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Late results of multimodality therapy of high-grade supratentorial astrocytomas
Late Results of Multimodality Therapy of High.Grade Supratentorial Astrocytomas Roll W. Seller, M.D.
Fifty-one patients with histologically proved astrocytomas grades III and IV treated with postoperative irradiation and chemotherapy were evaluated with serial computerized tomo. graphic (CT) scans and with special regard to their functional state 30 months after operation. Fourteen patients (27.4%) are still alive, but only 7 of them have a good performance status. The impaired functional state of 6 (11.7%) of the other 7 patients was caused by a secondary progressive dementia with radioiogical signs of diffuse cerebral atrophy and leukoencephalopathy, but no signs of recurrent tumors. The best explanation for this is a synergistic toxic action of whole brain irradiation and chemotherapy. Measuring survival time for evaluation of brain tumor therapy is of limited value without examination of the performance status and sequential CT scans.
A significantly greater number of patients who had received a combination treatment of radiotherapy and BCNU (N,N.bis.[2-chloroethyl]-N-nitrosourea) survived at the end of 18 months, as compared to those patients who had only received radiation therapy after the operation [13]. Among the long-term survivors were patients with progressive neurological deterioration but without clear-cut radiological evidence of mass effect or recurrent tumors [8, 12]. When considering only survival time to evaluate the oncolytic effect of a particular treatment, these patients were included in the successfully treated group despite their poor functional state. However, the ultimate aim of any treatment is to prolong a good quality of survival. Therefore, we analyzed the long-term survivors of our two multimodality therapy studies [10, 12] with special regard to their functional state. The late effect of the treatment to the brain was investigated with serial computerized tomographic (CT) scans. Materials and Methods The long-term survival of 51 patients with histologically proven high-grade (Kernohan grades III and IV) supratenFrom the Departmentof Neurosurgery,UniversityHospital, Bern, Switzerland. Address reprint requeststo Dr. RolfW. Seller, NeurochirurgischeKlinik, Universitlitsspital, CH-3010 Bem, Switzerland. Keywords:astrocytoma;brainneoplasm;chemotherapy;radiationtherapy. 88
torial astrocytomas was evaluated. All patients had had a total or subtotal tumor resection, and postoperative radiotherapy was administered using standard techniques. The total brain was first covered with 2 to 4 fields with cobalt 60 to a dose of 5,000 rads. Then, using the rotating electron beam of the betatron (25 to 35 MeV), the dose to the tumor alone was increased by 5,000 to 6,800 rads. With daily fractions of 200 rads, the radiotherapy was administered over a period of 6 to 7 weeks, beginning 2 to 4 weeks after the operation. Twenty of these patients had been treated according to a protocol evaluating the effect of postoperative irradiation combined with procarbazine, bleomycin, and CCNU (chloroethyl-cyclohex~?l-nitrosourea) [10]. The median survival time was 56 weeks for the 20 patients who had received the combined treatment compared with 51 weeks for 32 previously treated patients who had received only postoperative radiotherapy limited to the tumor volume. At 18 months after operation, 8 of the combined treatment patients and 9 of the control patients were alive. There was no statistical difference in survival between the two groups of patients. The other 31 patients were treated according to a second protocol evaluating the effect of an adjuvant chemotherapy with epipodophyllotoxin (VM 26) and CCNU after operation and radiotherapy in a randomized study [ 12]. The median progression-free interval was 65.6 weeks for the chemotherapy group (15 patients) and 40 weeks for the control group ( 16 patients) without chemotherapy. The difference was not statistically significant. Most of the recurrent tumors of the control group were treated with combination chemotherapy with VM 26 and CCNU [11]. All of the patients from these two studies who were living 30 months or more after operation were examined with serial CT scans with special regard to their functional state. The performance status was graded according to the criteria in Table 1 and compared to the functional state 3 months postoperatively. The 32 previously treated control patients of the first study could not be evaluated because CT was not available at that time. Results Thirty months after operation, 14 of the 51 patients (27.4%) were still alive. The pertinent clinical data of the long-term survivors are summarized in Table 2. Seven pa-
0090-3019/81/020088-04501.25 © 1980 by Little, Brown and Company (Inc.)
