Adjuvant immunochemotherapy with long-term OK-432 administration in colorectal cancer

A new clinical trial on immunochemotherapy as an adjuvant therapy of surgery for colorectal cancers was studied. Results were retrospectively evaluated against previous controls treated by chemotherapy alone. As an immunotherapeutic agent, a streptococcal preparation, OK-432 was used. The maintenance dosage of OK-432, was 5 KE once a week and was continued for at least 2 years after surgical resection. As chemotherapeutic agents, mitomycin C for 2 weeks postoperatively and tegafur for 1 year were administered. Delayed skin reactivity to SU-polysaccharide (SU-PS) extracted from Streptococcus pyogenes SU-strain and lymphoproliferative response to phytohemagglutinins (PHA) were significantly enhanced in the OK-432, immunochemotherapy group. Disease-free interval in the immunochemotherapy group (n = 49) was prolonged compared to that in the control group (n = 129), especially in the curative resection cases of Duke's C stage. There was statistical significance between the two groups (p less than 0.05). These results suggested that long-term administration of OK-432 after surgical resection of colorectal cancer was effective on growth inhibition of micrometastasis and could increase the postoperative survival rate.     

The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients

To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg(-1) i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day(-1)) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer.     

A randomized controlled trial of surgical adjuvant therapy with mitomycin C, 5-fluorouracil and OK-432 in patients with gastric cancer

The effect of postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as an adjuvant therapy after curative resection for gastric cancer. Immediately after surgery, patients were randomly allocated to the following three treatments: (A) chemotherapy with MMC and 5-FU (32 cases); (B) chemoimmunotherapy with MMC, 5-FU and OK-432 (33 cases); and (C) surgery alone as control (34 cases). There were no significant differences in the background factors influencing survival time among the groups, and there was no dose-distribution of chemotherapeutic agents between groups A and B. While the differences were not statistically significant, the survival rate and disease-free interval of group B were better than those of groups A or C. Side effects such as gastroenteric disorder, leukopenia (less than 3,000/mm3), thrombocytopenia (less than 7 X 10(4)/mm3) and increase of serum transaminase level (GPT greater than or equal to 100 units) were less frequently observed in group B than in group A. The results of the present study seemed to indicate that chemoimmunotherapy with OK-432 may be effective for surgical adjuvant therapy.     

Early postoperative chemotherapy following noncurative resection for patients with advanced gastric cancer.

We studied the effect of early postoperative chemotherapy, including 5-fluorouracil (5-FU) for 5 days for patients with gastric cancer following noncurative resection. The study was prospectively randomised and controlled, and 162 (87.1%) of 186 were eligible candidates for statistical assessment. Patients randomised to group A received therapy that is used widely to treat patients with gastric cancer in Japan; mitomycin C (MMC), OK-432, UFT and PSK. Patients randomised to group B received the same drugs given to group A plus 5-FU bolus injections for 5 days, beginning on postoperative day 2. There were no differences in prognostic factors and doses of the drugs prescribed, except for 5-FU. There was no difference in the toxicity rate between the groups. Generalised Wilcoxon test revealed a P value of 0.169, and the 50% survival rate improved 1.4-fold in patients with gastric cancer treated with early postoperative chemotherapy of MMC, OK-432 plus 5-FU injection.     

Dukes B期大肠癌患者术后辅助化疗的疗效评价

目的：探讨Dukes B期大肠癌患者根治性手术后辅助化疗的疗效及安全性。方法：选取102例已行根治手术的Dukes B期大肠癌患者进行分析。结果：辅助化疗组和单纯手术组患者3年无瘤生存率分别为80．0％和62．5％（P=0．019）；5年生存率分别为89．9％和66．7％（P=0．0129）。FCF辅助化疗的不良反应为食欲不振、恶心呕吐、脱发和局部色素沉着．多为1～2度。结论：Dukes B期大肠癌根治术后给予FCF方案辅助化疗能够提高患者3年无瘤生存率和5年生存率；3度不良反应发生率低、安全性好，患者耐受性好。     

A trial of adjuvant chemoimmunotherapy with mitomycin C and OK-432 for stage III gastric carcinoma.

