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Failure of accelerated neutron therapy to control high grade astrocytomas
0360-3Ol6/89 $3.00 + .OU Copyright 0 1989 Pergamon Press plc
Inf. I Radinrion Oncology Bid. Phys., Vol. 17, pp. 1295-1297 Printed in the U.S.A. All rights reserved.
l Phase I/II Clinical Trials
FAILURE OF ACCELERATED NEUTRON THERAPY TO CONTROL HIGH GRADE ASTROCYTOMAS K. R. SAROJA, M.D., JOANNE MANSELL, LIONEL COHEN,
M.D.
R.N.,
OCN,
AND ARLENE
F. R. HENDRICKSON,
LENNOX,
M.D.,
PH.D.
MidwestInstitute for Neutron Therapy at Fermilab, P.O. Box 5004, Batavia, IL 605 10 Sixty-two patients with high grade malignant astroeytoma were treated with fast neutrons using three different treatment schemes to evaluate the effect of shortening the overall time. Dose and fraction number were kept constant. The total dose was 16-18 neutron Gy delivered in six fractions, weekly for 6 weeks, twice a week over 3-4 weeks, or three times a week over 2 weeks. There were no obvious differences in survival times among the three groups. We conclude that accelerated neutron therapy does not improve survival of patients with grade 3 and 4 astrocytoma. Fast neutrons, Accelerated fractionation, Malignant astrocytoma.
INTRODUCTION
day (accelerated hyperfractionation). Fraction size and fraction number are less critical with neutrons and treatment times can be readily shortened (4). We received experience with 6 (weekly) fractions in the control arm of a concomitant misonidazole study (6). When this approach proved ineffective, the possible advantage of a shorter (3 week) course was explored. When this also failed to improve the outcome, the course was further shortened to 2 weeks, and the target volume was reduced to encompass the tumor alone rather than the whole brain so as to minimize possible late toxicity. These three groups of patients provide the material for the present report.
In this paper we report a negative result which may be important to researchers considering accelerated high LET radiation for brain tumors. In previous reports (6, 7) we reviewed our experience with the treatment of high grade malignant astrocytomas with fast neutron irradiation. The outcome of these studies was essentially negative, and survival was no better than historical experience with similar tumors treated with photons. Autopsy studies revealed that the tumor had been destroyed by the treatment in many patients, but survival was limited by the onset of fatal post-irradiation gliosis. This implies that therapeutic ratios were small and that no therapeutic window existed at which tumor control could be achieved without serious side effects. In these and similar studies reported from other institutions (2, 3), the treatment time ranged from 4-6 weeks with 1 to 3 neutron fractions per week. The authors considered that high grade astrocytomas might proliferate more rapidly than the supporting normal glia, and that shorter treatment times might be advantageous. With conventional low LET radiation, fraction size and the number of fractions are critical variables in preserving normal tissue tolerance. The number of fractions must be maintained even when the overall treatment time is shortened, and this can be achieved only by the use of multiple fractions per
Three groups of similarly treated patients were identified retrospectively for this analysis. They comprised a series of 62 patients with high grade malignant astrocytoma who had all received 16 to 18 Gy in six fractions over various intervals of time. Overall times ranged from 6 weeks (Group A), 3 to 4 weeks (Group B), down to 2 weeks (Group C). The characteristics of the beam and supporting facilities have been described previously (1). The three groups were not randomized (each was completed in sequence) and no attempt was made to match patients by age, grade or other prognostic variables. Of the 62 patients studied, 52 were grade 4 (glioblastoma)
Reprint requests to: Midwest Institute for Neutron Therapy at Fermilab, P.O. Box 5004; MS-301, Batavia, IL 60510. Acknowledgements-This investigationwas supported in part by PHS Grant Number CA1808 1, awarded by the National
Cancer Institute, DHHS. This material was prepared as an account of work performedby UniversitiesResearch Association, Inc., using facilitiesowned by the U.S. Department of Energy. Accepted for publication 15 June 1989.
METHODS
1295
AND
MATERIALS
1296
I. J.
RadiationOncology0 Biology0 Physics
December1989,Volume17,Number 6
Table 1.
