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Misonidazole in radiotherapy of supratentorial malignant brain gliomas in adult patients: a randomized double-blind study
Misonidazole in Radiotherapy of Supratentorial Malignant Brain Gliomas in Adult Patients: a Randomized Double-blind Study* EORTC
BRAIN
TUMOUR
GROlJPt
Abstract-The effect of misonidazole on the duration of the free interval (time to recurrence) and total survival of adults bearing malignant supratentorial brain gliomas was measured in a randomized double-blind study. Radiotherapy consisted of 9 X 3.5-Gy fractions given on alternate days during 3 weeks followed by 6 X 3-Gy fractions delivered in 2 weeks. Misonidazole, 1.3 g/m’, administrated 4 hr before the 9 first irradiations to 82 patients, had no effect on the duration of the free interval or total survival compared with 81 con&ols. The two groups were comparable in respect to the main prognostic factors: median age, performance status or tumour location. The overall tolerance of misonidazole was good.
[l] and 30.7 weeks [Z]. Unfortunately neither CCNU [l] nor the combination of VM-26 plus CCNU [2] was able to significantly increase the duration of the free interval. Because of the lack of efficacy of the adjuvant chemotherapy in patients with malignant gliomas, our group has tested in a double-blind and randomized trial the possibility of prolonging the free interval and/or survival by using misonidazole, a radiosensitizer, during radiotherapy. The results of this study are reported in the present paper.
INTRODUCTION
studies the EORTC Brain Tumour Group has been able to show that the free interval (FI), defined as the time interval between neurosurgery and relapse of neurological signs, can be measured reproducibly in selected adult patients with malignant supratentorial brain gliomas. In two consecutive studies the duration of free interval was found to be respectively 3 1 .O IN PREVIOUS
Accepted 20 July
1982. *An abstract of this study was presented at the 15th International Congress of Radiology, Brussels, June 1981. tThe members of the group who actively participate to this trial are: H. G. Aberle, Kantonspital Ziirich, Switzerland; J. Brotchi and M. Lemaire, HBpital de Bavitire, Universitbde LiPge, Belgium; L. Calliauw, A. Z. Gent, Belgium; M. Chatel, C.H.I’. Rennes, France; Th. de Barsy and J. Longueville,
MATERIALS
AND METHODS
The results reporred here are based on the 163 patients entered into this trial from October 1978 to November 1980. The criteria for patient’s selection were those used in our previous [l, 21 studies:
U.C.L. Brussels, Belgium; N. de Tribolet and S. Bernasconi. C.1J.V. Lausanne, Switzerland; J. Garfield and J. Punt, Wessex Neurological Centre, Southampton, U.K.; D. Gonzales, Wilhelmina Gasthuis, Amsterdam, The Netherlands; R. Greiner, Universititsklinik Bern, Switzerland; L. M. Haefliger, Hbpital Cantonal Gen&ve, Switzerland; G. Haferkamp, J. Gutenberg Universitit, Maim, F.R.G.; M. Hery, Centre A. Lacassagne, Nice, France; J. Hildebrandl and R. Regnier, Institut J. Bordet, Brussels, Belgium; F. Resche and S. Bourdin, C.H.U. Nantes, France; 0. Dalesio and G. Solbu, EORTC Data Center, Institut J. Bordet, Brussels, Belgium. SRequcsts for reprints should be addressed to: J. Hildebrand, Secretary of the EORTC Brain Tumour Group, HBpital Erasme, Route de Lennik 808, 1070 Brussels, Belgium.
