Hisashi Furue

Phase I study of recombinant human tumor necrosis factor

SummaryA phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x105 units/m2. The dose was escalated up to 16x105 units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x105 units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x105 units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x105 units/m2.

Clinical Efficacy of Lentinan on Neoplastic Diseases

Lentinan, a β-(1-3)-glucan with some β-(1-6)-gluco-pyranoside branchings, has been extracted and purified from Lentinus edodes a most popular edible mushroom in Japan. This substance has been shown to act as an immunostimulating agent through host defense mechanisms as reported by Chihara et al (1, 2). Lentinan exerts it’s antitumor activity on both syngeneic and spontaneous tumors. The cellular mechanisms of antitumor activity have been clarified by Hamuro et al (3), in that lentinan appears to stimulate host defense mechanisms to induce cytotoxic T cells, natural cytotoxicity and/or augmented macrophages against tumor cells. This suggests that lentinan may be effective for patients with malignant diseases. Based on the results of Phase I and II clinical trials conducted by Taguchi et al (4), the administration conditions for lentinan have been determined to be intravenous administration at doses of 0.5 to 1.0 mg/person/day once or twice a week in combination with chemotherapeutic agents for patients with advanced or recurrent cancer. In order to clarify the clinical efficacy of lentinan administration a Phase III randomized control trial has been conducted on patients with advanced or recurrent gastric or colorectal cancer.

Clinical evaluation of schizophyllan adjuvant immunochemotherapy for patients with resectable gastric cancer —A randomized controlled trial—

Adjuvant immunochemotherapy using schizophyllan (SPG), an extract from the culture broth ofSchizophyllum commune Fries, was prescribed at random for 326 Japanese patients with resectable gastric cancer. The overall survival rates for 3 years did not differ between the SPG and control groups. In 62 patients with stage I gastric cancer and 67 with stage II, there was little difference in the 3-year survival rates. The survival rates for 100 patients with stage III were enhanced at p=0.0811 in the SPG group, as compared to the controls. The survival rates in 97 patients with stage IV cancer were much the same. These results warrant further application of this immunopotentiating drug for treating patients with resectable gastric cancer.

Clinical outcome of postoperative adjuvant immunochemotherapy with sizofiran for patients with resectable gastric cancer: A randomised controlled study

Adjuvant immunochemotherapy using the antitumour polysaccharide sizofiran (SPG), an extract from the culture broth of Schizophyllum commune Fries, was prescribed randomly for 386 Japanese patients with resectable gastric cancer. Although the overall survival probability for 5 years did not differ between the SPG and control groups, in 264 patients with curatively resected cancer, the probability to 5 year survival and to recurrence in the sizofiran-administered patients was better than in the controls. In the multivariate analysis, four of six prognostic factors correlated with the prognosis of the 264 patients who underwent curative surgery, that is, nodal involvement (chi 2 = 21.426, P = less than 0.0001), age distribution (chi 2 = 9.262, P = 0.010), sizofiran administration (chi 2 = 6.507, P = 0.011), and primary tumour size (chi 2 = 9.345, P = 0.025). Thus, patients with a curatively resected gastric cancer had a better prognosis when sizofiran was prescribed in combination with antitumour drugs.

Effects of anti‐emetic drug (tropisetron) on quality of life during chemotherapy: Use of a diary‐type questionnaire and application of summary measures for assessment in a randomized, multicentre study

The role of tropisetron as an anti‐emetic drug in the prevention of delayed nausea and vomiting remains unclear. Therefore, effectiveness of tropisetron in patients receiving cancer chemotherapy was evaluated by application of summary measures using a quality of life (QOL) questionnaire. The diary‐type QOL self‐rating questionnaire was constituted by seven scales. A double‐blind randomized, multicentre study was performed in 33 hospitals. Quality of life was measured in 98 patients. Patients receiving cisplatin were randomized to group T (administration of tropisetron before and 4 days after cisplatin treatment) and group P (administration of tropisetron before cisplatin treatment and followed by placebo for 4 days). The rate of complete protection from delayed emesis in the groups T and P was 46.3 and 36.5%. All scales, except social wellbeing changed immediately in both groups and reached a nadir on days 2–3, after that returning to the control levels during 2 weeks after cisplatin treatment. Group T was significantly better than group P in physical wellbeing, mental wellbeing, functional wellbeing and global QOL scores summarized by area under the curve and Difmax (maximum differences of QOL scales’ score from the best score throughout the entire period). These results indicate that continuous administration of tropisetron could contribute to preventing patient QOL influenced by cisplatin treatment, and the combined use of summary measures may be useful for the evaluation of QOL in cancer clinical trial.