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UICC rTNM classification system
European Journal of Cancer (2015) xxx, xxx– xxx
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New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system Rui You a,b,1, Xiong Zou a,b,1, Shun-Lan Wang b,c,h,1, Rou Jiang a,b,1, Lin-Quan Tang a,b, Wei-Dong Zhang b,d, Li Li b,d, Meng-Xia Zhang a,b, Guo-Ping Shen b,g, Ling Guo a,b, Chao-Nan Qian a,b, Hai-Qiang Mai a,b, Jun Ma b,e, Ming-Huang Hong b,f, Ming-Yuan Chen a,b,⇑ a
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China c Department of Otorhinolaryngology, First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine, 16 Airfield Rd, Guangzhou 510405, PR China d Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China e Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China f Department of Clinical Trials Center, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China g Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China h Southern Medical University, Guangzhou, PR China b
Received 22 April 2015; accepted 14 May 2015
KEYWORDS Nasopharyngeal carcinoma Recurrence Staging Management Surgery Radiotherapy
Abstract Background: Recurrent tumour, node and metastasis (rTNM) stage system does not have an outstanding prognostic value for survival outcome of patients with recurrent nasopharyngeal carcinoma (rNPC) and it cannot aid the clinicians to choose the most suitable treatment for these patients. Methods: In total, 894 rNPC patients were consecutively enroled. All recurrent (r) tumour (T) stages (rT) and node (N) stages (rN) were stratified as resectable and unresectable based on the imaging data of the head and neck. These stages were re-subdivided into surgical T stages (sT) and surgical N stages (sN) with similar clinical characteristics and death risks and were re-integrated into a new ‘surgical’ stage using a Cox proportional hazards model.
⇑ Corresponding author at: Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong 510060, PR China. Tel.: +86 20 8734 3361; fax: +86 20 87343624. E-mail address: [email protected] (M.-Y. Chen). 1 Contributed equally to this study.
http://dx.doi.org/10.1016/j.ejca.2015.05.014 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Results: The 5-year overall survival (OS) was 72.0%, 55.1%, 21.1% and 10.1% in ‘surgical’ stages I, II, III and IV, respectively (P < 0.001). The ‘surgical’ stage was a significant independent prognostic factor for OS (hazard ratio [HR] 1.78, P < 0.001) and exhibited enhanced prognostic value compared with the rTNM staging system (area under receiver operating characteristics 0.68 versus 0.63, P < 0.001). Endoscopic nasopharyngectomy and intensity-modulated radiation therapy were significant independent positive prognostic factors for the OS of patients with primary lesions in ‘surgical’ stage I/II and ‘surgical’ stage III, respectively (P < 0.05). A combination of aggressive treatments for loco-regional lesions exhibited a beneficial trend for OS of patients with ‘surgical’ stage IV (P > 0.05). Conclusions: Compared with the rTNM stage system, the ‘surgical’ staging system exhibited enhanced prognostic value for rNPC patient survival and could aid clinicians in choosing the most suitable treatment for rNPC patients. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction The American Joint Committee on Cancer (AJCC/UICC) tumour, node and metastasis (TNM) staging [1] is the most commonly used cancer staging system for newly diagnosed nasopharyngeal carcinoma (NPC). According to the 2011 National Comprehensive Cancer Network (NCCN) guidelines for head and neck cancer [2], concurrent chemoradiotherapy with or without induction chemotherapy is the standard treatment for T1 N1-3 M0 or T2-4 N any M0 patients. In addition, palliative platinum-based combination chemotherapy is recommended as the primary treatment for patients with distant metastases (any T, any N and M1). The five-year overall survival (OS) rates for non-metastatic NPC patients treated with intensity-modulated radiation therapy (IMRT) were 100%, 94.3%, 83.6% and 70.4% for stages I, II, III and IV, respectively [3]. However, 8.4–10.9% of patients developed recurrent disease at the primary or/and regional site after definitive radiotherapy [4,5]. The current recurrent AJCC/UICC TNM stage system (rTNM) uses the ‘r’ prefix to denote the TNM stage for relapse patients. Therefore, rTNM staging ignores the striking differences between recurrent and primary patient populations, and the system may exhibit reduced critical accuracy when applied to recurrent diseases. For example, according to the sixth AJCC TNM staging manual [1], the survival of stage III recurrent nasopharyngeal carcinoma (rNPC) patients is similar to those re-staged as stage IV even when administered the same IMRT treatment method, thus indicating minimal difference between rT3 and rT4 [6,7]. Furthermore, rN classification exhibited no prognostic significance regarding OS [6]. As a well-established technique, radiotherapy plays an important role as a salvage treatment for rNPC patients and is applied in all rT1–rT4 classifications [6,7]. However, reduced radiation tolerance in the proximity of critical structures limits the application of salvage
re-irradiation to those types of recurrences [8]. Endoscopic nasopharyngectomy (ENPG) is the most reasonable choice for rNPC. However, only some patients with limited lesions are suitable for salvage surgery [9]. Chemotherapy is also applicable for the management of rNPC but only serves as a palliative treatment [10]. In general, many modalities, including salvage surgery, re-irradiation and chemotherapy, are effective treatments for rNPC patients; however, none of these treatments were indicated according to the rTNM classification system. Thus, clinicians find it difficult to choose the most suitable treatment for rNPC patients in each stage. This fact prompted us to develop a specialised staging system for rNPC to correctly predict the survival of rNPC patients, aid the clinicians in planning treatments and facilitate clinical data sharing among different countries and hospitals. 2. Materials and methods 2.1. Patient selection Between 1st January 2000 and 31st December 2009, a total of 1102 consecutive patients with histologically or radiologically confirmed loco-regional recurrent diseases (first failures) who received radical radiotherapy initially before recurrence at the Sun Yat-sen University Cancer Center (SYSUCC) were enroled in this study. All of the patients with rNPC were initially staged according to the 2002 AJCC/UICC classification system [1]. Our exclusion criteria included (1) patients with missing clinical data for TNM stage, surgical stage and survival analysis; (2) a Karnofsky performance status score less than 70; (3) a history of previous or synchronous malignant tumours and (4) patients who underwent combination treatment of salvage surgery and radiotherapy. Finally, a total of 894 patients were included in the present study. The clinical research ethics committee of SYSUCC approved this study, and the participants provided written informed consent.
