Journal of Surgical Oncology 45:169-172 (1990)

Adjuvant Chemotherapy Enhances long-Term Survival of Patients With Advanced Gastric Cancer Following Curative Resection YOSHlHlKO MAEHARA, MD, SUNAO MORIGUCHI, MD, YOSHlHlSA SAKAGUCHI, MD, YASUNORI EMI, MD, SHUNJI KOHNOE, MD, SHUNlCHl TSUJITANI, MD, AND KEIZO SUGIMACHI, MD From the Department of Surgery I I (Y.M., S.M., Y.S., S.T., K.S.) and Cancer Center of Kyushu University Hospital (Y.E., S.K., K.S.), Faculty of Medicine, Kyushu University, Fukuoka, lapan

We examined the effectiveness of postoperative adjuvant chemotherapy with mitomycin C (MMC), 1-(2-tetrahydrofury1)-5-fluorouracil (tegafur), plus PSK, an immunomodulator, for patients with advanced gastric cancer who underwent histological curative resection. The effect of chemotherapy on prognostic serosal (ps) invasion [ps(-) or ps(+)] and lymph node metastasis [n( -) or n( +)] was examined. One hundred eighteen patients were in the no-chemotherapy group and 137 were on the drugs. The median follow-up time for the 86 survivors at the time of analysis was 13.8 years. With regard to prognostic factors, there were no differences between the two groups. Generalized Wilcoxon test of the two survival patterns revealed a P value of .035 1, and the survival rate for 15 years was 45.7% for patients in the no-chemotherapy group and 56.9% for those of the chemotherapy group. In particular, adjuvant chemotherapy was effective for patients with ps(-)n(+) ( P < .05)and ps(+)n(-) ( P < .05), but not for those with ps( -)n( -) and ps( +)n( +). Our findings show that the concomitant prescription of MMC, tegafur, and PSK improves the 15-year survival rate for patients with advanced gastric cancer, following curative resection. As the survival rate is low for the patients with ps( +)n( +), an even more aggressive postoperative chemotherapy is recommended. KEYWORDS:mitomycin C, tegafur, PSK

INTRODUCTION Improvement in survival rates for patients with gastric cancer has been enhanced following emphasis on early diagnosis, operative techniques of extensive lymph node dissection [ 1,2], and postoperative adjuvant chemotherapy [3]. In a number of chemotherapy trials done in Japan [4-61, mitomycin C (MMC) was prescribed in combination with fluorinated pyrimidines, during the early postoperative period. Any delay in postoperative treatment can lead to negative results [7,8]. Fielding et al. [9] found no positive effects of adjuvant chemotherapy with MMC plus 5-fluorouracil(5-FU), but survival time was lengthened when treatment was begun within 1 month. Douglass [ 101 reported that postoperative chemotherapy 0 1990 Wiley-Liss, Inc.

should be initiated at the time of surgical resection. We followed for a median time of 13.8 years gastric cancer patients prescribed adjuvant chemotherapy consisting of MMC, 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur), and PSK, an immunomodulator [ 111. The treatment was initiated at the time of curative resection and the effect of chemotherapy on serosal invasion and lymph node metastasis was examined histologically.

Accepted for publication July 24, 1990. Address reprint requests to Yoshihiko Maehara, M.D., Department of Surgery 11, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan.

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Maehara et al. TABLE I. Comparison of Clinicopathological Characteristics Between No-Chemotherapy and Chemotherapy Groups

Factor Sex

Chemotherapy group (n = 137)

87 31

87 50

Male Female

Age Tumor maximal diameter (cm) Location of tumor Operation Borrmann

Histology Histological depth of invasion Histological lymph node metastasis a NS,

Category

No-chemotherapy group (n = 118)

52.9 3z 12.4 7.6 3.5

+

55.1 6.9

+ 11.1 + 3.1

Upper (C) Middle (M) Lower (A) Partial Total Type I Type 2 Type 3 Type 4 Type 5 Differentiated Undifferentiated ps (-1 ps (+I

35 45 38 71 47 6 30 47 25 60 58 40 78

35 40 62 91 46 2 41 60 15 19 77 60 37 100

n (-1 n (+I

45 73

44 93

10

P value NSa NS NS NS NS NS

NS NS NS

no significant difference.