I
Group
*
100
Total
Age
A
B
520 21-30 31-40 41-50 51-60 >60
3 4 0 10 7 6
0 4 0 4 4 3
2 4 5 5
3 9 2 18 16 14
Total
30
15
17
62
c
0 1
I
’
1
’
I
’
A- 6 WEEK COURSE o- 4 WEEK COURSE
90
l-
2 WEEK COURSE
80 70 60 50
and 10 were grade 3. The age distributions of the three groups studied are shown in Table 1. Details of treatment are shown in Table 2. Although all patients received six fractions, there was some variance in dose, time, and target volume. Group A patients were given 18 Gy to the tumor (12 Gy to the whole brain and 6 additional Gy to the enhancing lesion). Group B received 16 Gy ( 10 Gy to the whole brain and 6 Gy boost). Group C received 16 Gy but this was confined to the tumor volume with a 1 cm margin. These differences were introduced to minimize any possible risk of more severe damage associated with shorter treatment times. Also note (Table 2) that the nominal 6 weeks treatment varied over 34 to 46 days. The differences were caused by logistic considerations such as weekends, availability of beam, and transport problems; they were not related to patient reactions or performance. Similarly, the nominal 3- to 4-week period ranged from 18 to 32 days, and the 2-week period varied between 12 and 18 days. All patients had histologically confirmed grade 3 or grade 4 astrocytoma and were referred for irradiation following either incomplete resection or biopsy. All patients were ambulatory with varying degrees of neurological deficit, largely dependent on the location of the tumor. The Kamofsky score was at least 80 in all except three patients. These three patients were in Group A and all had grade 4 tumors. All patients received 12- 16 mg of dexamethasone at least 12-24 hr prior to initiation of neutron beam therapy and were gradually tapered off 4 weeks following the completion of therapy. The patients were followed on a regular basis at 1- and then 3-month intervals. CT scans were done every 3-4 months (sooner if clinically indicated) to assess the tumor response. If (or when) the patients deteriorated, a second craniotomy and biopsy were advised. Biopsy or autopsy
40 30 20 10 0 0
1
2
3
4
5
YEARS Fig. 1. Actuarial survival curves for 6-week, nominal 4-week, and 2-week treatment
course.
material was obtained in 21 patients. Results were analyzed retrospectively and survival curves were generated by the Kaplan-Meyer actuarial method (5).
RESULTS The primary endpoint of this study was survival time since we were attempting to determine whether accelerated fractionation had any impact on survival. Figure 1 plots the survival curves for the three treatment groups. The median survival for patients treated over 6 weeks was 10.8 months. For patients treated over 4 weeks the median survival period was 11.4 months, and for patients with a 2-week treatment time, it was 9.3 months. The expected dependence of outcome upon age and tumor grade is shown by the actuarial survival curves in Figure 2. The median survival time (for all treatment groups) was 14.4 months for grade 3 and 9.6 months for grade 4 astrocytomas.
Table 2. Group
A B C
Number patients 30 15 17
Grade 41 Grade 3
Dose (GY)
Fract.
Time (days)
Remarks
2416 1213 16/l
18 16 16
6 6 6
34-36 19-32 12-18
12 Gy to whole brain and 6 Gy boost 10 Gy to whole brain and 6 Gy boost 16 Gy to target volume only
Accelerated neutron therapy
n
for astrocytomas0 K. R.
1297
trons alone either in combination with photons or with hypoxic cell sensitizers (3, 7). Survival comparisons did not reveal any superiority for neutrons compared to conventional radiation. These authors concluded that neutrons can eradicate malignant glioma cells but in view of the severity of normal brain damage there appeared to be no identifiable therapeutic window at which local control could be achieved without lethal side effects. It was expected that with fast neutron irradiation a shorter overall time of treatment would improve the outcome because the tumor cells were thought to proliferate faster than associated normal tissue. However, this did not happen, and comparative survival periods for various overall treatment times are similar. It was felt that since the three groups described were studied sequentially, were neither randomized nor matched for prognostic variables, and were small in number, rigorous statistical analysis of any small differences
- GRADE 3
o-GRADE
SAROJA efal.
4
60
in outcome was inappropriate. Absence of proof is not proof of absence and while some difference might be detected in a more rigorous study, any such difference is
YEARS
Fig. 2. Actuarial survival curves for Grade 3 and 4 astrocytoma patients. Tissue from 2 1 patients was available for post-treatment pathological examination either as a result of second craniotomy with resection of tumor or by autopsy. Viable tumor cells and radiation necrosis were seen within the primary target volume in all cases. DISCUSSION Kurup et al. and Duncan et al. have reviewed the results of patients with malignant astrocytoma treated with neu-
likely to be small. We conclude that the accelerated (2 week) treatment is not substantially better than the more protracted (6 week) procedure. This result may have been predictable, given the usual progress of the disease, but not all clinicians are as pessimistic and many have expressed the view that shorter treatment times could be advantageous in this particular rapidly proliferating tumor. The major import of our observation is that we were unable to demonstrate any advantage of accelerated neutron therapy for gliomas. We suggest that future research on treatment of this tumor should probably be directed to avenues other than high LET and/or manipulation of time factors.
