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Effects of treatment on long-term survivors with malignant astrocytomas.

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Effects of Treatment on Long-Term
Survivors with Mahgnant Astrocytomas
Joseph P. Imperato, MD," Nina A. Paleologos, MD,? and Nicholas A. Vick, MDT
We reviewed the records of 160 consecutive patients with glioblastoma and anaplastic astrocytoma to evaluate the
long-term consequences of radiation therapy and chemotherapy. We defined long-term survivors as those patients with
glioblastoma or anaplastic astrocytoma who lived at least 100% longer than median survival of historical controls, for
example, 2 years for patients with glioblastoma and 4 years for patients with anaplastic astrocytoma. There were 9
(5.6%)long-term survivors. Three (30%) became demented and died without evidence of tumor recurrence. One, after
survival of 10 years, died of tumor recurrence. Of the remaining survivors, 2 (22%) have significantly impaired shortterm memory function and other neurological deficits such as gait apraxia. Three (30%) can function independently. It
is likely but cannot be proved that it is radiotherapy and not chemotherapy that is the causal factor of this dismal
therapeutic outcome. Our study suggests restraint in the use of radiotherapy for patients with brain tumors that have
more favorable prognoses than glioblastomas and anaplastic astrocytomas, such as low-grade astrocytomas and
oligodendrogliomas.
Imperato JP, Paleologos NA, Vick NA. Effects of treatment on long-term survivors
with malignant astrocytomas. Ann Neurol 1990;28:818-822
Patients and Results
There is considerable concerned opinion about the
lack of data regarding the long-term consequences of
brain radiotherapy [l-31. This is especially true of information concerning the potential combined impact
of radiation with chemotherapy [ 3 , 41. In general, it is
said that approximately 2 to 55% of patients with primary brain tumors develop radiation injury after treatment {Z, 5 , 61. This has been OUT experience as well
but does not consider the fact that almost all patients
die before this side effect is likely to appear.
The impetus for this study was our growing concern,
shared by many others, that because the natural history
of low-grade astrocytomas and oligodendrogliomas is
longer than previously thought [ 5 , 7-10}, and that
because increasing numbers of these tumors are identified by magnetic resonance (MR) scans in patients who
have had seizures, radiotherapy for these patients may
have detrimental long-term side effects. Indeed, it is
now generally agreed that there is insufficient evidence
to justify radiotherapy for the low-grade astrocytomas
and oligodendrogliomas on the basis of what is known
about its efficacy [B-11). We thought that if we could
demonstrate that the negative effects of postsurgical
treatment of long-term survivors with glioblastoma
and with anaplastic astrocytoma was substantial, there
would then be support for restraint in the treatment of
patients with gliomas of more indolent growth characteristics.
A consecutive series of 160 patients with glioblastoma and
anaplastic astrocytoma, defined histologically in accordance
with a three-tier grading scheme [12], was studied for survivorship of greater than 2 years for those patients with
glioblastoma and 4 years for those with anaplastic astrocytoma. This survivorship is 100% longer than median survival
of less than 1 year for patients with glioblastoma and 27
months for patients with anaplastic astrocytoma [12, 131.
There were 100 patients with glioblastoma and 60 with anaplastic astrocytoma. Eighty-two percent had chemotherapy
after radiotherapy. Of the 160 patients, there were 9 (5.6%)
long-term survivors as defined (Table). All 9 had gross total
resections of their tumors at the onset of disease. Two were
reoperated on at recurrence; 1 had three operations. Two
(22%) became profoundly demented and died without evidence of tumor recurrence. One became moderately demented and died of a myocardial infarction 7.5 years after
diagnosis. One died with histologically proved tumor recurrence after a 10-year survival with mild global dysfunction
that prevented employment. Three of the 5 living (30% of
total, 60% of living) have significant global neurological impairment. Two have impaired immediate recall and are
homebound with apraxic gaits. One is able to work as a
professional but at a reduced intellectual capacity; another is
employed part-time but unable to work at the profession for
which she was trained. One is normal in all respects. Sixty
percent of our 9 long-term survivors had treatment-related
neurological decline that they either died with or that now
causes them severe impairment.
From the Depmments of *Radiolom and tNeurolom, Northwestern Medical School, Evanston Hospital, Evanston, IL.
Address correspondence to Dr Vick, Division of Neurology, Evanston Hospital, Evanston, IL 60201.
Received Apr 23, 1990, and in revised form Jun 28. Accepted for
publication Jun 29, 1990.