PATIENTS AND METHODS Patients All patients included in this trial had advanced gastric cancer and underwent histological curative resection [ 111 in the Department of Surgery 11, Kyushu University Hospital, Fukuoka, Japan. From 1965 to 1983 255 patients accrued, with 118 patients in the no-chemotherapy group and 137 in the chemotherapy group. A comparison of clinicopathological characteristics between groups is shown in Table I. The protocol of chemotherapy was as follows: MMC 20 mg intravenous (i.v.) injection on the day of operation and 10 mg every 3 months for 1 year. Tegafur, 600 mg and PSK 3 g daily per 0s (p.0.) were prescribed from 7 to 10 days after the operation for as long as possible. PSK is a protein-bound polysaccharide preparation, extracted from Coriolus versicolor belonging to the Basidiomycetes class of fungi [12]. The criteria for patient selection were as follows: 1) histological diagnosis of gastric cancer; 2) histological diagnosis of a curative operation; 3) under age 76 years; 4) no evident synchronous or metachronous double cancer; 5 ) adequate organ system function (leukocyte > 4,000/mm3, GOT and GPT < 100 U); 6) grade of 0-3 in performance status [ 131. Pathological diagnosis and classification of the cases were evaluated according

to the General Rules for the Gastric Cancer Study in Surgery and Pathology in Japan [ 141.

Statistical Analysis The BMDP Statistical Package program for the IBM 4381 computer was used for all analyses [15]. The BMDP P4F and P3D programs were used for chi-square and t-tests to compare the two groups, with respect to clinicopathological characteristics. The BMDP P1L program was used to analyze survival rates, according to the method of Kaplan and Meier, and comparisons were made by the generalized Wilcoxon test. A P value of less than .05 was considered to be statistically significant. RESULTS Although the present study was not a prospective randomized trial, the distribution of patients between the two groups, according to clinicopathological characteristics, was balanced (Table I). Doses of Drugs For the chemotherapy group, the total doses prescribed over the entire duration of treatment were MMC 50.1 k 29.1 mg and tegafur 213.4 t 182.6 g in 137 cases, and PSK 11040.6 t 915.0 g in 88 cases. On the

Chemotherapy After Resection in Gastric Cancer

'OOm

0

5

10

15

Time after operation (years) Fig. 1. Survival curves for patients in no-chemotherapy and chemotherapy groups. TABLE 11. Actuarial 15-year Survival Rates of Patients in Each GrouD

No-chemotherapy grouu. %

Chemotherapy group, % 56.9 (137) 89.5 (19) 66.2 (18) 19.3 (29) 40.8 (75)

P value*

,0351 NSb

,029 1 ,0485 NS

*Generalized Wilcoxon test. aThe No. in parentheses is the case No. in each category bNS, no significant difference.

average, MMC was given four times, and tegafur and PSK were prescribed for 1 year.

Survival Rates Postoperative survival curves for the no-chemotherapy and chemotherapy groups are shown in Figure 1. At the time of this analysis, the median follow-up time for the 86 survivors was 13.8 years, and 169 (66.3%) of the 255 died. Generalized Wilcoxon test of the two survival patterns revealed a P value of .0351. Actuarial 15-year survival rates in each group are summarized in Table 11. The 15-year survival rates were 45.7% for the nochemotherapy group and 56.9% for chemotherapy group. The effect of treatment was evaluated according to pathological factors, particularly those influencing the prognosis: prognostic serosal invasion: ps( -) or ps( +) and presence or absence of metastasis to lymph nodes: n( -) or n( +) [ 14,161. The survival rates were better for patients with ps(+)n(-) (P < .05) and ps(-)n(+) ( P < .05), in the chemotherapy group, but not for those with ps( -)n( -) and ps( +)n( +).

