Glioblastoma Multiforme Survivors: a Population-based Study
Scott, N.B. Rewcastle, P.M.A. Brasher, D. Fulton, N.A. Hagen,
A. MacKinnon, G. Sutherland, J.G. Cairncross and P. Forsyth
Background: Long-term glioblastoma multiforme
survivors (LTGBMS) are uncommon. The frequency which these
occur in an unselected population and factors which produce
these unusually long survivors are unknown. Objectives:
To determine in a population-based study 1) the frequency
of LTGBMS in a population and 2) identify which patient, treatment
or tumor characteristics would predict which glioblastoma
(GBM) patient would become a LTGBMS. Methods: The Alberta
Cancer Registry was used to identify all patients diagnosed
with GBM in southern Alberta between 1/1/75 - 12/31/91. Patient
charts were reviewed and histology re-examined by a blinded
neuropathologist. LTGBMS were defined as GBM patients surviving
³ 3 years after diagnosis. Each LTGBMS was compared to three
age-, gender-, and year of diagnosis-matched controls to compare
patient, treatment, and tumor factors to GBM patients without
long-term survival. Results: There were 279
GBMs diagnosed in the study period. Five (1.8%) survived ³
three years (range, 3.2-15.8 years). Seven additional long-term
survivors, who carried a diagnosis of GBM, were excluded after
neuropathologic review; the most common revised diagnosis
was malignant oligodendroglioma. LTGBMS (avg. age = 45 years)
were significantly younger when compared to all GBM patients
(avg. age = 59 years, p = 0.0001) diagnosed in the study period.
LTGBMS had a higher KPS at diagnosis (p = 0.001) compared
to controls. Tumors from LTGBMS tended to have fewer mitoses
and a lower Ki-67 cellular proliferative index compared to
controls. Radiation-induced dementia was common and disabling
in LTGBMS. Conclusions: These data highlight
the dismal prognosis for GBM patients who have both a short
median survival and very small chance (1.8%) of long-term
survival. The LTGBMS were younger, had a higher performance
status, and their tumors tended to proliferate less rapidly
than control GBM patients. When long-term survival does occur
it is often accompanied by severe treatment-induced dementia.
J. Neurol. Sci. 1998; 25: 197
prognosis for patients with glioblastoma multiforme (GBM)
is very poor; the median survival with the best available
treatment is only twelve months and the survival rate has
changed little in the past twenty years.1,2 We
recently encountered a GBM patient who was alive fifteen years
after diagnosis and recognized this as highly unusual. We
were curious as to how commonly GBM patients survived for
a prolonged time in an unselected population of brain tumor
patients and sought to identify factors which might predict
long survival, as well as to determine if a histologic re-examination
of putative long-term GBM survivors (LTGBMS) would uncover
glioma subtypes3-5 which masqueraded as GBMs.
have been described by others6-14 as uncommon,
occurring in 1-17% of GBM patients. The factors found by these
studies that were associated with long-term survival were
unsurprising and included the use of multimodality therapy,
young age and a high performance status at diagnosis.6,7,10-13
There are two limitations of these reports. First, only
one of these9 was population-based. The others
were institutional series which contained highly selected
patients and therefore may not reflect the true incidence
of LTGBMS in the general population of brain tumor patients.
Second, previous comparisons between LTGBMS and their shorter
surviving counterparts have been uncontrolled for known prognostic
factors; this might mask other previously identified prognostic
characteristics specific for long-term survival. To address
these two issues, we performed a population-based, case-controlled
study and compared each identified LTGBMS with three age-,
gender, and year of diagnosis-matched control GBM patients.
study was designed to determine 1) the frequency of LTGBMS
in a population, and 2) to identify which patient, treatment
or tumor characteristics predicted which GBM patient became
a LTGBMS. Information regarding long-term treatment effects
and revised histologic diagnoses of putative LTGBMS was also
Alberta Cancer Registry is a population-based cancer registry
for the Province of Alberta which was established in 1941
by Provincial Legislature and is supported and funded by the
Ministry of Health. All hospitals, pathologic laboratories,
radiographic facilities and cancer treatment centres participate
and all patients with a clinical, radiographic or histologic
diagnosis of cancer (including those diagnosed only at autopsy)
are to be registered by statute.
identified all southern Alberta residents (population in 1996
of 1.2 million) diagnosed with GBM between January 1, 1975
and December 31, 1991 as recorded in the Cancer Registry.Ý
Each glioma patient's chart and pathology report was reviewed
to ensure concordance with the Cancer Registry data. For the
purposes of this study, a long-term survivor was defined as
a patient with a GBM who lived at least 36 months after the
time of tissue diagnosis. Patients in whom the diagnosis of
GBM was not confirmed on histological review, or whose length
of survival could not be determined, were excluded. Each LTGBMS
was compared to three age-, gender-, and year of diagnosis-matched
controls. A retrospective chart review of all GBM patients
was used to define clinical and treatment factors and subsequent
clinical outcomes. Long-term survivors or their relatives,
when possible, were contacted to obtain information regarding
current cognitive function and performance status. This study
received ethical approval by our Institutional Review Board.