Seller: Multimodal Therapy of Astrocytomas 89
Table 1. Grading of Performance Status Grade 0
in all cases. Three patients showed marked signs of leukoencephalopathy with hypodensity of the centrum semiovale and periventricular lucency (Fig. 3). No autopsy could be obtained of the patient who died of pneumonia.
Criteria for Performance Status Fully active
I II III IV
A m b u l a t o r y , c a p a b l e of light w o r k I n b e d u n d e r 50% o f t i m e , c a p a b l e of self-care I n b e d o v e r 50% of t i m e , l i m i t e d self-care Bedridden
tients (13.7%) are in a good functional state, being fully active or capable of part-time work. Only 1 of the 7 patients in a bad functional state had a proven tumor recurrence. The other 6 patients (11.7%) showed a slowly deteriorating course, starting between 1 and 2 years after the operation. It was characterized by a progressive psychoorganic syndrome without focal neurological symptoms or signs of increased intracranial pressure. In serial CT scans there was no evidence of recurrent tumors or progressive hydrocephalus. All patients had some degree of cortical atrophy or hydrocephalus ag a result of cerebral atrophy (Figs. I and 2). Tumor location was hypodense without enhancement
Discussion More than one quarter of all evaluated patients are still alive 2Y2 years after surgery. This high survival rate for malignant astrocytomas may be due to the aggressive treatment but also must be attributed to the selection of goodrisk cases in the second study. Only half of the long-term survivors are in a good functional state. The poor performance status of the others was not due to the primary brain lesion, because 3 months after operation all of these patients were in an improved condition. Most of them had had a frontal tumor, but an equal number of patients with good performance status also had had frontal tumors and corresponding hypodense tumor areas in the later CT scan (see Table 2). Tumor recurrence could not be demonstrated either clinically or radiologically except in one case, and metabolic difficulties and progressive hydrocephalus could be excluded. The poor functional state of these patients was
Table 2. S u m m a r y of Clinical Data
Patient
Age/Sex (Years)
1
25/F
2
29/M
3
30/F
4
32/F
5
36/M
6
39/M
7
45/F
8
50/M
9
54/F
10
55/M
11
56/M
12
56/M
13
61/F
14
62/F
Tumor Grade and Location
Radiotherapy (rads)
IV, left frontal Ill, left frontal IV, left frontal
6,600
IV, right frontal 111, right frontal 111, right frontal IV, right frontal III, left frontal III, right temporal Ill, left frontal IV, left frontal Ill, left frontal II1, right frontal Ill, right occipital
6,500 6,500
6,300 6,480 6,450 5,820 6,060 6,800 6,300 6,600 6,695 6,240 6,180
Chemotherapy VM 26, CCNU ... CCNU, PCB, BLM, VM 26 CCNU, VM 26 CCNU, PCB, BLM CCNU, PCB, BLM ... VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU
CT Findings 30 Months Postop.
Postop. Survival (Weeks)
Performance Status 3 Months Postop.
Performance Status 30 Months Postop.
Atrophy
165
0
0
...
Hypodense
130+
0
0
...
Hypodense
260+
0
0
...
Hypodense; calcification
...
149
3
4
++
+++
Hypodense
251+
3
l
++
++
Hypodense; calcification
Died of pneumonia ...
186
1
1
+
Hypodense
178+
0
0
...
Hypodense
Died of meningitis ...
162+
1
1
++
Hypodense
...
172
2
3
+
+
Hypodense
220+
2
4
+++
+
Hypodense
Died of recurrence ...
213+
1
3
+
+++
Hvpodense
...
190+
0
3
+
...
180+
I
4
+
+++
164+
2
4
++
+
Hypodense; calcification Hypodense; calcification Hypodense; calcification
Leukodystrophy
Tumor Appearance
Remarks Died of recurrence ...
... ...
VM 26 = epipodophyllotoxin; CCNU = chloroethyl-cyclohexyl-nitrosourea; PCB = procarbazine; BLM = bleomycin; + = slight; + + = moderate; + + + = marked; M = male; F = female.
90 SurgicalNeurology Vol 15 No 2 February 1981
Fig. 1. Patient 10. C T scan demonstrating marked cortical atrophy 30 months after operation.