We previously found that the ability to generate cytotoxic cells induced by in vitro activation of peripheral blood mononuclear cells (PBM) with OK-432, a bacterial immunopotentiator, was markedly increased following intravenous administration of a single dose of mitomycin C (MMC) in cancer patients. On the basis of this clinical finding, we designed a treatment regimen that consisted of MMC 12 mg/m2 intravenously on day 1 and OK-432 5 Klinische Einheit (KE) intradermally on days 6, 8, and 11, when the generation of OK-432 activated killer cells had been shown to be significantly augmented. Then, it was followed by long-term tegafur. Fifteen patients with stage III gastric carcinoma who had undergone curative resection were treated with the above regimen. The survival of these patients was significantly better than that of 26 comparable stage III patients concurrently treated with MMC 12 mg/m2 alone, followed by long-term tegafur (P less than 0.01). The results indicate that OK-432 combined with MMC may be effective against stage III gastric carcinoma, when these agents are used probably in an appropriate combination.     

Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: a prospective randomized study

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 14, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.     

Comparison of OK-432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial.

A prospective randomized study to compare the effectiveness of pleurodesis by two new sclerosing agents: OK-432 and mitomycin C were conducted in 53 patients with malignant pleural effusion caused by lung cancer. None of the patients received concomitant systemic chemotherapy or radiation therapy during the study. After complete drainage of pleural fluid, the patients were allocated randomly to receive 10 Klinische Einheit units of OK-432 or 8 mg of mitomycin C by intrapleural injection at weekly intervals. The treatment was terminated if the pleural effusion disappeared or the patients had received four consecutive procedures. There were 26 patients who received pleurodesis with OK-432 and 27, with mitomycin C. Patient characteristics in the two treatment groups (age, sex, histologic type, performance status, and prior treatment before pleurodesis) were compatible. These results showed that pleurodesis with OK-432 achieved a higher complete response rate (73%) than that of mitomycin C (41%). The rates of objective treatment response (complete response plus partial response) were comparable in both groups (88% for OK-432 and 67% for mitomycin C). The average number of intrapleural injections needed to achieve complete response was fewer in the OK-432 group (1.9 +/- 0.9) than in mitomycin C group (2.8 +/- 0.9). There was no significant difference in the median survival of the patients who received pleurodesis with OK-432 (5.8 months) or mitomycin C (5.1 months). However, the effusion-free period in the OK-432 group was significantly longer than that in the mitomycin C group (7.0 months versus 1.5 months). Patients who underwent OK-432 pleurodesis had a higher complication rate (80%) than did those in the mitomycin C group (30%). Transient febrile reaction was the most common reaction encountered. The immunologic study in OK-432 group showed an increase in peripheral leukocyte count and decrease in the OKT4/OKT8 ratio. The mitomycin C group had a mild reduction in peripheral blood leukocyte count and no significant change in the OKT4/OKT8 ratio. It was concluded that pleurodesis with OK-432 is an effective alternative treatment for malignant effusion in patients with lung cancer.     

The influence of enhanced postoperative inflammation by the intrapleural administration of streptococcal preparation (OK-432) on the prognosis of completely resected non-small-cell lung cancer

