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The treatment of cerebral metastases from breast cancer by cranial irradiation combined with CCNU and misonidazole (MISO)
@ Session VI Abstracts MISONIDAZOLE-RESULTS OF RANDOMIZED CONTROLLED CLINICAL TRIALS-AN EVALUATION
2. MISO: given in a daily oral dose of I g/m’ 3.5 hr prior to each radiation treatment except day I and day 8 when the dose IS increased to 1.2/m’. 3. CCNU: even on day I and 8 orally in a dose of 70 mplm”, 2.5 hr after the radiation treatment f6 hr after MISO).
STANLEY DISCHE Marie Curie Research Wing for Oncology. Regional Radiotherapy Center. Mount Vernon Hospital, Northwood. Middlesex HA6 ZRN, England
Marntenance
A great effort has been expended in the clinical testing of misonidazole as an hypoxic cell sensitizer in clinical radiotherapy. In the three years which followed the first administration of the drug as a sensitizer in November 1974. phase I and phase II testing led to the fairly general acceptance of 12 g per square meter of surface area as the total dose which may be given over a period of at least three weeks. The drug limitation was due to an incidence of peripheral neuropathy. Since 1978, when the drug was made available by the Roche Company for phase 111randomized controlled clinical trials. such studies have been established in all five continents and it is probable that at least 5000 patients have been included. Many are still in progress and in most only preliminary reports are available. The interpretation of the data is made complex by the different regimes for administration combined with radiotherapy which have been devised in order to make the best use of the permitted dose. We now have over 30 reports of randomized studies and all available will be brought up to date and their essential results with regard to local tumor control. survival and normal tissue effects reviewed. So far some evidence for benefit has been shown in some of the trials in head and neck cancer. With on exception no benefit has been obtained in the radiotherapy of glioblastomas and in all the studies so far available concerned with tumors of the bladder. uterine cervix, bronchus and esophagus no advantage has been demonstrated. The importance of these studies to the hypoxia cell sensitizer development programme and to the problem of hypoxia as a cause for radioreslstance in clmlcal radiotherapy will be discussed.
PHASE l/II STUDY OF MISONIDAZOLE IN STAGE III LUNG CANCER
C. J. H. FRYER. G. GUDALJSKAS, B. DRIEDGERAND C. DEDHAR A. Maxwell Evans Clinic, Cancer Control Agency of British Columbia, Vancouver, Canada V5Z 3J3 I, Evaluate pharmacokinetic data when Misonidazole (Miso) was administered orally m the fasting patient. 2. Compare toxicity of 10.0 Cm/m’ Miso given in three versus ten doses. 3. Evaluate normal tissue reaction in Miso and Placebo groups. Technique. Previously untreated patients with Stage 111non oat ceil bronchogenic carcinoma recieved 3000 cGy in IO fractions delivered five times per week. Miso was administered orally to the patient in the fasting state under supervision. Neurotoxicity. ototoxicity, and radiation reaction were recorded. Miso and Ro-9963 levels in serum and urine were measured using High Pressure Liquid Chromatography. Results; I. More rapid absorption and higher peak values. 2. A fatal toxic encephalopathy occurred in one patient receiving 3.3 Gm/m daily for three days (max. serum value 400 &ml). A new metabolic product was identified in the bile of this patient. 3. Subjective sensory changes and routine audiometry proved the most useful parameten for assessing neurotoxicity. 4. Potentiation of radiation reaction was Seen in the Misonidazole treated patients but too few patients were treated to assess statistical significance. Conclusions. I. Central Nervous System toxicity is most likely due to high peak serum values resulting in increase transfer across the blood brain barrier, in contrast to peripheral neuropathy which is due to total tissue exposure. 2. Concurrent controls must be used in all clinical sensitizer trials to assess potential enhancement of normal tissue reaction. Aims:
THE TREATMENT OF CEREBRAL METASTASES FROM BREAST CANCER BY CRANIAL IRRADIATION COMBINED WITH CCNL’ AND MlSONIDAZOLE (M&O)