Fig. 2. Patient 4. C T scan showing marked hydrocephalus with periventricular lucency 27 months after operation.
Fig. 3. Patient 11. C T scan showing marked hypodensity of the centrum semiovale 28 months after operation.
caused by secondary progressive dementia with radiological signs of diffuse cerebral atrophy and leukoencephalopathy. Ransohoff and co-workers [8] reported similar cases among patients of the Brain Tumor Study Group. Hochberg and Slomick [3] described progressive diffuse intellectual impairment in survivors with astrocytoma treated by radiotherapy and CCNU. Norman and associates [6] found
ventricular enlargement without obstruction in serial CT scans of 32% of patients with malignant gliomas undergoing chemotherapy and radiotherapy, and Marks and Gado [5] reported 24% in similarly treated cases. It is difficult to explain this clinical deterioration in the absence of CT scan evidence of tumor recurrence without histopathological examination, but the best explanation is radiation damage potentiated by chemotherapy. The potentially harmful effect of ionizing radiation on the central nervous system is well known [2, 4]. Results in the above-cited cases as well as in cases from the present study in which patients had been treated by radiation and cytostatic drugs suggest a synergistic toxic action of chemotherapy and irradiation. Poisson and colleagues [7] used VM 26 and CCNU prior to radiotherapy, and in their experience as well the chemotherapy seemed to potentiate the radiation effect on the central nervous system. Burger and co-authors [1] investigated the morphological effects of radiation administered therapeutically for intracranial gliomas in a postmortem study. Four of 17 patients who had received 5,000 to 6,000 rads developed radiation necrosis. Three of these 4 were treated with both irradiation and chemotherapy. These results again suggest a synergistic action. The radiation necrosis had a strong predilection for the white matter adjacent to the tumor with scant quantities of residual tumor and little mass effect. Degeneration of the white matter associated with varying degrees of gliosis suggestive of chronic cerebral edema was noted, in many of the radiated brains. These pathological changes within the white matter ipsilateral and contralateral to the neoplasm were again more pronounced in those patients who received radiation plus chemotherapy. The use of whole brain irradiation for high-grade astrocytomas is a widely accepted practice in radiotherapy. However, in a recent review of 417 intracranial astrocytomas treated radiotherapeutically at the Mayo Clinic from 1960 through 1969, Scanlon and Taylor [9] could not verify an increased effectiveness from the use of total brain irradiation for high-grade gliomas. In a CT study by Marks and Gado [5] of primary brain tumors following surgery, irradiation, and chemotherapy, the appearance of hydrocephalus as a result of cerebral atrophy in patients irradiated in large fields and its absence in patients irradiated in more limited fields suggested a relation between hydrocephalus and the more extensive radiation. In view of the risk of injury to surrounding cerebral tissues by commonly employed radiation techniques and given the better localization possibilities provided by modem CT methods, limited volume irradiation as opposed to whole brain radiotherapy should be reevaluated in a randomized study. The irradiation dose of 5,000 rads to the whole brain and an additional dose of 1,000 to 1,800 rads to the tumor used in our study was at the upper limit of the brain tolerance. The irradiation dosage may have to be reduced when it is combined
Seller: Multimodal Therapy of Astrocytomas
with cytostatic drugs because of the possible heightened toxicity. In combining whole brain radiotherapy and chemotherapy, the modest prolongation of survival time by this aggressive treatment should be weighed against the possible synergistic toxic action. Our analysis of the late results of a multimodality treatment demonstrates the limited value of measuring only the survival time in evaluating the effectiveness of brain tumor therapy. Each study measuring the oncolytic effect of any particular treatment for brain tumors should include repeated examinations of the patient's performance status along with sequential CT scans. References 1. Burger PC, Mahaley MS, Dudka L, Vogel FS: The morphologic effect of radiation administered therapeutically for intracranial gliomas. Cancer 44:1256-1272, 1979 2. Haldorff B: Radiation damage to the brain, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. New York: Elsevier-North Holland Pub. Co., 1975, Vol 23, pp 639-663 3. Hochberg FH, Slomick B: Neuropsychologic impairment in astrocytoma survivors. Neurology 30:172-177, 1980 4. Kramer S: The hazards of therapeutic irradiation of the central nervous system. Clin Neurosurg 15:301-318, 1968 5. Marks JE, Gado M: Serial CT of primary tumors following surgery, irradiation and chemotherapy. Radiology 125:119-125, 1977
