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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 Oncology 72 (2017) 65–72
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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 Pu-Yun OuYang a,1, Yao Xiao a,1, Kai-Yun You b,1, Lu-Ning Zhang c, Xiao-Wen Lan a, Xiao-Min Zhang a, Fang-Yun Xie a,⇑ a Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China b Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China c Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
a r t i c l e
i n f o
Article history: Received 10 March 2017 Received in revised form 5 July 2017 Accepted 8 July 2017
Keywords: AJCC Cancer staging Intensity-modulated radiotherapy Nasopharyngeal carcinoma
a b s t r a c t Objectives: We aimed to validate and compare the 7th and 8th edition of AJCC staging systems for nonmetastatic nasopharyngeal carcinoma, and proposed staging systems from Hong Kong, Guangzhou, and Guangxi. Materials and methods: We retrospectively included 899 patients treated between November 5, 2002 and May 27, 2010. Separation and discrimination of each staging system in overall survival were primarily compared. Results: Compared with the 7th AJCC, the 8th AJCC and all proposed staging systems well separated across T-classification. T-classification from Guangzhou seemed to perform best in discrimination (C-index 0.6454), followed by the 8th AJCC (0.6451), the 7th AJCC (0.6386), Hong Kong (0.6376) and Guangxi (0.5889). For N-classification, no staging systems improved the weakness of the 7th AJCC in separating N2 and N1, except that suggestion from Guangzhou showed higher potential (P = 0.096). Besides, N-classification from Guangzhou had a C-index of 0.6444, larger than that of the 8th AJCC (0.6235), the 7th AJCC (0.6179), Hong Kong (0.6175) and Guangxi (0.6175). Accordingly, stage group of staging system from Guangzhou showed higher discrimination (C-index 0.6839), compared with the 8th AJCC (0.6791), the 7th AJCC (0.6766), Hong Kong (0.6765) and Guangxi (0.6688), despite that stage I and II remained inseparable (P = 0.322). Conclusions: The 8th AJCC staging system appeared to be better than the 7th AJCC. But the proposed staging system from Guangzhou was more likely to improve the separation and discrimination abilities. Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Abbreviations: AJCC, american joint committee on cancer; CI, confidence interval; C-index, concordance index; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, epstein-Barr virus; HR, hazard ratio; IMRT, intensitymodulated radiotherapy; MRI, magnetic resonance imaging; NPC, nasopharyngeal carcinoma; OS, overall survival; PET/CT, [18F] fluorodeoxy glucose positron emission tomography and computed tomography. ⇑ Corresponding author at: Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 Dongfeng East Road, Guangzhou 510060, China. E-mail address: [email protected] (F.-Y. Xie). 1 Co-first authors
Proper classification and staging of cancer is essential for the physician to assign proper treatment, evaluate results of management and clinical trials, and to serve as the standard for local, regional and international reporting on cancer incidence and outcome. Since the publication of the 7th AJCC staging system for nasopharyngeal carcinoma (NPC) in 2009 [1], proposals emerged constantly from validation in different institutions with divergent imaging equipment and treatment schedules. The main controversial issues focused on (1) the proper classification of oropharynx and nasal fossa [2–5], medial and lateral pterygoid muscles [6,7] and paranasal sinus [8], (2) the potential significance of
http://dx.doi.org/10.1016/j.oraloncology.2017.07.011 1368-8375/Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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prevertebral muscles involvement [9,10], (3) the uniform application of anatomic nodal levels [11–13], (4) the prognostic value of nodal characteristics, such as nodal necrosis [12,14] and extranodal neoplastic spread [12,13], (5) the optimal cutoff point of nodal size [15], and (6) the possible simplification of current staging system [16–18]. Several proposed staging systems were thus composed from Hong Kong [16], Guangzhou [4], Guangxi [17] and Fujian [10], considering one or more above issues. For T-classification, the involvement of medial and lateral pterygoid muscles were moved out of the most advanced group in the four proposed staging systems. The proposed staging system from Guangzhou [4] suggested upstaging of the involvement of oropharynx or nasal cavity from T1 to T2. Specifically, the proposed staging system from Fujian [10] for the first time defined the involvement of prevertebral muscles as T2. Besides, the proposed staging systems from Hong Kong [16] and Guangxi [17] both merged adjacent T-classification groups for simplification. As for N-classification, the proposed staging system from Guangzhou [4] adopted the criteria of the 2008 Chinese staging system for NPC [19], which relied on nodal level and nodal characteristics extracted from images. And the proposed staging system from Fujian [10] replaced supraclavicular fossa by lower neck. No other essential changes existed. Recently, the proposed staging system from Fujian [10] has been adopted as the 8th AJCC staging system for NPC [20]. In this study, we attempted to compare the 7th [1] and 8th [20] AJCC staging systems and the proposed staging systems from Hong Kong [16], Guangzhou [4], and Guangxi [17] in a cohort of patients who were staged with magnetic resonance imaging (MRI) and irradiated by advanced intensity-modulated radiotherapy (IMRT). Materials and methods Patient’s eligibility This study was approved by the Sun Yat-sen University Cancer Center Institutional Review Board (No. B2016-060), and individual informed consent was waived given the anonymous analysis of routine data. All clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki. A total of 899 patients were finally enrolled. The following inclusion criteria were used: (1) newly diagnosed with nonkeratinizing NPC and treatment naïve patients; (2) scanned by MRI with a 1.5-Telsa system and contrast from calvaria vertex to clavicles before treatment; (3) confirmed no distant metastasis before treatment; (4) restaging was possible; (5) irradiated with IMRT between November 5, 2002 and May 27, 2010; and (6) free from any chemotherapy, or administrated with concurrent chemotherapy alone, induction plus concurrent chemotherapy, or concurrent plus adjuvant chemotherapy. The exclusion criteria were as follows: (1) receiving anticancer therapy elsewhere prior to the diagnosis in our hospital; (2) pregnancy or lactation; (3) diagnosed with other sort of cancer before or during the treatment, or during the follow-up; and (4) loss of follow up within 6 months from treatment. Staging assessment MRI of the nasopharynx and neck was performed for all patients to assess T-classification and N-classification. Chest radiography or computed tomography (CT), abdominal sonography or CT, and whole-body bone scan were used to detect distant metastasis. Two radiologists independently evaluated the MRI images, complying with the review by King et al. [21]. Two clinicians specializing in nasopharyngeal carcinoma separately restaged according to
the criteria of the 7th [1] and 8th [20] AJCC staging systems, and the proposed staging systems from [16], Guangzhou [4], and Guangxi [17] (Table 1). Any disagreements were resolved by consensus.
Treatment The cumulative radiation doses were 66 Gy or greater to the primary tumor, 60 Gy or greater to the involved neck area and 50 Gy or greater to potential sites of local infiltration and bilateral cervical lymphatics in 30–33 fractions. Further information of IMRT had been detailed previously [22]. Concurrent chemotherapy regimen was cisplatin/nedaplatin given weekly for up to seven cycles or every three weeks for two to three cycles. Induction chemotherapy regimen was docetaxel/paclitaxel plus cisplatin/nedaplatin, or cisplatin/nedaplatin plus fluorouracil, or docetaxel/paclitaxel plus cisplatin/nedaplatin plus fluorouracil given every three weeks for two to three cycles. Adjuvant chemotherapy regimen was cisplatin/ nedaplatin plus fluorouracil administrated every three weeks for two to three cycles.
Follow up Patients were observed at least once every three months during the first three years and every six months thereafter. Detailed history and physical examination were performed at each follow-up visit. Nasopharyngescopy with or without biopsy, MRI of the nasopharynx and neck, chest radiography or computed tomography (CT), abdominal sonography or CT, whole-body bone scan or [18F] fluorodeoxy glucose positron emission tomography and computed tomography (PET/CT) were performed to detect possible locoregional relapse and/or distant metastasis. Salvage treatment including reirradiation, surgery and/or chemotherapy was delivered to patients with confirmed relapse, distant metastasis or persistent disease.