BACKGROUND AND OBJECTIVES: It is not clear whether postoperative inflammation affects the prognosis of malignant disease. METHODS: We retrospectively reviewed the patients with non-small-cell lung cancer who underwent a complete resection at the National Kyushu Cancer Center from 1989 to 1996. For the treatment of prolonged air leakage after a pulmonary lobectomy, 25 patients received an intrapleural injection of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of the Streptococcus pyogenes group A3. All patients were males who were older than 50 years of age. As a control, we selected 164 male patients who were older than 50 years of age and not given OK-432 during the same period. RESULTS: The administration of OK-432 in most patients was performed on the 4th day after the operation. Pleural drainage could be terminated in a mean of 5.5 days after the intrapleural administration of OK-432. In the control group, the serum C-reactive protein (CRP) level reached a peak on day 4 after the operation and returned to almost a normal level on day 14 after the operation. In the OK-432 group, the peak CRP level, which was significantly higher than that in the control group, was observed on day 7 after the operation and the elevated CRP level was maintained until 28 days after the operation. The mean level of CRP in the OK-432 group was significantly higher than that in the control on days 7, 14, and 28 after the operation. No significant difference was observed in the disease-free survivals between the two groups. CONCLUSIONS: Based on the above findings, postoperative prolonged inflammation does not seem to affect the progression of subclinically residual tumor cells.     

Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur

Background We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).Methods Patients with stage II, III, or IV (Dukes B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2).Results A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group chemotherapy group control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups.Conclusion The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy.     

The role of adjunctive immunotherapy in superficial bladder cancer

Seventy-eight patients with superficial bladder cancer were entered into a randomized study. A streptococcal preparation, OK-432, was injected into bladder cancers before transurethral resection and instilled into the bladder for 6 months after resection to reduce the recurrence. The control group were only transurethrally resected, as usual. The recurrence rate for patients with primary disease was 3.6 in 100 months for the OK-432 group and 9.1 in 100 months for the control group (P less than 0.05). In the control group, multiple, large, sessile, and high-grade tumors had high recurrence rates. But in the OK-432 group, overall recurrence rates were low in both high-risk and low-risk patients. Supplementary immunotherapy is especially effective and is recommended in high-risk patients.     

Epidermal growth factor receptor in breast cancer: Correlation of quantitative immunocytochemical assays to prognostic factors

Summary Sixty-seven breast cancer patients with cytologically-confirmed malignant pleural effusion, who required intrapleural treatment, were analyzed retrospectively. The patients received their first thoracentesis between 1980 and 1990. Among them, 29 patients received intrapleural administration of OK-432, a streptococcal preparation, followed by the transfer of autologous pleural effusion lymphocytes cultured with interleukin-2. Other intrapleural treatments consisted of OK-432 alone (12 patients), chemotherapeutic agents alone (n = 9), a combination of OK-432 and chemotherapy (n = 16), or others (n = 1). Twenty-six of the 29 patients given OK-432 plus cultured effusion lymphocytes responded, while only 15 of the 38 patients who received other treatments did (p < 0.01). Median survival time and 5-year survival rate of patients who received OK-432 and cultured lymphocytes was 12 months and 36%, while those of the patients who received other treatments was 3 months and 0%, a significant (p< 0.001) difference in survival. Multivariate analysis using Cox's proportional hazard model revealed that the treatment (adoptive immunotherapy) was the most significant (p < 0.005) factor to prolong the survival of the patients among several prognostic factors. Thus, OK-432 and adoptive immunotherapy is a promising therapy that should be further evaluated in a prospective study.     

Hepatic resection plus hepatic artery infusion with implantable port for colorectal metastases

Hepatic resection of metastatic colorectal carcinoma offers a chance for long term survival and is being performed with increasing frequency. The aim of this study is to reduce the re relapse in the residual liver after curative hepatectomy. Nineteen patients with hepatic metastases from colorectal carcinoma who underwent hepatic resection plus hepatic artery infusion therapy using an implantable port (HR-HAI) were analyzed. As hepatic resection, lobectomies were performed in 6 patients, segmentectomies in 8 patients and wedge resection in 5 patients. As chemotherapeutic agents, adriamycin in 8 patients, mitomycin C in 7 patients and OK-432 in 4 patients were used. The drugs were administered through hepatic artery via a port every one month for one year at the out patient clinic. Eight out of 19 patients had no complication by HR-HAI therapy, but 3 patients had catheter obstruction within one year, 4 had gastrointestinal discomfort, 3 fever up and 1 liver tissue necrosis. The serious hepatotoxicity such as sclerosing cholangitis was not observed. Re-relapses were appeared in 15 patients and the sites were the residual liver in 10 patients, and 5 in the other organs. The 3-year survival rate of 19 treated patients was 40.0% higher than 33.3% of 52 patients undergone hepatic resection alone, but the difference was not statistically significant.     

