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We have experienced 4 cases of therapy-related leukemia (TRL) in 119 patients with multiple myeloma (MM) who had received combination chemotherapy including alkylating agents between 1988 and 1998. All 4 cases were acute myelogenous leukemia, 3 were males and 1 was female. Median age at diagnosis of MM was 60 years, and median time to TRL from diagnosis of MM was 5.5 years. The chromosome abnormalities were found in 3 of those cases. All 4 cases were resistant to antileukemic chemotherapy, and median survival time from TRL was only 5.5 months. The TRL in MM is thought to be a more important problem, because recently the treatment for this disease has become more intensive, including high-dose chemotherapy supported by autologous stem cell transplantation.

A randomized controlled study of patients with multiple myeloma was performed to evaluate the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF:KW-2228) in treating neutropenia induced by chemotherapy, and its influence on the dose intensity of, and response rate to, chemotherapy. As a rule, 3 courses of chemotherapy at intervals of 4 weeks were administered both to the untreated and KW-2228-treated groups. Among 98 eligible patients evaluated for neutrophil recovery, a markedly reduced duration of neutropenia was observed during each course in the KW-2228 treated group. No significant difference distinguished the two groups in terms of incidence or duration of infection. However, febrile neutropenia appeared only in the untreated group. There was no significant difference in terms of response rate or dose intensity. However, only patients in the untreated group withdrew from the study due to protracted neutropenia. These results demonstrated that KW-2228 is effective and safe, and has a significant effect on the acceleration of neutrophil recovery in patients with neutropenia induced by chemotherapy for multiple myeloma, and is useful for the completion of chemotherapy regimens.

We report a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), neurotoxicity and facial erythema induced by several anti-cancer drugs in a case of malignant lymphoma of thyroid gland. A 68-year-old male was admitted, complaining of neck tumor and dyspnea. On admission, he was treated with vincristine (VCR) for bronchostenosis due to malignant lymphoma. Neck tumor and mediastinal lymph node swelling reduced. On the ninth day after chemotherapy of VCR, a consciousness disturbance was found and he was diagnosed as having SIADH. Following chemotherapy of cyclophosphamide, SIADH was also induced so he was treated with irradiation for neck and mediastinal field, instead of chemotherapy. During irradiation, however, enlargement of systemic lymph nodes appeared, and the chemotherapy was resumed. He achieved partial remission, but somnolence after ifosfamide and facial erythema after ranimustine were observed. In spite of the difference in the chemical structure of these anti-cancer drugs, several side effects occurred. It is suggested that the direct effects of drugs on the nervous system were SIADH and neurotoxicity.

The management of a 12-year-old boy with hypothalamic anaplastic astrocytoma is reported herein. The pediatric patient underwent a subtotal removal of his brain tumor, and subsequently received multimodal treatment comprising radiotherapy (30.6 Gy to the whole brain and 50.4 Gy to the local lesion) and immunochemotherapy with MCNU (80 mg/m2, day 1), VP 16 (50 mg/day, days 2 to 6), and interferon-beta (3 x 10(6) units/day, initiating on day 2 for 4 weeks). The immunochemotherapy was given as of 4 weeks after radiotherapy. The administration of anti-cancer drugs caused severe nausea and vomiting, the intra-carotid infusion of MCNU being particularly emetogenic. The multi-modal treatment was then discontinued for a few weeks. A partial response was obtained, and the patient subsequently received 3 courses of maintenance therapy at six-month intervals using the same protocol as for the initial immunochemotherapy. During maintenance therapy, granisetron (40 micrograms/kg) was given intravenously 30 minutes before and one day after the injection of MCNU. Owing to the anti-emetic management of this patient, there were no complications throughout the chemotherapy. The patient has now survived for more than 3 years with a good quality of life, showing a Karnofsky performance score of 90.