Diagnosis of malignant glioma based on histology. Over 16 years old. The neurological examination had to either be normal or show deficits which could be assessed quantitatively and serve as criteria for further evaluation. Steroids therapy had to be stopped on the 10th day after neurosurgery, occasional administration of steroids being allowed only during radiotherapy. 39
40
EORTC
Brain Tumour
Expected survival of 8 weeks or more after neurosurgery. Normal hematopoietic, renal and liver function, and no major illness other than the brain neoplasia. All patients had an optimal removal of the brain tumour. Patients were irradiated 14-28 days after neurosurgery. The radiotherapy delivered 49.5 Gy in 15 fractions over 5 weeks on alternate days except Sundays. During each of the 9 first sessions 3.5 Gy were delivered to the whole brain in 134 patients, whereas in 25 patients the irradiation fields corresponded to the tumour area with large safety margins. The 6 last doses of radiotherapy consisted of 3 Gy delivered to the tumour site with a 2-cm margin. Misonidazole, 1.3 g/m*, or placebo was given in a double-blind fashion per OS 4 hr prior to the irradiation during the 9 first sessions of radiotherapy, up to a total dose of 12 g/m*. Twelve patients could not receive the scheduled dose of misonidazole, 9 because of early deterioration of neurological status. After the completion of the treatment patients were followed until the recurrence of clinical signs of tumour progression to measure the free interval. Three patients developed histologically proven metastases outside the field of the cranial irradiation: one in the lung, one in the thoracic spinal cord and one in the thoracic spinal meninges. It was considered that in these 3 patients the free interval ended with the discovery of these metastases, despite the fact that none of them had other clinical signs of progression of the primary tumour until death, which was due in all 3 cases to the metastatic lesions. For the present evaluation the duration of the total survival was available for 137 patients; 24 were still alive at the time of the analysis and 2 were lost for follow-up. Table 1 shows that the distribution of patients according to the main prognostic factors is comparable in the two groups.
Group Table 1.
Patient
characteristics Group
Patient characteristics
(control)
Total No. Age <50 yr >50 yr Sex: male female Pathology: glioblastoma mu1 tiform astrocytoma grade III-IV others Localization: frontal temporal parietal occipital deep other Resection: biopsy partial total other Karnofsky index: under 70% 70% or more *Two
stereotoxic
biopsies
1
Group 2 (misonidazole)
81 24 57 50 31
82 32 50 47 35
31
32
32 18 23 30 21 3 3 1 8* 38 20 15 28 53
28 22 32 20 20 7
in each treatment
1 2 7’ 34 22 19 26 56 arm.
patients for the duration of the free interval and of the total survival. The analyses of a series of prognostic factors is given in Table 3: the most significant are age, Karnofsky index and tumour location, frontal tumours having better prognosis when compared to the group of all other locations. Toxicity The following symptoms and signs observed during radiotherapy were considered as being possibly related to the treatment. Signs of mild peripheral neuropathy such as symmetrical par-
RESULTS of misonidazole and prognostic factors As shown in Figs 1 and 2, the administration of misonidazole during the first 3 weeks of radiotherapy has no effect on the free interval or on the length of the total survival time. From 82 patients treated with misonidazole 70 received the full dose of 12 mg/m’. Sixteen patients (10%) survived 2 yr or longer, 8 received misonidazole and 8 did not (Table 2). The main characteristics of these long-term survivors correspond to the most important prognostic factors found in the entire group of 163
Effect
Fig. 1. Duration of the free interual in 82 patients who received nisonidazote (---) during radiotherapy in 81 controls (-). The mean duration of the free interval was 30 weeks for each group.
Misonidazole
in Radiotherapy
41
of Brain Gliomas
DISCUSSION Our study failed to demonstrate any effect of misonidazole on the duration of the free interval or of the total survival time in patients with supratentorial malignant gliomas treated by tumour resection and radiotherapy. Apparently our data conflict with the results reported by Urtasun et al. [3]. However, there are
Duration of surv~al
(months
)
Fig. 2. Duration of the total survival in 82 patients who received misonidazole(---) during radiotherapy and in 81 controls (-). The mean duration of the total suruiual was respectively 44.5 and 46.1 weeks.
esthesia and/or decrease of tendon reflexes were observed in 4 patients before and in I1 during the administration of misonidazole, the corresponding figures in the control group being respectively 5 and 3 patients. Nausea or vomiting occurred in 21 patients, 11 of them received misonidazole. Skin rash was noticed in 10 cases, of which only 3 were treated by misonidazole. Twenty-four patients had a clinical relapse or died within two months following neurosurgery. In 6 patients, of which only one received misonidazole, death was due to major medical diseases: pulmonary emboli (4 patients), heart infarctus (1 patient) and Lyell’s disease (1 patient). Of the remaining 18 patients 6 died and 12 had an early recurrence of neurological symptoms. In all 18 patients death or progression were attributed to neurological disorders.
Table 2.
