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High dose radiation therapy in the treatment of malignant gliomas: Final Report
036&3Ol6/79/lOOl-1733$02.00/O
Inl. J. Radiation Oncology Biol. Phys Vol. 5. pp 1733-1740 OPergamon Press Ltd.1979. Printed in the U S.A.
l Original Contribution HIGH DOSE RADIATION THERAPY IN THE TREATMENT MALIGNANT GLIOMAS: FINAL REPORT”?
OMAR M.
SALAZAR,
M.D.,’ PHILIP RUBIN, M.D.,2 MICHAEL and ROBERT PIZZUTIELLO, M.S.4
OF
L. FELDSTEIN,
Ph.D.3
University of Rochester Cancer Center, 601 Elmwood Avenue, Rochester, New York 14642, U.S.A. One hundred patients with supratentorial malignant gliomas were prescribed to receive postoperative whole brain irradiation with doses A000 rad; 41 had astrocytoma grade III and 59 had grade IV tumors. The median survival was 91 weeks for patients with grade III tumors and only 42 weeks for those with grade IV (p < 0.01). For both grades, patients who were 545 years of age survived significantly better than patients who were older at diagnosis (p < 0.05). Patients with tumors at each grade were divided into three groups depending on the total dose delivered to the tumor; 5000,6000,7500 rad (median doses). For patients with grade IV tumors the median survival was 30, 42 and 56 weeks respectively; these differences were significant (p < 0.05) between the extremes hut not between consecutive dose groups and were maintained only up to 2 years from the initiation of treatment. For patients with grade III tumors, the median survival was 43,82 and 204 weeks respectively; these differences were significant (p < 0.05) between consecutive dose groups and between extremes and were maintained up to 4 years from the initiation of treatment. For 22 patients with grade IV who were treated with high-doses (7500 rad), the median time for recurrence was 43 weeks while for six patients with grade III tumors it was 158 weeks. The use of higher radiation doses was well tolerated; it did not compromise the quality of survival, and did not yield normal brain tissue necrosis. However, these doses did not seem to alter the total survival of patients, nor did they seem capable of sterilizing these tumors. Histopathological changes that were observed in normal brain tissue that was irradiated with 7000-8000 rad suggest that increasing total doses beyond this range might attain tumor sterilization, but could also lead to frank radiation necrosis in these patients. Radiation therapy, Malignant Gliomas, Glioblastoma multiforme, CNS radiation tolerance INTRODUCTION
increased the median survival of patients by 150%.14 However, the optimum dose required to control these aggressive tumors has not been firmly established. The present attempt to explore radiation therapy beyond conventional doses (5000-6000 rad) was initiated in 1972 as a high-risk pilot study prior to a randomized protocol which was recently completed by two national cooperative group& The rationale to explore higher doses was based on the concept of the equivalent area dose (EAD). EAD postulates that in order to achieve the maximum tumor control with acceptable normal tissue damage, high-dose schedules beyond conventional doses should be employed in a protracted fashion.” A prelimi-
Malignant gliomas of the brain constitute some of the most aggressive and rapidly disabling neoplasia in humans. Although the use of postoperative irradiation in these tumors is much debated, currently it constitutes one of the most important modalities in management of these tumors. In a recently completed randomized study by the Brain Tumor Study Group (BTSG), patients who received only conventional care following surgical resection had a median survival of 14 weeks; the median survival was 35 weeks for those who received postoperative whole brain irradiation with 5000-6000 rad. These results clearly demonstrated that radiation therapy *This paper was presented at the 20th Annual meeting of the American Society of Therapeutic Radiologists, Los Angeles,
ance in Radiation Physics, Michael Sortino in Biostatistics; Doris Commons and Laura Klinkon typed and edited the manuscript. Joseph V. McDonald, M.D. (Chief, Division of Neurosurgery) provided assistance and guidance. Reprint Requests to: O.M. Salazar, M.D. Accepted for publication 17 August 1979. *Radiation Therapy Oncology Group (RTOG No. 74-01) and Eastern Cooperative Oncology Group (ECOG No. 1374) Malignant Glioma Protocol. Available from RTOG Operations Office, Thomas Jefferson University Hospital, 1015 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
California, (October 31&November 4, 1978). tsupported in part by National Cancer Institute grants CA 11051 andCA 11198 ‘Associate Professor of Radiation Oncology, Division of Radiation Oncology 2Professor and Chairman, Division of Radiation Oncology ‘Assistant Professor of Oncology in Biostatistics & Statistics 41nstructor in Radiation Oncology, Radiation Physics Section, Division of Radiation Oncology Acknowledgements-Bowen Keller provided technical assist1733
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nary report published early in 1976” observed that high doses (>6000 rad) in grade IV astrocytomas seemed to increase the median survival somewhat, but appeared to have no effect on the overall survival of patients. At that time, cases of grade III tumors were too few in number for preliminary evaluation. After 1975, however, more patients were treated, and enough time has now elapsed to make firmer observations. Subsequent to the first report, we have been able to redefine dose ranges and now we consider very high doses only those that are ~7000 rad. At the same time, we have also expanded the scope of our study. In an attempt to correlate an increase in the total dose delivered with increases in survival, patients who had been treated for the past 15 years in our Division with whole brain ~5000 rad were included as a retrospective control group. Their data was analyzed according to the total doses received. This paper reports the outcome of our search for an optimal dose of radiation delivered with conventional fractionation for patients with malignant gliomas. Throughout this effort, optimum radiation has been understood as constituting maximal tumor cell kill with minimal normal brain necrosis, since such injury is synonymous with treatment failure. This report emphasizes the use of very high doses of radiation and indicates areas of special significance which should be considered in subsequent studies. METHODS
AND MATERIALS
One hundred patients with histologically confirmed supratentorial malignant gliomas were treated in the Division of Radiation Oncology, University of Rochester Cancer Center between January 1, 1963 and December 31, 1977. All patients were prescribed postoperative irradiation with whole brain doses of 5000 rad or more, with or without supplementary booster doses to the primary target. All patients were included in the series irrespective of whether they were able to complete the total prescribed treatment. During the 15-year span encompassed in the study, patients who were treated in our Division and who either were prescribed smaller doses, or actually were treated with partial brain fields, were excluded from the present analysis; a report regarding these patients has been published.” Patients were divided into groups according to the total radiation dose delivered to the tumor. These groups are: (1) The very-high-dose (VHD) group consisted of 28 patients who received 5000-6000 rad of whole brain irradiation plus an additional booster to the primary target for total doses that were r7000-18000 rad. This group constitutes the central focus of this report; it consists of consecutive patients with malignant gliomas *Eastern Cooperative Oncology (ECOG No. PA-578) Pilot for the Use of High-Dose Radiation Therapy and LowDose (Pulsed) BCNU in Malignant Gliomas. Available from
Study
October
1979, Volume 5, Number
10
who were treated in our Division from January 1972 to December 1976. (2) The median-high-dose (MHD) group consisted of 27 patients who received 6000 rad whole brain irradiation with or without a supplementary booster for total doses that were r5000-16500 rad. Patients in this dose-group were not consecutive patients and represent a retrospective control group. (3) The conventional-dose (CD) group with 34 patients who received whole brain doses ~5000&<5500 rad. Like those in the MHD, patients in this dose-group were not consecutive patients, and represent a retrospective control group. (4) The remaining 11 patients were treated with highdose irradiation (6000 rad to the whole brain plus a boost of 1000 rad to the target volume) and low-dose (20 mg/kg) k,3-bis(2-Chlorethyl)1-Nitrosourea (BCNU) pulsed 15 hours before the next radiation fraction, twice weekly for 6 weeks. These 11 patients comprised consecutive patients with malignant gliomas who were seen in our Division since January 1977 and who were eligible for a high-risk pilot study for the Eastern Cooperative Oncology Group.* They were purposely excluded from most survival calculations in this report and will constitute the subject of a separate publication.* All patients underwent surgical resection and were subsequently treated with megavoltage teletherapy equipment delivering photon radiation to source-skindistances (SSD) of 80 cm or more with five weekly fractions of 150-200 rad each. An attempt was made to define the tumor volume precisely. Thus, during the last 61/2years of the study in most patients head contours were taken for tumor localization and computerized dosimetry. Booster fields were arranged either as wedged or parallel-opposed fields according to criteria that were published previously.” All fields were treated daily. Most patients had serial isotope brain scans during the course of their ailment. Computerized axial tomography (CAT) scanning of the head was added to the armamentarium of diagnostic and follow-up tests during the last 3 years of the study. The follow-up was complete and lasted until death of the patient or to the closing date of this report (December 3 1, 1978). The minimum follow-up time was 12 months; the median follow-up time for the entire series was 70 months. Histologically, all tumors were classified as astrocytoma grade 111 or IV according to the grading system of Kernohan and Sayre.’ Since much controversy exists about the value, feasibility and reproducibility of this grading system ’ ‘.‘.’-’6.‘o.‘3,‘5it must be stated that a grading of IV was usually given to any glioblastoma multiforme with histopathologic evidence of tumor necrosis in addiECOG Operations Oflice, 905 University Madison, Wisconsin 537 15.