Twenty-six patients with cerebral malignant glioma (7 cases of astrocytoma Grade 3, and 19 of astrocytoma Grade 4) were treated by intra-arterial and local administration of MCNU. Nineteen patients were treated in combination with local radiation in a dose of 60 Gy. Intra-arterial administration of MCNU was performed by puncture of the ipsilateral common carotid artery and injection of 25mg of MCNU in 20 ml of physiological saline. Local administration of MCNU was performed by puncture of the Ommaya reservoir placed within the cavity after tumor resection. Objective tumor regression was observed on computerized tomography (CT) scans after intra-arterial and/or local administration of MCNU combined with radiotherapy in three of seven patients who had evaluable enhanced lesions on CT after surgery. It was also observed after chemotherapy alone in one of three patients with evaluable lesions. The response rate was 42.9% among patients treated with MCNU in combination with radiotherapy, and 33.3% in patients treated with MCNU alone. In two patients, local administration of MCNU induced brain edema, which was transient and caused no neurological sequelae. One patient suffered mild thrombocytopenia after seven intra-arterial doses of MCNU, however, no myelosuppression requiring administration of gamma-GCSF or blood transfusions was observed. These findings suggest that intra-arterial and local administration of MCNU can be expected to serve as effective and non-myelosuppressive chemotherapy in patients with cerebral malignant gliomas.

A total of 117 cases with hematological malignancies were treated with MCNU at doses of 70-100 mg/m2. Following are the results obtained. 1. MCNU showed a marked depression of cells in the cases with CML, polycythemia vera and thrombocythemia. The low level of cells was maintained for 2 to 7 months. 2. A good response was observed in several cases with blastic crises of CML. 3. No response was observed in two cases with acute leukemia. 4. Although a fair response was observed in several cases with malignant lymphoma or multiple myeloma, moderate bone marrow suppression was observed in a majority of the cases.

A phase I study on TA-077, a water-soluble nitrosourea, was performed by a 9-institution clinical group using 89 patients with various malignant tumors. The study consisted of single-dose i.v. administration and daily i.v. administration for 3-6 consecutive days. The dose-limiting factor was delayed leukopenia and thrombocytopenia which reached nadirs about 5 weeks and about 4 weeks after the initiation of administration and recovered in 2 to 3 weeks, respectively. Gastrointestinal toxicity, such as nausea, vomiting and anorexia, appeared in the early stage of treatment, although most of these symptoms were mild or moderate. Other side effects, including transient liver and renal dysfunctions observed in a few cases, were mild and appeared not to be dose-dependent. M.T.D. in single administration was considered to be more than 3,000 mg/m2 and M.T.D. in 5-day consecutive administration was considered to be 1,000 mg/m2/day. The recommended dose schedule for initiation of the phase II study was assumed to be 700 to 900 mg/m2/day for 5 consecutive days.

Sixty-seven patients with hematological malignancies and 4 with cancers were evaluated in this study. Standard administration of MCNU was instituted intravenously using 50-100 mg/m2 every 2 or 4 weeks, whereas some cases were treated with a higher dose therapy. Of 10 patients with chronic myelogenous leukemia, 7 achieved complete remission (CR), and 1 achieved partial remission (PR). A good response was also obtained in 9 of 10 patients with polycythemia vera and in all 4 patients with essential thrombocythemia. MCNU was less effective in malignant lymphoma (ML) and multiple myeloma (MM) than in myeloproliferative disorders. Two of 15 patients with ML and one of 21 patients with MM achieved CR, and two with ML and three MM achieved PR. Three patients with lung cancer and 1 with gastric cancer showed no response to MCNU. Delayed anemia, leukocytopenia and thrombocytopenia were observed in 38.7% of patients, and these were regarded as major side effects of MCNU. Nausea, vomiting, anorexia and elevated transaminase were also found in about 24% of patients, but only transiently. Our study indicates that MCNU is useful for chemotherapy of hematological malignancies, especially of myeloproliferative disorders. Therefore, further studies on combination chemotherapy with MCNU should be developed.

The use of drugs in combination for the management of cancer patients aims at the increased therapeutic advantage by elimination the problem of the heterogeneous sensitivity of cancer cells to anticancer drugs, and by delaying or preventing the development of drug resistance within given tumors. Theoretically, the effects of drugs in combination are classified as antagonistic, subadditive, additive and synergistic. Since these results hold for both tumors and hosts, the effects of combined drugs should be considered in terms of therapeutic index. From this viewpoint, the choice and administration schedule of drugs in combination must be synergistic or additive for the tumors and antagonistic or subadditive for the hosts in regard to combined effects. Thus, the rationale for combined drug therapy should be considered from the aspects of biochemical basis, drug resistance, cytokinetic and pharmacologic rationales, and toxicologic basis.

