Comparing the 7th and 8th editions of UICC/AJCC staging system for nasopharyngeal carcinoma in the IMRT era

A total of 300 patients with newly diagnosed, pathologically proven, non-distant metastatic NPC who were treated with SIB-IMRT at West China Hospital between February 2009 and December 2013 were included in our study. Table 1 summarizes the characteristics of all the patients. All the patients had no tumor history and did not receive any radiotherapy previously. The number of men was 215 (71.7%), whereas the number of women was 85 (28.3%). Median age was 47 years (range, 11–81 years). All patients received the following pretreatment evaluations: recording of completed patient history, haematological and biochemical profiles, physical examination, flexible fiberoptic endoscopic examination, MRI of the nasopharynx and neck, abdominal sonography, chest radiography or CT, and whole-body bone scan. All the patients were reclassified according to the 7th and 8th editions of the UICC/AJCC staging system by 2 clinicians. A third clinician was consulted to reach a consensus in case of disagreement.

All patients completed radical SIB-IMRT at the Tumor Center of West China hospital according to the guidelines for RT based on reduced volume IMRT [14]. RT is carried out in accordance with the guidelines of NCCN radiotherapy for NPC. The primary nasopharynx gross tumor volume (GTVnx) and metastatic cervical lymph nodes (GTVnd) included all gross diseases observed in the MRI scan (radiotherapy physician mainly based on the fusion of contrast-enhanced MRI and planning CT after induction chemotherapy, also referred to contrast-enhanced MRI and planning CT before induction). CTV-1 was defined as a high-risk region that included the primary nasopharynx tumor volume with a 5–10 mm margin and the entire nasopharynx. CTV-2 was defined as potentially involved region that included the skull base, pterygopalatine fossa, pterygoid processes, anterior third of the clivus and cervical vertebra, inferior sphenoid sinus and cavernous sinus, nasopharyngeal cavity (including the posterior region of the nasal cavity), maxillary sinus (5 mm anterior to the maxillary mucosa and posterior nares), posterior ethmoid sinus, parapharyngeal space, and bilateral retropharyngeal lymph nodal regions. The clinical target volume of the neck node regions (CTV-N) covered Levels II, III, IV, and V, prophylactic coverage of ipsilateral Level Ib lymph node level in CTVn2 (intermediate prophylactic dose) if there is: disease involvement of the submandibular gland or involvement of structures that drain to level Ib as the first echelon site (namely the oral cavity, anterior half of nasal cavity) or involvement of level II LNs with extracapsular extension. According to the recommendation of the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer delineation consensus. SIB-IMRT was administered for 1 month after the patients completed induction chemotherapy. The radiation doses delivered were 70 Gy to GTVnx and GTVnd in 33 fractions at 2.12 Gy per fraction, 60 Gy at 1.81Gy per fraction to CTV-1, and 56 Gy to CTV-2 and CTV-N in 33 fractions, 5 times per week.

A total of 173 patients received both induction chemotherapy and concurrent chemotherapy (cisplatin 80 mg/m² divided into 3 parts on days 1–3, every 3 weeks). The main induction chemotherapy regimen was TPF (paclitaxel 135 mg/m² day 1, cisplatin 80 mg/m² divided into 3 parts on days 1–3, and fluorouracil 750 mg/m² per day on days 1–5, every 3 weeks). Of the total, 67 patients received only concurrent chemotherapy and 42 patients received concurrent chemotherapy along with the adjuvant chemotherapy, and the main adjuvant chemotherapy regimen was TPF and PF (cisplatin 80 mg/m² divided into 3 parts on days 1–3, and fluorouracil 750 mg/m² per day on days 1–5, every 3 weeks).

The patients were followed up every 3 months during the first 3 years and every 6 months thereafter or until death. Each follow-up consisted of physical examination, basic serum chemistry, flexible fiberoptic endoscopy, MRI of the nasopharynx and neck, chest radiography or CT, abdominal sonography, and a whole-body bone scan. The above examinations were performed after SIB-IMRT to detect locoregional or distant relapse.

