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Validating the prognostic and discriminating value of the TNM-classification for gastric cancer – A critical appraisal

European Journal of Cancer, Volume 51, Issue 5, March 2015, Pages 577 - 586

Editorial comment from Professor Lordick:
Results of this important clinical-pathological study indicate that the current staging system of the UICC/AJCC for gastric cancer is suboptimal. Better prognostic classifiers are needed in order to optimize risk-adapted tumor therapy.

Abstract

Aim

We investigated the effect of the new tumour-, node-, metastasis- (TNM) classification on predicting and discriminating gastric cancer patient prognosis using the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program.

Patients and methods

From the SEER-database we retrieved gastric cancer patients with a primary adenocarcinoma, of Caucasian or Asian ethnicity and without distant metastases (M0). The pTNM-stage was determined according to the 7th edition of the union internationale contre le cancer (UICC) guidelines.

Results

Spanning the period 2004–2010, 6136 patients fulfilled all inclusion criteria including 3424 (55.8%) men, 2712 (44.2%) women, 4629 (75.4%) Caucasian and 1507 (24.6%) Asian patients. 1524 (24.8%) patients underwent total gastrectomy and 4612 (75.2%) non-total gastrectomy. Only in 41.2% of the patients were >15 lymph nodes resected. 1857 (31.0%) patients received radiotherapy. Patient survival depended on ethnicity, type of surgery and radiotherapy. The discriminating value of the UICC-stage grouping could not be validated for Caucasian patients with >15 lymph nodes resected and who had not received radiotherapy: stage groups IIB, IIIA, IIIB and IIIC showed substantial overlap in survival ranges. In addition, the tumour specific survival of the different T-/N-combinations was significantly different in stage groups IIIB and IIIC, respectively.

Conclusions

Our retrospective analysis of the SEER-database does not validate the discriminating value of stage grouping of the 7th edition of the UICC-stage grouping. A revision should be considered and more reliable prognostic biomarkers are urgently needed.

Keywords: Gastric cancer, TNM-classification, Prognosis, Stage grouping.

1. Introduction

Gastric cancer (GC) is the second leading cause of cancer related deaths in men and women [1] and [2]. The vast majority of GC patients are diagnosed with advanced stage disease with lymph node metastases already present, leading to poor prognosis [3], [4], [5], and [6]. Treatment options in patients with advanced GC are limited, but perioperative, adjuvant as well as palliative chemotherapy improve progression free and overall survival [7], [8], [9], and [10].

With regard to prognostic biomarkers, only the tumour- (T), node- (N), metastasis (M)-classification of the union internationale contre le cancer (UICC) is currently used on a routine basis. It is the most important instrument for tailoring oncologic treatment of cancer patients. Generally, the TNM-classification has stood the test of time and was never surpassed in multivariate analyses by another single prognostic biomarker, such as immunohistochemistry or RNA/DNA-based tests. The TNM-classification is used in clinical trials to select patients who are eligible for inclusion and in cancer registries to compare outcome between different series, across different countries, over different time periods (i.e. ethnicity, medical treatment developments, socio-cultural effects) and particularly between different studies. Thus, changes in the TNM-classification have many implications and effect directly cancer care patients receive.

A few years ago, the UICC published the 7th edition of the TNM classification, introducing many changes for GC [11] . Since then many studies aimed to validate the prognostic value of the new TNM-classification system for GC [12], [13], [14], [15], [16], [17], [18], [19], [20], and [21], particularly of the new stage grouping. Twice as many studies were carried out on Asian populations [12], [13], [14], [15], [17], [19], and [20] than on Western populations [16], [18], and [21]. However, concern arose whether the new stage grouping of GC is appropriate and clinically useful [16], [20], and [21]. Particularly, 32–65% of GC patients underwent stage migration from the 6th to the 7th edition of the TNM-classification scheme [14] and [21]. This raises concerns and in order to justify this substantial ‘patient migration’ among stage groups, stage grouping was either unnecessary for clinical purposes or it did not adequately reflect prognostic subgroups and needed urgent revision. What was the evidence for changing stage grouping and is the current TNM-classification more appropriate for the prediction of GC prognosis? Unfortunately, and different from national treatment guidelines [22] and [23], categories of evidence and consensus are not provided for the TNM-classification and decision processes are not publicised.

In view of the overwhelming number of Asian study cohorts and the paucity of Western study populations, we asked ourselves whether the Surveillance, Epidemiology and End Results (SEER)-database validates the prognostic and discriminating value of the novel UICC-stage grouping of GC and whether it may help to identify treatment effects on patient survival, which need to be considered, when the prognostic and discriminating value of the UICC-stage grouping of GC is validated.