REFERENCES 1. Awschalom,
M.; Rosenberg, I. Characterization of a p(66)Be(49)neutron therapy beam. II. Skin sparing and dose transition effects. Med. Phys. 8: 105-107; 198 1. 2. Caterall, M.; Bloom, H. J. G.; Ash, D. V.; Walsh, L.; Richardson, A.; Uttley, D.; Gowing, F. C. N.; Lewis, P.; Chanter, B. Fast neutrons compared with megavoltage X-rays in the treatment of patients with supratentorial glioblastoma: a controlled study. Int. J. Radiat. Oncol. Biol. Phys. 6:261266; 1980. 3. Duncan, W.; McLelland, J.; Jack, L. J. W.; Arnott, J.; Gordon, A.; Kerr, G. R.; Willis, J. R. Report of a randomized pilot-study of the treatment of patients with supratentorial gliomas using neutron irradiation. Br. J. Radiol. 59:373377; 1986.
4. Fowler, J. F. What to do with neutrons in radiotherapy. A suggestion. Radiother. Oncol. 13:233-235; 1988. 5. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-48 1; 1958. 6. Kurup, P. D.; Pajak, R. F.; Hendrickson, F. R.; Nelson, J. S.; Mansell, J.; Cohen, L.; Awschalom, M.; Rosenberg, 1.; and TenHaken, R. Fast neutrons and misonidazole for malignant astrocytomas. Int. J. Radiat. Oncol. Biol. Phys. 2:679-686; 1985. 7. Kurup, P. D.; Pajak, R. F.; Nelson, J. S.; Mansell, J.; Hendrickson, F. R.; Cohen, L.; Griffin, T. W. Fast neutron therapy for malignant astrocytomas, a review. J. Neuro-Oncol. 4:123-129; 1986.
Inf. I Radinrion Oncology Bid. Phys., Vol. 17, pp. 1295-1297 Printed in the U.S.A. All rights reserved.
l Phase I/II Clinical Trials
FAILURE OF ACCELERATED NEUTRON THERAPY TO CONTROL HIGH GRADE ASTROCYTOMAS K. R. SAROJA, M.D., JOANNE MANSELL, LIONEL COHEN,
M.D.
R.N.,
OCN,
AND ARLENE
F. R. HENDRICKSON,
LENNOX,
M.D.,
PH.D.
MidwestInstitute for Neutron Therapy at Fermilab, P.O. Box 5004, Batavia, IL 605 10 Sixty-two patients with high grade malignant astroeytoma were treated with fast neutrons using three different treatment schemes to evaluate the effect of shortening the overall time. Dose and fraction number were kept constant. The total dose was 16-18 neutron Gy delivered in six fractions, weekly for 6 weeks, twice a week over 3-4 weeks, or three times a week over 2 weeks. There were no obvious differences in survival times among the three groups. We conclude that accelerated neutron therapy does not improve survival of patients with grade 3 and 4 astrocytoma. Fast neutrons, Accelerated fractionation, Malignant astrocytoma.
INTRODUCTION
day (accelerated hyperfractionation). Fraction size and fraction number are less critical with neutrons and treatment times can be readily shortened (4). We received experience with 6 (weekly) fractions in the control arm of a concomitant misonidazole study (6). When this approach proved ineffective, the possible advantage of a shorter (3 week) course was explored. When this also failed to improve the outcome, the course was further shortened to 2 weeks, and the target volume was reduced to encompass the tumor alone rather than the whole brain so as to minimize possible late toxicity. These three groups of patients provide the material for the present report.