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DISCUSSION For patients who require long-term postoperative cancer chemotherapy, we prescribe a by-bolus injection of MMC in the very early postoperative period, and continuous oral administration of tegafur and PSK [4,12], an approach found to have a significant life-prolonging effect. Other investigators also reported the effectiveness of postoperative adjuvant MMC and tegafur for patients with gastric cancer, and in particular those with stage I11 and ps(+)n(+) [5,6]. These drugs are in wide use in Japan to treat patients with gastric cancer. In Western countries, chemotherapy is most often not started until 4 to 6 weeks postoperatively, presumably to wait for an adequate anastomotic healing [lo]. As the average doubling time of gastric cancers is -40-80 days, the first initiation of drugs 6 weeks postoperatively is a time when the total tumor load of the patient has already doubled [17]. Free cancer cells were detected in the peritoneal cavity in 44% of the patients with gastric cancer and serosal invasion [ 181. Therefore, the potential to control minimal residual disease is reduced when chemotherapy is started later. Tumor cell population growth kinetics indicates that the ideal approach to curative therapy of advanced tumors is to use a cell cycle-nonspecific agent followed by a cell cycle-specific agent [ 19,201. These studies suggest that earlier initiation and maintenance chemotherapy (MMC plus tegafur) results in improved survival rates. To examine the effect of postoperative adjuvant chemotherapy on the long-term survival for patients with gastric cancer, we followed for a median time of 13.8 years patients with gastric cancer who underwent curative resection. Our findings show that the postoperative chemotherapy of MMC, tegafur, and PSK, which was continued for 1 year, leads to an extended survival time for those patients. In an analysis based on factors of serosal invasion (ps) and lymph node metastasis (n), this adjuvant chemotherapy is effective for patients with ps( -)n( +) and ps( +)n( -). As the survival rate for the patients with ps( +)n( +) remains low, presumably because of a large number of residual cancer cells [20], a more aggressive chemotherapy is needed. ACKNOWLEDGMENTS We thank M. Ohara for critical comments. REFERENCES Boku T, Nakane Y, Okusa T, Okusa T, Hirozane N, Imabayashi N, Hiroki K, Yamamoto M: Strategy for lymphadenectomy of gastric cancer. Surgery 105:585-592, 1989. Kodama Y , Sugimachi K, Soejima K, Matsusaka T, Inokuchi K: Evaluation of extensive lymphy node dissection for carcinoma of the stomach. World J Surg 5:241-248, 1981. The Gastrointestinal Tumor Study Group: Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer. Cancer 49:1116-1122, 1982.

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4. Kaibara N, Soejima K, Nakamura T, Inokuchi K: Postoperative long term chemotherapy for advanced gastric cancer. Jpn J Surg 6:54-59, 1976. 5. Inokuchi K, Hattori T, Taguchi T, Abe 0, Ogawa N: Postoperative adjuvant chemotherapy for gastric carcinoma. Analysis of data on 1805 patients followed for 5 years. Cancer 53:2393-2397, 1984. 6. Hattori T, Inokuchi K, Taguchi T, Abe 0: Postoperative adjuvant chemotherapy for gastric cancer, the second report. Analysis of data on 2873 Datients followed for five years. Jun J Surg16:175-180, 1986. 7. Engstrom PF, Lavin PT, Douglass HO, Brunner KW: Postoperative adiuvant 5-fluorouracil DIUS methvl-CCNU therauv for gastric &ncer patients. Cancer 35:1868-1873, 1985. 8. Higgins GA, Amadeo JH, Smith DE, Humphrey EW, Keehn RJ: Efficacy of prolonged intermittent therapy with combined 5-FU and methy-CCNU following resection for gastric carcinoma. Cancer 52:1105-1112, 1983. 9. Fielding JWL, Fagg SL, Jones BG, Ellis D, Hockey MS, Minawa A, Brookes VS, Craven JL, Mason MC, Timothy A, Waterhouse JAH, Wrigley PFM: An interim report of a prospective, randomized, controlled study of adjuvant chemotherapy in operable gastric cancer: British Stomach Cancer Group. World J Surg 7:39&399. 1983. 10. Douglass HO: Gastric cancer: Overview of current therapies. Semh Oncol 12:57-62, 1985. 11. Kano T, Kumashiro R, Tamada R, Kodama Y, Inokuchi K: Late results of postoperative long term cancer chemotherapy for advanced carcinoma of the stomach. Jpn J Surg 11:291-296, 1981. 12. Tsukagoshi S, Hashimoto Y, Fuji G, Kobayashi H, Nomoto K, Orita K: Krestin (PSK). Cancer Treat Rev 11:131-155, 1984.

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Adjuvant chemotherapy enhances long-term survival of patients with advanced gastric cancer following curative resection.

We examined the effectiveness of postoperative adjuvant chemotherapy with mitomycin C (MMC), 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur), plus PSK,...
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