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J Cancer 2018; 9(19):3570-3576. doi:10.7150/jca.26351 This issue Cite

Research Paper

Proposal for a New TNM Stage based on the 7^th and 8^th American Joint Committee on Cancer pTNM Staging Classification for Gastric Cancer

Miao-Zhen Qiu^1*, Zi-Xian Wang^1*, Yi-Xin Zhou^2*, Da-Jun Yang³ , Feng-Hua Wang¹ , Rui-Hua Xu¹

1. Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China.;
2. Department of VIP, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China.;
3. Department of Experimental Research, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
*Miaozhen Qiu, Zi-Xian Wang and Yi-Xin Zhou contributed equally to the manuscript.

✉ Corresponding authors: Professor Da-jun Yang, MD, PhD, Department of Experimental Research, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel.: +86 20 8734 2285; Fax: +86 20 8734 2285; E-mail: yangdjorg.cn, Professor Feng-Hua Wang, Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel.: +86 20 8734 2490; Fax: +86 20 8734 2490; E-mail: wangfhorg.cn, Professor Rui-Hua Xu, Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel: +86-20-8734 3333; Fax: +86-20-8734 3295; E-mail: xurhorg.cn More

Abstract

Background: The 8^th edition of the American Joint Committee on Cancer (AJCC) staging system for gastric cancer incorporated several new changes. We aimed to assess the comparative prognostic values of the 7^th and 8^th AJCC pTNM staging systems in patients with gastric cancer (GC), and accordingly, to put forward a refined staging classification.

Methods: The SEER database was queried to identify GC patients between 2004 and 2009. GC patients from Sun Yat-sen University Cancer Center (SYSUCC) were used as external validation data. The Kaplan-Meier method and Cox proportional hazards regression models were used to analyze cause-specific survival (CSS). The prognostic performance of different staging schemes was assessed using the concordance index (c-index), Akaike's information criterion (AIC), and likelihood ratio χ² test.

Results: In the SEER cohort, stage migration occurred in 8.74% of patients. Survival analysis showed that it was better to treat T4bN0M0 + T4aN2M0 as stage IIIB and T4bN3bM0 as stage IV. Based on this, we established a new staging system which exhibited a superior c-index (0.7501) to the 7^th and 8^th AJCC staging systems (0.7498 and 0.7500, respectively). The new staging system also outperformed the 7^th and 8^th AJCC staging systems in terms of AIC and the likelihood ratio χ² test. The predictive superiority of the new staging system remained valid in the SYSUCC database.

Conclusions: We demonstrated that some stage modifications in the 8^th AJCC pathologic staging were unnecessary. Therefore we established a new staging system, which was superior to the 7^th and 8^th staging systems.

Keywords: Gastric Cancer, Prognosis, SEER, TNM staging classification

Introduction

Gastric cancer (GC) is the second most common cause of cancer-related deaths worldwide [1]. In 2015, more than 679,000 incident cases were estimated in China, and it was estimated to cause 498,000 deaths [2]. Until now the prognosis for GC patients remains poor. Accurate staging system is therefore essential to guide treatment and predict prognosis [3, 4].

The American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system that we are now using is the 7^th edition. The 8^th Edition Cancer Staging System will be taken into implementation on January 1, 2018.

Several important changes were incorporated into the 8^th edition staging system of GC. The 8^th classifications provide more comprehensive tools, including cTNM, ypTNM and pTNM for stage grouping of GC patients under different situation [5]. cTNM and ypTNM are new proposed and need to be validated in clinical practice. Though there is no change to the definition of pT, pN and pM classification, pN3a and pN3b are treated different in the final pTNM classification. The changes only happen on stage II and stage III, especially stage III. In detail, T1N3bM0 and T2N3bM0 are upstaged from stage IIB, IIIA in the 7^th edition to stage IIIB in the 8^th edition. T3N3bM0 is upstaged from stage IIIB in the 7^th edition to stage IIIC in the 8^th edition. T4bN0M0 and T4aN2M0 are downstaged from IIIB in the 7^th edition to IIIA in the 8^th edition. Moreover, T4aN3aM0 and T4bN2M0 tumors are downstaged from IIIC in the 7^th edition to IIIB in the 8^th edition.

Changes made to the TNM classification are based on survival analyses from National Cancer Database NCDB (U.S.) and Shizuoka Cancer Center (Japan) dataset. However, it remains unclear whether these changes are necessary or not. Lu J et al. compare the 7^th and 8^th editions of the AJCC TNM classification for stage III GC patients in China and found that the 8^th TNM edition may not provide significantly better accuracy in predicting prognosis of stage III GC patients [6, 7].