In this paper we report a negative result which may be important to researchers considering accelerated high LET radiation for brain tumors. In previous reports (6, 7) we reviewed our experience with the treatment of high grade malignant astrocytomas with fast neutron irradiation. The outcome of these studies was essentially negative, and survival was no better than historical experience with similar tumors treated with photons. Autopsy studies revealed that the tumor had been destroyed by the treatment in many patients, but survival was limited by the onset of fatal post-irradiation gliosis. This implies that therapeutic ratios were small and that no therapeutic window existed at which tumor control could be achieved without serious side effects. In these and similar studies reported from other institutions (2, 3), the treatment time ranged from 4-6 weeks with 1 to 3 neutron fractions per week. The authors considered that high grade astrocytomas might proliferate more rapidly than the supporting normal glia, and that shorter treatment times might be advantageous. With conventional low LET radiation, fraction size and the number of fractions are critical variables in preserving normal tissue tolerance. The number of fractions must be maintained even when the overall treatment time is shortened, and this can be achieved only by the use of multiple fractions per
Three groups of similarly treated patients were identified retrospectively for this analysis. They comprised a series of 62 patients with high grade malignant astrocytoma who had all received 16 to 18 Gy in six fractions over various intervals of time. Overall times ranged from 6 weeks (Group A), 3 to 4 weeks (Group B), down to 2 weeks (Group C). The characteristics of the beam and supporting facilities have been described previously (1). The three groups were not randomized (each was completed in sequence) and no attempt was made to match patients by age, grade or other prognostic variables. Of the 62 patients studied, 52 were grade 4 (glioblastoma)
Reprint requests to: Midwest Institute for Neutron Therapy at Fermilab, P.O. Box 5004; MS-301, Batavia, IL 60510. Acknowledgements-This investigationwas supported in part by PHS Grant Number CA1808 1, awarded by the National
Cancer Institute, DHHS. This material was prepared as an account of work performedby UniversitiesResearch Association, Inc., using facilitiesowned by the U.S. Department of Energy. Accepted for publication 15 June 1989.
METHODS
1295
AND
MATERIALS
1296
I. J.
RadiationOncology0 Biology0 Physics
December1989,Volume17,Number 6
Table 1.
I
Group
*
100
Total
Age
A
B
520 21-30 31-40 41-50 51-60 >60
3 4 0 10 7 6
0 4 0 4 4 3
2 4 5 5
3 9 2 18 16 14
Total
30
15
17
62
c
0 1
I
’
1
’
I
’
A- 6 WEEK COURSE o- 4 WEEK COURSE
90
l-
2 WEEK COURSE
80 70 60 50
and 10 were grade 3. The age distributions of the three groups studied are shown in Table 1. Details of treatment are shown in Table 2. Although all patients received six fractions, there was some variance in dose, time, and target volume. Group A patients were given 18 Gy to the tumor (12 Gy to the whole brain and 6 additional Gy to the enhancing lesion). Group B received 16 Gy ( 10 Gy to the whole brain and 6 Gy boost). Group C received 16 Gy but this was confined to the tumor volume with a 1 cm margin. These differences were introduced to minimize any possible risk of more severe damage associated with shorter treatment times. Also note (Table 2) that the nominal 6 weeks treatment varied over 34 to 46 days. The differences were caused by logistic considerations such as weekends, availability of beam, and transport problems; they were not related to patient reactions or performance. Similarly, the nominal 3- to 4-week period ranged from 18 to 32 days, and the 2-week period varied between 12 and 18 days. All patients had histologically confirmed grade 3 or grade 4 astrocytoma and were referred for irradiation following either incomplete resection or biopsy. All patients were ambulatory with varying degrees of neurological deficit, largely dependent on the location of the tumor. The Kamofsky score was at least 80 in all except three patients. These three patients were in Group A and all had grade 4 tumors. All patients received 12- 16 mg of dexamethasone at least 12-24 hr prior to initiation of neutron beam therapy and were gradually tapered off 4 weeks following the completion of therapy. The patients were followed on a regular basis at 1- and then 3-month intervals. CT scans were done every 3-4 months (sooner if clinically indicated) to assess the tumor response. If (or when) the patients deteriorated, a second craniotomy and biopsy were advised. Biopsy or autopsy
40 30 20 10 0 0
1
2
3
4
5
YEARS Fig. 1. Actuarial survival curves for 6-week, nominal 4-week, and 2-week treatment
course.
material was obtained in 21 patients. Results were analyzed retrospectively and survival curves were generated by the Kaplan-Meyer actuarial method (5).
