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Cancer Therapy Vol 5, page 243
Cancer Therapy Vol 5, 243-252, 2007
Management of recurrent high-grade gliomas
Research Article
!ihomir N. Eftimov1, Ivan D. Ivanov1, Alexander P. Petkov1, Emil Nakov2
1
2
Clinic of Neurosurgery
Laboratory of Pathomorphology, Military Medical Academy-Sofia, Bulgaria
__________________________________________________________________________________
*Correspondence: Tihomir Eftimov, M.D., Ph.D., Clinic of Neurosurgery, Military Medical Academy, 3, “Georgi Sofiiski” blvd.,
1606, Sofia, Bulgaria; e-mail: t_eftimov @ hotmail.com
Key words: recurrent high-grade gliomas, repeated surgical resection, chemotherapy, radiotherapy, interstitial chemotherapy, Gliadel,
Karnofsky Performance Scale (KPS), Quality of Life Questionnaire QLQ-C30
Abbreviations: anaplastic astrocytomas, (AAs); Computed Tomography, (CT); glioblastoma multiforme, (GBM); intracranial pressure,
(ICP); Karnofsky Performance Scale, (KPS); Magnetic Resonance Imaging, (MRI)
Received: 9 September 2007; Revised: 25 October 2007
Accepted: 29 October 2007; electronically published: November 2007
Summary
The biological behavior and clinical symptoms of high-grade gliomas are extremely variable. Treatment options in
cases of recurrence are usually limited after initial therapy. The objective of our study is to present the results of the
multimodal treatment in patients with recurrent high-grade gliomas and discuss some prognostic factors. Thirtytwo patients in five-year period (2001-2005) were treated with repeated surgery, chemotherapy, and re-irradiation
in the case of recurrent high-grade gliomas. Based on the histopathological examination the patients were divided
into two groups: 12 (37.5%) with recurrent anaplastic astrocytomas (AAs) and 20 (62.5%) with recurrent
glioblastoma multiforme (GBM). The volume of surgical resection was assessed by comparing the preoperative and
control Computed Tomography (CT) and(or Magnetic Resonance Imaging (MRI) findings. All patients were
assessed pre- and postoperatively by Karnofsky Performance Scale (KPS). The quality of life in all survived patients
was measured by EORTC QLQ-C30. Five of patients with recurrent GBM were treated with Temozolomide after
first operation and one patient obtained interstitial chemotherapy with Gliadel. Twelve (37.5%) operated patients
with recurrent high-grade gliomas had good results (KPS=80-100), 10 patients (31%) had different morbidity
(KPS=60-70), and 6 (19%) had poor outcome (KPS<50). Four patients (12.5%) died. The following surgical
complications were diagnosed by the control CT in the early postoperative period: hematoma in loco of the excised
tumor - in 5 patients (15.6%); brain edema with dislocation and herniation syndrome - in 4 (12.5%), and
hydrocephaly - in 2 (6%) patients. Surgical treatment of recurrent high-grade gliomas is appropriate in young
patients with solid or cystic part of the tumor without infiltration of eloquent area and deep brain structures and
longer interval between the primary operation and tumor recurrence.
remain asymptomatic (Vecht et al, 1990; Huber et al,
1993; Harsh, 1995, 1999; Lote et al, 1998; Hou et al,
2006).
The indications and choice for optimal treatment in
cases of tumor recurrence are controversial, and still
disputable. The new operative strategies and treatment
algorithms for recurrent high-grade gliomas are sought,
because the possibilities for treatment are limited after the
primary treatment (Ransohoff et al, 1978; Young et al,
1981; Ammirati et al, 1987; Harsh et al, 1987; Fadul et al,
1988; Voynov et al, 2002; Hou et al, 2006; Westphal et al,
2006).
Gross total surgical resection is, however, associated
with serious postoperative morbidity considering the
localization, sizes and the infiltrative nature of tumor.
