Comparison the sixth and seventh editions of the AJCC staging system for T1 gastric cancer: a long-term follow-up study of 2124 patients
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Abstract
Background/Aim
The aim of this study was to establish an appropriate TNM staging system for early gastric cancer.
Methodology
We evaluated 2124 patients who had undergone gastrectomy for early gastric cancer between 1989 and 2001.
Results
Using the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, we found no significant differences in tumor recurrence and survival between N1 and N2 cancers or between N3a and N3b cancers, whereas the survival curves for N2 and N3 cancers were quite different. Similarly, using the classification in the sixth edition of the AJCC staging system, we found no significant difference in survival between the N2 and N3 cancer groups, whereas the survival curves for N1 versus N2 or N3 cancers were quite different.
Conclusions
The classifications in the sixth and seventh editions of the AJCC staging system have a limitation for T1 gastric cancer (early gastric cancer).
Keywords
Early gastric cancer Nodal stage TNMIntroduction
Early gastric cancers (EGCs; T1 cancer) make up more than 50 % of all gastric cancers [1, 2]. The survival rate of patients with EGC exceeds 90 % in Japan [3, 4] and in Western countries [5]. Variable rates of recurrence of EGC have been reported in these countries, ranging from 2.1 to 12.4 % [6, 7, 8]. The seventh edition of the American Joint Committee on Cancer (AJCC) staging system was published in 2010. However, this new AJCC TNM staging stystem is inadequate for EGC but is appropriate for advanced gastric cancer [9]. In patients with EGC, survival is affected by the presence of invaded lymph nodes not by the depth of penetration of the lesion or its size [10]. Therefore, the aims of this study were to evaluate tumor recurrence and long-term survival of patients with EGC in relation to the AJCC TNM staging system on the basis of the results of a large-scale study with long-term follow-up and to recommend a new TNM staging system.
Methods
Data analysis flow diagram for this study. GC gastric cancer
We reviewed tumor recurrence patterns and prognosis of the patients undergoing gastrectomy for EGC, and related the results to the sixth and seventh editions of the AJCC staging system. We reclassified nodal stages to achieve appropriate staging for T1 gastric cancer: N1 as one to five lymph node metastases, N2 as six to ten lymph node metastases, and N3 as more than ten lymph node metastases.
We evaluated the categorical variables using the chi-square test and continuous variables using the Student t test. We evaluated the univariate risk factors for tumor recurrence using log-rank tests and evaluated multivariate risk factors using a Cox regression model, the hazard ratios, and the 95 % confidence intervals. The C index was evaluated to determine whether the most recent AJCC TNM staging system is suitable or not suitable for discrimination. The 95 % confidence intervals for the C index were obtained through the percentile bootstrap method (1000 replicates) [12]. Survival curves after tumor recurrence and recurrence probability curves after surgery were evaluated by the Kaplan–Meier method. All statistical analyses were performed with Statistical Package for the Social Sciences Windows version 19.0 (SPSS, Chicago, IL, USA). Significance was set at p < 0.05.
This study received institutional review board approval (protocol number 2012-0032).
Results
Clinicopathological characteristics for nonrecurrence and recurrence
| Characteristic | All patients | Nonrecurrence (n = 2027) | Recurrence (n = 97) | p |
|---|---|---|---|---|
| Sex | NS | |||
| Male | 1399 (65.9 %) | 1367 (66.0 %) | 62 (63.9 %) | |
| Female | 725 (34.1 %) | 690 (34.0 %) | 32 (36.1 %) | |
| Age (years) | 54.8 ± 11.5 | 54.7 ± 11.5 | 56.4 ± 11.8 | NS |
| Follow-up (months) | 151.8 ± 52.7 | 155.4 ± 49.6 | 79.0 ± 59.0 | <0.001 |
| Location of tumor | NS | |||
| Lower third | 1298 (61.1 %) | 1242 (61.3 %) | 56 (57.7 %) | |
| Middle third | 640 (30.1 %) | 607 (29.9 %) | 33 (34.0 %) | |
| Upper third | 188 (8.8 %) | 178 (8.8 %) | 6 (8.2 %) | |
| Tumor size (mm) | 30.5 ± 19.1 | 30.4 ± 19.1 | 32.7 ± 17.1 | NS |
| Gastrectomy | NS | |||
| Subtotal | 1886 (88.8 %) | 1801 (88.9) | 85 (87.6 %) | |
| Total | 238 (11.2 %) | 226 (11.1) | 12 (12.4 %) | |
| Depth of invasion | < 0.001 | |||