Statistical analysis Primary endpoint was overall survival (OS), calculated from the date of treatment to death from any cause or the last follow-up visit; other endpoints included distant failure-free survival (DFFS, time to distant metastasis), local failure-free survival (LFFS, time to local persistence or relapse), regional failure-free survival (RFFS, time to nodal persistence or relapse), and locoregional failure-free survival (LRFFS, time to local and/or nodal persistence or relapse). Survival by T-classification, N-classification and stage group of each staging system was assessed by Kaplan-Meier method and log-rank test. Hazard ratio (HR) with 95% confidence interval (CI) adjusting for age (continuous), sex (male/female), pathology (nonkeratinizing differentiated/nonkeratinizing undifferentiated) and chemotherapy (none/concurrent/induction plus concurrent/ concurrent plus adjuvant) was calculated using backward Cox regression model or Cox regression model with time-dependent covariates if the proportional hazards assumption did not hold on the basis of Schoenfeld residuals test. Besides, the discrimination performance was evaluated by Harrell’s concordance index (C-index) [23]. It is generally accepted that a higher C-index suggests a greater ability to discriminate the outcomes with the model. Statistical analyses were performed using Stata version 14.0 and R version 3.3.1. Two-sided P < 0.05 was considered to be significantly different.
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P.-Y. OuYang et al. / Oral Oncology 72 (2017) 65–72 Table 1 Criteria of the 7th and 8th edition of AJCC staging system and proposed staging systems from Hong Kong, Guangzhou and Guangxi. The 7th AJCC
The 8th AJCCy
Hong Kong
Guangzhou
Guangxi
T-classification T1: Nasopharynx, oropharynx or nasal cavity
T-classification T1. Nasopharynx, oropharynx, nasal fossa
T-classification T1: Nasopharynx
T2: Parapharyneal extension
T2. Parapharyngeal extension, prevertebral, medial and lateral pterygoid muscles
T-classification T1: Nasopharynx, oropharynx, nasal fossa, parapharyngeal extension, prevertebral, medial and lateral pterygoid muscles T2: Bony structure, paranasal sinuses
T-classification T1: Nasopharynx, oropharynx or nasal cavity, parapharyneal extension, bony structures and/or paranasal sinuses T2: Intracranial extension and/or cranial nerves, hypopharynx, orbit, or infratemporal fossa/masticatory space*
T3: Bony structures and/or paranasal sinuses
T3. Bony structure (skull base, cervical vertebra), paranasal sinuses
T3: Intracranial extension, cranial nerve, hypopharynx, orbit, infratemporal fossa (masticatory space)
T3: Bony structures, paranasal sinuses
T4: Intracranial extension and/or cranial nerves, hypopharynx, orbit, or infratemporal fossa/masticatory space*
T4. Intracranial extension, cranial nerve, hypopharynx, orbit, involvement beyond the lateral surface of lateral pterygoid muscle, parotid gland)
N-classification§ N0: None N1: Unilateral cervical, and/ or unilateral or bilateral retropharyngeal node(s), 6 cm, above the supraclavicular fossa N2: Bilateral cervical node (s), 6 cm, above the supraclavicular fossa N3a: > 6 cm N3b: In supraclavicular fossa
N-classification§ N0: None N1. Retropharyngeal (regardless of laterality); Cervical: unilateral, 6 cm, and above caudal border of cricoid cartilage
N-classification# N0: None N1a: Unilateral cervical, uni/ bi-lateral retropharyngeal, 6 cm, above supraclavicular fossa
N-classification§ N0: None N1: Unilateral or bilateral retropharyngeal node(s), unilateral level Ib, II, III, and Va involvement, and 3 cm
N2. Cervical: bilateral, 6 cm, and above caudal border of cricoid cartilage N3. > 6 cm and/or below caudal border of cricoid cartilage (regardless of laterality)
N1b: bilateral cervical node, 6 cm, above supraclavicular fossa N2:>6 cm/supraclavicular fossa
N2: Bilateral level Ib, II, III, and Va involvement, or >3 cm, or with extranodal neoplastic spread N3: Level IV, Vb involvement
Stage group I: T1N0M0 II: T1N1M0, T2N0-1M0 III: T1-2N2M0, T3N0-2M0 IVa: T4N0-2M0 IVb: Any T N3M0 IVc: Any T Any N M1
Stage group I: T1N0M0 II: T1N1M0, T2N0-N1M0 III: T1-2N2M0, T3N0-2M0 IVa: T4 or N3 M0 IVb: Any T Any N M1
Stage group I: T1N0–N1bM0 II: T2N0–N1bM0 III: T3 or N2M0 IV: Any T Any N M1
Stage group I: T1N0M0 II: T1N1M0, T2N0-1M0 III: T1-2N2M0, T3N0-2M0 IVa: T1-3N3M0, T4N0-3M0 IVb: Any T Any N M1
T2: Oropharynx, nasal cavity, parapharyneal extension, medial and lateral pterygoid muscles
T4: Intracranial extension and/or cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticatory space excluding medial and lateral pterygoid muscles N-classification§ N0: None N1: Unilateral cervical, and/ or unilateral or bilateral retropharyngeal node(s), 6 cm, above the supraclavicular fossa N2: Bilateral cervical node (s), 6 cm, above the supraclavicular fossa N3:>6 cm/supraclavicular fossa Stage group I: T1N0M0 II: T1N1-2M0, T2N0M0 III: T2N1-2M0 IVa: T1-2N3M0 IVb: Any T Any N M1
*
Masticator space primarily consists of the muscles of mastication. Anatomically, the superficial layer of the deep cervical fascia splits to enclose the muscles of mastication to enclose this space. These muscles are the medial and lateral pterygoid, masseter, and temporalis. The nodal size was based on the maximum dimension in any direction. # The nodal size was measured in cross-sectional maximum dimension. y The same as the proposed staging system from Fujian by Pan et al. §
Results Patients Overall, 899 patients were included, of which 75.8% were male and 96.0% were diagnosed with nonkeratinizing undifferentiated NPC. The median age were 45 years old. All patients were irradiated with IMRT. Chemotherapy was administered to 76.9% of patients, including concurrent chemotherapy (49.5%), induction followed by concurrent chemotherapy (19.9%) and concurrent plus adjuvant chemotherapy (7.5%). (Table 2). With a median follow up of 88 months (range, 3–156 months), 6.7% of patients experienced local failure, 3.1% of patients had regional failure, 8.9% of patients suffered from locoregional failure, 12.8% of patients had distant failure, and 18.1% of patients died. Overall, the 7-year survival rates were as followed: OS 82.84%, DFFS 86.87%, LFFS 92.89%, RFFS 96.74%, and LRFFS 90.51%. T-classification According to the 7th AJCC staging system [1], the distribution of T-classification was as follows: 16.1% of T1, 21.2% of T2, 36.7% of T3
Table 2 Characteristics of 899 patients. Age, median (range)
45 (13–84)
Sex, No. (%) Male Female
681 (75.8) 218 (24.2)
Histology, No. (%) Nonkeratinizing differentiated Nonkeratinizing undifferentiated
36 (4.0) 863 (96.0)
Chemotherapy, No. (%) None Concurrent Induction + concurrent Concurrent + adjuvant
208 (23.1) 445 (49.5) 179 (19.9) 67 (7.5)
and 25.9% of T4. Patients classified as T3 had lower 7-year OS rate than those categorized as T2, but this difference reached no statistical significance (P = 0.089). (Fig. 1A). When restaged per the 8th AJCC staging system [20], 16.1% of patients remained to be T1, and 22.8%, 45.1% and 16.0% were retrospectively diagnosed with disease of T2, T3 and T4. The 8th AJCC led to significant stratification across T-classification (P 0.031). (Fig. 1B). As proposed by
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Fig. 1. Overall survival curves by T-classification of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
the study from Hong Kong [16], 38.9%, 45.1% and 16.0% of patients were classified as T1, T2 and T3, respectively. The simplified T-classification resulted in bigger disparity gap of OS rates (P < 0.001). (Fig. 1C). When restaged per suggestions from Guangzhou [4], 15.0% had T1 disease, 23.9% had T2 disease, 45.1% had T3 disease and 16.0% had T4 disease. The newly distribution of T-classification contributed to excellent stratification (P 0.027). (Fig. 1D). In addition, following the proposed staging system from Guangxi [17], all patients were separated to T1 (74.1%) and T2 (25.9%). The simplified T-classification was excellent in stratifying patients (P < 0.001). (Fig. 1E). The 7th AJCC T-classification showed moderate power in predicting OS with a C-index of 0.6386 (95% CI 0.6002–0.6771), while the 8th AJCC T-classification achieved a higher C-index 0.6451 (95%
CI 0.6075–0.6826). The proposal from Hong Kong (C-index 0.6376, 95% CI 0.5991–0.6761) and Guangxi (C-index 0.5889, 95% CI 0.5510–0.6268) both lowered the discrimination power, but the suggestion from Guangzhou led to an improvement in performance with a C-index of 0.6454 (95% CI, 0.6081–0.6827). (Table 3). T-classification of the 7th and 8th AJCC, and all the proposed staging systems showed high prognostic significance with adjustment for age, sex, pathology and chemotherapy (P < 0.001). (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 1A–E, Table 3). In terms of LFFS (Supplementary Fig. 1F,J), only proposals from Hong Kong [16] and Guangxi [17] led to great separation, while the suggested staging system from Guangzhou [4] had the biggest C-index of discrimination (Table 3).
