Biomed & Pharmacother(l99 I) 45,121,124 0 Elsevier. Paris

121

M Niimoto’, T Hattori* ~~timoio Clinic. ~atoba~ho, i-8-16. r~i~mi-ku, Hiroshima 732; ~~aka~ru ffospi~al~ F~uoka, Japan

Summary - The efficacy of Bestatin as adjuvant immunochemotherapy in patients with resectable gastric cancer was investigated. Ninety-six patients with similar background factors were randomized into 2 groups: a control group and an experimental group, the patients in the latter group receiving a daily oral dose of 6Q mg Bestatin over a long period. Ail 96 patients were treated with a bolus int~venous injection of mit~ycin C (MMC) plus oral a~inis~ation of tegafur {FT-207. FT), The survival rate of the patients in the MMC+~+Bestatin group was more favorable than that of the patients in the MMC+PT group, but the difference was not statistically significant. The survival rates of the MMC+FT+Bestatin group patients in the stratification of stage III+IV and positive histological serosal invasion, ps(+). were significantly superior to those of the MMC+PT group patients (Logrank test: p c 0.05). Moreover, in patients with positive histological serosal invasion, the recurrence of peritoneal dissemination was significantly suppressed in the MMC+FT+Bestatin group. gastric cancer / chemotherapy / Besfatin Rhme - &de prospective et randomisie eontre t4moins des effets de la Bestatine au cows du cancer gastrique rMquable. Lrs auteurs explorent ici I’efficacite’ de la Bestatine comme immune-chimiothtrapie adjuvante ckez des malades porteurs dun cancer gastrique restfquable. Quatre vingt seize malades, au terrain par ailleurs semblable, ont Pte randomis& en dew groupcs: un groupc t&noin et un groupe experimental. Les malades du groupe experimental ont regu, sur une pcFriode prolongrlu, Ia Bestaiine per OS d Aa dose de 60 mg par jour. Les 96 malades ont PIP traitis par l’injection infraseineuse dun bolus de n~i~on~~cineC @iMC] et ~adntinistration orale de tagafar {FT-207, FT). Le taux de survie des n~alades dans ie groupe MMC + FT + Bestatine s’est revel& plus chortle que celui du groupe MMC + FT, mais ia d.#&ence nest pas statistiql~en~cnt signifcative. En revanche, les taut de survie du groupe MMC + FT + Bestatine darts sa stratification Stade III + IV et invasion s&reuse histologiquement positive @s+) ont Lite’significativement superieurs ri ceuz du groupe MMC + FT (p c &OS). En outre, chez les malades aver invasion sireuse histologiquement positive, les recidives de dissbu’nafion peritoneale ant ire’ significativement reduites dans le groupe MMC + FT + Bestatine.

cancer gastrique I’ chimtoth~rapie I Bestatine

Introduction PSK) was investigated [5]. Recently, postoperative adjuvant immunochemotberapy for resectable gastric cancer has been carried out by

sic&w,

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan has been studying the effects of the combined use of mitomycin C (MMC) and tegafur (FT-207, FT). In fact, the efficacy of FT administration after MMC induction therapy was reported by this group [I, 21. In a pilot study, the efficacy of postoperative immunochemotherapy using Krestin (protein-bound polysaccharide from Cariolus ver-

many investigators and has become popular practice in Japan. We present an analysis of the data obtained from administering postoperative adjuvant immunochemotherapy with MMC, FT and Bestatin, a biological response modifier, in resectable gastric cancer.

M Niimoto, T Hattori

122

Materials and Methods

lymphoma and another 2 were withdrawn for violation of protocol. Thus, a total of 96 patients

One hundred gastric cancer patients aged c 75 yr who underwent gastrectomy without any prior treatment were divided into 2 groups at random by the envelope method. Twenty mg of mitomycin C (MMC) was administered intravenously on the day of gastrectomy and an additional IO mg was given the next day in all cases, except those over the age of 70 yr, who weighed c 40 kg, or who had undergone a total gastrectomy with combined resection of the colon or pancreas. The group that received MMC plus tegafur (FI’-207, FT) comprised the active control group (group A) and a daily dose of m 600 mg was administered lo the patients in both groups. Bestatin, which was discovered in the culture filtrate of Sfreprum_vces olivoreticdi 163 and supplied by the Research Institute of Nihonkayaku Co, Ltd, was administered at a daily dose of 60 mg orally for 1 yr from = I wk after the operation, to the group B patients (fig 1).

were included in the final evaluation: 45 in group A (MMC+FT) and 51 in group B (MMC+FT+Bestatin). The x2 test was used to evaluate background uniformity and consequently there were no statistically significant differences between the 2 groups and uniformity of randomization was well maintained [7].