818 Copyright 0 1990 by the American Neurological Association
Clinical Data
Age At
Tumor
Onset
Radiotherapy (rads)
Whole Brain
Boost (fraction)
Onset of
Cognitive
Change
(Years
after
Survival
Chemotherapy Diagnosis) (yr)
Status
Patient Sex Type
(yr)
1
M
GBM
62
4,500 (180)
1,400
(200)
BCNU
1
2
F
GBM
65
...
F
GBM
22
4,835 (180)
4
M
AA
55
4,760 (180)
AZQ
CCNU
AZQ
BCNU
PCB
None
3
3
5,460
(160)
1,600
(160)
5
M
GBM
41
2,700 (150)
1,120
(160)
2
3.5
1,800 (560 None
3
neutron)
(150)
6
M
GBM
23
4,760 (200)
2 00
CCNU
4
7
M
GBM
61
4,320 (180)
BCNU
1
8
F
AA
57
4,700 (180)
BCNU
2
9
F
GBM
24
4,320 (180)
1,800
(180)
1,720
(200)
1,800
(200)
BCNU
..
GBM = glioblastoma multiforme; BCNU = bischloroethylnitrosourea;AZQ
trosourea; PCB = procarbazine;AA = anaplastic astrocytoma
Figures 1 through 4 illustrate the spectrum of brainimaging abnormalities that were observed in this group of 9
patients. Although the legends are largely self-explanatory, it
is worth mentioning a few observations about the group as a
whole. Only 1 patient with clinical impairment had an unimpressive computed tomographic (CT) or MR scan (see Fig 2).
This patient’s brain atrophy is confined to the region of the
tumor bed, yet his brain dysfunction is global. In another
instance, such as the patient illustrated in Figure 1, the brain
atrophy is generalized, as if the effects of the local boost dose
were not the deleterious factor at all. As seen in Figure 4, at
times MR may add little to C T except details.
The Table provides the radiotherapy data. One patient was
treated to a limited field only. The others all had whole brain
radiation (maximum was 4,960 rads) with boosts to the
tumor bed. The total doses to the primary tumor volume in
the entire group ranged from 4,500 to 6,435 rads. The daily
fraction sizes in all patients ranged from 150 to 200 rads. In
this group of 9 patients, no relation between the type of
radiotherapy (either whole brain or to tumor bed with margins) and outcome could be discerned. It is generally believed that the toxicity of radiation is related to volume
irradiated and, although the spechc relation remains undetermined, most radiotherapists try to avoid giving whole
brain irradiation. Of the 3 best survivors, 2 had whole brain
radiation plus boost to the tumor bed, and 1 was treated with
=
Apraxic gait, incontinent, global
cognitive dysfunction, unable to
care for himself.
Profoundly demented. No evidence
7
of tumor at time of death.
10
Mild to moderate global dysfunction. Employed at level below
(alive)
5 (allve)
7.5
her training.
Mild memory impairment, lived in-
dependently. No evidence of
tumor ar time of death.
Mild memory dysfunction. Em7.5
(alive)
ployed at level below previous
job.
10
Moderate global dysfunction, unable to work. Recurrence of
tumor at time of death.
Profoundly demented. No evidence
2.5
of tumor at time of death.
Profound memory dysfunction, dis4.5
abling gait apraxia.
(alive)
2 (alive) Normal.
aziridinylbenzoquinone;CCNU
=
cyclohexylchloroethyIni-
whole brain radiation plus a neutron rather than photon
boost to the tumor bed.
The role of chemotherapy in the production of neurological impairment in these 7 patients is unclear. Two had no
chemotherapy. One had a single dose of bischloroethylnitrosourea (BCNU). Three were treated with BCNU; one
had aziridinylbenzoquinone (AZQ) with cyclohexylchloroethylnitrosourea (CCNU), one had AZQ alone, and one
C C N U alone. One had AZQ, BCNU, and procarbazine. Of
the 3 patients who are functioning at the most normal level
(all with glioblastomas), 1 was not treated with chemotherapy, 1 had BCNU, and the other had AZQ. Of the 4 patients who died, l did not have chemotherapy.
