Postoperative Adjuvant Immunochemotherapy with Mitomycin C, Tegafur, PSK and/or OK-432 for Gastric Cancer, with Special Reference to the Change in Stimulation Index after Gastrectomy Takao HATrORI,l Toshifusa NAKAJIMA,2 Hiroaki NAKAZATO,3 Tatsuzo TANABE,4 Kaneo YdKUCm,5 0 s a h i k o A~E,6 Tatsuhei KONDO,7 Tetsuo TAGUCHI,8 Nobuhiko Ko~tI, 9 Keizo SU~IMACm,TM Suketami TOMINAGA,11 Sumiaki TsumTTM and Kiyoshi INOKUCHI1~ ABSTRACT: In order to evaluate the efficacy o f combined immunochemotherapy with mitomycin-C, tegafur, PSK a n d / o r OK-432 as an adjunct for curatively resected gastric cancer, a prospective randomized controlled study using the envelope method was performed, in which 266 institutions from a r o u n d J a p a n participated. T h e 3 year survival rates for all cases, and for ps(+)" n(+) cases, were insignificanfly higher in the immunochemotherapy groups receiving PSK a n d / o r OK-432 than in the control group. However, because 28.2 p e r cent o f the cases were excluded from the final statistical analyses, the results of this study may have questionable statistical credibility. Changes in the stimulation index (SI) suggest that the administration of PSK may result in an inhibition of the immunosuppressive activity of cancer patients. T h e high SI group showed a significantly higher 4 year survival rate than the low SI group. KEY WORDS:

gastric cancer, mitomycin-C, tegafur, PSK, OK-432


Manykinds o f non-specific immunotheraThe Cooperative Project No. 1 of the Japanese Foundationfor Multidisciplinary Treatment of Cancer IShakai-Hoken Nakabaru Hospital 2TheDivision of Surgery, CancerInstitute Hospital, JapaneseFoundationfor CancerResearch 3The Department of Gastroenterological Surgery, AichiCancerCenterHospital *TheSecondDepartment of Surgery, Hokkaido University,Schoolof Medicine 5SendaiNational Hospital eTheDepartment of Surgery, Keio UniversitySchool ofMedicine 7TokaiCentralHospital ~TheDepartment of Surgery, Research Institute for

peutic agents are clinically applied in the treatment of cancer in Japan, and the different mechanisms o f each d r u g have been reported. In Japan, PSK and OK-432 are the

Microbial Diseases, Osaka University 9The Department of Surgery, University of Tokushima School of Medicine 1~ Second Department of Surgery, Kyushu UniversityFaculty of Medicine ~lTheDivision of Epidemiology, Aichi CancerCenter ResearchInstitute 12TheDepartment of Bacteriology, National Defense Medical College *~SagaPrefecturalHospital Kouseikan Reprint requests to: Takao Hattori, MD, ShakaiHoken Nakabaru Hospital, Mitarai, Shime-machi, Kasuya-gun, Fukuoka 811-22,Japan

J~ANrSEJOURNALOF SURGERY,VOL.20, No. 2 pp. 127-136, 1990


Jpn. J. Surg. March 1990

Hattori et al.

non-specific immunostimulating agents most broadly used in clinical fields. It is interesting that PSK, when administered to normal mice showed no enhancing effect on immune activity,1 but when administered t o tumor bearing mice with reduced immune activity, a recovery effect was observed. O n the other hand, it has b e e n reported that the administration o f OK-432 to normal mice activated macrophages and T-lymphocytes2,3 and increased their immunoreaction? T h e combined use of these two agents thus seemed reasonable and was therefore selected for investigation. Cooperative project No. 1 of the Japanese Foundation for Multidisciplinary Treatment of Cancer was established for observing the effects of the combined use of PSK a n d / o r OK-432 as an adjuvant immunochemotherapy after surgery for gastric cancer. In this paper, the 3 year survival rates and changes in immunoparameters, such as the Stimulation Index (SI) 5 and Immunosuppressive Acidic Protein (IAP) 6 are reported. MATERIALS AND METHODS

