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.