| Mucosa | 1054 (49.6 %) | 1029 (50.8 %) | 25 (25.8 %) | |
| Submucosa | 1070 (50.4 %) | 998 (49.2 %) | 72 (74.2 %) | |
| Macroscopic finding | 0.025 | |||
| Superficial | 1783 (83.9 %) | 1711 (84.4 %) | 72 (74.2 %) | |
| Protruded | 122 (5.7 %) | 114 (5.6 %) | 8 (8.2 %) | |
| Excavated | 219 (10.3 %) | 202 (10.0 %) | 17 (17.5 %) | |
| Histological type | NS | |||
| Differentiated | 1090 (51.3 %) | 1043 (51.5 %) | 47 (48.5 %) | |
| Undifferentiated | 1034 (48.7 %) | 984 (48.5 %) | 50 (51.5 %) | |
| Lymph node metastasis | <0.001 | |||
| No | 1868 (87.9 %) | 1816 (89.6 %) | 52 (53.6 %) | |
| Yes | 256 (12.1 %) | 211 (10.4 %) | 45 (46.4 %) | |
| Lymphatic/venous invasion | <0.001 | |||
| No | 1925 (90.6 %) | 1852 (91.4 %) | 73 (75.3 %) | |
| Yes | 199 (9.4 %) | 175 (8.6 %) | 24 (24.7 %) | |
| Retrieved lymph nodes | 24.7 ± 12.7 | 24.8 ± 12.7 | 24.3 ± 12.9 | NS |
| Multiple cancers | NS | |||
| No | 2048 (96.4 %) | 1954 (96.4 %) | 94 (96.9 %) | |
| Yes | 76 (3.6 %) | 73 (8.6 %) | 4 (3.1 %) |
Risk factors for tumor recurrence and prognostic factors
Prognostic factors based on log-rank tests and a Cox regression model
| Characteristic | Number | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|
| Number | p | Hazard ratioa | p | ||
| Age (years) | 0.046 | ||||
| ≤55 | 1042 | 36 (3.5 %) | |||
| >55 | 1088 | 53 (4.9 %) | 1.54 (0.98–2.32) | NS | |
| Depth of invasion | <0.001 | ||||
| Mucosa | 1054 | 22 (2.1 %) | |||
| Submucosa | 1070 | 66 (6.1 %) | 1.35 (0.79–2.30) | NS | |
| Macroscopic findings | 0.013 | ||||
| Superficial | 1783 | 65 (3.6 %) | |||
| Protruded | 122 | 8 (6.5 %) | 1.14 (0.54–2.41) | NS | |
| Excavated | 219 | 16 (7.3 %) | 1.42 (0.82–2.48) | NS | |
| Lymph node metastasis | <0.001 | ||||
| No | 1868 | 41 (4.7 %) | |||
| Yes | 256 | 48 (18.7 %) | 7.41 (4.63–11.86) | <0.001 | |
| Lymphatic/venous invasion | <0.001 | ||||
| No | 1925 | 64 (3.3 %) | |||
| Yes | 199 | 25 (12.6 %) | 1.65 (0.97–2.74) | NS | |
Correlation with the seventh edition of the AJCC staging system
Recurrence and survival based on the Kaplan–Meier method using the log-rank test, according to the sixth and seventh editions of the American Joint Committee on Cancer (AJCC) staging system
| Characteristics | Number (n = 2124) | Tumor recurrence | Disease-related death | ||
|---|---|---|---|---|---|
| Number | p | Survival rate (%) | p | ||
| AJCC staging system, 7th edition | |||||
| N0 vs N1 | 1868 vs 156 | 52 (2.8 %) vs 18 (11.5 %) | <0.001 | 97.8 vs 85.9 | <0.001 |
| N1 vs N2 | 156 vs 75 | 18 (11.5 %) vs 8 (10.7 %) | NS | 85.9 vs 90.7 | NS |
| N1 vs N3 | 156 vs 25 | 18 (11.5 %) vs 19 (76.0 %) | <0.001 | 85.9 vs 24.0 | <0.001 |
| N2 vs N3 | 75 vs 25 | 8 (10.7 %) vs 19 (76.0 %) | <0.001 | 90.7 vs 24.0 | <0.001 |
| N3a vs N3b | 20 vs 5 | 14 (70.0 %) vs 5 (100.0 %) | NS | 30.0 vs 0.0 | NS |
| AJCC staging system, 6th edition | |||||
| N0 vs N1 | 1868 vs 231 | 52 (2.8 %) vs 26 (25.9 %) | <0.001 | 97.8 vs 87.4 | <0.001 |
| N1 vs N2 | 231 vs 20 | 26 (25.9 %) vs 14 (70.0 %) | <0.001 | 87.4 vs 30.0 | <0.001 |
| N1 vs N3 | 1868 vs 5 | 52 (2.8 %) vs 14 (70.0 %) | <0.001 | 87.4 vs 0.00 | <0.001 |
| N2 vs N3 | 20 vs 5 | 14 (70.0 %) vs 5 (100.0 %) | NS | 30.0 vs 0.00 | NS |
Survival by nodal stage. a There was no significant difference between N1 and N2 cancers in the seventh edition of the American Joint Committee on Cancer staging system. b There was no significant difference between N2 and N3 cancers in the sixth edition of the American Joint Committee on Cancer staging system. c Survival as defined by the proposed new nodal staging system. There were significant differences between N0 and N1 cancers, N1 and N2 cancers, and N2 and N3 cancers (p < 0.05); N1 corresponds to one to five lymph node metastases, N2 corresponds to six to ten lymph node metastases, and N3 corresponds to more than ten lymph node metastases
Correlation with the sixth edition of the AJCC staging system
The results of analyses of tumor recurrence and survival according to the sixth edition of the AJCC staging system are summarized in Table 3. There were significant differences in tumor recurrence between nodal stages (p < 0.05). However, there was no significant difference in survival between the N2 and N3 cancer groups (p > 0.05). Figure 2b presents the disease-related survival curves of the patients according to the classification in the sixth edition of the AJCC staging system. The survival curves for N1 cancer patients versus N2 or N3 cancer patients were quite different.
