A Comprehensive Multi-institutional Study on Postoperative Adjuvant Immunotherapy With Oral Streptococcal Preparation OK-432 for Patients
After
Gastric
Cancer Surgery
KYOTO RESEARCH GROUP FOR DIGESTIVE ORGAN SURGERY
The current study was designed to compare the effects of oral administration of the streptococcal preparation, OK432, as an adjuvant immunotherapy versus those of intradermal administration of OK432 on the survival of patients after surgery for gastric cancer. The patients were stratified into two groups after surgery: a curative surgery stratum and a palliative surgery stratum. Then the patients in each stratum were randomly assigned into three groups: an oral placebo group, an oral OK-432 group, and an intradermal OK-432 group. All of the patients were given fluoropyrimidines orally in combination with OK432 or placebo for 2 years after surgery. A total of 1011 patients were registered between 1982 and 1985, and 970 patients were eligible for statistical analysis. The survival rate of the oral OK432 group was significantly higher than those of the other two groups after curative surgery. There were no significant difference in the survival rates between the three groups after palliative surgery, however. The effect of oral OK432 was quite pronounced in patients after curative surgery for stage II to IV gastric cancer, especially in those patients with regional node involvement. Furthermore, it was found that the spleen is necessary for effective immunotherapy with oral OK432, because the survival rate of the oral OK432 group was significantly improved in patients whose spleens were preserved, when compared with splenectomized patients. These results demonstrate that oral adjuvant immunotherapy with OK432 is beneficial after curative surgery for gastric cancer.
From Kyoto University, Kyoto, Japan
last decade. The 5-year survival rates of patients after resection of advanced gastric cancer, however, have remained at 60% to 70% for stage II, 30% to 40% for stage III, and 5% to 15% for stage IV in Japan. 1-3 These results are not satisfactory, and accordingly surgeons have tried various adjuvant therapies after surgery to improve survival. Currently, cancer patients are treated according to the concept of multidisciplinary treatment. Patients with gastric cancer also have been treated with chemotherapy after surgery to reduce the recurrence of microscopic metastases in the lymph nodes and liver. Although many adjuvant chemotherapies have failed to demonstrate any clinical benefit,4-6 several trials have resulted in a prolongation of the survial period.7`9 Since the report by Mathe et al.,'0 a variety of immunotherapies have been developed, and most of these immunotherapies have employed various biologic response modifiers (BRMs), including bacille Calmette-Guerin, levamisole, PSK (Krestin), OK-432, etc. Among them, the streptococcal preparation OK-432 has been widely used in Japan and Korea, and previous reports have shown that immunotherapy with OK-432 is effective against gastric cancer.' ''4 OK-432 has been injected subcutaneously, intramuscularly, and intradermally. All injections cause various side effects, however, such as chills, fever, shock, skin induration, skin ulcer, etc. These side effects have been the major causes for the interruption of OK432 administration. It is well known that an extensive immune system is associated with the gut, and this immune system is comprehensively termed gut-associated lymphoid tissue (GALT). 15,6 It has been demonstrated that GALT plays an important role in the immunologic surveillance system against dietary antigens and microorganisms entering the gut. Furthermore, recent studies have shown that natural killer and T cells are widely distributed in the epithelium
ASTRIC CANCER iS one of the major causes of cancer deaths in Asian as well as Western countries. Methods of diagnosis, especially endoscopic techniques, have been developed, and mass screening has become popular in the last decade. About half the patients in Japan already have the advanced stage of the disease when first diagnosed, however. Furthermore, surgical techniques, especially methods to remove metastatic lymph nodes, also have improved highly, and this extensive, radical operation has become popular in the G
Address reprint requests to Yoshinoni Nio, M.D., Ph.D., First Department of Surgery, Kyoto University, Faculty of Medicine, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan. Accepted for publication November 4, 1991.