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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2.2. Stratified subgroups of each rT, rN, and rM stage based on the imaging data All patients underwent contrast-enhanced CT or MRI of the nasopharynx and neck during staging work-up. According to our institutional surgical practices for rNPC patients [9], all recurrent diseases restaged as rT1 and rT2a were resectable, whereas all rT4 diseases were unresectable for ENPG. However, ENPG was only applied in highly selected rT2b and rT3 patients with tumours confined in a ‘resectable area’ (Appendix Fig. 1). According to the definition of ‘resectable area,’ we subdivided the rT2b classification into rT2b-resectable when the tumour was confined in the superficial parapharyngeal space and rT2b-unresectable when the tumour extended beyond the superficial parapharyngeal space. rT3 classification was also subdivided into rT3-resectable when the tumour was confined in the base wall of the sphenoid sinus and rT3-unresectable when the tumour extended beyond the margin. According to the NCCN guidelines [2], we subdivided the rN1 classification into rN1-unresectable (serious invasion into the cervical vertebrae, brachial plexus, deep muscles of the neck, or carotid artery) and rN1-resectable (no invasion into these structures). Similarly, the rN2 and rN3 classifications were also divided into rN2-resectable/unresectable and rN3-resectable/unresectable in this manner. All image data were interpreted by consensus agreement of two experienced head and neck radiologists, blinded to the results of any prior or subsequent clinical or imaging study. Lesions were judged as resectable or un-resectable for all of the patients. 2.3. Treatment of recurrence at referral and follow-up Relevant contents are included in the Appendix (online only) [6,7,9,11]. 2.4. Statistical analysis Our primary outcome was OS. OS was calculated based on the time from salvage treatment to death due to any cause. All rT, rN and rM initially treated as dummy variables were included in the Cox proportional hazards model. According to the hazard ratio (HR) of each variable above, recurrent stages with similar HR and clinical characteristics were classified as the same ‘surgical’ T, N or M stage (sT, sN, sM). Then, all of these sT, sN and sM combinations were included in the Cox proportional hazards model and further classified as the same overall ‘surgical’ stage. OS was calculated using the Kaplan–Meier method. Survival curve differences were compared using the log-rank test. The following clinicopathological characteristics were also included in the analyses: age, gender,
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‘surgical’ stage of recurrence, rTNM stage, disease-free interval (DFI) and pathological type of recurrence. Covariates significantly associated (P<=0.2) with prognosis detected by univariate analyses were included in the Cox proportional hazards model. We used receiver operating characteristic (ROC) curves to compare the sensitivity and specificity of the TNM staging model and the ‘surgical’ staging model for survival predictions. A stratified analysis was performed to determine which treatment was associated with enhanced survival outcome for rNPC patients in each ‘surgical’ stage independent of age, gender and other independent prognostic factors of survival. Additional survival curves were plotted using the Cox multivariate model. All of the analyses were performed using Stata version 10.0, and a 2-tailed P less than 0.05 was considered statistically significant. 3. Results 3.1. Clinicopathological characteristics The clinicopathological characteristics of all 894 patients are presented in Appendix Table 1. On the final follow-up date (1st January 2013), the median follow-up was 50.35 months (range, 4.10–148.97 months) and a total of 494 patients died. The 5-year OS was 40.8%. 3.2. Recurrent T, N and M stages were converted into relative ‘surgical’ T, N and M stages Totally, 385 patients underwent contrast-enhanced CT and the remaining 509 patients underwent MR imaging. Based on these imaging data, rNPC patients with rT2b, rT3, rN1, rN2 and rN3 were stratified into resectable or unresectable. According to the HR, rT1 was classified as sT1 due to the lowest HR of 0.75. rT2a, rT2b-resectable and rT3-resectable were classified as sT2 due to the nearest HRs of 1.28–1.63. rT2b-unresectable, rT3-unresectable and rT4 were classified as sT3 due to the highest HRs of 2.46–3.17. Similarly, rN1-resectable, rN2-resectable and rN3-resectable were classified as sN1 due to the nearest HRs of 0.89–1.02. rN1-unresectable, rN2-unresectable and rN3-unresectable were classified as sN2 due to the highest HRs of 1.70–2.95. Finally, eight rT stages were converted into four ‘surgical’ T stages (sT), including sT0, sT1, sT2 and sT3. rN stages were transformed into three ‘surgical’ N stages (sN), including sN0, sN1 and sN2 (Table 1). 3.3. The combinations of different ‘surgical’ T, N and M stages Twelve possible combinations of ‘surgical’ T and N stages are theoretically available regardless of the rM
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Table 1 Multivariable Cox regression analysis of recurrent T, N and M stage for overall survival. Subgroups of rTNM stages
N (%)
Hazard ratio (95% CI)
P value
n (HR = en)
‘Surgical’ stage
Subgroups of rT classification rT0 rT1 rT2a rT2b-resectable rT2b-unresectable rT3-resectable rT3-unresectable rT4
211 (23.6%) 141 (15.8%) 36 (4.0%) 42 (4.7%) 69 (7.7%) 27 (3.0%) 194 (21.7%) 174 (19.5%)
Baseline 0.75 (0.50–1.12) 1.28 (0.75–2.19) 1.33 (0.77–2.29) 2.53 (1.72–3.74) 1.63 (0.85–3.14) 2.46 (1.77–3.43) 3.17 (2.22–4.53)
0.16 0.36 0.31 0.001 0.14 0.001 0.001
0.29 0.25 0.28 0.93 0.49 0.90 1.15
sT0 sT1 sT2 sT2 sT3 sT2 sT3 sT3
Subgroups of rN classification rN0 rN1-resectable rN1-unresectable rN2-resectable rN2-unresectable rN3-resectable rN3-unresectable
550 (61.5%) 223 (24.9%) 46 (5.1%) 33 (3.7%) 4 (0.4%) 7 (0.8%) 31 (3.5%)
Baseline 1.02 (0.76–1.36) 2.95 (1.95–4.46) 0.89 (0.51–1.56) 1.70 (0.41–6.97) 0.97 (0.23–4.04) 2.00 (1.21–3.31)
0.90 0.001 0.68 0.46 0.97 0.007
0.02 1.08 0.12 0.53 0.03 0.69
sN0 sN1 sN2 sN1 sN2 sN1 sN2
Subgroups of rM classification rM0 rM1
809 (90.5%) 85 (9.5%)
Baseline 1.69 (1.25–2.28)
0.001
0.52
sM0 sM1
Abbreviations: rT/N/M = recurrent; T/N/M stage; sT/N/M = ‘surgical’ T/N/M stage. According to the HR (n value) of each variable above, recurrent T, N and M stages with similar values were classified as the same ‘surgical’ T, N and M stages, respectively.