Correlation with the new recommended TNM staging system
Recurrence and survival based on the Kaplan–Meier method using the log-rank test, according to the recommended nodal stages
| Characteristic | Number (n = 2124) | Tumor recurrence | Disease related death | ||
|---|---|---|---|---|---|
| Number | p | Survival rate (%) | p | ||
| N0 vs N1 | 1868 vs 222 | 52 (2.8 %) vs 26 (11.7 %) | <0.001 | 97.8 vs 86.9 | <0.001 |
| N1 vs N2 | 222 vs 24 | 26 (11.7 %) vs 10 (41.6 %) | <0.001 | 86.8 vs 58.3 | <0.001 |
| N1 vs N3 | 222 vs 10 | 26 (11.7 %) vs 9 (90.0 %) | <0.001 | 86.9 vs 10.0 | <0.001 |
| N2 vs N3 | 24 vs 10 | 10 (41.6 %) vs 9 (90.0 %) | 0.012 | 58.3 vs 10.0 | 0.014 |
C index determined through the percentile bootstrap method (1000 replicates)
| C index | Recurrence | Death | Related death |
|---|---|---|---|
| AJCC staging system, 6th edition | 0.6992 (0.6475–0.7510) | 0.5611 (0.5415–0.5807) | 0.7310 (0.6774–0.7846) |
| AJCC staging system, 7th edition | 0.6994 (0.6475–0.7512) | 0.5613 (0.5416–0.5810) | 0.7318 (0.6780–0.7856) |
| New nodal staging system | 0.6993 (0.6475–0.7510) | 0.5611 (0.5415–0.5807) | 0.7310 (0.6774–0.7846) |
Discussion
Lymph node metastasis is a significant risk factor for EGC recurrence and the most valuable prognostic factor for EGC [13, 14, 15]. Early tumor recurrence has been associated with lymph node metastasis and a poor prognosis [7, 16, 17]. In our study we observed that tumor recurrence and prognosis of T1a (tumor invades mucosa) cancer were similar to those for T1b (tumor invades submucosa) cancer (p > 0.05), and we identified lymph node metastasis as an independent risk factor for tumor recurrence, as well as an independent prognostic factor. This result shows that T1 cancer (EGC) stages mostly depend on nodal status.
More than 50 % of all gastric cancers are diagnosed as T1 (invading the mucosa or submucosa) cancers, and early detection of gastric cancer is increasing steadily. However, the classification in the seventh edition of the AJCC staging system is based on advanced gastric cancer [9], and treatment modalities and survival predictions have followed the AJCC TNM staging system. So far, there has been no report focusing on a TNM staging system for T1 cancer. Therefore, we investigated tumor recurrence and survival of patients with T1 cancer on the basis of a large sample and long-term results, and we examined these results in relation to the classifications in the sixth and seventh editions of the AJCC staging system. We found that these classifications were not well distributed in the survival curve. Hence, we developed a new classification—N1, one to five lymph node metastases; N2, six to ten lymph node metastases; and N3, more than ten lymph node metastases—and found that this classification gave satisfactory survival curves. However, we could not prove that the most recent TNM classification is not appropriate in regard to survival prediction using the C index.
Our study had some limitations of note. This is a retrospective study. Lymph node metastasis is rare in EGC (12.1 % in our study). Furthermore, N2 or N3 cancers were very rare. Although we evaluated 2024 patients with EGC, 256 patients are really involved in the nodal group. So, the statistical power of our analysis was limited by the relatively small number of each TNM stage. Finally, our cutoff value of lymph node metastasis could not be high because lymph node metastasis was rare in EGC and the statistical power was not high. Therefore, the accuracy of this article still needs to be discussed.
In conclusion, the classifications in the sixth and seventh editions of the AJCC staging system have a limitation for disease-related death from T1 gastric cancer (EGC). However, we could not prove that the most recent TNM classification (seventh edition of the AJCC staging system) is appropriate in regard to survival prediction.
Notes
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standards
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for their being included in the study.
Supplementary material
References
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