Japanese Journal of Clinical Oncology 31:363-369 (2001)
© 2001 Foundation for Promotion of Cancer Research
Retrospective Comparison of the AJCC 5th Edition Classification for Nasopharyngeal Carcinoma with the AJCC 4th Edition: an Experience in Taiwan
1Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 2Department of Oncology, National Taiwan University Hospital, Taipei and 3Department of Radiation Therapy and Oncology, China Medical College Hospital, Taichung, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective: The aim of this study was to compare the new AJCC 5th edition classification system for nasopharyngeal carcinoma (NPC) with the AJCC 4th edition by re-evaluating the staging of patients treated in Taiwan.
Methods: From 1992 through 1996, 117 NPC patients without distant metastasis were treated using complete courses of radiotherapy. All patients had complete CT examinations of the nasopharynx and neck. Each patient was re-staged according to the 5th edition of the AJCC classification system. Their overall survival (OS), loco-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) were compared between the two staging systems, using the Kaplan–Meier method, log-rank test, Wilcoxon test and Cox proportional hazard model.
Results: After a median follow-up of 58.3 months, the 5-year OS for stage I, II, III and IV was 88, 86, 61 and 48%, respectively, according to the new staging. A more even distribution of patients was noted among the patients classified according to the AJCC 5th edition than the 4th edition. The distribution of stages I, II, III and IV was 13.7, 37.6, 15.4 and 33.3%, respectively, using the new staging system, whereas it was 0.8, 14.5, 20.5 and 64.2%, respectively, using the old staging system. More statistically significant differences among 5th edition stages and T classifications than the 4th edition were also noted.
Conclusions: The 5th edition of the AJCC staging system appears to have a more even distribution of patients and more statistically significant differences in predicting prognosis than the 4th edition, mostly in stages and T classification.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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There are many staging classifications for nasopharyngeal carcinoma (NPC) throughout the world (1–6). Nasopharyngeal carcinoma is one of the most prevalent cancers in southern China and Taiwan (7). The aim of this study was to compare the AJCC 4th edition (1988) with the AJCC 5th edition (1997) NPC classification (Table 1) in terms of patient distribution and survival/recurrence differences among patients with various stages of the disease.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patients’ Characteristics
From September 1992 through December 1996, 117 consecutive patients with previously untreated and histologically proven nasopharyngeal carcinoma (NPC) were treated with full courses of definitive radiotherapy (RT) at our institutes. All patients were uniformly staged using results after complete medical history, physical examination, nasopharyngeal endoscopy and tumor biopsy, chest radiograph, complete blood count, blood chemistry, CT scan of the nasopharynx and neck, abdominal ultrasonography and bone scan. Patients with distant metastasis were excluded. There were 85 men and 32 women enrolled in this study. Their ages ranged from 25 to 80 years with a median of 45 years. The distribution of histopathological diagnoses using the WHO grading system included four (3.4%) patients in grade I, 92 (78.4%) in grade II and 21 (18.2%) in grade III. All patients were staged prospectively according to the AJCC 4th edition and then re-staged retrospectively according to the AJCC 5th edition, based on the medical records and CT scans.