RESULTS The primary endpoint of this study was survival time since we were attempting to determine whether accelerated fractionation had any impact on survival. Figure 1 plots the survival curves for the three treatment groups. The median survival for patients treated over 6 weeks was 10.8 months. For patients treated over 4 weeks the median survival period was 11.4 months, and for patients with a 2-week treatment time, it was 9.3 months. The expected dependence of outcome upon age and tumor grade is shown by the actuarial survival curves in Figure 2. The median survival time (for all treatment groups) was 14.4 months for grade 3 and 9.6 months for grade 4 astrocytomas.
Table 2. Group
A B C
Number patients 30 15 17
Grade 41 Grade 3
Dose (GY)
Fract.
Time (days)
Remarks
2416 1213 16/l
18 16 16
6 6 6
34-36 19-32 12-18
12 Gy to whole brain and 6 Gy boost 10 Gy to whole brain and 6 Gy boost 16 Gy to target volume only
Accelerated neutron therapy
n
for astrocytomas0 K. R.
1297
trons alone either in combination with photons or with hypoxic cell sensitizers (3, 7). Survival comparisons did not reveal any superiority for neutrons compared to conventional radiation. These authors concluded that neutrons can eradicate malignant glioma cells but in view of the severity of normal brain damage there appeared to be no identifiable therapeutic window at which local control could be achieved without lethal side effects. It was expected that with fast neutron irradiation a shorter overall time of treatment would improve the outcome because the tumor cells were thought to proliferate faster than associated normal tissue. However, this did not happen, and comparative survival periods for various overall treatment times are similar. It was felt that since the three groups described were studied sequentially, were neither randomized nor matched for prognostic variables, and were small in number, rigorous statistical analysis of any small differences
- GRADE 3
o-GRADE
SAROJA efal.
4
60
in outcome was inappropriate. Absence of proof is not proof of absence and while some difference might be detected in a more rigorous study, any such difference is
YEARS
Fig. 2. Actuarial survival curves for Grade 3 and 4 astrocytoma patients. Tissue from 2 1 patients was available for post-treatment pathological examination either as a result of second craniotomy with resection of tumor or by autopsy. Viable tumor cells and radiation necrosis were seen within the primary target volume in all cases. DISCUSSION Kurup et al. and Duncan et al. have reviewed the results of patients with malignant astrocytoma treated with neu-
likely to be small. We conclude that the accelerated (2 week) treatment is not substantially better than the more protracted (6 week) procedure. This result may have been predictable, given the usual progress of the disease, but not all clinicians are as pessimistic and many have expressed the view that shorter treatment times could be advantageous in this particular rapidly proliferating tumor. The major import of our observation is that we were unable to demonstrate any advantage of accelerated neutron therapy for gliomas. We suggest that future research on treatment of this tumor should probably be directed to avenues other than high LET and/or manipulation of time factors.
REFERENCES 1. Awschalom,
M.; Rosenberg, I. Characterization of a p(66)Be(49)neutron therapy beam. II. Skin sparing and dose transition effects. Med. Phys. 8: 105-107; 198 1. 2. Caterall, M.; Bloom, H. J. G.; Ash, D. V.; Walsh, L.; Richardson, A.; Uttley, D.; Gowing, F. C. N.; Lewis, P.; Chanter, B. Fast neutrons compared with megavoltage X-rays in the treatment of patients with supratentorial glioblastoma: a controlled study. Int. J. Radiat. Oncol. Biol. Phys. 6:261266; 1980. 3. Duncan, W.; McLelland, J.; Jack, L. J. W.; Arnott, J.; Gordon, A.; Kerr, G. R.; Willis, J. R. Report of a randomized pilot-study of the treatment of patients with supratentorial gliomas using neutron irradiation. Br. J. Radiol. 59:373377; 1986.
4. Fowler, J. F. What to do with neutrons in radiotherapy. A suggestion. Radiother. Oncol. 13:233-235; 1988. 5. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-48 1; 1958. 6. Kurup, P. D.; Pajak, R. F.; Hendrickson, F. R.; Nelson, J. S.; Mansell, J.; Cohen, L.; Awschalom, M.; Rosenberg, 1.; and TenHaken, R. Fast neutrons and misonidazole for malignant astrocytomas. Int. J. Radiat. Oncol. Biol. Phys. 2:679-686; 1985. 7. Kurup, P. D.; Pajak, R. F.; Nelson, J. S.; Mansell, J.; Hendrickson, F. R.; Cohen, L.; Griffin, T. W. Fast neutron therapy for malignant astrocytomas, a review. J. Neuro-Oncol. 4:123-129; 1986.