stage (Appendix Table 2). However, sT1sN1sM0 and sT2sN1sM0 patients were re-classified into the same group due to rare cases and similar clinical characteristics of recurrent diseases that were confined into ‘resectable’ areas. Similarly, sT0sN2sM0, sT1sN2sM0, sT2sN2sM0, sT3sN2sM0 patients were also classified into the same group. All of the patients with M1 disease, regardless of sT and sN classifications, were staged in one group. Finally, all patients were classified into eight groups, denoted as groups I–VIII (Table 2). 3.4. The establishment of overall ‘surgical’ stages According to the HR of each group (Table 2), groups I and IV were classified as ‘surgical’ stage I due to the lowest HR. Similarly, groups III, VI and VII were classified as ‘surgical’ stage III with an HR of 4.34–5.40, whereas group VIII was defined as ‘surgical’ stage IV given its highest HR of 7.01. Although the HR of group V was less than that of group IV, the value was invalid potentially due to the small number of cases (only 18 cases), and the HR could not accurately reflect the condition of these patients. Thus, groups V and II were classified as ‘surgical’ stage II with the closest HR (1.28– 2.13). We subsequently divided rNPC into four overall stages, denoted as ‘surgical’ stage I–IV (Fig. 1). 3.5. The selection of independent prognostic factors of survival Univariate analyses demonstrated that advanced overall ‘surgical’ stages were associated with
significantly poor survival outcomes with a 5-year OS of 72.0%, 55.1%, 21.1% and 10.1% in ‘surgical’ stages I– IV, respectively (P < 0.001, Fig. 2A). Other potential prognostic factors for OS, such as rTNM stage, age and DFI, were selected (P<=0.20) (Appendix Table 3). All of these potential prognostic factors were considered in the Cox proportional hazards model. Overall ‘surgical’ stage (HR 1.78, 95% confidence interval (CI) 1.54–2.07; P < 0.001, Fig. 2B) and age were significant independent prognostic factors for OS, whereas rTNM stage did not maintain its significance (HR 1.06, 95% CI 0.92–1.21; P = 0.43) (Appendix Table 4). 3.6. Comparison between the TNM staging and ‘surgical’ staging systems In ROC analysis to compare the sensitivity and specificity of overall survival prediction, the ‘surgical’ staging system exhibited enhanced prognostic value compared with the TNM staging system. The areas under the curves are 0.68 versus 0.63, P < 0.001 (Fig. 3). 3.7. The ‘surgical’ staging system is an outstanding indicator of the treatment choice For ‘surgical’ stage I patients with sT1sN0sM0, ENPG was associated with a better OS than 2D-CRT and IMRT (5-year OS 93.4%, 26.8% and 71.1%, respectively; P < 0.001). The mortality risk of patients treated by ENPG was 91.0% and 76.0% lower than those patients treated by 2D-CRT and IMRT (P < 0.05). For patients with sT0sN1sM0, salvage neck dissection
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
Stage IV Group VIII
Group VI Group VII
Abbreviations: American Joint Committee on Cancer (AJCC/UICC); CI = confidence interval; rTNM , recurrent tumour, node and metastasis.
Stage IV ‘surgical’ stage IV 0.001 7.01 (4.60–10.68)
1.95
Stage II, III, IV Stage II, III, IV Stage III, IV Stage II, III, IV ‘surgical’ stage III ‘surgical’ stage III 0.001 0.001 5.40 (3.48–8.38) 5.09 (3.16–8.20)
1.69 1.63
I I, II, III II, III, IV II, III II, III Stage Stage Stage Stage Stage III III, IV III III I II, II, II, II, Stage Stage Stage Stage Stage ‘Surgical’ ‘Surgical’ ‘Surgical’ ‘Surgical’ ‘Surgical’ 0.76 1.47 0.26 0.24 0.001 0.001 0.23 0.61 Baseline 2.13 (1.37–3.32) 4.34 (3.02–6.24) 1.30 (0.85–1.99) 1.28 (0.50–3.26)
sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM1 sN0 sN0 sN0 sN1 sN1 sN1 sN1 sN2 sN2 sN2 sN2 Nany sT1 sT2 sT3 sT0 sT1 sT2 sT3 sT0 sT1 sT2 sT3 Tany I II III IV V Group Group Group Group Group
‘Surgical’ M stage ‘Surgical’ N stage ‘Surgical’ T stage
Table 2 Multivariable Cox regression analysis of eight groups.
Hazard ratio (95% CI)
P value
n (HR = en)
‘Surgical’ stage
stage stage stage stage stage
I II III I II
rTNM stage (2002 AJCC/UICC)
rTNM stage (2009 AJCC/UICC)
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tended to exhibit a better OS than re-irradiation; however, the difference was not significant (5-y OS 72.3% versus 69.5%; P = 0.24). In ‘surgical’ stage II, ENPG was associated with a better OS than IMRT for sT1/2 patients (5-year OS 61.8% versus 53.8%; P = 0.14). The mortality risk of patients treated by ENPG decreased by 47% compared with that of patients treated by IMRT (patients who underwent 2D-CRT were not included in the analysis because there were only eight cases). Most sN1 patients underwent salvage neck dissection (13/18, 72.2%) with an OS of 67.3%. In ‘surgical’ stage III, IMRT was associated with a better OS than 2D-CRT and chemotherapy alone for sT3 patients with ‘unresectable’ local recurrent lesions (5-year OS 27.7%, 15.9% and 16.2%, respectively; P = 0.022). The mortality risk of patients treated by IMRT was 34% and 27% reduced compared with patients treated by chemotherapy alone and 2D-CRT. Most sT1/2 patients with ‘resectable’ local recurrent lesions underwent re-irradiation (9/11, 81.8%) with an OS of 20.8%. For sN2 patients with recurrent ‘unresectable’ lesions in the neck, IMRT offered a better OS than 2D-CRT and chemotherapy alone without statistical significance (5-year OS, 23.4% versus 14.7% or 19.4%, respectively; P = 0.577). For sN1 patients with ‘resectable’ regional lesions, salvage neck dissection did not present a significant survival benefit compared with IMRT and 2D-CRT (5-year OS 28.7%, 18.3% and 0%, respectively; P = 0.418). In ‘surgical’ stage IV, a combination of aggressive treatment (surgery or re-irradiation) for the recurrent primary or/and neck lesions and palliative chemotherapy was associated with an enhanced 5-year OS compared with palliative chemotherapy alone and no treatment; however, the differences did not achieve statistical significance (OS 16.4%, 8.1% and 0%, respectively; P = 0.482) (Fig. 4).
4. Discussion An excellent staging system should both have a good prognostic value for survival outcome and be a good indicator of treatment choice. However, accumulating data have demonstrated that the popular rTNM staging system for rNPC does not meet these standards. Various specially designed recurrent staging systems were reported to demonstrate enhanced prognostic value for patients with recurrent head and neck cancers, such as recurrent laryngeal, oral cavity and oropharyngeal carcinoma [12,13]. However, no further benefit for aiding clinicians in choosing the most suitable treatment for these recurrent patients was evident. Therefore, we first developed the ‘surgical’ stage model based on the rTNM staging system for rNPC and classified patients as minimal (stage I), limited (stage II), extensive (stage III) and
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Fig. 1. The ‘surgical’ staging model. sT/N/M = surgical T/N/M stage; detailed surgical T, N and M stages are shown in Table 2.
