Clinicopathological Characteristics and Outcome Indicators of Stage II Gastric Cancer According to the Japanese Classification of Gastric Cancer HITOSHI OJIMA 1, KEN-ICHIRO ARAKI 1, TOSHIHIDE KATO 1, KAORI OKAMURA 1, RYOKUHEI MANDA 1, ISAO HIRAYAMA 1, YASUO HOSOUCHI 1, YASUJI NISHIDA 1 and HIROYUKI KUWANO 2 1 Department of Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, 564-1 Kami-shinden, Maebashi, Gunma 371-0821; 2 Department of General Surgical Science, Gunma University Faculty of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan Abstract. Background: The characteristics of stage II gastric cancer according to the Japanese Classification of Gastric Cancer (JCGC) were examined and the high-risk factors predicting poor prognosis were detected. Patients and Methods: In total, 107 patients, who underwent clinically curative gastrectomy with D2 lymphadenectomy for stage II gastric cancer, were included. Survival curves of the depth of invasion, lymph node metastasis, the ratio of involved: resected lymph nodes and chemotherapy treatment were compared. Results: The survival curves were related to tumor invasion depth and lymph node metastasis. The ratio of involved resected lymph nodes was a good prognostic indicator compared to the classification of regional lymph node metastasis (N classification). Survival rates with adjuvant chemotherapy were slightly higher than without adjuvant chemotherapy, but the difference was not significant. Conclusion: pt2pn1 (stage II) gastric cancers according to the JCGC, especially psspn1 cases, included stage IIIB and IV gastric cancers according to the International Union Against Cancer / American Joint Committee on Cancer (UICC/AJCC); therefore, the prognosis of these might be poor. With psspn1 cases, according to the JCGC, anticancer chemotherapy equivalent to that required for stage III gastric cancer cases is necessary. The staging system for gastric cancer is very important for prognostic assessment. Classification of the local extent Correspondence to: Hitoshi Ojima, MD, Ph.D., Department of Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, 564-1 Kamishinden, Maebashi, Gunma 371-0821, Japan. Tel: 81(Japan)-27-252- 6011, Fax: 81(Japan)-27-253-0390, e-mail: hojima@showa.gunmau.ac.jp Key Words: Adjuvant chemotherapy, gastric cancer, prognostic factor. (T classification) of gastric cancer is identical in the International Union Against Cancer / American Joint Committee on Cancer (UICC/AJCC) system (1) and the Japanese classification (2). However, the classification of regional lymph node metastasis (N classification) differs. According to the UICC/AJCC, when the number of examined lymph nodes is insufficient for diagnosis, nodal stage might be underestimated; this is so-called stage migration. This discrepancy between classifications is, therefore, a problem for post-operative anticancer treatment. Early gastric cancer, especially stage I, can be almost completely cured by surgery alone. Stage III gastric cancer patients, on the other hand, are the target for adjuvant therapies, since a considerable number recur even after curative resection (3). The 5-year survival rate of stage II gastric cancer is about 70%; 30% recur (4-10) and there is no definitive treatment policy for this stage. This study focused on stage II gastric cancer classified according to the Japanese Classification of Gastric Cancer (JCGC) in order to determine the high-risk factors predicting recurrence in patients who had received curative resection. The indication for adjuvant chemotherapy in stage II gastric cancer patients was also examined. Patients and Methods One hundred and seven consecutive patients (74 men and 33 women; average age: 63.9±12.6 years) diagnosed with stage II gastric cancer were retrospectively reviewed. All had undergone curative gastrectomy between 1993 and 2004 at the Gunma University Faculty of Medicine or Gunma Prefecture Saiseikai- Maebashi Hospital, Japan. Total and distal gastrectomies were performed on 36 (33.6%) and 69 patients (66.4%), respectively. All received en bloc resection with D2 lymph node dissection according to the JCGC, with curative intent. Clinical and pathological classifications were determined according to the JCGC. Regional lymph nodes were also evaluated according to the UICC/AJCC. For multiple gastric carcinomas, 0250-7005/2006 $2.00+.40 1385