Whole abdominal irradiation of ovarian cancer in combined treatment with OK-432 picibanil

One hundred seventeen patients with postoperative ovarian cancer who were treated with whole abdominal irradiation by the open-field technique were analyzed as to the effectiveness of combined therapy with or without OK-432. OK-432, 0.2 to 2.0 (KE) (kev) daily, has been used to prevent bone marrow suppression since 1978 at NIRS. Cumulative five-year survival rates were 63.6% in the OK-432 group (37 patients) and 54.5% in the NON-OK-432 group (34 patients). The complete rates of previously arranged treatment schedules were 81% and 66% in the two groups, respectively, as we originally intended.     

The presence of a systemic inflammatory response predicts poorer survival in patients receiving adjuvant 5-FU chemotherapy following potentially curative resection for colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in survival following curative resection for colorectal cancer. The present study evaluated the relationship between C-reactive protein concentrations and survival in a cohort of patients receiving adjuvant 5-fluorouracil (5-FU) chemotherapy following potentially curative resection for colorectal cancer. In all, 222 patients undergoing potentially curative resection for colorectal cancer were studied. Of these, 50 patients received adjuvant 5-FU-based chemotherapy. Circulating concentrations of C-reactive protein were measured prior to surgery. The minimum follow-up was 15 months; the median follow-up of the survivors was 38 months. During this period 61 patients died, 32 patients of their cancer and 29 of intercurrent disease. In those patients who did not receive adjuvant chemotherapy, age (P < 0.001), Dukes stage (P < 0.05) and an elevated C-reactive protein (P < 0.01) were significantly associated with survival. In those patients who did receive adjuvant chemotherapy, an elevated C-reactive protein concentration (P < 0.01) was significantly associated with survival. The presence of a systemic inflammatory response is an independent predictor of poor outcome in patients receiving adjuvant 5-FU-based chemotherapy following potentially curative resection for colorectal cancer.     

不同年龄组大肠癌预后多因素分析的比较

目的研究青年、中年和老年组大肠癌预后的影响因素,指导临床治疗。方法对842例行根治术后的大肠癌患者,按发病年龄分为青年组（≤40岁）、中年组（41～64岁）和老年组（≥65岁）。用SPSS软件分别对3组患者的35个临床病理因素进行单因素生存分析和多因素Cox比例风险模型回归分析。结果842例大肠癌的5,10,15年生存率分别为66．3％、54、2％和48．5％,青年组大肠癌的5,10年生存率分别为53．13％和42．7％,低于其他年龄组患者。多因素分析显示,Dukes分期和家族肿瘤史为青年和中年组大肠癌患者的共同影响因素;慢性便秘是中年组大肠癌预后的独立影响因素;肠梗阻、手术时间、转移淋巴结数为老年组大肠癌的预后因素。病程（从出现症状到手术时间）不是影响青年组大肠癌的主要原因。青年组Dukes A期患者的5,10年生存率分别为82．6％和64．5％,B期分别为73.3％和67．4％,C期分别为37、3％和27．13％,D期分别为33．3％和22．2％。青年组A期和B期患者生存率与中老年组相近,但C期和D期的生存率低于中老年组。有家族肿瘤史的青年组患者预后好,其5,10年生存率分别为73．1％和64．5％,显著高于无家族肿瘤史患者的48．1％和37、3％。结论不同年龄组大肠癌预后影响因素有差异,青年组大肠癌的生存率明显低于其他年龄组。在青年组,大肠癌Dukes分期晚和无家族肿瘤史的患者预后差,病程不是影响预后的因素,青年组大肠癌患者预后羞与就诊时间晚、延误诊断无关。     