H. K. AWWAD,H. ABD EL BAKI. R. HAMZAAND H. AKOVSH Departments of Radiotherapy and Medical Oncology, National Cancer Institute Fom El Khalig. Kasr El Aini Street, Cairo, Egypt The objective of the study is to improve the remission rate and duration after cranial irradiation in patients having cerebral met&stases from breast cancer. The principles of the proposed protocol are: A-Cerebral mefrom breast cancer are treatable by irradiation. B-CCNU is active against breast cancer and penetrates the bloodbrain barrier. C-Misonidazole (MISO) is a hypoxic cell radiosensitizer and can also enhance the chemotherapeutic effect of CCNU in viva. MIS0 also penetrates the blood-brain barrier. The slow clearance of the drug in man permits its use in combination with irradiation and CCNU when given sequentially on the same day with the possibility of enhancing both modalities. Initial
combrnarion
[herap
CCNU in a dose of 100 g/m’ is given every six weeks for one year. This is combined with MIS0 in an oral dose of I g/m’ given 3.5 hr before CCNU. This is started six weeks after the mltial treatment. A pilot feasibility study has been completed. The initial combination treatment was well tolerated by all patients. Transient grade I peripheral neuropathy was experienced by about 50% of patients I-2 weeks after the end of the initial treatment. However this did not interfere with subsequent administration of MIS0 during the mamtenance therapy. All patients showed either CR 150%) or a PR (50%) before the start of maintenance therapy. Long remissions lasting for more than I2 months were obtained in two patients. Based on this pilot study a randomised trial was started. Eligible patients are random&d between a-radiotherapy alone, b-radiotherapy plus MISO, c-RT + CCNU. d-RT -c MIS0 + CCNU.
Table I. Dose schedule
trearmenr
Comprising: I. Whole brain irradiation: IO fractions 3.0 Gy apiece, I F/day on a 5 F/week basis. I811
Dose Gm/m’
No. pts.
2.0 x I 3.3 x I 5.0x I Placebo
3 3 3 5
Dose Cm/m’ 2.0 2.5 3.3 I.0
x x x x
3 3 3 IO
No. pts. 5 7 3 9
2. MISO: given in a daily oral dose of I g/m’ 3.5 hr prior to each radiation treatment except day I and day 8 when the dose IS increased to 1.2/m’. 3. CCNU: even on day I and 8 orally in a dose of 70 mplm”, 2.5 hr after the radiation treatment f6 hr after MISO).
STANLEY DISCHE Marie Curie Research Wing for Oncology. Regional Radiotherapy Center. Mount Vernon Hospital, Northwood. Middlesex HA6 ZRN, England
Marntenance
A great effort has been expended in the clinical testing of misonidazole as an hypoxic cell sensitizer in clinical radiotherapy. In the three years which followed the first administration of the drug as a sensitizer in November 1974. phase I and phase II testing led to the fairly general acceptance of 12 g per square meter of surface area as the total dose which may be given over a period of at least three weeks. The drug limitation was due to an incidence of peripheral neuropathy. Since 1978, when the drug was made available by the Roche Company for phase 111randomized controlled clinical trials. such studies have been established in all five continents and it is probable that at least 5000 patients have been included. Many are still in progress and in most only preliminary reports are available. The interpretation of the data is made complex by the different regimes for administration combined with radiotherapy which have been devised in order to make the best use of the permitted dose. We now have over 30 reports of randomized studies and all available will be brought up to date and their essential results with regard to local tumor control. survival and normal tissue effects reviewed. So far some evidence for benefit has been shown in some of the trials in head and neck cancer. With on exception no benefit has been obtained in the radiotherapy of glioblastomas and in all the studies so far available concerned with tumors of the bladder. uterine cervix, bronchus and esophagus no advantage has been demonstrated. The importance of these studies to the hypoxia cell sensitizer development programme and to the problem of hypoxia as a cause for radioreslstance in clmlcal radiotherapy will be discussed.
