An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer.

To reappraise the benefits of the long supported chemotherapy with carmofur, a meta-analysis based on individual patient data from the three clinical trials was performed by pooling 614 patients from three trials, there is a statistically significant survival benefit (2p=0.032) and disease-free survival (DFS) benefit (2p=0.021) for carmofur; and a highly significant advantage for carmofur in DFS (2p=0.0004) and in survival (2p=0.004) in Dukes' C patients. This IPD meta-analysis strongly suggested an effect of oral carmofur in a long supported chemotherapy for curatively resected colorectal carcinoma.

A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer.

To investigate the usefulness of oral doxifluridine (5'-DFUR), an active intermediate metabolite of capecitabine (XELODA), in gastric cancer patients after curative resection, we conducted a phase III randomized controlled study to compare oral 5'-DFUR and oral 5-fluorouracil (5-FU). 485 gastric cancer patients with Stage II or III operative findings at curative resection were registered and administered 5'-DFUR (460 mg/m2/day, daily, for two years) or 5-FU (115 mg/m2/day, daily, for the same period). Although no differences in overall survival or disease-free survival were detected, subset analysis showed 5'-DFUR was more effective in reducing peritoneal recurrence than 5-FU (p = 0.047), and in patients with Stage III or stage IIIb (histologic findings) in the 5'-DFUR group had more favorable disease-free survival curves and survival curves than the 5-FU group with similar stages.

Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials.

BACKGROUND: Oral 5-fluorouracil and its prodrugs (tegafur, carmofur) is now being studied for adjuvant chemotherapy of curatively resected colorectal cancers. To evaluate the effect of these oral fluoropyrimidines (o-FPs), an individual patient data (IPD) meta-analysis of randomized clinical trials was performed in Japan as an inter-trialist group study. METHODS: Data from the three clinical trials in which postoperative adjuvant therapy with o-FPs was compared with surgery alone in patients with colorectal cancer were sought. IPD from a total of 4960 patients with follow-up periods of at least 5 years were analyzed. RESULTS: The results of the meta-analysis on an 'intention to treat' basis demonstrated a significant benefit of o-FPs in terms of the disease-free survival (DFS) of the total patients [risk ratio (RR) 0.830, 95% confidence interval (CI) 0.742-0.929, P = 0.001]. o-FPs were also demonstrated to be effective for survival in rectal cancer (RR 0.857, 95% CI 0.734-0.999, P = 0.049) and in Dukes'C colorectal cancer (RR 0.828, 95% CI 0.711-0.965, P = 0.016). CONCLUSION: The results suggest the advantage of long term o-FPs, possibly with the injection of mitomycin C, for prognosis for curatively resected colorectal cancer patients.

Human placental leucine aminopeptidase/oxytocinase. A new member of type II membrane-spanning zinc metallopeptidase family.

The serum level of placental leucine aminopeptidase (P-LAP) increases during pregnancy. P-LAP degrades several peptide hormones such as oxytocin and vasopresin, suggesting a role in maintaining homeostasis during pregnancy. In the study reported here, we have isolated a cDNA clone with 4084 base pairs encoding P-LAP from a human placental cDNA library. The amino acid sequence deduced from the cDNA contained all of the sequences of the peptide fragments obtained by digestion of the purified protein with trypsin. The predicted P-LAP contains the HEXXH consensus sequence of zinc metallopeptidases, indicating that the enzyme belongs to this family, which includes aminopeptidase N and aminopeptidase A. The deduced sequence also contains a hydrophobic region near the N terminus, suggesting that the enzyme is a type II integral membrane protein. Northern blot analysis revealed that P-LAP was expressed in several tissues, some of which expressed two forms of mRNAs. These results suggest that the enzyme is synthesized as an integral membrane protein and is released into blood under some physiological conditions.

Randomized study with mitomycin C + 5-fluorouracil+cytosine arabinoside (MFC)+5-fluorouracil, MFC+tegafur and uracil (UFT), and MF+UFT in advanced gastric cancer: interinstitutional differences in a multicenter study in Japan.