A total of 48 patients with various malignant disorders, mostly from hemopoietic organs, entered to phase I study of MCNU given orally. Fifty-six percent of the patients given MCNU at the doses of 50-125 mg/m2 complained of gastrointestinal symptoms including nausea and vomiting, which were however mild and well tolerated. In the following study employing administration of 50 mg/day of MCNU for consecutive 2-6 days, the gastrointestinal toxicities were reduced to 26.1%, and hematological toxicities of delayed leukopenia and thrombocytopenia were derived 4-6 weeks after oral intake of the drug. The hematological recovery required 1-2 weeks after the nadir of leukocyte and thrombocyte count. A recommended dose for phase II study of MCNU by the route of oral administration was 50 mg/body/day for consecutive 4-6 days in every 8 weeks interval. The peak value of blood concentration of MCNU was obtained 60-120 minutes after p.o. administration at the doses of 50-100 mg. Elimination half-life was estimated to be 40-45 minutes. No concentration of the drug was detected in blood 24 hours after the administration.

In order to evaluate the efficacy of surgical adjuvant chemotherapy in patients undergoing gross curative resection for colorectal cancer (excluding m and sm cancer), a randomized controlled study was conducted from January, 1982 to October, 1983. Four hundred and ninety-one institutions participated in this study. The schedules for drug administration differed according to each district. In the Hokkaido and Shikoku districts, the patients were divided into the following two groups, one was a combination of ACNU and Futraful (FT) and the other was FT only. In the Chubu and Kinki districts, three groups were studied, namely those receiving a combination of ACNU and FT, those receiving FT only and those given no adjuvant chemotherapy. In the Tohoku and Kanto districts, a combination of MMC and FT and administration of FT only were studied. In the Chugoku and Kyushu districts, the patients were divided into a combination of ADM and FT, and FT only group. Among the 3,926 registered cases, 3,421 cases were valid for the study. As to the background factors, there were no significant differences among the groups in each district. There were no significant differences in one-year survival rates and one-year disease-free rates. No serious adverse effects were observed in any of the groups.

A total of 71 cases with primary brain tumors (44 cases) and metastatic brain tumors (30 cases) were entered into our clinical studies with MCNU and radiation therapy or MCNU alone. With regard to tumor reduction on CT scan, the response rates obtained for MCNU and radiation were 21.7% for malignant gliomas and 50.0% for metastatic brain tumors. With regard to improvement of neurological signs, the response rates obtained for MCNU and radiation were 62.9% for malignant gliomas and 71.4% for metastatic brain tumors. The response rates for MCNU were 5.8% for malignant gliomas and 46.1% for metastatic brain tumors. In the improvement of performance status, the response rates for MCNU and radiation were 51.8% for malignant gliomas and 64.2% for metastatic brain tumors. The response rates for MCNU were 46.1% for malignant gliomas and 30.7% for metastatic brain tumors. A minimal degree of hematological toxicity occurred but this gradually disappeared. These results suggested that MCNU has relatively effective antitumor activity against metastatic brain tumors and an enhanced effect with radiation against malignant gliomas.

We describe a 11-year-old boy with NHL, who developed interstitial pneumonitis following high-dose MCNU with autologous peripheral stem cell transfusion. Non-productive cough, malaise and progressive dyspnea on exertion were noticed 7 weeks after high-dose MCNU (600 mg/kg) treatment, and chest X-ray revealed a bibasilar reticular pattern. Arterial blood was hypoxemic and pulmonary function showed the development of a restrictive ventilatory effect and a reduced diffusing capacity for carbon monoxide (DLCO). Clinical Symptoms were resolved after 3 courses of m-PSL pulse therapy and 6 months prednisolone, but an isolated reduction in DLCO has been present. This case suggests that pulmonary toxicity is a dose limiting factor for MCNU treatment.

Leptomeningeal dissemination is one of the major causes which increase the morbidity and mortality of the patients with malignant brain tumors. The incidence of this complication is increasing, however, no sufficient treatment is available at present. Therefore, in an attempt to establish a new treatment, we studied toxicity and therapeutic effect of intrathecal ACNU (nimustine hydrochloride) using experimental animals. Systemic and local toxicity was tested in normal rats that received ACNU intracisternally. The animals given ACNU more than 3.0 mg/kg progressively lost their body weight, and ACNU 6.0 mg/kg was fatal in 80% of animals. Animals given ACNU less than 1.5 mg/kg gained weight in the same rate as in control animals. Increased capillary permeability to intravenous Evans blue was observed in the subpial region of the brain in the rats given ACNU 6.0 mg/kg intracisternally. The increase of capillary permeability was dominant along the ambient cistern, hypocampal fissure, and at the base of the brain. Demyelinization and loss of neurons were seen in the same areas as well. These changes were not observed in the animal given ACNU less than 1.5 mg/kg. Therapeutic effect of intrathecal ACNU against the leptomeningeal tumor was studied in rats with meningeal carcinomatosis which was induced by intracisternal inoculation of 1 X 10(4) cells of Walker 256 carcinosarcoma. The median survival times of the animal given ACNU 1.5 mg/kg intrathecally on day 2 or 5 after tumor inoculation were prolonged by 55 to 64%, and 64 to 145%, respectively, as compared to those of untreated control animals (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