44
VOl. 216.- NO. I
45
POSTOPERATIVE ORAL IMMUNOTHERAPY WITH OK432 FOR GASTRIC CANCER
TABLE 1. Patient Stratification and Randomization*
Stratification Curative surgery
Randomization -
(n = 819)
Eligible (n = 273) 256 (n = 274) 262- 781 (n = 272) * 263 -
Oral OK-432 group Oral placebo group Intradennal OK-432 group
Surgery (n= 1011)
Palliative surgery -
(n = 192) *
(n= 62) * 601 64 j 189 (n = 64) (n = 66) -65
Oral OK-432 group Oral placebo group Intradermal OK-432 group
970 (96%)
Registration: 1982.2- 1985.8
and lamina propria of the gut; this suggests that GALT also may play an important role in antitumor immunity.'7" 8 Accordingly, augmenting the antitumor activity of GALT could be an effective approach to immunotherapy for malignancies of the digestive organs. From these viewpoints, we have studied oral immunotherapy with OK-432 in animal models and humans. In the murine model, oral OK-432 significantly inhibited the growth of cecal tumors.'9'20 In a phase I clinical study, oral OK432 showed no significant side effects.2' In phase II studies, oral OK-432 showed an augmenting effect on natural killer cell activity and boosted their response to an autologous tumor extracts in patients with gastric or colorectal cancer.2224 These results strongly suggest the possible clinical applications of oral OK-432 as an adjuvant immunotherapy for digestive organ cancer. The current study was designed to compare the effects of oral administration of OK-432 as an adjuvant immunotherapy, versus those ofintradermal administration of OK-432, on the survival of patients who had undergone a gastric cancer resection.
Patients and Methods Stratification and Randomization of the Patients This clinical study, carried out by the Kyoto Research Group for Digestive Organ Surgery, was open to patients from February 1982 to September 1985. One thousand eleven patients with primary, previously untreated gastric cancer were registered in the study. Forty-one patients were excluded from the study due to misregistration. All patients underwent surgery and afterwards were stratified into two strata: a curative surgery stratum and a palliative surgery stratum. Then, in each stratum, patients were randomly assigned into two groups by a closed-envelope method: group A, the oral administration group, and group B, the intradermal administration group. The patients from group A were further divided into two groups by a double-blind classification and were orally administered with either a placebo (placebo group) or OK-432 (oral OK-432 group). The patients from group B were
given OK-432 intradermally (intradermal OK-432 group). The stratification and randomization of the patients are summarized in Table 1.
Treatment Protocol All patients were intravenously administered with a bolus injection of mitomycin-C (MMC, 10 to 20 mg) during surgery. After the patients had started on solid food (usually from day 7 after surgery), they were administered orally one of the following fluoropyrimidines daily for 2 years: 5-fluorouracil (5-FU) at 5 mg/kg/day, tegafur at 12 mg/kg/day, or carmofur at 15 mg/kg/day. If toxicities appeared, then doses were reduced or the administration was discontinued (Fig. 1). OK-432 OK-432 is a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, group A type 3 (Picibanil, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan). The Klinische Einheit (KE) unit is used to express the dosage of the preparation; 1 KE of OK-432 contains 0.1 mg of the dried bacillus. Intradermal injections ofOK-432 were started at a dose of 1 KE, usually from day 7 after the operation (day 0), twice a week during the admission. The dose was gradually increased to 2, 3, 4, and finally 5 KE. The maintenance dose was 5 KE. After discharge, the injections continued weekly for 2 years. Group A patients were given oral placebo (powdered sugar) or OK-432 at 5 KE orally, once per week for 2 years. If the patients survived for longer than 2 years, the continuation or ces-
ISurgery 4
dayl1
2 years
day 7 ..
t
I
MMC 10-20 mg
i.v.I
Fluoropyrimidine p.o., daily oral placebo or OK-432 (5 KE) or Intradermal OK-432 (5 KE), weekly
FIG. 1. Treatment protocol.
TABLE 3. Background Factors: Curative Surgery Stratum
sation of the treatments was determined by their respective doctors.
