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Clinical trial of razoxane and radiotherapy for inoperable carcinoma of the bronchus
Int. J. Radiation Oncology Biol. Phys.: f Pergamon Press Ltd.. 1979. Printed
Vol. 5, pp. m the U.S.A.
1649-1651
??Other Drugs
CLINICAL TRIAL OF RAZOXANE AND RADIOTHERAPY FOR INOPERABLE CARCINOMA OF THE BRONCHUS MARGARET F. SPITTLE, F.R.C.R.,? HAYDN BUSH, M.R.C.P.,? SALLY E. JAMES, Ph.D.,$ KURT HELLMANN, D.M., D.Phi1.S One hundred thirteen patients with inoperable carcinoma of the bronchus were ramdomly allocated to receive either radiotherapy or radiotherapy plus razoxane. They were stratified according to histology and analyzed according to whether they had oat-cell or non oat-cell carcinomas and whether they tolerated only 1 ,course (3,000 rad) or 2 courses (6,000 rad) of radiotherapy. Of the patients who had 2 courses of radiothempy, only 7% developed leukopenia and the same percentage developed severe esophagitis; but of those who had the combined treatment, 32% developed leukopenia and the same pecentage developed severe esophagitis. Although the median survival time was greater in those who received the combined treatment in both one treatment and two treatment groups, neither achieved statistical SignifEance. Sixty four percent of patients who had two treatments (i.e. 6,000 rad plus razoxane) survived 12 months; this compares favorably with most other published clinical trials of inoperable carcinoma of the bronchus. Razoxane, Bronchus carcinoma.
INTRODUCTION Razoxane (ICRF 159) has shown radiopotentiation in animal experiments and in man.2*4 In soft tissue sarcomas, the combination of radiation and razoxane has given a statistically significant decrease in recurrence rates3 and chondrosarcomas5 have responded to this combination in an open trial. On the other hand, in squamous cell carcinoma of the head and neck no such differences have been observed.’ There have been sporadic reports of potential benefit in a variety of other tumors, particularly carcinoma of the stomach and ovary. A randomized controlled clinical trial was therefore set up in carcinoma of the bronchus stratified by histology.
Patients of any age and sex who fulfilled the eligibility criteria entered into the trial. These criteria were: 1. Diagnosis of carcinoma of the bronchus made by histological examination of mediastinoscopy or bronchoscopy material. Diagnosis based solely on sputum cytology was not accepted. 2. No clinical or radiographic evidence of spread of the tumor beyond the supraclavicular nodes. 3. Performance status of > 60% (Karnofsky scale). Patients who fulfilled these eligibility criteria were assigned by random number allocation to either of two treatment groups within each histology classification. Treatment assignment was either to radiotherapy alone or to radiotherapy in combination with razoxane. Follow-up examinations were performed at 1 month intervals for the first 3 months after radiotherapy completion and thereafter at approximately 3 monthly intervals.
METHODS AND PATIENTS Patients with inoperable carcinoma of the bronchus confined to the thorax were given either radiotherapy alone or radiotherapy and razoxane. Operability was decided by the referring surgeon after bronschoscopy and mediastinoscopy. All patients had a‘detailed clinical examination including chest radiographs and full blood count. Histological examination was made of the bronchoscopy or mediastinoscopy material or on sputum cytology and was typed according to the WHO classification.
Radiotherapy
All patients received 3,000 rad midline in 10 fractions over 12 days to the tumor and mediastinum, using opposed fields on an 8 Mev Linear Accelerator. After 4 weeks, patients who showed symp-
tMiddlesex Hospital, London, England *Westminster Hospital, London, England 1649
1650
Radiation Oncology 0 Biology 0 Physics
Table 1. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus
lccc RT : 72 Evaluable L 1 1 RT : 20 Exclusions:
September 1979.