Avenue,
Suite
415,
High Dose Radiation Therapy in The Treatment
of Malignant
Table 1. Patient population
Grade ASTR. Cr. III
ASTR. Cr. IV
Category
No. pts.
Gliomas,
SALAZAR etal.
1735
characteristics?
Male:
Median minim.
Med. age (yrs)
fem. ratio
dose (rad) 7300 5150 5000 7150 5137
27200 25500 >5000 r7200 25000
5 5 r 5 >
Median max. dose (rad)
Median max. dose (ret)
8000 6200 5500 7500 8000
7450 5800 5203 7303 5965
1946 1637 1480 1995 1647
54 85 91 12 II
91
Median dose range (rad)
Median follow-up (mo.)
Median survival (mo.)
VHD MHD CD HD + CT*
6 12 18 5
44 43 39 31
Subtotal
41
41
5:l 3:9 9:9 4:l 21:20
VHD MHD CD HD + CT* Subtotal
22 I5 16 6 59
51 54 49 52 51
13:9 8:7 719 5:l 33~26
1254 5821 5000 7000 6198
r7000 ~5000 r5000 ~7000 r5000
5 5 5 r 5
8000 6500 5500 7200 8000
7520 5998 5221 7136 6410
1905 1637 1480 1906 1705
52 60 110 13
56 42 30 **
66
42
100
41
54:46
6009
r5000
5 8000
6263
1681
IO
54,
Total
204 82 43 **
tfor abbreviations please refer to the text. *HD + CT = High-dose radiation therapy plus pulsed BCNU (see text). **Data is preliminary, results will be reported separately (see text).
tion to the usual findings of pleomorphism, pseudopalisading, mitosis and endothelial cell proliferation. Survival estimates were obtained by the method of Kaplan and Meier.4 The Wilcoxon-Gehan test’ was employed to assess statistical validity among the different comparisons in this report. There was a 40% autopsy rate for the entire series. All autopsy reports were carefully analyzed for indications of possible radiation-induced brain necrosis. Of particular interest were a group of 10 autopsies obtained in the VHD group of patients; 3 were obtained during the first year, 3 during the second year, 2 during the third year and 2 during the fourth year after treatment. One patient in the VHD group is still alive at this writing, and was recently reoperated upon for a recurrence which occurred 4.3 years after the original diagnosis. Patients who were referred to radiation oncology following surgery were receiving Dexamethasone, but total daily doses of this medication never exceeded 16 mg. The mean dose was actually 10.2 mg per day. During whole brain irradiation patients were maintained on the same daily steroid doses after surgery. However, it has been our practice to begin tapering the steroids toward the completion of whole brain irradiation. Consequently, within a short peroid of time (which never exceeded 3 weeks following completion of all radiation therapy) all patients were no longer receiving Dexamethasone. Steroids were never reinstituted unless the patient had an obvious symptomatic recurrence. Tumor recurrence is defined in this report as a definite deterioration in neurologic performance status or an increase in tumor volume as determined by brain scans, whichever occurred first. In some instances one could document progressive increase in tumor size radiologically without corresponding symptomatology and/or
neurologic deterioration.” The recurrence-free interval is equivalent to the time elapsed from the initiation of treatment to tumor recurrence. The recurrence interval designates the time elapsed from recurrence to death or last follow-up. RESULTS The main characteristics of each dose and grade-group appear in Table 1. Since VHD group of patients constitutes the central focus of this report, an analysis by dose delivered to these 28 patients appears in Table 2. Almost 50% of these patients received total doses of 7500 rad or more. When each dose-group was considered separately by histologic grade, there were striking differences in median survival. For grade IV tumors the median survival times of VHD, MHD and CD groups were 56,42 and 30 weeks respectively (Figure la). The differences between the two extremes (VHD and CD; 56 vs 30 weeks) were statistically significant (p > 0.05). However, the differences between consecutive dose-groups (VHD and MHD; 56 vs 42 weeks) (MHD and CD; 42 vs 30 weeks) were not statistically significant (p > 0.05). By 2 years, all curves superimposed and the overall survival became the same for each dose-group (Figure la). For patients with astrocytoma grade III the median Table 2. Total doses very high dose (VHD) group Number of patients Dose-range (rad)
Grade III
Grade IV
Overall
< 7500 ~7500 < 8000 >8000 < 8200
3 2 I
12 9 I
15 11 2
>7000
Radiation
1736
Oncology
l Biology 0 Physics
October 1979, Volume 5, Number
10
80 <
$ 60
5
v, 40 R
0
20
40
60
80
100
120
140
160
180
200
220
240
260
TIME (weeks)
0
Fig. la. Survival according to increase in total dose, astrocytoma grade IV. Abbreviations: VHD = Very-high-dose; MHD = Median-high-dose; CD = Conventional dose. PiSTR GW\DE ,I,
20
40
60
80
100
120
140
160
180
200
220
240
260
TIME (weeks)
Fig. I b. Survival according to increase in total dose, astrocytoma grade III. Abbreviations: VHD = Very-high-dose; MHD = Median-high-dose; CD = Conventional dose. times for the VHD, MHD, CD groups were 204, 82 and 43 weeks respectively (Figure lb). The differences in median survival between consecutive dosegroups and between extremes were statistically significant (p < 0.05). This also indicated a linear increase of the median survival as the total dose was increased. However, by 4 years all curves appeared to join and the overall survival became similar for each dose-group (Figure lb). Although each dose-group had a relatively small number of patients, results were considered significant, particularly when they were analyzed by grade. All 22 patients with grade IV tumors in the VHD group are now dead and thus all conclusions are final; five of the six patients with grade III tumors in this group are at risk beyond 4 years after treatment and consequently valid observations can be made. In any consecutive series of glioblastoma, grade IV tumors are more common than grade III. An analysis according to performance status in this final report yielded almost identical conclusions about the quality of survival in the VHD group as those published in the preliminary report.” It would be more illuminating to analyze the quality of survival of the 28 patients in the VHD group by assessing the recurrencefree and the recurrence time-intervals (Figure 2). For survival
0
40
20
60
80
100
120
140
160
180
200
220
240
TIME (weeks) Fig. 2. Recurrence-free interval and symptomatic-relapse time for patients with astrocytoma grades 111 and IV who were treated with very high doses (VHD) (-7500 rad).
