables were included in the Cox proportional and advanced N category may more likely to develop dis- hazards model with backward conditional: age (≤ 50 vs. ease failure. Male, aged (> 50 years old), prevertebral muscle > 50 years), gender (female vs. male), paranasal sinus, skull extension, skull base infiltration, cranial nerve invasion and base infiltration, medial pterygoid muscle, lateral pterygoid more advanced N category of 8th edition were found to be muscle, prevertebral muscle, 8th edition N category, and the independent factors for OS (Table. 5). chemotherapy (no vs. yes). Multivariate Cox regression ana- lyses showed that prevertebral muscle extension and medial N classification pterygoid muscle extension were the independent factors Cox multivariate regression analysis showed that the N for local failure. Gender, prevertebral muscle extension, cra- category classifications of both editions were independ- nial nerve invasion and N category of 8th edition were ent prognostic factors for local recurrence free survival Table 2 Distribution of T categories as defined by the 7th and 8th editions 8th edition T1 T2 T3 T4 Total 7th edition T1 324 (24.6%) 8 (0.6%) 332 (25.2%) T2 166 (12.6%) 166 (12.6%) T3 420 (31.8%) 420 (31.8%) T4 19 (1.4%) 116 (8.8%) 264 (20.0%) 399 (30.3%) Total 324 (24.6%) 193 (14.6%) 536 (40.7%) 264 (20.0%) 1317 Yang et al. BMC Cancer (2018) 18:606 Page 5 of 11 Table 3 Distribution of N categories as defined by the 7th and 8th editions 8th edition N0 N1 N2 N3 Total 7th edition N0 250 (19.0%) 250 (19.0%) N1 719 (54.6%) 12 (0.9%) 731 (55.4%) N2 252 (19.1%) 26 (2.0%) 278 (21.1%) N3a 16 (1.2%) 16 (1.2%) N3B 42 (3.2%) 42 (3.2%) Total 250 (19.0%) 719 (54.6%) 252 (19.1%) 96 (7.3%) 1317 and overall survival (P < 0.001, Fig. 3). For example, sig- respectively, Fig. 5); therefore, it was reasonable to merge nificant separations in distant metastasis-free survival T4 and N3 disease. Compared to the 7th edition, the 8th (DMFS) were observed between adjacent N categories of edition provided better segregation of long-term DFS and the 8th edition (Fig. 3), but the differences between N3a OS between adjacent clinical stages (Fig. 5). and N1, N2, N3b of the 7th edition were insignificant (P =0.286, P = 0.915, P = 0.288, respectively, Fig. 3). The Discussion small number of patients with N3a (n = 16) disease may The UICC/AJCC TMN staging system is the authoritative have reduced statistical power. Moreover, the differences method of assessing the extent of local invasion, regional in OS between N0 and N1, and N2 and N3 (including lymphatic spread and distant metastasis, and is considered N3a and N3b in the 7th edition) were not significant (all the most valuable prognostic factor in NPC. Although the th P > 0.05, Fig. 3), though the difference between N0 and N1 8 edition was only published one year ago, several studies was slightly larger for the 8th edition than 7th edition. have attempted to validate its clinical applicability. Pan et Subgroup analysis was conducted to assess the value of al. reported clear separation was not observed between altering SCF to the lower neck in the 8th edition. Patients stage I and II (P =0.07 and P =0.10, respectively) of the upstaged from N1 and N2 in the 7th edition to N3 in the 7th and 8th editions. Tang et al. [18] and Xu et al. [19] 8th edition were staged as NX (lymph nodes above SCF found no significant differences between stage II and III but below the caudal border of the cricoid cartilage) in the (all P > 0.05) of either edition. However, overlapping subgroup analysis; the other criteria were the same as the between these cohorts was inevitable, as the patients 7th N categories, apart from the lower neck alteration. No were from the same center and treated during the same statistically significant differences in 4-year DMFS and OS period [21, 22]. OuYang et al. [20] compared the proposed were detected between Nx and N3a or N3b (P = 0.288, Guangzhou, Hong Kong, Guangxi staging system with P = 0.991, respectively, Fig. 4). the 7th and 8th editions of the AJCC/UICC staging system using a cohort of 899 patients. They found the Overall stage N classification of the 8th edition had better prognostic The overall stage classifications of both editions were inde- performance than the 7th, while the T category classification pendent prognostic factors for death, disease failure, local still required further optimization. In this study, a total failureand diseasefailure in Cox multivariate regression of 1317 patients treated with IMRT at two different analysis (P < 0.001, Fig. 5). For DFS and OS, the differences hospitals were assessed to compare the prognostic between stage IVA (T4 N0–2) and IVB (T1-3 N3) of the value of the 7th and 8th editions of the UICC/AJCC 7th edition were not significant (P = 0.057, P = 0.365, staging system. Table 4 Distribution of