LTGBMS tumor specimens were reviewed by a single neuropathologist
(NBR) in a blinded fashion to confirm the diagnosis and assess
identified histologic features. The accepted histologic criteria
for a GBM included a malignant astrocytic neoplasm with the
presence of vascular and endothelial proliferation, as well
as necrosis. All paraffin-embedded hematoxylin and eosin (H&E)
stained sections of tissue submitted to the laboratory were
used. Several features were graded as either present or absent
(necrosis, increased vascularity, and lymphocytic infiltrates),
while others were qualitatively graded (endothelial proliferation,
nuclear pleomorphism and size). Mitoses were counted in 5
contiguous microscope fields examined at 400 x magnification
(0.2 mm2 / 400 x field, for a total of 1.0 mm2)
starting in the area of the greatest pleomorphism and cellularity.
Ki-67 immunostaining was performed according to established
protocols (Immunotech, Marseille, France). The area with the
highest number of labeled cells was identified. In this area,
the percentage of Ki-67-positive nuclei (called the labelling
index) was determined by counting 1,000 nuclei in contiguous
microscopic fields at 400 x magnification. Cells recognizable
as pertaining to blood vessels (e.g., endothelial cells and
pericytes) were not counted. A nucleus was considered positive
if it demonstrated either a diffuse or strong punctate distribution
of reaction product.
analyses were carried out according to the Statistical Analysis
System (SAS Institute Inc., SAS/STAT User's Guide, Version
6, Fourth Edition, Cary, NC). Univariate conditional logistic
regression was used to examine the influence of prognostic
variables. In one case, (Ki-67) near perfect prediction was
encountered (that is in each matched set the value for Ki-67
in the LTGBMS was less than its control cases) and so unconditional
logistic regression was used.
identified 286 patients who were residents of southern Alberta
diagnosed with GBM over the 27 year study period. Of these
286 GBM patients, only 5 (1.8%) were confirmed LTGBMS after
histological review. Their clinical characteristics are summarized
in Table 1. Two were women and three were men; the
mean age was 45 years (range, 32-58 yrs). The LTGBMS were
significantly younger when compared to all GBM patients diagnosed
in the study period (average age, 59 years) (p = 0.0001; t-test).
[International Classification of Diseases for Oncology
topography codes C71.- (Brain) and multiple morphology codes
designed to capture all GBMs or gliosarcomas (94-403, 413,
423) and all gliomas (93-803, 823, 923: 94-001, 003, 013,
113, 203, 513) with a grade 4 and an unknown or missing grade.]
J. Neurol. Sci. 1998; 25: 198
1: Clinical characteristics of LTGBMS1 in southern Alberta.
= Long-term GBM survivor; GBM patients surviving ³
three years after tissue diagnosis.
= Karnofsky Performance Status at presentation and
diagnosis (100 = normal function and 0 = dead).
= seizure; V = visual symptoms; MSC = mental status
change; Hp = hemiparesis.
of symptoms from symptom onset to diagnosis.
status at follow-up: NED = no evident disease; PD
= progressive disease.
radiation-induced dementia; graded from + (mild) to
of survival from diagnosis.
= unable to assess cognitive status.
2: Clinical comparisons between LTGBMS and control GBM patients.
of LTGBMS or controls having the respective factor
(a single patient may present with ³ 1 symptom).
from conditional logistic regression; only p values
< 0.05 are reported.
= Karnofsky performance status at diagnosis to measure
functional status (100 = normal function and 0 =
duration before diagnosis.
radiotherapy dose < or ³ 6000 cGy.
one LTGBMS received CCNU and one control patient
Comparisons Between LTGBMS and Control GBM Patients
LTGBMS are compared to their respective control GBM patients
in Table 2. All LTGBMS and control patients underwent
a subtotal surgical debulking of their tumors and none had
a gross total resection. Post-operatively, all patients received
external beam radiation therapy with the exception of a single
control patient who died several days after the tissue diagnosis
was made. Four LTGBMS received whole brain plus boost to involved
field, while the fifth LTGBMS received local plus boost therapy.
