1. No category

CLINICAL PRACTICE GUIDELINE CNS-001
version 3
GLIOBLASTOMA
Effective Date: September, 2012
The recommendations contained in this guideline are a consensus of the Alberta Provincial CNS Tumour Team
synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature.
Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the
context of individual clinical circumstances to direct care.
CLINICAL PRACTICE GUIDELINE CNS-001
version 3
BACKGROUND
By the end of 2012, it is estimated that approximately 2800 Canadian adults will be diagnosed with
primary brain tumours, and 1850 will die from their disease.1 Primary brain tumours are a heterogeneous
group of neoplasms with varied treatment strategies and outcomes. The Alberta Provincial Central
Nervous System (CNS) Tumour Team uses the classification system of the World Health Organization
(WHO) to describe CNS tumours, which is based on histologic features of the tumour.2 Table 1 outlines
the grades and histologic characteristics:
Table 1. World Health Organization Grading of Central Nervous System Tumours2
WHO Grade
Grade I
Grade II
Grade III
Grade IV
Histologic Characteristics
Includes lesions with low proliferative potential and a frequently discrete nature; surgical resection
is the main treatment.
Includes lesions that are generally infiltrating and low in mitotic activity but recur. Some tumour
types tend to progress to higher grades of malignancy.
Includes lesions with histologic evidence of malignancy, generally in the form of mitotic activity,
clearly expressed infiltrative capabilities, and anaplasia.
Includes lesions that are mitotically active with vascular proliferation, necrosis-prone, and
generally associated with a rapid preoperative and postoperative evolution of disease.
Glioblastoma (GBM), a WHO grade IV tumour, is the most common and aggressive of the primary brain
tumours, accounting for approximately 40 percent of all CNS malignancies. In patients over the age of 60,
the rate of GBM greatly increases, and thus accounts for the majority of primary brain tumours in this
population.3 Despite recent advances in treatment, the prognosis for patients with GBM is dismal. The
overall survival rates after diagnosis have been reported to range between 5 and 12 months; long-term
survivors are usually young, in good health, and able to undergo multimodality treatment for their disease.
GUIDELINE QUESTIONS
•
•
•
•
•
Is resection better than biopsy for patients with glioblastoma?
Is adjuvant chemotherapy beneficial for patients with glioblastoma?
Is adjuvant chemotherapy of benefit to elderly patients with glioblastoma?
What is the optimal radiation therapy plan for patients with glioblastoma?
Is adjuvant radiation of benefit to elderly patients with glioblastoma?
DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial CNS Tumour Team. Members of the
Alberta Provincial CNS Tumour Team include medical oncologists, radiation oncologists, neurosurgeons,
neurologists, nurses, neuropathologists, and pharmacists. Evidence was selected and reviewed by a
working group comprised of members from the Alberta Provincial CNS Tumour Team and a Knowledge
Management Specialist from the Guideline Utilization Resource Unit. A detailed description of the
methodology followed during the guideline development process can be found in the Guideline Utilization
Resource Unit Handbook.
This guideline was originally developed in April, 2008. This guideline was revised in February, 2010 and
September, 2012.
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SEARCH STRATEGY
Medical journals were searched using the Medline (1950 to July Week 4, 2012), Embase (1980 to July
Week 4, 2012) Cochrane Database of Systematic Reviews (2nd Quarter, 2012), and Pubmed databases.