Age/sex
Misonidazole given
many methodological differences between the two studies, as shown in Table 4. The main difference is the total dose of irradiation, which was reduced in Urtasun et al.‘s study, whereas the dose of radiotherapy used in our trial was according to the EDF formula [4] equivalent in the convential treatment of 6000 rads given in 6 weeks in our previous studies. The rationale for changing the schedule and the daily dose of radiotherapy is based on experimental data indicating that the radiosensitizers are more active when combined with high single doses of irradiation [5,6]. An arm using the convential radiotherapy was not included in the present study, but the comparison with the historical controls from our previous trials [l, 21 indicate that the effect on the mean survival and duration of the free interval is not modified by the change of the radiotherapy schedule. In this trial 24 patients (15%) relapsed or died within 8 weeks after neurosurgery. This rate appears excessive when compared to that of less than 5% observed in our two previous consecutive trials [ 1,2]. These findings cannot be attributed to the administration of misonidazole since 15 patients receive no radiosensitizer, although it is possible that the same patients who received misonidazole developed an encephalopathy due to its administration. An alternative interpreta-
Characteristics of patients suruiuing at least two years Karnofsky index
59 M 53 M
NO YES
60 60
38 M 21 F 34 M 26F 40 M 27 M 24 M 46 F 47 F 41 M 39M 46 M 58 M 32 M
YES YES NO NO NO NO YES YES NO NO NO YES YES YES
80 90 90 90 80 80 100 90 100 90 80 70 80 80
Main tumor location Temporal
Pathology
,. Astrocytoma
9.
Corpus callosum Frontal ., .. 1, Parietal Frontal ., Temporal
multiform
Glioblastoma
1. Frontal
3, 3. .. grades
III and IV
3,
1, (1 0 Oligodendroblastoma I. 9, II II ..
42
EORTC Table 3. Prognostic
Brain Tumour
Analysis of prognostic factors Duration of free interval (weeks)
factors (No. of patients)
39 1 24 37 25 1 22 34 > 31 1 25 34 27 ) 32 25 20
Age: <50 yr (56) >50yr (107) Tumour location: frontal (55) others (108) Initial Karnofsky index: <70 (54) 270 (109) Pathology: glioblastoma multiforme (63) others ( 100) Extent of tumour resection: total (54) partial (94) No. of lobes involved by the tumour: 1 lobe (105) 2 lobes (52) 3 lobes (6)
Table 4.
Comparison
Group
Significance log rank test P ~0.0001 P
Duration of total survival (weeks)
Radiosensitizer Single dose* No. of doses Total radiotherapy (rads) Radiotherapy fractionation
Urtasun’s study
P ~0.0001
60 1 41 581 41/ 38 49 1 44 > 45 49 42 1 46 44 38
between treatments used in Urtasun et a1.S and the EORTC
Treatment
Significance log rank test
P <0.0003 P GO.002 N.S. N.S. N.S.
studies
EORTC study
Metronidazole 6 g/m2 9 in 3 weeks 3000 300 rads X 9 in 3 weeks
Misonidazole 1.3 g/m2 9 in 3 weeks 4950 (a) 350 rads X 9 in 3 weeks with misonidazole (b) 300 rads X 6 in 2 weeks without misonidazole
*Given 4 hr before irradiation.
tion for the unusually high rate of early relapses or deaths is that the radiotherapy schedule using higher daily doses is less well tolerated by patients with brain tumours. However, this explanation remains hypothetical. The overall tolerance of misonidazole appeared to be fairly good in this study. The incidence of digestive symptoms and skin rash was no higher
in patients receiving the radiosensitizer than in controls. Symptoms of mild peripheral neuropathy were observed in 10% of patients who received misonidazole. The low incidence of peripheral neuropathy and the lack of severity observed in our patients could be related to the administration of dexamethazone and of antiepileptic drugs.
REFERENCES 1.
6.
EORTC BRAIN TUMOUR GROUP. Effect of CCNU on survival rate, objective remission and duration of free interval in patients with malignant brain glioma. Final evaluation. Eur / Cancer 1978, 14, 851-856. EORTC BRAIN TUMOUR GROUP. Evaluation of CCNU, VM-26 plus CCNU and procarbazin in supratentorial brain gliomas. J Neurosurg 1981, 55, 27-31. URTASUN R, BAND P, CHAPMAN JD et al. Radiation and high-dose metronidazole in supratentorial glioblastomas. N Engl/ Med 1976, 294, 1364-1367. ORTON CG, ELLIS F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radio1 1973,46, 529-537. VAN PU~EN LM. Effect of Ro 07-0582 and radiation on a poorly reoxygenating mouse osteosarcoma. In: Modification of Radiosensitivity of Biological Systems. IAEE, Vienna, 1976, Vol. 179. DISCHE S, SAUNDERS MI, LEE ME et al. Clinical testing of radiosensitizer Ro 07-0582. Experience with multiple doses. Br J Cancer 1977, 35, 567-579.