Fig. 2. Kaplan–Meier curves of overall survival according to ‘surgical’ stage (A) and survival curves plotted using the Cox multivariate model (B). S* stage = surgical stage, Obs* = observed number of events. Distinct survival curves were noted for each surgical stage (A, B). The surgical stage was a significant independent prognostic factor for overall survival and the difference between any two of the surgical stages was statistically significant (B).
Fig. 3. Comparisons of the sensitivity and specificity for the prediction of overall survival using the tumour, node and metastasis (TNM) staging system and ‘surgical’ staging model.
disseminated recurrence (stage IV). The survival curves were distinctly separated between these stages. The ‘surgical’ stage was a significant independent prognostic factor for OS. In addition, ROC analysis suggested that the ‘surgical’ staging system exhibited a better prognostic value than the rTNM staging system. Furthermore, salvage surgeries were associated with enhanced survival surgical stage I/II patients compared with re-irradiation. However, IMRT was a positive prognostic factor for OS for surgical stage III patients. Aggressive treatments for loco-regional lesions combined with palliative chemotherapy tended to have a better OS in patients with distant metastases (stage IV) without statistical significance, compared with chemotherapy alone. Finally, ‘surgical’ stages I and II were defined as ‘resectable’ stages, whereas ‘surgical’ stages III and IV were considered ‘unresectable’ stages. Relative surgical treatments are more suitable options for rNPC patients with ‘resectable’ disease (‘surgical’ stages I and II). Salvage surgery is theoretically the best option for rNPC patients due to the ability to
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Fig. 4. Kaplan–Meier curves for overall survival according to the treatment patterns in the ‘surgical’ stages (A, B, C) and additional survival curves plotted using the Cox multivariate model (A0 , B0 , C0 ). Obs* = observed number of events; HR = hazard ratio; CI = confidence interval; chemo* = chemotherapy alone. In surgical stage I, endoscopic nasopharyngectomy (ENPG) was associated with a better overall survival (OS) than 2D-CRT and intensity-modulated radiation therapy (IMRT) for patients with sT1sN0 and ENPG was a significant positive prognostic factor for OS independent of age (A0 ). In surgical stage II, ENPG was associated with better OS than IMRT for sT1/2 patients. In addition, ENPG was a significant positive prognostic factor for OS independent of age (B0 ). In surgical stage III, IMRT was associated with a better OS than 2D-CRT and chemotherapy alone for sT3 patients and IMRT was a significant positive prognostic factor for OS independent of age (C0 ).
remove radioresistant disease and to avoid serious post-radiotherapy complications. Regarding nasopharynx lesions, previous studies reported a good survival outcome and high quality of life for rNPC patients treated by salvage surgical resection, including
internal-nasal approaches, such as ENPG, and external-nasal approaches, such as the maxillary swing approach [11,14]. However, ENPG provides more comprehensive protection of critical normal tissues without direct exposure of the nasopharynx compared with
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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traditional external-nasal approaches. An increasing number of studies have validated the efficacy of endoscopic surgery, including en bloc resection or ablation for rNPC [9,15]. Furthermore, a previous study reported that an endoscopic approach was independently associated with improved outcome compared with open surgery for rT3/4 disease in selected patients [16]. Regarding neck lesions, although we only detected a trend towards a benefit from salvage neck dissection and no significant difference was noted given the relatively limited number of cases, it has been recommended in the recent 2 decades that surgery rather than re-irradiation should be the first choice for cervical residue or recurrence of NPC after definitive radiotherapy [17]. Various previous studies reported that surgery results in better tumour control and long-term survival with fewer complications compared with re-irradiation [18,19]. Effective aggressive therapies may be essential to improve the survival outcome of ‘unresectable’ patients (‘surgical’ stage III and IV) even advanced stage patients. IMRT is beneficial for the survival of patients with ‘unresectable’ ‘surgical’ stage III local disease. This finding is consistent with previous studies that reported improved survival for rNPC patients treated by IMRT, with a 5-year OS of 30.3 to 44.9% [6,7,20]. For patients with ‘resectable’ local or regional lesions with corresponding ‘unresectable’ regional or local diseases, the decision to choose IMRT or salvage surgeries requires further study due to the limited number of cases in the current study. For rNPC patients with distant metastases (‘surgical’ stage IV), neither current nor previous studies confirm the role of chemotherapy. However, it is widely accepted that palliative chemotherapy is beneficial for the survival of newly diagnosed NPC patients with distant metastases [21]. Furthermore, previous studies reported an improved OS with radiotherapy combined with chemotherapy for patients with primary lesions compared with chemotherapy alone [22,23]. In the current study, it seems that aggressive therapy, such as radiotherapy or surgery for the primary or neck lesions, is beneficial for the survival outcome of rNPC patients with distant metastases. However, the efficacy of palliative chemotherapy or treatment of local–regional lesions in rNPC patients requires further study. This study design has several potential limitations. First, given the complexity of the surgery and different surgical techniques in various institutions, there may be limitations when applying the ‘surgical’ staging system to other medical institutions. However, this ‘surgical’ staging system was formulated based on our institution’s surgical indication for rNPC, and we hoped to offer a template for other clinicians to develop their own surgical staging systems. Second, the patients in ‘surgical’ stage III accounted for approximately half of all of the patients. However, given the increased use of
endoscopic surgery, more advanced techniques should be further developed to enlarge the ‘resectable area,’ thus enabling more rNPC patients to be considered suitable for surgical treatment. In conclusion, compared with the rTNM staging system, the ‘surgical’ staging system exhibits better prognostic value for rNPC patient survival, and the system can aid clinicians in selecting the most suitable treatment option for rNPC patients. However, we acknowledge that more studies are needed to validate this new ‘surgical’ staging system. Conflict of interest statement None declared. Acknowledgements This work was supported in part by the Program for New Century Excellent Talents in University of China (NCET-12-0562), Sun Yat-sen University – China Clinical Research 5010 Program (201310), Guangdong Provincial Natural Science Foundation of China (S2013020012726) and National High Technology Research and Development Program of China (863 Program, No. 2012AA02A501). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.05.014. References [1] Greene FL, Page DL. AJCC cancer staging handbook. 6th ed. New York, NY: Springer-Verlag; 2002. p. 50. [2] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancer, Version 2, 2011.. [3] Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, et al. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiother Oncol 2014;110(3):398–403. [4] Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, et al. How does intensity-modulated radiotherapy versus conventional twodimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80(3):661–8. [5] Yu KH, Leung SF, Tung SY, Zee B, Chua DT, Sze WM, et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005;27(5):397–405. [6] Hua YJ, Han F, Lu LX, Mai HQ, Guo X, Hong MH, et al. Longterm treatment outcome of recurrent nasopharyngeal carcinoma treated with salvage intensity modulated radiotherapy. Eur J Cancer 2012;48(18):3422–8. [7] Han F, Zhao C, Huang SM, Lu LX, Huang Y, Deng XW, et al. Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-
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New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system Rui You a,b,1, Xiong Zou a,b,1, Shun-Lan Wang b,c,h,1, Rou Jiang a,b,1, Lin-Quan Tang a,b, Wei-Dong Zhang b,d, Li Li b,d, Meng-Xia Zhang a,b, Guo-Ping Shen b,g, Ling Guo a,b, Chao-Nan Qian a,b, Hai-Qiang Mai a,b, Jun Ma b,e, Ming-Huang Hong b,f, Ming-Yuan Chen a,b,⇑ a
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China c Department of Otorhinolaryngology, First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine, 16 Airfield Rd, Guangzhou 510405, PR China d Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China e Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China f Department of Clinical Trials Center, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, PR China g Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China h Southern Medical University, Guangzhou, PR China b
Received 22 April 2015; accepted 14 May 2015
KEYWORDS Nasopharyngeal carcinoma Recurrence Staging Management Surgery Radiotherapy
Abstract Background: Recurrent tumour, node and metastasis (rTNM) stage system does not have an outstanding prognostic value for survival outcome of patients with recurrent nasopharyngeal carcinoma (rNPC) and it cannot aid the clinicians to choose the most suitable treatment for these patients. Methods: In total, 894 rNPC patients were consecutively enroled. All recurrent (r) tumour (T) stages (rT) and node (N) stages (rN) were stratified as resectable and unresectable based on the imaging data of the head and neck. These stages were re-subdivided into surgical T stages (sT) and surgical N stages (sN) with similar clinical characteristics and death risks and were re-integrated into a new ‘surgical’ stage using a Cox proportional hazards model.