All control patients received whole brain plus boost therapy.
The total radiation therapy dose used was 6600 ± 310
cGy (LTGBMS 6750 ± 520) and controls 6540 ± 380
cGy). Only a single LTGBMS, and no control patients, received
adjuvant chemotherapy at the time of documented tumor recurrence.
Three LTGBMS and a single control patient had a re-operation
and further debulking at tumor recurrence.
were significantly more likely to have a higher level of function
as determined by the Karnofsky Performance Status (KPS; all
were > 90) at diagnosis than their controls (p = 0.001);
only three (20%) control patients had a KPS of 90 and most
were disabled at diagnosis. There was a trend for the symptom
duration before diagnosis to be longer in the LTGBMS (average
52 weeks; range 8-104) than controls (average 7.2 weeks; range
1-52), although this did not reach statistical significance
(p = 0.098). Other clinical factors were similar between the
two groups. All LTGBMS for whom sufficient follow-up information
was available were demented.
Comparisons Between LTGBMS and Control GBM Patients
comparisons are summarized in Table 3. The tumors from
the long-term survivors tended to have fewer mitotic figures
(p = 0.122) and a lower Ki-67 labelling index (p = 0.094)
compared to controls, although these did not reach statistical
significance. Other pathologic factors were similar between
the two groups.
Survivors With a Revised Histological Diagnosis
were seven patients (2.4%) who survived more than three years
whose histologic diagnosis was revised during our review (Table
4). These did not meet the criteria of GBM and were excluded
from our analysis. As expected, the largest excluded group
of tumors were either malignant oligo-
J. Neurol. Sci. 1998; 25: 199
3: Histologic comparisons between LTGBMS and control GBM patients.
of Mitotic Figures2
Significant: - presence of endothelial proliferation
or lymphocytic infiltrates
nuclear size or pleomorphism
from conditional (or *unconditional) logistic regression.
figures per 1.0 mm2 as determined by measuring 5
fields x (0.2 mm2 / 400 x Mag field).
index or percentage of Ki-67-labelled nuclei.
= standard error of the mean.
4: Long-Term Survivors With Revised Histological Diagnosis.1
mixed oligodendroglioma-astrocytoma (2)
not diagnostic of neoplasm (1)
Seven of twelve long-term surviving patients (survived
³ three years) whose original diagnosis of GBM was changed
on pathological review.
or malignant mixed gliomas which both contained necrosis.
We did not encounter other specific glioma subtypes (e.g.,
pilocytic astrocytoma15) on our pathological review which
could have initially masquaraded as GBMs.
study confirms that long-term survival is possible in GBM
patients but rare; only 1.8% of patients in our population
survived more than three years. This emphasizes the dismal
prognosis for conventionally treated patients with GBMs who
have both a short median survival of 8-12 months1,2 and
a very small chance of long-term survival.
two most powerful prognostic factors in GBM patients are age
and performance status. The present study and others10-13,16
confirm this observation in LTGBMS. Our LTGBMS were
younger than most GBMs and each had a KPS of 90 at diagnosis
which was significantly higher than the shorter-surviving
GBM patients. Other favorable prognostic factors, such as
a long duration of symptoms before diagnosis and the presence
of seizures, have been reported less consistently. However,
the LTGBMS in our series tended to have a longer symptom duration
before diagnosis and most LTGBMS presented following a seizure.
Other reports describing treatment factors which are associated
with long-term survival include multimodality therapy consisting
of gross total resection, irradiation, and adjuvant chemotherapy.
We did not find differences in treatment between the two groups
and this reflects the uniform care given in our centrally
coordinated cancer care system. However, this uniformity of
treatment prevented us from determining whether, for example,
there was a dose-response relationship for radiotherapy or
if a complete surgical resection was superior to biopsy.
observed two potential prognostic factors amongst the tumor
characteristics studied which might predict long survival,
although they did not reach the traditional levels of statistical
significance. Tumors from LTGBMS tended to have both fewer
mitoses and a lower proliferative index. High mitotic counts
were almost always associated with a high proliferative index
with the exception of three control patients whose tumors
displayed few mitoses but had clearly elevated proliferative
indices. We initially speculated that LTGBMS may have more
lymphocytic infiltrates, reflecting a better host response,
but this was uncommon in both the study and control groups.