The search terms included: Glioblastoma [MeSH heading], Glioma [MeSH heading], Brain Neoplasms
[MeSH heading], Astrocytoma [MeSH heading], high-grade gliomas, anaplastic gliomas, practice
guidelines, systematic reviews, meta-analyses, randomized controlled trials, and clinical trials. The
references and bibliographies of articles identified through these searches were scanned for additional
sources. Articles were excluded from the review if they: had a non-English abstract, were not available
through the library system, were case studies involving less than 10 patients, involved pediatric patients,
involved anaplastic astrocytomas or anaplastic oligodendrogliomas as the only high-grade gliomas, or
were published prior to the year 2000. All retrieved articles were graded using the criteria outlined by Lau
et al.4
A search for new or updated clinical practice guidelines published from January 2000 to July 2012 was
also conducted, and yielded nine published guidelines by the following organizations: Cancer Care Ontario
(CCO), the British Columbia Cancer Agency (BCCA), Cancer Care Nova Scotia (CCNS), the National
Comprehensive Cancer Network (NCCN), the National Cancer Institute (NCI), the National Institute for
Health and Clinical Excellence (NICE), the Australian Cancer Network, the European Society for Medical
Oncology (ESMO), and the Canadian GBM Recommendations Committee.
TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 18 years. Different
principles may apply to pediatric patients.
RECOMMENDATION
1. Surgery is the initial recommended approach for both debulking and obtaining of tissue for diagnosis.
Whenever possible, safe, maximal resection is preferred in the management of GBM. A larger
resection after initial biopsy is left to the discretion of the surgeon depending on the location of tumour
and other factors.
2. Adjuvant chemo-radiation therapy is considered the standard of care following surgery for patients with
newly diagnosed GBM. Whenever possible, surgery should be followed by radiotherapy and
concurrent temozolomide chemotherapy, followed by six cycles of adjuvant temozolomide. For patients
who show improvement on therapy, additional cycles of temozolomide may be considered.
3. External beam radiation therapy should be given in standard fractionation to a maximum total dose of
60Gy using 3D conformal planning techniques. The volume treated should be partial brain irradiation
and not whole brain irradiation. There is no strong evidence to recommend a total dose greater than 60
Gy in standard fractionation, and alternative fractionation schedules have not proven to be more
beneficial.
4. Determination of MGMT promoter methylation status may assist in determination of prognosis.
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5. The course of radiotherapy may be abbreviated to 40 Gy in 15 fractions in elderly patients (≥60 years
old). For elderly patients with a poor performance status, consideration may be given to adjuvant
radiation therapy alone.
6. Concurrent and/or adjuvant treatment with temozolomide may be considered in patients older than 60
years of age with a good performance status (KPS >70).
DISCUSSION
Surgery
Biopsy versus Surgical Resection. Although prospective, randomized trials addressing surgery for GBM
are lacking, there is a consensus among the published clinical practice guidelines that surgical resection is
the main treatment for alleviation of symptoms and prolongation of life in patients with GBM.5-10 Members
of the Alberta Provincial CNS Tumour Team therefore recommend surgery as the initial approach for both
debulking and obtaining of tissue for diagnosis (recommendation #1).
Over the past fifteen years, several small studies and retrospective analyses have addressed the impact
of biopsy versus surgical resection on overall survival in patients with high grade gliomas, and the results
of these studies are summarized in Table 2.11-14 Hart et al. recently conducted a comprehensive and
systematic search of the literature to address whether surgical resection was superior to biopsy for highgrade gliomas. They identified only one randomized phase III trial, published by Vuorinen et al. in 2003,
which met their search criteria. Although many of the other studies they identified did report a survival
advantage for resection over biopsy, Hart et al. suggested that these studies be interpreted with caution as
most were not designed to answer this question, were underpowered, and had methodological flaws.15 In
another recent systematic review, Tsitlakidis et al. reported the results of a meta-analysis of five studies
addressing biopsy versus surgical resection for malignant gliomas.16 The results suggested a significant
survival benefit for patients treated with resection instead of biopsy (HR 0.61, 95% CI 0.52-0.71; p
<0.0001). In addition, the authors reported that quality of life appeared to be improved in patients treated
with resection rather than biopsy.