I. Introduction
The biological behavior and clinical symptoms of
high-grade gliomas are extremely variable (Muller et al,
1977; Burger et al, 1985; Kaluza and Pyrich, 1994; Harsh,
1995, 1999; Alba et al, 1999). Irrespective of the
aggressive primary treatment (radicalism of surgical
resection and multimodal adjuvant chemotherapy and
radiotherapy) high-grade gliomas tend to reoccur within
averagely 6 to 11 months after the primary treatment (Vick
et al, 1989; Vecht et al, 1990; Dirks et al, 1993; Rostomily
et al, 1994; Gomori et al, 2002; Salvati et al, 1998).
Recurrent high-grade gliomas demonstrate different
clinical symptoms. Epilepsy alone can be controlled by
drugs therapy, while patients with focal neurological
deficit and increased intracranial pressure (ICP) demand
operative treatment. Some of recurrent high-grade gliomas
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Eftimov et al: Management of recurrent high-grade gliomas
interval between the two operative interventions was recorded.
The diagnosis was defined on the base of neurological
examination, CT and MRI findings and histopathological results.
The tumor localization was identified as „superficial” (cortical
and subcortical) in 11 (34%) patients and „profound” (basal
ganglia, corpus callosum, ventricular infiltration) in 21 (66%)
patients.
Median time to recurrence was in AAs group 49, 3 weeks
and in GBM group - 20,7 weeks after the initial operation.
The extension of surgical resection was assessed by
comparing the preoperative and control CT and MRI findings. In
all patents early postoperative CT scans were done: Postoperative
MRI in the first month after reoperation was provided in 12
(37,5%) patients. According to the results of early postoperative
neuroimaging investigations the patients were divided into three
groups: 1. with partial tumor resection (< 50%); 2. with subtotal
tumor resection (50% - 90%) and 3. with “gross total” tumor
resection (> 90%).
All patients were assessed pre- and postoperatively by
Karnofsky Performance Scale (KPS): 1. minor disability (80-100
points); 2. moderate disability (60-70 points) and 3. severe
disability (10-50 points). The quality of life in all survived
patients was measured by QLQ-C30 comparing preoperative and
postoperative scores.
The postoperative complications were divided into surgical
(edema with “mass effect" and herniation syndromes, hematoma
in loco of tumor resection, hydrocephaly, deterioration or new
neurological deficit etc.) and non-surgical ones.
The
radiotherapy
(including
stereotaxic
radiosurgery) may be contraindicated because the
maximum tolerable dose was already reached with
preceding exposures.
The chemotherapy is an alternative, despite the
limited drugs available for these types of tumors and the
possible onset of acquired drug resistance.
Interstitial chemotherapy with Gliadel and interstitial
radiotherapy are not a routine treatment options.
It is extremely difficult to determine the indications
for re-operation in patients with recurrent high-grade
gliomas as the main goal is to prolong and safe the quality
of life in treated patients. When deciding for repeated
surgical interventions, the potential surgical complications,
including lethal outcome should be taken into
consideration. Would a new reoperation be appropriate in
patients without clinical symptoms, but with CT and MRI
evidence for a tumor recurrence? Are the clinical
symptoms and neuroimaging evidence rather directly
related to the tumor recurrence or a result of a
radionecrotic or inflammatory process? What other
therapy following the operative treatment could be
proposed?
The objective of our study is to present the results of
the reoperative treatment in patients with recurrent highgrade gliomas and discuss some prognostic factors:
pathomorphology of the primary and recurrent tumor,
patients’ age, preoperative neurological and performing
status, intervals between the first and second operation,
volume of the operative intervention etc.
III. Results
All patients with recurrent high-grade gliomas were
operated on. Two operative interventions underwent 24
(75%) patients (14 with AAs and 10 with GBM). Three
and more operations were done in 8 (25%) patients (6 with
AAs and 2 with GBM). The volume of tumor resection at
first reoperation is shown on Figure 1.