overall stage as defined by the 7th and 8th editions 8th edition I II III IVA Total 7th edition I 93 (7.1%) 2 (0.2%) 95 (7.3%) II 283 (21.5%) 9 (0.7%) 292 (22.2%) III 473 (35.9%) 17 (1.3%) 490 (37.2%) IVA 10 (0.8%) 113 (8.6%) 259 (19.7%) 382 (29.0%) IVB 58 (4.4%) 58 (4.4%) Total 93 (7.1%) 295 (22.4%) 586 (44.5%) 343 (26.0%) 1317 Yang et al. BMC Cancer (2018) 18:606 Page 6 of 11 Fig. 1 Survival analyses for the T category classifications of the 7th and 8th edition staging systems. a and c: Local relapse-free survival and overall survival for T categories defined by the 7th edition; b and d: local relapse-free survival and overall survival for T categories defined by the 8th edition Study limitations same center showed c-index in the previous edition was Firstly, this study was a retrospective study of 1317 patients slightly higher than the latest one [18]. from two centers in Guangdong Province of China. In In this study, the 8th edition failed to solve the prob- some subgroups, especially the subgroups with PSI and lem of similar survival between adjacent T-classification, MSI, a small number of patients limited the reliability of which has been exited since 7th edition; indeed, the lack our conclusions. Larger-scale analyses are needed to con- of significance between T categories was more obvious firm this study. Secondly, only 372 (28.2%) patients received for the 8th edition, which mainly own to the alteration PET-CT before treatment. Thirdly, other factors such as of ITF/MS. In fact, IFT/MS involvement has long been EBV DNA [21]and primarytumor volume [22], which included in the UICC/AJCC staging system as a T4 cri- have been found to have a profound influence on progno- terion, though the exact anatomical boundaries for these sis, were not considered in this study. structures have varied between editions [23, 24]. In the 5th and 6th editions, the ITF/MS did not involve the medial pterygoid (MP) or lateral pterygoid (LP) [25], T classification while the 7th edition definition of the MS included all In a study which compared different staging systems in- four masticatory muscles: MP, LP, temporalis and mas- cluding the 7th, 8th edition of AJCC/UICC staging system seter [14]. It was laudable that descriptions in the latest and Guangzhou, Hongkong, Guangxi staging system, edition were more specific. However, the best classifica- Guangzhou staging system led to the highest c-index in T tion of IFT /MS had not reach a consensus. Pan et al. classification and the 8th edition ranked the second [20]. found patients without T3 or T4 criteria but MP/LP in- Minor difference was found between these two systems, volvement achieved much better 5-year OS than patients which was extension of Oropharynx or nasal cavity was with T4 disease with other criteria except for MP/LP in- staged as T1 disease in the 8th edition but T2 in volvement (93% vs. 71%, respectively, P = 0.003) [15]. A Guangzhou system. Nevertheless, validation between 7th similar result was reported by Tang et al. [26], though and 8th edition of AJCC/UICC staging system from the different degrees of MS invasion did not significantly Yang et al. BMC Cancer (2018) 18:606 Page 7 of 11 Fig. 2 Survival analyses for the masticatory space subset compared with other subsets using the 7th edition of the staging system. a and b: Local relapse-free survival and overall survival for MSI without other T3/T4 criteria; c and d: Local relapse-free survival and overall survival for MSI without other T4 criteria affect LRFS or OS (P = 0.34 and P = 0.54, respectively). In another study of 816 patients, including 283 (36.4%) patients with MS invasion, MS involvement was an inde- pendent prognostic factor for local control (P = 0.007) and OS (P = 0.024) in multivariate analyses, and patients Table 5 Independent prognostic survival factors for local relapse, with MP involvement had similar survival rates as T2 or disease failure and death in multivariate Cox regression analyses T3 disease (all P > 0.1), though the outcomes for patients End-point Factor Value HR 95% HR with LP involvement were similar to T4 disease (P > 0.1) [27]. In this study, limited number of patients in the Local failure Prevertebral muscle 0.048 1.319 1.003–1.734 subgroup showed that MS involvement with T3 criteria Medial pterygoid muscle 0.011 1.607 1.116–2.315 had similar survival outcomes to T4 disease in this study Disease failure Gender (female vs. male) 0.012 1.539 1.100–2.154 (P = 0.134 for LRFS, P = 0.292 for OS). Such discrepan- Prevertebral muscle < 0.001 1.339 1.171–1.532 cies may be due to the varied demographics, inclusion Cranial nerve < 0.001 1.675 1.291–2.171 criteria, treatment strategies and follow-up times in each 8th edition N category < 0.001 1.692 1.461–1.960 study, and the a larger-scale, multicenter study is wanted to figure the staging of MS. Death Gender 0.007 1.715 