BRAIN
TUMOUR
GROlJPt
Abstract-The effect of misonidazole on the duration of the free interval (time to recurrence) and total survival of adults bearing malignant supratentorial brain gliomas was measured in a randomized double-blind study. Radiotherapy consisted of 9 X 3.5-Gy fractions given on alternate days during 3 weeks followed by 6 X 3-Gy fractions delivered in 2 weeks. Misonidazole, 1.3 g/m’, administrated 4 hr before the 9 first irradiations to 82 patients, had no effect on the duration of the free interval or total survival compared with 81 con&ols. The two groups were comparable in respect to the main prognostic factors: median age, performance status or tumour location. The overall tolerance of misonidazole was good.
[l] and 30.7 weeks [Z]. Unfortunately neither CCNU [l] nor the combination of VM-26 plus CCNU [2] was able to significantly increase the duration of the free interval. Because of the lack of efficacy of the adjuvant chemotherapy in patients with malignant gliomas, our group has tested in a double-blind and randomized trial the possibility of prolonging the free interval and/or survival by using misonidazole, a radiosensitizer, during radiotherapy. The results of this study are reported in the present paper.
INTRODUCTION
studies the EORTC Brain Tumour Group has been able to show that the free interval (FI), defined as the time interval between neurosurgery and relapse of neurological signs, can be measured reproducibly in selected adult patients with malignant supratentorial brain gliomas. In two consecutive studies the duration of free interval was found to be respectively 3 1 .O IN PREVIOUS
Accepted 20 July
1982. *An abstract of this study was presented at the 15th International Congress of Radiology, Brussels, June 1981. tThe members of the group who actively participate to this trial are: H. G. Aberle, Kantonspital Ziirich, Switzerland; J. Brotchi and M. Lemaire, HBpital de Bavitire, Universitbde LiPge, Belgium; L. Calliauw, A. Z. Gent, Belgium; M. Chatel, C.H.I’. Rennes, France; Th. de Barsy and J. Longueville,
MATERIALS
AND METHODS
The results reporred here are based on the 163 patients entered into this trial from October 1978 to November 1980. The criteria for patient’s selection were those used in our previous [l, 21 studies:
U.C.L. Brussels, Belgium; N. de Tribolet and S. Bernasconi. C.1J.V. Lausanne, Switzerland; J. Garfield and J. Punt, Wessex Neurological Centre, Southampton, U.K.; D. Gonzales, Wilhelmina Gasthuis, Amsterdam, The Netherlands; R. Greiner, Universititsklinik Bern, Switzerland; L. M. Haefliger, Hbpital Cantonal Gen&ve, Switzerland; G. Haferkamp, J. Gutenberg Universitit, Maim, F.R.G.; M. Hery, Centre A. Lacassagne, Nice, France; J. Hildebrandl and R. Regnier, Institut J. Bordet, Brussels, Belgium; F. Resche and S. Bourdin, C.H.U. Nantes, France; 0. Dalesio and G. Solbu, EORTC Data Center, Institut J. Bordet, Brussels, Belgium. SRequcsts for reprints should be addressed to: J. Hildebrand, Secretary of the EORTC Brain Tumour Group, HBpital Erasme, Route de Lennik 808, 1070 Brussels, Belgium.
Diagnosis of malignant glioma based on histology. Over 16 years old. The neurological examination had to either be normal or show deficits which could be assessed quantitatively and serve as criteria for further evaluation. Steroids therapy had to be stopped on the 10th day after neurosurgery, occasional administration of steroids being allowed only during radiotherapy. 39
40
EORTC
Brain Tumour
Expected survival of 8 weeks or more after neurosurgery. Normal hematopoietic, renal and liver function, and no major illness other than the brain neoplasia. All patients had an optimal removal of the brain tumour. Patients were irradiated 14-28 days after neurosurgery. The radiotherapy delivered 49.5 Gy in 15 fractions over 5 weeks on alternate days except Sundays. During each of the 9 first sessions 3.5 Gy were delivered to the whole brain in 134 patients, whereas in 25 patients the irradiation fields corresponded to the tumour area with large safety margins. The 6 last doses of radiotherapy consisted of 3 Gy delivered to the tumour site with a 2-cm margin. Misonidazole, 1.3 g/m*, or placebo was given in a double-blind fashion per OS 4 hr prior to the irradiation during the 9 first sessions of radiotherapy, up to a total dose of 12 g/m*. Twelve patients could not receive the scheduled dose of misonidazole, 9 because of early deterioration of neurological status. After the completion of the treatment patients were followed until the recurrence of clinical signs of tumour progression to measure the free interval. Three patients developed histologically proven metastases outside the field of the cranial irradiation: one in the lung, one in the thoracic spinal cord and one in the thoracic spinal meninges. It was considered that in these 3 patients the free interval ended with the discovery of these metastases, despite the fact that none of them had other clinical signs of progression of the primary tumour until death, which was due in all 3 cases to the metastatic lesions. For the present evaluation the duration of the total survival was available for 137 patients; 24 were still alive at the time of the analysis and 2 were lost for follow-up. Table 1 shows that the distribution of patients according to the main prognostic factors is comparable in the two groups.