Treatment schedule Two h u n d r e d and sixty six institutions participated in this co-operative study in which gastric cancer patients aged under 75 years, who had undergone no previous treatment, including surgery, radiation, chemotherapy, or immunotherapy, and whose disease complied with the following conditions, were entered. 1. Cases of Stages II or III, diagnosed macroscopically, and curative resection cases, excluding m. n o classified according to the General Rules for Gastric Cancer Study.~ 2. Cases in which a histologically definite diagnosis o f gastric cancer had b e e n obtained. 3. Cases having no malignant cancer in any other region at the same or different times. 4. Cases having no multiple gastric cancers

Mitomycin-C 20rag (lOmg). ~ I Group A It I Op. 2W


[ 8Mo

Mitomycin-C 20rag (10 rag). Group B l i I Op. 2W]

Tegafur PSK

Mitomycin-C 20mg (lOrag) ~1 2W I Group C IL...I Op t

Tegafur 0K-432


Mitomycin-C 20mg (10 rag) Group D I I ~ 2WI Op. L__]

Tegafur PSK 0K-432





Fig. 1. Treatment regimen in each group. Tegafur: 600 mg/day, to a total 150 g (p.o.) PSK: 3 g/day, to a total 750 g (p.o.) OK-432:0.5~5.0 KE/day, to a total 100 KE (i.c. or i.m.) at the time of operation. All cases were randomly allocated to One of 4 therapeutic groups as shown below (Fig. 1) by using the envelope method. I n each group, mitomycin C (MMC) was administered intravenously on the day of operation and the following day, at dosages of 20 mg and 10 mg respectively. However, the additional 10 mgwas not given in cases where the patient's body weight was less than 40 kg or if the age was 70 years or over, or in cases where surgery was accompanied by complicated resection of other organs. In Group & 600 m g / d a y of Tegafur was administered orally for 8 months, commencing from 2 weeks after the operation, until a total dose of 150 g had b e e n given. In Group B, PSK was added to the regimen o f Group A at a dose of 3 g/day, administered orally, also commencing from 2 weeks after the operation and continuing for 8 months, until a total dose o f 750 g of PSK had b e e n given, In Group C, OK-432 was added to the regimen of Group A, commencing with an intradermal injection o f OI(-432 on the day of the operation, after which the dose was in-

Volume 20 Number 2

tmmunochemotherapyfor gastric cancer

creased gradually in the following manner: 0.5 KE on the day o f the operation, 1 ICE on the 3rd day, 2 KE o n the 5th day, 5 KE on the 7th day, then 5 K E / w e e k for the following 3 weeks, and thereafter 5 KE once every two weeks for 8 months. Immunological parameters 1. Serum o f the patients. Serum was collected from 523 patients in 51 institutions preoperatively, then, 3 months, 6 months, 9 months, 18 months, and 24 m o n t h s after surgery. Analysis o f the s e r u m was performed in the Department o f Bacteriology at the National Defense Medical College. 2. Stimulation I n d e x (SI). Lymphocytes were obtained from the spleen o f C57BL/6 mice. Twenty five /A o f a test serum, or normal serum as a control, diluted 4 fold with PRMI 1640, and 25/xl o f a solution o f PHA-P (Gibco) in RPMI 1640 (4.0 /tl/ml) were then added to 50 /tl o f lymphocytesuspension (107 cells/ml in PRMI 1640). T h e mixture was cultivated at 37~ u n d e r 5 per


cent CO 2 for 68 hrs, and after the addition of 10/~1 o f 3H-thymidine (0.1/~Ci//xl), the mixture was incubated for 4 hrs. Radioactivity was measured by a liquid scintillation counter, and SI was calculated by the following formula. SI={PHA (+) -- PHA (--)}/PHA (--) where PHA (+) was the radioactivity in the system with PHA; and P H A (--) was the radioactivity in the system without PHA. 3. I m m u n o s u p p r e s s i v e Acidic Protein (LAP). A total o f 888 cases from 51 institutions were investigated for serum analysis. IAP was m e a s u r e d by using a single radial i m m u n o diffusion agarose plate containing anti-LAP serum. RESULTS

Three year survival rates A total 7637 J a p a n e s e patients with gastric cancer who underwent curative gastrectomy at 266 institutions from a r o u n d J a p a n be-