2. Materials and methods

2.1. Patients

The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program registries are among the most accurate and complete population-based cancer registries in the world. The SEER Program is comprised of 18 cancer registries across the United States, including state, central, metropolitan and the Alaska Native registries. Together, they gather data from approximately 28% of the U.S. population ( http://seer.cancer.gov/ ). From the SEER database we retrieved GC patients using the following inclusion and exclusion criteria ( Suppl. Table 1 ). Patients were included when the primary tumour localisation was the stomach (C16.1 through C16.9), the patient was aged ⩾18 years, the patient was of Caucasian or Asian ethnicity (Chinese, Japanese, Korean or Vietnamese), histology had confirmed an adenocarcinoma (ICD-0-3M-8140/3, M-8142/3 through M-8145/3, M-8210/3, M-8211/3, M-8255/3, M-8260/3 through M-8263/3, M-8310/3, M-8323/3, M-8480/3, M-8481/3, M-8490/3). Patients were excluded when distant metastases were apparent (M1), histology identified a tumour type other than adenocarcinoma, T-category was not documented, patients suffered from more than one malignant tumour. We also excluded carcinoma of the cardia (C16.0), as these are classified either as GC or oesophageal cancer, depending on the extent of the disease. The pTNM-stage of all study patients was determined according to the 7th edition of the UICC guidelines.

2.2. Statistics

Statistical analyses were carried out with SPSS 20.0 (IBM Corporation, Armonk, NY, USA). Median overall and tumour specific survival was determined using the Kaplan–Meier method, and log-rank test was used to determine significance. For comparison, the median survival time, its standard deviation and 95% confidence interval were indicated. For continuous variables, differences between subgroups were tested using the T-test. A value of p ⩽ 0.05 was considered statistically significant. No adjustments were made.

3. Results

3.1. Study cohort and UICC

6136 patients fulfilled all inclusion criteria and were operated between 2004 and 2010. 55.8% of the patients were male (n = 3424) and 44.2% female (n = 2712). The age ranged from 18 to 100 years (Caucasian patients: median age 70 years; Asian patients: median age 69 years). The median overall survival time (OS) was 38.0 months, the median tumour specific survival (TSS) time was 75.0 months. The median overall 5-year survival rate was 42.0% (OS) and 51.7% (TSS). 1524 (24.8%) underwent total or near total gastrectomy and 4612 (75.2%) a non-total or non-near total gastrectomy. 1857 (31.0%) patients received radiotherapy. Patient characteristics are summarised in Table 1 .

Table 1 Clinico-pathological patients’ characteristics.

Characteristic   All Asian Caucasian
    n (%) n (%) n (%)
All patients   6136 1507 (24.6) 4629 (75.4)
Age at diagnosis <70 years 2997 (48.8) 770 (51.1) 2227 (48.1)
⩾70 years 3139 (51.2) 737 (48.9) 2402 (51.9)
Gender Male 3424 (55.8) 830 (55.1) 2594 (56.0)
Female 2712 (44.2) 677 (44.9) 2035 (44.0)
Localisation C16.1 (Fundus) 275 (4.5) 44 (2.9) 231 (5.0)
C16.2 (Gastric corpus) 770 (12.5) 179 (11.9) 591 (12.8)
C16.3 (Gastric antrum) 2153 (35.1) 622 (41.3) 1531 (33.1)
C16.4 (Pylorus) 348 (5.7) 76 (5.0) 272 (5.9)
C16.5 (Lesser curvature) 915 (14.9) 254 (16.9) 661 (14.3)
C16.6 (Greater curvature) 402 (6.6) 83 (5.5) 319 (6.9)
C16.8 (Overlapping regions) 564 (9.2) 114 (7.6) 450 (9.7)
C16.9 (Stomach NOS) 709 (11.6) 135 (9.0) 574 (12.4)
T-category T1a/b 1536 (25.1) 509 (33.9) 1027 (22.2)
T2 780 (12.7) 179 (11.9) 601 (13.0)
T3 1998 (32.6) 420 (27.9) 1578 (34.1)
T4a 1311 (21.4) 307 (20.4) 1004 (21.7)
T4b 502 (8.2) 88 (5.9) 414 (9.0)
Lymph nodes examined Median (Range) 14.0 (1–90) 16.0 (1–90) 13.0 (1–90)
Positive lymph nodes Median (Range) 1 (0–67) 1 (0–62) 1 (0–67)
N-category N0 2422 (41.8) 671 (46.0) 1751 (40.4)
N1 992 (17.1) 227 (15.5) 765 (17.6)
N2 976 (16.8) 215 (14.7) 761 (17.6)
N3a 965 (16.7) 234 (16.0) 731 (16.9)
N3b 440 (7.6) 113 (7.7) 327 (7.5)
Union internationale contre le cancer (UICC)-stage IA 1123 (19.4) 397 (27.3) 726 (16.8)
IB 568 (9.8) 157 (10.8) 411 (9.5)
IIA 826 (14.3) 169 (11.6) 657 (15.2)
IIB 695 (12.0) 162 (11.1) 533 (12.3)
IIIA 700 (12.1) 134 (9.2) 566 (13.1)
IIIB 1011 (17.5) 232 (15.9) 779 (18.0)
IIIC 863 (14.9) 205 (14.1) 658 (15.2)
Grading G1/G2 1696 (29.0) 414 (28.4) 1282 (29.1)
G3/G4 4152 (71.0) 1040 (71.6) 3112 (70.9)
Type of surgery Non-total gastrectomy 4612 (75.2) 1205 (80.0) 3407 (73.6)
Total gastrectomy 1524 (24.8) 302 (20.0) 1222 (26.4)
Radiotherapy No radiotherapy 4129 (67.3) 999 (66.3) 3130 (67.6)
Radiotherapy 1857 (30.3) 483 (32.1) 1374 (29.7)
Radiotherapy unknown 150 (2.4) 25 (1.7) 125 (2.7)

