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Irradiation with misonidazole and hyperbaric oxygen: Final report on a randomized trial in advanced head and neck cancer
Inl. J Radiofion OncorogY Biol. Phyx. Vol. 12, pp. 1343-1346 Printed in the U.S.A. All rights reserved.
Copyright
0
0360-3016/86 1986 Pergamon
$3.00 + .oO Journals Ltd.
??Session IV
IRRADIATION WITH MISONIDAZOLE AND HYPERBARIC OXYGEN: FINAL REPORT ON A RANDOMIZED TRIAL IN ADVANCED HEAD AND NECK CANCER R. SEALY, F.R.C.R.,* S. CRIDLAND, PH.D.,? L. BARRY, M.S.R.* AND R. NORRIS, B.Sc. (HoNs.)~ Groote Schuur Hospital and University of Cape Town One hundred and thirty patients with locally advanced squamous carcinoma of the head and neck were treated in a prospective randomized trial to compare conventional irradiation (63.00 Gy in 30 fractions) with a combination sensitizer regimen of misonidazole and hyperbaric oxygen. The drug (2.0 gm/m’) was given with each of six fractions of 6.0 Gy in hyperbaric oxygen at 3 ATA. The results support a previous study and favor the comblltion at 1 year at better than the 10% level. This regimen could be useful for bulky primary or nodal disease. Misonidazole,
Hyperbaric oxygen, Head and neck cancer, Fractionation.
INTRODUCTION
Patient background It can be seen that the two sides of the trial contained highly comparable groups of typically middle-aged, good performance status, male smokers, most of whom used significant amounts of alcohol (Table 1). Patients with a history of hypertension, neurological disease or major deviations from normal serum chemistry levels were excluded. About 5’4had a past history of significant pulmonary disease.
The background of this study has been previously reported’ and the purpose of this paper is to provide a definitive report. The poor results of conventional radiotherapy, chemotherapy and radiotherapy, radiotherapy and hyperbaric oxygen and misonidazole warranted a new approach to sensitization. It was, therefore, felt that a combination of an efficient, but poorly penetrating sensitizer (oxygen) with a less efficient, but better penetrating agent (misonidazole), warranted investigation.
METHODS
AND
Randomization and strati’cation Randomization was by means of previously prepared batches of sealed envelopes. The person(s) preparing and drawing the envelopes was not the clinician concerned. There was stratification for sex, tumor site, t3 vs. t disease, and extent of nodal involvement (Q, nl vs. n2 n3), as well as, histological differentiation (well and moderately differentiated tumors vs. poorly differentiated or histologically not assessable tumors). Following randomization, six patients were withdrawn from the trial, two on the air and four on the combined
MATERIALS
Patient eligibility Trial entry was offered to patients with locally advanced previously untreated squamous carcinoma of the mouth or fixed neck nodes. The details have been previously reported.’ Ethical Committee approval was obtained and informed consent sought prior to randomization. Patients entered the study from September 1980 to March 1984.
Presented at the Chemical Modifiers of Cancer Treatment Conference, Clearwater, Florida, 20-24 October 1985. * Dept. of Radiotherapy. t Dept. of Pharmacology. $ Dept. of Medical Physics. Reprint requests to: Professor R. Sealy, Radiotherapy Department, Groote Schuur Hospital, 7925 Observatory, Cape Town, South Africa.