Table 1. Cases of Exclusion and Withdrawal A





Total Cases Entered








381 (21.1)

325 (16.7)

352 (18.5)

338 (17.9)

1396 (18.3)

113 96 22 34 59 9 4 17 2 82 4

90 90 21 24 43 3 4 22 2 69 3

99 89 21 28 39 4 6 21 7 82 5

89 78 27 27 42 1 9 22 4 83 2

391 353 91 113 183 17 23 82 14 316 13

Withdrawal due to Treatment Schedule

159 (8.4)

191 (9.8)

192 (10.1)

215 (11.4)

757 (9.9)

Exclusion plus Withdrawal

540 (28.5)

516 (26.5)

544 (28.5)

553 (29.2)

2153 (28.2)

Eligible Cases

1357 (71.5)

1426 (73.4)

1363 (71.4)

1338 (70.8)

5484 (71.8) (%)

m no Stage I or IV Non curative resection Over 76 years of age Multiple cancers Double cancers Previous treatment Non-gastric cancer Unclear description Randomization error Others

Jpn. J. Surg. March 1990

Hattori et al.


tween April, 1981 and August, 1983, were entered in this trial. However, 1396 patients were excluded (18.3 per cent) for the following reasons: 391 had m" n o early cancer, 353 h a d Stage I or IV, 91 w e r e resected nocuratively, 113 were over 76 years old, 200 h a d multiple cancers, 23 had received previous treatment, 82 did not have cancer, 14 were reported with an unclear description, and 316 had randomization error or violadon. An additional !3 patients were withdrawn for other reasons and another 757 (9.9 per cent) were withdrawn from this study due to difficulties involving the administration regimens. Thus, a total 5484 patients (71.8 per cent) were included in the final Table 2.

ps(+)'n(+) Cases

SI of the patient's serum The SI o f the serum collected preoperatively was compared with that of the healthy volunteers from the National Defense Medi-

3 Year Survival Rates for All Cases and ps(+)" n(+) Cases*

Group All cases

analysis (Table 1). The 3 year survival rates (Kaplan-Meier method) for all cases were: 69.6 p e r cent in 9 Group A, 71.6 per cent in Group B, 68.7 per cent in Group C and 69.1 per cent in Group D, respectively. Furthermore, the 3 year survival rates for the ps(+)" n(+) cases were: 50.3 per c e n t in Group A, 53.9 per cent in Group B, 52.6 per cent in Group C, and 54.9 per cent in Group D, respectivelY (Table 2). No significant differences were observed between the 4 groups.






No. of cases Survival rate (%)

1357 69.6

1426 71.6

1363 68.7

1338 69.1

5484 69.8

No. of cases Survival rate (%)

576 50.3

574 53.9

590 52.6

585 54.9

2325 52.9

Generalized Wilcoxon test (pairwise p) All cases A vs B p=0.277 B vs C p=0.178 A vs C p=0.820 B vs D p=0.260 A vs D p=0.972 C vs D p=0.844 ps(+) 9n(+) A vs B p=0.450 B vs C p=0.970 A vs C p=0.392 B vs D p=0.461 cases A vs D p=0.129 C vs D p=0.482 *ps(+) means histologically positive for serosal invasion n(+) means histologically positive for lymphnode metastasis Table 3. SI (Stimulation Index) of the Serum from Healthy Volunteers and Patients with Cancer Age

Healthy Volunteers No. of SI Cases (mean_SE)

Patients with Cancer No. of SI Cases (mean_SE)

20--29 30~39 40~49 50--59 60~69 70--79

20 15 20 20 20 17

19.18-t-0.32 19.07__.0.39 17.20_--_0.22 16.37+__0.40 15.08-1-0.22 16.99-t-0.30

2 39 71 168 157 59

17.90-t-4.10 "12.94___1.28 *10.81-t-0.69 *11.00___0.53 *10.65-t-0.58 *11.59-t-0.98

Eligible Cases





9 Significance p

or OK-432 for gastric cancer, with special reference to the change in stimulation index after gastrectomy.

In order to evaluate the efficacy of combined immunochemotherapy with mitomycin-C, tegafur, PSK and/or OK-432 as an adjunct for curatively resected ga...
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