In a phase III randomized trial of adjuvant chemotherapy for gastric cancer, interinstitutional differences were analyzed. A trial of three regimens: mitomycin C, 5-fluorouracil(5-FU) and CA (MFC) + continuous oral 5-FU (Group C); MFC + continuous oral UFT(tegafur and uracil) (Group B); and MF + UFT (Group C) after operation was conducted in 466 patients with gastric cancer (stage II and III) at four hospitals in Japan (CIH, CAD, ACC and NCC). Patients were stratified by the institution, stage, and tumor size (8 cm ><). The 5-year survival rates were in the order of Group A (79.0%) > B (70.0%) > C (61.0%) (P = 0.1228) in total, A (95.0%) > B (80.0%) > C (58.0%) (P < 0.05) at CAD (82 patients), A > C > B at CIH (215), C > A > B at ACC (95), and B > A > C at NCC (78). The survival rate of patients with S2(serosal exposure), 8 cm < and N0-1 cancer was higher at CIH than at the other institutions. The interinstitutional differences in patient characteristics and surgical technique were more powerful than the differences among the three groups.

Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer.

In Japan the standard adjuvant treatment after resection of gastric cancer is intravenous mitomycin plus oral fluorouracil. We have assessed the efficacy of protein-bound polysaccharide (PSK) in addition to standard chemotherapy in patients who had undergone curative gastrectomy at 46 institutions in central Japan. 262 patients were randomly assigned standard treatment alone or with PSK. The minimum follow-up time was 5 years (range 5-7 years). PSK improved both the 5-year disease-free rate (70.7 vs 59.4% in standard treatment group, p = 0.047) and 5-year survival (73.0 vs 60.0%, p = 0.044). The two regimens had only slight toxic effects, consisting of nausea, leucopenia, and liver function impairment, and there were no significant differences between the groups. The treatments were clinically well tolerated and compliance was good. Addition of PSK to adjuvant chemotherapy with mitomycin and fluorouracil is beneficial as treatment after curative gastrectomy.

[An effect of adjuvant immunochemotherapy using krestin and 5-FU on gastric cancer patients with radical surgery (first report)--a randomized controlled trial by the cooperative study group. Study Group of Immuno-chemotherapy with PSK for Gastric Cancer].

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 gastrectomy 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.

[Adjuvant chemotherapy for gastric cancer--the third study. First report: central randomization by telephone method and analysis of patients' background factors].

JFMTC conducted the third adjuvant chemotherapy study for gastric cancer patients after curative surgery from 1982 to 1983. Patients were randomly allocated to one of the three arms by telephone method controlled at the headquarters of the foundation. This method resulted in the marked reduction of ineligible cases (253 cases, 6.0% of 4,236 cases), compared with those in the first study (18.3%). Main reasons of ineligibility were the violation of entry criteria due to the misjudgment of noncancer, duplicate cancers and operative curability. Telephone method for random allocation seems to contribute to the improvement in the data quality of a clinical trial.

[A randomized controlled trial comparing short-term MF chemotherapy with MF plus long-term HCFU chemotherapy as an adjuvant to a curative resection of stomach cancer: Mifurol Study Group for Stomach Cancer].

In order to clarify the clinical response of long-term adjuvant chemotherapy using Carmofur (HCFU), a comparative multicenter trial has been performed by a randomized controlled method. Curative resected patients suffering from stomach cancer were randomly allocated into two arms. Arm A consisted of short-term MF chemotherapy (mitomycin C 0.04 mg/kg plus 5-fluorouracil 5.0 mg/kg x 6 bolus i.v.) and arm B consisted of arm A plus long-term HCFU chemotherapy (HCFU 6-12 mg/kg/day over 12 weeks, p.o.). The difference of overall survival probability between the two studied arms significantly supported arm B therapy (generalized Wilcoxon test: p = 0.0405) up to 5 years after surgery. The difference of the survival curves was clearer in the case of patients with cancers in the advanced stage, such as a positive serosal inversion and a lymph node metastases [ps(+).n(+)]. The side effects of HCFU, most patients experiencing subjective symptoms such as gastrointestinal toxicities, polyuria, and hot sensation, were reversible. Our results suggest that HCFU maintenance therapy has effect on preventing the postsurgical recurrences of stomach cancer and elongating the patient's survival.

[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.

[A randomized controlled trial comparing short-term MF chemotherapy with MF and long-term carmofur chemotherapy as an adjuvant to curative resection of stomach cancer].

In order to clarify the clinical response to long-term adjuvant chemotherapy with carmofur (HCFU), a comparative multicenter trial has been performed by a randomized controlled method. Curatively resected patients suffering from stomach cancer were randomly allocated into two arms. Arm A consisted of those receiving short-term MF chemotherapy (mitomycin C, 0.04 mg/kg + 5-fluorouracil, 5.0 mg/kg X 6, IVr) and arm B consisted of arm A plus long-term carmofur chemotherapy (Mifurol, 6-12 mg/kg/day over 12 weeks, PO). The difference of overall survival probability between the two study arms was significant in fabior of arm B (P less than 0.05) up to three years after surgery. The difference of survival curves was more distinct (P less than 0.01) in the case of the advanced stage of the cancer such as serosal inversion [ps (+)] and lymph node metastasis [n (+)]. The side effects of carmofur, mostly subjective symptoms such as gastrointestinal toxicities, pollakisuria, and sensation of hotness, were reversible. From the results, it is suggested that carmofur maintenance therapy is effective for the prevention of postsurgical recurrence of stomach cancer by means of the prolongation of patient survival.