patients with grade IV tumors, the median recurrencefree interval was 43 weeks while the overall median survival was 56 weeks. This indicates a period of recurrence which seldom exceeded 3 months for grade IV patients. For patients with grade III tumors, the median recurrence-free-interval was 158 weeks while the overall median survival was 204 weeks. This indicates a longer period of recurrence than for grade IV tumors which at times lasted 8-10 months. These differences in symptomatic-relapse-intervals between grades were attributed to the aggressiveness and rapid growth of grade IV tumors. Although patients in the MHD and CD groups were not monitored as closely as the VHD group, there were no significant differences in the recurrence period of these groups compared to that of the VHD group. This period was somewhat, but not significantly, shorter in the VHD than in the other two dose-groups. Analysis of tumor recurrences in the VHD group clearly shows the distinct differences in biologic behavior between the histologic grades (Figure 3). For grade IV
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--rr//:, 60
80
100 TIME
120
140
&+y!;; , 160
180
200
220
1 240
(weeks)
Fig. 3. Recurrence time for patients with astrocytoma, III and IV who were treated with very high doses (-7500 rad).
grades (VHD)
tumors the mean recurrence time was 57 weeks, and the median recurrence time was 43 weeks; by 19 months, 90% of all recurrences had been detected. For grade III tumors the mean recurrence time was 159 weeks and the median recurrence time was 158 weeks; at 18 months less than 15% of the patients had recurrence. For grade III
High Dose Radiation Therapy in The Treatment of Malignant Gliomas,
SALAZAR
1737
et al.
DISCUSSION
I,
0
20
40
60
80
/
100 120 140 160 180 200 220 240 260 TIME (weeks)
Fig. 4. Survival according
to histopathologic
grade
had been detected only 3’/2 80% of all recurrences years or more after treatment. Finally, certain important prognostic factors concerning glioblastoma multiforme* became evidence in the present analysis: (1) Astrocytoma, grade IV was more common (59%) than grade III (41%) (Table 1); (2) Patients with astrocytoma grade 111 survived satistically better (p < 0.01) than the patients with grade IV tumors (Figure 4); (3) Grade for grade, the younger the patient at diagnosis, the better the survival (Figures 5a-b). These prognostic factors should be considered when these tumors are studied and/or treated. tumors
ASTR
100
0
20
40
Fig. 5a. Survival
0
20
40
60
80
GRADE
IV
100 120 140 160 180 200 220 240 260 TIME (weeks)
according to age for patients toma grade IV
60
80
Fig. 5b. Survival acording
*In the classification
with astrocy-
100 120 140 160 180 200 220 240 %O TIME (weeks)
to age for patients grade III
with astrocytoma
The value of postoperative irradiation for the treatment of malignant gliomas has often been questioned by clinicians who are involved in the management of brain tumor patients. Usual objections have pertained to whether this treatment modality enhances survival and quality of survival of patients in whom it is employed. However, many reports over the past 20 years have supported its implementation, and the value of postoperative irradiation in these tumors has now become firmly established by recent national cooperative group studies.14 In fact, with the exception of postoperative irradiation, to date there has not been any other single, primary or adjuvant, therapy which has been able to attain significant and substantial palliation for patients with these tumors. The present study, committed to exploring the question of optimal radiation dose for treating malignant gliomas, has contributed data in this regard, but has also raised further questions; one of the most important questions is whether the use of higher than conventional doses is justified in treating these tumors. USE OF HIGHER
DOSES
Increases in the total tumor dose beyond 5000 rad seem to prolong the median life-span of patients with malignant gliomas. This was the outcome of the preliminary analysis reported earlier” which has been substantiated not only in the present study as a whole, but also by other investigators.’ For example, a recent retrospective analysis of 621 patients who were treated by the Brain Tumor Study Group (BTSG) for the last 10 years allowed Walker et al. to pool data and divide these patients according to the radiation dose delivered.15 The results of this analysis, which involved patients who had received ~4500, 5000, 5500, and 6000 rad to the whole brainIs were: patients who had received ~4500 rad did so poorly that they were not comparable to patients who received >5000 rad; patients who had received 5000, 5500 or 6000 rad showed an increase in median life-span directly proportional to the increase in the total dose delivered; this increase in median life-span could not be attributed to any factor? other than the increase of radiation dose. As a result of this proportional dose-effect relationship, the authors wondered whether the maximum therapeutic doses had been achieved.” The present analysis adds data with regard to higher dose ranges. For patients with grade IV tumors, the median survival increased as the doses were increased from (median doses) 5200 to 6000 to 7500 rad (Figures l-2). Though this increase in median survival for grade IV patients was only significant between the extremes and not between the intermediate dose range and the
of Kernohan
and Sayre’ the term
astrocytoma” is used for tumors which in general correspond
glioblastoma multiforme is employed grade III and grade 1V; in Rubinstein’s
both for astrocytoma classification6 this term
Kernohan and Sayre’s grade III tumors. tMany of the BTSG patients also received chemotherapy.
is employed for grade IV tumors and the term “anaplastic
to
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Radiation Oncology 0 Biology 0 Physics
extremes, there was a significant difference in median survival between all dose ranges for patients with astrocytoma grade III, (Figure lb). Indeed, the media survival for patients with grade III tumors increased significantly, from 82 to 204 weeks, as a result of the increase in dose from GO00 to 7500 rad (Figure 2). These facts, along with the acceptable quality of survival and the absence of significant morbidity accompanying doses of 7000-8000 rad delivered with conventional fractionation over a period of 779 weeks, warrants further investigation in the use of these doses, particularly in patients with grade III tumors. Although the median survival and median time for recurrence have been improved with the use of higher doses, the aim of any therapeutic approach in oncology should be to try to control and cure the patient’s affliction and thus result in a gain in overall survival. Survival estimates for patients with glioblastoma multiforme who were treated with conventional postoperative irradiation (5000-6000 rad) have consistently yielded 5-year figures which range between O-9%.‘.” In this present series, the observed increase in the median life-span of patients who were treated with higher radiation doses was not reflected in the overall survival, beyond two years for grade IV tumors (Figure 1a) and 4 years after treatment for grade III tumors (Figure lb). This was a clear indication that high doses, which at times were as high as 8000 rad, were not able to “cure” more patients with malignant gliomas than conventional radiation doses. Moreover, 26 of 28 patients (93%) in the VHD group had recurrence of their tumors and 24 patients (96%) had died either of tumor persistence or recurrence when the study was closed. In fact, 10 autopsies and one reoperation in these patients clearly demonstrated recurrent (viable) tumor in the heavily irradiated areas, indicating that tumor sterilization was not attained with doses of 7000-8000 rad. Frank (gross or microscopic) radiation-induced necrosis of normal brain tissue in non-tumor areas was not seen in any of the specimens obtained in VHD patients; however, necrosis associated with tumor recurrences was a common finding. Brain radiation necrosis is a diagnosis by exclusion and as such is often difficult to diagnose and document even microscopically. Although specimens obtained at necropsy or reoperation 3-4’/2 years after treatment with VHD do not show focal or confluent areas of necrosis in the heavily irradiated normal brain tissue, certain changes suggestive of marked radiation effect have been seen in normal tissue at the periphery of recurrent tumors (Figures 6 & 7). These changes have been described in blood vessels (hyalinization, sclerosis, thickening and necrosis of the walls) and in the parenchyma itself (reactive pleomorphic gliosis, fibrosis, focal demyelinization, focal hemorrhages and coagulation necrosis). All of these changes were microscopic and many of them can be seen with recurrent tumors: however, some (i.e., coagulation necrosis) were observed and described by the neuropathologists to have been
October 1979, Volume 5, Number 10
Fig. 6. Specimen from 46 year old patient with astrocytoma grade 111 who died of tumor recurrence 4% years following postoperative irradiation with a total dose of 8000 rad. A cavity lined by recurrent tumor is shown. There is preservation of the normal anatomy
of the contralateral
hemisphere.
