Search

Aims: The efficacy and the toxicity of oral fluorouracil derivative S-1 plus low-dose cisplatin in unresectable or recurrent gastric cancer were evaluated by a phase II study., Methods: S-1 was administered orally for 28 days following 14 days' rest at 80-120 mg/body/day, depending on body surface area. During administration of S-1, cisplatin was given twice a week at the recommended dose (10 mg/m(2)), which was determined by a phase I study. Data from 34 patients in phase II and 8 patients treated with the recommended dose of cisplatin in phase I were analyzed. The primary endpoint was objective response., Results: The response rate was 47.1%. The median survival time was 11.0 months and the median progression-free survival was 6.9 months. The grade 3/4 toxicities observed in 10% or more of the treated patients were neutropenia (16.7%), anemia (16.7%) and anorexia (11.9%). The serum concentration of cisplatin was 794 ± 341 ng/ml at day 25 of the first course., Conclusions: S-1 plus low-dose cisplatin may be a clinically useful regimen for unresectable or recurrent gastric cancer because of its infrequent adverse events in spite of considerable efficacy and its convenience of no hydration and no hospitalization., (Copyright © 2011 S. Karger AG, Basel.)

We report a case of angiosarcoma of the right atrium presenting superior vena cava syndrome. The patient was a 61-year-old man. Echocardiography, CT and MRI revealed a tumor arising in the anterior wall of the right atrium. The tumor was hen-egg sized and unresectable because of the invasion of the pericardium, the right ventricular wall and the superior vena cava. An open biopsy and left brachiocephalic vein-right atrium bypass grafting were performed. The pathological diagnosis was angiosarcoma. The patient agreed to chemotherapy with docetaxel, which is known to be often effective against angiosarcoma of the scalp or face. After 5 courses of docetaxel administration (30 mg/m2 on day 1, 8 and 15 followed by 14 days. rest as one course), echocardiography and CT showed a remarkable tumor reduction, which was evaluated as a partial response. The chemotherapy was suspended for 8 months because of neutropenia and general fatigue as side effects of docetaxel. The administration of docetaxel was resumed and 4 courses were performed. The tumor, however, became resistant to docetaxel and formed metastatic involvements in the liver. Following treatments with paclitaxel, IL-2 and CPT-11 were ineffective for the primary tumor and liver metastases. He died of cardiac tamponade caused by massive hemorrhage into the pericardiac space from the tumor surface. He had long-term survival 31 months after the diagnosis. An effective treatment for cardiac angiosarcoma has not yet been established. Chemotherapy with docetaxel should be considered in the treatment of patients with cardiac angiosarcoma.

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.

Background: The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma., Methods: Thirty-eight patients were enrolled in the study. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks unless disease progression was observed., Results: A combined total of 173 courses of S-1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1-18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0-56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305-490 days), and the 1-year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment-related death was observed during the study., Conclusions: Orally administered S-1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option., (Copyright 2004 American Cancer Society.)

Purpose: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer., Experimental Design: S-1 was administered orally at 80-120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses., Results: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course., Conclusions: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.

The patient was a 61-year-old man who had gastric cancer with metastasis to cervical lymph nodes and pulmonary lymphangitis carcinomatosa. He received daily oral administration of 120 mg of TS-1 (day 1-21) and systemic administration of 100 mg of CDDP (day 8) as one treatment course. As the metastatic lesions had disappeared after chemotherapy, he underwent total gastrectomy. Histopathological examination of resected regional lymph nodes revealed marked fibrosis and a small amount of scattered cancer cells. Although much peritoneal dissemination was observed macroscopically, histopathological examination of these tumors revealed only fibrosis with no cancer cells. These findings supported the effect of this neoadjuvant chemotherapy. He died of recurrence of the carcinoma 203 days after surgery, without any sign of recurrence of metastasis to cervical lymph nodes or pulmonary lymphangitis carcinomatosa.

Background: Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study., Methods: Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30 mg/m(2) and 50 mg/m(2); level 2, 35 and 50 mg/m(2); level 3, 40 and 50 mg/m(2); level 4, 40 and 60 mg/m(2); and level 5, 50 and 60 mg/m(2). The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle., Results: Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages., Conclusion: Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35 mg/m(2) and 50 mg/m(2), respectively.

Background: Because docetaxel and cisplatin are both active against gastric cancer and have different mechanisms of action, this combination may provide additive or synergistic effects against gastric cancer. This article presents a phase I study designed to determine the recommended dose of cisplatin combined with a fixed dose of docetaxel, and a subsequent phase II study that evaluated the clinical efficacy and feasibility of this combination regimen., Methods: Patients enrolled in the study had to have histologically confirmed advanced or recurrent gastric cancer with measurable disease and adequate organ function, and to be aged 20 to 75 years, with a performance status (PS) of 0 to 2. In the phase I study, docetaxel was administered at a fixed dose of 60 mg/m(2) on day 1. Cisplatin was also administered on day 1, at dose levels of 60, 70, and 80 mg/m(2). Where dose-limiting toxicities were not observed in more than 33.3% of patients, three patients were accrued for each dose level., Results: Recommended doses for the phase II evaluation were determined to be 60 mg/m(2) of docetaxel and 80 mg/m(2) of cisplatin. Although grade 3 or more severe leukopenia and neutropenia were observed in 71.4% and 82.1% of the patients, respectively, nonhematological toxicities were not severe. The overall response rate at the recommended dose level was 25.0% (7/28 patients), and the rate was 40% (6/15) for patients with liver metastases. The median survival time was 9.7 months and the 1-year survival rate was 39.3%., Conclusion: Although this study failed to demonstrate a high response rate, this regimen was feasible and might be of value in further investigations in respect to the relatively high response rate in patients with liver metastasis and the favorable survival.

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.

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.

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.

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.

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.

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.

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.

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.

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.