91
6. Norman D, Enzmann DR, Levin VA, Wilson CB, Newton TH: Computed tomography in the evaluation of malignant glioma before and after therapy. Radiology 121:85-88, 1976 7. Poisson M, HauwJJ, Pouillart P, Bataini JP, Mashaly R, Pertuiset BF, Metzger J: Malignant gliomas treated after surgery by combination chemotherapy and delayed radiation therapy. Acta Neurochir (Wien) 51:27-42, 1979 8. Ransohoff J, Lieberman A, Walker MD: Multiple therapies in the management of malignant gliomas, in Paoletti P, Walker MD, Butti G, Knerich R (eds): Neurooncology. Vol 1, Multidisciplinary Aspects of Brain Tumor Therapy. New York: Elsevier-North Holland Pub. Co., 1979, pp 55-68 9. Scanlon PW, Taylor WF: Radiotherapy of intracranial astrocytomas: Analysis of 417 cases treated from 1960 through 1969. Neurosurgery 5:301-307, 1979 10. Seller RW, Greiner RH, Zimmermann A, Markwalder H: Radiotherapy combined with procarbazine, bleomycin and CCNU in the treatment of high-grade supratentorial astrocytomas, l Neurosurg 48:861-865, 1978 l 1. Seller RW, Vassella F, Markwalder H: Combination chemotherapy with VM 26 and CCNU in primary malignant brain tumors. Surg Neurol 11:237-242, 1979 12. Seller RW, ZimmermannA, Markwalder H: Adjuvant chemotherapy with VM 26 and CCNU after operation and radiotherapy for highgrade supratentorial astrocytomas. Surg Neurol 13:65-68, 1980 13. Walker MD, Alexander E, Jr, Hunt WE, MacCarty CS, Mahaley MS, Jr, Mealey J, Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative study. J Neurosurg 49:333, 1978
Fifty-one patients with histologically proved astrocytomas grades III and IV treated with postoperative irradiation and chemotherapy were evaluated with serial computerized tomo. graphic (CT) scans and with special regard to their functional state 30 months after operation. Fourteen patients (27.4%) are still alive, but only 7 of them have a good performance status. The impaired functional state of 6 (11.7%) of the other 7 patients was caused by a secondary progressive dementia with radioiogical signs of diffuse cerebral atrophy and leukoencephalopathy, but no signs of recurrent tumors. The best explanation for this is a synergistic toxic action of whole brain irradiation and chemotherapy. Measuring survival time for evaluation of brain tumor therapy is of limited value without examination of the performance status and sequential CT scans.
A significantly greater number of patients who had received a combination treatment of radiotherapy and BCNU (N,N.bis.[2-chloroethyl]-N-nitrosourea) survived at the end of 18 months, as compared to those patients who had only received radiation therapy after the operation [13]. Among the long-term survivors were patients with progressive neurological deterioration but without clear-cut radiological evidence of mass effect or recurrent tumors [8, 12]. When considering only survival time to evaluate the oncolytic effect of a particular treatment, these patients were included in the successfully treated group despite their poor functional state. However, the ultimate aim of any treatment is to prolong a good quality of survival. Therefore, we analyzed the long-term survivors of our two multimodality therapy studies [10, 12] with special regard to their functional state. The late effect of the treatment to the brain was investigated with serial computerized tomographic (CT) scans. Materials and Methods The long-term survival of 51 patients with histologically proven high-grade (Kernohan grades III and IV) supratenFrom the Departmentof Neurosurgery,UniversityHospital, Bern, Switzerland. Address reprint requeststo Dr. RolfW. Seller, NeurochirurgischeKlinik, Universitlitsspital, CH-3010 Bem, Switzerland. Keywords:astrocytoma;brainneoplasm;chemotherapy;radiationtherapy. 88
