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This interim analysis of the JFMTC study as of May, 1998 covers 321 gastrectomized patients with far-advanced stomach cancer from 135 institutions between November, 1993 and March, 1996. The intensive therapy group (I-group) received CDDP i.p. administration on resective surgery with 70 mg/m2 followed by CDDP i.v. of 80 mg/m2 (day 1, i.v.), accompanying 5-FU of 350 mg/m2/day (day 1-5, c.v.i.) in the 4th, 8th and 12th weeks. The I-group was randomly compared with the standard therapy group (S-group) of MMC of 6 mg/m2 i.v. in the 4th, 8th and 12th weeks and UFT of 3-4 capsules daily for postoperative one year. The results obtained were that 1. adverse reactions were found more in the I-group than in the S-group, particularly notable in the decrease in blood cells, loss of appetite and nausea/vomiting, and incidence of grade 3 or more being 13% (neutrophile leukocytes), 26% and 21%, respectively; 2. there was no significant difference between I- and S-groups in terms of 3-year survival or disease-free survival rates. (JFMTC: Japanese Foundation of Multidisciplinary Treatment for Cancer).

This interim report, for findings as of May, 1998, covers data on 435 gastrectomized patients with semi-advanced stomach cancer collected from 144 institutions between November, 1993 and March, 1996. The active arm of the study involved CDDP i.p. administration of 70 mg/m2 at the time of resective surgery, followed by UFT oral administration for one year at 3-4 capsules daily. A randomized control involved no adjuvant therapy after CDDP i.p. administered as in the active arm. The results obtained indicated no significant difference between the groups in terms of 3 year survival or disease free survival rates. Reports appearing elsewhere have suggested that 3-4 capsules/day of UFT may be insufficient to reach the threshold of the effective tissue level, and that 6 capsules may be necessary to obtain the expected results. (JFMTC: Japanese Foundation of Multidisciplinary Treatment for Cancer).

This is a case report of a 37-year-old Japanese married female with laryngeal sarcoma, treated by direct electric current so as to obtain remission for more than 4 years without signs of recurrence. Due to her hoarseness and laryngeal numb feeling she underwent a laryngeal examination including a biopsy, resulting in a diagnosis of sarcoma. She refused a total laryngectomy and was given Cobalt treatment of 40 Grey. In the following several months, no improvement was observed, objectively or subjectively. In Nagoya University Hospital the patient then received direct electric current therapy of 36 Coulombs through two platinum electrodes inserted into the tumor under a CT guide, pericutaneously. Two months later, as the hoarseness remained in spite of some improvement, she underwent another session of direct electric current therapy of 14.4 Coulombs through the platinum electrodes by bronchoscope-guided direct insertion. Her hoarseness soon disappeared thereafter and there was a regression of the tumor in 6 months. She did well thereafter without any signs of recurrence for 4 years. Clinical treatment of solid tumors with electric treatment with direct electric current has been done in more than 8,000 cases with CR in 25% of all cases and PR in 50%. Its mechanism, however, remains unclear. In our experimental animal studies, apoptosis was observed. It is considered that this electric therapy using direct electric current will be recognized as one method to treat solid tumors.

There is now good evidence that a series of genetic lesions in both dominant oncogenes and tumor suppressor genes are involved in the pathogenesis of human digestive tract carcinomas. Small intestinal carcinomas are very rare, accounting for only about 0.19% of all primary gastrointestinal malignant tumors in Japan, so there are few reports investigating genetic changes of small intestinal carcinoma. We analyzed 3 microsatellite loci and the status of K-ras and p53 genes isolated from tumors and surrounding normal tissue samples obtained during surgery. The polymerase chain reaction (PCR) technique used frequent genetic instability to assess differences between tumor and matched DNAs. Replication errors (RERs) were observed in 3 of the 29 cases (10%) of gastric carcinoma and in 11 of the 72 cases (15%) of colorectal carcinoma. None of the 13 (0%) esophageal carcinoma cases showed any RER, but 5 of 11 cases of small intestinal carcinoma (45%) had RERs, reflecting a significantly high incidence. None of the 11 small intestinal carcinoma cases exhibited K-ras gene mutations. Of 7 case amplified successfully by polymerase chain reaction (PCR) in exon 5-8 loci in p53 gene, 2 exhibited abnormally migrated bands in polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. It is thus clear that the genetic carcinogenesis in the small intestine is different from other parts of the digestive tract. These results suggest that genetic instability plays an important role in the pathogenesis of small intestinal carcinomas.