In the entire study cohort, overall (OS) and tumour specific survival (TSS) correlated significantly with UICC-stage grouping of GC (p < 0.001; Fig. 1 A and B; Suppl. Table 2A ). No difference was found in OS and TSS between men and women (data not shown).

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Fig. 1 Kaplan–Meier survival curves: The overall and tumour specific survival of the entire study population (n = 6136 patients) according to the stage grouping of the 7th edition of the union internationale contre le cancer (UICC)-stage grouping is shown in (A) and (B), respectively. Asian (n = 1507) and Caucasian (n = 4629) patients show highly significantly different tumour specific survival curves (C). A subgroup analysis of Caucasian patients (>15 lymph nodes resected, no radiotherapy) compared nine T-/N-combinations, each of which included >4% of the study population (D). Kaplan–Meier curves were not significantly different between a variety of T-/N-combinations (see also Suppl. Table 2B ).

3.2. Ethnicity

First we studied the influence of ethnicity. The OS and TSS differed significantly between Asian (median OS 74.0 months; 95%CI: not calculable) and Caucasian patients (median OS: 32.0 months; 95%CI: 29.4–34.6 months; p < 0.001; Fig. 1 C; Suppl. Table 3 ). To explore, whether survival differences were a result of different tumour stages, we correlated ethnicity with T-category, N-category and UICC-stages. No significant differences were found ( Table 1 ). In view of the significant survival differences between Asian and Caucasian patients we subsequently focused on Caucasian patients.

3.3. Gastrectomy

Next we explored the influence of surgery on patient survival in Caucasian patients. The cohort was separated into total or near-total gastrectomy [hereafter referred as total gastrectomy; 1222 (26.4%) patients] and non-total or non-near total gastrectomy [hereafter referred as non-total gastrectomy; 3407 (73.6%) patients]. Median OS and TSS were significantly better for patients with non-total gastrectomy ( Table 2 ; p < 0.001). No difference was found between men and women with regard to type of surgery. Interestingly, total gastrectomy was carried out significantly more commonly in younger patients (mean ± SD: 64.3 ± 13.2 years; median age 65.0 years) compared with non-total gastrectomy (mean ± SD: 67.0 ± 13.2 years; median age: 68.0 years; p < 0.001).

Table 2 Influence of type of surgery, number of lymph nodes resected and radiotherapy on overall and tumour specific patient survival in Caucasian patients.