present to a greater extent than would be expected with tumor recurrences. Thus, though it may be suggested that doses higher than 7500 rad might attain tumor sterilization in these patients, the present authors consider it probable that higher doses may lead to frank radiation necrosis and, of course, defeat the intended purpose of treatment. The present study lacks randomized prospective controls; this may indicate that differences in median survival seen among patients treated with high versus conventional radiation doses could conceivably result from an element of selection and/or the size of the study sample. However, the present study clearly demonstrates that the use of very high doses in grade IV tumors only achieves trivial increases in median survival which do not seem to affect the overall survival of these unfortunate patients significantly. The authors would recommend further exploration of this therapeutic strategy only for the more favorable group of younger patients with grade 111 tumors, in whom the use of high-doses yielded a very significant gain by prolonging their median survival. The authors would also like to express their concern about exploring total doses higher than 7500 rad since these
Fig. 7. Microscopic section from 36 year old patient with astrocytoma grade III who was reoperated for tumor recurrence 4.3 years following postoperative irradiation with a total dose of 7500 rad. A. 40x. Homogenization and necrosis of blood vessel wall. Neoplastic cells surround hyalinized blood vessel. B. 35x.
Non-neoplastic area with coagulation focal areas of hemorrhage.
C. 25x.
Thickening
necrosis
and
and hyalinization of blood vessels in the midst of neoplastic tissue.
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Radiation Oncology 0 Biology 0 Physics
very high doses may lead to a frank incidence of radiation-induced normal brain tissue necrosis in a group of patients who would be expected to survive longer; the development of this complication would defeat the intended therapeutic achievement. The present study was performed with the idea of exploring an optimal radiation dose that could be delivered to patients with malignant gliomas. It was originally thought that with the determination of an optimal radiation dose, combinations of postoperative radiation and other adjuvant therapies could be pursued with better effect. In the most recent analysis of the BTSG, the combination of 6000 rad whole brain irradiation and
October 1979, Volume 5, Number 10
BCNU administered postoperatively, resulted in small increases in median survival which were not reflected in overall survival.14 Fast neutron irradiation has also failed to alter the overall survival of patients;12 yet since this form of therapy has demonstrated sterilization of some malignant gliomas, the authors of the present study feel that the use of mixed photon-neutron beams represents a direction that might be followed gainfully. It is further considered possible that the addition of radiosensitizers, in optimal combination with other chemotherapeutic agents of independent toxicities, would improve the effect of surgery and radiation in the control and intended cure of malignant
gliomas.
REFERENCES 1. Earle, K.M.: The proper nomenclature for glioblastoma multiforme. Int. J. Rad. 0~01. Biol. Phys. 1: 805-808, 1976. 2. Gehan, E.A.: A generalized Wilcoxon test for comparing 52: 2033 arbitrarily singly-censored samples. Biometrika 223,
1965.
3. Gehan,
patients
E.A. and Walker, with brain tumors.
Tumor
Therapy:
Laboratory
M.D.: Prognostic factors for In Modern Concepts in Brain and Clinical
tion Therapy with Low-Dose (Pulsed) BCNU in Malignant Gliomas. In preparation. 9. Salazar, O.M. and Rubin, P.: The spread of glioblastomas as a determining factor in the radiation treated volume. Int. J. Rad. Oncol. Biol. Phys. 1: 6277637,
Oncol. Biol. Phys. 1:717-727,
Investigations.
J.C. Bailar & E.K. Weisberger (eds), National Cancer Institute (NCI) monograph 46, Bethesda, NC1 1977, pp 189-196. 4. Kaplan, E.L. and Meier, P.: Nonparametric estimation for incomplete observations. J. Am. Stat. Assoc. 53: 457748 1.
I I. Salazar,
12.
1958. 5. Kernohan,
J.W. and Sayre, G.P.: Tumors of the central nervous system. In Atlas of Tumor Pathology, Sec. 10, Fascicles 35 and 37, Washington, D.C., Armed Forces Institute of Pathology (AFIP), 1952, pp 17-42. 6. Rubinstein, L.J.: Tumors of the Central Nervous System. In Atlas of Tumor Pathology, Fascicle 6, Washington, D.C., Armed Forces Institute of Pathology (AFIP) 1972, pp 422130. 7. Salazar, O.M.: Moments of Decision in Primary Brain Tumors. Rubin, P. and Preston, W. (eds). Chicago, III., American College of Radiology (ACR), 1977, pp 39-77. 8. Salazar, O.M., Malaker, D., Bennett, J.J., Rubin, P., Feldstein, M.L. and Pizzutiello, R.J.: For the Eastern Cooperative Oncology Group (ECOG): High-Dose Radia-
1976.
10. Saiazar, O.M., Rubin, P., McDonald, J.V. and Feldstein, M.L.: High-dose radiation therapy in the treatment of glioblastoma multiforme: A preliminary report. Int. J. Rad.
13.
14.
15.
1976.
O.M., Rubin, P., McDonald, J.F. and Feldstein, M.L.: Patterns of failure in intracranial astrocytomas after irradiation: Analysis of dose and field factors. Am. J. Roentgenol. 126: 279-292, 1976. Shaw, C.M., Sumi, SM., Alvord, E.C.. Gerdes, A.J., Spence, A. and Parker, R.G.: Fast-neutron irradiation of glioblastoma multiforme. J. Neurosurg. 49:1-12, 1978. Sheline, G.: The importance of distinguishing tumor grade in malignant gliomas: Treatment and prognosis. Int. J. Rad. Oncol. Biol. Phys. 1: 781-786, 1976. Walker, M.D., Alexander, E. Jr., Hunt, W.E., MacCarty, C.S., Mahaley, M. Jr., Mealey, J. Jr., Norrell, H.A., Owens, G., Ransohoff, J., Wilson, C.B., Gehan, E.A., Strike, T.A.: (for the Brain Tumor Study Group). Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J. Neurosurg. 49: 333-343, 1978. Walker, M.D., Strike, T.A. and Sheline, G.E.: for the Brain Tumor Study Group (BTSG). An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Rad. Oncol. Biol. Phys. 5: Ott, 172551731, 1979.
