Makoto Ogawa

Effect of granulocyte colony‐stimulating factor on neutropenia due to chemotherapy for non‐Hodgkin's lymphoma

The authors administered recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) to 16 patients with advanced non‐Hodgkins lymphoma treated with combination chemotherapy. Groups of three to five patients were treated with 50, 100, 200, and 400 μ/m2 per day of rhG‐CSF by intravenous infusion for 14 days, beginning 3 days after chemotherapy. There was a strong linear relationship between the dose and the area under the curve over this dose range. The rhG‐CSF was rapidly cleared from serum, with a mean half‐life of 5.97 hours for the second phase (t1/2). In patients treated with a dose of more than 100 μg/m2 per day, the duration of neutropenia (P < 0.01) and the duration of fever (P < 0.05) were significantly decreased. The rhG‐CSF was well tolerated and the only clinical observation that appeared relating to rhG‐CSF administration was slight bone pain. This study strongly suggests that an optimum dose of rhG‐CSF in patients after chemotherapy is 100 to 200 μg/m2. Our study shows that rhG‐CSF is a clinically useful drug for patients treated with myelosuppressive chemotherapy.

Antitumor activity of mitoxantrone against murine experimental tumors: comparative analysis against various antitumor antibiotics.

Summary1,4-Dihydroxy-5,8-bis{{{{2-[(2-hydroxyethyl)amino]ethyl}amino}}-9,10-anthracenedione dihydrochloride (mitoxantrone) was tested for antitumor activity against experimental tumors in mice and the results were compared with those of seven antitumor antibiotics: adriamycin (ADM), daunomycin (DM), aclarubicin, mitomycin C (MMC), bleomycin, neocarzinostatin, and chromomycin A3. The drugs were given IP or IV, in general on days 1,5, and 9 following tumor inoculation. Mitoxantrone given IP at the optimal dose (1.6 mg/kg/day; as a free base) produced a statistically significant number of 60-day survivors (curative effect) in mice with IP implanted L1210 leukemia. The curative effect was not observed with any of the other antibiotics. In the case of IV implanted L1210 leukemia, there was an increase in lifespan (ILS) by more than 100% in the mice following IV treatment with mitoxantrone or DM. In IP implanted P388 leukemia, the curative effect was elicited by IP treatment with mitoxantrone or MMC. In IP implanted B16 melanoma, both the curative effect and a more than 100% ILS in mice that did die were produced by IP treatment with mitoxantrone or ADM. In SC implanted Lewis lung carcinoma, mitoxantrone and ADM administered IV also showed effective antitumor activities and produced a 60% and a 45% ILS, respectively. In conclusion, mitoxantrone and ADM had a wider spectrum of antitumor activity against mouse tumors, including two leukemias and two solid tumors, than did the other drugs; however, mitoxantrone elicited higher antitumor effects than ADM on mouse leukemias, especially on L1210 leukemias. Moreover, mitoxantrone possessed much higher therapeutic indices than ADM against IP implanted P388 (optimal dose/ILS40; >128 versus 15.2) and L1210 (optimal dose/ILS25; 72.7 versus 4.8) leukemias. In addition, mitoxantrone showed moderate activity against DM-resistant L1210 leukemia.

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Forty‐five previously‐untreated adult patients with acute myelogenous leukemia (AML) were treated with N4‐behenoyl‐1‐β‐D‐arabinofuranosyl‐cytosine (BHAC) in a multi‐institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea–anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti‐leukemic drugs. Cancer 56: 1913‐1917, 1985.

Clinical and immunological studies of human fibroblast interferon

SummaryHuman fibroblast interferon (HFIF) was used in 26 patients with various malignant diseases, most of whom had received previous chemotherapy. The dosages used were 3x106IU or 6x106IU HFIF IV daily. Of 24 evaluable patients, two attained partial remissions (one with chronic lymphocytic leukemia and one with multiple myeloma), and seven (stomach Ca two, multiple myeloma two, CLL one, malignant melanoma one, and non-Hodgkins lymphoma one) attained stable disease. The majority of patients experienced fever with body temperature exceeding 38° C and chills, which became uncommon after several days of treatment. Other side-effects included myelosuppression, general malaise, anorexia, hepatic dysfunction, and renal dysfunction, which were mild and tolerable.Lymphocyte natural killer (NK) activity against culture cell lines was measured before and at various times after HFIF treatment. The majority of patients reached the highest NK activity at 18–24 h, mostly at 24 h after the initiation of HFIF therapy. In one group of patients NK activity subsequently remained at the highest level during HFIF treatment, while in another group of patients NK activity declined even with daily infusion of HFIF but usually remained above the pretreatment level. There seemed to be no correlation between NK activity and clinical activity. In contrast to NK activity against culture cell lines, no increase in lymphocyte cytotoxic activity against autologous tumor cells was observed following HFIF treatment. Mixed lymphocyte tumor cell reactions were tested in six patients and showed a slight increase of 3H-thymidine uptake in one patient, but the others had no change. In vitro sensitization to assess the in vitro generation of cytotoxic cells was negative in all six patients. Lymphocyte blastogenic responses to nonspecific mitogens showed no significant change. The delayed-type hypersensitivity reaction to recall antigens was increased in about half the patients after HFIF treatment.