Castrectomy Croup A

1 lll(lkl .. fi-Futratul

2

3

4 -

h/day) CroupB

1 ii-

5 Weeks Futraful catwded (600mg/day&al)

1

..” c-Futraful MMC (20+10)mghea

suppository--

The 7-yr survival rates were 37.6% in group A and 56.5% in group B, respectively. The group B survival rate was higher than that of group A in all cases; however, the differences observed between group A and B were not significant (fig 2). Survival studied by stratification

To outpatient 1 suppository-

Overall survival

Futraful capsule-

(600mg/day,oral) h/day) Bestatin (bOmg/day.oral) of early gastric cancer are excluded

Ps (+I Tine 7-yr survival rates of the patients with positive histological serosal invasion, ps (+), were 13.3% in group A and 48.3% in group B, respectively. The comparison between groups A and B was statistically significant (Logrank test: p c 0.05) (fig 3).

Fig 1. Trealment schedule for the administration of adjuvant immunochemothempy in gastric cancer patients.

Stage ZZZ+ZV

The General Rules for Gastric Cancer Study in Surgery and Pathology [ 31 were used for the histopathological findings. As immunological parameters, PPD (purified tuberculin derivative) skin test and lymphocyte blastogenesis to PHA (phytohemagglutinin) were investigated before and after gastrectomy. The differences in background factors of the 2 groups were evaluated by the II’ test before examining survival rates, and survival probabilities for a given time period were described by the Kaplan-Meier method. Comparisons between the 2 groups were carried out by the Logrank test and the generalized Wilcoxon test.

showed a significantly longer survival time than group A (Logrank test: p c 0.05) (fig 4).

Survival patients

rate in the 2 groups was compared with stage III and IV disease. Group

A 37.6%(n=45)

Results A total of 100 gastric cancer patients

who underwent curative gastrectomy in the surgical department of Hiroshima University Hospital between November 1980 and April 1984 were studied. Four patients were eliminated from the study (4%) for the following reasons: 2 had malignant

in B

-T-

0

2

3

Years after

4

5

6

7 (Y)

Gastrectomy

Fig 2. Overall survival curves. Two groups tested; L-R: 0.1644, G-W: 0.2112 (L-R: Logrank Lest, G-W: generalized Wilcoxon test).

in resectable gastric cancer

Bestatin

123

Table L Recurrent period of peritonealdisserninafon afm

(%I

gastrectomy.

‘““Pi

Yr Noof cases afier gastrectomy

0

1

2

3

4

5

* 7(Y)

6

GrqB**

44

52

s (11.4)

Tota 96

-2 -3 Over 3

3 (6.8) 2 (4.5) 3 (6.8)

3 (5.8) l(1.9) l(1.9) 3 (5.8)

g (8.3) 4 (4.2) 3 (3.1) 6 (6.3)

Total

13 (29.5)

8 (15.4)

21 (21.9)

-1

A 13.3%(n=24)

GrcatrpA*

( ):% + Grottp A: mitomycinC+W-20% ** Group B: mitomycin

Years after Castrectomy

C+FT-207+Eestatin.

Fig 3. Survival curves of the ps(+) cases. Two groups tested; L-R: 0.0399, G-W: 0.1238.

Tabte II. Co~latiou~tw~n~~tone~

di~rn~ti~~d

histologicalserosal invasion.

ceases Pw** Peritoneal Dissemination (+I

GrottoA *** Grozw8 *** 23 13/23 (56.5%)*

31 7l31 (22.6%!*

* p < 0.05, ** ps bistologkal peritooeai divines table I for footnote.

A lSS%(n=26)

I

1

2

3

yCi1F5

iiftcr

4

5

6

7

(Y)

Gastrcctomy

Fig 4. Survival curves of the stage Ill + IV cases. Two groups tested: L-R: 0.0275. G-W: 0.0870.

Cases

of recur~etzce

Recurrence of peritoneal dissemination was seen within 2 yt of gastrectamy in both groups. However, the preventive effectiveness of Bestatin was suggested by findings of postoperative peritoneal recurrence in cases with positive histological invasion into the veins of the stomach wall (table I). Among the positive cases of peritoneal serosal invasion, recurrence of peritoneal dissemination was seen less frequently in the Bestatin-treated group than in group A (table II).