In 14 (44%) patients neuronavigation control was
used during the first reoperation and in 6 (19) patients during the second reoperation, with satisfactory
postoperative results (Figures 2, 3, 4).
The adjuvant postoperative chemotherapy with
Temodal was achieved in 5 (25%) of reoperated patients
with recurrent GBM. Other patients were treated with
CCNU. Radiotherapy alone was administered in 3 (9%)
II. Material and Methods
Thirty-two patients with recurrent high-grade gliomas have
been hospitalized and operated on at the Clinic of Neurosurgery
of the Military Medical Academy-Sofia over a five-year period
(2001-2005).
The mean age of patients with recurrent high-grade
gliomas was 56.28 years +(- 10.54 with sex ratio: men/women =
1.3.
Based on the histopathological examination after
reoperation the patients were divided into two groups: 12
(37.5%) with recurrent anaplastic astrocytomas (AAs) and 20
(62.5%) with recurrent glioblastoma multiforme (GBM). The
Figure 1. Volume of tumor resection
of the recurrent high-grade gliomas
at the first reoperation.
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Cancer Therapy Vol 5, page 245
Figure 2. Deep situated recurrent GBM in corpus callosum (a) and basal ganglions (b) and (c) with partial tumor resection.
Figure 3. Clinical case 1. 32 year-old man who underwent reoperation due to recurrent GBM of the corpus callosum. One year later,
control MRI was performed on which tumor recurrence was found (a), (b), (c). The control CT (d) and MRI (e), (f) after the reoperation
showed partial tumor excision. The outcome was lethal 18 months after the first operation.
Figure 4. Clinical case 2. A 37 year-old man who underwent reoperation due to recurrent GBM 6 months after the first operation –
prereoperative MRI (a), (b) and early CT-control after the reoperation - subtotal tumor resection (c).
245
Eftimov et al: Management of recurrent high-grade gliomas
patients. Combined adjuvant chemotherapy and fractioned
radiotherapy was administered in 8 (25%) patients to the
maximum tolerated dose of 60 Gy with the concurrent
administration of Temodal - 75 mg/m2 over 6 weeks, in 5
consecutive days. The adjuvant radiotherapy (alone or in
conjunction with Temodal) was administered in those
patients who had not been administered radiotherapy after
the first operation. In one of our patients we were able to
perform the interstitial chemotherapy by intraoperative
application of Gliadel, in conjunction with postoperative
systemic chemotherapy with Temodal (Figure 5).
One month after the reoperation, however, we
observed pronounced adverse effects (skin rush and acute
abdominal pains), which are generally reported at the
administration of Gliadel (Figure 6a). The chemotherapy
with Temozolomide was administrated. In 2 months MRIcontrol showed a tumor recurrence, great in size, with
pronounced grow infiltrativeness. After the third operation
the histopathology confirmed GBM. The lethal outcome
set in 10,2 months after the primary diagnostics (Figure
6b).
Figure 5. Clinical case 3. A 47 year-old man who underwent reoperation due to recurrent GBM 8 months after the first operation –
prereoperative MRI (a). Intraoperatively Gliadel Implant 61,6 mg was placed into resection cavity (b). Early postoperative CT-imaging
showed subtotal tumor resection and Gliadel placement into resection cavity (c).
Figure 6. Rush-syndrome after implantation of Gliadel (a). Control MRI-imaging in 2 months after reoperation and interstitial
chemotherapy with Gliadel.
The following surgical complications were diagnosed
by the control CT in the early postoperative period:
hematoma in loco of the excised tumor recurrence - in 5
patients (15.6%); brain edema with dislocation and
herniation syndrome - in 4 (12.5%), and hydrocephaly - in
2 (6%) patients. No lethal surgical complications were
observed.
Twelve (37.5%) operated patients with recurrent
high-grade gliomas had good results (KPS=80-90), 10
patients (31%) had different morbidity (KPS=60-70), and
6 (19%) had poor outcome (KPS<50). Four patients
(12.5%) had lethal outcome due to somatic complications
(pulmonary
thromboembolism,
cardio-vascular
insufficiency, gastro-intestinal hemorrhage) in early
postoperative period (Table 1).