Table 2. Studies of Surgical Resection versus Biopsy for Glioblastoma: 1995 to 2012
Author
Study Design
* Vuorinen et al.,
11
2003
12
Laws et al., 2003
RCT
Prospective
13
Retrospective
* Kowalczuk et al.,
14
1997
Retrospective
Kreth et al., 1999
* Kiwit et al., 1996
* Quigley et al.,
18
1995
17
Retrospective
Retrospective
Treatment
Allocation
Resection
Biopsy
Biopsy
Resection
Resection
Biopsy
Biopsy
STR
GTR
Biopsy
Resection
Biopsy
STR
GTR
N
Patient Age
10
13
84
329
126
99
13
33
29
40
40
23
31
9
66-80 yrs
67-79 yrs
Overall mean
58 yrs
Mean 58 yrs
Mean 57 yrs
Mean 63 yrs
Mean 49 yrs
Mean 54 yrs
Mean 58 yrs
Mean 60 yrs
Overall mean
57.6 yrs
Median
Survival
171 days
85 days
21.0 wks
45.3 wks
37 wks
33 wks
56 wks
116 wks
143 wks
184 days
292 days
10 mos
11 mos
27 mos
p-Value
0.0346
<0.0001
0.09
0.039
(biopsy vs. STR + GTR)
<0.05
Biopsy versus:
•
STR = 0.35
•
GTR <0.001
* Includes anaplastic astrocytomas (grade III) and glioblastoma (grade IV) tumours
Abbreviations: RCT=randomized controlled trial, STR=subtotal resection, GTR=gross total resection.
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Extent of Surgical Resection. There remains considerable debate in the literature regarding the impact
of the extent of resection on overall survival in patients with GBM. While some studies have failed to show
a benefit with more complete tumour resection, others have demonstrated an increase in overall survival
for patients with GBM who undergo more complete resections of their tumours. Further, the extent of
resection, in addition to important factors such as the age of the patient, Karnofsky Performance Status
(KPS) score, and the location and volume of the tumour, has been identified as a prognostic indicator of
overall survival in patients with GBM.13,16-20
Several recent systematic reviews have addressed the issue of survival benefit for gross total resection
versus partial resection in patients with GBM. In a thorough systematic review of the literature up to 2004,
Taylor et al., along with the Neuro-oncology Disease Site Group of Cancer Care Ontario reviewed five
retrospective studies and five prospective studies comparing gross total resection (GTR) to subtotal
resection (STR) in terms of survival.8 Apart from one preliminary prospective analysis published in 1990,
all of the studies included in their review reported a significant improvement in survival for patients
undergoing GTR compared to STR (p<0.05).8 However, the authors identified several confounding factors,
including the trend for more aggressive surgery in younger patients with a better KPS score, and therefore
recommended that the results be interpreted with caution.
In 2005, Proescholdt et al. analyzed the methodological aspects and level of evidence of studies
addressing the extent and impact of surgical resection on outcomes in patients with grade III and grade IV
malignant gliomas.21 The authors identified 120 publications, the majority of which were retrospective
studies with an individual case-control design, and none of the studies were rated as having a high level of
evidence. Although 72.5 percent of the identified studies did report some positive effect of radical
resection on various outcomes, the authors identified methodological limitations to many of the reviewed
studies.21 In a 2008 review of 28 high-grade glioma studies, Sanai et al. also identified persistent
limitations in the quality of the available data, but estimated an overall improvement in survival time of 2.9
months for patients who undergo a GTR versus a STR.22
Table 3 includes summaries of the trials conducted from 1995 to the present which have compared GTR
with STR in patients with newly diagnosed GBM. The strongest data to date come from a European
multicentre phase III trial conducted by the ALA Glioma Study Group, in which fluorescence-guided
resection with 5-aminolevulinic acid (ALA) was studied as a way to improve the extent of resection in
patients with high-grade gliomas.23,24 In the original analysis, the authors reported that the use of 5aminolevulinic acid resulted in a higher rate of complete resections compared to conventional
microsurgery with white light (65% versus 36%), and a better 6-month progression-free survival rate
(41.0% versus 21.1%, p=0.0003) in patients with high-grade gliomas.23 In a subsequent analysis of the
ALA trial, Stummer et al. stratified the 243 patients from the ALA trial who specifically had a diagnosis of
GBM into those who underwent complete versus incomplete resections, irrespective of their original study
arm.23 The median overall survival from the time of surgery was 11.8 months in patients with incomplete
resections and 16.9 months in patients with complete resections, and this difference was highly significant
in univariate analysis (p<0.0001). In multivariate analysis, when they accounted for factors which could
influence survival (age, KPS, post-operative therapies, eloquent location of tumour), the authors reported
an independent and overwhelming prognostic impact of complete resection on survival (HR=1.752, 95%
CI 1.258 - 2.438; p< 0.0004).