  n Number of lymph nodes examined p-Value (T-test) Number of lymph node metastases p-Value (T-test) Lymph node ratio p-Value (T-test) Overall survival p-Value (Median) Tumour specific survival p-Value (Median)
Mean [SD] Median Mean [SD] Median Mean [SD] Median Mean ± SD 95% CI Median ± SD 95% CI Mean ± SD 95% CI Median ± SD 95% CI
Any gastrectomy 4629 15.8 ± 0.2 13   4.6 ± 0.1 1   0.28 ± 0.01 0.01   42.3 ± 0.6 41.2–43.4 32.0 ± 1.3 29.4–34.6 49.0 ± 0.6 47.8–50.1 53.0 n.c.
Any gastrectomy; with radiotherapy 1374 17.4 ± 0.3 15 <0.001 5.6 ± 0.2 3 <0.001 0.34 ± 0.01 0.25 <0.001 46.3 ± 1.0 44.3–48.2 38.0 ± 2.7 32.7–43.3 <0.001 50.5 ± 1.0 48.5–52.6 50.0 n.c. 0.001
Any gastrectomy; no radiotherapy 3130 15.0 ± 0.2 12 4.0 ± 0.1 0 0.25 ± 0.01 0 40.7 ± 0.7 39.3–42.0 29.0 ± 1.6 25.9–32.1 48.5 ± 0.7 47.1–49.9 59.0 n.c.
Any gastrectomy, N ⩽ 15 2514 8.3 ± 0.1 8 <0.001 2.3 ± 0.1 1 <0.001 0.27 ± 0.01 0.08 0.007 42.5 ± 0.8 41.0–44.0 32.0 ± 1.9 28.3–35.7 0.513 49.5 ± 0.8 47.9–51.0 56.0 n.c. 0.570
Any gastrectomy; N > 15 1799 26.3 ± 0.3 23 7.8 ± 0.2 4 0.29 ± 0.01 0.16 43.0 ± 0.9 41.2–44.9 33.0 ± 2.2 28.6–37.4 48.6 ± 1.0 46.7–50.5 49.0 n.c.
Any gastrectomy, N > 15, with radiotherapy 634 26.5 ± 0.4 23 0.500 8.3 ± 0.3 6 0.077 0.32 ± 0.01 0.23 0.005 46.6 ± 1.5 43.7–49.5 42.0 ± 4.5 33.2–50.8 <0.001 51.1 ± 1.5 48.2–54.1 59.0 n.c. <0.001
Any gastrectomy; N > 15; no radiotherapy 1102 26.1 ± 0.3 23 7.5 ± 0.3 2.5 0.28 ± 0.01 0.11 41.1 ± 1.2 38.7–43.5 30.0 ± 2.4 25.2–34.8 47.2 ± 1.2 44.7–49.6 44.0 n.c.
Total gastrectomy 1222 20.0 ± 0.4 17 <0.001 (versus Non-total) 7.2 ± 0.3 3 <0.001 (versus Non-total) 0.35 ± 0.01 0.24 <0.001 (versus Non-total) 35.0 ± 1.0 33.0–37.0 21.0 ± 1.3 18.5–23.5 <0.001 (versus Non-total) 40.8 ± 1.1 38.6–43.0 26.0 ± 2.1 21.9–30.1 <0.001 (versus Non-total)
Total gastrectomy; with radiotherapy 411 20.7 ± 0.7 18 0.188 7.4 ± 0.4 5 0.460 0.37 ± 0.02 0.29 0.126 37.8 ± 1.7 34.5–41.1 26.0 ± 2.5 21.1–30.9 <0.001 42.2 ± 1.8 38.6–45.7 32.0 ± 3.2 25.7–38.3 0.003
Total gastrectomy; no radiotherapy 777 19.5 ± 0.5 17 7.0 ± 0.4 2 0.34 ± 0.01 0.18 33.5 ± 1.3 30.9–36.1 18.0 ± 1.4 15.2–20.8 39.8 ± 1.4 37.0–42.6 23.0 ± 2.9 17.4–28.6
Total gastrectomy, N ⩽ 15 498 9.2 ± 0.2 10 <0.001 3.1 ± 0.2 1 <0.001 0.33 ± 0.02 0.20 0.127 36.1 ± 1.6 32.9–39.2 21.0 ± 1.5 18.1–23.9 0.527 42.0 ± 1.7 38.6–45.3 27.0 ± 3.9 19.3–34.7 0.353
Total gastrectomy, N > 15 668 28.1 ± 0.5 24 10.3 ± 0.4 7 0.36 ± 0.01 0.27 34.8 ± 1.4 32.0–37.6 21.0 ± 1.9 17.4–24.6 40.2 ± 1.5 37.2–43.2 26.0 ± 2.8 20.5–31.5
Total gastrectomy, N > 15, with radiotherapy 240 28.2 ± 0.8 24 0.884 9.9 ± 0.7 7 0.565 0.35 ± 0.02 0.27 0.711 36.0 ± 2.2 31.7–40.3 24.0 ± 3.0 18.2–29.8 0.031 41.5 ± 2.4 36.7–46.2 31.0 ± 4.9 21.4–40.6 0.023
Total gastrectomy, N > 15, no radiotherapy 404 28.1 ± 0.6 24 10.4 ± 0.6 6.5 0.36 ± 0.02 0.25 33.9 ± 1.9 30.2–37.5 18.0 ± 2.5 13.1–22.9 39.0 ± 2.0 35.1–42.9 23.0 ± 3.7 15.8–30.2
Non-total gastrectomy 3407 14.2 ± 0.2 12 <0.001 (versus Total) 3.6 ± 0.1 1 <0.001 (versus Total) 0.25 ± 0.01 0.09 <0.001 (versus Total) 45.0 ± 0.7 43.7–46.3 38.0 ± 2.2 33.7–42.3 <0.001 (versus Total) 52.0 ± 0.7 50.7–53.3 77.0 n.c. <0.001 (versus Total)
Non-total gastrectomy; with radiotherapy 963 15.9 ± 0.4 14 <0.001 4.8 ± 0.2 3 <0.001 0.33 ± 0.01 0.25 <0.001 49.7 ± 1.2 47.3–52.1 50.0 ± 5.6 39.1–60.9 <0.001 53.8 ± 1.2 51.4–56.1 n.c. n.c. 0.007
Non-total gastrectomy; no radiotherapy 2353 13.4 ± 0.2 11 3.0 ± 0.1 0 0.21 ± 0.01 0 43.1 ± 0.8 41.5–44.7 34.0 ± 2.4 29.3–38.7 51.5 ± 0.8 49.9–53.1 77.0 n.c.
Non-total gastrectomy, N ⩽ 15 2016 8.1 ± 0.1 8 <0.001 2.1 ± 0.1 1 <0.001 0.25 ± 0.01 0.07 0.866 44.1 ± 0.8 42.4–45.8 36.0 ± 2.6 30.8–41.2 0.003 51.3 ± 0.9 49.6–53.0 71.0 n.c. 0.068
Non-total gastrectomy, N > 15 1131 25.3 ± 0.3 22 6.3 ± 0.2 3 0.25 ± 0.01 0.12 48.1 ± 1.2 45.8–50.5 50.0 ± 6.0 38.3–61.7 53.7 ± 1.2 51.4–56.1 n.c. n.c.
Non-total gastrectomy, N > 15; with radiotherapy 698 25.5 ± 0.5 23 0.472 7.3 ± 0.4 5 0.003 0.30 ± 0.01 0.21 <0.001 73.0 n.c. n.c. n.c. <0.001 56.8 ± 1.8 53.2–60.4 n.c. n.c. 0.002
Non-total gastrectomy, N > 15; no radiotherapy 394 25.0 ± 0.4 22 5.8 ± 0.3 1 0.22 ± 0.01 0.06 45.4 ± 1.5 42.4–48.5 41.0 ± 6.7 27.8–54.2 52.1 ± 1.6 49.1–55.2 n.c. n.c.