Inl. J. Radiation Oncology Biol. Phys Vol. 5. pp 1733-1740 OPergamon Press Ltd.1979. Printed in the U S.A.
l Original Contribution HIGH DOSE RADIATION THERAPY IN THE TREATMENT MALIGNANT GLIOMAS: FINAL REPORT”?
OMAR M.
SALAZAR,
M.D.,’ PHILIP RUBIN, M.D.,2 MICHAEL and ROBERT PIZZUTIELLO, M.S.4
OF
L. FELDSTEIN,
Ph.D.3
University of Rochester Cancer Center, 601 Elmwood Avenue, Rochester, New York 14642, U.S.A. One hundred patients with supratentorial malignant gliomas were prescribed to receive postoperative whole brain irradiation with doses A000 rad; 41 had astrocytoma grade III and 59 had grade IV tumors. The median survival was 91 weeks for patients with grade III tumors and only 42 weeks for those with grade IV (p < 0.01). For both grades, patients who were 545 years of age survived significantly better than patients who were older at diagnosis (p < 0.05). Patients with tumors at each grade were divided into three groups depending on the total dose delivered to the tumor; 5000,6000,7500 rad (median doses). For patients with grade IV tumors the median survival was 30, 42 and 56 weeks respectively; these differences were significant (p < 0.05) between the extremes hut not between consecutive dose groups and were maintained only up to 2 years from the initiation of treatment. For patients with grade III tumors, the median survival was 43,82 and 204 weeks respectively; these differences were significant (p < 0.05) between consecutive dose groups and between extremes and were maintained up to 4 years from the initiation of treatment. For 22 patients with grade IV who were treated with high-doses (7500 rad), the median time for recurrence was 43 weeks while for six patients with grade III tumors it was 158 weeks. The use of higher radiation doses was well tolerated; it did not compromise the quality of survival, and did not yield normal brain tissue necrosis. However, these doses did not seem to alter the total survival of patients, nor did they seem capable of sterilizing these tumors. Histopathological changes that were observed in normal brain tissue that was irradiated with 7000-8000 rad suggest that increasing total doses beyond this range might attain tumor sterilization, but could also lead to frank radiation necrosis in these patients. Radiation therapy, Malignant Gliomas, Glioblastoma multiforme, CNS radiation tolerance INTRODUCTION
increased the median survival of patients by 150%.14 However, the optimum dose required to control these aggressive tumors has not been firmly established. The present attempt to explore radiation therapy beyond conventional doses (5000-6000 rad) was initiated in 1972 as a high-risk pilot study prior to a randomized protocol which was recently completed by two national cooperative group& The rationale to explore higher doses was based on the concept of the equivalent area dose (EAD). EAD postulates that in order to achieve the maximum tumor control with acceptable normal tissue damage, high-dose schedules beyond conventional doses should be employed in a protracted fashion.” A prelimi-
Malignant gliomas of the brain constitute some of the most aggressive and rapidly disabling neoplasia in humans. Although the use of postoperative irradiation in these tumors is much debated, currently it constitutes one of the most important modalities in management of these tumors. In a recently completed randomized study by the Brain Tumor Study Group (BTSG), patients who received only conventional care following surgical resection had a median survival of 14 weeks; the median survival was 35 weeks for those who received postoperative whole brain irradiation with 5000-6000 rad. These results clearly demonstrated that radiation therapy *This paper was presented at the 20th Annual meeting of the American Society of Therapeutic Radiologists, Los Angeles,
ance in Radiation Physics, Michael Sortino in Biostatistics; Doris Commons and Laura Klinkon typed and edited the manuscript. Joseph V. McDonald, M.D. (Chief, Division of Neurosurgery) provided assistance and guidance. Reprint Requests to: O.M. Salazar, M.D. Accepted for publication 17 August 1979. *Radiation Therapy Oncology Group (RTOG No. 74-01) and Eastern Cooperative Oncology Group (ECOG No. 1374) Malignant Glioma Protocol. Available from RTOG Operations Office, Thomas Jefferson University Hospital, 1015 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
California, (October 31&November 4, 1978). tsupported in part by National Cancer Institute grants CA 11051 andCA 11198 ‘Associate Professor of Radiation Oncology, Division of Radiation Oncology 2Professor and Chairman, Division of Radiation Oncology ‘Assistant Professor of Oncology in Biostatistics & Statistics 41nstructor in Radiation Oncology, Radiation Physics Section, Division of Radiation Oncology Acknowledgements-Bowen Keller provided technical assist1733
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1734
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nary report published early in 1976” observed that high doses (>6000 rad) in grade IV astrocytomas seemed to increase the median survival somewhat, but appeared to have no effect on the overall survival of patients. At that time, cases of grade III tumors were too few in number for preliminary evaluation. After 1975, however, more patients were treated, and enough time has now elapsed to make firmer observations. Subsequent to the first report, we have been able to redefine dose ranges and now we consider very high doses only those that are ~7000 rad. At the same time, we have also expanded the scope of our study. In an attempt to correlate an increase in the total dose delivered with increases in survival, patients who had been treated for the past 15 years in our Division with whole brain ~5000 rad were included as a retrospective control group. Their data was analyzed according to the total doses received. This paper reports the outcome of our search for an optimal dose of radiation delivered with conventional fractionation for patients with malignant gliomas. Throughout this effort, optimum radiation has been understood as constituting maximal tumor cell kill with minimal normal brain necrosis, since such injury is synonymous with treatment failure. This report emphasizes the use of very high doses of radiation and indicates areas of special significance which should be considered in subsequent studies. METHODS
AND MATERIALS
One hundred patients with histologically confirmed supratentorial malignant gliomas were treated in the Division of Radiation Oncology, University of Rochester Cancer Center between January 1, 1963 and December 31, 1977. All patients were prescribed postoperative irradiation with whole brain doses of 5000 rad or more, with or without supplementary booster doses to the primary target. All patients were included in the series irrespective of whether they were able to complete the total prescribed treatment. During the 15-year span encompassed in the study, patients who were treated in our Division and who either were prescribed smaller doses, or actually were treated with partial brain fields, were excluded from the present analysis; a report regarding these patients has been published.” Patients were divided into groups according to the total radiation dose delivered to the tumor. These groups are: (1) The very-high-dose (VHD) group consisted of 28 patients who received 5000-6000 rad of whole brain irradiation plus an additional booster to the primary target for total doses that were r7000-18000 rad. This group constitutes the central focus of this report; it consists of consecutive patients with malignant gliomas *Eastern Cooperative Oncology (ECOG No. PA-578) Pilot for the Use of High-Dose Radiation Therapy and LowDose (Pulsed) BCNU in Malignant Gliomas. Available from
Study
October
1979, Volume 5, Number
10
who were treated in our Division from January 1972 to December 1976. (2) The median-high-dose (MHD) group consisted of 27 patients who received 6000 rad whole brain irradiation with or without a supplementary booster for total doses that were r5000-16500 rad. Patients in this dose-group were not consecutive patients and represent a retrospective control group. (3) The conventional-dose (CD) group with 34 patients who received whole brain doses ~5000&<5500 rad. Like those in the MHD, patients in this dose-group were not consecutive patients, and represent a retrospective control group. (4) The remaining 11 patients were treated with highdose irradiation (6000 rad to the whole brain plus a boost of 1000 rad to the target volume) and low-dose (20 mg/kg) k,3-bis(2-Chlorethyl)1-Nitrosourea (BCNU) pulsed 15 hours before the next radiation fraction, twice weekly for 6 weeks. These 11 patients comprised consecutive patients with malignant gliomas who were seen in our Division since January 1977 and who were eligible for a high-risk pilot study for the Eastern Cooperative Oncology Group.* They were purposely excluded from most survival calculations in this report and will constitute the subject of a separate publication.* All patients underwent surgical resection and were subsequently treated with megavoltage teletherapy equipment delivering photon radiation to source-skindistances (SSD) of 80 cm or more with five weekly fractions of 150-200 rad each. An attempt was made to define the tumor volume precisely. Thus, during the last 61/2years of the study in most patients head contours were taken for tumor localization and computerized dosimetry. Booster fields were arranged either as wedged or parallel-opposed fields according to criteria that were published previously.” All fields were treated daily. Most patients had serial isotope brain scans during the course of their ailment. Computerized axial tomography (CAT) scanning of the head was added to the armamentarium of diagnostic and follow-up tests during the last 3 years of the study. The follow-up was complete and lasted until death of the patient or to the closing date of this report (December 3 1, 1978). The minimum follow-up time was 12 months; the median follow-up time for the entire series was 70 months. Histologically, all tumors were classified as astrocytoma grade 111 or IV according to the grading system of Kernohan and Sayre.’ Since much controversy exists about the value, feasibility and reproducibility of this grading system ’ ‘.‘.’-’6.‘o.‘3,‘5it must be stated that a grading of IV was usually given to any glioblastoma multiforme with histopathologic evidence of tumor necrosis in addiECOG Operations Oflice, 905 University Madison, Wisconsin 537 15.