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Table 3. Studies of Gross Total Resection versus Subtotal Resection for Glioblastoma: 1995 to 2012
Author
Stummer et al.,
24
2008
Lacroix et al.,
25
2001
Keles et al.,
26
1999
Study
Design
RCT
Retrospective
Retrospective
Mohan et al.,
27
1998
Retrospective
Slotman et al.,
28
1996
29
Nitta et al., 1995
Prospective
Prospective
Treatment
Allocation
Partial resection
Complete resection
< 98% resection
> 98% resection
< 25% resection
25-49% resection
50-74% resection
75-99% resection
GTR
Biopsy
STR
GTR
< 75% resection
> 75% resection
Partial resection
STR
GTR
N
Patient Age
121
122
219
197
25
21
18
20
23
53
42
7
8
20
39
26
36
N=51 <60 yrs, N=51 >60 yrs
N=72 <60 yrs, N=50 >60 yrs
Overall mean 53 yrs
Median 53.5 yrs
Median 48.5 yrs
Median 50.5 yrs
Median 45 yrs
Median 53 yrs
Overall mean 74.5 yrs
Overall mean 56 yrs
Overall mean 55.4 yrs
Median
Survival
11.8 mos
16.9 mos
8.8 mos
13.0 mos
32 weeks
57 weeks
63 weeks
89 weeks
93 weeks
3.4 mos
7.2 mos
17.3 mos
31 weeks
42 weeks
11 mos
12 mos
20 mos
p-Value
<0.0001
0.0001
<0.0005
GTR vs. STR:
<0.0001
<0.05
GTR vs. STR +
PR: <0.01
STR vs. PR:
0.123
Abbreviations: RCT=randomized controlled trial, STR=subtotal resection, GTR=gross total resection.
Based on the results of the trials published to date, as well as findings from systematic reviews and
published clinical practice guidelines consensus statements, the members of the Alberta Provincial CNS
Tumour Team currently recommend maximal tumour resection for patients with GBM whenever possible.
A larger resection after initial biopsy should be left to the discretion of the surgeon, depending on the
location of tumour and other factors (recommendation #1).
Adjuvant Treatment
Adjuvant chemo-radiation therapy is considered the standard of care following surgery for patients with
newly diagnosed GBM (recommendation #2).
Radiotherapy. The use of external-beam radiotherapy is a well-established recommendation for patients
with newly diagnosed GBM following surgical resection. Most of the randomized clinical trials involving
whole brain radiotherapy (WBRT) following surgery were performed in the1970s, 1980s, and early 1990s,
and in many cases, little distinction was made between the different histologies of malignant gliomas.
Therefore, the recommendations for the use of radiotherapy are based on trials that included both WHO
Grade III and IV gliomas. A meta-analysis based on six of these early randomized clinical trials, published
by Cancer Care Ontario (CCO), reported an overall risk ratio of 0.81 (95% CI 0.74 - 0.88; p<0.00001)
favouring post-operative conformal radiotherapy compared to no post-operative radiotherapy.30 More
recent trials of radiotherapy in GBM have focused on varying techniques and dosing of radiation following
surgical resection, as well as on comparisons between post-operative radiotherapy alone and in
combination with chemotherapy.
