Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

Moderate neutropenia with S-1 plus low-dose cisplatin may predict a more favourable prognosis in advanced gastric cancer.

AIMS: The effects of haematological adverse events on the prognosis of patients with gastric cancer were investigated. MATERIALS AND METHODS: We retrospectively analysed the association between haematological adverse events and prognosis in 23 patients with far advanced or recurrent gastric cancer treated with a JFMC27-9902 regimen consisting of an oral fluorouracil derivative S-1 plus low-dose cisplatin. RESULTS: The patients who suffered grade 2-3 neutropenia (n = 10; median survival time [MST] 679 days) were found to have significantly more favourable prognoses than patients who developed grade 0-1 (n = 10; MST 271 days) or grade 4 neutropenia (n = 3; MST 408 days) (P = 0.0039 and 0.0112, respectively), although no significant differences were found among the clinicopathological factors of any grade groups. With respect to anaemia or thrombocytopenia, there were no significant differences among the MSTs of the groups stratified by toxicity grade. Multivariate survival analysis revealed that grade 2-3 neutropenia is an independent predictor of a more favourable prognosis (hazard ratio = 38.693, P = 0.0004). CONCLUSIONS: These results suggest that S-1 plus low-dose cisplatin against gastric cancer may contribute to long survival when it induces moderate neutropenia.

Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis.

BACKGROUND: The polymorphic enzyme cytochrome P450 2C19 affects omeprazole metabolism. This influence on metabolism might affect serum gastrin levels, and safety, during long-term treatment of reflux oesophagitis. AIM: To examine the relationship between cytochrome P450 2C19 genotype and the safety profile of long-term omeprazole treatment. METHODS: A total of 119 Japanese patients with recurrent reflux oesophagitis underwent cytochrome P450 2C19 genotyping prior to receiving daily omeprazole 10 mg or 20 mg for 6-12 months, during which adverse event frequency, serum gastrin levels and endoscopic findings were monitored. RESULTS: The incidences of adverse events, serious adverse events and adverse events leading to withdrawal did not differ between homozygous extensive metabolizer (n = 46), heterozygous extensive metabolizer (n = 53) or poor metabolizer (n = 20) groups. In all genotype groups, serum gastrin increased during the first 3 months of dosing but stabilized thereafter. No significant differences were seen either in the rate of reflux oesophagitis healing or symptom improvement among genotype groups. CONCLUSIONS: Long-term treatment with omeprazole was well-tolerated in Japanese patients, irrespective of their cytochrome P450 2C19 metabolic genotype, indicating that dose adjustment depending on metabolic genotype is not required during treatment with omeprazole.

Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group.

This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m(-2) day(-1) for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25-48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity.

[A late phase II study of raltitrexed (ZD 1694) in chemotherapy-naive patients with advanced colorectal cancer].

A multicenter co-operative late phase II study of raltitrexed (ZD1694), a specific thymidylate synthase (TS) inhibitor, was conducted in chemotherapy-naive patients with advanced colorectal cancer. Raltitrexed was infused intravenously over 15 minutes once every three weeks. Between April 1996 and September 1998, 61 patients were enrolled and 58 were eligible. Fourteen patients experienced a partial response (PR), 22 no change (NC), 20 progressive disease (PD) and 2 no evaluable (NE). The overall response rate was 24.1% (95% CI: 13.9-37.2%). Responses were seen in lung (22.7%), liver (22.9%) and deep lymph nodes (10.0%). Median survival was 11.6 months. Grade 3 or 4 toxicities were: leukopenia (13.8%), neutropenia (24.1%), hemoglobin decrease (15.5%), FBC decrease (6.9%), hematocrit decrease (6.9%), thrombocytopenia (6.9%), transient SGPT increase (6.9%), nausea/vomiting (20.7%), anorexia (15.5%), and asthenia (6.9%). These adverse reactions were considered to be manageable. Only one death was associated with drug treatment. These results suggest that raltitrexed provides an effective and convenient treatment for patients with advanced and previously untreated colorectal cancer.

An early phase II study of oral S-1, a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. The S-1 Gastrointestinal Cancer Study Group.

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to alpha-fluoro-beta-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4-68.1% and C 8.4-30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21. 4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35. 7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.

Phase II study of raltitrexed (Tomudex) in chemotherapy-pretreated patients with advanced colorectal cancer. Tomudex Cooperative Study Group.