We confined our study to histologic descriptions; others have
examined molecular phenotypes13,17-19 but have
not found consistent associations between expression of p53
or epidermal growth factor receptor with long-term survival.
study has several limitations. First, few of our patients
received adjuvant chemotherapy which reflected institutional
practice patterns during the study period. Since adjuvant
chemotherapy increases the proportion of patients surviving
to ³ 18 months20,21 the incidence of LTGBMS we
observed may not apply to populations where such therapy is
routinely given. A second limitation of our study is conceptual.
We initially believed that LTGBMS were biologically "different"
from their shorter-surviving counterparts and this formed
the premise of our study. However, this assumption may not
be valid since all but one LTGBMS either died or had progressive
disease. "LTGBMS" may be only a statistical effect where these
patients simply represent the extreme tail of a distribution
and are not categorically different. But one of our very long
surviving patients (> 15 years after diagnosis) and other
patients reported elsewhere, suggested to us that LTGBMS may
be a distinct but rare entity. A third limitation is the small
number of LTGBMS we observed. This means that only very large
differences between the groups would be statistically significant.
cognitive deterioration was observed in three of our five
LTGBMS who displayed severe dementia in the absence of documented
tumor recurrence. All five had received whole-brain irradiation
which caused their dementia. It is distressing that dementia
and a loss of independence may be the usual outcomes for LTGBMS
and malignant glioma survivors22 when aggressive therapy successfully
controls the tumor. This may be less common now that local
radiation therapy has replaced whole-brain treatment.
important implication of this study is that a re-evaluation
of the original histology be considered when a GBM patient
with a long survival is encountered. Most of our putative
GBM patients with long-term survival are initially misdiagnosed;
others report similar findings.9,23 This is not
unexpected as several tumors may superficially resemble a
GBM histologically5,13,15 and, now that malignant
oligodendrogliomas have been recognized as being highly chemo-sensitive,24
gliomas with necrosis are more carefully examined and not
necessarily called GBM. The most common revised diagnosis
in our patients and others5 was malignant oligodendroglioma
(pure or mixed); others have found more indolently growing
tumors such as pleomorphic xanthoastrocytoma13 in
long term survivors. The confusion
J. Neurol. Sci. 1998; 25: 200
a GBM and a malignant oligodendroglioma may account for some
unusual patients in the literature who have long survivals
and good responses to adjuvant chemotherapy.5
conclusion, this population-based study of GBM patients shows
that long-term survival is rare and highlights the clinical
challenge of this disease. Young age and a high pre-operative
KPS favor long-term survival but these were non-specific factors
and do not assist the clinician in developing a management
strategy for an individual patient. In our population, we
were not able to identify other clinical features or therapeutic
interventions which were associated with long-term survival.
Pathological features which tended to be found in long-term
survivors were a low mitotic count and proliferative index.
Having assembled this group of patients we are extending our
clinical study to a larger population where adjuvant chemotherapy
is more commonly used.
thank our patients and their families for participating in
this study and Ms. Jackie Appleton and Tom Snodgrass for their
expert technical and supportive assistance. This study was
supported in part by an infrastructural grant from the Alberta
Fine HA. The basis for current treatment recommendations for
malignant gliomas. J Neuro-Oncol 1994; 20: 111-120.
Forsyth PA, Cairncross JG. Treatment of malignant glioma in
adults. Curr Opin Neurol 1995; 8: 414-418.
Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma:
a distinctive meningocerebral glioma of young subjects with
relatively favorable prognosis. Cancer 1979; 44: 1839-1852.
Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading
of astrocytomas: a simple and reproducible method. Cancer
1988; 62: 2152-2165.
Balmaceda C, Goldman J, Fetell MR. Long-term survival in malignant
astrocytomas re-evaluated: are they really oligodendrogliomas?
Neurology 1996; 46(2): A451 (Abstr).
Elvidge AR, Barone BM. Long-term postoperative survival in
two cases of glioblastoma multiforme. J Neurosurg 1965; 22:
Müller H, Brock M, Ernst H. Long-term survival and recurrence-free
interval in combined surgical, radio- and chemotherapy of
malignant brain gliomas. Clin Neurol Neurosurg 1985; 87(3):
Imperato JP, Paleologos NA, Vick NA. Effects of treatment
on long-term survivors with malignant astrocytomas. Ann Neurol
1990; 28: 818-822.
Ullén H, Mattsson B, Collins VP. Long-term survival
after malignant glioma: a clinical and histopathological study
on the accuracy of the diagnosis in a population-based cancer
registry. Acta Oncol 1990; 29: 875-878.
Vertosick FT, Selker RG. Long-term survival after the diagnosis
of malignant glioma: a series of 22 patients surviving more
than 4 years after diagnosis. Surg Neurol 1992; 38: 359-363.