Table 2. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus
138 1 Randomized --y
: 62” 4 2 RT : 42
Volume 5. Number 9
Survival - MST (mths) 1 x RT: 3,000rad RT 3.5 3.5
RT/Rz. : 66 Evaluable 4 1 1 RT/Rz. : 23
Incomplete radiotheapy Prior lobectomy Razoxane default Extra chemotherapy Withdrawn/ administrative
: 5 1+
Oat cell Non oat-cell
RTIRz. 3.0 6.0
1 RT/Rz. : 28 Table 3. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus Survival - MST (mths)
error
2 x RT : 6,000 rad RT 11.0 12.0
Oat cell Non oat-cell
RTiRz .
14.0 13.0
tomatic and radiological improvement received a second course of radiotherapy to a total dose of 6,000 rad using 2 wedged fields. Razoxane Patients assigned to the razoxaneiradiotherapy treatment group received razoxane from the outset to completion of radiotherapy, including where applicable, the interval between the 2 courses of 3,000 rad. The drug was administered orally at a dose of 125 mg b.d. Failure of drug compliance or withdrawal of the drug due to leukopenia resulted in secondary withdrawal of patients from the trial (as did extra chemotherapy or incomplete irradiationTable 1.1 Treatment evaluation Assessment of treatment effect was made on the basis of survival which was measured from the 1st day of radiotherapy to time of death. The difference in survival times between the two treatment groups was analyzed by the logrank rest. Results are shown in Tables l-4. DISCUSSION Although there was no statistical difference in any of the groups receiving the combination as opposed to those receiving radiotherapy alone, the combination groups had, with one exception a longer survival time. Since no accurate information is available on the terminal events of these patients and because leukopenia was four times as common in the combined treatment group, it seems entirely likely that remediable infective terminal episodes may have been more common in the combination group than in
Table 4. Treatment radiotherapy/razoxane
with radiotherapy (6,000 rad) vs. in treating patients with carcinoma of the bronchus Toxicity
Leukopenia Esophagitis (i) mild (ii) severe
: :
3142 ( 7%)
9128 (32%)
13/42 (3 1%) 3142 ( 7%)
8/28 (2%) 9/28 (32%)
the radiotherapy alone group. For this reason a trial is now underway to test the validity of this hypothesis. A median survival time of 14 months for oat-cell carcinoma patients seems to be a considerable improvement on survival times of this group compared with other drugs or methods. However, the number of patients is too few to be able to obtain a statistically significant difference even with an increase of 27% in the median survival time. Kamofsky rating is one of the prognostic variables in carcinoma of the bronchus and patients sorted themselves out into those with a poor Karnofsky rating who were not able to tolerate a second course of treatment and those with a good Karnofsky rating who were able to do so. Despite their poor outlook, of those patients who could only tolerate 1 treatment 5123 (2%) survived for more
Razoxane and bronchus carcinoma 0 M. F. SPITTLE et al.
than 1 year on the combination treatment. Only l/20 (5%) of patients in this group on radiotherapy alone survived more than 1 year. The
conclusion
is that
there
seems
to be a bene-
1651
ficial trend in adding razoxane to radiotherapy treatment but for reasons which have yet to be discovered it has not reached statistical significance in the present
trial.
REFERENCES 1. Bakowski,
(?)1,2-di(3,5ICRF 159, M.T.: dioxopiperazin-1-yl) propane NSC-129,943: Razoxane.
Cancer
Treat. Rev. 3:95-107,
1976.
2. Hellmann, K., Murkin, G.E.: Synergism of ICRF 159 and radiotherapy in treatment of experimental tumours. Cancer 34: 1033-1039, 1974. 3. Hellmann, K., Ryail, R.D.H., MacDonald, E., Newton, James, S.E., Jones, S.: Comparison of K.A., radiotherapy with and without razoxane (ICRF 159) in
the treatment of soft tissue sarcomas. Cancer 41: lOO107, 1978. 4. Rhomberg, W.U.: Radiotherapy combined with ICRF 159 (NSC 129943). Int. J. Radiat. Oncol. Biol. Phys. 4:121-126, 1978. 5. Ryail, R.D.H., Bates, T., Newton, K.A., Hellmann, K.: Combination of radiotherapy and razoxane (ICRF 159) for Chondrosarcoma. Cancer, in press.