Follow-up of the Patients All patients were followed by physical examination, general x-ray examination, routine hematologic and biochemical examinations, and serum tumor marker assays. If any recurrence was discovered, the patients were treated according to their respective doctors. Statistical Evaluation
The effects of the adjuvant immunotherapies were evaluated with respect to the survival rate after surgery. Chi square and Mann-Whitney U-tests were used to compare patient backgrounds ofthe three groups. A statistical comparison ofthe survival rates between the three groups was made by the generalized Wilcoxon test, and Cox's proportional hazard general linear model was applied to estimate the survival rate by correcting for the differences in patients' background factors. Results Patient Exclusion and Comparison of Patients' Back-
grounds Ofthe 1011 registered patients, 41 (4.1%) patients were excluded from this study for misregistration (27 patients, TABLE 2. Background Factors: Overall Eligible Patients
M
F
Age (yr)
After
Gastric
Cancer Surgery
KYOTO RESEARCH GROUP FOR DIGESTIVE ORGAN SURGERY
The current study was designed to compare the effects of oral administration of the streptococcal preparation, OK432, as an adjuvant immunotherapy versus those of intradermal administration of OK432 on the survival of patients after surgery for gastric cancer. The patients were stratified into two groups after surgery: a curative surgery stratum and a palliative surgery stratum. Then the patients in each stratum were randomly assigned into three groups: an oral placebo group, an oral OK-432 group, and an intradermal OK-432 group. All of the patients were given fluoropyrimidines orally in combination with OK432 or placebo for 2 years after surgery. A total of 1011 patients were registered between 1982 and 1985, and 970 patients were eligible for statistical analysis. The survival rate of the oral OK432 group was significantly higher than those of the other two groups after curative surgery. There were no significant difference in the survival rates between the three groups after palliative surgery, however. The effect of oral OK432 was quite pronounced in patients after curative surgery for stage II to IV gastric cancer, especially in those patients with regional node involvement. Furthermore, it was found that the spleen is necessary for effective immunotherapy with oral OK432, because the survival rate of the oral OK432 group was significantly improved in patients whose spleens were preserved, when compared with splenectomized patients. These results demonstrate that oral adjuvant immunotherapy with OK432 is beneficial after curative surgery for gastric cancer.
From Kyoto University, Kyoto, Japan
last decade. The 5-year survival rates of patients after resection of advanced gastric cancer, however, have remained at 60% to 70% for stage II, 30% to 40% for stage III, and 5% to 15% for stage IV in Japan. 1-3 These results are not satisfactory, and accordingly surgeons have tried various adjuvant therapies after surgery to improve survival. Currently, cancer patients are treated according to the concept of multidisciplinary treatment. Patients with gastric cancer also have been treated with chemotherapy after surgery to reduce the recurrence of microscopic metastases in the lymph nodes and liver. Although many adjuvant chemotherapies have failed to demonstrate any clinical benefit,4-6 several trials have resulted in a prolongation of the survial period.7`9 Since the report by Mathe et al.,'0 a variety of immunotherapies have been developed, and most of these immunotherapies have employed various biologic response modifiers (BRMs), including bacille Calmette-Guerin, levamisole, PSK (Krestin), OK-432, etc. Among them, the streptococcal preparation OK-432 has been widely used in Japan and Korea, and previous reports have shown that immunotherapy with OK-432 is effective against gastric cancer.' ''4 OK-432 has been injected subcutaneously, intramuscularly, and intradermally. All injections cause various side effects, however, such as chills, fever, shock, skin induration, skin ulcer, etc. These side effects have been the major causes for the interruption of OK432 administration. It is well known that an extensive immune system is associated with the gut, and this immune system is comprehensively termed gut-associated lymphoid tissue (GALT). 15,6 It has been demonstrated that GALT plays an important role in the immunologic surveillance system against dietary antigens and microorganisms entering the gut. Furthermore, recent studies have shown that natural killer and T cells are widely distributed in the epithelium
ASTRIC CANCER iS one of the major causes of cancer deaths in Asian as well as Western countries. Methods of diagnosis, especially endoscopic techniques, have been developed, and mass screening has become popular in the last decade. About half the patients in Japan already have the advanced stage of the disease when first diagnosed, however. Furthermore, surgical techniques, especially methods to remove metastatic lymph nodes, also have improved highly, and this extensive, radical operation has become popular in the G
Address reprint requests to Yoshinoni Nio, M.D., Ph.D., First Department of Surgery, Kyoto University, Faculty of Medicine, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan. Accepted for publication November 4, 1991.
