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Localized shaped field radiotherapy of malignant glioblastoma multiforme
Int. 3. R-n
Oncolosy
Bid.
Phys..
15%. Vol.
1, pp. 713716.
Peqmmon
Press.
Printed
in the U.S.A.
??Brief Communications LOCALIZED SHAPED FIELD RADIOTHERAPY OF MALIGNANT GLIOBLASTOMA MULTIFORME ANDRE?DE SCHRWER, M.D.,? TORGNY GREITZ, M.D.* and NILS FORSBY, M.D.8 KarolinskaHospital,Stockholm,6OSweden
and ARNE BRUN, M.D. Institute of Pathology, University
Glioblastemamukfforme, Radiotherapy,
of Lund,
Sweden
Anatomic hnlization.
INTRODUCTION The value of postoperative radiotherapy in the treatment of high-grade astrocytoma still does not seem to be generally accepted,6 although most authors would agree that irradiation may prolong useful life for at least a limited number of patients.‘J9 Results at this hospital, during the period from 1958 to 1966,’being at least as poor as in most other places, it was agreed, together with neurosurgeons and neuroradiologists, to concentrate all common efforts on optimizing the established method (surgery plus irradiation).
histologically confirmed diagnosis of astrocytoma Grades 3 or 4, with the exception of 4 in whom biopsy had been considered unfeasible because of the anatomical site of
the lesion. In the absence of post-mortem data, diagnosis of malignant gliomatous tumor was based, in these cases, on augiographic criteria such as neoplastic vessels, shunting veins, in conjunction with a positive scan and the absence of signs pointing to extracranial malignancy. Ages ranged from 29 to 68 years (median: 51 years). There were 23 males and 25 females. Because of the heavy treatment load on the available high-voltage facilities, some selection was considered unavoidable and only patients who could be considered for surgery in the first place (unless inoperability was determined by the location of the disease in a nonresectable part of the brain) and were not unconscious or wholly hemiparetic or otherwise incapable of some collaboration were considered for full course megavoltage radiotherapy. During the period covered by this study, 16 patients (25% of all those seen) were refused for megavoltage treatment. They were not included in this study. All patients
?Present address, reprint requests to: And& de Schryver, M.D., Kliniek Voor Radiotherapie en Kemgeneeskunde, 9000 Gent, de Pintelaan 135,
Belgium. *Department of Neuroradiology. 9Department of Tumor Pathology.
METHODS AND MATERIALS The patients The 48 patients entering this series all had a
713
714
Radiation Oncology ??Biology 0 Physics
1976, Vol. 1, Number 7 and Number 8
were available for 1 year follow up, 35 for 2 years and 24 for 3 years. None were lost. Pathology The histological material consisted of sec-
tions stained with hematoxylineosin, van Gieson’s stain for connective tissue and, in a few cases, phosphotungstic acid-hematoxylin for neuroglial fibrils. All slides were reviewed blindly by two pathologists (N. Forsby and A. Brun-authors). The gliomas were graded according to the classification of Kemohan and Sayre,’ the most anaplastic part of the section determining the grade of malignancy. As others,‘**we have used the term “glioblastoma” throughout as synonymous with “high grade” or “Grades 3 and 4” astrocytoma. Treatment
In 36 patients, radiation therapy was given as a postoperative course; in 12, radiotherapy was the only treatment. Radiation was given either with a 6 MeV linear accelerator or with a @Co unit, the total dose being 5000 rad in 6 weeks with daily increments of 175 rad, one field being treated per day. The target zone was determined by the neuroradiologist from AP and lateral postoperative angiograms, augmented with a 2-3 cm wide margin; it included, in operated patients, the angiographically “silent” zone, corresponding to the resected tissue (Fig. 1). Treatments were given with the patient immobilized in a mould, port lilxns being run for each field at least three times during the course of the treatment series. Patients were not on corticosteroids as a routine, but only if necessary. Seven patients received between 1 and 7 oral courses of CCNU (l-(2 chloroethyl)-3cyclohexyl-lnitrosourea) (130 mg/m*) while showing signs of progressive disease.
Fig. 1. Example of dose distribution. A, volume corresponding to radio@ical extent of tumor; B, added marginal volume.
RESULTS A total of 27 patients were classified as having Grade 4 or 3-4 astrocytoma, while 17 were given Grade 3. The survival figures are ‘5; summarized in Fig. 2 (curve A). Of 48, 31 YEARS (64%) survived for at least 1 year, while 15 of Fig. 2. Survival curves. A, present material; B, 35 (43%) survived for 2 years and 8 of 24 for 3 same corrected for chemotherapy (patients having years (33%). The overall median survival was received CCNU considered dead from that mo15 months. For the 12 patients whose sole ment); C, the 1933-66material.’