The significant difference in survival may also reflect different disease stages, i.e. total gastrectomy was carried out more commonly in more advanced cases with a more unfavourable prognosis [24] and [25]. To test this hypothesis we analysed the T-category: 76.9% of the patients with total gastrectomy had T3/T4-tumours, compared with 59.9% of the non-total-gastrectomy patients. Thus, patients undergoing total gastrectomy had locally more advanced tumours.

3.4. Lymph node dissection

The extent of lymph node dissection (i.e. D2-lymphadenectomy) has been shown to improve significantly patient outcome and also depends on the type of surgery (i.e. total versus non-total gastrectomy). To test this in the study cohort, we analysed the number of lymph nodes resected, the number of lymph nodes with metastases and the lymph node (LN)-ratio. All three variables were significantly different between total and non-total gastrectomy. Patients who underwent total gastrectomy had significantly more lymph nodes resected, a greater number of lymph node metastases and also a significantly higher LN-ratio ( Table 2 ).

The UICC currently recommends that at least 16 lymph nodes should be examined prior to classify a GC as pN0. Next we divided the patients into two categories, i.e. ⩽15 and >15 lymph nodes resected. Most interestingly, the number of resected lymph nodes (⩽15 versus >15) did not correlate with OS or TSS in either the entire study cohort (=any gastrectomy) or the total gastrectomy group ( Table 2 ). This seemingly contradicts the general assumption that the extent of lymph node dissection improves patient prognosis.