Phase II study of paclitaxel (BMS-181339) intravenously infused over 3 hours for advanced or metastatic breast cancer in Japan

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6–49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6–100) days to onset of and median duration of response was 125 (36–305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1–3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1–3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.

Phase I clinical trial of a new anthracycline: 4′-o-tetrahydropyranyl adriamycin

SummaryThe phase I study of a new anthracycline, 4′-o-tetrahydropyranyl adriamycin, was performed. A dose limiting factor was leukopenia while thrombocytopenia was less frequent and a maximum tolerated dose was determined as 54 mg/m2. Mild gastrointestinal toxicities including anorexia, nausea and vomiting occurred in about half of the patients, while very minimal alopecia was seen in only one patient. A recommended dose for phase II study was established: 40 mg/m2 at 3-week intervals.

Current status of nitrosoureas under development in Japan.

Three nitrosourea compounds [1–4], BCNU, CCNU, and methyl CCNU (MeCCNU) have demonstrated clinical efficacy in a variety of human malignancies including lung cancer, gastrointestinal tumors, lymphomas, melanomas, and brain tumors. But delayed and cumulative hematologic toxicity has been an obstacle to clinical use.

A Pharmacokinetic Study of Idarubicin in Japanese Patients With Malignant Lymphoma: Relationship With Leukocytopenia and Neutropenia

To clarify the pharmacokinetic properties of idarubicin (IDA) in Japanese patients and to clarify the relationship between the pharmacokinetic parameters of IDA or idarubicinol (IDAol), an active metabolite of IDA, and leukocytopenia or neutropenia, we examined the pharmacokinetics of IDA in patients with malignant lymphoma. Nine of 21 patients registered in an early phase II study of IDA were enrolled in the pharmacokinetic study. IDA (12 or 15 mg/mp2) was administered by intravenous infusion for 5 minutes. The elimination half lives (tb1/2) of IDA were 11.0 hours and 12.5 hours after administration of 12 and 15 mg/mp2 IDA, respectively. IDAol appeared rapidly both in plasma and in blood cells, and its concentrations exceeded those of IDA within 4 hours. IDAol had a very long tb1/2 (69.2 hours and 70.0 hours for 12 and 15 mg/mp2, respectively). The areas under the concentra-tion curves of IDAol in plasma were 3.4 and 5.8 times higher than those of IDA after administration of 12 and 15 mg/mp2 IDA, respectively.The tb1/2 of IDAol in plasma correlated significantly with the nadir of neutrophils, and the steady-state volume of distribution of IDA in plasma and in blood cells correlated significantly with the nadirs of white blood cells and neutrophils. These results suggest that both IDA and IDAol play an important role in leukocytopenia or neutropenia. No substantial differences between Japanese and Caucasian people in the pharmacokinetics of IDA were apparent.

Chemotherapy of disseminated gastric cancer. A joint effort of the Northern California oncology group and the Japanese gastric cancer chemotherapy group

A consortium of Northern California and Japanese investigators studied 142 patients with advanced gastric adenocarcinoma. Patients were randomized to one of two combination chemotherapy programs in each nation (one common therapy shared and one therapy unique to each nation). Median duration of survial ranged between 5 and 45 weeks, depending on performance status, extent of disease, and chemotherapy program. More importantly, there was considerable comparability with respect to toxicity and outcome between patients in the US and Japan. Overall median survival was 26 weeks for Japanese and 27 weeks for US patients. This study helps provide the basis for future comparative multinational trials.

Phase I study of 7-N-(p-hydroxyphenyl)-mitomycin C

SummaryThe Phase I study of N-7-(p-hydroxyphenyl)-mitomycin C (KW 2083, M 83) was performed. The dose-limiting toxicity was leukopenia and thrombocytopenia and a maximum tolerable dose was 70 mg/m2. Nonhematologic toxicities included nausea (44%), vomiting (13%), diarrhea (2.7%), azotemia (8.1%), proteinuria (5.4%), alopecia (8.1%) and elevated hepatic enzymes (2.7%). This Phase I study indicates that the recommended starting dose for Phase II studies for patients without significant myelosuppression would be 50 mg/m2 at 6 week intervals in an intravenous push. KW 2083 should be avoided in patients with impaired renal functions and proteinuria because of permanent renal damages caused by the drug.