Avenue,
Suite
415,
High Dose Radiation Therapy in The Treatment
of Malignant
Table 1. Patient population
Grade ASTR. Cr. III
ASTR. Cr. IV
Category
No. pts.
Gliomas,
SALAZAR etal.
1735
characteristics?
Male:
Median minim.
Med. age (yrs)
fem. ratio
dose (rad) 7300 5150 5000 7150 5137
27200 25500 >5000 r7200 25000
5 5 r 5 >
Median max. dose (rad)
Median max. dose (ret)
8000 6200 5500 7500 8000
7450 5800 5203 7303 5965
1946 1637 1480 1995 1647
54 85 91 12 II
91
Median dose range (rad)
Median follow-up (mo.)
Median survival (mo.)
VHD MHD CD HD + CT*
6 12 18 5
44 43 39 31
Subtotal
41
41
5:l 3:9 9:9 4:l 21:20
VHD MHD CD HD + CT* Subtotal
22 I5 16 6 59
51 54 49 52 51
13:9 8:7 719 5:l 33~26
1254 5821 5000 7000 6198
r7000 ~5000 r5000 ~7000 r5000
5 5 5 r 5
8000 6500 5500 7200 8000
7520 5998 5221 7136 6410
1905 1637 1480 1906 1705
52 60 110 13
56 42 30 **
66
42
100
41
54:46
6009
r5000
5 8000
6263
1681
IO
54,
Total
204 82 43 **
tfor abbreviations please refer to the text. *HD + CT = High-dose radiation therapy plus pulsed BCNU (see text). **Data is preliminary, results will be reported separately (see text).
tion to the usual findings of pleomorphism, pseudopalisading, mitosis and endothelial cell proliferation. Survival estimates were obtained by the method of Kaplan and Meier.4 The Wilcoxon-Gehan test’ was employed to assess statistical validity among the different comparisons in this report. There was a 40% autopsy rate for the entire series. All autopsy reports were carefully analyzed for indications of possible radiation-induced brain necrosis. Of particular interest were a group of 10 autopsies obtained in the VHD group of patients; 3 were obtained during the first year, 3 during the second year, 2 during the third year and 2 during the fourth year after treatment. One patient in the VHD group is still alive at this writing, and was recently reoperated upon for a recurrence which occurred 4.3 years after the original diagnosis. Patients who were referred to radiation oncology following surgery were receiving Dexamethasone, but total daily doses of this medication never exceeded 16 mg. The mean dose was actually 10.2 mg per day. During whole brain irradiation patients were maintained on the same daily steroid doses after surgery. However, it has been our practice to begin tapering the steroids toward the completion of whole brain irradiation. Consequently, within a short peroid of time (which never exceeded 3 weeks following completion of all radiation therapy) all patients were no longer receiving Dexamethasone. Steroids were never reinstituted unless the patient had an obvious symptomatic recurrence. Tumor recurrence is defined in this report as a definite deterioration in neurologic performance status or an increase in tumor volume as determined by brain scans, whichever occurred first. In some instances one could document progressive increase in tumor size radiologically without corresponding symptomatology and/or
neurologic deterioration.” The recurrence-free interval is equivalent to the time elapsed from the initiation of treatment to tumor recurrence. The recurrence interval designates the time elapsed from recurrence to death or last follow-up. RESULTS The main characteristics of each dose and grade-group appear in Table 1. Since VHD group of patients constitutes the central focus of this report, an analysis by dose delivered to these 28 patients appears in Table 2. Almost 50% of these patients received total doses of 7500 rad or more. When each dose-group was considered separately by histologic grade, there were striking differences in median survival. For grade IV tumors the median survival times of VHD, MHD and CD groups were 56,42 and 30 weeks respectively (Figure la). The differences between the two extremes (VHD and CD; 56 vs 30 weeks) were statistically significant (p > 0.05). However, the differences between consecutive dose-groups (VHD and MHD; 56 vs 42 weeks) (MHD and CD; 42 vs 30 weeks) were not statistically significant (p > 0.05). By 2 years, all curves superimposed and the overall survival became the same for each dose-group (Figure la). For patients with astrocytoma grade III the median Table 2. Total doses very high dose (VHD) group Number of patients Dose-range (rad)
Grade III
Grade IV
Overall
< 7500 ~7500 < 8000 >8000 < 8200
3 2 I
12 9 I
15 11 2
>7000
Radiation
1736
Oncology
l Biology 0 Physics
October 1979, Volume 5, Number
10
80 <
$ 60
5
v, 40 R
0
20
40
60
80
100
120
140
160
180
200
220
240
260
TIME (weeks)
0
Fig. la. Survival according to increase in total dose, astrocytoma grade IV. Abbreviations: VHD = Very-high-dose; MHD = Median-high-dose; CD = Conventional dose. PiSTR GW\DE ,I,
20
40
60
80
100
120
140
160
180
200
220
240
260
TIME (weeks)
Fig. I b. Survival according to increase in total dose, astrocytoma grade III. Abbreviations: VHD = Very-high-dose; MHD = Median-high-dose; CD = Conventional dose. times for the VHD, MHD, CD groups were 204, 82 and 43 weeks respectively (Figure lb). The differences in median survival between consecutive dosegroups and between extremes were statistically significant (p < 0.05). This also indicated a linear increase of the median survival as the total dose was increased. However, by 4 years all curves appeared to join and the overall survival became similar for each dose-group (Figure lb). Although each dose-group had a relatively small number of patients, results were considered significant, particularly when they were analyzed by grade. All 22 patients with grade IV tumors in the VHD group are now dead and thus all conclusions are final; five of the six patients with grade III tumors in this group are at risk beyond 4 years after treatment and consequently valid observations can be made. In any consecutive series of glioblastoma, grade IV tumors are more common than grade III. An analysis according to performance status in this final report yielded almost identical conclusions about the quality of survival in the VHD group as those published in the preliminary report.” It would be more illuminating to analyze the quality of survival of the 28 patients in the VHD group by assessing the recurrencefree and the recurrence time-intervals (Figure 2). For survival
0
40
20
60
80
100
120
140
160
180
200
220
240
TIME (weeks) Fig. 2. Recurrence-free interval and symptomatic-relapse time for patients with astrocytoma grades 111 and IV who were treated with very high doses (VHD) (-7500 rad).
