[Early phase II trial of oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer. ETP 21 Study Group--Cervical-Ovarian Cancer Group].

We conducted multi-site early phase II trial or oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer in cooperation with 19 institutes. Fifty mg/body of oral etoposide was administered daily for 21 consecutive days. Cycles were repeated every 28 days. In cervical cancer, 24 patients were enrolled and 17 of them were evaluated. The overall response rate including CR and PR was 23.5% (4/17). In ovarian cancer, 18 patients out of 21 enrolled were evaluated. The overall response rate was 16.7% (3/18). The primary toxicity observed was myelosuppression such as leukopenia, neutropenia, hemoglobin decrease and thrombocytopenia. Other adverse effects were anorexia, nausea, vomitting, fatigue, alopecia and stomatitis. From these results we concluded that oral etoposide administered for 21 consecutive days was effective against cervical cancer.

Phase I study of NKT-01.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

Relation between the hormonal and epidemiological aspects of ovarian cancer patients in Japan.

We compared the hormonal and epidemiological aspects of ovarian cancer patients in search of the etiology of this neoplasia. Case-control studies of Japanese women with and without cancer were conducted in parallel, with regard to both the excretion of 14 urinary steroids and the pertinent physical and physiological parameters. The results obtained are as follows: 1) premenopausal ovarian cancer patients before and after radical ovariectomy and postmenopausal-postoperative patients were associated with a specified steroid deviation profile characterized by a combination of general depression of androgens, progestins and corticosteroids with sole rescue of tetrahydrocortisol (THF) in urine. 2) The deviation profile of postmenopausal-preoperative cancer patients was distinguished from the 3 partner profiles by its preservation of normalcy in the excretions of androgen and progestin in urine. 3) Ovarian cancer patients were associated with growth retardation, when compared with urban healthy controls and patients with either breast cancer or endometrial cancer by the age-matching method. Ovarian cancer patients were also less fertile than age-matched normal controls, and were as infertile as age-matched patients with either breast cancer or endometrial cancer. 4) Epidemiological evidence was presented to suggest that the incidence of ovarian cancer in Japan was increasing in parallel with the recent increase of social tension in Japan. The possible relevance of the hormonal characteristics of ovarian cancer patients to both the epidemiological characteristics of the same cancer patients and the genesis of this neoplasia is discussed in the light of the 2-step carcinogenesis theory.

[Phase I study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate)].

Phase I study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside (Ara-C), was conducted by cooperative study groups between January 1986 and June 1987. The dosage for the single and 5-day oral administration ranged 50 to 1,200 and 100 to 900 mg/body/day, respectively. The main adverse effects were myelo-suppression and gastrointestinal toxicities such as nausea, vomiting, anorexia and diarrhea. In the single administration, the maximum tolerated dose (MTD) could not be determined, however, in the 5-day schedule MTD was considered to be 700 to 900 mg/body/day, and the dose limiting factor to be thrombocytopenia. After the single administration (800 mg/body/day) of YNK01, the plasma concentration of Ara-C, an active metabolite of YNK01, was 3.43 ng/ml (Cmax) at 24 hrs. and 0.82 ng/ml at 72 hrs. During the 5-day administration for 300 mg/body/day and 500 mg/body/day, the Ara-C concentration changed from 2.3 to 4.1 ng/ml, and from 1.5 to 11.9 ng/ml respectively, and sustained almost the same concentration as to during the administration period until the 2nd day after the completion of the administration.

Proliferative cell index in endometrial adenocarcinoma of different nuclear grades.

Proliferative cell indices (PCI) in 20 cases of endometrial adenocarcinoma were obtained by staining DNA polymerase alpha. The PCI ranged from 11.1 to 42.1, averaging 24.7 +/- 8.7. Four cases of stage III all exhibited fairly large PCI (30.4-32.9). In contrast, in 16 cases of stage I the values were spread over a wide range. In 13 cases with histological grade (HG) 1 of stage I, larger PCI were obtained in the nuclear grade (NG) 2 group; the mean PCI values of HG 1-NG 1 and HG 1-NG 2 were 16.5 +/- 4.6 and 25.6 +/- 5.2, respectively. Because of the good correlation between PCI and HG or NG, PCI may be useful as an additional prognostic factor in endometrial adenocarcinoma, especially in stage I cases.

[Phase I study and early phase II of SM-108 (4-carbamoylimidazolium-5-olate) in lung cancer. SM-108 Study Group].