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P.-Y. OuYang et al. / Oral Oncology 72 (2017) 65–72 Table 3 C-index of each edition of staging system. The 7th AJCC
The 8th AJCC
Hong Kong
Guangzhou
Guangxi
T-classification Overall survival Distant failure-free survival Local failure-free survival
0.6386 (0.6002–0.6771) 0.6286 (0.5849–0.6724) 0.6559 (0.5909–0.7209)
0.6451 (0.6075–0.6826) 0.6399 (0.5968–0.6830) 0.6663 (0.6015–0.7311)
0.6376 (0.5991–0.6761) 0.6306 (0.5857–0.6754) 0.6667 (0.6027–0.7306)
0.6454 (0.6081–0.6827) 0.6406 (0.5976–0.6835) 0.6689 (0.6053–0.7325)
0.5889 (0.5510–0.6268) 0.5730 (0.5289–0.6171) 0.6215 (0.5582–0.6847)
N-classification Overall survival Distant failure-free survival Regional failure-free survival
0.6179 (0.5779–0.6579) 0.6346 (0.5899–0.6794) 0.5930 (0.5093–0.6767)
0.6235 (0.5833–0.6636) 0.6452 (0.5998–0.6907) 0.6265 (0.5374–0.7157)
0.6175 (0.5777–0.6574) 0.6350 (0.5901–0.6798) 0.5927 (0.5092–0.6761)
0.6444 (0.6039–0.6849) 0.6540 (0.6079–0.7001) 0.6281 (0.5373–0.7188)
0.6175 (0.5777–0.6574) 0.6350 (0.5901–0.6798) 0.5927 (0.5092–0.6761)
Stage group Overall survival Distant failure-free survival Locoregional failure-free survival
0.6766 (0.6384–0.7149) 0.6552 (0.6091–0.7012) 0.6123 (0.5564–0.6682)
0.6791 (0.6436–0.7147) 0.6703 (0.6280–0.7126) 0.6344 (0.5799–0.6889)
0.6765 (0.6380–0.7149) 0.6615 (0.6159–0.7072) 0.6124 (0.5529–0.6719)
0.6839 (0.6489–0.7189) 0.6724 (0.6304–0.7145) 0.6369 (0.5823–0.6915)
0.6688 (0.6311–0.7065) 0.6627 (0.6194–0.7060) 0.5808 (0.5200–0.6415)
N-classification Respectively, 21.1%, 51.5%, 22.4%, 1.8% and 3.2% of patients were staged as N0, N1, N2, N3a and N3b based on the 7th AJCC staging system. Significant disparities in OS rate were observed across N-classification, except the comparison of N2 with N1 (P = 0.857) and N3a with N3b (P = 0.445). (Fig. 2A). In the 8th AJCC staging system [20], supraclavicular fossa was replaced by the lower neck, which migrated some patients with N1 or N2 to N3 (21.1% as N0, 49.4% as N1, 20.1% as N2 and 9.3% as N3). But the issue of inseparable OS curves between N2 and N1 was remained (P = 0.777). (Fig. 2B). The proposal for N-classification from Hong Kong [16] actually made minimal stage migration (21.1% of N0, 51.5% of N1a, 22.4% of N1b and 5.0% of N2). Thereby N1a remained similar to N1b in OS as expected (P = 0.857). (Fig. 2C). Previously, the study from Guangzhou suggested the utilization of the N-classification criteria defined in the Chinese 2008 staging system [4]. As presented in Fig. 2D, 21.1%, 42.3%, 27.9% and 8.7% of patients were staged as N0, N1, N2 and N3, retrospectively; patients were more likely to be separated by OS differences, although N2 was marginally significant inferior to N1 (P = 0.096). The study from Guangxi [17] just advised to merge N3a and N3b to N3, so the survival separation by N-classification and discrimination power was totally the same as Hong Kong’s proposal [16] (Fig. 2E). The C-index of 0.6179 (95% CI 0.5779–0.6579) indicated acceptable discrimination performance in predicting OS using the 7th AJCC; excitingly, the 8th AJCC achieved a bit improvement in C-index (0.6235, 95% CI 0.5833–0.6636). The proposed staging system from Hong Kong and Guangxi similarly showed smaller C-index of 0.6175 (95% CI 0.5777–0.6574). But the suggested N-classification criteria of Guangzhou led to the highest C-index of 0.6444 (95% CI 0.6039–0.6849). (Table 3). N-classification of all staging systems showed good prognostic value (P 0.037) in multivariate analysis by adjusting for age, sex, pathology and chemotherapy. (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 2A–E, Table 3). In terms of RFFS, all the staging systems showed poor separation (Supplementary Fig. 2F,J), although the suggested staging system from Guangzhou had a slightly improved discrimination ability with the highest C-index (Table 3).
Stage group Overall, 6.9% patients had stage I disease and 21.2%, 42.3%, 24.6% and 5.0% patients had stage II, III, IVa and IVb disease per the 7th AJCC staging system, respectively. OS was well segregated between adjacent stage group, except for insignificant differences between I and II (P = 0.147), II and III (P = 0.092). (Fig. 3A). If staged by the 8th AJCC [20], the fresh distribution of stage groups was as
follows: 6.9% of stage I, 21.4% of stage II, 47.2% of stage III and 24.6% of stage IVa. The 8th AJCC failed to improve the insignificant differences in separation between stage I and II (P = 0.207) as observed in the 7th AJCC. (Fig. 3B). When patients were restaged by the proposed staging system from Hong Kong [16], 37.2% had stage I disease, 42.2% had stage II disease and 20.7% had III stage disease. OS was perfectly separated across stage groups (P 0.001). (Fig. 3C). In accordance with the proposed staging system from Guangzhou [4], 6.7%, 19.9%, 49.5% and 23.9% patients had stage I, II, III and IVa disease. Similar to the 7th AJCC, stage I and II disease did not significantly differ in OS (P = 0.322), but the other stage groups had quite different OS rates (P 0.024). (Fig. 3D). Following the advice from Guangxi [17], 17.5%, 56.6%, 20.9% and 5.0% were respectively classified as stage I, II, III and IVa. OS rates of its stage groups were different from each other (P 0.015). (Fig. 3E). The 7th AJCC stage group showed good discrimination with a Cindex of 0.6766 (95% CI 0.6384–0.7149). The C-index (0.6791, 95% CI 0.6436–0.7147) of the 8th AJCC stage group was improved a little when compared to the 7th AJCC, but it was smaller than that of the proposed staging system from Guangzhou (C-index 0.6839, 95% CI 0.6489–0.7189). Proposals from Hong Kong and Guangxi both slightly dropped the discrimination performance with smaller C-index (0.6765, 95% CI 0.6380–0.7149; 0.6688, 95% CI 0.6311– 0.7065; respectively). (Table 3). Stage group of each staging system played the most important role in predicting OS after accounting for age, sex, pathology and chemotherapy (P 0.001). (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 3A–E, Table 3). In terms of LRFFS, all the suggested staging systems, except the one from Guangxi [17], enhanced the discrimination ability (Supplementary Fig. 3F,J) in comparison with the 7th AJCC, but made no significant improvement in separation (Table 3).