Group Table 1.
Patient
characteristics Group
Patient characteristics
(control)
Total No. Age <50 yr >50 yr Sex: male female Pathology: glioblastoma mu1 tiform astrocytoma grade III-IV others Localization: frontal temporal parietal occipital deep other Resection: biopsy partial total other Karnofsky index: under 70% 70% or more *Two
stereotoxic
biopsies
1
Group 2 (misonidazole)
81 24 57 50 31
82 32 50 47 35
31
32
32 18 23 30 21 3 3 1 8* 38 20 15 28 53
28 22 32 20 20 7
in each treatment
1 2 7’ 34 22 19 26 56 arm.
patients for the duration of the free interval and of the total survival. The analyses of a series of prognostic factors is given in Table 3: the most significant are age, Karnofsky index and tumour location, frontal tumours having better prognosis when compared to the group of all other locations. Toxicity The following symptoms and signs observed during radiotherapy were considered as being possibly related to the treatment. Signs of mild peripheral neuropathy such as symmetrical par-
RESULTS of misonidazole and prognostic factors As shown in Figs 1 and 2, the administration of misonidazole during the first 3 weeks of radiotherapy has no effect on the free interval or on the length of the total survival time. From 82 patients treated with misonidazole 70 received the full dose of 12 mg/m’. Sixteen patients (10%) survived 2 yr or longer, 8 received misonidazole and 8 did not (Table 2). The main characteristics of these long-term survivors correspond to the most important prognostic factors found in the entire group of 163
Effect
Fig. 1. Duration of the free interual in 82 patients who received nisonidazote (---) during radiotherapy in 81 controls (-). The mean duration of the free interval was 30 weeks for each group.
Misonidazole
in Radiotherapy
41
of Brain Gliomas
DISCUSSION Our study failed to demonstrate any effect of misonidazole on the duration of the free interval or of the total survival time in patients with supratentorial malignant gliomas treated by tumour resection and radiotherapy. Apparently our data conflict with the results reported by Urtasun et al. [3]. However, there are
Duration of surv~al
(months
)
Fig. 2. Duration of the total survival in 82 patients who received misonidazole(---) during radiotherapy and in 81 controls (-). The mean duration of the total suruiual was respectively 44.5 and 46.1 weeks.
esthesia and/or decrease of tendon reflexes were observed in 4 patients before and in I1 during the administration of misonidazole, the corresponding figures in the control group being respectively 5 and 3 patients. Nausea or vomiting occurred in 21 patients, 11 of them received misonidazole. Skin rash was noticed in 10 cases, of which only 3 were treated by misonidazole. Twenty-four patients had a clinical relapse or died within two months following neurosurgery. In 6 patients, of which only one received misonidazole, death was due to major medical diseases: pulmonary emboli (4 patients), heart infarctus (1 patient) and Lyell’s disease (1 patient). Of the remaining 18 patients 6 died and 12 had an early recurrence of neurological symptoms. In all 18 patients death or progression were attributed to neurological disorders.
Table 2.
