Mitsunori Hino

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer

Purpose: CPT-11 (60 mg/m2 on days 1, 8 and 15) in combination with CDDP (80 mg/m2 on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m2 together with CDDP at 27 mg/m2 (level 1, 6 patients), 33 mg/m2 (level 2, 12 patients), and 40 mg/m2 (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m2 CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity.

Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease.

Objectives:  The proteolytic enzyme serrapeptase (SER) is widely used in clinical practice in Japan. We investigated the effect of SER on sputum properties and symptoms in patients with chronic airway diseases.

Lung cancer screening—Comparison of computed tomography and X-ray

Recent studies on lung cancer screening with CT disclosed a discrepancy between its efficiency in detecting early lung cancer and a lack of proof for decreasing mortality from lung cancer. The present study, in a city in Japan where an X-ray screening program is provided, bi-annual CT screening was performed for X-ray screening negative subjects for 4 years. Ten patients with lung cancer were detected among 22,720 person-year subjects (0.044%) through the X-ray screening. Among the X-ray screening-negative subjects, 3305 subjects participated in a CT screening program resulting in the detection of 15 patients with lung cancer (0.454%). All 15 cases detected by CT screening and 5 of the 10 cases detected by X-ray screening were at stage IA. In respect of gender, histological type and CT findings, patients detected by CT screening had a better prognostic profile than those detected by X-ray screening. Survival was significantly better in the former than the latter, both in its entirety comparison and in a comparison limited to patients who underwent surgery. In conclusion, CT screening might have the potential to detect lung cancer with good prognostic factors not limited to early detection. Sufficiently long follow-up time, therefore, would be required to evaluate the efficacy for decreasing lung cancer mortality with CT screening.

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 thec/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.

Evaluation of Right Ventricular Function in Patients With COPD

BACKGROUND: Pulmonary hypertension is an independent risk factor for death in patients with COPD. Current prognostic models of COPD do not include sufficient indicators of right ventricular (RV) function to enable accurate assessment of changes in RV function over time. The aim of the present study was to test the hypothesis that it would be useful to include noninvasive markers of RV function in the routine assessment and prognostic models of early stage COPD with or without pulmonary hypertension. METHODS: We reviewed the clinical records of 49 male subjects who had COPD but no other conditions that might affect physical status or prognosis, who underwent cardiac ultrasonography. Various echocardiographic parameters of pulmonary circulation and RV function were compared with indices of physical status and prognosis. RESULTS: The Medical Research Council dyspnea score was higher in subjects with echocardiographic findings suggestive of pulmonary hypertension than those without (mean ± SD 3.17 ± 1.23 vs 2.26 ± 0.81, P = .02). RV ejection time, RV isovolumetric relaxation time, RV isovolumetric contraction time + RV isovolumetric relaxation time, and RV total ejection isovolume index differed significantly between subjects with echocardiographic findings suggestive of pulmonary hypertension and those without. The RV total ejection isovolume index was strongly correlated with the MRC score (P < .001), and was significantly correlated with the overall survival rate (hazard ratio 5.31, 95% CI 1.91–14.77) and hospital-free survival rate (hazard ratio 3.26, 95% CI 1.48–7.16). CONCLUSIONS: It may be valuable to add assessment of RV function to the routine evaluation of physical status in patients with COPD.

Assessment of the relationship between right ventricular function and the severity of obstructive sleep-disordered breathing

Some complications of obstructive sleep‐disordered breathing (OSDB), such as heart failure including right ventricular (RV) overload, are more serious than an increase of the apnea–hypopnea index (AHI) or respiratory disturbance index (RDI). These serious complications may contribute to the worsening of OSDB.