The course of changes in the PPD skin test after gastr~ctomy was investigated, and the postopera-

Tot& 54 20154 (37.0%) ***

See

tive test values after 6 montbs were found to btslightly higker than those prior to the operation in group B. The changes in lymphocyte blastogenesis induced by PHA in the peripheral blood of patients were not significantly different between the 2 groups. Side-effects No side-effects associated with the administration of Bestatin were detected and the effectiveness of Bestatin was confirmed by postoperative changes revealed by liver function tests, especially GOT and GPT.

Discussion PSK, a protein-bound polysacch~ide extracted from Coriolus versicoh, is the most common immunostimulant agent and it has also been reported that adjuvant immunochemotherapy with MMC, IT-207 and PSK yielded better survival in overall

124

M Niimoto, T Hattori

survival curves [5]. The adjuvant effect of PSK was prominent among patients who had a positive PPD reaction before gastrectomy. On the other hand, levamisole, a synthetic antihelminthic used in postoperative adjuvant immunochemotherapy, is controversial with regard to its clinical benefit

141. The reaction to the PPD skin test did not increase remarkably when using Bestatin. Furthermore, the changes in lymphocyte blastogenesis induced by PHA in the peripheral bliood of the patients were not signi~~an~y different between the 2 groups. Nevertheless, analyses of the present study indicated that immunotherapy with Bestatin prolonged survival significantly. An analysis of patient survival characteristics showed significantly better results in the ps(+) cases of the Bestatin-treated group than in those of group A. In the ps(+) cases, the number of cases of recurrent peritoneal dissemination were fewer in group I3 than in group A (table II). The effectiveness of Bestatin was also shown in the treatment of peritoneal dissemination relapse. In our pilot study, maintenance treatment with oral Bestatin and FT administmtion after an MMC bolus injection seemed to improve the 5-yr survival rate of patients with ps(+).

Conclusion The results of this pilot study on reseetable gastric cancer indicate the useftllness of adjuvant immunochemotherapy combined with MMC, tegafur and biological response modifiers. However, although good results were obtained for stage III and stage IV advanced gastric cancer, it is difficult to investigate a sufficient number of cases at only one institution. Randomized trials with Bestatin in the treatment of gastric cancer have not yet provided conclusive results and thus, an adju-

vant immunochemotherapy trial for gastric cancer patients in the form of multi-institutional cooperative studies might be required.

References Hattori T, Inokuchi K, Taguchi T, Abe 0, Inoue K, Kondo T, Kikuchi K, Kasaif Y (6985) Postoperative long-term adjuvant chemotherapy for gastric cancer. Second study of five-year survival. in: Recent Advances in Chemotherapy. Anticuncer Section II (Ishigami J, ed) Univ of Tokyo Press Tokyo, 1270 Inokuchi K, Hattori T, Taguchi T, Abe 0, Ogawa N (1984) Postoperative adjuvant chemotherapy for gastric cancer. Analysis of data on the 18% patients followed for 5 years. Cancer 53, 2393 Japanese Research Society for Gastric Cancer (1975) The general rules for the gastric cancer study in surgery and pathology. JPN J Surg 11, 12 Niimoto M, Hattori T, Ito I, Tamada R, Inokuchi K, Orita K, Furue H, Ogawa N, Toda T, Furusawa M, Koga S, Hashimoto S, Kondo T, Fujimoto S, Sugimachi Y, Abe 0, Oya M (1984) Levamisole in postoperative adjuvant immunochemotherapy for gastric cancer. A randomized controlled study of the MMC f Tegafur regimen with or without levamisole. Report 1. Cancer immunol immunother 18, 1 Niimoto M, Hattori T, Tamada R. Sugimachi K, Inokuchi K. Ogawa Nf (1988) Postoperative adjuvant immunochemotherapy with mitomycin C, futrafull and PSK for gastric cancer. An analysis of data on 579 patients followed for five years. .@n J Surg 18, 681 Umezawa H (1978) Small molecular microbial products enhancing immune response. Antibiot Chemother 24, 9 Yoshinaka K, Tanaka T, Takagami S, Saeki T, Nishiyama M, Toge T, Niimoto M, Hattori T (1958) Prospective randomized controlled study on Bestatin in gastric cancer surgery. Gun to Kagak~-R~oho~ (Jpn J Cancer Cllemother~ 15, 493 (Abstr in English)