patients with grade IV tumors, the median recurrencefree interval was 43 weeks while the overall median survival was 56 weeks. This indicates a period of recurrence which seldom exceeded 3 months for grade IV patients. For patients with grade III tumors, the median recurrence-free-interval was 158 weeks while the overall median survival was 204 weeks. This indicates a longer period of recurrence than for grade IV tumors which at times lasted 8-10 months. These differences in symptomatic-relapse-intervals between grades were attributed to the aggressiveness and rapid growth of grade IV tumors. Although patients in the MHD and CD groups were not monitored as closely as the VHD group, there were no significant differences in the recurrence period of these groups compared to that of the VHD group. This period was somewhat, but not significantly, shorter in the VHD than in the other two dose-groups. Analysis of tumor recurrences in the VHD group clearly shows the distinct differences in biologic behavior between the histologic grades (Figure 3). For grade IV
-------r------x=““T
,
7
2b 4b
Y
0
.A
.’
--rr//:, 60
80
100 TIME
120
140
&+y!;; , 160
180
200
220
1 240
(weeks)
Fig. 3. Recurrence time for patients with astrocytoma, III and IV who were treated with very high doses (-7500 rad).
grades (VHD)
tumors the mean recurrence time was 57 weeks, and the median recurrence time was 43 weeks; by 19 months, 90% of all recurrences had been detected. For grade III tumors the mean recurrence time was 159 weeks and the median recurrence time was 158 weeks; at 18 months less than 15% of the patients had recurrence. For grade III
High Dose Radiation Therapy in The Treatment of Malignant Gliomas,
SALAZAR
1737
et al.
DISCUSSION
I,
0
20
40
60
80
/
100 120 140 160 180 200 220 240 260 TIME (weeks)
Fig. 4. Survival according
to histopathologic
grade
had been detected only 3’/2 80% of all recurrences years or more after treatment. Finally, certain important prognostic factors concerning glioblastoma multiforme* became evidence in the present analysis: (1) Astrocytoma, grade IV was more common (59%) than grade III (41%) (Table 1); (2) Patients with astrocytoma grade 111 survived satistically better (p < 0.01) than the patients with grade IV tumors (Figure 4); (3) Grade for grade, the younger the patient at diagnosis, the better the survival (Figures 5a-b). These prognostic factors should be considered when these tumors are studied and/or treated. tumors
ASTR
100
0
20
40
Fig. 5a. Survival
0
20
40
60
80
GRADE
IV
100 120 140 160 180 200 220 240 260 TIME (weeks)
according to age for patients toma grade IV
60
80
Fig. 5b. Survival acording
*In the classification
with astrocy-
100 120 140 160 180 200 220 240 %O TIME (weeks)
to age for patients grade III
with astrocytoma
The value of postoperative irradiation for the treatment of malignant gliomas has often been questioned by clinicians who are involved in the management of brain tumor patients. Usual objections have pertained to whether this treatment modality enhances survival and quality of survival of patients in whom it is employed. However, many reports over the past 20 years have supported its implementation, and the value of postoperative irradiation in these tumors has now become firmly established by recent national cooperative group studies.14 In fact, with the exception of postoperative irradiation, to date there has not been any other single, primary or adjuvant, therapy which has been able to attain significant and substantial palliation for patients with these tumors. The present study, committed to exploring the question of optimal radiation dose for treating malignant gliomas, has contributed data in this regard, but has also raised further questions; one of the most important questions is whether the use of higher than conventional doses is justified in treating these tumors. USE OF HIGHER
DOSES
Increases in the total tumor dose beyond 5000 rad seem to prolong the median life-span of patients with malignant gliomas. This was the outcome of the preliminary analysis reported earlier” which has been substantiated not only in the present study as a whole, but also by other investigators.’ For example, a recent retrospective analysis of 621 patients who were treated by the Brain Tumor Study Group (BTSG) for the last 10 years allowed Walker et al. to pool data and divide these patients according to the radiation dose delivered.15 The results of this analysis, which involved patients who had received ~4500, 5000, 5500, and 6000 rad to the whole brainIs were: patients who had received ~4500 rad did so poorly that they were not comparable to patients who received >5000 rad; patients who had received 5000, 5500 or 6000 rad showed an increase in median life-span directly proportional to the increase in the total dose delivered; this increase in median life-span could not be attributed to any factor? other than the increase of radiation dose. As a result of this proportional dose-effect relationship, the authors wondered whether the maximum therapeutic doses had been achieved.” The present analysis adds data with regard to higher dose ranges. For patients with grade IV tumors, the median survival increased as the doses were increased from (median doses) 5200 to 6000 to 7500 rad (Figures l-2). Though this increase in median survival for grade IV patients was only significant between the extremes and not between the intermediate dose range and the
of Kernohan
and Sayre’ the term
astrocytoma” is used for tumors which in general correspond
glioblastoma multiforme is employed grade III and grade 1V; in Rubinstein’s
both for astrocytoma classification6 this term
Kernohan and Sayre’s grade III tumors. tMany of the BTSG patients also received chemotherapy.
is employed for grade IV tumors and the term “anaplastic
to
1738
Radiation Oncology 0 Biology 0 Physics
extremes, there was a significant difference in median survival between all dose ranges for patients with astrocytoma grade III, (Figure lb). Indeed, the media survival for patients with grade III tumors increased significantly, from 82 to 204 weeks, as a result of the increase in dose from GO00 to 7500 rad (Figure 2). These facts, along with the acceptable quality of survival and the absence of significant morbidity accompanying doses of 7000-8000 rad delivered with conventional fractionation over a period of 779 weeks, warrants further investigation in the use of these doses, particularly in patients with grade III tumors. Although the median survival and median time for recurrence have been improved with the use of higher doses, the aim of any therapeutic approach in oncology should be to try to control and cure the patient’s affliction and thus result in a gain in overall survival. Survival estimates for patients with glioblastoma multiforme who were treated with conventional postoperative irradiation (5000-6000 rad) have consistently yielded 5-year figures which range between O-9%.‘.” In this present series, the observed increase in the median life-span of patients who were treated with higher radiation doses was not reflected in the overall survival, beyond two years for grade IV tumors (Figure 1a) and 4 years after treatment for grade III tumors (Figure lb). This was a clear indication that high doses, which at times were as high as 8000 rad, were not able to “cure” more patients with malignant gliomas than conventional radiation doses. Moreover, 26 of 28 patients (93%) in the VHD group had recurrence of their tumors and 24 patients (96%) had died either of tumor persistence or recurrence when the study was closed. In fact, 10 autopsies and one reoperation in these patients clearly demonstrated recurrent (viable) tumor in the heavily irradiated areas, indicating that tumor sterilization was not attained with doses of 7000-8000 rad. Frank (gross or microscopic) radiation-induced necrosis of normal brain tissue in non-tumor areas was not seen in any of the specimens obtained in VHD patients; however, necrosis associated with tumor recurrences was a common finding. Brain radiation necrosis is a diagnosis by exclusion and as such is often difficult to diagnose and document even microscopically. Although specimens obtained at necropsy or reoperation 3-4’/2 years after treatment with VHD do not show focal or confluent areas of necrosis in the heavily irradiated normal brain tissue, certain changes suggestive of marked radiation effect have been seen in normal tissue at the periphery of recurrent tumors (Figures 6 & 7). These changes have been described in blood vessels (hyalinization, sclerosis, thickening and necrosis of the walls) and in the parenchyma itself (reactive pleomorphic gliosis, fibrosis, focal demyelinization, focal hemorrhages and coagulation necrosis). All of these changes were microscopic and many of them can be seen with recurrent tumors: however, some (i.e., coagulation necrosis) were observed and described by the neuropathologists to have been
October 1979, Volume 5, Number 10
Fig. 6. Specimen from 46 year old patient with astrocytoma grade 111 who died of tumor recurrence 4% years following postoperative irradiation with a total dose of 8000 rad. A cavity lined by recurrent tumor is shown. There is preservation of the normal anatomy
of the contralateral
hemisphere.