torial astrocytomas was evaluated. All patients had had a total or subtotal tumor resection, and postoperative radiotherapy was administered using standard techniques. The total brain was first covered with 2 to 4 fields with cobalt 60 to a dose of 5,000 rads. Then, using the rotating electron beam of the betatron (25 to 35 MeV), the dose to the tumor alone was increased by 5,000 to 6,800 rads. With daily fractions of 200 rads, the radiotherapy was administered over a period of 6 to 7 weeks, beginning 2 to 4 weeks after the operation. Twenty of these patients had been treated according to a protocol evaluating the effect of postoperative irradiation combined with procarbazine, bleomycin, and CCNU (chloroethyl-cyclohex~?l-nitrosourea) [10]. The median survival time was 56 weeks for the 20 patients who had received the combined treatment compared with 51 weeks for 32 previously treated patients who had received only postoperative radiotherapy limited to the tumor volume. At 18 months after operation, 8 of the combined treatment patients and 9 of the control patients were alive. There was no statistical difference in survival between the two groups of patients. The other 31 patients were treated according to a second protocol evaluating the effect of an adjuvant chemotherapy with epipodophyllotoxin (VM 26) and CCNU after operation and radiotherapy in a randomized study [ 12]. The median progression-free interval was 65.6 weeks for the chemotherapy group (15 patients) and 40 weeks for the control group ( 16 patients) without chemotherapy. The difference was not statistically significant. Most of the recurrent tumors of the control group were treated with combination chemotherapy with VM 26 and CCNU [11]. All of the patients from these two studies who were living 30 months or more after operation were examined with serial CT scans with special regard to their functional state. The performance status was graded according to the criteria in Table 1 and compared to the functional state 3 months postoperatively. The 32 previously treated control patients of the first study could not be evaluated because CT was not available at that time. Results Thirty months after operation, 14 of the 51 patients (27.4%) were still alive. The pertinent clinical data of the long-term survivors are summarized in Table 2. Seven pa-
0090-3019/81/020088-04501.25 © 1980 by Little, Brown and Company (Inc.)
Seller: Multimodal Therapy of Astrocytomas 89
Table 1. Grading of Performance Status Grade 0
in all cases. Three patients showed marked signs of leukoencephalopathy with hypodensity of the centrum semiovale and periventricular lucency (Fig. 3). No autopsy could be obtained of the patient who died of pneumonia.
Criteria for Performance Status Fully active
I II III IV
A m b u l a t o r y , c a p a b l e of light w o r k I n b e d u n d e r 50% o f t i m e , c a p a b l e of self-care I n b e d o v e r 50% of t i m e , l i m i t e d self-care Bedridden
tients (13.7%) are in a good functional state, being fully active or capable of part-time work. Only 1 of the 7 patients in a bad functional state had a proven tumor recurrence. The other 6 patients (11.7%) showed a slowly deteriorating course, starting between 1 and 2 years after the operation. It was characterized by a progressive psychoorganic syndrome without focal neurological symptoms or signs of increased intracranial pressure. In serial CT scans there was no evidence of recurrent tumors or progressive hydrocephalus. All patients had some degree of cortical atrophy or hydrocephalus ag a result of cerebral atrophy (Figs. I and 2). Tumor location was hypodense without enhancement
Discussion More than one quarter of all evaluated patients are still alive 2Y2 years after surgery. This high survival rate for malignant astrocytomas may be due to the aggressive treatment but also must be attributed to the selection of goodrisk cases in the second study. Only half of the long-term survivors are in a good functional state. The poor performance status of the others was not due to the primary brain lesion, because 3 months after operation all of these patients were in an improved condition. Most of them had had a frontal tumor, but an equal number of patients with good performance status also had had frontal tumors and corresponding hypodense tumor areas in the later CT scan (see Table 2). Tumor recurrence could not be demonstrated either clinically or radiologically except in one case, and metabolic difficulties and progressive hydrocephalus could be excluded. The poor functional state of these patients was
Table 2. S u m m a r y of Clinical Data
Patient
Age/Sex (Years)
1
25/F
2
29/M
3
30/F
4
32/F
5
36/M
6
39/M
7
45/F
8
50/M
9
54/F
10
55/M
11
56/M
12
56/M
13
61/F
14
62/F
Tumor Grade and Location
Radiotherapy (rads)
IV, left frontal Ill, left frontal IV, left frontal
6,600
IV, right frontal 111, right frontal 111, right frontal IV, right frontal III, left frontal III, right temporal Ill, left frontal IV, left frontal Ill, left frontal II1, right frontal Ill, right occipital
6,500 6,500
6,300 6,480 6,450 5,820 6,060 6,800 6,300 6,600 6,695 6,240 6,180
Chemotherapy VM 26, CCNU ... CCNU, PCB, BLM, VM 26 CCNU, VM 26 CCNU, PCB, BLM CCNU, PCB, BLM ... VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU VM 26, CCNU
CT Findings 30 Months Postop.