The enhanced effects due to the combined use of oral administration of S-1 and intraperitoneal administration of Cisplatin (CDDP) were examined with gastric cancer xenografts (NUGC 4). S-1, a new anticancer drug, was daily administered at 10 mg/kg (qld x 5 x 3 weeks). 5-FU level in blood was 1 microgram/ml at two hours after the treatment. Antitumor activity was not found in mice with only the CDDP treatment. But antitumor activity by S-1 and daily low-dose (1 mg/kg) or intermittent treatment (5 mg/kg) of CDDP showed better results than daily S-1 treatment. The daily low-dose CDDP treatment showed similar efficacy to the intermittent administration at the same total dose, but the daily low-dose CDDP treatment was better in the light of toxicities. These results suggest that treatment with S-1 and daily low-dose CDDP was effective for gastric cancer.

The experimental studies in vitro and in vivo were performed to investigate the effects of carcinostatic agents in the adhesion of cancer cells to endothelial cells. Certain carcinostatic agents induce the expression of E-selectin on endothelial cells and enhance the expression of carbohydrate ligands on cancer cells. Consequently, increased adhesion of cancer cells to endothelial cells was observed by the treatment of carcinostatic agents. In the trans-splenic hepatic metastasis model using nude mice, the augmentation of cancer metastasis was observed by the treatment of carcinostatic agents. From the above, we concluded that carcinostatic agents may increase the metastatic ability of cancer cells in patients with cancer.

Twenty-one evaluable patients with primary gastric cancer/local invasion, liver metastasis and peritoneal metastasis were entered in a pilot study of neoadjuvant chemotherapy that used continuous 24-hour infusion 5-FU, 330 mg/m2/day plus low dose CDDP, 6 mg/m2 daily by bolus infusion d1-5. This regimen was repeated for 4 weeks. The overall response rate was 52%, including one complete and ten partial responses. The response rate of differentiated adenocarcinomas was significantly higher than that of poorly differentiated adenocarcinomas. In 15 patients (71%), gastrectomy and lymphadenectomy could be done after this regimen. chemotherapy-induced downstaging from the initial clinical stage was pathologically found in 5 patients who underwent gastrectomy. Toxicity was primarily hematologic. Leukopenia and thrombocytopenia of grade 3 or 4 occurred in 19% and 14% of patients, respectively. The patients were able to take meals during therapy and preserved good quality of life. Median survival time was 11 months for the cancers with liver metastasis and five of the 8 locally advanced cancers are alive 11 months after the therapy. This therapy was effective for patients with high-grade advanced gastric cancer.

We report a case of double cancer of esophagus and stomach treated with 5-fluorouracil and consecutive low-dose cisplatin. The patient was a 58-year-old man with liver cirrhosis. Using upper gastrointestinal fiberscopy, a superficial depressed lesion (O-IIc) in the middle thoracic part of the esophagus and Borrmann 2 type lesion in the fundus of the stomach were also detected. Microscopic examination of the biopsy specimen revealed moderately differentiated squamous cell carcinoma and adenocarcinoma. But laparotomy could not be done due to impaired liver function (KICG 0.051, ICGR15 45.2%). The patient was treated for 28 days with continuous 24 hour infusion 5-FU, 250 mg/body/day plus low dose CD-DP, 10 mg/body daily by bolus infusion d1-5, 8-12, 15-19, 22-26. One month after the chemotherapy, both the gastric cancer and the esophageal cancer were remarkably reduced (diagnosis: PR), and showed no malignancy in the histology. There was no change in the histological findings of the esophageal lesion at 31 months after the chemotherapy. This therapy is effective for patients with gastric cancer and esophageal cancer.