Patients over 60 years age with KPS below 50 score
formed the greatest absolute number and relative share in
comparison to the younger patients with poor outcome
(p<0.05) (Figure 7).
The postoperative results show that the rate of
patients with KPS<60-70 points is lower than the preoperative rate, on the account of increased relative share of
the patients with good results (KPS=80-100), and those
whose neurological status has deteriorated postoperatively
(KPS<50) (Figure 8).
Good postoperative results (KPS=80-100) are related
to “superficial” (cortical and subcortical) tumor
localization, and are limited to the temporal, frontal and
occipital lobe, whereas bad results, leading to high
disability rate, are related to deep (basal ganglia) and
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Cancer Therapy Vol 5, page 247
bilateral (corpus callosum) localization of the recurrent
tumor.
Measuring quality of life by EORTC QLQ-C30 in all
survived patients after and before reoperation we found an
improvement in 12(37,5%) and deteriorating in 16(50%)
retreated patients (Table 2). Statistically significant
differences were observed for 5 of the QLQ-C30 scales:
physical functioning (p<0.001), role functioning
(p<0.001), fatigue (p<0.01), nausea and vomiting
(p<0.05) and global quality of life (p<0.01).
Kaplan-Mayer curves show 4,6 months median
survival in patients with recurrent GBM and 6,7 months in
patients with recurrent AAs (p=0,1256) after the last
operation (Figure 9).
The management of recurrent high-grade gliomas
varies from repeated efforts at aggressive surgical
resection combined with chemotherapy and radiotherapy
to no therapeutic intervention at all (Young et al, 1981;
Ammirati et al, 1987; Harsh et al, 1987; Vecht et al, 1990;
Dirks et al, 1993; Voynov et al, 2002; Chang et al, 2006;
Hou et al, 2006). Regardless of the used surgical
technique, however, “superfluous aggressiveness” of the
surgeon in profound recurrent gliomas cannot be justified.
Cytoreductive therapy is a fundamental part of the
treatment of most systematic malignant diseases;
therefore, there exists a significant correlation between the
volume of excised neoplasm and the outcome of operative
treatment (Salcman, 1994). In high-grade gliomas the
dependency between the residual tumor size and
postoperative results (interval for tumor recurrence,
quality of life and survival time) has not been clearly
determined yet (Ciric et al, 1989; Salcman et al, 1982;
Devita, 1983; Harsh, 1999; Hou et al, 2006). Some studies
(Devita, 1983; Ammirati et al, 1987; Burger et al, 1985;
Ciric et al, 1989; Vick et al, 1989; Winger et al, 1989;
Vecht et al, 1990; Salcman, 1994; Alba et al, 1999)
confirm that the surgical intervention volume is an
important prognostic factor (AAs 76 - 90 weeks in total
resection vs. 19-43 weeks in subtotal; GBM 39.5 - 50.6
weeks vs. 21 - 33 weeks for subtotal excision). This is
consistent with our results too, i.e. high-grade gliomas
treated by partial resection tend to recur in shorter period.
IV. Discussion
Recurrent high-grade gliomas are evidence for the
failure of even primarily aggressive multimodal treatment
- surgery, chemotherapy and radiotherapy (Devita, 1983;
Burger et al, 1985; Garcia et al, 1985; Kaluza and Pyrich,
1994; Rostomily et al, 1994; Alba et al, 1999; Harsh,
1999; Chang et al, 2006). There are different factors
limiting their effectiveness, e.g. the surgical access to the
recurrent tumor which determines the risk of serious
postoperative morbidity, gliomas’ infiltrative nature etc.
Regardless of the “gross total” tumor excision the control
CT and MRI, as well as the stereotactic biopsy in adjacent
to the tumor areas show presence of microscopic
infiltrations with tumor cells (Ciric et al, 1989; Dirks et al,
1993; Salcman, 1994; Gomori et al, 2002).