Postop. Survival (Weeks)
Performance Status 3 Months Postop.
Performance Status 30 Months Postop.
Atrophy
165
0
0
...
Hypodense
130+
0
0
...
Hypodense
260+
0
0
...
Hypodense; calcification
...
149
3
4
++
+++
Hypodense
251+
3
l
++
++
Hypodense; calcification
Died of pneumonia ...
186
1
1
+
Hypodense
178+
0
0
...
Hypodense
Died of meningitis ...
162+
1
1
++
Hypodense
...
172
2
3
+
+
Hypodense
220+
2
4
+++
+
Hypodense
Died of recurrence ...
213+
1
3
+
+++
Hvpodense
...
190+
0
3
+
...
180+
I
4
+
+++
164+
2
4
++
+
Hypodense; calcification Hypodense; calcification Hypodense; calcification
Leukodystrophy
Tumor Appearance
Remarks Died of recurrence ...
... ...
VM 26 = epipodophyllotoxin; CCNU = chloroethyl-cyclohexyl-nitrosourea; PCB = procarbazine; BLM = bleomycin; + = slight; + + = moderate; + + + = marked; M = male; F = female.
90 SurgicalNeurology Vol 15 No 2 February 1981
Fig. 1. Patient 10. C T scan demonstrating marked cortical atrophy 30 months after operation.
Fig. 2. Patient 4. C T scan showing marked hydrocephalus with periventricular lucency 27 months after operation.
Fig. 3. Patient 11. C T scan showing marked hypodensity of the centrum semiovale 28 months after operation.
caused by secondary progressive dementia with radiological signs of diffuse cerebral atrophy and leukoencephalopathy. Ransohoff and co-workers [8] reported similar cases among patients of the Brain Tumor Study Group. Hochberg and Slomick [3] described progressive diffuse intellectual impairment in survivors with astrocytoma treated by radiotherapy and CCNU. Norman and associates [6] found
ventricular enlargement without obstruction in serial CT scans of 32% of patients with malignant gliomas undergoing chemotherapy and radiotherapy, and Marks and Gado [5] reported 24% in similarly treated cases. It is difficult to explain this clinical deterioration in the absence of CT scan evidence of tumor recurrence without histopathological examination, but the best explanation is radiation damage potentiated by chemotherapy. The potentially harmful effect of ionizing radiation on the central nervous system is well known [2, 4]. Results in the above-cited cases as well as in cases from the present study in which patients had been treated by radiation and cytostatic drugs suggest a synergistic toxic action of chemotherapy and irradiation. Poisson and colleagues [7] used VM 26 and CCNU prior to radiotherapy, and in their experience as well the chemotherapy seemed to potentiate the radiation effect on the central nervous system. Burger and co-authors [1] investigated the morphological effects of radiation administered therapeutically for intracranial gliomas in a postmortem study. Four of 17 patients who had received 5,000 to 6,000 rads developed radiation necrosis. Three of these 4 were treated with both irradiation and chemotherapy. These results again suggest a synergistic action. The radiation necrosis had a strong predilection for the white matter adjacent to the tumor with scant quantities of residual tumor and little mass effect. Degeneration of the white matter associated with varying degrees of gliosis suggestive of chronic cerebral edema was noted, in many of the radiated brains. These pathological changes within the white matter ipsilateral and contralateral to the neoplasm were again more pronounced in those patients who received radiation plus chemotherapy. The use of whole brain irradiation for high-grade astrocytomas is a widely accepted practice in radiotherapy. However, in a recent review of 417 intracranial astrocytomas treated radiotherapeutically at the Mayo Clinic from 1960 through 1969, Scanlon and Taylor [9] could not verify an increased effectiveness from the use of total brain irradiation for high-grade gliomas. In a CT study