⇑ Corresponding author at: Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong 510060, PR China. Tel.: +86 20 8734 3361; fax: +86 20 87343624. E-mail address: [email protected] (M.-Y. Chen). 1 Contributed equally to this study.
http://dx.doi.org/10.1016/j.ejca.2015.05.014 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Results: The 5-year overall survival (OS) was 72.0%, 55.1%, 21.1% and 10.1% in ‘surgical’ stages I, II, III and IV, respectively (P < 0.001). The ‘surgical’ stage was a significant independent prognostic factor for OS (hazard ratio [HR] 1.78, P < 0.001) and exhibited enhanced prognostic value compared with the rTNM staging system (area under receiver operating characteristics 0.68 versus 0.63, P < 0.001). Endoscopic nasopharyngectomy and intensity-modulated radiation therapy were significant independent positive prognostic factors for the OS of patients with primary lesions in ‘surgical’ stage I/II and ‘surgical’ stage III, respectively (P < 0.05). A combination of aggressive treatments for loco-regional lesions exhibited a beneficial trend for OS of patients with ‘surgical’ stage IV (P > 0.05). Conclusions: Compared with the rTNM stage system, the ‘surgical’ staging system exhibited enhanced prognostic value for rNPC patient survival and could aid clinicians in choosing the most suitable treatment for rNPC patients. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction The American Joint Committee on Cancer (AJCC/UICC) tumour, node and metastasis (TNM) staging [1] is the most commonly used cancer staging system for newly diagnosed nasopharyngeal carcinoma (NPC). According to the 2011 National Comprehensive Cancer Network (NCCN) guidelines for head and neck cancer [2], concurrent chemoradiotherapy with or without induction chemotherapy is the standard treatment for T1 N1-3 M0 or T2-4 N any M0 patients. In addition, palliative platinum-based combination chemotherapy is recommended as the primary treatment for patients with distant metastases (any T, any N and M1). The five-year overall survival (OS) rates for non-metastatic NPC patients treated with intensity-modulated radiation therapy (IMRT) were 100%, 94.3%, 83.6% and 70.4% for stages I, II, III and IV, respectively [3]. However, 8.4–10.9% of patients developed recurrent disease at the primary or/and regional site after definitive radiotherapy [4,5]. The current recurrent AJCC/UICC TNM stage system (rTNM) uses the ‘r’ prefix to denote the TNM stage for relapse patients. Therefore, rTNM staging ignores the striking differences between recurrent and primary patient populations, and the system may exhibit reduced critical accuracy when applied to recurrent diseases. For example, according to the sixth AJCC TNM staging manual [1], the survival of stage III recurrent nasopharyngeal carcinoma (rNPC) patients is similar to those re-staged as stage IV even when administered the same IMRT treatment method, thus indicating minimal difference between rT3 and rT4 [6,7]. Furthermore, rN classification exhibited no prognostic significance regarding OS [6]. As a well-established technique, radiotherapy plays an important role as a salvage treatment for rNPC patients and is applied in all rT1–rT4 classifications [6,7]. However, reduced radiation tolerance in the proximity of critical structures limits the application of salvage
re-irradiation to those types of recurrences [8]. Endoscopic nasopharyngectomy (ENPG) is the most reasonable choice for rNPC. However, only some patients with limited lesions are suitable for salvage surgery [9]. Chemotherapy is also applicable for the management of rNPC but only serves as a palliative treatment [10]. In general, many modalities, including salvage surgery, re-irradiation and chemotherapy, are effective treatments for rNPC patients; however, none of these treatments were indicated according to the rTNM classification system. Thus, clinicians find it difficult to choose the most suitable treatment for rNPC patients in each stage. This fact prompted us to develop a specialised staging system for rNPC to correctly predict the survival of rNPC patients, aid the clinicians in planning treatments and facilitate clinical data sharing among different countries and hospitals. 2. Materials and methods 2.1. Patient selection Between 1st January 2000 and 31st December 2009, a total of 1102 consecutive patients with histologically or radiologically confirmed loco-regional recurrent diseases (first failures) who received radical radiotherapy initially before recurrence at the Sun Yat-sen University Cancer Center (SYSUCC) were enroled in this study. All of the patients with rNPC were initially staged according to the 2002 AJCC/UICC classification system [1]. Our exclusion criteria included (1) patients with missing clinical data for TNM stage, surgical stage and survival analysis; (2) a Karnofsky performance status score less than 70; (3) a history of previous or synchronous malignant tumours and (4) patients who underwent combination treatment of salvage surgery and radiotherapy. Finally, a total of 894 patients were included in the present study. The clinical research ethics committee of SYSUCC approved this study, and the participants provided written informed consent.