Acknowledgements-Thanks are due to the Medical Superintendent at Groote Schuur Hospital, for permission to publish the case material; to F. Hoffmann-La Roche and Company, for the supply of misonidazole and support; and also to Dr. I. LenoxSmith. The data were collated by Mrs. C. van der Merwe and the manuscript typed by Mrs. D. Godley. Accepted for publication 27 February 1986. I343
I. J. Radiation Oncology 0 Biology0 Physics
1344
Table 1. Patient background Air
MIS0 and HBO
No. patients
66
64
Age. Mean years
55
56
Sex % Male
91
87
Race % Black Mixed Caucasian
35 38 27
33 47 20
Mean weight kg height cm
60 168
57 166
Mean Systolic B.P. (mmHg) Diastolic B.P. (mmHg)
128 84
128 82
Performance status Zubrod 1
2
% 98
Significant Smoking history Use of alcohol Total abstinence
94 74 6
95 79 6
9
8
Mean Hb. gms
13.5
13.5
Past history chest disease
21
26
Positive serology syphilis
Marginally abnormal multichannel analysis
August 1986, Volume 12, Number 8
dose of 42.0 Gray in 20 fractions in air or 18.0 or 24.0 Gy in 3 or 4 fractions with the sensitizer combination. Radiation treatment given On the air side of the trial, the mean tumor dose actually delivered was 62.7 Gy (range 69-l 1) in 29.4 fractions (range 33-5), in a mean of 45.6 days (range 66-10). On the sensitizer side, two patients did not complete irradiation in oxygen and received conventional treatment in air. If these are excluded the mean tumor dose was 35.7 Gy (range 24-42) in 5.9 fractions (range 4-7), in 22.3 days (range 1l-8 I). Radiation reactions There would appear to be no differences in the early and late reactions between the two sides of the trial (see Table 3).‘s2 Toxicity of misonidazole and hyperbaric oxygen Neuropathy was graded, as previously described.2 The results are shown in Table 4. With the combination, 27
Table 2. Tumor characteristics Air
MIS0 and HBO
66 3.4
64 3.7
%
%
6 6 15 13
9 3 17 23
8 65 33
12 65 26
7 10 31
3 28 26
Stage t3 4 n O/l 213
51 48 59 40
61 38 55 46
Tumor site Tongue Floor mouth Fauces Other
42 23 29 6
39 27 32 2
Histology Well dill. Mod. diff. Poorly diff. N.S.
38 36 8 16
38 38 12 12
No. patients Mean duration history (mos.) Presenting symptoms
50
45
sensitizer side. Three declined treatment; one was found to have a positive sputum for tuberculosis; one required urgent chemotherapy for rapidly progressive disease; and one was found to have been incorrectly randomized. Tumor characteristics The two sides of the trial are again seen to be wellbalanced (Table 2). They are similar to those usually seen in the Department. Technique and dosage The radiation technique has been previously described. ’ Those patients randomized to receive conventional treatment in air were scheduled to receive a tumor dose of 63.0 Gy in 30 fractions daily, in 38 days, while those randomized to be irradiated in hyperbaric oxygen were prescribed a tumor dose of 36.0 Gy in six fractions, in 17 days. The maximum acceptable variation in tumor dose was 10%. Misonidazole (2.0 gms/m* p.o. per fraction) and hyperbaric oxygen (three atmospheres absolute) were used, as previously described.’ Prophylactic irradiation was given to clinically uninvolved neck nodes to a planned
Systemic Tiredness Weakness Loss appetite Loss weight Local Hemorrhage Mouth/facial pain Otalgia Swelling Facial Mouth Neck
1345
Misonidazole and hyperbaric oxygen 0 R. SEALY et al.
Table 3. Radiation reactions
Total number of patients Acute. Erythema None Mild Moderate Deep Not scored Membrane None Mild Moderate Confluent Not scored “Severe reaction” Chronic. At 1 year No. patients, assessable Skin changes None Mild Moderate Severe Mucosal changes None Mild Moderate Severe Salivary gland atrophy None Mild Moderate Severe Bone necrosis At any time
Air
MIS0 and HBO
64
60
2 8 25 17 12
3 8 14 24 11
10 1 29 13 10 4
7 2 23 18 10 9
16
17
6 10 0 0
2 12 5 0
5 7 4 0
1 12 4 0
6 3 6 1
4 8 4
15
18
tion. As previously reported,’ the death was associated with a very high alcohol intake. The convulsion took place in hyperbaric oxygen, in a patient who suppressed a history of fits and would otherwise not have been offered irradiation in hyperbaric oxygen.
Drug monitoring Fifty-nine patients had 3 13 specimens of venous blood taken at the end of treatment for serum misonidazole levels. Assay was by means of high performance thin layer liquid chromatography. These ranged from 8 to 169 pgm/ ml (mean 89).
Results of treatment There is apparently improved local control at 12 5). This months (43%compared to 28% p = 0.08-Table tendency is continued at 24 months. It can also be seen that 6/64 patients died of other causes in the air group, whereas 12/60 did so in the combination group. The greatest improvements in local control at 12 months are seen in those groups with an expected poorer control rate (td and n&. Six patients (three in each group) developed palpable nodes in the neck in areas which had received prophylactic irradiation.
Table 5. Outcome of treatment Air
No. pts.