The issue of radiation volume was addressed by several early studies which reported that recurrent
malignant gliomas following WBRT develop within 2 cm of the original tumour site in 80 to 90 percent of
cases.31,32 One recently published randomized trial and several smaller trials have demonstrated that while
there is no statistically significant benefit in overall survival associated with localized external beam
radiotherapy, the use of this technique leads to a decrease in excessive radiation to normal brain tissue,
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and therefore may lead to improvements in quality of life. In a prospective trial of 68 patients with
anaplastic astrocytomas and GBM, Phillips et al. randomized patients to receive 60 Gy of localized
radiotherapy in 30 fractions or 35 Gy of WBRT in 10 fractions.33 The authors reported a small, nonsignificant increase in median survival for patients treated with the localized radiotherapy (10.3 months
versus 8.7 months, p=0.37). Similarly, Sharma et al. randomized 50 patients with anaplastic gliomas and
GBM to receive either 50 Gy of localized external beam radiotherapy in 25 fractions with a boost of 10 Gy
in 5 fractions, or 40 Gy of WBRT delivered in 20 fractions with a boost of 20 Gy in 10 fractions.34 The
authors reported a small, non-significant six-month overall survival benefit in the localized radiotherapy
group (66.7% vs. 50.7%, p >0.1), as well as a statistically significant improvement the KPS of the patients
treated with localized radiotherapy (80% versus 56% improved, p<0.01). The introduction and widespread
use of computerized tomography (CT) and magnetic resonance imaging (MRI) techniques has further
contributed to improving the accuracy of target volumes for external beam radiotherapy.35
In a key trial addressing radiotherapy dosing, Bleehen and Stenning randomized 474 patients with
anaplastic gliomas or GBM to receive either 45 Gy of post-operative radiation in 20 fractions over four
weeks or 60 Gy in 30 fractions over six weeks.36 The authors reported a statistically significant difference
in median survival of the higher dose group versus the lower dose group (12 months versus 9 months;
HR=0.75, p=0.007). In addition, when the authors performed a subgroup analysis based on prognostic
indicators, the effect of the higher dose on overall survival was still evident in even the poorest prognostic
group.
To date, doses higher than 60 Gy have not convincingly demonstrated a meaningful improvement in
overall survival. In a recent trial addressing dose-escalation to 90 Gy for high-grade gliomas, Chan et al.
reported no significant improvement in survival for patients treated with 70, 80, or 90 Gy using a 3D
conformal intensity-modulated radiotherapy (IMRT) technique.37
Alternative fractionation schedules, particularly hyperfractionation, have not demonstrated a statistically
significant survival advantage for patients with newly diagnosed GBM.38,39 In a thorough review of 21
phase II and III altered fractionation studies published during a five-year period, Neider et al. concluded
that while altered fractionation shortens the overall treatment time for adult patients with high-grade
gliomas, it does not result in a significant improvement in overall survival.40 Similarly, in a pooled analysis
of seven randomized trials of hyperfractionated radiation dosing for anaplastic gliomas and GBM, the CCO
reported no statistically significant survival benefit for hyperfractionated radiotherapy compared with
conventional radiotherapy (RR=0.89; 95% CI 0.73 – 1.09; p=0.27).40
With regards to radiotherapy timing, a recent retrospective analysis of 172 patients with anaplastic
astrocytoma or GBM demonstrated clinically significant reductions in survival associated with delay in
receiving radiotherapy.41 When they adjusted for age and tumour grade, the authors reported that every
additional week of delay until the start of radiotherapy was associated with an increased likelihood for
death (HR=1.089, 95% CI 1.020 – 1.161; p=0.010). They concluded that, for a typical patient with a highgrade glioma, a delay of six weeks in starting radiotherapy post-surgery was associated with an 11 week
decrease in median survival. Similarly, in their retrospective analysis of 182 patients with anaplastic
gliomas and GBM, Do et al. reported that older age, reduced dose, and prolonged waiting time from
presentation were all significantly associated with worse survival, and the risk of death increased by two
percent for each day of waiting for radiotherapy.42
Based on the published results of radiotherapy for patients with newly diagnosed GBM to date, the Alberta
Provincial CNS Tumour Team members recommend that external beam radiation therapy should be given
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in standard fractionation to a maximum total dose of 59.4 to 60 Gy using 3D conformal planning
techniques. The volume treated should be partial brain irradiation and not whole brain irradiation. There is
no strong evidence to recommend a total dose greater than 60 Gy in standard fractionation, and
alternative fractionation schedules have not proven to be more beneficial (recommendation #3).
