[Effectiveness of docetaxel plus cisplatin in large cell lung cancer showing little response to prior chemotherapy with MVP].

The present patient was a 53-year-old male who had large cell lung cancer of c-T4N1M0. We administered multi-drug regimen including mitomycin C, vindesine and cisplatin (CDDP) because of cancer invasion into the great vessels seen on a chest CT. After 3 courses, the cancer showed no change in size. Therefore, we adopted chemotherapy of docetaxel (Taxotere: TXT) and CDDP. After 4 courses, the size of the mass had decreased (partial response). The only major toxic defect was grade 3 neutropenia. A good response to TXT and CDDP could lead to complete resection of lung cancer. It is suggested that TXT is effective in the treatment of large cell lung cancer.

Pilot trial of a combination comprising of consecutive oral administration of UFT, and two-divided administration of CDDP in non-small cell lung cancer.

A pilot study of a combination therapy comprising of consecutive oral administration of UFT, and two-part divided administration of CDDP was undertaken in patients with inoperative non-small cell lung cancer, based on the synergistic effects of CDDP and 5FU. UFT was administered orally at a dosage of 400 mg/m2 for two consecutive weeks (Day 1-Day 14) and CDDP was administered twice by intravenous infusion, once on Day 4 and again on Day 8. The unit dose of CDDP was increased sequentially, from 40 mg/m2 in step 1, to 50 mg/m2 in step 2, and then to 60 mg/m2 in step 3, with safety being confirmed during the process. The numbers of patients registered for each dose level were 3, 3, and 20, respectively. Evaluation of toxicities could be conducted for all the patients except one. No toxicities of grade 3 or higher were observed in step 1 or 2. There was no problem with continuous administration of UFT. The following toxicities of grade 3 or higher were observed in step 3: leukocytopenia in 2 patients; reduction of the hemoglobin count in 1; decrease in creatinine clearance in 2; anorexia in 3; and nausea and vomiting in 3. Bone marrow suppression was mild and transient. Renal failure and digestive symptoms, which were proved to be transient and treatable by symptomatic treatment, were also observed. The step 3 administration was effective in 8 (47.1%) of the 17 patients with measurable lesions (95% CI: 23-71%). In conclusion, since it was determined that the dose employed in step 3 should be recommended and that it could be expected to exhibit antitumour effects with mild bone-marrow suppression, a large scale phase II study should be conducted in no prior treatment non-small cell lung cancer.

In vitro investigation of a combination of two drugs, cisplatin and carboplatin, as a function of the area under the c/t curve.

The log/log relationship between the IC50 of cisplatin or carboplatin and the exposure time, determined by human tumor clonogenic assay (HTCA) and MTTAI (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with additional incubation) using PC-14 cells, exhibited a straight line with a slope of -1, indicating that both drugs have AUC-dependent cytotoxicity (AUC, area under the c/t curve). The combined effect of cisplatin and carboplatin was estimated by the median-effect analysis using HTCA, and it was additive when the AUC ratio (AUC of free platinum from carboplatin/that from cisplatin) was low (3.2, 6.5 or 13.1 in each of PC-7, PC-9, PC-14, H-69, and K562). However, it was significantly worse at a higher AUC ratio (19.5 in PC-7, PC-9, and PC-14). The log/log relationship of each drug, determined by MTTAI using human bone marrow cells, showed that each drug exerts an AUC-dependent cytotoxicity on marrow granulocytes. When cisplatin and carboplatin were combined at an AUC ratio of 14, the therapeutic index was significantly better than that of carboplatin alone and less than that of cisplatin alone using K562, PC-9 and PC-14, indicating the usefulness of this combined therapy for tumor cells with high sensitivity to platinum compounds at this AUC ratio.

[Phase I clinical study of 21-consecutive-day oral administration of etoposide].

We conducted a multi-institutional phase I clinical study on a 21-consecutive-day oral administration of etoposide in 12 patients with malignant tumor. The initial dose was 25 mg/body/day and then raised to 50 mg/body/day and eventually to 75 mg/body/day. The dose limiting factor was leukopenia and the maximum tolerated dose (MTD) was 75 mg/body/day. Leukopenia was observed in all 4 patients registered at 75 mg/body/day. Two of 4 patients showed WBC count nadirs of less than 2,000/microliters. The two patients had less than 1.5 m2 body surface area. Thrombocytopenia and hemoglobin decrease were mild compared to leukopenia. Other adverse reactions were as follows; anorexia (75.0%), nausea/vomiting (58.3%) alopecia (46.1%). No sign of accumulation after 21-consecutive-day oral administration of etoposide was seen on pharmacokinetic parameters. As for anti-tumor efficacy, a partial response was noted in a patient with lung metastasis of cervical cancer at the 75 mg/body/day dose level. A recommended dose for phase II study was 75 mg/body/day for 21 consecutive days with a one-week interval. However, for a patient with a body surface area less than 1.5 m2 or with a severe prior chemotherapy, 50 mg/body/day would be considered appropriate.