Treatment
All patients were treated with external radiotherapy, using 6 MV photons generated from linear accelerators (Siemens, Mevatron KDS-2). These patients were initially treated with bilateral opposing fields and one anterior low-neck field to include nasopharynx, skull base and whole neck lymphatic drainage for 46.8 Gy. Primary tumors were further boosted with 10 MV X-rays to 68.4–73.8 Gy in most cases (99.1%) with a median dose of 68.4 Gy. Bilateral neck lymphatic drainage was boosted with electron beams of appropriate energy. The nodal doses ranged from 56.8 to 80.8 Gy and were >66.8 Gy in all patients with clinically palpable lymph nodes. The main constraint was to keep the cumulative spinal cord dose <50 Gy. The RT dose was prescribed at the midpoint (bilateral opposing field), 3 cm depth (low anterior neck field) or 85–90% depth dose (for electrons). The fractionation schedule used was five daily fractions of 1.8–2 Gy per week and all fields were treated daily. RT was started when the position was verified by the verification film on the first treatment day. Intra-cavity high dose rate radiotherapy (ICHDR) with Ir-192 treatment was given to 109 (93.2%) patients (once for 22 patients and twice for 87 patients) with Nucletron, microselection HDR192Ir. The IC-HDR delivered a dose of 3 Gy/2 cm off-axis weekly. Three courses of adjuvant chemotherapy (mostly cisplatin 80 mg/m2 on day 3 and Ftoral 1000 mg/m2 on days 1–5) were suggested for AJCC 4th edition stage III/IV patients. Forty-seven (47%) patients received this adjuvant chemotherapy.
Follow-up
After completion of treatment, patients were followed up every 2 months for the first 2 years, then every 3 months. Physical examination and nasopharyngeal endoscopy were performed during each follow-up examination, and CT scan of the nasopharynx region and neck, abdominal sonography, chest X-ray and bone scan were done every year. At the time of analysis, 103 (88%) patients had been regularly followed up at least biannually or until their death. Twelve (10%) patients were finally followed up by telephone, which revealed regular local medical follow-up in seven, well-being without regular medical follow-up in three and death with uncertain causes in two patients. Two patients were lost to follow-up owing to moving overseas. The period of follow-up ranged from 5.8 to 99 months (median, 58.3 months; average, 57.7 months). For the 78 patients who were still alive at the last follow-up/telephone call, the median follow-up was 73 months (range, 11–99 months).
Statistical Analysis
The endpoints were death (cause-specific or not), loco-regional relapse and distant metastasis. Overall survival (OS), disease-specific survival (DSS), loco-regional relapse-free survival (LRRFS), distant metastases-free survival (DMFS) and disease-free survival (DFS) were defined as the common definition (8). The period of time was from the first day of radiotherapy to the day of first loco-regional failure or distant failure, or death or last medical follow-up/telephone call (for LRRFS, DMFS and DFS); or to the day of death or the day of the last follow-up/telephone call (for DSS and OS). The Kaplan–Meier method was used in the calculation of OS, DSS, LRRFS, DMFS and DFS. The log-rank and Wilcoxon tests were used to test the significance of the differences among different stages/classifications. The Cox proportional hazard model was used to assess the risk ratio of different overall stages/T/N classifications
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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At the time of analysis, 68 (58%) patients were alive without known recurrent disease under regular medical follow-up in our institutes (60 cases), regular medical follow-up in other institutes (five cases) or by telephone call (three cases). Eight (7%) patients were alive with local relapse (five cases) or distant metastasis (three cases) under regular medical follow-up in our institutes (six cases) or regular medical follow-up in other institutes (two cases). Among the 39 (33%) patients who died, 29 died of disease (eight loco-regional recurrence, 19 distant metastasis, two regional recurrence and distant metastasis), one died of local complication, seven died of inter-current diseases and two died of unknown causes. Two patients were lost to follow-up but no evidence of disease was found in their last follow-up.
Patient Distribution
According to the AJCC 4th edition classification system, there was only one patient (0.8%) in stage I, 16 (14%) in stage II and 75 (64%) in stage IV. The AJCC 5th edition classification resulted in a more even distribution among the different stages (Table 2).
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Overall Statistical Differences Among Different Endpoint Measurements vs Stage/T/N Classification
The overall log-rank test and Wilcoxon test for different endpoint measurements (OS, DSS, LRRFS, DMFS, DFS) vs stage/T/N classification are shown in Table 3. Statistical significance (p < 0.05) was found in all different endpoint measurements vs stage and T classification, but it was only found in OS vs 5th edition N classification.