1
patients experienced 30 toxicities; whereas on the air side of the trial, seven patients experienced seven toxicities. On the combination side, both patients experiencing severe neuropathy continued against advice to take large amounts of alcohol, as did those experiencing ataxia and mental confusion. The latter two symptoms were all reversed with withdrawal of alcohol, bed rest, and rehydra-
At risk 1 year Alive and well 1 year Died other causes in interval At risk 2 years Alive and well 2 years Died other causes in interval Local disease-free 12 months related to stage f3 f4
“o/l n2/3
Table 4. Misonidazole and hvnerbaric oxveen toxicitv
No. patients Neuropathy Mild Moderate Severe Ataxia Mental confusion Convulsion Death
Air
MIS0 and HBO
64
60 16 4 2 2 5 1 I
MIS0 and HBO
Floor of mouth/ tongue/jaw Palate/fauces/tonsil Causes of death other than disease site. New primary Metastases Uncertain Cardiovascular Trauma Misonidazole/Alcohol
64 18 (28%)
60 26 (43%)*
3 58 9 (15%)
5 50
3
12 (24%) 7
14132
19137
413 I 13137 5126
8/23t 16132 1 l/28
12143 6120
19140 8120
1 2 2 1
3 4 2 1 1 1
All deaths of whatever cause are counted as treatment failures. * Sig. 8% level (x2 = 3.1). t Sig. 6% level (x2 = 3.6).
1346
I. J. Radiation Oncology 0 Biology 0 Physics
August 1986, Volume 12, Number 8
DISCUSSION
The level of statistical significance in this randomized study has improved with the increasing numbers of patients available for analysis at 1 year.’ Since this study is now closed, this will not improve through further patient accrual, but the marked consistency of the two studies very strongly supports the conclusion that there is improved local control. A multicenter study involving larger numbers of patients could be expected to achieve higher levels of statistical significance. (The material reported here is very similar to that reported in the pilot study involving 31 patients’ with regard to sex, mean age, site of lesion, and histological differentiation. The patients in the pilot study had slightly more advanced disease [64% ta and 55% n2,,]. Fit&n patients in this study were diseasefree at 1 year. When all 9 1 patients in both groups who received the sensitizer combination are compared with the sixty-four patients treated in air, there is a significant favoring of the combination at the 4% level [x2 = 4.51). Many of the patients treated in this series had significantly greater disease burdens (t4) than in our previous series of patients treated with misonidazole’ (t3) alone where 22% ( 1 l/50) were free of disease in the irradiated area at one year.* Yet, the results reported here seem to be better. The tendency to improvement in the larger tumors (t4 and n2/3, Table 5) is of interest and it might be in tumors of this type that this approach could find its application. The mechanism of action remains a matter for speculation, but disproportionately increased effects in this type of tumor would suggest improved access or distribution, rather than a general increase in efficacy.
This randomized study was executed by one clinician and, as such, the patterns of assessment were reasonably constant and similar to a previous study.* The two sides of the trial are evenly balanced for patient and tumor characteristics. The acute radiation reactions are similar to those previously reported’,* and do not demonstrate a statistically significant increase in the reactions in the sensitizer group although there is a tendency to an increase in deep erythematous and confluent membranous reactions in this group. Furthermore, while there is possibly a tendency to a minor increase, there is no significant increase in the late clinical effects, in spite of the large fraction size,3 as judged at 1 year; but we have no information as to how this group of patients would tolerate surgery. Apart from one uneventful block dissection, the only surgery performed was sequestrectomy for mandibular necrosis. This condition was distressingly common at 23 and 30%, respectively, but these patients had gross disease, often closely related to bone. Nine had prior bone erosion and many very poor dentition. The misonidazole toxicity is similar to that previously reported by us* and the neuropathy rate in this series (36%) is not statistically significantly greater than in our previous series treated in air (26%) (x2 = 1.3). As previously stated, disastrous effects only seem to occur when excessive amounts of alcohol are combined with the drug. The control rate at 1 year with the combination is similar to that previously reported in a pilot study (48%)’
REFERENCES 1. Scaly, R., Cridland, S.: The treatment
of locally advanced head and neck cancer with misonidazole, hyperbaric oxygen and irradiation: an interim report. Znt. J. Radiat. Oncol. Biol. Phyx 10: 1721-1723, 1984. 2. Sealy, R., Williams, A., Cridland, S., Stratford, M., Minchinton, A., Hallet, C.: A report on misonidazole in a ran-
domized trial in locally advanced head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 8: 339-342, 1982. 3. Withers, H.R., Thames, H.D., Flow, B.L., Mason, K.A.,
Hussey, D.H.: The relationship of acute to late skin injury in 2 and 5 fraction/week y-ray therapy. Int. J. Radiat. Oncol. Biol. Phys. 4: 595-601,
1978.