Chemotherapy. For patients with a good KPS, a high level of evidence supports the use of daily
temozolomide administered with postoperative radiotherapy and followed by six cycles of adjuvant
temozolomide.43-47 Three phase II clinical trials conducted by Stupp et al., Lanzetta et al., and Athanassiou
et al. all reported better one-year survival rates with the addition of temozolomide compared to
radiotherapy alone (58%, 58%, 56.3%, respectively).43,45,46 In 2005, Stupp et al. published the results of a
large, randomized, multicentre phase III trial that included 573 patients with newly diagnosed GBM from
85 European and Canadian centres.47 Following surgical resection, patients were randomized to receive
radiotherapy alone or in combination with chemotherapy. In the chemotherapy arm, patients received
radiotherapy with concurrent low dose temozolomide (75 mg/m2) for six weeks, followed by a four week
break and then six cycles of temozolomide (150 – 200 mg/m2/day on days 1-5 of a 28 day cycle). The
median overall survival was 14.6 months (95% CI 13.2 – 16.8) for the radiotherapy plus temozolomide
group versus 12.1 months (95% CI 11.2 – 13.0) for the radiotherapy alone group. In addition, the two-year
survival rate was 26.4 percent for the radiotherapy plus temozolomide group versus 10.4 percent for the
radiotherapy alone group (p<0.001).47 The results of the five-year analysis from this trial were recently
published. At five years, the overall survival was 9.8 percent for the group treated with temozolomide
versus 1.9 percent for the group treated with radiotherapy alone (HR 0.6, 95% CI 0.5 – 0.7; p<0.0001).44
The Canadian GBM Recommendations Committee recommends that for patients with stable symptoms
during combined radiotherapy and temozolomide, completion of at least three cycles of adjuvant therapy is
advised before a decision is made about whether or not to continue treatment.48 This is because, in the
first few weeks or months following radiotherapy, MRI changes alone are not reliable to determine true
disease progression. In a recent retrospective analysis, Roldán et al. reported on the incidence of
radiographic pseudo-progression in a population-based cohort of 43 patients with GBM.49 Twenty-five of
the patients (58%) exhibited radiographic progression on the first MRI scan after concurrent treatment,
and of the twenty patients who went on to receive adjuvant treatment with temozolomide, ten
demonstrated pseudo-progression (50%). The results of the Roldán et al. study confirm previously
published observations by Brandes et al., and Taal et al., in which pseudo-progression was reported in 58
and 50 percent of the cases, respectively.50,51
Based on the results of trials published to date, the Alberta Provincial CNS Tumour Team recommends
that, whenever possible, surgery should be followed by radiotherapy and concurrent temozolomide
chemotherapy, followed by six cycles of adjuvant temozolomide. For patients who show improvement on
therapy, additional cycles of adjuvant temozolomide may be considered (recommendation #2).
MGMT Promoter Methylation Status
In a companion to the 2005 Stupp et al. publication, Hegi et al. reported an analysis of 206 patients who
were treated as part of the clinical trial.52 The authors examined the relationship between occurrence of
epigenetic silencing of the O6- methylguanine – DNA methyltransferase (MGMT) gene by promoter
methylation and overall survival. Among the patients with MGMT promoter methylation, the median
survival was 21.7 months for those treated with temozolomide versus 15.3 months for those treated with
radiotherapy alone (p=0.007). In patients with tumours without a methylated MGMT promoter, the
administration of concurrent and monthly temozolomide only marginally improved median survival when
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compared to radiotherapy alone (12.7 months versus 11.8 months, p=0.06). The authors also reported
that, irrespective of treatment, MGMT promoter methylation was an independent favourable prognostic
factor for patients with GBM (HR=0.45, 95% CI 0.32 – 0.61; p<0.001).