[Influence of immunopotentiators on the activation of 5-FU derivatives].

As it has been shown that various kinds of immunopotentiators inhibit the hepatic microsomal drug-metabolizing enzymes and reduce the activation of masked compounds such as tegafur, we investigated the influence of immunopotentiators (OK-432 and PSK) on the activation of carmofur (HCFU), which is known to be transformed spontaneously in to the tumor-active substance, 5-fluorouracil (5-FU), in vivo, and compared the results to those obtained for tegafur. After oral administration of tegafur, the area under the plasma concentration curves of 5-FU in rats pretreated with OK-432 and PSK were 72% and 79% of those in untreated rats, while in the case of HCFU almost similar plasma concentration curves for 5-FU were obtained in both treated and untreated rats. These results show that the activation of HCFU to 5-FU is not influenced by treatment with these immunopotentiators. Furthermore, our clinical investigation showed that the survival curves of cancer patients given combination therapy of tegafur with OK-432 tended to be lower than those given a single therapy of tegafur, supporting the above mentioned basic results.

[A controlled study of surgical adjuvant chemoimmunotherapy with FT-207 and OK-432 for advanced stomach cancer: the fourth study].

A prospective randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. Immediately after surgery, one hundred and forty-seven patients were randomized to receive either chemoimmunotherapy with FT-207 plus OK-432 (group A) or chemotherapy with only FT-207 (group B). The number of patients subjected to this analysis was 134 cases (group A: 70 cases, group B: 64 cases) because thirteen patients were excluded. FT-207 was administered orally and OK-432 was administered intracutaneously. There were no differences in the background factors influencing survival time between the two groups. While the survival rate of group A patients was higher than that of group B patients, the difference in the survival rate between the two study groups was not statistically significant. However, in patients with less differentiated cancer (poorly differentiated adenocarcinoma, signet-ring cell carcinoma) the survival rate of group A patients was significantly (p less than 0.05) higher than that of group B patients. The results of the present study show that OK-432 administered intracutaneously is effective in elevating the survival rate of patients receiving chemotherapy with FT-207 for advanced stomach cancer (especially for less differentiated cancer).

[Immunological approach and surgical treatment of cancer].

It is first mentioned that there is a method of evaluation for the effect on immunochemotherapy as an adjuvant and supporting therapy to surgery. The availability of clinical immunotherapy with surgical treatment was studied by using some prospectively randomized trials. The results were summarized as follows; A combined modality therapy of nonspecific and host mediate immunotherapy and chemotherapy as an adjuvant to surgery was effective on long survival, and the therapy had simultaneously a protective effect of toxicity based on some chemotherapeutic agents. The therapy was effective on the patients who had rather immunologically high response such as curatively or non-curatively resected case than those of nonresectable case. In some combination, combined modality therapy may have not effect, so it should be used under paying attention to the points that are type and dose of agents, timing and interval of administration, and combination method of surgical, chemical and immunological treatments.

[Adjuvant immunochemotherapy combined with OK-432 following surgery of stomach cancer].

Postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as adjuvant therapy for curative resection in the cases of gastric cancer. One hundred and twenty-two patients (28 were excluded) were randomly assigned to 3 groups: Group A-MMC and 5-FU (28 cases); Group B-MMC, 5-FU and OK-432 (33 cases); Group C-control (33 cases). There were no differences in the back ground factors influencing survival time among each group. Group B showed better results in survival rate and disease free interval as compared with Group A or C. Minor and reversible side effects such as enterogastric disorder, leukopenia (less than 3000/mm3), thrombo cytopenia (less than 7 X 10(4)/mm3) and elevation of serum transaminase (S-GPT greater than or equal to 100 unit) were equivalently observed in frequency in each Group A and B, but they were milder in Group B than Group A.

A controlled study of maintenance chemoimmunotherapy vs immunotherapy alone immediately following palliative gastrectomy and induction chemoimmunotherapy for advanced gastric cancer. Tokai cooperative study group for adjuvant chemoimmunotherapy of stomach cancer.

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 less than 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.