Kodama Y, Kano T, Tamada R, Kumashiro R, Okamura T, Inokuchi K.
Effectiveness of prophylactic extensive lymph node dissection (PELD) plus postoperative long term combination chemotherapy (PLCC) for patients with curatively resected gastric carcinoma was assessed in terms of the degree of serosal invasion and lymph node metastasis. Either the Group 1 and Group 2 lymph nodes were eradicated by PELD. PLCC included intermittent intravenous administration of mitomycin C (0.4 mg/kg intraoperatively followed by 0.2 mg/kg every 3 months) and oral administration of Tegafur (600-800 mg/day) and PSK (3.0 g/day), an immunostimulator, for as long a period as possible. PELD alone resulted in a cure when the malignancy was confined to the mucosal and muscular layers of the stomach as well as to the Group 1 lymph nodes. In cases when the carcinoma involved the serosa and/or the Group 2 lymph nodes, the 5 year survival rate was about 55 per cent the PELD and PLCC groups, such being significantly higher than about 27 per cent in the PELD alone group. Therefore, PELD plus PLCC is highly effective for advanced gastric carcinoma, under a condition of curative resection.
A randomized controlled study was carried out on curatively resected gastric cancer patients in a cooperative study involving 16 institutions in order to evaluate the effect of an alternative long-term adjuvant immunochemotherapy using Esquinon (CQ) and Krestin (PSK). One week after surgery, CQ was given at a dose of 2mg/m2 once a week for 3 weeks and this was repeated every 6 weeks. CQ was administered intravenously in the 1st course and thereafter orally up to 9 courses. Three postoperative week, immunotherapy was then started in which PSK was given orally in 3 divided doses of
2g/m2/day from the day when CQ therapy ended for 4 consecutive weeks, and this performed for every course. Estimated survival rate and cumulative survival curves were compared utilizing the data up to 7 years after surgery in the chemotherapy group given CQ alone and in the immunochemotherapy group given CQ + PSK. The survival curve in all cases showed a favorable form in the CQ + PSK group for up to 36 months, and thereafter it crossed with that of the CQ group for up to 68 months. Both curves twisted at 68 months and then deviated from each other, showing that the effect in the CQ + PSK group beneficial. The curve showed a twisting configuration throughout the treatment period. There was no statistically significant difference between the survival curves of the two groups. Retrospective survival analysis was then performed on separate subgroups classified into the category of S1, S2, N1, and N2. The CQ + PSK group was better than the CQ alone group in its survival rate for the S1 + S2 (N1-2) group, the percentage being 11.5%, and a statistically significant difference was observed between the two groups (p = 0.089).
The most effective treatment for gastric cancer is complete surgical resection with lymphadenectomy. However, a number of patients experience recurrence of the cancer even after curative surgery. This review focuses on comparative trials studying the use of adjuvant therapy with chemotherapy plus immunotherapy in the treatment of patients with curatively resected gastric cancer. Preoperative and intraperitoneal therapy, and therapy for advanced or recurrent gastric cancer are also discussed. At present, some subset analyses of adjuvant trials have shown favorable results suggesting that the biological response modifiers (BRMs), PSK or OK-432, add a benefit to chemotherapy. For advanced gastric cancer, although gastric cancer cells are generally not very sensitive to most of the currently available chemotherapeutic agents, it has been reported that biochemical modulation with treatments including low-dose cisplatin + 5-FU (fluorouracil) have high response rates and exert an immunomodulatory effect especially when used in combination with BRMs. The impact of splenectomy and some of the
promising newly developed drugs are discussed.
Up to now, the three main weapons against cancer have been surgery, radiotherapy and chemotherapy. Although these classical methods of treatment have given fairly good results in general, the results have yet to be improved, especially in late cases. Thus for many years, the search for a more effective means of anti-cancer treatment has been going on world-wide. An ideal drug would of course be one that could directly kill all the cancer cells without harming the normal tissues, and also without causing general toxicity. However, at present a more practical approach is to use drugs that would either enhance the biological effects of radiation or of cytotoxic agents, or strengthen the organism’s immunological defenses. In recent years, several such drugs have been undergoing clinical trials, for example, Misonidazole, RS 2508, OK-432, PSK, etc.
The purpose of this study was to determine if immunotherapy with Krestin can prolong the durations of complete remission and survival. The patients were placed at random in the chemotherapy and chemoimmunotherapy groups. The median durations of complete remission and survival were longer in the chemoimmunotherapy group than in the chemotherapy group. The complete remission rate of the second induction was higher in the chemoimmunotherapy group than in the chemotherapy group. The cell-mediated immunity was somewhat enhanced in the chemoimmunotherapy group, while it was not enhanced in the chemotherapy group. These results suggested that Krestin administration for maintenance therapy was useful for prolongation of the durations of remission and survival time in patients with acute leukemia.
To evaluate the efficacy of PSK for adjuvant immuno-chemotherapy in patients who had undergone radical gastrectomy, a randomized controlled trial has been in progress in collaboration with 46 institutions in the Chubu district of Japan. A total of 262 patients were registered for this trial during the two years from July 1985 to June 1987 with a centralized registration system, and were allocated into the 5-FU+PSK group (Group P) and 5-FU alone group (Group C) by the minimization method following the random permuted blocks method. Between the two groups, the parameters of sex, age, serosal invasion (S), lymph-node metastasis (N), and the combination of S . N factor levels were distributed without significant differences. An induction treatment with MMC 6 mg/m2 was given to all patients following curative mastectomy and on the 7th post-operative day. Two weeks after surgery, Group P received alternately PSK 3 g/day for 4 week and 5-FU 150 mg/day for 4 weeks as one course, and 10 courses were given. Group C received 5-FU alone for 4 weeks using alternate rest interval for 4 weeks. Since both experimental and clinical studies suggested that alternate treatments using PSK and anticancer agents were effective, treatment in this trial alternated PSK and 5-FU. A final follow-up study will be completed in June 1992, when all patients shall have survived more than 5 years after surgery. The administration of 5-FU was completed by January. 1989, but PSK has been administered to group P. The period from 18 to 42 months after surgery was reached in all eligible patients (253) at the end of December 1988. The disease-free survival curves and overall survival curves of group P were significantly (p = 0.018 and p = 0.045,) better than those of group C.