A randomized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer. The schedules for drug administration were different in four districts: ACNU + Futraful (FT) group and FT alone group in the Hokkaido-Shikoku district; the same schedule groups plus untreated group in the Chubu-Kinki district; MMC+FT group, FT alone group in the Tohoku-Kanto district; and ADM+FT group and FT alone group in the Chugoku-Kyushu district. The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study. The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer, but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies. In n2 (+) or a2(s) rectal cancer in particular, combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate, and the rate of local recurrence was significantly lower with ADM+FT.

UFT, an antitumor drug combined of Tegafur 1 and Uracil 4, was administered preoperatively to 23 cancer patients including 11 cases of breast, 8 of gastric, 2 of colon and 2 of other cancers. Tissue specimens of different sites and serum samples were collected during the operation: cancer tissues, normal breast, normal gastric, colon or rectal wall, lymph nodes and subcutaneous fatty tissues, etc., and concentrations of tegafur (FT), 5-fluorouracil (5-FU) and uracil were studied using HCLP or GC-MF methods. In most cases, 5-FU and uracil concentrations detected in cancer tissues from the patients were higher than those found in non cancer sites. FT and 5-FU fractions in cancer tissues were found to be higher than those of the patients receiving only 800 mg of Tegafur fine granules as previously reported. Patients with benign tumor having mastopathy or were reported to show very low 5-FU concentration in tissue which was almost undetectable. From the above results, it has been suggested that UFT is a useful drug in cancer chemotherapy.

In a phase II study of THP, fifty-six patients with advanced or recurrent breast cancer were evaluated, and a response rate of 23.2% including 1.8% with complete response and 21.4% with partial response, was obtained. Response rates of THP varied according to the location of metastasis and the highest rate was shown to be 38.5% in patients with soft tissue metastasis. The median dose for inducing response was 100 mg with a range from 60 mg to 160 mg. Toxicities such as leukopenia and gastrointestinal disorders were observed during THP treatment. The favorable response to THP was close to that of adriamycin, but it was noteworthy that a lower frequency of alopecia occurred.

In order to evaluate the efficacy of surgical adjuvant chemotherapy in patients undergoing gross curative resection for colorectal cancer (excluding m and sm cancer), a randomized controlled study was conducted from January, 1982 to October, 1983. Four hundred and ninety-one institutions participated in this study. The schedules for drug administration differed according to each district. In the Hokkaido and Shikoku districts, the patients were divided into the following two groups, one was a combination of ACNU and Futraful (FT) and the other was FT only. In the Chubu and Kinki districts, three groups were studied, namely those receiving a combination of ACNU and FT, those receiving FT only and those given no adjuvant chemotherapy. In the Tohoku and Kanto districts, a combination of MMC and FT and administration of FT only were studied. In the Chugoku and Kyushu districts, the patients were divided into a combination of ADM and FT, and FT only group. Among the 3,926 registered cases, 3,421 cases were valid for the study. As to the background factors, there were no significant differences among the groups in each district. There were no significant differences in one-year survival rates and one-year disease-free rates. No serious adverse effects were observed in any of the groups.

To evaluate the efficacy of surgical adjuvant chemotherapy for patients with curatively resected colorectal cancer (excluding m and sm cancer), a randomized controlled study was performed from January 1982 to October 1983. The schedules for drug administration were different in four districts, and four randomly assigned protocols were studied using tegafur (FT), ACNU, MMC and ADM. A total of 4,906 cases from 491 institutions were entered and 4,206 cases were varied for the study. There were no significant differences in 3-year survival rate in each district protocol. According to Dukes C for rectal cancer patients, ADM + FT group was higher than the FT only group in 3-year survival rate (p = 0.092) and had a significantly longer survival than FT only group in 3-year disease-free rate (p = 0.011). The rate of local recidivation in colon cancer resected curatively was higher in ACNU + FT group than in FT only group (p less than 0.05). A tendency for decreased liver metastasis was observed in FT group compared with the control group, and liver metastasis of ADM + FT group was lower than that of FT only group. No serious adverse effects were observed in any protocol.