The Canadian GBM Recommendations Committee states that since MGMT status appears to be a
prognostic factor for increased survival and possibly for better response to temozolomide treatment,
sufficient tissue should be obtained during surgery for cytogenetic analysis and tumour banking.48 On the
basis of this recommendation, the members of the Alberta Provincial CNS Tumour Team agree that,
whenever possible, determination of MGMT promoter methylation status should be conducted, as it may
assist in determination of prognosis (recommendation #4).
Management of GBM in Older Patients
The incidence of GBM greatly increases in patients over the age of sixty, and thus accounts for the
majority of primary brain tumours in this population.3 Advanced age has also been repeatedly identified as
one of the most powerful predictors of a poor prognosis in patients with high-grade gliomas, and therefore
becomes an important factor in planning treatment strategies.53-56However, the causal relationship
between age and poor prognosis is not fully understood; since survival time and quality of life are often
poor in older patients, many are offered only supportive care with no further interventions, and this itself
may have a negative impact on disease outcome.54,57
Radiotherapy. The Alberta Provincial CNS Tumour Team members recommend that the course of
radiotherapy may be abbreviated to 40 Gy in 15 fractions in elderly patients. For those with a poor
performance status, consideration may be given to adjuvant radiation therapy alone (recommendation #5).
These recommendations are based on the results from two key studies. In the first trial, Roa et al.
randomized 100 patients over the age of 60 to receive either standard radiotherapy (60 Gy in 30 fractions)
or an abbreviated course (40 Gy in 15 fractions) within six weeks of surgery. The authors reported similar
median survival times for the two groups of patients (5.1 months standard versus 5.6 months abbreviated,
p=0.57). In addition, they did not report any significant differences in KPS over time between the two
groups. They concluded that a shorter course of radiotherapy is a reasonable treatment option for older
patients with GBM, and may be considered particularly appropriate in patients with a poor performance
status where survival after a standard six-week course of radiotherapy is short.
In the second trial, Keime-Guibert et al. randomized 81 patients over the age of 70 with a good KPS (>70)
to receive either supportive care alone or supportive care in combination with radiotherapy (50 Gy in 1.8
fractions/day x 5 days/week).58 The authors reported a median survival of 29.1 weeks in the patients
receiving radiotherapy compared to 16.9 weeks for those receiving only supportive care (HR=0.47, 95% CI
0.29 – 0.76; p=0.002). In addition, quality of life and cognitive evaluations did not differ significantly
between the two treatment groups.
Chemotherapy. The response of patients with high-grade gliomas to chemotherapy is inversely
proportional to the age of the patient, and is generally limited to patients with a good KPS (i.e. > 70).53,59
The Alberta Provincial CNS Tumour Team members recommend that concurrent and/or adjuvant
treatment with temozolomide may be considered in patients older than 60 with good performance status
(recommendation #6). This recommendation is based on results from several small prospective trials. In
2003, Brandes et al. reported the results of a study involving 79 patients over the age of 65 who were
treated with either radiotherapy alone, radiotherapy and adjuvant chemotherapy with procarbazine,
lomustine, and vincristine (PCV), or radiotherapy and adjuvant temozolomide.60 The authors reported that,
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for elderly patients with a KPS score greater than 70, aggressive management with radiation therapy and
adjuvant temozolomide offered a significant survival advantage over radiotherapy alone (14.9 months
versus 11.2 months, p=0.002). In addition, while there was no significant difference in overall survival for
patients treated with adjuvant temozolomide compared to adjuvant PCV chemotherapy (14.9 months
versus 12.7 months), the temozolomide was better tolerated, with a lower rate of grade 3-4 hematologic
toxicity. In 2008, Combs et al. reported the results of a study involving 43 patients over the age of 65
treated with postoperative radiotherapy plus temozolomide.61 Thirty-five patients received concurrent