Discussion This study for the first time directly compared the 7th and 8th AJCC staging system and other proposed staging systems from Hong Kong, Guangzhou, and Guangxi, not only the separation ability across adjacent classification groups but also the discrimination ability in predicting treatment outcomes. As a result, the 8th AJCC staging system improved both separation and discrimination abilities compared with the 7th AJCC, but the proposed staging system from Guangzhou [4] seemed to perform better. For T-classification, the 8th AJCC and all the proposed staging systems showed slightly better separation while T3 and T2 by the 7th AJCC had similar 7-year OS and DFFS rates. Considering the relative good prognosis of the involvement of medial and lateral pterygoid muscles as observed in the study by Sze et al. [7], the principal alteration of down-staging them from T4 in the 7th
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Fig. 2. Overall survival curves by N-classification of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
AJCC to T2 in the 8th AJCC [20] and the suggested staging system from Guangzhou [4] exactly widened the survival difference with T3. This well explained why the 8th AJCC [20] and the proposed staging system from Guangzhou [4] both had better separation and discrimination abilities than the 7th AJCC staging system. Of note, as supported by the report from Low et al. [3], upstaging of the involvement of oropharynx or nasal cavity to T2 was again suggested in the study from Guangzhou [4] by comparison of the 6th and the 7th AJCC staging system. Consequently, this maybe exactly explained why the C-index of the T-classification of the proposed staging system from Guangzhou [4] was larger than that of the 8th AJCC [20], albeit that separation ability in survival of T1 and T2 was still similar. Certainly, further investigation is warranted given that only 10 patients was upstaged as a result and the increase of C-index was subtle. In addition to the down-staging
of the involvement of medial and lateral pterygoid muscles, T1 and T2 were merged as well in the staging system from Hong Kong [16], so the according proposed staging system achieved wonderful separation. Similarly, T-classification of the staging system from Guangxi [17] was extremely simplified by merging T1, T2 and T3 to T1, and renaming T4 as T2, which unsurprisingly separated well between each other. But unfortunately, both simplification approaches from Hong Kong [16] and Guangxi [17] lowered the discrimination power in predicting OS. As for LFFS, only the extreme simplification of the staging systems from Hong Kong [16] and Guangxi [17] resulted in significant improvement in separation, but the staging system from Guangzhou [4] showed better discrimination performance with the highest C-index. For N-classification, proposals from Hong Kong [16] and Guangxi [17] made no intrinsic changes to the 7th AJCC staging
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Fig. 3. Overall survival curves by stage group of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
system. The 8th AJCC [20] only replaced supraclavicular fossa by lower neck, similar to level IV and Vb. But as what found in the original analysis from Fujian [10], the present external validation also indicated that the 8th AJCC had no improvement in separation or discrimination when compared to the 7th AJCC. Along with bilateral cervical nodes, the suggested N2 criteria from Guangzhou [4] included nodal level, nodal size and extranodal neoplastic spread; N3 was defined as enlarged lymph nodes in level IV and Vb. Application of more precise and sufficient information from images accounted for its considerable advantage in separation and discrimination, especially for OS and DFFS. Although the weakness of inseparable OS and DFFS curves of N2 and N1 and close RFFS rates between N0, N1 and N2 were retained, the suggested staging system from Guangzhou was more likely to achieve improvement. The result of a prior study [24] highly supported the consequence.
Based on the slightly improved T-classification and N-classification, stage group of the suggested staging system from Guangzhou [4] seemed to be of higher prognostic value. Further improvement is awaited if bigger survival differences between stage I, II and III could happen. The presented data was derived from a renowned institution in an endemic area with expertise in diagnosing and treating this disease, which provided the accuracy in cancer staging and utility in treatment, especially the IMRT technique. Besides, 94.0% of survived patients were followed up for at least 5 years, which suggested the good longitudinal follow up rate. For the first time, we externally validated and head-to-head compared the 7th and 8th edition of AJCC staging systems and current proposals from different endemic areas. It was a limitation that the small number of patients with certain structure involvement, such as oropharynx or nasal cavity, provided relative low power to convince the
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differences between staging systems. Further investigations are definitely warranted. Chemotherapy approaches were not unified because of the retrospective design and the long time span between the first and the last included case. Besides, patients were treated according to the 6th edition of AJCC staging system. This could be the sources of bias and limitations for the correct interpretation of the results. The absolute improvement from the 7th AJCC to the 8th AJCC, or the net advantage of the proposed staging system from Guangzhou over other editions of staging systems was not considerable when taking account for the overlap of the 95% CI of C-index. But this is actually acceptable, on the premise of the global availability of a fundamental TNM staging system. For individualized prognostication, additional independent factors, such as tumor volume and Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) [25] may be promising. But the main questions are how to easily get the value of tumor size before patients receive induction chemotherapy, how to detect and address the collinearity between tumor size and T-classification, and how to analyze the value of tumor size. As EBV DNA is not routinely available in most of hospital, application is still limited. Moreover, no consensus on measuring EBV DNA, defining its reference value, or analyzing the value has been reached. Researchers are attempting to incorporate these prognostic factors into nomogram [26,27]. This appeared to be an encouraging direction [28], but further extensive validation is warranted. Conflict of interest None declared. Acknowledgments This work was partly supported by the Sun Yat-sen University Clinical Research 5010 Program (2015020), the National Natural Science Foundation of China (No. 81672665), the Sci-Tech Project Foundation of Guangdong Province (No. 2016A020215087) and the Natural Science Foundation of Guangdong Province (No. 2015A030313024). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.oraloncology. 2017.07.011. References [1] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009. [2] Mao YP, Xie FY, Liu LZ, Sun Y, Li L, Tang LL, et al. Re-evaluation of 6th edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement based on magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;73:1326–34. [3] Low JS, Heng DM, Wee JT. The question of T2a and N3a in the UICC/AJCC (1997) staging system for nasopharyngeal carcinoma. Clin Oncol (R Coll Radiol) 2004;16:581–3. [4] OuYang PY, Su Z, Ma XH, Mao YP, Liu MZ, Xie FY. Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. Br J Cancer 2013;109:2987–97. [5] Liu MZ, Tang LL, Zong JF, Huang Y, Sun Y, Mao YP, et al. Evaluation of sixth edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement. Int J Radiat Oncol Biol Phys 2008;70:1115–23.