Copyright
0
0360-3016/86 1986 Pergamon
$3.00 + .oO Journals Ltd.
??Session IV
IRRADIATION WITH MISONIDAZOLE AND HYPERBARIC OXYGEN: FINAL REPORT ON A RANDOMIZED TRIAL IN ADVANCED HEAD AND NECK CANCER R. SEALY, F.R.C.R.,* S. CRIDLAND, PH.D.,? L. BARRY, M.S.R.* AND R. NORRIS, B.Sc. (HoNs.)~ Groote Schuur Hospital and University of Cape Town One hundred and thirty patients with locally advanced squamous carcinoma of the head and neck were treated in a prospective randomized trial to compare conventional irradiation (63.00 Gy in 30 fractions) with a combination sensitizer regimen of misonidazole and hyperbaric oxygen. The drug (2.0 gm/m’) was given with each of six fractions of 6.0 Gy in hyperbaric oxygen at 3 ATA. The results support a previous study and favor the comblltion at 1 year at better than the 10% level. This regimen could be useful for bulky primary or nodal disease. Misonidazole,
Hyperbaric oxygen, Head and neck cancer, Fractionation.
INTRODUCTION
Patient background It can be seen that the two sides of the trial contained highly comparable groups of typically middle-aged, good performance status, male smokers, most of whom used significant amounts of alcohol (Table 1). Patients with a history of hypertension, neurological disease or major deviations from normal serum chemistry levels were excluded. About 5’4had a past history of significant pulmonary disease.
The background of this study has been previously reported’ and the purpose of this paper is to provide a definitive report. The poor results of conventional radiotherapy, chemotherapy and radiotherapy, radiotherapy and hyperbaric oxygen and misonidazole warranted a new approach to sensitization. It was, therefore, felt that a combination of an efficient, but poorly penetrating sensitizer (oxygen) with a less efficient, but better penetrating agent (misonidazole), warranted investigation.
METHODS
AND
Randomization and strati’cation Randomization was by means of previously prepared batches of sealed envelopes. The person(s) preparing and drawing the envelopes was not the clinician concerned. There was stratification for sex, tumor site, t3 vs. t disease, and extent of nodal involvement (Q, nl vs. n2 n3), as well as, histological differentiation (well and moderately differentiated tumors vs. poorly differentiated or histologically not assessable tumors). Following randomization, six patients were withdrawn from the trial, two on the air and four on the combined
MATERIALS
Patient eligibility Trial entry was offered to patients with locally advanced previously untreated squamous carcinoma of the mouth or fixed neck nodes. The details have been previously reported.’ Ethical Committee approval was obtained and informed consent sought prior to randomization. Patients entered the study from September 1980 to March 1984.
Presented at the Chemical Modifiers of Cancer Treatment Conference, Clearwater, Florida, 20-24 October 1985. * Dept. of Radiotherapy. t Dept. of Pharmacology. $ Dept. of Medical Physics. Reprint requests to: Professor R. Sealy, Radiotherapy Department, Groote Schuur Hospital, 7925 Observatory, Cape Town, South Africa.
Acknowledgements-Thanks are due to the Medical Superintendent at Groote Schuur Hospital, for permission to publish the case material; to F. Hoffmann-La Roche and Company, for the supply of misonidazole and support; and also to Dr. I. LenoxSmith. The data were collated by Mrs. C. van der Merwe and the manuscript typed by Mrs. D. Godley. Accepted for publication 27 February 1986. I343
I. J. Radiation Oncology 0 Biology0 Physics
1344
Table 1. Patient background Air
MIS0 and HBO
No. patients
66
64
Age. Mean years
55
56
Sex % Male
91
87
Race % Black Mixed Caucasian
35 38 27
33 47 20
Mean weight kg height cm
60 168
57 166
Mean Systolic B.P. (mmHg) Diastolic B.P. (mmHg)
128 84
128 82
Performance status Zubrod 1
2
% 98
Significant Smoking history Use of alcohol Total abstinence
94 74 6
95 79 6
9
8
Mean Hb. gms
13.5
13.5
Past history chest disease
21
26
Positive serology syphilis
Marginally abnormal multichannel analysis
August 1986, Volume 12, Number 8
dose of 42.0 Gray in 20 fractions in air or 18.0 or 24.0 Gy in 3 or 4 fractions with the sensitizer combination. Radiation treatment given On the air side of the trial, the mean tumor dose actually delivered was 62.7 Gy (range 69-l 1) in 29.4 fractions (range 33-5), in a mean of 45.6 days (range 66-10). On the sensitizer side, two patients did not complete irradiation in oxygen and received conventional treatment in air. If these are excluded the mean tumor dose was 35.7 Gy (range 24-42) in 5.9 fractions (range 4-7), in 22.3 days (range 1l-8 I). Radiation reactions There would appear to be no differences in the early and late reactions between the two sides of the trial (see Table 3).‘s2 Toxicity of misonidazole and hyperbaric oxygen Neuropathy was graded, as previously described.2 The results are shown in Table 4. With the combination, 27
Table 2. Tumor characteristics Air
MIS0 and HBO
66 3.4
64 3.7
%
%
6 6 15 13
9 3 17 23
8 65 33
12 65 26
7 10 31
3 28 26
Stage t3 4 n O/l 213
51 48 59 40
61 38 55 46
Tumor site Tongue Floor mouth Fauces Other
42 23 29 6
39 27 32 2
Histology Well dill. Mod. diff. Poorly diff. N.S.