44
VOl. 216.- NO. I
45
POSTOPERATIVE ORAL IMMUNOTHERAPY WITH OK432 FOR GASTRIC CANCER
TABLE 1. Patient Stratification and Randomization*
Stratification Curative surgery
Randomization -
(n = 819)
Eligible (n = 273) 256 (n = 274) 262- 781 (n = 272) * 263 -
Oral OK-432 group Oral placebo group Intradennal OK-432 group
Surgery (n= 1011)
Palliative surgery -
(n = 192) *
(n= 62) * 601 64 j 189 (n = 64) (n = 66) -65
Oral OK-432 group Oral placebo group Intradermal OK-432 group
970 (96%)
Registration: 1982.2- 1985.8
and lamina propria of the gut; this suggests that GALT also may play an important role in antitumor immunity.'7" 8 Accordingly, augmenting the antitumor activity of GALT could be an effective approach to immunotherapy for malignancies of the digestive organs. From these viewpoints, we have studied oral immunotherapy with OK-432 in animal models and humans. In the murine model, oral OK-432 significantly inhibited the growth of cecal tumors.'9'20 In a phase I clinical study, oral OK432 showed no significant side effects.2' In phase II studies, oral OK-432 showed an augmenting effect on natural killer cell activity and boosted their response to an autologous tumor extracts in patients with gastric or colorectal cancer.2224 These results strongly suggest the possible clinical applications of oral OK-432 as an adjuvant immunotherapy for digestive organ cancer. The current study was designed to compare the effects of oral administration of OK-432 as an adjuvant immunotherapy, versus those ofintradermal administration of OK-432, on the survival of patients who had undergone a gastric cancer resection.
Patients and Methods Stratification and Randomization of the Patients This clinical study, carried out by the Kyoto Research Group for Digestive Organ Surgery, was open to patients from February 1982 to September 1985. One thousand eleven patients with primary, previously untreated gastric cancer were registered in the study. Forty-one patients were excluded from the study due to misregistration. All patients underwent surgery and afterwards were stratified into two strata: a curative surgery stratum and a palliative surgery stratum. Then, in each stratum, patients were randomly assigned into two groups by a closed-envelope method: group A, the oral administration group, and group B, the intradermal administration group. The patients from group A were further divided into two groups by a double-blind classification and were orally administered with either a placebo (placebo group) or OK-432 (oral OK-432 group). The patients from group B were
given OK-432 intradermally (intradermal OK-432 group). The stratification and randomization of the patients are summarized in Table 1.
Treatment Protocol All patients were intravenously administered with a bolus injection of mitomycin-C (MMC, 10 to 20 mg) during surgery. After the patients had started on solid food (usually from day 7 after surgery), they were administered orally one of the following fluoropyrimidines daily for 2 years: 5-fluorouracil (5-FU) at 5 mg/kg/day, tegafur at 12 mg/kg/day, or carmofur at 15 mg/kg/day. If toxicities appeared, then doses were reduced or the administration was discontinued (Fig. 1). OK-432 OK-432 is a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, group A type 3 (Picibanil, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan). The Klinische Einheit (KE) unit is used to express the dosage of the preparation; 1 KE of OK-432 contains 0.1 mg of the dried bacillus. Intradermal injections ofOK-432 were started at a dose of 1 KE, usually from day 7 after the operation (day 0), twice a week during the admission. The dose was gradually increased to 2, 3, 4, and finally 5 KE. The maintenance dose was 5 KE. After discharge, the injections continued weekly for 2 years. Group A patients were given oral placebo (powdered sugar) or OK-432 at 5 KE orally, once per week for 2 years. If the patients survived for longer than 2 years, the continuation or ces-
ISurgery 4
dayl1
2 years
day 7 ..
t
I
MMC 10-20 mg
i.v.I
Fluoropyrimidine p.o., daily oral placebo or OK-432 (5 KE) or Intradermal OK-432 (5 KE), weekly
FIG. 1. Treatment protocol.
TABLE 3. Background Factors: Curative Surgery Stratum
sation of the treatments was determined by their respective doctors.
Follow-up of the Patients All patients were followed by physical examination, general x-ray examination, routine hematologic and biochemical examinations, and serum tumor marker assays. If any recurrence was discovered, the patients were treated according to their respective doctors. Statistical Evaluation
The effects of the adjuvant immunotherapies were evaluated with respect to the survival rate after surgery. Chi square and Mann-Whitney U-tests were used to compare patient backgrounds ofthe three groups. A statistical comparison ofthe survival rates between the three groups was made by the generalized Wilcoxon test, and Cox's proportional hazard general linear model was applied to estimate the survival rate by correcting for the differences in patients' background factors. Results Patient Exclusion and Comparison of Patients' Back-
grounds Ofthe 1011 registered patients, 41 (4.1%) patients were excluded from this study for misregistration (27 patients, TABLE 2. Background Factors: Overall Eligible Patients
M
F
Age (yr)