We sought to evaluate the discriminative ability of the AJCC 8^th edition staging system and to study the impact of stage shift on stratification of survival using the Surveillance, Epidemiology, and End Results (SEER) database and a Chinese institutional cohort. Based on this analysis, we made some modification and put forward a new staging classification, aiming to better predict the prognosis.

Methods

Database

The SEER database is the largest publicly available cancer dataset. The exact dataset we used for this analysis was SEER Program (www.seer.cancer.gov) Research Data (1973-2014) based on the November 2016 submission, “Incidence-SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2014 Sub (1973-2014 varying)”. The study population was based on the SEER cancer registry. Inclusion criteria were: 1) adults (aged 18 years or older) patients; 2) gastric adenocarcinoma (also including mucinous adenocarcinoma and signet ring cell carcinoma) from 2004 to 2009; 3) with clear record of TNM 7^th stage. Exclusion criteria were: 1) patients without follow-up records (survival time code of 0 months); 2) patients without TNM stage. Patients were staged using the 7^th and 8^th editions of the AJCC TNM staging systems. Because SEER is public-use data, institutional review board approval and informed consent was waived.

Another cohort from the Sun Yat-sen University Cancer Center (SYSUCC) was used as external validation data. It included all the gastric adenocarcinoma cancer patients who received therapy and had full record of follow-up in SYSUCC during 2001 and 2012 (Supplementary table 1). The study protocol for the Chinese cohort was approved by the independent Ethics Committees at SYSUCC.

A new TNM stage classification

Based on our analysis, we suggested setting up a new TNM staging system. In this new system, both T4aN2M0 and T4bN0M0 were classified as IIIB. Moreover, since there was no significant survival difference between patients with T4bN3bM0 and with stage IV. We restaged T4bN3bM0 as stage IV (Supplementary table 2).

Statistical Methods

The primary endpoint of this study was 5-year cause specific survival (CSS). Survival function estimation and comparison among different variables were performed using Kaplan-Meier estimates and the log-rank test. The multivariate Cox proportional hazard model was used to evaluate the hazard ratio (HR) and the 95 % CI for all the known prognostic factors, including location, race/ethnicity, histology, grade, TNM stage, grade and therapy (Surgery with or without radiotherapy). The discriminatory ability of the staging schemes was measured using the concordance index (C-index) [8] and the Akaike's information criterion (AIC). The prognostic homogeneity of the staging schemes was assessed using the Likelihood ratio χ² test. The higher the C-index and the likelihood ratio χ² value, or the lower the AIC value, the better performance of the staging scheme. We used the Intercooled Stata 13.0 (Stata Corporation, College Station, TX) and R software v. 3.2.3 (http://www.r-project.org) for analysis. Statistical significance was set at two-sided P < 0.05.

Results

Patient Demographics in SEER database

The study identified 18,125 gastric adenocarcinoma patients from SEER database (Table 1). Of these patients, 11,357 (62.66%) were male and 6,768 (37.34%) were female. The median age of the whole group was 66 years old. The patient distribution from 2004 to 2009 was balanced. Over two thirds of patients were Caucasian and about 15% of the patients were Asian. Most of the patients had poorly differentiated tumors and 23% of the patients had signet ring cell carcinoma. The most common tumor sites were cardia (27.54%) and antrum (21.51%). About 40% of the patients did not receive surgery. The surgery methods included palliative resection and radical resection. About half of the patients (47.81%) were diagnosed with metastatic diseases.

The average number of dissected lymph nodes was 10.45 ± 14.86 (mean ± SD) (median 6). The mean number of metastatic nodes was 6.54 ± 15.05 (median 2).

There were 2922 patients with N3 tumors including 1890 N3a (64.68%) and 1032 N3b (35.32%).

Stage Migration

Among the 18,125 gastric cancer patients, 16,540 (91.26%) of them have same stage in these 2 TNM classification systems including stage IA, IB, IIA and IV (Table 2). Stage migration only happened in 8.74% of GC patients, including 1.56% (282/18125) of patients migrating to a higher tier (the stage in the AJCC 8^th system was higher than the stage in the 7^th system) and 7.19% (1303/18125) migrating to a lower tier (the stage in the AJCC 8^th system was lower than the stage in the 7^th system). Only 15 (0.08%) patients were upstaged from stage IIB to stage IIIB and these patients were stage T1N3bM0. All the rest changes happened on stage III, including 27 patients (T2N3bM0) from stage IIIA to stage IIIB, 240 patients (T3N3bM0) from stage IIIB to stage IIIC, 477 (T4aN2M0) and 160 (T4bN0M0) from stage IIIB to stage IIIA, 515 (T4aN3aM0) and 151 (T4bN2M0) patients from stage IIIC to stage IIIB.

 Figure 1 

5-year cause specific survival between patients from two adjacent groups.