PHASE l/II STUDY OF MISONIDAZOLE IN STAGE III LUNG CANCER
C. J. H. FRYER. G. GUDALJSKAS, B. DRIEDGERAND C. DEDHAR A. Maxwell Evans Clinic, Cancer Control Agency of British Columbia, Vancouver, Canada V5Z 3J3 I, Evaluate pharmacokinetic data when Misonidazole (Miso) was administered orally m the fasting patient. 2. Compare toxicity of 10.0 Cm/m’ Miso given in three versus ten doses. 3. Evaluate normal tissue reaction in Miso and Placebo groups. Technique. Previously untreated patients with Stage 111non oat ceil bronchogenic carcinoma recieved 3000 cGy in IO fractions delivered five times per week. Miso was administered orally to the patient in the fasting state under supervision. Neurotoxicity. ototoxicity, and radiation reaction were recorded. Miso and Ro-9963 levels in serum and urine were measured using High Pressure Liquid Chromatography. Results; I. More rapid absorption and higher peak values. 2. A fatal toxic encephalopathy occurred in one patient receiving 3.3 Gm/m daily for three days (max. serum value 400 &ml). A new metabolic product was identified in the bile of this patient. 3. Subjective sensory changes and routine audiometry proved the most useful parameten for assessing neurotoxicity. 4. Potentiation of radiation reaction was Seen in the Misonidazole treated patients but too few patients were treated to assess statistical significance. Conclusions. I. Central Nervous System toxicity is most likely due to high peak serum values resulting in increase transfer across the blood brain barrier, in contrast to peripheral neuropathy which is due to total tissue exposure. 2. Concurrent controls must be used in all clinical sensitizer trials to assess potential enhancement of normal tissue reaction. Aims:
THE TREATMENT OF CEREBRAL METASTASES FROM BREAST CANCER BY CRANIAL IRRADIATION COMBINED WITH CCNL’ AND MlSONIDAZOLE (M&O)
H. K. AWWAD,H. ABD EL BAKI. R. HAMZAAND H. AKOVSH Departments of Radiotherapy and Medical Oncology, National Cancer Institute Fom El Khalig. Kasr El Aini Street, Cairo, Egypt The objective of the study is to improve the remission rate and duration after cranial irradiation in patients having cerebral met&stases from breast cancer. The principles of the proposed protocol are: A-Cerebral mefrom breast cancer are treatable by irradiation. B-CCNU is active against breast cancer and penetrates the bloodbrain barrier. C-Misonidazole (MISO) is a hypoxic cell radiosensitizer and can also enhance the chemotherapeutic effect of CCNU in viva. MIS0 also penetrates the blood-brain barrier. The slow clearance of the drug in man permits its use in combination with irradiation and CCNU when given sequentially on the same day with the possibility of enhancing both modalities. Initial
combrnarion
[herap
CCNU in a dose of 100 g/m’ is given every six weeks for one year. This is combined with MIS0 in an oral dose of I g/m’ given 3.5 hr before CCNU. This is started six weeks after the mltial treatment. A pilot feasibility study has been completed. The initial combination treatment was well tolerated by all patients. Transient grade I peripheral neuropathy was experienced by about 50% of patients I-2 weeks after the end of the initial treatment. However this did not interfere with subsequent administration of MIS0 during the mamtenance therapy. All patients showed either CR 150%) or a PR (50%) before the start of maintenance therapy. Long remissions lasting for more than I2 months were obtained in two patients. Based on this pilot study a randomised trial was started. Eligible patients are random&d between a-radiotherapy alone, b-radiotherapy plus MISO, c-RT + CCNU. d-RT -c MIS0 + CCNU.
Table I. Dose schedule
trearmenr
Comprising: I. Whole brain irradiation: IO fractions 3.0 Gy apiece, I F/day on a 5 F/week basis. I811
Dose Gm/m’
No. pts.
2.0 x I 3.3 x I 5.0x I Placebo
3 3 3 5
Dose Cm/m’ 2.0 2.5 3.3 I.0
x x x x
3 3 3 IO
No. pts. 5 7 3 9