Raltitrexed (Tomudex), a novel folate-based inhibitor of thymidylate synthase, has demonstrated anti-tumour efficacy comparable with 5-fluorouracil and leucovorin in patients with advanced colorectal cancer (CRC). This phase II study was conducted to evaluate the anti-timor efficacy and tolerability of raltitrexed in patients with advanced CRC who had received one previous chemotherapy regimen. Raltitrexed was administered at a dose of 3.0 mg/m2 i.v. over 15 min once every 3 weeks. Of 43 eligible patients, 53% had colon cancer and 47% rectal cancer. Objective responses were observed in 16% of patients [95% confidence interval (CI): 7-31%; seven partial responses). The median duration of response was 101 days (range: 45-239 days), the median overall duration of response was 145 days (range: 104-302 days) and the median survival was 11.6 months (95% CI: 9.4-14.7 months). Liver metastases showed a 17% (three of 18) response rate and lung metastases a 12% (three of 25) response rate. Adverse events of grade 3 or 4 reported for more than 5% of patients were neutropenia (23%), leukopenia (9%), reversible SGPT increase (7%) nausea/vomiting (19%), anorexia (14%), asthenia (9%) and hypotension (7%). Grade 3 or 4 diarrhea, stomatitis and alopecia were not observed. In summary, raltitrexed had an acceptable toxicity profile and promising anti-tumor activity against advanced CRC in patients who had received prior chemotherapy. Further clinical trials of combination chemotherapy using raltitrexed are warranted.

Detection of APC mutations by a yeast-based protein truncation test (YPTT).

APC gene mutations play a role in the initiation step of colorectal carcinogenesis in both familial adenomatous polyposis (FAP) and non-FAP patients. Almost all of the APC mutations are nonsense or frameshift mutations, which truncate the APC protein and are thought to inactivate normal APC function. We show a novel method for detecting nonsense and frameshift APC gene mutations by using Saccharomyces cerevisiae. Polymerase chain reaction (PCR)-amplified APC fragments are cloned directly into yeast expression vectors in vivo, and the yeast expresses a hemagglutinin epitope (HA)-tagged APC peptide. When an APC fragment contains a nonsense or frameshift mutation, HA-tagged truncating APC peptide can be detected by Western blotting using an anti-HA antibody. We identified both germ-line and somatic APC mutations in patients with FAP and non-FAP colorectal tumors, respectively. This method, called the yeast-based protein truncation test (YPTT), is simple and fairly cheap, and it can be applied to any genes that are inactivated by protein truncating mutations.

Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients.

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil (5-FU). CDHP inhibits dihydropyrimidine dehydrogenase (DPD), an enzyme which degrades 5-FU, and maintains prolonged 5-FU concentrations in the blood and tumours. Oxo is distributed in the gastrointestinal tract at a high concentration after oral administration and alleviates gastrointestinal toxicity due to 5-FU. S-1 improves the tumour-selective toxicity of 5-FU by the actions of two modulators, CDHP and Oxo. We conducted a late phase II clinical trial of S-1 as an open trial in patients with advanced gastric cancer, to confirm its antitumour effect and adverse reactions. 51 patients with advanced gastric cancer were enrolled in the trial. S-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2/day. One course consisted of consecutive administration for 28 days and 14 days' rest. Administration was repeated over four courses. A complete response was obtained in 1 patient and partial responses in 24 patients, producing a response rate of 49% (25/51) (95% confidence interval (CI) 35.9-62.3%). The incidence of adverse reactions was 78% (40/51) and that of adverse reactions of grades 3 and 4 was 20%. Adverse reactions of grades 3 and 4 included a decrease in the haematocrit, leucopenia, granulocytopenia, diarrhoea, malaise and proteinuria. No serious unexpected adverse reactions were observed. In conclusion, S-1 was effective and well tolerated in patients with advanced gastric cancer.

Induction of natural killer (NK) activity in mice by injection of chromomycin A3.

Intravenously or intraperitoneally administered Chromomycin A3 (CHRM), an anticancer drug, augmented natural killer (NK) activity of both spleen cells and peritoneal exudate cells in BALB/c mice. When CHRM was administered intravenously, NK activity increased to about five fold that in nontreated mice on the 3rd to the 5th day, then rapidly decreased by the 7th day. On the other hand, when CHRM was administered by the intraperitoneal route, a peak of increased NK activity was observed on 5th to 7th day followed by a more gentle decrease. Augmentation of NK activity by CHRM was enhanced by additional administration of Interferon- gamma (IFN-gamma). Experimental evidence that NK activity could be augmented by CHRM in various strains of mice, independent of H-2 haplotype, suggested that involvement of genetic control within class I region of major histocompatibility complex could be excluded. When BALB/c mice inoculated subcutaneously with Meth A cells were treated with i.p. injection of CHRM, or CHRM in combination with IFN-gamma, the growth of the tumor cells was inhibited, indicating in vivo significance for the increased NK activity. Since this inhibitory effect was decreased by the injection of anti Asialo GM1 antibody (alpha-ASGM1), the effector cells presumably exerting killing activity against Meth A cells were concluded to be Asialo GM1 antigen positive.