[6] Zhang GY, Huang Y, Cai XY, Chen XP, Xu T, Wu J, et al. Prognostic value of grading masticator space involvement in nasopharyngeal carcinoma according to MR imaging findings. Radiology 2014;273:136–43. [7] Sze H, Chan LL, Ng WT, Hung AW, Lee MC, Chang AT, et al. Should all nasopharyngeal carcinoma with masticator space involvement be staged as T4? Oral Oncol 2014;50:1188–95. [8] Zhang Y, Peng H, Guo R, Li WF, Chen L, Liu X, et al. Should all nasopharyngeal carcinoma with paranasal sinus invasion be staged as T3 in the intensitymodulated radiotherapy era? a study of 1811 cases. J Cancer 2016;7:1353–9. [9] Zhou GQ, Mao YP, Chen L, Li WF, Liu LZ, Sun Y, et al. Prognostic value of prevertebral space involvement in nasopharyngeal carcinoma based on intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2012;82:1090–7. [10] Pan JJ, Ng WT, Zong JF, Chan LL, O’Sullivan B, Lin SJ, et al. Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer 2016;122:546–58. [11] Yue D, Xu YF, Zhang F, Lin L, Mao YP, Li WF, et al. Is replacement of the supraclavicular fossa with the lower level classification based on magnetic resonance imaging beneficial in nasopharyngeal carcinoma? Radiother Oncol 2014;113:108–14. [12] Li WF, Sun Y, Mao YP, Chen L, Chen YY, Chen M, et al. Proposed lymph node staging system using the international consensus guidelines for lymph node levels is predictive for nasopharyngeal carcinoma patients from endemic areas treated with intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:249–56. [13] Mao YP, Liang SB, Liu LZ, Chen Y, Sun Y, Tang LL, et al. The N staging system in nasopharyngeal carcinoma with radiation therapy oncology group guidelines for lymph node levels based on magnetic resonance imaging. Clin Cancer Res 2008;14:7497–503. [14] Lan M, Huang Y, Chen CY, Han F, Wu SX, Tian L, et al. Prognostic value of cervical nodal necrosis in nasopharyngeal carcinoma: analysis of 1800 patients with positive cervical nodal metastasis at MR imaging. Radiology 2015;276:536–44. [15] Chen L, Mao YP, Xie FY, Liu LZ, Sun Y, Tian L, et al. The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China. Radiother Oncol 2012;104:331–7. [16] Lee AWM, Ng WT, Chan LK, Chan OSH, Hung WM, Chan CC, et al. The strength/ weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement. Oral Oncol 2012;48:1007–13. [17] Kang M, Long J, Li G, Yan H, Feng G, Liu M, et al. A new staging system for nasopharyngeal carcinoma based on intensity-modulated radiation therapy: results of a prospective multicentric clinical study. Oncotarget 2016;7:15252–61. [18] Zong J, Lin S, Lin J, Tang L, Chen B, Zhang M, et al. Impact of intensitymodulated radiotherapy on nasopharyngeal carcinoma: validation of the 7th edition AJCC staging system. Oral Oncol 2015;52:254–9. [19] CCSNPC. Report on revision of the Chinese. Staging system for nasopharyngeal carcinoma. J Radiat Oncol 2013(2):233–40. [20] Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. [21] King AD. Magnetic resonance imaging staging of nasopharyngeal carcinoma in the head and neck. World J Radiol 2010;2:159. [22] 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;110:398–403. [23] Harrell FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361–87. [24] Pan J, Xu Y, Qiu S, Zong J, Guo Q, Zhang Y, et al. A comparison between the Chinese 2008 and the 7th edition AJCC staging systems for nasopharyngeal carcinoma. Am J Clin Oncol 2015;38:189–96. [25] Lu L, Li J, Zhao C, Xue W, Han F, Tao T, et al. Prognostic efficacy of combining tumor volume with Epstein-Barr virus DNA in patients treated with intensitymodulated radiotherapy for nasopharyngeal carcinoma. Oral Oncol 2016;60:18–24. [26] Pan JJ, Ng WT, Zong JF, Lee SW, Chol HC, Chan LL, et al. Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer 2016;122:3307-15. [27] Tang LQ, Li CF, Li J, Chen WH, Chen QY, Yuan LX, et al. 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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 Pu-Yun OuYang a,1, Yao Xiao a,1, Kai-Yun You b,1, Lu-Ning Zhang c, Xiao-Wen Lan a, Xiao-Min Zhang a, Fang-Yun Xie a,⇑ a Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China b Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China c Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
a r t i c l e
i n f o
Article history: Received 10 March 2017 Received in revised form 5 July 2017 Accepted 8 July 2017
Keywords: AJCC Cancer staging Intensity-modulated radiotherapy Nasopharyngeal carcinoma
a b s t r a c t Objectives: We aimed to validate and compare the 7th and 8th edition of AJCC staging systems for nonmetastatic nasopharyngeal carcinoma, and proposed staging systems from Hong Kong, Guangzhou, and Guangxi. Materials and methods: We retrospectively included 899 patients treated between November 5, 2002 and May 27, 2010. Separation and discrimination of each staging system in overall survival were primarily compared. Results: Compared with the 7th AJCC, the 8th AJCC and all proposed staging systems well separated across T-classification. T-classification from Guangzhou seemed to perform best in discrimination (C-index 0.6454), followed by the 8th AJCC (0.6451), the 7th AJCC (0.6386), Hong Kong (0.6376) and Guangxi (0.5889). For N-classification, no staging systems improved the weakness of the 7th AJCC in separating N2 and N1, except that suggestion from Guangzhou showed higher potential (P = 0.096). Besides, N-classification from Guangzhou had a C-index of 0.6444, larger than that of the 8th AJCC (0.6235), the 7th AJCC (0.6179), Hong Kong (0.6175) and Guangxi (0.6175). Accordingly, stage group of staging system from Guangzhou showed higher discrimination (C-index 0.6839), compared with the 8th AJCC (0.6791), the 7th AJCC (0.6766), Hong Kong (0.6765) and Guangxi (0.6688), despite that stage I and II remained inseparable (P = 0.322). Conclusions: The 8th AJCC staging system appeared to be better than the 7th AJCC. But the proposed staging system from Guangzhou was more likely to improve the separation and discrimination abilities. Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Abbreviations: AJCC, american joint committee on cancer; CI, confidence interval; C-index, concordance index; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, epstein-Barr virus; HR, hazard ratio; IMRT, intensitymodulated radiotherapy; MRI, magnetic resonance imaging; NPC, nasopharyngeal carcinoma; OS, overall survival; PET/CT, [18F] fluorodeoxy glucose positron emission tomography and computed tomography. ⇑ Corresponding author at: Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No. 651 Dongfeng East Road, Guangzhou 510060, China. E-mail address: [email protected] (F.-Y. Xie). 1 Co-first authors
Proper classification and staging of cancer is essential for the physician to assign proper treatment, evaluate results of management and clinical trials, and to serve as the standard for local, regional and international reporting on cancer incidence and outcome. Since the publication of the 7th AJCC staging system for nasopharyngeal carcinoma (NPC) in 2009 [1], proposals emerged constantly from validation in different institutions with divergent imaging equipment and treatment schedules. The main controversial issues focused on (1) the proper classification of oropharynx and nasal fossa [2–5], medial and lateral pterygoid muscles [6,7] and paranasal sinus [8], (2) the potential significance of
http://dx.doi.org/10.1016/j.oraloncology.2017.07.011 1368-8375/Ó 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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prevertebral muscles involvement [9,10], (3) the uniform application of anatomic nodal levels [11–13], (4) the prognostic value of nodal characteristics, such as nodal necrosis [12,14] and extranodal neoplastic spread [12,13], (5) the optimal cutoff point of nodal size [15], and (6) the possible simplification of current staging system [16–18]. Several proposed staging systems were thus composed from Hong Kong [16], Guangzhou [4], Guangxi [17] and Fujian [10], considering one or more above issues. For T-classification, the involvement of medial and lateral pterygoid muscles were moved out of the most advanced group in the four proposed staging systems. The proposed staging system from Guangzhou [4] suggested upstaging of the involvement of oropharynx or nasal cavity from T1 to T2. Specifically, the proposed staging system from Fujian [10] for the first time defined the involvement of prevertebral muscles as T2. Besides, the proposed staging systems from Hong Kong [16] and Guangxi [17] both merged adjacent T-classification groups for simplification. As for N-classification, the proposed staging system from Guangzhou [4] adopted the criteria of the 2008 Chinese staging system for NPC [19], which relied on nodal level and nodal characteristics extracted from images. And the proposed staging system from Fujian [10] replaced supraclavicular fossa by lower neck. No other essential changes existed. Recently, the proposed staging system from Fujian [10] has been adopted as the 8th AJCC staging system for NPC [20]. In this study, we attempted to compare the 7th [1] and 8th [20] AJCC staging systems and the proposed staging systems from Hong Kong [16], Guangzhou [4], and Guangxi [17] in a cohort of patients who were staged with magnetic resonance imaging (MRI) and irradiated by advanced intensity-modulated radiotherapy (IMRT). Materials and methods Patient’s eligibility This study was approved by the Sun Yat-sen University Cancer Center Institutional Review Board (No. B2016-060), and individual informed consent was waived given the anonymous analysis of routine data. All clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki. A total of 899 patients were finally enrolled. The following inclusion criteria were used: (1) newly diagnosed with nonkeratinizing NPC and treatment naïve patients; (2) scanned by MRI with a 1.5-Telsa system and contrast from calvaria vertex to clavicles before treatment; (3) confirmed no distant metastasis before treatment; (4) restaging was possible; (5) irradiated with IMRT between November 5, 2002 and May 27, 2010; and (6) free from any chemotherapy, or administrated with concurrent chemotherapy alone, induction plus concurrent chemotherapy, or concurrent plus adjuvant chemotherapy. The exclusion criteria were as follows: (1) receiving anticancer therapy elsewhere prior to the diagnosis in our hospital; (2) pregnancy or lactation; (3) diagnosed with other sort of cancer before or during the treatment, or during the follow-up; and (4) loss of follow up within 6 months from treatment. Staging assessment MRI of the nasopharynx and neck was performed for all patients to assess T-classification and N-classification. Chest radiography or computed tomography (CT), abdominal sonography or CT, and whole-body bone scan were used to detect distant metastasis. Two radiologists independently evaluated the MRI images, complying with the review by King et al. [21]. Two clinicians specializing in nasopharyngeal carcinoma separately restaged according to
the criteria of the 7th [1] and 8th [20] AJCC staging systems, and the proposed staging systems from [16], Guangzhou [4], and Guangxi [17] (Table 1). Any disagreements were resolved by consensus.