Table 1. Patients’ outcome assessed by distinction in postoperative and preoperative KPS score.
Distinction in postoperative and preoperative Karnofsky score
+ 20
+ 10
0
-10
-20
death
N = 32
1
6
16
3
2
4
%
3%
19%
50%
9.3%
6.2%
12.5%
Figure 7. Dependency between
treatment outcome and patients’ age.
247
Eftimov et al: Management of recurrent high-grade gliomas
Figure 8. Pre- and postoperative
results in reoperated patients
assessed by KPS.
Table 2. Analysis (ANOVA) of EORTC QLQ-C30 scores before and after retreatment. Reproduced from Aaronson et a,
1993.
IMPROVED PATIENTS (N=12)
PRETREATMENT POSTTREATMENT
MEAN
SD
MEAN
SD
Functioning scales
Physical
58.1
(p<0.001)
Role (p<0.001)
55.9
Cognitive
79.9
Emotional
63.3
Social
78.1
Global quality of
53.3
life
Symptom scales/items
Fatigue (p<0.01)
43.1
Nausea and
11.8
vomiting
Pain
32.8
Dyspnea
48.0
Sleep disturbance
29.4
Appetite loss
30.4
Constipation
28.4
DETERIORATED PATIENTS (N=16)
PRETREATMENT
POSTTREATMENT
MEAN
SD
MEAN
SD
27.1
67.5
22.6
67.8
27.6
54.7
32.0
36.4
22.0
26.2
29.5
21.8
67.6
80.9
74.5
79.7
62.9
34.6
21.4
18.1
28.9
19.4
60.1
78.1
69.8
73.6
56.2
38.7
22.5
21.3
29.8
25.5
44.3
74.2
72.5
67.9
50.5
39.2
27.2
23.1
30.8
25.0
27.6
20.7
40.1
14.7
26.0
20.8
42.6
9.9
25.7
18.4
53.2
26.4
27.7
29.2
31.1
28.7
33.6
37.0
36.8
15.7
41.2
20.6
30.4
22.5
20.9
29.7
28.4
38.8
31.5
32.7
44.4
33.8
31.2
24.5
34.0
31.6
33.3
37.9
33.2
25.2
40.6
33.8
40.9
28.7
28.4
30.7
35.0
39.2
36.5
Recurrent high-grade gliomas (especially AAs) show
faster infiltrative growth in contrast to the primary tumor
(Figure 10). This change in the gliomas’ biological
behavior makes them resistant to any subsequent
treatment. The shorter interval between the first operation
and expressed clinical symptoms are often related to fast
tumor regrowth and pessimistic prognosis (Muller et al,
1977; Vertosick et al, 1991; Dirks et al, 1993; Kaluza and
Pyrich, 1994; Harsh, 1999; Gomori et al, 2002).
Prognostic factors in recurrent high-grade gliomas
are related to the tumor biology (histology, invasiveness,
proliferate activity), tumor resectability (anatomical access
and physiological permissiveness); the results from the
primary chemotherapy and radiotherapy; patients’ age and
preoperative performing status KPS. The important
prognostic factors for recurrent high-grade gliomas are:
Histological finding. Recurrent high-grade gliomas
show more aggressive growth. Most authors find
statistically significant dependency on the histological
finding after the second operation and life duration of the
operated patients (Muller et al, 1977; Young et al, 1981;
Gomori et al, 2002).
Time to tumor recurrence. The time between the first
and second operation is an important prognostic factor,
which better explains the biological tumor activity, as well
as its sensitiveness and resistibility to chemotherapy and
radiotherapy. The longer the interval, the longer life
duration after the second operation is (Wilson, 1975;
Muller et al, 1977; Burger et al, 1985; Fadul et al, 1988;
Alba et al, 1999; Huber et al, 1993).