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Risk Ratio for Different Endpoint Measurements vs Different Stages
For 5th edition NPC staging, a statistically significant risk ratio (p < 0.05) was found when stage IV was compared with stage I while OS, LRRFS, DMFS and DFS were measured. For 4th edition NPC staging, a statistically significant risk ratio (p < 0.05) was found only when stage IV was compared with stage II while LRRFS was measured (Table 4).
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Risk Ratio for Different Endpoint Measurements vs Different T Classifications
For 5th edition NPC staging, a statistically significant risk ratio (p < 0.05) was found when T3 was compared with T1 while OS, DSS, DMFS and DFS were measured and when T4 was compared with T1 while OS, DSS, LRRFS, DMFS and DFS were measured. For 4th edition NPC staging, a statistically significant risk ratio (p < 0.05) was found only when T4 was compared with T2 while OS, DSS, LRRFS, DMFS and DFS were measured (Table 5).
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Risk Ratio for Different Endpoint Measurements vs Different N Classifications
For 5th edition NPC staging, a statistically significant risk ratio (p < 0.05) was not found. For 4th edition NPC staging, a statistically significant risk ratio (p < 0.05) was found only when N3 was compared with N0 while LRRFS and DFS were measured (Table 6).
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Significance of Chemotherapy, Parapharyngeal Space Invasion and Low Neck Involvement
For the five different measurements (OS, DSS, LRRFS, DMFS, DFS), no statistically significant differences were obtained among patients with/without C/T, with/without parapharyngeal space invasion or with/without low neck lymph node involvement.
Differences Among New T3/T4
For all measurements (OS, DSS, LRRFS, DMFS and DFS), there was no statistical significance among new T3/T4 in the overall log-rank test and Wilcoxon test and the risk ratio (T3/T4) also showed no statistical significance. The only exception was the Wilcoxon test for LRRFS (p = 0.04).
Differences Among Old N1/N2 in Patients with New N1
For all measurements (OS, DSS, LRRFS, DMFS and DFS), there was no statistical significance among old N1/N2 in the overall log-rank test and Wilcoxon test and the risk ratio (N1/N2) also showed no statistical significance.
Differences Among Old N1–2/N3 in Patients with New N3
For all measurements (OS, DSS, LRRFS, DMFS and DFS), there was no statistical significance among old N1–2/N3 in the overall log-rank test and Wilcoxon test and the risk ratio (N1–2/N3) also showed no statistical significance.
Differences Among New Stage II/Stage III/Stage IV in Patients with Old Stage IV
The major difference in old/new staging was that many patients who were pooled together in old stage IV were separated. Seventy-five (64%, 75/117) old stage IV patients were divided to 19 new stage II, 18 new stage III and 38 new stage IV cases. For all measurements (OS, DSS, LRRFS, DMFS and DFS), new stage II vs stage III, stage II vs stage IV and stage III vs stage IV were compared. The most obvious statistical difference was found in stage II vs stage IV when LRRFS was compared (p = 0.03). There was also a borderline statistical significance in stage III vs stage IV when LRRFS and DFS were compared (for LRRFS, Wilcoxon test p value = 0.07, risk ratio =1.7, 95% confidence level = 0.087–3.28; for DFS, Wilcoxon test p value = 0.07, risk ratio = 1.86, 95% confidence level = 0.82–4.12).
Survival Status
The 5-year OS vs stage/T/N classification is shown in Table 7. The 5-year OS for stages I–IV was 88, 86, 61 and 48, respectively, according to the new staging. The Kaplan–Meier curves for OS vs stage are shown in Figs 1 and 2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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There are many staging systems with controversial issues for the classification of patients with NPC (1–6,9–14). The drawbacks of the AJCC 4th edition include the uneven patient distribution (15–17) in which too many patients were pooled into stage IV (15). The new system provided a more even distribution of patients in our study (Table 2), which has also been reported in other studies (15–17).