[Subsets of peripheral blood lymphocytes and tumor infiltrating lymphocytes in cancer patients received chemotherapy].

Forty-three patients with advanced cancer were evaluated for the changes of absolute counts of peripheral blood lymphocytes and lymphocyte subsets during chemotherapy or chemoimmunotherapy. In 27 patients who did not respond to the therapy, whole lymphocytes, T cells, helper/inducer T cells and NK cells decreased significantly in number. In contrast, they showed little decrease in 16 cases responded to the therapy. In situ immunohistochemical analysis of the tumor infiltrating lymphocytes was performed on the carcinoma tissues obtained from 25 gastric cancer patients. T cell infiltration, in which helper/inducer T cells were predominant over suppressor/cytotoxic T cells, and NK cell infiltration were found in most of the tissues comprised various carcinoma types of histology. Furthermore, an analysis of a gastric cancer patient treated with systemic administration of 3 BRMs and intratumoral injection of OK-432 indicated that infiltration of cytotoxic T cells and NK cells augmented by cytokines such as IFN-gamma produced from activated helper/inducer T cells and NK cells. Therefore, it is suggested that movements of helper/inducer T cells and NK cells relate to the response to chemotherapy and participate in prognosis of advanced cancer patients.

Responsiveness of peripheral blood lymphocytes from cancer patients and healthy donors to interleukin-2 (IL-2).

The proliferative response of the peripheral mononuclear cells (MNC) from cancer patients and healthy individuals to IL-2 was studied by use of the quantitative microwell assay of the 3H-TdR incorporation into the cells in vitro. After the addition of phytohemagglutinin (PHA), MNC acquired the reactivity to IL-2 within 3 hr, and reached a maximum after 12 to 17 hr of incubation. Although the IL-2 response of PHA-activated MNC from cancer patient was lower than that from healthy donor, there was no significant difference in the kinetics of proliferation. The maximum response of PHA-activated MNC from both cancer patients and healthy donors to IL-2 was observed at 96 hr and 84 hr, respectively. When monocytes were removed from MNC, IL-2-associated growth of the remaining fraction of MNC was decreased to 40-70% in both cancer patients and healthy donors. Furthermore, monocytes from cancer patients did not affect the IL-2 responsiveness of lymphocytes from healthy donors, and vice versa. The number of T lymphocytes having IL-2 receptors (IL-2R) from cancer patients was lower than that from healthy donors. These facts indicated that the lower IL-2 response of MNC from cancer bearer was due to the decreased number of T lymphocytes possessing IL-2R, and not due to monocytes themselves.

Imbalance of T cell subsets in cancer patients and its modification with bestatin, a small molecular immunomodifier.

The peripheral T lymphocyte subsets and natural killer (NK) cells of patients with cancer were studied by monoclonal antibody assays in comparison with those of non-cancer individuals. An imbalance of immunoregulatory T cell subsets was frequently found in the group of cancer patients (n = 26), being characterized by a relatively high proportion of OKT8+ cells (45.0 +/- 12.0%, p less than 0.01) and a low OKT4+/OKT8+ ratio (1.29 +/- 0.56, p less than 0.05). T cell level showed no significant difference as assessed by either OKT3 or rosette formation with sheep erythrocytes (E). The effect of bestatin was examined in 10 of these cancer patients. The relative proportion of T cell subsets tended to normalize 2 to 6 weeks after starting the daily doses of 30 mg per body. The mean percentage of OKT8+ cells decreased from 47.2 to 33.4 (p less than 0.01), while the helper to suppressor ratio increased from 1.18 to 1.79 (p less than 0.01). A significant increase was also found in the percentage and number of OKT4+ cells and HNK-1+ cells after the drug administration, while T cell level tended to converge to a normal range.

[Clinical trial of K-247].

The clinical trial of K-247, an anticancer drug showing antitumor effect by new mechanism of action, was performed in a total of 22 patients with a variety of advanced cancers, consisting of 10 cases administered singly and 12 cases combined with other anticancer agents. All patients were treated three or four times every day with oral administration of K-247 (600-800 mg/day). Including one patient receiving a high dosage (over 200 g totally) of K-247, in all cases, no appreciable side effect causing suspension of the administration was recognized. In combination therapies with other anticancer drugs there was rather found a tendency to rescue WBC from decrease. As a clinical result, although all cases tested were insusceptible to prior chemotherapy with various anticancer drugs, one case, which has received palliative operation for rectal cancer accompanied with pelvic infiltration, was experienced after administration of K-247 only, in which the destructive lesion of left sacral on X-ray photograph was restored to almost normal condition and the patient's complaints such as severe pain in the lower legs and difficulty in walking were completely disappeared.