Treatment The cumulative radiation doses were 66 Gy or greater to the primary tumor, 60 Gy or greater to the involved neck area and 50 Gy or greater to potential sites of local infiltration and bilateral cervical lymphatics in 30–33 fractions. Further information of IMRT had been detailed previously [22]. Concurrent chemotherapy regimen was cisplatin/nedaplatin given weekly for up to seven cycles or every three weeks for two to three cycles. Induction chemotherapy regimen was docetaxel/paclitaxel plus cisplatin/nedaplatin, or cisplatin/nedaplatin plus fluorouracil, or docetaxel/paclitaxel plus cisplatin/nedaplatin plus fluorouracil given every three weeks for two to three cycles. Adjuvant chemotherapy regimen was cisplatin/ nedaplatin plus fluorouracil administrated every three weeks for two to three cycles.
Follow up Patients were observed at least once every three months during the first three years and every six months thereafter. Detailed history and physical examination were performed at each follow-up visit. Nasopharyngescopy with or without biopsy, MRI of the nasopharynx and neck, chest radiography or computed tomography (CT), abdominal sonography or CT, whole-body bone scan or [18F] fluorodeoxy glucose positron emission tomography and computed tomography (PET/CT) were performed to detect possible locoregional relapse and/or distant metastasis. Salvage treatment including reirradiation, surgery and/or chemotherapy was delivered to patients with confirmed relapse, distant metastasis or persistent disease.
Statistical analysis Primary endpoint was overall survival (OS), calculated from the date of treatment to death from any cause or the last follow-up visit; other endpoints included distant failure-free survival (DFFS, time to distant metastasis), local failure-free survival (LFFS, time to local persistence or relapse), regional failure-free survival (RFFS, time to nodal persistence or relapse), and locoregional failure-free survival (LRFFS, time to local and/or nodal persistence or relapse). Survival by T-classification, N-classification and stage group of each staging system was assessed by Kaplan-Meier method and log-rank test. Hazard ratio (HR) with 95% confidence interval (CI) adjusting for age (continuous), sex (male/female), pathology (nonkeratinizing differentiated/nonkeratinizing undifferentiated) and chemotherapy (none/concurrent/induction plus concurrent/ concurrent plus adjuvant) was calculated using backward Cox regression model or Cox regression model with time-dependent covariates if the proportional hazards assumption did not hold on the basis of Schoenfeld residuals test. Besides, the discrimination performance was evaluated by Harrell’s concordance index (C-index) [23]. It is generally accepted that a higher C-index suggests a greater ability to discriminate the outcomes with the model. Statistical analyses were performed using Stata version 14.0 and R version 3.3.1. Two-sided P < 0.05 was considered to be significantly different.
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P.-Y. OuYang et al. / Oral Oncology 72 (2017) 65–72 Table 1 Criteria of the 7th and 8th edition of AJCC staging system and proposed staging systems from Hong Kong, Guangzhou and Guangxi. The 7th AJCC
The 8th AJCCy
Hong Kong
Guangzhou
Guangxi
T-classification T1: Nasopharynx, oropharynx or nasal cavity
T-classification T1. Nasopharynx, oropharynx, nasal fossa
T-classification T1: Nasopharynx
T2: Parapharyneal extension
T2. Parapharyngeal extension, prevertebral, medial and lateral pterygoid muscles
T-classification T1: Nasopharynx, oropharynx, nasal fossa, parapharyngeal extension, prevertebral, medial and lateral pterygoid muscles T2: Bony structure, paranasal sinuses
T-classification T1: Nasopharynx, oropharynx or nasal cavity, parapharyneal extension, bony structures and/or paranasal sinuses T2: Intracranial extension and/or cranial nerves, hypopharynx, orbit, or infratemporal fossa/masticatory space*
T3: Bony structures and/or paranasal sinuses
T3. Bony structure (skull base, cervical vertebra), paranasal sinuses
T3: Intracranial extension, cranial nerve, hypopharynx, orbit, infratemporal fossa (masticatory space)
T3: Bony structures, paranasal sinuses
T4: Intracranial extension and/or cranial nerves, hypopharynx, orbit, or infratemporal fossa/masticatory space*
T4. Intracranial extension, cranial nerve, hypopharynx, orbit, involvement beyond the lateral surface of lateral pterygoid muscle, parotid gland)
N-classification§ N0: None N1: Unilateral cervical, and/ or unilateral or bilateral retropharyngeal node(s), 6 cm, above the supraclavicular fossa N2: Bilateral cervical node (s), 6 cm, above the supraclavicular fossa N3a: > 6 cm N3b: In supraclavicular fossa
N-classification§ N0: None N1. Retropharyngeal (regardless of laterality); Cervical: unilateral, 6 cm, and above caudal border of cricoid cartilage
N-classification# N0: None N1a: Unilateral cervical, uni/ bi-lateral retropharyngeal, 6 cm, above supraclavicular fossa
N-classification§ N0: None N1: Unilateral or bilateral retropharyngeal node(s), unilateral level Ib, II, III, and Va involvement, and 3 cm
N2. Cervical: bilateral, 6 cm, and above caudal border of cricoid cartilage N3. > 6 cm and/or below caudal border of cricoid cartilage (regardless of laterality)
N1b: bilateral cervical node, 6 cm, above supraclavicular fossa N2:>6 cm/supraclavicular fossa
N2: Bilateral level Ib, II, III, and Va involvement, or >3 cm, or with extranodal neoplastic spread N3: Level IV, Vb involvement
Stage group I: T1N0M0 II: T1N1M0, T2N0-1M0 III: T1-2N2M0, T3N0-2M0 IVa: T4N0-2M0 IVb: Any T N3M0 IVc: Any T Any N M1
Stage group I: T1N0M0 II: T1N1M0, T2N0-N1M0 III: T1-2N2M0, T3N0-2M0 IVa: T4 or N3 M0 IVb: Any T Any N M1
Stage group I: T1N0–N1bM0 II: T2N0–N1bM0 III: T3 or N2M0 IV: Any T Any N M1
Stage group I: T1N0M0 II: T1N1M0, T2N0-1M0 III: T1-2N2M0, T3N0-2M0 IVa: T1-3N3M0, T4N0-3M0 IVb: Any T Any N M1
T2: Oropharynx, nasal cavity, parapharyneal extension, medial and lateral pterygoid muscles
T4: Intracranial extension and/or cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticatory space excluding medial and lateral pterygoid muscles N-classification§ N0: None N1: Unilateral cervical, and/ or unilateral or bilateral retropharyngeal node(s), 6 cm, above the supraclavicular fossa N2: Bilateral cervical node (s), 6 cm, above the supraclavicular fossa N3:>6 cm/supraclavicular fossa Stage group I: T1N0M0 II: T1N1-2M0, T2N0M0 III: T2N1-2M0 IVa: T1-2N3M0 IVb: Any T Any N M1
*
Masticator space primarily consists of the muscles of mastication. Anatomically, the superficial layer of the deep cervical fascia splits to enclose the muscles of mastication to enclose this space. These muscles are the medial and lateral pterygoid, masseter, and temporalis. The nodal size was based on the maximum dimension in any direction. # The nodal size was measured in cross-sectional maximum dimension. y The same as the proposed staging system from Fujian by Pan et al. §