3.5. Radiotherapy

1374 (29.7%) Caucasian patients received radiotherapy. In view of the missing correlation between patient prognosis and extent of lymph node dissection we hypothesised that radiotherapy interferes with the effects of the surgical procedures (i.e. extent of lymph node dissection): radiotherapy was applied slightly more commonly in the total gastrectomy (33.6%) compared with the non-total gastrectomy group (28.3%). We next explored in further detail the influence of radiotherapy on patient outcome.

Radiotherapy significantly prolonged OS and TSS in the entire cohort and in all subgroups ( Table 2 ).

The NCCN-guidelines recommend postoperative chemoradiation for GC based on tumour stage, nodal status, surgical margins and the extent of lymph node dissection [22] . To test, whether radiotherapy was applied in more advanced disease stages, we correlated the number of positive lymph nodes and the LN-ratio with radiotherapy. This showed that patients receiving radiotherapy had more lymph node metastases and a higher LN-ratio in the entire study cohort (=any gastrectomy), in the subgroup of any gastrectomy and >15 lymph nodes resected, the subgroups of non-total gastrectomy and non-total gastrectomy with >15 lymph nodes resected ( Table 2 ). These data show that radiotherapy was administered in more advanced stages of GC with greater number of positive lymph nodes and a higher LN-ratio improving OS and TSS.

3.6. Prognostic value of UICC-stage grouping

Collectively these data show that when it comes to validating the prognostic and discriminating value of the UICC-stage grouping, radiotherapy and extent of lymph node dissection should be considered. Both influence significantly OS and TSS and are not applied equally across all stage groups. Finally, we aimed to validate the prognostic and discriminative value of UICC-stage grouping in patients in whom >15 lymph nodes were resected and who had not received any radiotherapy. We investigated the 5-year TSS for the 25 different combinations of the T- and N-category ( Fig. 2 ; Suppl. Table 4 ). In general, 5-year TSS progressively declined with increasing T-category and increasing N-category ( Fig. 2 A). However, when the 25 different T-/N-combinations were ordered according to the stage grouping of the 7th edition, TSS was either similar between different stage groups (e.g. T3N1 in stage group IIB versus T4bN2 in stage group IIIC) or significantly different within a stage group (e.g. T3N2 versus T4aN1 in stage group IIIA; Fig. 2 B). To further analyse this heterogeneity, we carried out Kaplan Meier-analyses. These confirmed that 5-year TSS for the different T-/N-combinations was significantly different within stage group IIIB and IIIC ( Fig. 3 ). These significant differences were also found for the entire cohort (data not shown). These data show that the current UICC-staging system unites T-/N-combinations with very heterogeneous survival rates.

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Fig. 2 5-year tumour specific survival of all possible T-/N-combinations: The union internationale contre le cancer (UICC)-classification enables 25 different combinations of local tumour growth (T-category) and nodal spread (N-category). These were analysed for the entire cohort (n = 5786 patients; 350 missing values; blue bar) and the Caucasian gastric cancer patients with >15 lymph nodes resected and without radiotherapy (n = 1100; two missing values; red bar). Subsequently the different T-/N-combinations were ordered according to increasing T- and N-category (A) or according to the stage grouping of the UICC (B). Note the heterogeneity within the subgroups and similarity of survival rates between different subgroups.

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Fig. 3 Kaplan–Meier survival curves: Stage group IIB through IIIC of the union internationale contre le cancer (UICC)-classification combines between four and five different T-/N-combinations. The Kaplan–Meier analysis of these different T-/N-combinations in Caucasian gastric cancer patients with >15 lymph nodes resected and without radiotherapy showed that the 5-year tumour specific survival was significantly different in stage groups IIIB and IIIC.

Despite the large number of patients retrieved from the SEER-database, sixteen T-/N-combinations enclosed <4% (range 0.2–3.5%) of the patients. In the final step, we aimed to identify the most prevalent T-/N-combinations and studied the Kaplan–Meier curves of nine T-/N-combinations, each of which included >4% (range 4.4–18.6%) of the study population ( Fig. 1 D; Suppl. Table 2B ). This added up to 821 (73%) Caucasian patients, in whom >15 lymph nodes were resected and who had not received radiotherapy. Interestingly, Kaplan–Meier curves were not significantly different between a variety of T-/N-combinations ( Fig. 1 D; Suppl. Table 2B ).