lesions that had invaded the deeper layers of the stomach, or that were the largest in diameter when multiple lesions invaded the same layer, were considered representative in all patients in this study. No consistent chemotherapeutic regimens had been followed. Forty-seven patients (41.1%) had undergone adjuvant chemotherapy: with tegafur (16 cases), with 5-Fluorouracil / cisplatin (5-FU / CDDP) (25 cases), or with other chemotherapeutics (6 cases). Because of the different regimens, the outcome of adjuvant chemotherapy could not be evaluated. The survival curves of all patients were analyzed using the Kaplan- Meier method and the log-rank test. Statview software was used for all the statistical analyses and significance was established at p<0.05. Results The clinical and pathological features of the 107 patients are presented in detail in Table I. The occurrence and patterns of recurrence and survival were analyzed. The features of stage II gastric cancer were: m n2, in no case, sm n2 in 6 cases, mp n1 in 26 cases, ss n1 in 51 cases and se n0 in 24 cases. Curative resection (curability A and B) was performed for all 107 patients. According to the JCGC, N1 was seen in 77 cases, N2 in 6 and N3 in 0 cases. On the other hand, according to the AJCC/UICC classification, N1 (1-6 involved regional lymph nodes) was seen in 73 cases, N2 (7-15 involved regional lymph nodes) in 6 and N3 (16 or more involved regional lymph nodes) in 4 cases. The distributions of n-classification between the JCGC and UICC/AJCC were different. Type 0 and 1 tumors were observed more frequently in recurrent-free cases (p<0.05). There were no significant differences with regard to gender, age, tumor location, histology, depth of invasion, operation method, lymph node metastasis, lymphatic invasion, venous invasion or curability between recurrent and recurrent-free cases. The survival curves for stage II gastric carcinomas, depending on the depth of invasion and lymph node metastasis, are provided in Figure 1. The 5- year survival rates according to the depth of invasion were 100% for sm n2 invasion, 88.5% for mp n1 invasion, 56.8% for ss n1 invasion and 79.2% for se n0 invasion. There were no significant differences between the groups, but the depth of tumor invasion and lymph node metastasis were related to prognosis. The survival rate of se n0 cases was slightly higher compared to the ss n1 cases. The survival curves, according to the N number of the UICC/AJCC classification, are provided in Figure 2. The 5-year survival rates according to the number of involved lymph nodes were 79.2% for N0, 76.8% for N1 and 75.0% for N2, respectively, and the 2-year survival rate for N3 was 50.0%. The survival curves virtually overlapped between N0 and N2. The N3 cases had a very poor prognosis compared to the overall 5-year survival rate of stage II gastric cancer. There were no significant differences between the groups. Table I. Clinicopathological features of recurrence in stage II gastric cancer patients. Feature Total Recurrent Recurrence- p-value n=107 cases free cases n=30 n=77 Gender Male 74 22 52 n.s Female 33 8 25 Age (mean ±SD; years) 63.9±12.6 74.3±10.3 60.9±12.5 n.s Tumor type 0 19 4 15 0.011746 1 7 0 7 2 28 8 20 3 39 13 26 4 12 5 7 5 2 0 2 Location of tumor Upper third 17 5 12 n.s Middle third 47 10 37 Lower third 37 13 24 Unknown 6 2 4 Histology Intestinal 35 13 32 n.s Diffuse 62 17 45 Depth of invasion # m 0 0 0 n.s sm 6 0 6 mp 26 3 23 ss 51 22 29 se 24 5 19 Operation Total gastrectomy 36 10 26 n.s Distal gastrectomy 69 20 49 Other 2 0 2 Lymph node metastasis (JCGC) n0 24 5 19 n.s n1 77 25 52 n2 6 0 6 n3 0 0 0 Lymph node metastasis (UICC/AJCC) n0 24 5 19 n.s n1 73 19 54 n2 6 4 2 n3 4 2 2 Lymphatic invasion ly0 5 1 4 n.s ly1 52 10 42 ly2 33 8 25 ly3 17 11 6 Venous invasion v0 47 12 35 n.s v1 42 13 29 v2 15 4 11 v3 3 1 2 Curability * A 74 21 53 n.s B 33 9 24 C 0 0 0 JCGC: Japanese Classification of Gastric Carcinoma. UICC/AJCC: International Union Against Cancer / American Joint Committee on Cancer. # m: mucosa; sm: submucosa; mp: muscularis propria; ss: subserosa; se: serosa expose. *A: No residual tumors, highly curable; B: No residual tumors but lower curability than A; C: Definitive residual tumors. n.s: not significant 1386