present to a greater extent than would be expected with tumor recurrences. Thus, though it may be suggested that doses higher than 7500 rad might attain tumor sterilization in these patients, the present authors consider it probable that higher doses may lead to frank radiation necrosis and, of course, defeat the intended purpose of treatment. The present study lacks randomized prospective controls; this may indicate that differences in median survival seen among patients treated with high versus conventional radiation doses could conceivably result from an element of selection and/or the size of the study sample. However, the present study clearly demonstrates that the use of very high doses in grade IV tumors only achieves trivial increases in median survival which do not seem to affect the overall survival of these unfortunate patients significantly. The authors would recommend further exploration of this therapeutic strategy only for the more favorable group of younger patients with grade 111 tumors, in whom the use of high-doses yielded a very significant gain by prolonging their median survival. The authors would also like to express their concern about exploring total doses higher than 7500 rad since these
Fig. 7. Microscopic section from 36 year old patient with astrocytoma grade III who was reoperated for tumor recurrence 4.3 years following postoperative irradiation with a total dose of 7500 rad. A. 40x. Homogenization and necrosis of blood vessel wall. Neoplastic cells surround hyalinized blood vessel. B. 35x.
Non-neoplastic area with coagulation focal areas of hemorrhage.
C. 25x.
Thickening
necrosis
and
and hyalinization of blood vessels in the midst of neoplastic tissue.
1740
Radiation Oncology 0 Biology 0 Physics
very high doses may lead to a frank incidence of radiation-induced normal brain tissue necrosis in a group of patients who would be expected to survive longer; the development of this complication would defeat the intended therapeutic achievement. The present study was performed with the idea of exploring an optimal radiation dose that could be delivered to patients with malignant gliomas. It was originally thought that with the determination of an optimal radiation dose, combinations of postoperative radiation and other adjuvant therapies could be pursued with better effect. In the most recent analysis of the BTSG, the combination of 6000 rad whole brain irradiation and
October 1979, Volume 5, Number 10
BCNU administered postoperatively, resulted in small increases in median survival which were not reflected in overall survival.14 Fast neutron irradiation has also failed to alter the overall survival of patients;12 yet since this form of therapy has demonstrated sterilization of some malignant gliomas, the authors of the present study feel that the use of mixed photon-neutron beams represents a direction that might be followed gainfully. It is further considered possible that the addition of radiosensitizers, in optimal combination with other chemotherapeutic agents of independent toxicities, would improve the effect of surgery and radiation in the control and intended cure of malignant
gliomas.
REFERENCES 1. Earle, K.M.: The proper nomenclature for glioblastoma multiforme. Int. J. Rad. 0~01. Biol. Phys. 1: 805-808, 1976. 2. Gehan, E.A.: A generalized Wilcoxon test for comparing 52: 2033 arbitrarily singly-censored samples. Biometrika 223,
1965.
3. Gehan,
patients
E.A. and Walker, with brain tumors.
Tumor
Therapy:
Laboratory
M.D.: Prognostic factors for In Modern Concepts in Brain and Clinical
tion Therapy with Low-Dose (Pulsed) BCNU in Malignant Gliomas. In preparation. 9. Salazar, O.M. and Rubin, P.: The spread of glioblastomas as a determining factor in the radiation treated volume. Int. J. Rad. Oncol. Biol. Phys. 1: 6277637,
Oncol. Biol. Phys. 1:717-727,
Investigations.
J.C. Bailar & E.K. Weisberger (eds), National Cancer Institute (NCI) monograph 46, Bethesda, NC1 1977, pp 189-196. 4. Kaplan, E.L. and Meier, P.: Nonparametric estimation for incomplete observations. J. Am. Stat. Assoc. 53: 457748 1.
I I. Salazar,
12.
1958. 5. Kernohan,
J.W. and Sayre, G.P.: Tumors of the central nervous system. In Atlas of Tumor Pathology, Sec. 10, Fascicles 35 and 37, Washington, D.C., Armed Forces Institute of Pathology (AFIP), 1952, pp 17-42. 6. Rubinstein, L.J.: Tumors of the Central Nervous System. In Atlas of Tumor Pathology, Fascicle 6, Washington, D.C., Armed Forces Institute of Pathology (AFIP) 1972, pp 422130. 7. Salazar, O.M.: Moments of Decision in Primary Brain Tumors. Rubin, P. and Preston, W. (eds). Chicago, III., American College of Radiology (ACR), 1977, pp 39-77. 8. Salazar, O.M., Malaker, D., Bennett, J.J., Rubin, P., Feldstein, M.L. and Pizzutiello, R.J.: For the Eastern Cooperative Oncology Group (ECOG): High-Dose Radia-
1976.
10. Saiazar, O.M., Rubin, P., McDonald, J.V. and Feldstein, M.L.: High-dose radiation therapy in the treatment of glioblastoma multiforme: A preliminary report. Int. J. Rad.
13.
14.
15.
1976.
O.M., Rubin, P., McDonald, J.F. and Feldstein, M.L.: Patterns of failure in intracranial astrocytomas after irradiation: Analysis of dose and field factors. Am. J. Roentgenol. 126: 279-292, 1976. Shaw, C.M., Sumi, SM., Alvord, E.C.. Gerdes, A.J., Spence, A. and Parker, R.G.: Fast-neutron irradiation of glioblastoma multiforme. J. Neurosurg. 49:1-12, 1978. Sheline, G.: The importance of distinguishing tumor grade in malignant gliomas: Treatment and prognosis. Int. J. Rad. Oncol. Biol. Phys. 1: 781-786, 1976. Walker, M.D., Alexander, E. Jr., Hunt, W.E., MacCarty, C.S., Mahaley, M. Jr., Mealey, J. Jr., Norrell, H.A., Owens, G., Ransohoff, J., Wilson, C.B., Gehan, E.A., Strike, T.A.: (for the Brain Tumor Study Group). Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J. Neurosurg. 49: 333-343, 1978. Walker, M.D., Strike, T.A. and Sheline, G.E.: for the Brain Tumor Study Group (BTSG). An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Rad. Oncol. Biol. Phys. 5: Ott, 172551731, 1979.