Radiotherapy of malignantglioblastomamultiforme
Table 1. Comparison
0 A.
DE SCHRWER et al.
715
between the 1958-66 and present materials
No. of patients with final diagnosis of high-grade supratentorial astrocytoma accepted for full course supervoltage radiotherapy. Median age One-year survival rate Two-year survival rate No. of patients with clinically and radiologically suspected high-grade supratentorial astrocytomat refused for full course supervoltage radiotherapy
1958-66
1970-73
23
48
53 yr 43% 9% 16(41%)
51 yr 64% 43% 16(25%)
(per cent of total no. of cases seen) tBecause
of the patient’s poor condition, excisional biopsy is mostly lacking.
treatment consisted of radiotherapy, median survival was 11.5 months against 15.5 months for those who received both surgery and irradiation. For Grade 3 cases, median survival was 21 months and for the 3-4 or 4 patients, 12 months. The four patients with radiological diagnosis only, survived for 12, ‘16,34 and 50 months, respectively. In order to exclude any beneficial effect CCNU might have had on survival, a separate curve was obtained where the 7 patients having received the drug were supposed to have died the moment they received their first course (Fig. 2, curve B). In fact, there was no difference, indicating that CCNU, as used in these patients, did not improve overall survival. DISCUSSION It would appear that the results obtained in this, admittedly small, series are better than in “purely surgical” ones, for whom a median survival time of 4.5 months has been calculated by Walkers in a compiled study of over 2ooO cases. There is, of course, no way to know whether the radiation parameters used were optimal. Systematic treatment of a larger volume, for example the total brain, could of course be considered in view of the infiltrative nature of these tumors,’ and has, in fact, been recommended by Concannon et al.* Furthermore, a higher dose than 5000 rad in 6 weeks
can probably be given safely to a restricted target volume. The fact that CCNU did not improve survival markedly did not come as a surprise since it was given to a few patients only and, in those, uniformly late in the course of the disease. On comparing the present survival figures with those obtained at this same hospital a few years ago (Fig. 2, curve C), the differences are obvious and require some explanation. A marked shift in pathological grading seems unlikely as both sets of slides were examined by pathologists belonging to the same institute. If anything, the present grading would probably result in a less favorable selection than in the previous series. Surgical techniques were similar. Patient selection was more liberal than in the earlier series where 16 cases (41% of all patients seen) were refused for treatment, against only 25% with our present policy (Table 1). In our opinion, only some degree of improvement in the quality of the radiotherapy given, is likely to explain the differences in survival curves. In fact, since the previous series was treated, a number of changes in the treatment set-up were introduced such as postoperative angiograms for the reevaluation of the tumor volume, the strict immobilization of the patient in a perspex mould and the running of repeated simulator films.
REFERENCES 1. Bloom,
H.J.G., Peckham, M-J., Richardson, A.E., Alexander, P.A., Payne, P.M.: Glioblastoma multiforme: a controlled trial to assess the
value of specific immunotherapy in patients treated by radical surgery and radiotherapy. Br. J. Cancer 27; 253-267, 1973.
716
Radiation Oncology ??Biology 0 Physics
2. Bouchard, J.: Radiotherapy in the management of primary brain tumors. Ann. N.Y. Acad. Sci. 159: 563-570,1%9. 3. Bull, J.W.D., Rovit, R.L.: The radiographic localixation of intracerebral gliomata. J. Fat. Radiol. 8: 147-157, 1957. 4. Concannon, J.P., Kramer, S., Berry, R.: The extent of intracranial gliomata at autopsy and its relationship to techniques used in radiation therapy of brain tumors. Am. J. Roentgenol. 84: 99-lcr7,1960. 5. Kernohan, J.W., Sayre, G.P.: Tumors of the central nervous system. In Atlas of Tumor Pathology, Section X, Fascicles 35 and 37, Washington D.C., Armed Forces Institute of
1976, Vol. 1, Number 7 and Number 8
Pathology, 1952. 6. Segelov, J.N., Vanderfield, G.K., Gye, R.S., Morson, S.M.: The value of treatment of cerebral tumours. Med. I. Aus?. 2: 48-53,1%7. 7. Stenberg, B., Moberg, A.: Radiotherapy of intracerebral astrocytomas. Acta Radio/. Ther. Phys. Biol. 10: 27-32, 1971. 8. Walker, M.D.: Brain and peripheral nervous system tumors. In Cancer Medicine, ed. by’ Holland, J.F., Frei, E.,III. Philadelphia, Lea & Febiger, 1973, pp. 1385-1401. 9. Weir, B.: The relative signkance of factors affecting postoperative survival in astrocytomas grades 3 and 4. J. Neurosurg. 38: 448-452, 1973.