Concerning the statistical difference among stages/T classification/N classification, the 5th edition is superior to the 4th edition in stages and T classification (Tables 4 and 5), but is not definitely better in N classification [better in overall Wilcoxon test (Table 3), but worse in the relative risk in N3 vs N0 when LRRFS and DFS were measured (Table 6)].
CT scans made the diagnosis and staging of NPC more accurate (18,19). Soft tissue invasion, such as parapharyngeal space invasion, is more clearly delineated using magnetic resonance imaging (MRI) images (19–21). Our study appears to confirm the value of routine CT scans in staging NPC.
In 1998, Cooper et al. (15) compared patients using three classification systems, the AJCC 4th and AJCC 5th editions and a system described by Ho (3); discrimination among stages in OS was not obvious, only a more even patient distribution was noted with the AJCC 5th edition. The treatment period for these patients was from 1971 through 1994 and staging using CT scans was not clearly mentioned.
Lee et al. (16) reported a comparison among Ho, AJCC 1992 (4th edition) and AJCC 1997 (5th edition) among 5037 patients treated from 1975 through 1985. The AJCC 5th edition showed more discrimination than the AJCC 4th edition. However, only 15% of the patients in this study were staged using CT scanning.
Ozyar et al. (17) reported a comparison between the AJCC 4th and 5th editions among patients using CT/MRI-based staging. A more even patient distribution was noted with the 5th edition. The AJCC 5th edition was better than the 4th edition in stages when OS and DMFS were compared. However, the AJCC 4th edition is better in stages when LRRFS was compared. The AJCC 4th and 5th editions had similar performances among T classifications in the LRRFS (no differences for either staging) and among N classifications in the DMFS (differences in N0–N3, N1–N3 and N2–N3 in either staging).
There were three major differences in the T classification between the new and old systems. First, the old T1 and T2 were not easily separated, which is supported by many studies (5,16,17) and there were only four 4th edition T1 patients in our study. Second, the importance of parapharyngeal space invasion was included in the new T classification as T2b. The importance of parapharyngeal space invasion has been mentioned in many reports in the literature (18,22). However, it was not statistically discriminated in our study. Third, the old T4 was divided into new T3 and T4. The advantages have also been reported in many studies (5,15). In the current study, the 34 old T4 patients can be divided to 14 new T3 cases and 19 new T4 cases. The overall 5-year LRRFS is 45% using the old T4, whereas it is 42% using the new T4 and 50% using the new T3 and a statistical difference is observed (Wilcoxon test p = 0.04, risk ratio = 1.96, 95% confidence level = 0.85–4.54).
Concerning the N staging, nodal size >6 cm, unilateral/bilateral and low-neck involvement were emphasized in the new staging (16). The 40 new N1 cases can be divided to 15 old N1 cases and 25 old N2 cases, based on the nodal size, but there is no survival/event difference between them. Lower neck disease had been reported to be an important prognostic factor (16,20,23). Lee et al. suggested that those with nodes >6 cm at the greatest diameter and those with extension to the supraclavicular fossa should be treated as N3 (9). The prognostic differences between N3a and N3b were not obvious in our study. Our results will be re-evaluated using more cases and longer follow-up.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Our retrospective study showed that the AJCC 5th edition for NPC has a more even distribution of patients compared with the AJCC 4th edition. It also showed that the 5th edition is better than the 4th edition in stages and T classification. The distinction between the new and old N classifications was not so obvious.
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FOOTNOTES |
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+ For reprints and all correspondence: Fang-Jen Lin, Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Shi-Lin, Taipei, Taiwan. E-mail: a0080@ms2.hinet.net
Abbreviations: AJCC, American Joint Committee on Cancer; CT, computed tomography; DFS, disease-free survival; DMFS, distant metastasis-free survival; DSS, disease-specific survival; ICHDR, intra-cavity high dose rate; LRRFS, loco-regional relapse-free survival; NPC, nasopharyngeal carcinoma; OS, overall survival
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REFERENCES |
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Received February 19, 2001; accepted May 7, 2001.
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