Is the stage migration necessary?

To better understand the stage migration in the 8^th edition of TNM classification, we compared the 5-year CSS between patients from two adjacent groups (Figure 1, supplementary table 3). We found that patients with stage IIIA had significantly better survival than patients with stage T4bN0M0 + T4aN2M0, P=0.0005. While there was no significant survival difference between patients with stage IIIB and stage T4bN0M0 + T4aN2M0, P=0.1705. Therefore it was better to treat T4bN0M0 + T4aN2M0 as stage IIIB as they were in the AJCC TNM 7^th edition. Patients with stage T4aN3aM0 + T4bN2M0 did have a better prognosis than patients with stage IIIC and there was no significant survival difference between patients with stage T4aN3aM0 + T4bN2M0 and stage IIIB. It is reasonable to change T4aN3aM0 + T4bN2M0 from stage IIIC to stage IIIB as in the 8^th edition. Patients with stage T3N3bM0 had a significantly better prognosis than stage IIIC and significantly worse prognosis than stage IIIB. Furthermore, we compared the survival among patients with stage T3N3bM0, T4aN3bM0, T4bN3aM0, T4bN3bM0 and TxNxM1 (Figure 3). We found that there was no significant difference among patients with stage T3N3bM0, T4aN3bM0 and T4bN3aM0, P=0.3041 and no survival difference between patients with stage T4bN3bM0 and TxNxM1, P=0.0551.

Survival analysis

The mean follow-up for the entire SEER cohort was 28.59 months. The overall 5-year CSS for the whole group of patients was 27.42% (95% CI: 26.73%-28.10%), with median survival of 13.0 months. Figure 2 showed the survival curve of patients according to the TNM 7^th edition (2A), TNM 8^th edition (2B) and the new TNM stage (2C). The median survival for patients with stage IA to stage IIA was not reached yet. The median survival for patients with stage IIB and stage IV remained the same in all the three TNM stage systems. The median survival for patients with stage from IIIA to IIIC was 29 months, 19 months and 14 months in the TNM 7^th edition, 26 months, 18 months and 12 months in the TNM 8^th edition and 26 months, 19 months and 12 months in the new TNM stage systems (Table 1).

The univariated analysis showed that ethnicity, tumor grade, location, histology subtype, surgery, TNM stage were all significantly related to the CSS (Table 1). Multivariated analysis for factors that had significant correlation with CSS showed that ethnicity, tumor grade, location, surgery and TNM stage were all independent prognostic factors. The performance of the 7^th, 8^th and the new staging system were assessed by the C-index, AIC and likelihood ratio χ2 value (Table 3). The new staging system had the highest C-index, likelihood ratio χ2 value and lowest AIC which suggested that the new staging system was best in predicting the prognosis.

Validation using GC patients from SYSUCC

In order to validate the value of the new staging system, we compared the three staging classification in Chinese GC patients from SYSUCC and we also found that the new staging system was best with the highest C-index as well as likelihood ratio χ2 value and lowest AIC (Table 3).

 Figure 2 

Survival curve of patients according to the TNM 7^th edition (A), TNM 8^th edition (B) and the new TNM stage (C).

 Figure 3 

Survival comparison among patients with stage T3N3bM0, T4aN3bM0, T4bN3aM0, T4bN3bM0 and TxNxM1.

Discussion

Accurate staging is essential to guide treatment and predict prognosis. In order to ensure that the cancer care community has the necessary infrastructure in place for documenting the 8^th Edition stage, the AJCC Executive Committee made the decision to delay the implementation of the 8^th Edition Cancer Staging System to January 1, 2018. New to the 8^th edition of the AJCC Cancer Staging Manual for epithelial cancers of the esophagus and esophagogastric junction are separate, temporally related cancer classifications: 1) before treatment decision (clinical); 2) after esophagectomy alone (pathologic); and 3) after preoperative therapy followed by gastrectomy (post-neoadjuvant pathologic). The addition of clinical and post neoadjuvant pathologic stage groupings needed to be validated in the clinical practise. Here, in our present study, we analysed the change to the pathologic TNM classification.

Compared to the change from 6^th edition to 7^th edition, the 8^th pTNM edition only made small changes. In the pTNM 8^th edition, pN3a and pN3b were treated differently in the final pTNM classification [5]. Stage migration only happened in 8.74% of GC patients. Basically, the main change happened in stage III patients. Only 15 (0.08%) patients were from stage IIB and they were upstaged to stage IIIB. In the TNM 8^th edition, the percentage of stage IIIA increased, while stage IIIB and IIIC decreased. Though the 8^th staging system had higher c-index than the 7^th edition, the difference was not significant. Lu J et al. evaluated the prognostic value of the AJCC TNM 8^th classification in comparison with the 7^th edition for stage III GC patients in China [6] and they found that the 8^th TNM edition was more accurate in predicting stage III gastric cancer patients' prognosis than the 7^th edition. However the C-index of 7^th and 8^th staging systems in Lu's research had no big difference. Similar results were reported in other malignancy diseases [9-14].