Age/sex
Misonidazole given
many methodological differences between the two studies, as shown in Table 4. The main difference is the total dose of irradiation, which was reduced in Urtasun et al.‘s study, whereas the dose of radiotherapy used in our trial was according to the EDF formula [4] equivalent in the convential treatment of 6000 rads given in 6 weeks in our previous studies. The rationale for changing the schedule and the daily dose of radiotherapy is based on experimental data indicating that the radiosensitizers are more active when combined with high single doses of irradiation [5,6]. An arm using the convential radiotherapy was not included in the present study, but the comparison with the historical controls from our previous trials [l, 21 indicate that the effect on the mean survival and duration of the free interval is not modified by the change of the radiotherapy schedule. In this trial 24 patients (15%) relapsed or died within 8 weeks after neurosurgery. This rate appears excessive when compared to that of less than 5% observed in our two previous consecutive trials [ 1,2]. These findings cannot be attributed to the administration of misonidazole since 15 patients receive no radiosensitizer, although it is possible that the same patients who received misonidazole developed an encephalopathy due to its administration. An alternative interpreta-
Characteristics of patients suruiuing at least two years Karnofsky index
59 M 53 M
NO YES
60 60
38 M 21 F 34 M 26F 40 M 27 M 24 M 46 F 47 F 41 M 39M 46 M 58 M 32 M
YES YES NO NO NO NO YES YES NO NO NO YES YES YES
80 90 90 90 80 80 100 90 100 90 80 70 80 80
Main tumor location Temporal
Pathology
,. Astrocytoma
9.
Corpus callosum Frontal ., .. 1, Parietal Frontal ., Temporal
multiform
Glioblastoma
1. Frontal
3, 3. .. grades
III and IV
3,
1, (1 0 Oligodendroblastoma I. 9, II II ..
42
EORTC Table 3. Prognostic
Brain Tumour
Analysis of prognostic factors Duration of free interval (weeks)
factors (No. of patients)
39 1 24 37 25 1 22 34 > 31 1 25 34 27 ) 32 25 20
Age: <50 yr (56) >50yr (107) Tumour location: frontal (55) others (108) Initial Karnofsky index: <70 (54) 270 (109) Pathology: glioblastoma multiforme (63) others ( 100) Extent of tumour resection: total (54) partial (94) No. of lobes involved by the tumour: 1 lobe (105) 2 lobes (52) 3 lobes (6)
Table 4.
Comparison
Group
Significance log rank test P ~0.0001 P
Duration of total survival (weeks)
Radiosensitizer Single dose* No. of doses Total radiotherapy (rads) Radiotherapy fractionation
Urtasun’s study
P ~0.0001
60 1 41 581 41/ 38 49 1 44 > 45 49 42 1 46 44 38
between treatments used in Urtasun et a1.S and the EORTC
Treatment
Significance log rank test
P <0.0003 P GO.002 N.S. N.S. N.S.
studies
EORTC study
Metronidazole 6 g/m2 9 in 3 weeks 3000 300 rads X 9 in 3 weeks
Misonidazole 1.3 g/m2 9 in 3 weeks 4950 (a) 350 rads X 9 in 3 weeks with misonidazole (b) 300 rads X 6 in 2 weeks without misonidazole
*Given 4 hr before irradiation.
tion for the unusually high rate of early relapses or deaths is that the radiotherapy schedule using higher daily doses is less well tolerated by patients with brain tumours. However, this explanation remains hypothetical. The overall tolerance of misonidazole appeared to be fairly good in this study. The incidence of digestive symptoms and skin rash was no higher
in patients receiving the radiosensitizer than in controls. Symptoms of mild peripheral neuropathy were observed in 10% of patients who received misonidazole. The low incidence of peripheral neuropathy and the lack of severity observed in our patients could be related to the administration of dexamethazone and of antiepileptic drugs.
REFERENCES 1.
6.
EORTC BRAIN TUMOUR GROUP. Effect of CCNU on survival rate, objective remission and duration of free interval in patients with malignant brain glioma. Final evaluation. Eur / Cancer 1978, 14, 851-856. EORTC BRAIN TUMOUR GROUP. Evaluation of CCNU, VM-26 plus CCNU and procarbazin in supratentorial brain gliomas. J Neurosurg 1981, 55, 27-31. URTASUN R, BAND P, CHAPMAN JD et al. Radiation and high-dose metronidazole in supratentorial glioblastomas. N Engl/ Med 1976, 294, 1364-1367. ORTON CG, ELLIS F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radio1 1973,46, 529-537. VAN PU~EN LM. Effect of Ro 07-0582 and radiation on a poorly reoxygenating mouse osteosarcoma. In: Modification of Radiosensitivity of Biological Systems. IAEE, Vienna, 1976, Vol. 179. DISCHE S, SAUNDERS MI, LEE ME et al. Clinical testing of radiosensitizer Ro 07-0582. Experience with multiple doses. Br J Cancer 1977, 35, 567-579.