Discussion
There are several studies that adequately document
brain injury in brain tumor patients treated with radiotherapy 11, 3, 4, 14-16]. Nonetheless, t h e actual irnpact of t h e problem has not been made clear because
of lack of attention to the survivorship of the population of patients being studied. If the treatment of patients with glioblastoma and anaplastic astrocytoma is
unambitious and palliative, with t h e expectation that
few are unlikely to live beyond t h e current median
survival time, then our concern about the impact of
Imperato et al: Radiation Injury
819
A
B
Fig 1. In 1983, this 41-year-old man (Patient 5 in the Table)
had a generalized seizure. A right frontal g1iobla.rtom.a was resected, followed by 4.500 photon rads to the whole brain and
560 neutron rads to the tumor bed. The sran on the left (A)is
from 1983, immediately after radiotherapy. He had no chemotherapy. The scan on the right (B) is from 1989. He has a
problem with short-term memory function but works productively.
A
B
Fig 2. In 1984, this 62-year-old man (Patient 1 in the Table)
had progressive motor and sensory impairment of his right limbs.
A Itfit frontoparietal parasagittal glioblastom was resected followed by 4,500 photon rads t o the whole brain with a 1,400rad boost 80 the tumor bed. He had one cycle of bischloroethylni-
trosourea chemotherapy. The computed tomographicscan o n the
left (A) is from 1985. The magnetic resonance scan on the right
(B)is from 1989. He is ambulatory but cannot be ldt alone due
to memory dysfunction and episodes of global confusion and
sphincter incontinence.
820 Annals of NeurolL.,y
Vol 28
No 6 December 1990
B
Fig 3. In 1986, thzs 61-year-old man (Patient 7 zn the Table)
developed zntermittent sensory symptoms of his mght limbs, followed by nonjuent aphasia. A glroblastoma was resected from
hzs lejit temporal lobe followed by 4,320 rads to the whole brain
with a 1,800-rad boost t o the tumor bed. Bischloroethylnztrotourea chemotherapy was grven thereafter. He zmproved steadzly
and had no recuwence evident by computed tomography or magnetic resonance (MR) (A)when, late in 1986, he began t o declzne, with regard to both memory function and gazt Early in
1981, a pearfrom the ttme of dzagnosis, he mas pojioundb impaired and an M R scan (B)showed severe white matter change
He became bedrzdden,profound4 demented, and died 28 months
a f f r radzotherapy was completed
Fzg 4. In 1981, this 65-year-old woman (Patient 2 in the
Table) developed hedches and was found by computed tomography (CT)t o have a right frontal mass that proved on resection
to be a glzoblastoma. Surgery was followed by 5,460 photon rads
to the tumor bed. After recuwence in 1982, she was reoperated
on and received cyclohexylchlo~th~ln~trosourea
and azzrtdtnylbenzoquinone chemothwap?. B, 1984, she had gazt aprama and
memory zmpairment. She gradually became severely demented,
and she died in 1988. The last zmagzng studies. C T zn (A) and
magnetic resonance in (B),were done 5 months before her death.
Imperato et al: Radiation Injury
821
radiotherapy on a long-term basis is excessive. If, however, newer modalities of treatment are to have any
meaningful value for these patients, then the high proportion of brain injury in long-surviving radiated patients becomes consequential. Aggressive surgical resection, as was done in all 9 of our long-term survivors,
is a major positive variable in prognosis [17-211. Aggressive chemotherapy will at times yield impressive
responses, and improvement in response rates in the
future are reasonable to expect [18,22-25}. Nonetheless, at present, sustained and clinically meaningful responses to treatment for glioblastoma and anaplastic
astrocytoma are so infrequent that our results do not
compel us to think that the current manner of treating
patients with glioblastoma and anaplastic astrocytoma
with radiotherapy should be altered. Radiotherapy increases median survival by 100 to 150% {18, 22, 26,
271. Unfortunately, no other present form of postsurgical treatment has any promise of this magnitude
of benefit. On the other hand, we are convinced that
results such as we have shown in these 160 patients
strongly suggest that radiotherapy not be given to
patients who have more indolent gliomas such as
low-grade astrocytomas and oligodendrogliomas unless
there are unequivocal signs of tumor progression and
lack of other treatment options. It is well known that
the MR scanning has shown that these tumors are far
more common and appear to have a much more indolent course than was previously recognized. Until firm
natural history data emerge in the MR era about these
tumors, or the results of carefully controlled clinical
studies emerge, there appears to be little if any justification for subjecting patients with these tumors to a
form of treatment with potentially devastating longterm consequences.
This study was supported by National Institutes of Health Grant
P50 NS200323 and the W. Freeman Memorial Fund.
The assistance of Annette Walsh, RN, is acknowledged.
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Vol 28 No 6 December 1990
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