To analyse whether these were changes necessary, we compared the survival between patients from two adjacent groups. There was no significant difference between stage T1N3bM0 and stage IIIB, so it was reasonable to change stage T1N3bM0 from stage IIB to stage IIIC. However, there were only 15 patients in the category T1N3bM0 and 27 patients in the category T2N3bM0. The changes in these two categories did not affect a great number of patients. We found that patients with stage T4bN0M0+T4aN2M0 had no significant survival difference with stage IIIB, but worse survival than stage IIIA. Therefore it is better to treat T4bN0M0 + T4aN2M0 as stage IIIB as they were in the AJCC TNM 7^th edition. Patients with stage T4aN3aM0 + T4bN2M0 had a better prognosis than patients with stage IIIC and no survival difference with stage IIIB. So it is reasonable to change T4aN3aM0 + T4bN2M0 from stage IIIC to stage IIIB. Patients with stage T3N3bM0 had a significantly better prognosis than stage IIIC and significantly worse prognosis than stage IIIB. Stage IIIC included T4aN3bM0, T4bN3aM0 and T4bN3bM0. Further analysis showed that there was no survival difference among patients with stage T3N3bM0, T4aN3bM0 and T4bN3aM0. Moreover patients with stage T4bN3bM0 had similar survival with stage IV patients. Based on this analysis, we established a new staging system. We restaged T4bN0M0 + T4aN2M0 as stage IIIB, T4bN3bM0 as stage IV in the new staging system. We found that the new staging system was best in predicting the prognosis with the SEER database. Moreover, the prognostic superiority of the new staging system was validated in Chinese GC patients.

From 6^th to 7^th edition, several studies showed that 7^th edition TNM system performed better than the 6^th edition in several aspects, including our previous study [4, 15, 16]. Though the 8^th TNM staging classification seemed better than the 7^th, we found that there were several unnecessary stage modifications in the 8^th edition. By avoiding these unnecessary stage modifications and introducing more reasonable stage regrouping, we put forward a new staging classification which was better than both the 7^th and 8^th staging systems in predicting the prognosis. However, we need to realize that the value of TNM staging classification in predicting patients' prognosis has reached a plateau, because the newly proposed TNM staging showed only numerically but not statistically significantly improved C-index. To better predict patients' prognosis, other variables should be taken into consideration, such as histological and molecule phenotypes [17, 18]. It might be worthwhile to combine TNM classification system with molecular phenotypes [19-21].

The strength of this study included that we not only used the data from SEER, but also include dataset from our own hospital. Moreover, we put forward some modifications to the 8th TNM staging system, trying to make it better. Potential limitations of our study should be taken into consideration. Unmeasured factors in SEER database, such as chemotherapy and tumor biology might play roles in patient outcome. We did not put these factors into the cox regression analysis.

In conclusion, we demonstrated that it was more reasonable to treat T4bN0M0 + T4aN2M0 as stage IIIB. Furthermore we found that patients with stage T4bN3bM0 had similar survival with stage IV patients. Accordingly, we established a new staging system, which outperformed the 7^th and 8^th staging systems. However, the value of TNM staging classification in predicting patients' prognosis has reached a plateau.

Supplementary Material

Supplementary tables.

Acknowledgements

We would like to thank the staff members of the National Cancer Institute and their colleagues across the United States and at Information Management Services, Inc., who have been involved with the Surveillance, Epidemiology and End Results (SEER) Program.

Funding

This work was supported by National Natural Science Foundation of China (Grant number. 81602066, 81772587); the Fundamental Research Funds for the Central Universities (Grant number. 16ykpy25); the third outstanding young talents training plan of Sun Yat-sen University cancer center; Science and Technology Planning Project of Guangdong Province, China (Grant number. 2013A022100023); Natural Science Foundation of Guangdong Province, China (Grant number. 2014A030312015).

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding authors: Professor Da-jun Yang, MD, PhD, Department of Experimental Research, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel.: +86 20 8734 2285; Fax: +86 20 8734 2285; E-mail: yangdjorg.cn, Professor Feng-Hua Wang, Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel.: +86 20 8734 2490; Fax: +86 20 8734 2490; E-mail: wangfhorg.cn, Professor Rui-Hua Xu, Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China. Tel: +86-20-8734 3333; Fax: +86-20-8734 3295; E-mail: xurhorg.cn

Received 2018-3-28
Accepted 2018-7-27
Published 2018-9-8

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