Misonidazole and CCNU chemotherapy for recurrent primary brain tumor.

CCNU chemotherapy prolongs survival of patients with primary brain tumor when given at the time of tumor progression following radiation therapy. Used as single agent, response rates of 30 to 80 per cent have been reported with median response durations of five to six months. Experimentally, tumor cytotoxicity is enhanced using the combination of misonidazole and CCNU, without increasing myelotoxicity. In this phase I/II study, 23 patients with primary brain tumor which progressed following radiation therapy were treated with combined CCNU and misonidazole. In all patients either the diagnosis of high grade glioma was made at the time of initial diagnosis prior to radiation therapy or the tumor transformed from low grade to high grade glioma at the time of progression following radiation therapy. CCNU 120 mg/M2 was given four hours following misonidazole 3.5 g/M2 every six weeks, with dosage adjustments for myelotoxicity. Treatment was continued for one year or until tumor progression. Of the 17 patients in the study for one year or more, 11 (65 per cent) survived for one year, and six (35 per cent) remained free of tumor progression for one year. Median time to tumor progression from start of CCNU plus misonidazole chemotherapy was 27 weeks and median survival was 80 weeks. No severe complications resulted from myelotoxicity. One patient developed mild peripheral neuropathy which disappeared following discontinuation of misonidazole.

Multiple daily fractionated radiation therapy and misonidazole in the management of malignant astrocytoma. A preliminary report.

Various attempts have been made to improve the effectiveness of radiation in the treatment of cerebral malignant astrocytomas. A trend favoring multiple daily fractionated (MDF) radiation therapy over conventional single daily fractionated (CF) radiation therapy was identified in our previous study. In order to assess the effect of MDF with and without misonidazole, a province-wide prospective randomized trial was initiated in January 1981. By March 1984, 124 patients with histologically verified grade III and IV astrocytomas were randomized to CF (5800 cGy/6 weeks/30 fractions), MDF (6141 cGy/4.5 weeks/69 fractions at 89 cGy every 3-4 hours, three times a day) and MDF in combination with misonidazole (1.25 g/m2 three times weekly for the first 3 weeks). Thirty-eight patients were randomized to CF, 43 patients to MDF, and 43 patients to MDF and misonidazole. At the preliminary assessment in July 1984, the median survival time was 27 weeks for the CF group, 39 weeks for the MDF group and 49 weeks for MDF and misonidazole group. The 1-year actuarial survival rate from surgery was 20% for CF group, 41% for MDF group, and 45% for MDF and misonidazole group. There is a statistically significant difference (P less than 0.001) between the CF and MDF group. However, the addition of misonidazole does not significantly alter survival.

Misonidazole combined with hyperfractionation in the management of malignant glioma.

Multiple daily fractionated radiation therapy (MDF) may be more effective than conventionally fractionated radiation therapy (CF) in the treatment of malignant glioma. The hypoxic cell sensitizer misonidazole (MISO) could be more effective when employed with small fractions of radiation every 4 hours to take advantage of the long half-life of the drug. To evaluate MDF and MDF in combination with MISO, a randomized prospective trial was initiated. Between January 1981, and December 1982, patients with histologically verified astrocytoma with anaplastic foci or glioblastoma multiforme were randomized to CF (5800 cGy, 30 fractions, 6 weeks), MDF (6141 cGy, 69 fractions, 4 1/2 weeks, at 89 cGy every 4 hours 3 times daily) and MDF in combination with MISO (1.25 gm/M2 three times weekly for the first 3 weeks). In January 1983, the CF arm was dropped and a high dose MDF arm added (7120 cGy, 80 fractions, 5 1/2 weeks, at 89 cGy per fraction every 4 hours 3 times daily). CCNU chemotherapy was given at the time of tumor progression. One hundred and twenty-eight patients were evaluated (38 CF, 42 MDF, 37 MDF plus MISO, and 11 high dose MDF). Median survival was 29 weeks for CF, 45 weeks for MDF and 50 weeks for MDF plus MISO. Survival was significantly improved for patients treated with MDF compared to patients treated with CF (p less than .002). The addition of MISO to MDF did not result in further improvement in survival. Acute toxicity was acceptable. No clinically apparent delayed toxicity was observed.