Phase I/II study of docetaxel and S-1, an oral fluorinated pyrimidine, for untreated advanced non-small cell lung cancer

The purpose of this phase I/II study is to evaluate a new combination chemotherapy consisting of docetaxel and S-1 as front-line therapy for patients with untreated advanced non-small cell lung cancer (NSCLC). The treatment included docetaxel on day 1 and oral S-1 at a fixed dose of 40mg/m(2) administered twice daily on days 1-14 and repeated every 3 weeks. In phase I, docetaxel at escalating doses of 40 (level 0), 50 (level 1) and 60mg/m(2) (level 2) was administered starting from level 1. Because only one patient among the 6-patient cohort at level 1 and no patient among the 3-patient cohort at level 2 experienced defined dose-limiting toxicity (DLT), level 2 was determined as the recommended dose. In phase II, 60 patients were treated at the recommended dose for median 3 cycles, and the overall response rate was 30% (95% confidence interval [CI], 18.9-43.2%), and the median overall and progression-free survival times were 15.2 (95% CI: 10.5-17.7) and 4.9 (95% CI: 3.5-5.6) months, respectively. The most frequent toxicities experienced were neutropenia, febrile neutropenia and appetite loss; all toxicities were however well manageable. The present regimen showed a potent activity with mild toxicity in untreated NSCLC.

Phase I studies of nogitecan hydrochloride for Japanese.

AbstractBackground. SmithKline Beecham synthesized camptothecin analogs and identified nogitecan hydrochloride (topotecan) with a broad spectrum of antitumor activity and less toxicity than camptothecin. Because preclinical and overseas clinical data indicated the antitumor effect of nogitecan hydrochloride with a 5-day repeat-dose schedule, we carried out phase I studies in Japan to determine the maximum tolerated dose (MTD), pharmacokinetics, and antitumor effect of nogitecan hydrochloride. Methods. Phase I studies of nogitecan hydrochloride given by single and 5-day repeat dosing were carried out in patients with various solid tumors at 15 medical institutions in Japan. Pharmacokinetic evaluations were performed for both single and 5-day repeated dosing. Results. The dose-limiting factor (DLF) was reversible leucopenia, and the maximum tolerated dose (MTD) was higher than 22.5 mg/m2 in the single-dose study. In the 5-day repeat-dose study, the DLF was also reversible leucopenia, and the MTD was estimated to be 1.5 mg/m2 per day. The plasma concentration of nogitecan hydrochloride increased with increasing dose, and the half-life after single dosing ranged from 3 to 5 h. There was no evidence of accumulation or delayed excretion during 5-day repeat dosing. Conclusion. Based on these results and the finding that there were responders among patients treated at 1.5 mg/m2 per day by 5-day repeat dosing in overseas studies, 5-day repeat dosing of 1.2 mg/m2 per day, one dose level lower than the MTD, was selected for phase II studies in Japan.

Phase II study of nimustine hydrochloride (ACNU) plus paclitaxel for refractory small cell lung cancer.

PURPOSE Bi-weekly administrations of nimustine hydrochloride (ACNU) plus paclitaxel were evaluated in this phase II study in patients with refractory small cell lung cancer (SCLC). METHODS Patients who had disease progression within 3 months after treatment with irinotecan (CPT-11)-containing regimens were entered. They were treated with every other week administrations of ACNU 50 mg/m(2) plus paclitaxel 110 mg/m(2) on day 1 over 2 weeks. RESULTS Twenty-four patients (20 males and 4 females, median age of 64 years, 17 patients with Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1 and 7 patients with PS 2) participated in the trial. Of the 24 refractory patients after CPT-11 containing regimens, 17 patients had been given etoposide plus platinum. There were six partial responses, and an overall response rate of 25% (95% confidence interval, 10-46%) was obtained. The median time to progression and the median survival time after enrollment into this study were 2.8 and 5.8 months, respectively. The median overall survival from the first-line treatment was 19.5 months. The major toxicity was myelosuppression. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia was observed in 13% of patients. There was one treatment-related death, attributed to pneumonitis. CONCLUSION Bi-weekly administrations of ACNU plus paclitaxel provided a practical and well-tolerated regimen that was active for CPT-11-refractory SCLC.

Arterial blood lactate is a useful guide to when rehabilitation should be instigated in COPD

Background and objective:  Systemic effects of COPD include skeletal muscle dysfunction; the lactate threshold (LT) is an index of such dysfunction. However, it is not feasible in daily clinical practice to accurately determine the LT in all patients with COPD. There is no simple, practical and non‐invasive index for determining the time at which rehabilitation should start. Previous studies have shown that the LT corresponds to the point at which the blood lactate concentration is 0.5 mmol/L above baseline (LTΔ0.5 mmol/L). The aim of the study was to assess the value of LTΔ0.5 mmol/L as an index of selecting candidates for pulmonary rehabilitation in COPD patients.