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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2.2. Stratified subgroups of each rT, rN, and rM stage based on the imaging data All patients underwent contrast-enhanced CT or MRI of the nasopharynx and neck during staging work-up. According to our institutional surgical practices for rNPC patients [9], all recurrent diseases restaged as rT1 and rT2a were resectable, whereas all rT4 diseases were unresectable for ENPG. However, ENPG was only applied in highly selected rT2b and rT3 patients with tumours confined in a ‘resectable area’ (Appendix Fig. 1). According to the definition of ‘resectable area,’ we subdivided the rT2b classification into rT2b-resectable when the tumour was confined in the superficial parapharyngeal space and rT2b-unresectable when the tumour extended beyond the superficial parapharyngeal space. rT3 classification was also subdivided into rT3-resectable when the tumour was confined in the base wall of the sphenoid sinus and rT3-unresectable when the tumour extended beyond the margin. According to the NCCN guidelines [2], we subdivided the rN1 classification into rN1-unresectable (serious invasion into the cervical vertebrae, brachial plexus, deep muscles of the neck, or carotid artery) and rN1-resectable (no invasion into these structures). Similarly, the rN2 and rN3 classifications were also divided into rN2-resectable/unresectable and rN3-resectable/unresectable in this manner. All image data were interpreted by consensus agreement of two experienced head and neck radiologists, blinded to the results of any prior or subsequent clinical or imaging study. Lesions were judged as resectable or un-resectable for all of the patients. 2.3. Treatment of recurrence at referral and follow-up Relevant contents are included in the Appendix (online only) [6,7,9,11]. 2.4. Statistical analysis Our primary outcome was OS. OS was calculated based on the time from salvage treatment to death due to any cause. All rT, rN and rM initially treated as dummy variables were included in the Cox proportional hazards model. According to the hazard ratio (HR) of each variable above, recurrent stages with similar HR and clinical characteristics were classified as the same ‘surgical’ T, N or M stage (sT, sN, sM). Then, all of these sT, sN and sM combinations were included in the Cox proportional hazards model and further classified as the same overall ‘surgical’ stage. OS was calculated using the Kaplan–Meier method. Survival curve differences were compared using the log-rank test. The following clinicopathological characteristics were also included in the analyses: age, gender,
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‘surgical’ stage of recurrence, rTNM stage, disease-free interval (DFI) and pathological type of recurrence. Covariates significantly associated (P<=0.2) with prognosis detected by univariate analyses were included in the Cox proportional hazards model. We used receiver operating characteristic (ROC) curves to compare the sensitivity and specificity of the TNM staging model and the ‘surgical’ staging model for survival predictions. A stratified analysis was performed to determine which treatment was associated with enhanced survival outcome for rNPC patients in each ‘surgical’ stage independent of age, gender and other independent prognostic factors of survival. Additional survival curves were plotted using the Cox multivariate model. All of the analyses were performed using Stata version 10.0, and a 2-tailed P less than 0.05 was considered statistically significant. 3. Results 3.1. Clinicopathological characteristics The clinicopathological characteristics of all 894 patients are presented in Appendix Table 1. On the final follow-up date (1st January 2013), the median follow-up was 50.35 months (range, 4.10–148.97 months) and a total of 494 patients died. The 5-year OS was 40.8%. 3.2. Recurrent T, N and M stages were converted into relative ‘surgical’ T, N and M stages Totally, 385 patients underwent contrast-enhanced CT and the remaining 509 patients underwent MR imaging. Based on these imaging data, rNPC patients with rT2b, rT3, rN1, rN2 and rN3 were stratified into resectable or unresectable. According to the HR, rT1 was classified as sT1 due to the lowest HR of 0.75. rT2a, rT2b-resectable and rT3-resectable were classified as sT2 due to the nearest HRs of 1.28–1.63. rT2b-unresectable, rT3-unresectable and rT4 were classified as sT3 due to the highest HRs of 2.46–3.17. Similarly, rN1-resectable, rN2-resectable and rN3-resectable were classified as sN1 due to the nearest HRs of 0.89–1.02. rN1-unresectable, rN2-unresectable and rN3-unresectable were classified as sN2 due to the highest HRs of 1.70–2.95. Finally, eight rT stages were converted into four ‘surgical’ T stages (sT), including sT0, sT1, sT2 and sT3. rN stages were transformed into three ‘surgical’ N stages (sN), including sN0, sN1 and sN2 (Table 1). 3.3. The combinations of different ‘surgical’ T, N and M stages Twelve possible combinations of ‘surgical’ T and N stages are theoretically available regardless of the rM
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Table 1 Multivariable Cox regression analysis of recurrent T, N and M stage for overall survival. Subgroups of rTNM stages
N (%)
Hazard ratio (95% CI)
P value
n (HR = en)
‘Surgical’ stage
Subgroups of rT classification rT0 rT1 rT2a rT2b-resectable rT2b-unresectable rT3-resectable rT3-unresectable rT4
211 (23.6%) 141 (15.8%) 36 (4.0%) 42 (4.7%) 69 (7.7%) 27 (3.0%) 194 (21.7%) 174 (19.5%)
Baseline 0.75 (0.50–1.12) 1.28 (0.75–2.19) 1.33 (0.77–2.29) 2.53 (1.72–3.74) 1.63 (0.85–3.14) 2.46 (1.77–3.43) 3.17 (2.22–4.53)
0.16 0.36 0.31 0.001 0.14 0.001 0.001
0.29 0.25 0.28 0.93 0.49 0.90 1.15
sT0 sT1 sT2 sT2 sT3 sT2 sT3 sT3
Subgroups of rN classification rN0 rN1-resectable rN1-unresectable rN2-resectable rN2-unresectable rN3-resectable rN3-unresectable
550 (61.5%) 223 (24.9%) 46 (5.1%) 33 (3.7%) 4 (0.4%) 7 (0.8%) 31 (3.5%)
Baseline 1.02 (0.76–1.36) 2.95 (1.95–4.46) 0.89 (0.51–1.56) 1.70 (0.41–6.97) 0.97 (0.23–4.04) 2.00 (1.21–3.31)
0.90 0.001 0.68 0.46 0.97 0.007
0.02 1.08 0.12 0.53 0.03 0.69
sN0 sN1 sN2 sN1 sN2 sN1 sN2
Subgroups of rM classification rM0 rM1
809 (90.5%) 85 (9.5%)
Baseline 1.69 (1.25–2.28)
0.001
0.52
sM0 sM1
Abbreviations: rT/N/M = recurrent; T/N/M stage; sT/N/M = ‘surgical’ T/N/M stage. According to the HR (n value) of each variable above, recurrent T, N and M stages with similar values were classified as the same ‘surgical’ T, N and M stages, respectively.