Results Patients Overall, 899 patients were included, of which 75.8% were male and 96.0% were diagnosed with nonkeratinizing undifferentiated NPC. The median age were 45 years old. All patients were irradiated with IMRT. Chemotherapy was administered to 76.9% of patients, including concurrent chemotherapy (49.5%), induction followed by concurrent chemotherapy (19.9%) and concurrent plus adjuvant chemotherapy (7.5%). (Table 2). With a median follow up of 88 months (range, 3–156 months), 6.7% of patients experienced local failure, 3.1% of patients had regional failure, 8.9% of patients suffered from locoregional failure, 12.8% of patients had distant failure, and 18.1% of patients died. Overall, the 7-year survival rates were as followed: OS 82.84%, DFFS 86.87%, LFFS 92.89%, RFFS 96.74%, and LRFFS 90.51%. T-classification According to the 7th AJCC staging system [1], the distribution of T-classification was as follows: 16.1% of T1, 21.2% of T2, 36.7% of T3
Table 2 Characteristics of 899 patients. Age, median (range)
45 (13–84)
Sex, No. (%) Male Female
681 (75.8) 218 (24.2)
Histology, No. (%) Nonkeratinizing differentiated Nonkeratinizing undifferentiated
36 (4.0) 863 (96.0)
Chemotherapy, No. (%) None Concurrent Induction + concurrent Concurrent + adjuvant
208 (23.1) 445 (49.5) 179 (19.9) 67 (7.5)
and 25.9% of T4. Patients classified as T3 had lower 7-year OS rate than those categorized as T2, but this difference reached no statistical significance (P = 0.089). (Fig. 1A). When restaged per the 8th AJCC staging system [20], 16.1% of patients remained to be T1, and 22.8%, 45.1% and 16.0% were retrospectively diagnosed with disease of T2, T3 and T4. The 8th AJCC led to significant stratification across T-classification (P 0.031). (Fig. 1B). As proposed by
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Fig. 1. Overall survival curves by T-classification of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
the study from Hong Kong [16], 38.9%, 45.1% and 16.0% of patients were classified as T1, T2 and T3, respectively. The simplified T-classification resulted in bigger disparity gap of OS rates (P < 0.001). (Fig. 1C). When restaged per suggestions from Guangzhou [4], 15.0% had T1 disease, 23.9% had T2 disease, 45.1% had T3 disease and 16.0% had T4 disease. The newly distribution of T-classification contributed to excellent stratification (P 0.027). (Fig. 1D). In addition, following the proposed staging system from Guangxi [17], all patients were separated to T1 (74.1%) and T2 (25.9%). The simplified T-classification was excellent in stratifying patients (P < 0.001). (Fig. 1E). The 7th AJCC T-classification showed moderate power in predicting OS with a C-index of 0.6386 (95% CI 0.6002–0.6771), while the 8th AJCC T-classification achieved a higher C-index 0.6451 (95%
CI 0.6075–0.6826). The proposal from Hong Kong (C-index 0.6376, 95% CI 0.5991–0.6761) and Guangxi (C-index 0.5889, 95% CI 0.5510–0.6268) both lowered the discrimination power, but the suggestion from Guangzhou led to an improvement in performance with a C-index of 0.6454 (95% CI, 0.6081–0.6827). (Table 3). T-classification of the 7th and 8th AJCC, and all the proposed staging systems showed high prognostic significance with adjustment for age, sex, pathology and chemotherapy (P < 0.001). (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 1A–E, Table 3). In terms of LFFS (Supplementary Fig. 1F,J), only proposals from Hong Kong [16] and Guangxi [17] led to great separation, while the suggested staging system from Guangzhou [4] had the biggest C-index of discrimination (Table 3).
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P.-Y. OuYang et al. / Oral Oncology 72 (2017) 65–72 Table 3 C-index of each edition of staging system. The 7th AJCC
The 8th AJCC
Hong Kong
Guangzhou
Guangxi
T-classification Overall survival Distant failure-free survival Local failure-free survival
0.6386 (0.6002–0.6771) 0.6286 (0.5849–0.6724) 0.6559 (0.5909–0.7209)
0.6451 (0.6075–0.6826) 0.6399 (0.5968–0.6830) 0.6663 (0.6015–0.7311)
0.6376 (0.5991–0.6761) 0.6306 (0.5857–0.6754) 0.6667 (0.6027–0.7306)
0.6454 (0.6081–0.6827) 0.6406 (0.5976–0.6835) 0.6689 (0.6053–0.7325)
0.5889 (0.5510–0.6268) 0.5730 (0.5289–0.6171) 0.6215 (0.5582–0.6847)
N-classification Overall survival Distant failure-free survival Regional failure-free survival
0.6179 (0.5779–0.6579) 0.6346 (0.5899–0.6794) 0.5930 (0.5093–0.6767)
0.6235 (0.5833–0.6636) 0.6452 (0.5998–0.6907) 0.6265 (0.5374–0.7157)
0.6175 (0.5777–0.6574) 0.6350 (0.5901–0.6798) 0.5927 (0.5092–0.6761)
0.6444 (0.6039–0.6849) 0.6540 (0.6079–0.7001) 0.6281 (0.5373–0.7188)
0.6175 (0.5777–0.6574) 0.6350 (0.5901–0.6798) 0.5927 (0.5092–0.6761)
Stage group Overall survival Distant failure-free survival Locoregional failure-free survival
0.6766 (0.6384–0.7149) 0.6552 (0.6091–0.7012) 0.6123 (0.5564–0.6682)
0.6791 (0.6436–0.7147) 0.6703 (0.6280–0.7126) 0.6344 (0.5799–0.6889)
0.6765 (0.6380–0.7149) 0.6615 (0.6159–0.7072) 0.6124 (0.5529–0.6719)
0.6839 (0.6489–0.7189) 0.6724 (0.6304–0.7145) 0.6369 (0.5823–0.6915)
0.6688 (0.6311–0.7065) 0.6627 (0.6194–0.7060) 0.5808 (0.5200–0.6415)
N-classification Respectively, 21.1%, 51.5%, 22.4%, 1.8% and 3.2% of patients were staged as N0, N1, N2, N3a and N3b based on the 7th AJCC staging system. Significant disparities in OS rate were observed across N-classification, except the comparison of N2 with N1 (P = 0.857) and N3a with N3b (P = 0.445). (Fig. 2A). In the 8th AJCC staging system [20], supraclavicular fossa was replaced by the lower neck, which migrated some patients with N1 or N2 to N3 (21.1% as N0, 49.4% as N1, 20.1% as N2 and 9.3% as N3). But the issue of inseparable OS curves between N2 and N1 was remained (P = 0.777). (Fig. 2B). The proposal for N-classification from Hong Kong [16] actually made minimal stage migration (21.1% of N0, 51.5% of N1a, 22.4% of N1b and 5.0% of N2). Thereby N1a remained similar to N1b in OS as expected (P = 0.857). (Fig. 2C). Previously, the study from Guangzhou suggested the utilization of the N-classification criteria defined in the Chinese 2008 staging system [4]. As presented in Fig. 2D, 21.1%, 42.3%, 27.9% and 8.7% of patients were staged as N0, N1, N2 and N3, retrospectively; patients were more likely to be separated by OS differences, although N2 was marginally significant inferior to N1 (P = 0.096). The study from Guangxi [17] just advised to merge N3a and N3b to N3, so the survival separation by N-classification and discrimination power was totally the same as Hong Kong’s proposal [16] (Fig. 2E). The C-index of 0.6179 (95% CI 0.5779–0.6579) indicated acceptable discrimination performance in predicting OS using the 7th AJCC; excitingly, the 8th AJCC achieved a bit improvement in C-index (0.6235, 95% CI 0.5833–0.6636). The proposed staging system from Hong Kong and Guangxi similarly showed smaller C-index of 0.6175 (95% CI 0.5777–0.6574). But the suggested N-classification criteria of Guangzhou led to the highest C-index of 0.6444 (95% CI 0.6039–0.6849). (Table 3). N-classification of all staging systems showed good prognostic value (P 0.037) in multivariate analysis by adjusting for age, sex, pathology and chemotherapy. (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 2A–E, Table 3). In terms of RFFS, all the staging systems showed poor separation (Supplementary Fig. 2F,J), although the suggested staging system from Guangzhou had a slightly improved discrimination ability with the highest C-index (Table 3).