Vol. 5, pp. m the U.S.A.
1649-1651
??Other Drugs
CLINICAL TRIAL OF RAZOXANE AND RADIOTHERAPY FOR INOPERABLE CARCINOMA OF THE BRONCHUS MARGARET F. SPITTLE, F.R.C.R.,? HAYDN BUSH, M.R.C.P.,? SALLY E. JAMES, Ph.D.,$ KURT HELLMANN, D.M., D.Phi1.S One hundred thirteen patients with inoperable carcinoma of the bronchus were ramdomly allocated to receive either radiotherapy or radiotherapy plus razoxane. They were stratified according to histology and analyzed according to whether they had oat-cell or non oat-cell carcinomas and whether they tolerated only 1 ,course (3,000 rad) or 2 courses (6,000 rad) of radiotherapy. Of the patients who had 2 courses of radiothempy, only 7% developed leukopenia and the same percentage developed severe esophagitis; but of those who had the combined treatment, 32% developed leukopenia and the same pecentage developed severe esophagitis. Although the median survival time was greater in those who received the combined treatment in both one treatment and two treatment groups, neither achieved statistical SignifEance. Sixty four percent of patients who had two treatments (i.e. 6,000 rad plus razoxane) survived 12 months; this compares favorably with most other published clinical trials of inoperable carcinoma of the bronchus. Razoxane, Bronchus carcinoma.
INTRODUCTION Razoxane (ICRF 159) has shown radiopotentiation in animal experiments and in man.2*4 In soft tissue sarcomas, the combination of radiation and razoxane has given a statistically significant decrease in recurrence rates3 and chondrosarcomas5 have responded to this combination in an open trial. On the other hand, in squamous cell carcinoma of the head and neck no such differences have been observed.’ There have been sporadic reports of potential benefit in a variety of other tumors, particularly carcinoma of the stomach and ovary. A randomized controlled clinical trial was therefore set up in carcinoma of the bronchus stratified by histology.
Patients of any age and sex who fulfilled the eligibility criteria entered into the trial. These criteria were: 1. Diagnosis of carcinoma of the bronchus made by histological examination of mediastinoscopy or bronchoscopy material. Diagnosis based solely on sputum cytology was not accepted. 2. No clinical or radiographic evidence of spread of the tumor beyond the supraclavicular nodes. 3. Performance status of > 60% (Karnofsky scale). Patients who fulfilled these eligibility criteria were assigned by random number allocation to either of two treatment groups within each histology classification. Treatment assignment was either to radiotherapy alone or to radiotherapy in combination with razoxane. Follow-up examinations were performed at 1 month intervals for the first 3 months after radiotherapy completion and thereafter at approximately 3 monthly intervals.
METHODS AND PATIENTS Patients with inoperable carcinoma of the bronchus confined to the thorax were given either radiotherapy alone or radiotherapy and razoxane. Operability was decided by the referring surgeon after bronschoscopy and mediastinoscopy. All patients had a‘detailed clinical examination including chest radiographs and full blood count. Histological examination was made of the bronchoscopy or mediastinoscopy material or on sputum cytology and was typed according to the WHO classification.
Radiotherapy
All patients received 3,000 rad midline in 10 fractions over 12 days to the tumor and mediastinum, using opposed fields on an 8 Mev Linear Accelerator. After 4 weeks, patients who showed symp-
tMiddlesex Hospital, London, England *Westminster Hospital, London, England 1649
1650
Radiation Oncology 0 Biology 0 Physics
Table 1. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus
lccc RT : 72 Evaluable L 1 1 RT : 20 Exclusions:
September 1979.