stage (Appendix Table 2). However, sT1sN1sM0 and sT2sN1sM0 patients were re-classified into the same group due to rare cases and similar clinical characteristics of recurrent diseases that were confined into ‘resectable’ areas. Similarly, sT0sN2sM0, sT1sN2sM0, sT2sN2sM0, sT3sN2sM0 patients were also classified into the same group. All of the patients with M1 disease, regardless of sT and sN classifications, were staged in one group. Finally, all patients were classified into eight groups, denoted as groups I–VIII (Table 2). 3.4. The establishment of overall ‘surgical’ stages According to the HR of each group (Table 2), groups I and IV were classified as ‘surgical’ stage I due to the lowest HR. Similarly, groups III, VI and VII were classified as ‘surgical’ stage III with an HR of 4.34–5.40, whereas group VIII was defined as ‘surgical’ stage IV given its highest HR of 7.01. Although the HR of group V was less than that of group IV, the value was invalid potentially due to the small number of cases (only 18 cases), and the HR could not accurately reflect the condition of these patients. Thus, groups V and II were classified as ‘surgical’ stage II with the closest HR (1.28– 2.13). We subsequently divided rNPC into four overall stages, denoted as ‘surgical’ stage I–IV (Fig. 1). 3.5. The selection of independent prognostic factors of survival Univariate analyses demonstrated that advanced overall ‘surgical’ stages were associated with
significantly poor survival outcomes with a 5-year OS of 72.0%, 55.1%, 21.1% and 10.1% in ‘surgical’ stages I– IV, respectively (P < 0.001, Fig. 2A). Other potential prognostic factors for OS, such as rTNM stage, age and DFI, were selected (P<=0.20) (Appendix Table 3). All of these potential prognostic factors were considered in the Cox proportional hazards model. Overall ‘surgical’ stage (HR 1.78, 95% confidence interval (CI) 1.54–2.07; P < 0.001, Fig. 2B) and age were significant independent prognostic factors for OS, whereas rTNM stage did not maintain its significance (HR 1.06, 95% CI 0.92–1.21; P = 0.43) (Appendix Table 4). 3.6. Comparison between the TNM staging and ‘surgical’ staging systems In ROC analysis to compare the sensitivity and specificity of overall survival prediction, the ‘surgical’ staging system exhibited enhanced prognostic value compared with the TNM staging system. The areas under the curves are 0.68 versus 0.63, P < 0.001 (Fig. 3). 3.7. The ‘surgical’ staging system is an outstanding indicator of the treatment choice For ‘surgical’ stage I patients with sT1sN0sM0, ENPG was associated with a better OS than 2D-CRT and IMRT (5-year OS 93.4%, 26.8% and 71.1%, respectively; P < 0.001). The mortality risk of patients treated by ENPG was 91.0% and 76.0% lower than those patients treated by 2D-CRT and IMRT (P < 0.05). For patients with sT0sN1sM0, salvage neck dissection
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
Stage IV Group VIII
Group VI Group VII
Abbreviations: American Joint Committee on Cancer (AJCC/UICC); CI = confidence interval; rTNM , recurrent tumour, node and metastasis.
Stage IV ‘surgical’ stage IV 0.001 7.01 (4.60–10.68)
1.95
Stage II, III, IV Stage II, III, IV Stage III, IV Stage II, III, IV ‘surgical’ stage III ‘surgical’ stage III 0.001 0.001 5.40 (3.48–8.38) 5.09 (3.16–8.20)
1.69 1.63
I I, II, III II, III, IV II, III II, III Stage Stage Stage Stage Stage III III, IV III III I II, II, II, II, Stage Stage Stage Stage Stage ‘Surgical’ ‘Surgical’ ‘Surgical’ ‘Surgical’ ‘Surgical’ 0.76 1.47 0.26 0.24 0.001 0.001 0.23 0.61 Baseline 2.13 (1.37–3.32) 4.34 (3.02–6.24) 1.30 (0.85–1.99) 1.28 (0.50–3.26)
sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM0 sM1 sN0 sN0 sN0 sN1 sN1 sN1 sN1 sN2 sN2 sN2 sN2 Nany sT1 sT2 sT3 sT0 sT1 sT2 sT3 sT0 sT1 sT2 sT3 Tany I II III IV V Group Group Group Group Group
‘Surgical’ M stage ‘Surgical’ N stage ‘Surgical’ T stage
Table 2 Multivariable Cox regression analysis of eight groups.
Hazard ratio (95% CI)
P value
n (HR = en)
‘Surgical’ stage
stage stage stage stage stage
I II III I II
rTNM stage (2002 AJCC/UICC)
rTNM stage (2009 AJCC/UICC)
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tended to exhibit a better OS than re-irradiation; however, the difference was not significant (5-y OS 72.3% versus 69.5%; P = 0.24). In ‘surgical’ stage II, ENPG was associated with a better OS than IMRT for sT1/2 patients (5-year OS 61.8% versus 53.8%; P = 0.14). The mortality risk of patients treated by ENPG decreased by 47% compared with that of patients treated by IMRT (patients who underwent 2D-CRT were not included in the analysis because there were only eight cases). Most sN1 patients underwent salvage neck dissection (13/18, 72.2%) with an OS of 67.3%. In ‘surgical’ stage III, IMRT was associated with a better OS than 2D-CRT and chemotherapy alone for sT3 patients with ‘unresectable’ local recurrent lesions (5-year OS 27.7%, 15.9% and 16.2%, respectively; P = 0.022). The mortality risk of patients treated by IMRT was 34% and 27% reduced compared with patients treated by chemotherapy alone and 2D-CRT. Most sT1/2 patients with ‘resectable’ local recurrent lesions underwent re-irradiation (9/11, 81.8%) with an OS of 20.8%. For sN2 patients with recurrent ‘unresectable’ lesions in the neck, IMRT offered a better OS than 2D-CRT and chemotherapy alone without statistical significance (5-year OS, 23.4% versus 14.7% or 19.4%, respectively; P = 0.577). For sN1 patients with ‘resectable’ regional lesions, salvage neck dissection did not present a significant survival benefit compared with IMRT and 2D-CRT (5-year OS 28.7%, 18.3% and 0%, respectively; P = 0.418). In ‘surgical’ stage IV, a combination of aggressive treatment (surgery or re-irradiation) for the recurrent primary or/and neck lesions and palliative chemotherapy was associated with an enhanced 5-year OS compared with palliative chemotherapy alone and no treatment; however, the differences did not achieve statistical significance (OS 16.4%, 8.1% and 0%, respectively; P = 0.482) (Fig. 4).