Oncolosy
Bid.
Phys..
15%. Vol.
1, pp. 713716.
Peqmmon
Press.
Printed
in the U.S.A.
??Brief Communications LOCALIZED SHAPED FIELD RADIOTHERAPY OF MALIGNANT GLIOBLASTOMA MULTIFORME ANDRE?DE SCHRWER, M.D.,? TORGNY GREITZ, M.D.* and NILS FORSBY, M.D.8 KarolinskaHospital,Stockholm,6OSweden
and ARNE BRUN, M.D. Institute of Pathology, University
Glioblastemamukfforme, Radiotherapy,
of Lund,
Sweden
Anatomic hnlization.
INTRODUCTION The value of postoperative radiotherapy in the treatment of high-grade astrocytoma still does not seem to be generally accepted,6 although most authors would agree that irradiation may prolong useful life for at least a limited number of patients.‘J9 Results at this hospital, during the period from 1958 to 1966,’being at least as poor as in most other places, it was agreed, together with neurosurgeons and neuroradiologists, to concentrate all common efforts on optimizing the established method (surgery plus irradiation).
histologically confirmed diagnosis of astrocytoma Grades 3 or 4, with the exception of 4 in whom biopsy had been considered unfeasible because of the anatomical site of
the lesion. In the absence of post-mortem data, diagnosis of malignant gliomatous tumor was based, in these cases, on augiographic criteria such as neoplastic vessels, shunting veins, in conjunction with a positive scan and the absence of signs pointing to extracranial malignancy. Ages ranged from 29 to 68 years (median: 51 years). There were 23 males and 25 females. Because of the heavy treatment load on the available high-voltage facilities, some selection was considered unavoidable and only patients who could be considered for surgery in the first place (unless inoperability was determined by the location of the disease in a nonresectable part of the brain) and were not unconscious or wholly hemiparetic or otherwise incapable of some collaboration were considered for full course megavoltage radiotherapy. During the period covered by this study, 16 patients (25% of all those seen) were refused for megavoltage treatment. They were not included in this study. All patients
?Present address, reprint requests to: And& de Schryver, M.D., Kliniek Voor Radiotherapie en Kemgeneeskunde, 9000 Gent, de Pintelaan 135,
Belgium. *Department of Neuroradiology. 9Department of Tumor Pathology.
METHODS AND MATERIALS The patients The 48 patients entering this series all had a
713
714
Radiation Oncology ??Biology 0 Physics
1976, Vol. 1, Number 7 and Number 8
were available for 1 year follow up, 35 for 2 years and 24 for 3 years. None were lost. Pathology The histological material consisted of sec-
tions stained with hematoxylineosin, van Gieson’s stain for connective tissue and, in a few cases, phosphotungstic acid-hematoxylin for neuroglial fibrils. All slides were reviewed blindly by two pathologists (N. Forsby and A. Brun-authors). The gliomas were graded according to the classification of Kemohan and Sayre,’ the most anaplastic part of the section determining the grade of malignancy. As others,‘**we have used the term “glioblastoma” throughout as synonymous with “high grade” or “Grades 3 and 4” astrocytoma. Treatment
In 36 patients, radiation therapy was given as a postoperative course; in 12, radiotherapy was the only treatment. Radiation was given either with a 6 MeV linear accelerator or with a @Co unit, the total dose being 5000 rad in 6 weeks with daily increments of 175 rad, one field being treated per day. The target zone was determined by the neuroradiologist from AP and lateral postoperative angiograms, augmented with a 2-3 cm wide margin; it included, in operated patients, the angiographically “silent” zone, corresponding to the resected tissue (Fig. 1). Treatments were given with the patient immobilized in a mould, port lilxns being run for each field at least three times during the course of the treatment series. Patients were not on corticosteroids as a routine, but only if necessary. Seven patients received between 1 and 7 oral courses of CCNU (l-(2 chloroethyl)-3cyclohexyl-lnitrosourea) (130 mg/m*) while showing signs of progressive disease.
Fig. 1. Example of dose distribution. A, volume corresponding to radio@ical extent of tumor; B, added marginal volume.
RESULTS A total of 27 patients were classified as having Grade 4 or 3-4 astrocytoma, while 17 were given Grade 3. The survival figures are ‘5; summarized in Fig. 2 (curve A). Of 48, 31 YEARS (64%) survived for at least 1 year, while 15 of Fig. 2. Survival curves. A, present material; B, 35 (43%) survived for 2 years and 8 of 24 for 3 same corrected for chemotherapy (patients having years (33%). The overall median survival was received CCNU considered dead from that mo15 months. For the 12 patients whose sole ment); C, the 1933-66material.’