4. Discussion

Our study of the SEER-database shows that a validation study for the prognostic and discriminative value of the TNM-classification has to consider ethnicity of the patient population, type of surgery and oncological treatment administered, as all significantly affect patient outcome and hence the utility of the data obtained. In the decade anteceding the publication of the 7th edition of the TNM-classification, seminal studies have set the basis for perioperative and adjuvant chemo(radio-)therapy of GC in Western countries [8] and [26], whilst in eastern Asia, adjuvant chemotherapy was already standard of care. Using the SEER-database, we identified significant effects of radiotherapy, which improved patient survival and is in line with previous investigations [27], [28], and [29]. Several recent validation studies of the 7th TNM-classification from eastern Asia included a substantial number of patients who received postoperative chemotherapy [15], [17], and [19]. Other studies failed to specify, whether adjuvant chemotherapy was administered, although being highly likely ( Table 3 ) [12], [13], and [20]. Even studies on Western patient populations already included 25% of patients with adjuvant or neoadjuvant chemotherapy [18] . The data provided by these studies are biased by therapeutic interventions and are inadequate to validate the prognostic utility of UICC-stage grouping, when the effects of surgery and chemotherapy on patient survival are not considered.

Table 3 Overview of recent validation studies of the 7th edition of the TNM-classification of gastric cancer. Recent validation studies are heterogeneous and several include patients who received pre- or postoperative (radio-) chemotherapy.

Reference Publication date Patient number Study period Ethnicity (City, Country) Perioperative or adjuvant chemotherapy
Ahn et al. [12] 2010 9998 1986–2006 Asian (Seoul, Korea) No preoperative chemotherapy. However, no data on postoperative/adjuvant chemotherapy
Kim et al. [15] 2011 464 1992–2009 Asian (Seoul, Korea) The systematic anticancer chemotherapy following the gastrectomy was a standard treatment regimen
Chae et al. [13] 2011 295 2002–2006 Asian (Korea) No information provided. Note: anticancer chemotherapy following the gastrectomy was a standard treatment regimen in Korea and Seoul [see Kim et al. [15] ]
Yoon et al. [20] 2012 1799 2001–2005 Asian (South Korea) Patients receiving preoperative chemotherapy were excluded; no information on post-operative chemotherapy
Fang et al. [14] 2011 1380 1987–2006 Asian (Taiwan) Adjuvant chemotherapy or radiotherapy after curative surgery was not performed routinely except when tumour recurrence was diagnosed or highly suspected
Qiu et al. [17] 2011 1000 1996–2006 Asian (South China) 50.6% of the patients received adjuvant chemotherapy
Sun et al. [19] 2012 1998 1980–2010 Asian (China) 61.4% of the patients received post-operative adjuvant chemotherapy
Warneke et al. [21] 2011 554 1997–2009 Caucasian (Germany) No chemotherapy
Reim et al. [18] 2013 1767 1989–2011 Caucasian (Germany) 6.6% of the patients received adjuvant chemotherapy
19% of the patients received neoadjuvant chemotherapy
Marrelli et al. [16] 2012 2090 1991–2005 Caucasian (Italy) No chemotherapy
McGhan et al. [43] 2012 13,547 2004–2007 Caucasian, African-American & Other (U.S.) All gastric cancer patients, T- and N-staging not solely based on pathological-anatomical investigation: 60% underwent cancer-directed surgery, 26% received radiation therapy
Current study 2014 6136 2004–2010 Caucasian & Asian (U.S.) 40.6% of the patients received radiotherapy
Total   41.028 1980–2011    

Several studies carried out on U.S. patient populations have shown that ethnicity impacts on patient survival probably reflecting a difference in tumour biology of GC [30], [31], [32], [33], [34], [35], and [36]. The impact of ethnicity on patient survival was also evident in our analysis and, irrespective of treatment standards, validation studies of the TNM-classification carried out on Asian patients cannot be directly compared with Caucasian patients: studies of mixed patient populations carry the risk of providing data, which intrinsically lead to an either over- or underestimation of the patient’s individual prognosis.

The UICC currently recommends that pN0 should only be applied when >15 lymph nodes have been resected. However, only 41.8% of the patients fulfilled this criterion in our analysis. There is overwhelming evidence that nodal status is strongly influenced by the number of lymph nodes resected and examined: the N-stage category increases proportionally with the number of lymph nodes examined [37] . Whilst the median number of lymph nodes resected and examined increased over time [24], [38], and [39], it has not minimised the risk of understaging due to low lymph node count [40] and [41]. Thus, TNM-stage grouping of GC carries a major risk of understaging and is not applicable to every GC patient, as a substantial number of elderly GC patients may not be eligible for gastrectomy with D2-lymph node dissection. The effect of understaging might be evident in Fig. 2 . The 5-year survival rate of T1N0- and T3N0-patients improved after patients were excluded with <15 lymph nodes resected and was probably related to the exclusion of patients with a false negative nodal status.