temozolomide at a dose of 50 mg/m2 and eight patients received concurrent temozolomide at a dose of 75
mg/m2. Only five patients were prescribed adjuvant doses of temozolomide in this study. The median
overall survival for all patients was 11 months, and the actuarial overall survival rate was 48 percent at one
year and eight percent at two years. Similar results were published in 2008 by Minniti et al., who reported
an overall survival of 10.6 months in 32 patients older than 70 years with GBM treated with standard
radiotherapy plus concurrent and adjuvant temozolomide.62
In 2009, Minniti et al. published the results of a prospective trial examining hypofractionated radiotherapy
followed by adjuvant temozolomide.63 In this study, 43 patients over the age of 70 with a KPS of 60 or
more received 30 Gy of radiotherapy (6 fractions of 5 Gy each over 2 weeks) followed by up to 12 cycles
of adjuvant temozolomide (150 – 200 mg/m2). The median overall and progression-free survival was 9.3
months and 6.3 months, respectively. The authors suggested that hypofractionated radiotherapy with
adjuvant temozolomide may be a reasonable therapeutic approach for patients with less favourable
prognostic factors. A further phase II study, also by Minniti et al., addressed short-course radiotherapy (40
Gy in 15 fractions over 3 weeks) plus concomitant and adjuvant temozolomide in patients ≥ 70 years with
a KPS of 60 or more. The investigators reported a median overall survival of 12.4 months, and a median
progression free survival of 6 months.64
Taken together, this data suggest that treatment with concurrent and adjuvant temozolomide in elderly
patients with a good performance status is well tolerated and may increase the length of both overall and
progression-free survival. At the present time, however, several questions regarding the optimal
combination of temozolomide and radiotherapy in elderly patients, many of which will hopefully be
answered by the findings from several ongoing clinical trials.65
The management of GBM in elderly patients with poor performance status is not well established. Gallego
Perez-Larraya et al. conducted a non-randomized phase II trial of temozolomide alone (150-200 mg/m2
per day for 5 days, every 4 weeks until disease progression) in patients 70 years or older with a median
KPS of 60. The median overall survival was 25 weeks, and the median progression free survival was 16
weeks. In the 31 tumours evaluated for MGMT promoter methylation, a methylated status was associated
with longer progression free survival (26 versus 11 weeks, p=0.03) and overall survival (31 versus 19
weeks, p=0.03).66
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CLINICAL PRACTICE GUIDELINE CNS-001
version 3
GLOSSARY OF ABBREVIATIONS
Acronym
ALA
CCO
CI
CNS
CT
GBM
GTR
HR
IMRT
KPS
MGMT
MRI
PCV
RCT
RR
STR
WBRT
WHO
Description
5-aminolevulinic acid
Cancer Care Ontario
confidence interval
central nervous system
computed tomography
glioblastoma
gross total resection
hazard ratio
intensity-modulated radiotherapy
Karnofsky performance status
O6- methylguanine – DNA methyltransferase
magnetic resonance imaging
procarbazine + lomustine + vincristine
randomized controlled trial
risk ratio
subtotal resection
whole brain radiotherapy
World Health Organization
DISSEMINATION
•
•
•
Present the guideline at the local and provincial tumour team meetings and weekly rounds.
Post the guideline on the Alberta Health Services website.
Send an electronic notification of the new guideline to all members of CancerControl Alberta.
MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2013. If critical new
evidence is brought forward before that time, however, the guideline working group members will revise
and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Provincial CNS Tumour Team in the development of this guideline
has been voluntary and the authors have not been remunerated for their contributions. There was no
direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta
recognizes that although industry support of research, education and other areas is necessary in order to
advance patient care, such support may lead to potential conflicts of interest. Some members of the
Alberta Provincial CNS Tumour Team are involved in research funded by industry or have other such
potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an
unbiased manner.
Page 11 of 15
CLINICAL PRACTICE GUIDELINE CNS-001
version 3
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