1.162–2.530 Involvement of the prevertebral muscles, mentioned Age (≤ 50 vs. > 50) 0.031 1.365 1.028–1.817 for the first time in the 8th edition as a T2 criterion, has Prevertebral muscle 0.001 1.308 1.111–1.541 been shown to increase the risk of local and distance Skull base infiltration 0.011 1.582 1.113–2.248 failure. In a study of 506 patients, prevertebral space in- Cranial nerve < 0.001 1.860 1.454–2.379 vasion (PSI) was associated with similar survival to T4 8th edition N category < 0.001 1.615 1.362–1.191 disease, but not T3 [28]. However, due to the lack of a HR hazard ratio, CI confidence interval significant difference in OS between PSI and MS Yang et al. BMC Cancer (2018) 18:606 Page 8 of 11 Fig. 3 Survival analyses for the N category classifications of the 7th and 8th editions of the UICC/AJCC staging system. a and c: Distant metastasis-free survival and overall survival for the N categories of the 7th edition; Panels b and d: Distant metastasis-free survival and overall survival for the N categories of the 8th edition Fig. 4 Survival analyses for the lower neck subset compared with other subsets using the 7th edition of the UICC/AJCC staging system. a and b: Distant metastasis-free survival and overall survival for the change from the supraclavicular fossa in the 7th edition to the lower neck in the 8th edition Yang et al. BMC Cancer (2018) 18:606 Page 9 of 11 Fig. 5 Survival analyses for the overall stages of the 7th and 8th editions of the UICC/AJCC staging system. a and c: Disease-free survival and overall survival for the T categories of the 7th edition; b and d: Disease-free survival and overall survival for the T categories of the 8th edition invasion reported by Pan et al. [15], single PSI was N classification classified as T2 in the 8th edition. Unfortunately, only In Ouyang’s study, which compared five staging systems, eight patients had PSI without T2, T3 or T4 criteria N-classification in the 8th edition of AJCC/UICC staging in this study; this sample size was too small conduct system owned higher C-index for OS, DMFS and RRFS subgroup analysis. However, multivariate analysis than the previous edition [20]. Another validation of showed PSI was independent prognostic factor for the 8th edition also supported that the new prognos- LRFS, DFS and OS. More detailed studies of a lager tic model of N-classification predicted outcomes fairly cohort are required. well [18]. The marginal differences in prognosis between adjacent Compared to the N category classification of the 7th T categories of the 7th and 8th editions (Fig. 1) reflect de- edition, the 8th edition became consistent with the con- velopments in diagnosis and treatment. On the one hand, sensus guidelines used for other head-and-neck cancers the widespread use of MRI makes skull base erosion easier [33], making the staging system more convenient in clin- to detect [3, 29]. Although MRI can more precisely detect ical practice, and also resulting in better segregation of deep tumor infiltration and has improved LRFS by around both DMFS and OS (Fig. 2). 20% [30], some early micro-migration—which can only be The 8th edition uses the caudal border of the cricoid detected by MRI—may have a better prognosis than the cartilage to differentiate N1–2 and N3 [15], in other obvious invasion easily observed on CT scans in other pa- words, the LL is a demarcating criterion for N3. The tients with the same T category. Compared to the erosion data supporting the proposal of the 8th edition did not easily detected on CT, skull-base erosion detectable on show this replacement improved prognostic value, MRI but undetectable on CT may have a more favorable though there was little controversy about the alternation. prognosis [30, 31]. On the other hand, the popularity of SCF, defined by the superior margin of the sternal end of IMRT and addition of chemotherapy have also reduced the clavicle, the superior margin of the lateral end of the local failure [32]. Distant metastasis remains the main fail- clavicle and the point where the neck meets the shoulder ure pattern in NPC, further emphasizing the importance [34], is not a reliable radiological landmark in this IMRT of accurate N category classification. era when MRI is widely used for diagnosis while the new Yang et al. BMC Cancer (2018) 18:606 Page 10 of 11 boundary - lower level (LL), defined as the area below Abbreviations AJCC: American Joint Committee on Cancer; DFS: disease-free survival; the caudal border of the cricoid cartilage -is an anatomical DMFS: distant metastasis-free survival; IMRT: intensity-modulated landmark that can be reliably defined on physical examin- radiotherapy; ITF: Infratemporal fossa; LL: Lower level; LP: Lateral pterygoid; ation and also accurately located in cross-sectional images. LRFS: Local relapse-free survival; MAD: Maximal axial diameter; MP: Medial