Stage group Overall, 6.9% patients had stage I disease and 21.2%, 42.3%, 24.6% and 5.0% patients had stage II, III, IVa and IVb disease per the 7th AJCC staging system, respectively. OS was well segregated between adjacent stage group, except for insignificant differences between I and II (P = 0.147), II and III (P = 0.092). (Fig. 3A). If staged by the 8th AJCC [20], the fresh distribution of stage groups was as
follows: 6.9% of stage I, 21.4% of stage II, 47.2% of stage III and 24.6% of stage IVa. The 8th AJCC failed to improve the insignificant differences in separation between stage I and II (P = 0.207) as observed in the 7th AJCC. (Fig. 3B). When patients were restaged by the proposed staging system from Hong Kong [16], 37.2% had stage I disease, 42.2% had stage II disease and 20.7% had III stage disease. OS was perfectly separated across stage groups (P 0.001). (Fig. 3C). In accordance with the proposed staging system from Guangzhou [4], 6.7%, 19.9%, 49.5% and 23.9% patients had stage I, II, III and IVa disease. Similar to the 7th AJCC, stage I and II disease did not significantly differ in OS (P = 0.322), but the other stage groups had quite different OS rates (P 0.024). (Fig. 3D). Following the advice from Guangxi [17], 17.5%, 56.6%, 20.9% and 5.0% were respectively classified as stage I, II, III and IVa. OS rates of its stage groups were different from each other (P 0.015). (Fig. 3E). The 7th AJCC stage group showed good discrimination with a Cindex of 0.6766 (95% CI 0.6384–0.7149). The C-index (0.6791, 95% CI 0.6436–0.7147) of the 8th AJCC stage group was improved a little when compared to the 7th AJCC, but it was smaller than that of the proposed staging system from Guangzhou (C-index 0.6839, 95% CI 0.6489–0.7189). Proposals from Hong Kong and Guangxi both slightly dropped the discrimination performance with smaller C-index (0.6765, 95% CI 0.6380–0.7149; 0.6688, 95% CI 0.6311– 0.7065; respectively). (Table 3). Stage group of each staging system played the most important role in predicting OS after accounting for age, sex, pathology and chemotherapy (P 0.001). (Supplementary Table 1). Results were similar for DFFS (Supplementary Fig. 3A–E, Table 3). In terms of LRFFS, all the suggested staging systems, except the one from Guangxi [17], enhanced the discrimination ability (Supplementary Fig. 3F,J) in comparison with the 7th AJCC, but made no significant improvement in separation (Table 3).
Discussion This study for the first time directly compared the 7th and 8th AJCC staging system and other proposed staging systems from Hong Kong, Guangzhou, and Guangxi, not only the separation ability across adjacent classification groups but also the discrimination ability in predicting treatment outcomes. As a result, the 8th AJCC staging system improved both separation and discrimination abilities compared with the 7th AJCC, but the proposed staging system from Guangzhou [4] seemed to perform better. For T-classification, the 8th AJCC and all the proposed staging systems showed slightly better separation while T3 and T2 by the 7th AJCC had similar 7-year OS and DFFS rates. Considering the relative good prognosis of the involvement of medial and lateral pterygoid muscles as observed in the study by Sze et al. [7], the principal alteration of down-staging them from T4 in the 7th
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Fig. 2. Overall survival curves by N-classification of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
AJCC to T2 in the 8th AJCC [20] and the suggested staging system from Guangzhou [4] exactly widened the survival difference with T3. This well explained why the 8th AJCC [20] and the proposed staging system from Guangzhou [4] both had better separation and discrimination abilities than the 7th AJCC staging system. Of note, as supported by the report from Low et al. [3], upstaging of the involvement of oropharynx or nasal cavity to T2 was again suggested in the study from Guangzhou [4] by comparison of the 6th and the 7th AJCC staging system. Consequently, this maybe exactly explained why the C-index of the T-classification of the proposed staging system from Guangzhou [4] was larger than that of the 8th AJCC [20], albeit that separation ability in survival of T1 and T2 was still similar. Certainly, further investigation is warranted given that only 10 patients was upstaged as a result and the increase of C-index was subtle. In addition to the down-staging
of the involvement of medial and lateral pterygoid muscles, T1 and T2 were merged as well in the staging system from Hong Kong [16], so the according proposed staging system achieved wonderful separation. Similarly, T-classification of the staging system from Guangxi [17] was extremely simplified by merging T1, T2 and T3 to T1, and renaming T4 as T2, which unsurprisingly separated well between each other. But unfortunately, both simplification approaches from Hong Kong [16] and Guangxi [17] lowered the discrimination power in predicting OS. As for LFFS, only the extreme simplification of the staging systems from Hong Kong [16] and Guangxi [17] resulted in significant improvement in separation, but the staging system from Guangzhou [4] showed better discrimination performance with the highest C-index. For N-classification, proposals from Hong Kong [16] and Guangxi [17] made no intrinsic changes to the 7th AJCC staging
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Fig. 3. Overall survival curves by stage group of the 7th AJCC staging system (A), the 8th AJCC staging system (B), and the proposed staging system from Hong Kong (C), Guangzhou (D), and Guangxi (E).
system. The 8th AJCC [20] only replaced supraclavicular fossa by lower neck, similar to level IV and Vb. But as what found in the original analysis from Fujian [10], the present external validation also indicated that the 8th AJCC had no improvement in separation or discrimination when compared to the 7th AJCC. Along with bilateral cervical nodes, the suggested N2 criteria from Guangzhou [4] included nodal level, nodal size and extranodal neoplastic spread; N3 was defined as enlarged lymph nodes in level IV and Vb. Application of more precise and sufficient information from images accounted for its considerable advantage in separation and discrimination, especially for OS and DFFS. Although the weakness of inseparable OS and DFFS curves of N2 and N1 and close RFFS rates between N0, N1 and N2 were retained, the suggested staging system from Guangzhou was more likely to achieve improvement. The result of a prior study [24] highly supported the consequence.
Based on the slightly improved T-classification and N-classification, stage group of the suggested staging system from Guangzhou [4] seemed to be of higher prognostic value. Further improvement is awaited if bigger survival differences between stage I, II and III could happen. The presented data was derived from a renowned institution in an endemic area with expertise in diagnosing and treating this disease, which provided the accuracy in cancer staging and utility in treatment, especially the IMRT technique. Besides, 94.0% of survived patients were followed up for at least 5 years, which suggested the good longitudinal follow up rate. For the first time, we externally validated and head-to-head compared the 7th and 8th edition of AJCC staging systems and current proposals from different endemic areas. It was a limitation that the small number of patients with certain structure involvement, such as oropharynx or nasal cavity, provided relative low power to convince the
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differences between staging systems. Further investigations are definitely warranted. Chemotherapy approaches were not unified because of the retrospective design and the long time span between the first and the last included case. Besides, patients were treated according to the 6th edition of AJCC staging system. This could be the sources of bias and limitations for the correct interpretation of the results. The absolute improvement from the 7th AJCC to the 8th AJCC, or the net advantage of the proposed staging system from Guangzhou over other editions of staging systems was not considerable when taking account for the overlap of the 95% CI of C-index. But this is actually acceptable, on the premise of the global availability of a fundamental TNM staging system. For individualized prognostication, additional independent factors, such as tumor volume and Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) [25] may be promising. But the main questions are how to easily get the value of tumor size before patients receive induction chemotherapy, how to detect and address the collinearity between tumor size and T-classification, and how to analyze the value of tumor size. As EBV DNA is not routinely available in most of hospital, application is still limited. Moreover, no consensus on measuring EBV DNA, defining its reference value, or analyzing the value has been reached. Researchers are attempting to incorporate these prognostic factors into nomogram [26,27]. This appeared to be an encouraging direction [28], but further extensive validation is warranted. Conflict of interest None declared. Acknowledgments This work was partly supported by the Sun Yat-sen University Clinical Research 5010 Program (2015020), the National Natural Science Foundation of China (No. 81672665), the Sci-Tech Project Foundation of Guangdong Province (No. 2016A020215087) and the Natural Science Foundation of Guangdong Province (No. 2015A030313024). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.oraloncology. 2017.07.011. References [1] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009. [2] Mao YP, Xie FY, Liu LZ, Sun Y, Li L, Tang LL, et al. Re-evaluation of 6th edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement based on magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;73:1326–34. [3] Low JS, Heng DM, Wee JT. The question of T2a and N3a in the UICC/AJCC (1997) staging system for nasopharyngeal carcinoma. Clin Oncol (R Coll Radiol) 2004;16:581–3. [4] OuYang PY, Su Z, Ma XH, Mao YP, Liu MZ, Xie FY. Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. Br J Cancer 2013;109:2987–97. [5] Liu MZ, Tang LL, Zong JF, Huang Y, Sun Y, Mao YP, et al. Evaluation of sixth edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement. Int J Radiat Oncol Biol Phys 2008;70:1115–23.
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