Misonidazole with dexamethasone rescue: an escalating dose toxicity study.

Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. Furthermore, in that study we have observed that DEXA did not alter the plasma pharmacokinetics of misonidazole. We are presently investigating the use of DEXA (2 mg t.i.d. during treatment), with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO ranging from 13.5 to 17.5 gm/M2 given in 9 equally divided doses over 3 weeks. DEXA, 2 mg t.i.d. is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M2. One grade I PN occurred in the first four patients receiving 15.5 gm/M2. Six additional patients were entered at this dose level and no further incidence of PN was observed. Patients are being entered at the next step of 17.5 gm/M2.

Radiation and nitroimidazoles in supratentorial high grade gliomas: a second clinical trial.

As a continuation of a previous controlled trial using "high-dose" metronidazole as a specific sensitizer of hypoxic cells, we used a more efficient nitroimidazole derivative (misonidazole, MISO) in combination with higher doses of radiation in patients with supratentorial high-grade astrocytomas. Sixty-six patients were stratified according to functional level and histological grading, and randomly allocated within 2 weeks of operation of 1 of 3 therapeutic groups: 1, conventional radiation alone; 2, large fractions of radiation with high-dose metronidazole; and 3, radiation as in Group 2 but with equitoxic doses of MISO. We examined survival as the principal end-point of the study. Neither by increasing the dose of radiation over the previous study, nor by using a more efficient sensitizer, were we able to improve survival over the current conventional daily fractionated radiation.

High dose misonidazole with dexamethasone rescue: a possible approach to circumvent neurotoxicity.

With a view to modifying misonidazole (MISO) neurotoxicity, we initiated a randomized clinical study to assess a possible drug interaction and toxicity protection when dexamethasone (DXM) is administered concomittantly with MISO. The ongoing study consists of: 1. Pharmacokinetic evaluation; 2. Assessment of toxicity. Fourteen patients undergoing radiation therapy for different types of malignant neoplasia (excluding brain tumors) have been randomized to receive either MISO alone, or DXM one week prior and during treatment with MISO. Five of seven patients receiving MISO alone developed peripheral neuropathies while only one out of 7 patients that received MISO with DXM coverage developed a transient and mild neuropathy. Pharmacokinetic evaluation of MISO in plasma and urine of those patients receiving DXM has shown no evidence of drug interaction. It is postulated that the mechanism of action of DXM is at the nerve cell membrane level, restoring and stabilizing cell surface properties. In future studies we will investigate the use of DXM with increasing doses of MISO above the recommended maximum dose of 12 gm/m2, hoping to achieve a higher tumor tissue level of MISO while avoiding unacceptable toxicity. The effect of Allopurinol on the plasma kinetics of MISO was studied in four additional patients, observing also no evidence of drug interaction.

Pharmacokinetic interaction of BCNU and misonidazole in humans.

Although considerable laboratory in vitro and in vivo evidence is now available suggesting that misonidazole (MISO) enhances chemotherapy tumor responses, experience with human tumors is limited. Further, the mechanism of this enhancement is not definitely known. One possible mechanism is that MISO alters the pharmacokinetics of the chemotherapeutic agent, vice versa or both. We studied a group of patients with recurrent malignant gliomas, following radiotherapy. After proven recurrence, they were treated with i.v. BCNU in combination with oral MISO in an 8 week cycle. Our aims were: 1. To obtain a second remission; 2. To assess the toxicity of this combination; 3. To assess the plasma pharmacokinetics of each drug alone and in combination. Six patients entered the protocol. Four of six patients obtained either a partial or subpartial response. Prolonged moderate myelosuppression was observed in 2/6 patients after 3 cycles; 2/6 patients experienced seizures after the first cycle of chemotherapy for the first time in the course of their disease. The plasma pharmacokinetic data indicates no evidence of a MISO-BCNU drug interaction.