pterygoid; MRI: Magnetic resonance imaging; MS: Masticatory space; Replacing the SCF with the LL is sensible and practicable NPC: Nasopharyngeal carcinoma; OS: Overall survival; PSI: Prevertebral space as the LL corresponds to the entire area of levels IVa, IVb, invasion; SCF: Supraclavicular fossa; UICC: International Union against Cancer Vb and Vc as defined by the 2013 International Consensus Acknowledgements Guidelines [33]. Yue et al. found that, compared to Ho’s The authors acknowledge the department of medical records for permission SCF, the LL provided more distinct separation of DMFS, to access the linked databases. DFS and OS between adjacent N categories [11]. A similar result was obtained in this study. Moreover, 38 patients Funding This work was supported by the Natural Science Foundation of Guangdong (about 3%) in our cohort were upstaged from 7th edition Province, China [grant number 2016A020215083]; Medical Science and N1 or N2 to 8th edition N3 because of this change, and Technology Research Foundation of Guangdong Province, China [grant these patients achieved closer survival outcomes to N3 number A02016031]. The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the than N1 or N2 (Fig. 4). Therefore, it is reasonable to as- manuscript. This work was supported by a grant from the Medical Research sign lymph node(s) metastasis in the LL as a new N3 Foundation of Sun Yat-sen University of Guangdong Province, China. criterion. Although Lee et al. [35] found maximal axial diameter Availability of data and materials The datasets used and analyzed during the current study were available (MAD) was a significant independent predictor of sur- from the corresponding author on reasonable request. vival, other relevant studies such as Teo et al. [36] and Heng et al. [37] deemed the prognostic value of MAD Authors’ contributions was mainly due to the fact large lymph nodes are more YXL, WY and LSB contributed to the conception and design of the study, data acquisition, data analysis, data interpretation and the draft of the frequent at lower nodal levels. Only 25 (1.9%) patients manuscript. HSS, and CHY carried out the acquisition and interpretation of had lymph node(s) with a MAD larger than 6 cm, of data. CDM performed the data analysis and data interpretation. LLX and CY whom eight had lymph node involvement extending to contributed with the conception and design of the study, data acquisition, data interpretation and critical edit of the manuscript. All authors read and the SCF (7th edition N3b). Similar overlaps have also approved the final manuscript. been reported in other studies [10, 15]. Furthermore, the similar DMFS and DFS rates for N3a and N3b indicate Ethics approval and consent to participate The study protocol was designed in accordance with the guidelines outlined that this sub-category separation is unnecessary. in the Declaration of Helsinki and was approved by the Ethics Committee of the First Hospital of Foshan and Sun Yat-Sen University Cancer Center (South China). The requirement for informed consent was waived due to Clinical stage the retrospective nature of the study. Stages IVA and IVB of the 7th edition were merged into Competing interests stage IVA in the 8th edition, and naturally, previous The authors declare that they have no competing interests. stage IVC was upgraded to IVB. The differences in DFS and OS between IVA and IVB of the 7th edition were in- Publisher’sNote significant, whereas the overall stages of the 8th edition Springer Nature remains neutral with regard to jurisdictional claims in resulted in better separation of the DFS and OS curves. published maps and institutional affiliations. Although no significant difference in OS was observed Author details between stage I and II in either the 7th and 8th editions Department of Radiation Oncology, The First Affiliated Hospital of Sun (P = 0.157 and P = 0.171, respectively), the distinction be- Yat-sen University, Guangzhou 510060, Guangdong, People’s Republic of China. Department of Radiation Oncology, Sun Yat-sen University Cancer tween stage I and II is necessary as chemotherapy may Center, Guangzhou, China. State Key Laboratory of Oncology in South benefit patients with stage II. China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Department of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan Affiliated to Sun Yat-sen University, Foshan, China. The Sixth Affiliated Hospital of Sun Conclusion Yat-sen University, Guangzhou, China. Department of Radiation Oncology, The 8th edition of the UICC/AJCC staging system for Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou NPC has superior prognostic value compared to the 7th 510060, Guangdong, People’s Republic of China. edition, especially as the 8th edition N categories and overall stages. 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