The endpoints of this study were overall survival (OS; time to death due to any cause), disease-free survival (DFS; time to treatment failure or death from any cause), distant failure-free survival (DMFS; time to distant metastasis), and locoregional recurrence-free survival (LRRFS; time to locoregional persistence or recurrence). All the events were estimated from historical diagnosis. OS, DFS, DMFS, and LRRFS were calculated using the Kaplan–Meier method [15], and survival curves were estimated using log-rank tests [15]. Statistical Package for the Social Sciences, version 23.0, was used for statistical analysis.

Of the 89 patients with stage T4 NPC according to the 7th edition, 61 were downgraded to T3 considering the 8th edition as the cancer had reached to the medial or lateral pterygoid. A total of 2 patients with stage T1 NPC according to the 7th edition were reclassified as stage T2 considering the 8th edition on the basis of prevertebral muscle extension (Table 2).

Table 3 presents the 5-year survival rates for different end points of T categories in the 7th and 8th editions. Figure 1a and b show the OS curves for the T categories in the 7th and 8th editions. There were significant differences between T4 and T1, T4 and T2, and T4 and T3 categories in the 7th and 8th editions (P < 0.001 for T4 and T1, T4 and T2; P = 0.007 for T4 and T3 in the 7th edition; P = 0.004 for T4 and T3 in the 8th edition). The OS rates between T3 and T2, and T3 and T1 categories in the 7th edition were not significantly different (P = 0.106 and P = 0.066, respectively), whereas these categories in the 8th edition were considerably different (P = 0.008 and P = 0.004, respectively). Figure 1c and d show the LRRFS rates of T categories in both the staging systems. In the 8th edition, the difference between T2 and T4 was statistically significant, while that in the 7th edition was not (P = 0.070 and P = 0.011, respectively). Therefore, the 8th edition had improved the prognosis value of NPC compared with the.

7th edition. Figure 1e and f show the DFS curves; except for the difference between T1 and T2 categories, the difference between all other combinations of classifications were statistically significant.

In the 8th edition, the supraclavicular fossa (SCF) was replaced with the lower neck (below the caudal border of the cricoid cartilage), which led to the upstaging of 18 patients from N2 to N3 (Table 2).

Table 3 presents the 5-year survival rates for different end points of N categories in the 7th and 8th editions. Figure 2 shows the OS, DFS, and DMFS survival curves for each staging system. The OS and DFS in the 7th edition system for N2 and N3a stages were not significantly different (P = 0.472 and P = 0.954, respectively, Fig. 2a, c), whereas the OS and DFS for N2 and N3 using the 8th edition were statistically different (P = 0.046 and P = 0.043, respectively, Fig. 2b, d). Thus, the 8th edition had a superior prognosis value compared with the 7th edition with respect to N category classification. Additionally, there was no significant difference between classifications N3a and N3b in the 7th edition system (P = 0.785 for OS, P = 0.241 for DFS, and P = 0.910 for DMFS; Fig. 2a, c, e). The DFS curves for N3a and N3b even overlapped in the 7th edition (Fig. 2c). Therefore, merging N3a and N3b stages in the 8th edition was reasonable.

Considering the 8th edition, 40 patients with stage IV disease were downgraded to stage III (Table 2). No deaths were reported for stage I patients. Table 3 presents the 5-year survival rates for different end points of clinical stages in the 7th and 8th editions. Figure 3 shows the OS and DFS survival curves for each staging system. In both the staging systems, significant differences in OS and DFS were observed for clinical stages (P < 0.05) except for stages IVA and IVB, and I and II (P = 0.893 for OS and P = 0.711 for DFS; P = 0.549).

To further discover prognostic factors, three factors were involved in multivariate analysis: age (<45 vs. ≥45), sex (male vs. female) and T category or N category. Table 4 shows the results of multivariate analysis by adjusted age, sex and T category or N category of the two editions. The results indication differences of hazard of deaths between T1 and T2, N1 and N2 were non statistical significance.