4. Discussion An excellent staging system should both have a good prognostic value for survival outcome and be a good indicator of treatment choice. However, accumulating data have demonstrated that the popular rTNM staging system for rNPC does not meet these standards. Various specially designed recurrent staging systems were reported to demonstrate enhanced prognostic value for patients with recurrent head and neck cancers, such as recurrent laryngeal, oral cavity and oropharyngeal carcinoma [12,13]. However, no further benefit for aiding clinicians in choosing the most suitable treatment for these recurrent patients was evident. Therefore, we first developed the ‘surgical’ stage model based on the rTNM staging system for rNPC and classified patients as minimal (stage I), limited (stage II), extensive (stage III) and
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Fig. 1. The ‘surgical’ staging model. sT/N/M = surgical T/N/M stage; detailed surgical T, N and M stages are shown in Table 2.
Fig. 2. Kaplan–Meier curves of overall survival according to ‘surgical’ stage (A) and survival curves plotted using the Cox multivariate model (B). S* stage = surgical stage, Obs* = observed number of events. Distinct survival curves were noted for each surgical stage (A, B). The surgical stage was a significant independent prognostic factor for overall survival and the difference between any two of the surgical stages was statistically significant (B).
Fig. 3. Comparisons of the sensitivity and specificity for the prediction of overall survival using the tumour, node and metastasis (TNM) staging system and ‘surgical’ staging model.
disseminated recurrence (stage IV). The survival curves were distinctly separated between these stages. The ‘surgical’ stage was a significant independent prognostic factor for OS. In addition, ROC analysis suggested that the ‘surgical’ staging system exhibited a better prognostic value than the rTNM staging system. Furthermore, salvage surgeries were associated with enhanced survival surgical stage I/II patients compared with re-irradiation. However, IMRT was a positive prognostic factor for OS for surgical stage III patients. Aggressive treatments for loco-regional lesions combined with palliative chemotherapy tended to have a better OS in patients with distant metastases (stage IV) without statistical significance, compared with chemotherapy alone. Finally, ‘surgical’ stages I and II were defined as ‘resectable’ stages, whereas ‘surgical’ stages III and IV were considered ‘unresectable’ stages. Relative surgical treatments are more suitable options for rNPC patients with ‘resectable’ disease (‘surgical’ stages I and II). Salvage surgery is theoretically the best option for rNPC patients due to the ability to
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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Fig. 4. Kaplan–Meier curves for overall survival according to the treatment patterns in the ‘surgical’ stages (A, B, C) and additional survival curves plotted using the Cox multivariate model (A0 , B0 , C0 ). Obs* = observed number of events; HR = hazard ratio; CI = confidence interval; chemo* = chemotherapy alone. In surgical stage I, endoscopic nasopharyngectomy (ENPG) was associated with a better overall survival (OS) than 2D-CRT and intensity-modulated radiation therapy (IMRT) for patients with sT1sN0 and ENPG was a significant positive prognostic factor for OS independent of age (A0 ). In surgical stage II, ENPG was associated with better OS than IMRT for sT1/2 patients. In addition, ENPG was a significant positive prognostic factor for OS independent of age (B0 ). In surgical stage III, IMRT was associated with a better OS than 2D-CRT and chemotherapy alone for sT3 patients and IMRT was a significant positive prognostic factor for OS independent of age (C0 ).
remove radioresistant disease and to avoid serious post-radiotherapy complications. Regarding nasopharynx lesions, previous studies reported a good survival outcome and high quality of life for rNPC patients treated by salvage surgical resection, including
internal-nasal approaches, such as ENPG, and external-nasal approaches, such as the maxillary swing approach [11,14]. However, ENPG provides more comprehensive protection of critical normal tissues without direct exposure of the nasopharynx compared with
Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014
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traditional external-nasal approaches. An increasing number of studies have validated the efficacy of endoscopic surgery, including en bloc resection or ablation for rNPC [9,15]. Furthermore, a previous study reported that an endoscopic approach was independently associated with improved outcome compared with open surgery for rT3/4 disease in selected patients [16]. Regarding neck lesions, although we only detected a trend towards a benefit from salvage neck dissection and no significant difference was noted given the relatively limited number of cases, it has been recommended in the recent 2 decades that surgery rather than re-irradiation should be the first choice for cervical residue or recurrence of NPC after definitive radiotherapy [17]. Various previous studies reported that surgery results in better tumour control and long-term survival with fewer complications compared with re-irradiation [18,19]. Effective aggressive therapies may be essential to improve the survival outcome of ‘unresectable’ patients (‘surgical’ stage III and IV) even advanced stage patients. IMRT is beneficial for the survival of patients with ‘unresectable’ ‘surgical’ stage III local disease. This finding is consistent with previous studies that reported improved survival for rNPC patients treated by IMRT, with a 5-year OS of 30.3 to 44.9% [6,7,20]. For patients with ‘resectable’ local or regional lesions with corresponding ‘unresectable’ regional or local diseases, the decision to choose IMRT or salvage surgeries requires further study due to the limited number of cases in the current study. For rNPC patients with distant metastases (‘surgical’ stage IV), neither current nor previous studies confirm the role of chemotherapy. However, it is widely accepted that palliative chemotherapy is beneficial for the survival of newly diagnosed NPC patients with distant metastases [21]. Furthermore, previous studies reported an improved OS with radiotherapy combined with chemotherapy for patients with primary lesions compared with chemotherapy alone [22,23]. In the current study, it seems that aggressive therapy, such as radiotherapy or surgery for the primary or neck lesions, is beneficial for the survival outcome of rNPC patients with distant metastases. However, the efficacy of palliative chemotherapy or treatment of local–regional lesions in rNPC patients requires further study. This study design has several potential limitations. First, given the complexity of the surgery and different surgical techniques in various institutions, there may be limitations when applying the ‘surgical’ staging system to other medical institutions. However, this ‘surgical’ staging system was formulated based on our institution’s surgical indication for rNPC, and we hoped to offer a template for other clinicians to develop their own surgical staging systems. Second, the patients in ‘surgical’ stage III accounted for approximately half of all of the patients. However, given the increased use of
endoscopic surgery, more advanced techniques should be further developed to enlarge the ‘resectable area,’ thus enabling more rNPC patients to be considered suitable for surgical treatment. In conclusion, compared with the rTNM staging system, the ‘surgical’ staging system exhibits better prognostic value for rNPC patient survival, and the system can aid clinicians in selecting the most suitable treatment option for rNPC patients. However, we acknowledge that more studies are needed to validate this new ‘surgical’ staging system. Conflict of interest statement None declared. Acknowledgements This work was supported in part by the Program for New Century Excellent Talents in University of China (NCET-12-0562), Sun Yat-sen University – China Clinical Research 5010 Program (201310), Guangdong Provincial Natural Science Foundation of China (S2013020012726) and National High Technology Research and Development Program of China (863 Program, No. 2012AA02A501). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.05.014. References [1] Greene FL, Page DL. AJCC cancer staging handbook. 6th ed. New York, NY: Springer-Verlag; 2002. p. 50. [2] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancer, Version 2, 2011.
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Please cite this article in press as: You R. et al., New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.05.014