Phase I study with a new oral purine antagonist, SM-108, was conducted in a total of 73 cases in a 5-day consecutive schedule with the dosage ranging from 20-2,500 mg/m2 at II institutes. The incidences of subjective and objective side effects were 20.5% (15/73) and 31.5% (23/73), respectively, however the correlation between these effects and their dosages was unclear. MTD and DLF values were not determined. SM-108 levels in serum reached maximum in 2-4 hours after oral administration of SM-108, and exhibited a dose-response relationship up to the dosage of 2,000 mg/m2/day. Forty to 60% of the administered drug was excreted into urine in 24 hrs; thus, the main excretory pathway was considered to be renal. An early phase II study was undertaken in patients with lung cancer in 5 cancer centers and university hospitals. Each patient had received 400 mg/m2/day (in two divided doses) or 600 mg/m2/day (in three divided doses) for more than 2 weeks. Only one case (adenocarcinoma) showed a minor response out of 27 cases but not reached partial response according to our criteria. In the 400 mg/m2/day group and the 600 m/m2/day group the incidences of subjective side effects (mainly GI tract disturbance) were 33.3% (4/12) and 40.0% (6/15), while objective side effects (hematological changes) were 16.7% (2/12) and 26.7% (4/15) respectively. In conclusion, we could not determine the dose limiting factor and maximum tolerated dose from our phase I clinical study and early phase II study for lung cancer.

Detection of proliferative cells in dysplasia, carcinoma in situ, and invasive carcinoma of the uterine cervix by monoclonal antibody against DNA polymerase alpha.

The distribution of DNA polymerase alpha-positive cells in neoplasia of the uterine cervix and in normal cervical epithelium was studied using a monoclonal antibody against DNA polymerase alpha. The positive cells were found only in the parabasal layer of normal cervical epithelium and only in the nonkeratinized areas of the cancer nests of invasive keratinizing carcinoma. Most cells in cancer nests of an invasive nonkeratinizing carcinoma were found to be DNA polymerase alpha-positive. In cases of mild or moderate dysplasia DNA polymerase alpha-positive cells were found only in the lower half of the epithelium. DNA polymerase alpha-positive cells in severe dysplasia to carcinoma in situ were distributed throughout the full thickness of the epithelium. The percentages of DNA polymerase alpha-positive cells in mild or moderate dysplasia, severe dysplasia to carcinoma in situ, and invasive carcinoma were 32.2%, 45.7%, and 53.7%, respectively. The authors previously developed immunohistochemical methods for detecting DNA polymerase alpha by monoclonal antibody that allowed the proliferative activity of cells in normal and neoplastic tissues to be estimated.

[Characteristics of urinary steroid excretions in ovarian cancer patients].

We performed a case-control study to investigate the urinary steroid excretions in ovarian cancer patients. The use of gas-liquid chromatography permitted the estimation of 14 urinary steroids. Data on 139 urine specimens from 36 cancer patients were compared with those on age-matched controls. A general depression of adreno-corticosteroid excretions was consistently observed in the cancer patients as compared with the control women. The possible role of observed steroidal disorders in the genesis of ovarian neoplasia is discussed in light of the epidemiological and biological aspects of this tumor.

Clinical basis of chemotherapy for gastric cancer with uracil and 1-(2'-tetrahydrofuryl)-5-fluorouracil.

Studies were performed on the clinical basis of chemotherapy for human cancer with uracil and 1-(2'-tetrahydrofuryl)-5-fluorouracil (FT). In 62 operated patients with stomach, breast, and uterine cancers, the concentration of 5FU and FT were compared in serum, tumor and normal tissues 1, 2, 4, 6, 8, and 12 hours following the administration of 300 mg of UFT (300 mg of FT plus 672 mg uracil, a uracil/FT molar ratio of 4), or FT alone. It was found that the level of 5-FU in tumor tissue remained above 0.05 mcg/g over 12 hours. This value for 5-FU corresponds to a minimum inhibitory concentration in the Vitro experiment with L1210 cells. BLood levels of 5-FU increased up to 0.1 mcg/ml 1 hour after UFT administration and then decreased below 0.05 mcg/ml. The drug concentration in normal tissues was lower than that of the tumor tissues. On the basis of the above findings and phase I study, a protocol of UFT-therapy was made and applied for the treatment of gastric cancer. Our patients were given an oral dose of 300 mg of UFT twice a day per 50 kg body weight (12 mg/kg BW). Therapeutic effects were detectable in 7 of 20 cases. In addition, a combination of mitomycin C (6 mg i.v. weekly) with UFT seemed to improve the response rate (5/7). Diarrhea (15%) and skin pigmentation (10%) were major side effects of UFT.