38 36 8 16
38 38 12 12
No. patients Mean duration history (mos.) Presenting symptoms
50
45
sensitizer side. Three declined treatment; one was found to have a positive sputum for tuberculosis; one required urgent chemotherapy for rapidly progressive disease; and one was found to have been incorrectly randomized. Tumor characteristics The two sides of the trial are again seen to be wellbalanced (Table 2). They are similar to those usually seen in the Department. Technique and dosage The radiation technique has been previously described. ’ Those patients randomized to receive conventional treatment in air were scheduled to receive a tumor dose of 63.0 Gy in 30 fractions daily, in 38 days, while those randomized to be irradiated in hyperbaric oxygen were prescribed a tumor dose of 36.0 Gy in six fractions, in 17 days. The maximum acceptable variation in tumor dose was 10%. Misonidazole (2.0 gms/m* p.o. per fraction) and hyperbaric oxygen (three atmospheres absolute) were used, as previously described.’ Prophylactic irradiation was given to clinically uninvolved neck nodes to a planned
Systemic Tiredness Weakness Loss appetite Loss weight Local Hemorrhage Mouth/facial pain Otalgia Swelling Facial Mouth Neck
1345
Misonidazole and hyperbaric oxygen 0 R. SEALY et al.
Table 3. Radiation reactions
Total number of patients Acute. Erythema None Mild Moderate Deep Not scored Membrane None Mild Moderate Confluent Not scored “Severe reaction” Chronic. At 1 year No. patients, assessable Skin changes None Mild Moderate Severe Mucosal changes None Mild Moderate Severe Salivary gland atrophy None Mild Moderate Severe Bone necrosis At any time
Air
MIS0 and HBO
64
60
2 8 25 17 12
3 8 14 24 11
10 1 29 13 10 4
7 2 23 18 10 9
16
17
6 10 0 0
2 12 5 0
5 7 4 0
1 12 4 0
6 3 6 1
4 8 4
15
18
tion. As previously reported,’ the death was associated with a very high alcohol intake. The convulsion took place in hyperbaric oxygen, in a patient who suppressed a history of fits and would otherwise not have been offered irradiation in hyperbaric oxygen.
Drug monitoring Fifty-nine patients had 3 13 specimens of venous blood taken at the end of treatment for serum misonidazole levels. Assay was by means of high performance thin layer liquid chromatography. These ranged from 8 to 169 pgm/ ml (mean 89).
Results of treatment There is apparently improved local control at 12 5). This months (43%compared to 28% p = 0.08-Table tendency is continued at 24 months. It can also be seen that 6/64 patients died of other causes in the air group, whereas 12/60 did so in the combination group. The greatest improvements in local control at 12 months are seen in those groups with an expected poorer control rate (td and n&. Six patients (three in each group) developed palpable nodes in the neck in areas which had received prophylactic irradiation.
Table 5. Outcome of treatment Air
No. pts.