[An early phase II trial combining cisplatin and carboplatin in advanced non-small cell lung cancer].

We conducted an early phase II trial in advanced non-small cell lung cancer (NSCLC) to evaluate response efficacy of a combination of Cisplatin (CDDP) and Carboplatin (CBDCA). The twenty-six patients in the study had had no previous treatment. They received a sequential administration of 300 mg/m2 CBDCA and 80 mg/m2 CDDP with approximately 3,500 ml of hydration on day 1 every 4 weeks. All patients were evaluable for response and toxicity. Ten (38.5%) of all assessable patients achieved a partial response (95% confidence interval, 19.8-57.2%). Response rates for patients with stage III A, III B and IV- disease were 40.0 (2/5), 70.0 (7/10) and 9.1% (1/11), respectively. Response rates for patients with squamous cell carcinoma, adenocarcinoma and large cell carcinoma were 35.7 (5/14), 45.5 (5/11) and 0.0% (0/1), respectively. The median survival time (MST) of all patients was 11 months. The MST for patients with stage III disease was 14 months; for those with stage IV disease it was 7 months. The MST for responding patients was 15 months and for not responding patients 5 months. Major toxicities were hematologic and gastrointestinal, and the dose-limiting factor was thrombocytopenia. This combination chemotherapy was effective against NSCLC with tolerable toxicities. Further trials are warranted to determine the efficacy of the combination chemotherapy.

[Quality of life (QOL) and nutrition].

We thought that nutritional parameters in laboratory data might be able to express quality of life (QOL). Therefore, in 70 patients with malignant chest diseases (NSCLC, 42 patients; SCLC, 15; lung metastasis, 7; others, 6), the correlation between nutritional parameters of total protein (Tp), serum albumin (Alb), and serum (cholinesterase (ChE] and Karnofsky Performance Status scale (KPS) was investigated. Then, in 24 patients with them (NSCLC, 12; SCLC, 6; lung metastasis, 4; others 2), Alb and ChE were compared to the EORTC Core Quality of Life Questionnaire and Lung Cancer-Specific Questionnaire Module (QS). Results were as follows: 1) KPS and nutritional parameters correlated (Tp. r = 0.55, p less than 0.001; Alb, r = 0.60, p less than 0.001, ChE, r = 0.60; p less than 0.001). 2) The cores for Functional Status (FS) and Disease and Treatment-related symptoms (Sym) in QS and parameters of Alb and ChE correlate (FS v.s. Alb, p less than 0.01; Sym v.s. Alb, p less than 0.01; FS v.s. ChE, p less than 0.05; and Sym v.s. ChE, p less than 0.05). Moreover, the scores of Psychological Distress in QS and Alb showed a correlation (p less than 0.05). It is considered that nutrition and part of QOL (KPS and FS + Sym in QS, that is to say, "objective" functional activity and "subjective" functional activity and symptoms) correlate, and that nutritional parameters are useful to evaluate QOL.

[Probability of the combination use of cisplatin and carboplatin].

To investigate whether each of cisplatin (CDDP) and carboplatin (CBDCA) was AUC (Area Under the Curve)-dependent or time-dependent drug, Human Tumor Clonogenic Assays (HTCA) were performed in various exposure times of CDDP or CBDCA using PC-9 cells. From the result of this study, it was shown that CDDP and CBDCA were AUC dependent drugs. Furthermore, to evaluate the combination effect of CDDP and CBDCA, we carried out HTCA using PC-9 and PC-14 (human lung adenocarcinoma cell lines) cells, and evaluated the combination effect by the median effect analysis of Chou, T.C. and Talalay, P. The combination effects were above the additive effects at the AUC ratios of free Pt in the exposure medium of 3.2, 6.5, 13.1 (CBDCA/CDDP). Especially in the combination of 3 hours exposure of CBDCA followed by 1 hour exposure of CDDP, the Combination Index by median effect analysis was from 0.74 to 0.86 at the AUC ratio of 13.1. But the combination effect was antagonistic at that of 19.5. CDDP and CBDCA, which are AUC dependent drugs, have shown different side effects in previous clinical practice. And the combination effect of both drugs is more than additive effect at the AUC ratios of free Pt of 3.2, 6.5, 13.1 (CBDCA/CDDP). It is considered that the combination chemotherapy of CDDP and CBDCA for patients of lung adenocarcinoma may be useful.