Radiotherapy of malignantglioblastomamultiforme
Table 1. Comparison
0 A.
DE SCHRWER et al.
715
between the 1958-66 and present materials
No. of patients with final diagnosis of high-grade supratentorial astrocytoma accepted for full course supervoltage radiotherapy. Median age One-year survival rate Two-year survival rate No. of patients with clinically and radiologically suspected high-grade supratentorial astrocytomat refused for full course supervoltage radiotherapy
1958-66
1970-73
23
48
53 yr 43% 9% 16(41%)
51 yr 64% 43% 16(25%)
(per cent of total no. of cases seen) tBecause
of the patient’s poor condition, excisional biopsy is mostly lacking.
treatment consisted of radiotherapy, median survival was 11.5 months against 15.5 months for those who received both surgery and irradiation. For Grade 3 cases, median survival was 21 months and for the 3-4 or 4 patients, 12 months. The four patients with radiological diagnosis only, survived for 12, ‘16,34 and 50 months, respectively. In order to exclude any beneficial effect CCNU might have had on survival, a separate curve was obtained where the 7 patients having received the drug were supposed to have died the moment they received their first course (Fig. 2, curve B). In fact, there was no difference, indicating that CCNU, as used in these patients, did not improve overall survival. DISCUSSION It would appear that the results obtained in this, admittedly small, series are better than in “purely surgical” ones, for whom a median survival time of 4.5 months has been calculated by Walkers in a compiled study of over 2ooO cases. There is, of course, no way to know whether the radiation parameters used were optimal. Systematic treatment of a larger volume, for example the total brain, could of course be considered in view of the infiltrative nature of these tumors,’ and has, in fact, been recommended by Concannon et al.* Furthermore, a higher dose than 5000 rad in 6 weeks
can probably be given safely to a restricted target volume. The fact that CCNU did not improve survival markedly did not come as a surprise since it was given to a few patients only and, in those, uniformly late in the course of the disease. On comparing the present survival figures with those obtained at this same hospital a few years ago (Fig. 2, curve C), the differences are obvious and require some explanation. A marked shift in pathological grading seems unlikely as both sets of slides were examined by pathologists belonging to the same institute. If anything, the present grading would probably result in a less favorable selection than in the previous series. Surgical techniques were similar. Patient selection was more liberal than in the earlier series where 16 cases (41% of all patients seen) were refused for treatment, against only 25% with our present policy (Table 1). In our opinion, only some degree of improvement in the quality of the radiotherapy given, is likely to explain the differences in survival curves. In fact, since the previous series was treated, a number of changes in the treatment set-up were introduced such as postoperative angiograms for the reevaluation of the tumor volume, the strict immobilization of the patient in a perspex mould and the running of repeated simulator films.
REFERENCES 1. Bloom,
H.J.G., Peckham, M-J., Richardson, A.E., Alexander, P.A., Payne, P.M.: Glioblastoma multiforme: a controlled trial to assess the
value of specific immunotherapy in patients treated by radical surgery and radiotherapy. Br. J. Cancer 27; 253-267, 1973.
716
Radiation Oncology ??Biology 0 Physics
2. Bouchard, J.: Radiotherapy in the management of primary brain tumors. Ann. N.Y. Acad. Sci. 159: 563-570,1%9. 3. Bull, J.W.D., Rovit, R.L.: The radiographic localixation of intracerebral gliomata. J. Fat. Radiol. 8: 147-157, 1957. 4. Concannon, J.P., Kramer, S., Berry, R.: The extent of intracranial gliomata at autopsy and its relationship to techniques used in radiation therapy of brain tumors. Am. J. Roentgenol. 84: 99-lcr7,1960. 5. Kernohan, J.W., Sayre, G.P.: Tumors of the central nervous system. In Atlas of Tumor Pathology, Section X, Fascicles 35 and 37, Washington D.C., Armed Forces Institute of
1976, Vol. 1, Number 7 and Number 8
Pathology, 1952. 6. Segelov, J.N., Vanderfield, G.K., Gye, R.S., Morson, S.M.: The value of treatment of cerebral tumours. Med. I. Aus?. 2: 48-53,1%7. 7. Stenberg, B., Moberg, A.: Radiotherapy of intracerebral astrocytomas. Acta Radio/. Ther. Phys. Biol. 10: 27-32, 1971. 8. Walker, M.D.: Brain and peripheral nervous system tumors. In Cancer Medicine, ed. by’ Holland, J.F., Frei, E.,III. Philadelphia, Lea & Febiger, 1973, pp. 1385-1401. 9. Weir, B.: The relative signkance of factors affecting postoperative survival in astrocytomas grades 3 and 4. J. Neurosurg. 38: 448-452, 1973.