Ojima et al: Clinicopathological Characteristics of Stage II Gastric Cancer Figure 1. Survival curves according to the depth of invasion. There were no significant differences between the groups. m: mucosa, sm: submucosa, mp: muscularis propria, ss: subserosa, se: serosa expose. Figure 2. Survival curves according to lymph node metastasis (the UICC/AJCC classification). There were no significant differences between the groups. The number of involved lymph nodes depends on the number of total dissected lymph nodes; therefore, the involved lymph node ratio was investigated. The survival curves, according to the ratio of resected lymph nodes involved, are shown in Figure 3. The 5-year survival rates were 79.2% for a positive lymph node ratio of 1387
Figure 3. Survival curves according to the ratio of involved to resected lymph nodes. There were no significant differences between the groups. 0%, 85.0% for a positive lymph node ratio of 1-19% and 69.6% for a positive lymph node ratio of 20-49%, while the 2-year survival rate for a positive lymph node ratio over 50% was 25%. A positive lymph node ratio over 50% represented a poor prognosis, but there were no significant differences between the groups. The relationship between the JCGC and UICC/AJCC classifications is depicted in Figure 4. With pt3pn0 (stage II) cases, the JCGC was consistent with the UICC/AJCC. However, pt1pn2 cases according to the JCGC might become pt1pn1 (stage IB), pt1pn2 (stage II) and pt1pn3 (stage IV) according to the UICC/AJCC, while pt2pn1 according to the JCGC might become pt2pn1 (stage II), pt2pn2 (stage IIIA) and pt2pn3 (stage IV) according to the UICC/AJCC, depending on the number of involved lymph nodes. In our study, the following cases shifted: pt1pn2 (stage II) to pt1pn1 (stage IB), 5 cases, pt2pn1 (stage II) to pt2pn2 (stage IIIA), 5 cases and pt2pn1 (stage II) to pt2pn3 (stage IV), 4 cases. Although the pt1pn2 cases shifted in a positive direction, the pt2pn1 cases shifted negatively. The survival curves depending on adjuvant chemotherapy are presented in Figure 5. The 5-year survival rates with and without adjuvant chemotherapy were 70.5% and 65.2%, respectively. Patients who had undergone adjuvant chemotherapy showed slightly better survival rates compared to those who had not, but this difference was not significant. The characteristics of the patients who had received adjuvant chemotherapy and those who had not are presented in Table II. There were no significant differences with regard to the depth of invasion and involved lymph nodes between the 2 groups. Discussion Advances have been made in the curative surgery, anticancer chemotherapy and related adjuvant treatments for gastric cancer. With curative surgical techniques, the prognoses of stage I and II gastric cancer according to the JCGC and UICC/AJCC classifications were shown to be excellent and 5-year survival rates of stage IA, IB and II exceeded 90%, 80% and 70%, respectively (11). Stage I gastric cancer can be almost completely cured by surgery alone; in contrast, the 5-year survival rate of stage III gastric cancer is 50% (4-10) and curative surgery and anticancer chemotherapy are required. The efficacy of adjuvant chemotherapy is, however, controversial (12-17). The efficacy of adjuvant chemotherapy for stage II gastric cancer is also controversial, since no information is available as to whether curative surgery alone is sufficient for stage II gastric cancer or whether anticancer chemotherapy after curative surgery is also required. This study aimed to elucidate this by examining the characteristics of stage II gastric cancer. The degree of gastric wall invasion (T factor) and the extent of lymph node metastasis (N factor) have been shown to be significant prognostic factors in gastric cancer patients (4, 8, 9). Our treatment results of stage II gastric cancer according to the JCGC were consistent with this, except with regard to ss invasion. The discrepancy in ss invasion might be related to the N as well as the T factor. The JCGC and UICC/AJCC define nodal metastasis in gastric cancer differently; the extent of lymph node metastasis is classified according to anatomical location in the JCGC 1388