Independently from the risk of understaging, due to low lymph node count accurate stage grouping is unrealistic in almost 60% of the patients. GC is a disease of the elderly and comorbidities may prohibit curative gastrectomy and D2-lymph node dissection. In our analysis, the median patient age was 68 years for Caucasian patients and total gastrectomy was carried out significantly more commonly in younger patients. Individuals aged ⩾65 years comprise two thirds of patients diagnosed with GC every year in the United States [42] and they are less likely to receive cancer directed surgery even for curable disease [25] . Patient age correlates inversely with percentage of total gastrectomy, number of lymph nodes resected and adjuvant therapy [24] . Thus, alternative systems are necessary to increase the number of patients, in whom prognosis can be predicted more accurately in the real clinical setting. Integration of the lymph node ratio in the TNM-classification was suggested and may be more sensible in order to assess patient prognosis independently form lymph node counts. Different systems have been published to categorise lymph node ratios. However, independent validation of these lymph node ratio based stage groupings is still missing [40] and [41].

Finally, we were unable to validate the discriminative value of the current stage grouping of the 7th of the UICC-classification, after effects of ethnicity, chemotherapy and surgery were excluded. A comparison of the 5-year TSS of the 25 different possible T-/N-combinations showed a great heterogeneity within and between different stage groups ( Fig. 2 & Fig. 3 ). This finding is in line with previous observations made in other Western patient populations [16] and [21]. We were also unable to identify any pattern of T-/N-combinations, which would justify either a ‘mathematical’ or tumour biologically meaningful sorting into seven subgroups of patients without distant metastases (M0). Currently, the stage grouping reflects mainly a mathematical model, where the addition of the values of the T- and N-category equals the same sum total in each subgroup, e.g. in stage IIA [(T)1 + (N)2 = 3; (T)2 + (N)1 = 3; (T)3 + (N)0 = 3] etc. Validation of the prognostic value of the stage grouping was further compromised in the majority (16 out of 25) of T-/N-combinations by low patient counts (<4% of the patient population) showing large standard errors. In a final step we focused on nine T-/N-combinations, which enclosed at least 4% of the patient population and represented 73% of the entire population ( Fig. 1 C). However, again some T-/N-combinations falling into different stage groups did not show significant differences in their survival rates. Thus, stage grouping may need also revision with regard to the number of stage groups. Three instead of seven categories may be more meaningful, e.g. a low risk group with >60% 5-year survival rate (T1N0, T2N0, T3N0), an intermediate risk group with 20–60% 5-year survival rate (T3N1, T3N2, T3N3a, T4aN3a) and a high risk group with <20% 5-year survival rate (T3N3b, T4N3b). For many other T-/N-combinations there are no sufficient data yet, to classify them according to any stage grouping.

GC comprises an extremely heterogeneous disease group, which may prohibit any meaningful stage grouping based solely on local tumour growth and nodal spread. Further variables have shown to significantly influence patient survival such as histological phenotype and resection status. The SEER-database does not provide any information with regard to resection status and we did not include phenotype in our analysis, as this necessitates a centralised surgical pathological re-assessment of all cases.

In summary, our retrospective analysis of the SEER-database does not validate the prognostic and discriminating value of stage grouping of the 7th edition of the UICC-stage grouping. A revision should be considered also including lymph node ratios in order to prognosticate patient’s survival for those patients, in whom ⩽15 lymph nodes are resected, i.e. more than half of the GC patients. Furthermore, novel prognostic biomarkers are urgently needed, which reliably distinguish different patient groups independent from tumour type.

Conflict of interest statement

None declared.

Appendix A. Supplementary data

 

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Supplementary Table 1 Selection criteria of study population from the SEER-database illustrating the step-by-step case filtering procedure carried out in the study.

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Supplementary Table 2A Statistical analysis to Figure 1A & B. The Kaplan-Meier curves of the different stage groups according to the 7th edition of the UICC-classification were compared.

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Supplementary Table 3 Overall and tumour specific survival of Caucasian and Asian patients with gastric cancer in different UICC-stages.

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Supplementary Table 4A Raw-data of the 5-year survival rate of the 25 different T-/N-combinations of the 7th edition of the UICC ordered by ascending T- and N-category (complementary to Figure 2A including colour code).

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Footnotes

Department of Pathology, Christian-Albrechts-University, Kiel, Germany

Corresponding author at: Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, Haus 14, D-24105 Kiel, Germany. Tel.: +49 0 431 597 3401; fax: +49 0 431 597 3462.