1
patients experienced 30 toxicities; whereas on the air side of the trial, seven patients experienced seven toxicities. On the combination side, both patients experiencing severe neuropathy continued against advice to take large amounts of alcohol, as did those experiencing ataxia and mental confusion. The latter two symptoms were all reversed with withdrawal of alcohol, bed rest, and rehydra-
At risk 1 year Alive and well 1 year Died other causes in interval At risk 2 years Alive and well 2 years Died other causes in interval Local disease-free 12 months related to stage f3 f4
“o/l n2/3
Table 4. Misonidazole and hvnerbaric oxveen toxicitv
No. patients Neuropathy Mild Moderate Severe Ataxia Mental confusion Convulsion Death
Air
MIS0 and HBO
64
60 16 4 2 2 5 1 I
MIS0 and HBO
Floor of mouth/ tongue/jaw Palate/fauces/tonsil Causes of death other than disease site. New primary Metastases Uncertain Cardiovascular Trauma Misonidazole/Alcohol
64 18 (28%)
60 26 (43%)*
3 58 9 (15%)
5 50
3
12 (24%) 7
14132
19137
413 I 13137 5126
8/23t 16132 1 l/28
12143 6120
19140 8120
1 2 2 1
3 4 2 1 1 1
All deaths of whatever cause are counted as treatment failures. * Sig. 8% level (x2 = 3.1). t Sig. 6% level (x2 = 3.6).
1346
I. J. Radiation Oncology 0 Biology 0 Physics
August 1986, Volume 12, Number 8
DISCUSSION
The level of statistical significance in this randomized study has improved with the increasing numbers of patients available for analysis at 1 year.’ Since this study is now closed, this will not improve through further patient accrual, but the marked consistency of the two studies very strongly supports the conclusion that there is improved local control. A multicenter study involving larger numbers of patients could be expected to achieve higher levels of statistical significance. (The material reported here is very similar to that reported in the pilot study involving 31 patients’ with regard to sex, mean age, site of lesion, and histological differentiation. The patients in the pilot study had slightly more advanced disease [64% ta and 55% n2,,]. Fit&n patients in this study were diseasefree at 1 year. When all 9 1 patients in both groups who received the sensitizer combination are compared with the sixty-four patients treated in air, there is a significant favoring of the combination at the 4% level [x2 = 4.51). Many of the patients treated in this series had significantly greater disease burdens (t4) than in our previous series of patients treated with misonidazole’ (t3) alone where 22% ( 1 l/50) were free of disease in the irradiated area at one year.* Yet, the results reported here seem to be better. The tendency to improvement in the larger tumors (t4 and n2/3, Table 5) is of interest and it might be in tumors of this type that this approach could find its application. The mechanism of action remains a matter for speculation, but disproportionately increased effects in this type of tumor would suggest improved access or distribution, rather than a general increase in efficacy.
This randomized study was executed by one clinician and, as such, the patterns of assessment were reasonably constant and similar to a previous study.* The two sides of the trial are evenly balanced for patient and tumor characteristics. The acute radiation reactions are similar to those previously reported’,* and do not demonstrate a statistically significant increase in the reactions in the sensitizer group although there is a tendency to an increase in deep erythematous and confluent membranous reactions in this group. Furthermore, while there is possibly a tendency to a minor increase, there is no significant increase in the late clinical effects, in spite of the large fraction size,3 as judged at 1 year; but we have no information as to how this group of patients would tolerate surgery. Apart from one uneventful block dissection, the only surgery performed was sequestrectomy for mandibular necrosis. This condition was distressingly common at 23 and 30%, respectively, but these patients had gross disease, often closely related to bone. Nine had prior bone erosion and many very poor dentition. The misonidazole toxicity is similar to that previously reported by us* and the neuropathy rate in this series (36%) is not statistically significantly greater than in our previous series treated in air (26%) (x2 = 1.3). As previously stated, disastrous effects only seem to occur when excessive amounts of alcohol are combined with the drug. The control rate at 1 year with the combination is similar to that previously reported in a pilot study (48%)’
REFERENCES 1. Scaly, R., Cridland, S.: The treatment
of locally advanced head and neck cancer with misonidazole, hyperbaric oxygen and irradiation: an interim report. Znt. J. Radiat. Oncol. Biol. Phyx 10: 1721-1723, 1984. 2. Sealy, R., Williams, A., Cridland, S., Stratford, M., Minchinton, A., Hallet, C.: A report on misonidazole in a ran-
domized trial in locally advanced head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 8: 339-342, 1982. 3. Withers, H.R., Thames, H.D., Flow, B.L., Mason, K.A.,
Hussey, D.H.: The relationship of acute to late skin injury in 2 and 5 fraction/week y-ray therapy. Int. J. Radiat. Oncol. Biol. Phys. 4: 595-601,
1978.