Table 2. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus
138 1 Randomized --y
: 62” 4 2 RT : 42
Volume 5. Number 9
Survival - MST (mths) 1 x RT: 3,000rad RT 3.5 3.5
RT/Rz. : 66 Evaluable 4 1 1 RT/Rz. : 23
Incomplete radiotheapy Prior lobectomy Razoxane default Extra chemotherapy Withdrawn/ administrative
: 5 1+
Oat cell Non oat-cell
RTIRz. 3.0 6.0
1 RT/Rz. : 28 Table 3. Treatment with radiotherapy vs. radiotherapyirazoxane in treating patients with carcinoma of the bronchus Survival - MST (mths)
error
2 x RT : 6,000 rad RT 11.0 12.0
Oat cell Non oat-cell
RTiRz .
14.0 13.0
tomatic and radiological improvement received a second course of radiotherapy to a total dose of 6,000 rad using 2 wedged fields. Razoxane Patients assigned to the razoxaneiradiotherapy treatment group received razoxane from the outset to completion of radiotherapy, including where applicable, the interval between the 2 courses of 3,000 rad. The drug was administered orally at a dose of 125 mg b.d. Failure of drug compliance or withdrawal of the drug due to leukopenia resulted in secondary withdrawal of patients from the trial (as did extra chemotherapy or incomplete irradiationTable 1.1 Treatment evaluation Assessment of treatment effect was made on the basis of survival which was measured from the 1st day of radiotherapy to time of death. The difference in survival times between the two treatment groups was analyzed by the logrank rest. Results are shown in Tables l-4. DISCUSSION Although there was no statistical difference in any of the groups receiving the combination as opposed to those receiving radiotherapy alone, the combination groups had, with one exception a longer survival time. Since no accurate information is available on the terminal events of these patients and because leukopenia was four times as common in the combined treatment group, it seems entirely likely that remediable infective terminal episodes may have been more common in the combination group than in
Table 4. Treatment radiotherapy/razoxane
with radiotherapy (6,000 rad) vs. in treating patients with carcinoma of the bronchus Toxicity
Leukopenia Esophagitis (i) mild (ii) severe
: :
3142 ( 7%)
9128 (32%)
13/42 (3 1%) 3142 ( 7%)
8/28 (2%) 9/28 (32%)
the radiotherapy alone group. For this reason a trial is now underway to test the validity of this hypothesis. A median survival time of 14 months for oat-cell carcinoma patients seems to be a considerable improvement on survival times of this group compared with other drugs or methods. However, the number of patients is too few to be able to obtain a statistically significant difference even with an increase of 27% in the median survival time. Kamofsky rating is one of the prognostic variables in carcinoma of the bronchus and patients sorted themselves out into those with a poor Karnofsky rating who were not able to tolerate a second course of treatment and those with a good Karnofsky rating who were able to do so. Despite their poor outlook, of those patients who could only tolerate 1 treatment 5123 (2%) survived for more
Razoxane and bronchus carcinoma 0 M. F. SPITTLE et al.
than 1 year on the combination treatment. Only l/20 (5%) of patients in this group on radiotherapy alone survived more than 1 year. The
conclusion
is that
there
seems
to be a bene-
1651
ficial trend in adding razoxane to radiotherapy treatment but for reasons which have yet to be discovered it has not reached statistical significance in the present
trial.
REFERENCES 1. Bakowski,
(?)1,2-di(3,5ICRF 159, M.T.: dioxopiperazin-1-yl) propane NSC-129,943: Razoxane.
Cancer
Treat. Rev. 3:95-107,
1976.
2. Hellmann, K., Murkin, G.E.: Synergism of ICRF 159 and radiotherapy in treatment of experimental tumours. Cancer 34: 1033-1039, 1974. 3. Hellmann, K., Ryail, R.D.H., MacDonald, E., Newton, James, S.E., Jones, S.: Comparison of K.A., radiotherapy with and without razoxane (ICRF 159) in
the treatment of soft tissue sarcomas. Cancer 41: lOO107, 1978. 4. Rhomberg, W.U.: Radiotherapy combined with ICRF 159 (NSC 129943). Int. J. Radiat. Oncol. Biol. Phys. 4:121-126, 1978. 5. Ryail, R.D.H., Bates, T., Newton, K.A., Hellmann, K.: Combination of radiotherapy and razoxane (ICRF 159) for Chondrosarcoma. Cancer, in press.