A Phase II Study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with various solid tumors was carried out by 44 cooperative study institutions. Seven hundred fifty-six patients administered the drug intravenously were entered into this study. Of these, 499 patients were evaluated for objective responses. THP was given mainly at a dose of 40 to 60 mg/body every 3 to 4 weeks or 20 to 30 mg/body once a week. Response rates were 18.8% for head and neck cancer, 13.1% for stomach cancer, 21.4% for breast cancer, 22.2% for bladder cancer, 30% for renal pelvic and urinary tract tumor, 26.8% for ovarian cancer and 24.2% for uterine cancer. Overall response rate was 15.4% including 10 complete responses and 67 partial responses. Adverse reactions were similar to those previously reported in the phase I study, including gastrointestinal toxicities and myelosuppression. Alopecia and stomatitis, which are major side effects of other anthracyclines, were rather mild. Incidence of ECG changes was 2.8% and no congestive heart failure was observed.

A 57-year-old female was admitted for advanced ascending colon cancer with a solitary pulmonary metastasis measuring 1.5 cm in diameter. As laparotomy revealed an absolute noncurable tumor of stage V (H0, p2, s2 n1 (+], palliative right hemicolectomy was performed. A pathological diagnosis of well differentiated adenocarcinoma was made postoperatively. A daily dose of 400 mg of UFT was given orally. After 8 months, plain chest film and tomography revealed a reduction in the size of the pulmonary metastasis to 1.0 cm in diameter. The metastatic lung tumor was controlled for a period of 1 year and 9 months. It was suggested that UFT was rather effective for pulmonary metastasis from colon cancer.

The addition of Futraful to MMC therapy of gastric carcinoma was evaluated. Nationwide 297 institutions participated in a randomized controlled study and cumulative five-year survival rate was calculated. A total of 1,673 cases was studied. These were divided in two groups: Group A, without Futraful, and Group B, with Futraful. Futraful was administered postoperatively for 3 months. The MMC treatment was done by moderate intermittent administration (Method I) or by large dose administration (Method II). Futraful improved survival rates regardless of the method of MMC treatment. Especially, Group B' (more than 60 g of Futraful) showed significantly better results in patients with metastases and positive serosal invasion in both methods, and beta type infiltration in Method I. Furthermore the Group B' patients had higher survival than Group A patients in Method II for patients in stage III and gamma type infiltration. Method II, a large dose MMC, plus Futraful was suggestive of particular effectiveness in preventing peritoneal metastases in curatively resected cases.

The composite substance of Mitomycin C (MMC) and polymer by low temperature radiating polymerization has a characteristic of slow release, the possibility of applying it to local chemotherapy was clinically studied. Buttom-formed preparation (MMC 20 mg) and needle-formed preparation (MMC 5 mg) were applied to the lesions, respectively, by sewing and piercing in 220 cancer patients with non resectable infiltrative lesions. The treatment had a pain-relieving effect in 70 out of 117 cases (60.0%) of painful cancer in the pancreas, biliary duct, liver, etc, and improved the symptoms of digestive organs in 31 out of 93 cases (33.3%). However, the tumor-reducing effect was recognized only in minute localized lesions of hepatic cancer, etc., and the survival period was not prolonged. The treatment caused no severe side effects. From the above results, the local chemotherapy with slow-releasing MMC preparation was concluded to be a useful means of palliative therapy in non-resectable, though its formulation may to be further improved.

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan with the participation of 334 institutes nation-wide had conducted the secondary study in order to investigate the usefulness of futraful in long term treatment, based on the results obtained by the primary study. The following method was taken for the study and patients were randomly divided into three groups: A group-given a high dose of MMC immediately after operation; B group-given futraful for one year after MMC administration; C group-given futraful alone for long-term. The number of eligible cases for data analysis was 3,o30. Side effects observed during the long term treatment with futraful were considered to be minor. Although the occurrence of hematocytopenia was slightly frequent because of possible increase of influence by the concomitant use of MMC, no tendency of hepatic disorders and any subjective side effects to be strengthened by MMC combination was observed at all. As for 2-year survival, an elevated survival was found in the group of concomitant use of MMC and futraful; Especially, a significantly high survival was found in the cases of stage III and n (+) . ps (+). Furthermore, the survival was elevated in proportion to the increase of total dosage of futraful. This suggested the usefulness of futraful for long term treatment.