In 26 patients with cancer of the stomach, bone marrow function, cell mediated immunity and plasma CEA level were examined after administration of ACN-U. ACNU was given intravenously and intermittently with 5-FU given orally daily. Results 1) Delayed myelosuppression was observed in every cases and reached to the nadir in 2-7 weeks after ACNU administration. 2) Bone marrow suppression and recovery therefrom were observed earlier in platelet counts than in RBC and WBC counts. 3) Suppression of cell mediated immunity was not observed later than 4 weeks after ACNU administration. 4) Plasma CEA level decreased or stopped to increase after ACNU administration in 5 out of 8 patients having a high CEA level before treatment. 5) Regression of tumor size was observed in 4 out of 5 patients in whom a tumor was palpable. Conclusion ACNU has a strong antitumor activity and may be more effective if combined with antimetabolite agent, such as 5FU. Total dosage of ACNU given safely in one series was considered to be 150-200mg. Next series of ACNU administration should be started after restoration of platelet counts more than 100,000/mm3 was obtained.

A phase II study of the oral agent methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU tablet) for myeloproliferative disorders was performed. Fifty-two patients were treated with MCNU tablets and 43 patients were evaluated for clinical effects and 45 for adverse effects. The standard regimen was as follows; oral administration of 50mg (one tablet)/body/day every 4-6 days was considered as one course, and this was repeated at 6-8-week intervals if possible, with certain modifications according to dosage, period of administration and dose interval wherever necessary. Of 16 patients with chronic myelogenous leukemia (CML) in the chronic phase, 13 achieved complete remission (CR), and 3 achieved partial remission (PR). The overall response ratio was 100%. Rapid reduction of leucocytes was detected within two weeks. One patient with CML in blast crisis achieved PR (100%). Of 15 patients with polycythemia vera, 13 showed an excellent effect (87%), and 1 a moderate effect (6.7%), the overall response ratio being 93%. In essential thrombocythemia, an excellent effect (70%) was obtained in 7 of 10 patients. One patient with myelofibrosis showed an excellent effect (100%). Nausea & vomiting (33%) and anorexia (13%) were major adverse effects, but these symptoms were observed only transiently. Liver dysfunction was also seen in 8.9% of patients, but no patient showed severe manifestations. Our study supports the contention that MCNU tablet is a useful agent against myeloproliferative disorders.

Nineteen patients with renal cell carcinoma who had undergone radical nephrectomy have been treated with a combination of chemotherapy and partly hormonal therapy using ACNU, vinblastine and chloromadinone acetate. The efficacy of the combination therapy in advanced renal cell carcinoma was studied and only one out of nineteen cases having lung and pleural metastasis shows no change lasting from one to eighteen months. The prophylactic efficacy was studied in eighteen patients with stage I to IVA renal cell carcinoma (contained one patient with stage IVA renal cell carcinoma who had undergone radical nephrectomy and coecum resection for coecum invasion). Tumor recurrence occurred in 5 cases, that is 5 cases within 1 year and 1 case within 2 years. The combination of chemotherapy using ACNU & vinblastine must be used carefully for severe side effects.

A 77-year-old male was admitted to the hospital because of left hemiparesis secondary to multifocal cerebral metastases from adenocarcinoma of the stomach. He was treated with combination of radiotherapy and chemotherapy consisting of ACNU, Tegafur and PSK. He was in good condition, but abruptly developed severe dyspnea 40 days after administration of Tegafur and 28 days after that of ACNU. Chest X-ray at that time revealed diffuse opacity involving entire lung fields associated with marked hypoxia. The patient expired 9 days after this episode. The autopsy revealed acute interstitial pneumonitis associated with hyaline membrane formation consistent with adult respiratory distress syndrome involving entire lobes of both lungs without metastases. As to the etiology of the ARDS in this case, we concluded that the administration of Tegafur was the most likely as to the cause, although the possibility of betamethasone was not ruled out. The remaining factors were not likely as to the cause of the ARDS in this case.