Chandler KL, Prados MD, Malec M, Wilson CB. Long-term survival
in patients with glioblastoma multiforme. Neurosurgery 1993;
Salcman M, Scholtz H, Kaplan RS, Kulik S. Long-term survival
in patients with malignant astrocytoma. Neurosurgery 1994;
Morita M, Rosenblum MK, Bilsky MH, Fraser RAR, Rosenfeld MR.
Long-term survivors of glioblastoma multiforme: clinical and
molecular characteristics. J Neuro-Oncol1996; 27: 259-266.
Olivera C, Bartley M, Ferrall S, Phuphanich S. Long-term malignant
glioma survivors over ten years: prognostic factors. Proceedings
of ASCO 1997; 16: 407a (Abstr).
Forsyth PA, Shaw E, Scheithauer B, Layton D, O'Fallon J. 51
Cases of supratentorial pilocytic astrocytoma: a clinicopathologic,
prognostic, and flow-cytometric study. Cancer 1993; 72: 1335-1342.
Byar DP, Green SB, Strike TA, et al. Prognostic factors for
malignant glioma. In: Walker MD, ed. Oncology of the Nervous
System. Boston: Marinus Nijhoff, 1983: 379-395.
Jaros E, Perry R, Adam L, et al. Prognostic implications of
p53 protein, epidermal growth factor receptor, and Ki-67 labelling
in brain tumors. Br J Cancer 1992; 66: 373-385.
Dorward NL, Hawkins RA, Whittle IR. Epidermal growth factor
receptor activity and clinical outcome in glioblastoma and
meningioma. Br J Neurosurg 1993; 7: 197-199.
Pigott TJ, Robson DK, Palmer J, Ward LM. Expression of epidermal
growth factor receptor in human glioblastoma multiforme. Br
J Neurosurg 1993; 7: 261-265.
Fine HA, Dear KBG, Loeffler JS, et al. Meta-analysis of radiation
therapy with and without adjuvant chemotherapy for malignant
gliomas in adults. Cancer 1993; 71: 2585-2597.
Walker MD, Green SB, Byar DP, et al. Randomized comparisons
of radiotherapy and nitrosoureas for the treatment of malignant
glioma after surgery. N Engl J Med 1980; 303: 1323-1329.
Archibald YM, Lunn D, Ruttan LA, et al. Cognitive functioning
in long-term survivors of high grade glioma. J Neurosurg 1994;
Salford L, Brun A, Nirfalk S. Ten-year survival among patients
with supratentorial astrocytomas grade III and IV. J Neurosurg
1988; 69: 506-509.
Cairncross JG, MacDonald DR, Ludwin S, et al. Chemotherapy
for anaplastic oligodendroglioma. J Clin Oncol 1994; 12: 2013-2021.
J. Neurol. Sci. 1998; 25: 201
the Departments of Clinical Neurosciences and Pediatrics,
The University of Calgary and Department of Medicine, Foothills
Hospital and Tom Baker Cancer Centre (TBCC), Calgary, (J.N.S.,
N.A.H., G.S., P.F.); Department of Pathology and Clinical
Neurosciences, The University of Calgary and Department of
Medicine, Foothills Hospital, Calgary, (N.B.R.); Department
of Epidemiology, Prevention and Screening. Alberta Cancer
Board and Community Health Sciences, The University of Calgary,
Calgary, (P.M.A.B.); Department of Radiation Oncology, Cross
Cancer Institute (CCI) and Department of Medicine/Neurology,
University of Alberta, Edmonton, (D.F.); Department of Radiation
Oncology, Tom Baker Cancer Centre (TBCC), The University of
Calgary, Calgary, (J.A.M.); Departments of Clinical Neurological
Sciences and Oncology, University of Western Ontario and London
Regional Cancer Centre, London, Ontario, (J.G.C.).
November 6, 1997. Accepted in final form February 10, 1998.
in abstract form at the 1996 American Academy of Neurology
Meeting. Scott, J.N., Rewcastle, N.B., Brasher, P., MacKinnon,
J., Hagen, N., Cairncross, J.G., Forsyth, P. Which GBM patient
will be a longterm GBM survivor (LTGBMS)? A case-controlled
population-based study in southern Alberta. Neurology 1996;
requests to: P. Forsyth, Department of Medicine, Tom Baker
Cancer Centre, 1331 - 29 Street N.W., Calgary, Alberta,
Canada T2N 4N2
J. Neurol. Sci. 1998; 25: 197-201