by Marks and Gado [5] of primary brain tumors following surgery, irradiation, and chemotherapy, the appearance of hydrocephalus as a result of cerebral atrophy in patients irradiated in large fields and its absence in patients irradiated in more limited fields suggested a relation between hydrocephalus and the more extensive radiation. In view of the risk of injury to surrounding cerebral tissues by commonly employed radiation techniques and given the better localization possibilities provided by modem CT methods, limited volume irradiation as opposed to whole brain radiotherapy should be reevaluated in a randomized study. The irradiation dose of 5,000 rads to the whole brain and an additional dose of 1,000 to 1,800 rads to the tumor used in our study was at the upper limit of the brain tolerance. The irradiation dosage may have to be reduced when it is combined
Seller: Multimodal Therapy of Astrocytomas
with cytostatic drugs because of the possible heightened toxicity. In combining whole brain radiotherapy and chemotherapy, the modest prolongation of survival time by this aggressive treatment should be weighed against the possible synergistic toxic action. Our analysis of the late results of a multimodality treatment demonstrates the limited value of measuring only the survival time in evaluating the effectiveness of brain tumor therapy. Each study measuring the oncolytic effect of any particular treatment for brain tumors should include repeated examinations of the patient's performance status along with sequential CT scans. References 1. Burger PC, Mahaley MS, Dudka L, Vogel FS: The morphologic effect of radiation administered therapeutically for intracranial gliomas. Cancer 44:1256-1272, 1979 2. Haldorff B: Radiation damage to the brain, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. New York: Elsevier-North Holland Pub. Co., 1975, Vol 23, pp 639-663 3. Hochberg FH, Slomick B: Neuropsychologic impairment in astrocytoma survivors. Neurology 30:172-177, 1980 4. Kramer S: The hazards of therapeutic irradiation of the central nervous system. Clin Neurosurg 15:301-318, 1968 5. Marks JE, Gado M: Serial CT of primary tumors following surgery, irradiation and chemotherapy. Radiology 125:119-125, 1977
91
6. Norman D, Enzmann DR, Levin VA, Wilson CB, Newton TH: Computed tomography in the evaluation of malignant glioma before and after therapy. Radiology 121:85-88, 1976 7. Poisson M, HauwJJ, Pouillart P, Bataini JP, Mashaly R, Pertuiset BF, Metzger J: Malignant gliomas treated after surgery by combination chemotherapy and delayed radiation therapy. Acta Neurochir (Wien) 51:27-42, 1979 8. Ransohoff J, Lieberman A, Walker MD: Multiple therapies in the management of malignant gliomas, in Paoletti P, Walker MD, Butti G, Knerich R (eds): Neurooncology. Vol 1, Multidisciplinary Aspects of Brain Tumor Therapy. New York: Elsevier-North Holland Pub. Co., 1979, pp 55-68 9. Scanlon PW, Taylor WF: Radiotherapy of intracranial astrocytomas: Analysis of 417 cases treated from 1960 through 1969. Neurosurgery 5:301-307, 1979 10. Seller RW, Greiner RH, Zimmermann A, Markwalder H: Radiotherapy combined with procarbazine, bleomycin and CCNU in the treatment of high-grade supratentorial astrocytomas, l Neurosurg 48:861-865, 1978 l 1. Seller RW, Vassella F, Markwalder H: Combination chemotherapy with VM 26 and CCNU in primary malignant brain tumors. Surg Neurol 11:237-242, 1979 12. Seller RW, ZimmermannA, Markwalder H: Adjuvant chemotherapy with VM 26 and CCNU after operation and radiotherapy for highgrade supratentorial astrocytomas. Surg Neurol 13:65-68, 1980 13. Walker MD, Alexander E, Jr, Hunt WE, MacCarty CS, Mahaley MS, Jr, Mealey J, Jr, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative study. J Neurosurg 49:333, 1978