Cooperative studies on surgical adjuvant immunochemotherapy for prevention of postoperative recurrence of gastric cancer

A controlled clinical trial of surgical adjuvant immunochemotherapy of gastric cancer was started in July, 1974 involving twelve institutes (Chairman; T. Kondo) in Japan. Patients with gastric cancer undergone curative resection were eligible. These patients were divided into 3 groups; Group A, mitomycin C (MMC) + 5-fluorouracil (5-FU): Group B, MMC + 5-FU + PSK or MMC + 5-FU + OK-432; and Group C, surgery alone. Of 1412 patients accumulated up to December 1977, 848 cases were evaluable: Group A-264 cases, group B-290 and group C-294. Side effects such as leukopenia, thrombopenia, elevated GOT and GPT, albuminuria and digestive disorders, were observed in 54 cases (20.5%) of group A and in 59 cases (20.3%) of group B. The 3-year survival rates of total cases were 79.2% with group A, 77.0% with group B and 85.2% with group C. The 2-year survival rates of histological stage II cases were 93.4% with group A, 90.5% with group B and 80.7% with group C. The difference in survival rate between A and C (12.7%) was statistically significant (p less than 0.05). The efficacy was not related to the histological type of gastric cancer. Adjuvant immunochemotherapy using OK-432 was significantly effective on a 1-year survival rate of stage IV gastric cancer.     

A controlled study of maintenance chemoimmunotherapy vs immunotherapy alone immediately following palliative gastrectomy and induction chemoimmunotherapy for advanced gastric cancer

Summary A randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. First, all patients received the same induction chemoimmunotherapy with MFC (mitomycin C, 5-fluorouracil, and cytosine arabinoside) plus OK-432 for 6 weeks after surgery. The patients were then randomized to receive either chemoimmunotherapy with MFC plus OK-432 (group A) or immunotherapy with OK-432 alone (group B) for maintenance. The survival rate of patients was significantly higher in group B (44 cases) than in group A (39 cases) during the first 9 months after the start of induction therapy (P<0.05). A further division of patients in terms of carcinoma histology revealed a difference in survival rate only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma and signet-ring cell carcinoma), and not in those with a differentiated histology (papillary, tubular, and mucinous adenocarcinomas). These results indicate that simple immunotherapy with OK-432 is better for maintenance than chemoimmunotherapy involving MFC, particularly in patients with undifferentiated gastric carcinomas.Chairman of the Study Group: K. Ota     

Adjuvant chemotherapy of colorectal cancer--results of prospective randomized trials

The group of research for colorectal cancer treatments-Kajitani-group (chief T. Kajitani) has carried out the co-operative study for the evaluation of adjuvant chemotherapy after curative resection of colorectal cancer. During the period 1975 and 1978, a series of 1,156 cases of cancer of colon and rectum were entered into the prospective randomized controlled study which consisted of three treatment programs. There included chemotherapy of 2 modes of regimen combining MMC with Tegaful and non adjuvant treatment as control. In colon cancer, adjuvant chemotherapy combining MMC with Tegaful was effective on the increasing of survival rates, especially significantly (p = 0.017) in the cases of Dukes B stage (85-88% vs 69.2% in survival rates of 8 year). In rectal cancer, systemic intravenous administration of MMC 4 mg, two times a week for immediately postoperative three weeks, combined with postoperatively prolonged oral administration of Tegaful 800 mg/day more than three months was also significantly effective, especially in the cases of Dukes C stage (52.3% vs 40% in survival rates of 8 year). However, the analysis of recurrence did not prove that the intra-operative local intra vessel administration of MMC 10 mg was useful for the prevention of liver metastasis in colon cancer or pelvic recurrence in rectal cancer respectively.