Ojima et al: Clinicopathological Characteristics of Stage II Gastric Cancer Figure 4. Relationship between the JCGC and UICC/AJCC classifications. Figure 5. Survival curves according to adjuvant chemotherapy. There were no significant differences between the 2 groups. definition, while the number of positive to regional nodes is defined in the UICC/AJCC definition; both classifications have specific benefits. According to the UICC/AJCC, if the number of examined lymph nodes is insufficient, diagnosis is incomplete. In this study, the average number of dissected lymph nodes was 26.6 and the minimum was 18; therefore, stage migration was not detected. Siewert et al. reported that extirpation of more than 25 lymph nodes had a prognostic impact on survival in patients with stage II and IIIA cancers (9). However, staging based on the number of lymph nodes dissected might not be accurate because it is dependent on the total number of dissected lymph nodes. Staging of lymph Table II. Characteristics of involved lymph nodes and depth of invasion in patients who had undergone adjuvant chemotherapy and those who had not. Chemotherapy ( ) Chemotherapy (+) No. 60 47 LN-positive number (AVG) 4.57 4.36 LN-positive ratio (AVG) 12.9 13.8 psm pn2 1 5 pmp pn1 17 9 pss pn1 29 22 pse pn0 13 11 p=0.322424. 1389
node metastasis should, therefore, be based on the number of involved lymph nodes, as reported elsewhere (18-20). The ratio of involved to resected lymph nodes was a good indicator of prognosis compared to the number of metastatic lymph nodes (18-20). In this study, cut-off points of 20% and 50% had been randomly chosen. As a result, cases showing a ratio of over 50% represented poor prognosis, while the 5- year survival rate of those with a ratio of less than 50% was about 70%, with a similar prognosis as standard stage II gastric cancer cases. We suggest that cases showing a ratio of over 50% should undergo the same post-operative treatment as stage III gastric cancer cases. Although pt1pn2 (stage II) cases, according to the JCGC classification, shifted to pt1pn1 (stage IB) cases according to the UICC/AJCC classification, no cases shifted to pt1pn3 (stage IV) according to the UICC/AJCC. On the other hand, since the pt2pn1 cases according to the JCGC shifted negatively, this result was consistent with the poor prognosis of psspn1 stage II gastric cancer. In our study, the 5-year survival rates were 100% for stage IA, 90.9% for stage IB, 69.2% for stage II, 60.1% for stage IIIA, 29.1% for stage IIIB and 4.7% for stage IV (data not shown). The 5-year survival rate of psspn1 cases was 56.8%, which was very close to that of stage IIIA cases. In conclusion, the prognosis of stage II gastric cancer according to the JCGC varied depending on the pathological features of the patient. Because pt2pn1 (stage II) gastric cancer according to the JCGC, especially psspn1 cases, includes stage IIIB and stage IV gastric cancer according to the UICC/AJCC, the prognosis might be poor. Moreover, with psspn1 cases, according to the JCGC, it is necessary to perform anticancer chemotherapy equivalent to cases representing stage III gastric cancer. The N number according to the UICC/AJCC reflected prognosis compared to that of the JCGC. We suggest that the staging of lymph node metastasis should be based on the relative number of involved lymph nodes. Cases showing a ratio of involved to resected lymph nodes over 50% should also undergo the same post-operative treatment as stage III gastric cancer cases. The prognosis of stage II gastric cancer was slightly improved by adjuvant chemotherapy; however, there were no significant differences between those patients who had received adjuvant chemotherapy and those who had not. Investigations using larger patient populations are required to further clarify the findings of the present study. References 1 Sobin LH and Wittekind CH: International Union Against Cancer. TNM Classification of Malignant Tumors, 6th edition. New York, John Wiley & Sons, 2002. 2 Japanese Classification of Gastric Carcinoma - 2nd English Edition - Japanese Gastric Cancer Association. 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