Patient’s preoperative status. Patients with recurrent
high-grade gliomas and Karnofsky score > 60 have better
prognosis, which is confirmed by our results too (Salcman
et al, 1982; Salvati et al, 1998; Alba et al, 1999; Hou et al,
2006).
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Cancer Therapy Vol 5, page 249
Figure 10. Time for doubling of tumor cell population. Reproduced from Harsh, 1999.
Patient’s age is a statistically significant factor.
Elderly have poorer postoperative results (Burger et al,
1985; Winger et al, 1989; Vecht et al, 1990; Huber et al,
1993).
Tumor recurrence localization - patients with
cortical and subcortical localization of the tumor
recurrence have better prognosis in comparison to
extensive tumor invasion of basal ganglia (Ammirati et al,
1987; Fadul et al, 1988; Vertosick et al 1991; Hou et al,
2006).
Macroscopic characteristics of tumor recurrence - in
recurrent high-grade gliomas with cystic component
optimal postoperative results could be achieved after a
new operative intervention (Garfield, 1986; Kaluza and
Pyrich, 1994, Harsh, 1999).
Most authors advocate second operative intervention
in young patients with good preoperative status (KPS >
60) with local tumor recurrence in anatomically accessible
place and long period after the first operation (Alba et al,
1999; Ammirati et al, 1987; Burger et al, 1985; Hou et al,
2006; Huber et al, 1993; Winger et al, 1989). Others
(Garfield, 1986; Harsh et al, 1987; Fadul et al, 1988;
Vecht et al, 1990) have published results of operative
treatment in recurrent high-grade gliomas with low
morbidity and lethality (0-5.1%), which are comparable
with the results after the first intervention. Naturally, a
new surgical intervention is connected with a real risk of:
intracranial infections (0-21%), wound healing (0-13%)
and intraoperative problems with hemostasis (0-4%).
Hematomas in loco of tumor resection were CT diagnosed
in 5 (15.6%) operated patients in our study.
If the neurological deterioration is a result of
invasion of deep structures, then the possibilities for
surgical treatment are seriously limited. If, however, the
neurological deficit is caused by increased intracranial
pressure (ICP) or compression without destruction, then
we would anticipate improvement in the patients’ status
after the tumor resection (Wilson, 1975; Young et al,
1981; Vecht et al, 1990; Harsh, 1999; Hou et al, 2006).
The results of this study and literature data suggest
that possibilities for an adequate multimodal treatment of
recurrent gliomas are still limited. Because malignant
growth of gliomas is infiltrative, the reoperation, like an
initial resection, is not curative. The justification for
reoperation is the clinical palliation that results in tumor
cytoreduction and enhancement of the effect of subsequent
chemotherapy and radiotherapy against a reduced
population of neoplastic cells. The operative risks appear
no greater and the benefits are substantial.
Some impending randomized trials (Westphal et al,
2006) have to define the effect of new options for
multimodal treatment in patients with recurrent high-grade
gliomas. New chemotherapeutic agents (Temozolomide
and antiangiogenesis targeting agents - Genfitinib,
Erlotinib) in combination with interstitial chemotherapy
(Gliadel) or interstitial radiotherapy (GliaSite Radiation
Therapy System) are some new investigated treatment
options (Figure 11).
In conclusion the surgical treatment of recurrent
high-grade gliomas is appropriate in young patients with
solid or cystic part of the recurrent tumor without
infiltration of eloquent area and deep brain structures and
longer interval between the first operation and tumor
reappearance. In contrast, high-grade recurrent gliomas
infiltrating deep brain structures in short time after first
operation and in old patients with poor performing status
(KPS<60) are related with negative prognosis and poor
outcome. Extent of surgical resection does also improve
quality of life even when overall survival is not extended.
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Eftimov et al: Management of recurrent high-grade gliomas
Figure 11. Effect on survival time of different options for multimodal treatment in patients with recurrent high-grade gliomas.
Reproduced from VII-th Congress of EANO – Vienna, 2006.
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