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INVITED MANUSCRIPT
Radiation therapy of pathologically confirmed newly diagnosedglioblastoma in adults
John Buatti Æ Timothy C. Ryken Æ Mark C. Smith Æ Penny Sneed ÆJohn H. Suh Æ Minesh Mehta Æ Jeffrey J. Olson
Received: 9 January 2008 / Accepted: 19 May 2008
� Springer Science+Business Media, LLC. 2008
Recommendations
Level 1
Radiation therapy is recommended for the treatment of
newly diagnosed malignant glioma in adults. Treatment
schemes should include dosage of up to 60 Gy given in
2 Gy daily fractions that includes the enhancing area.
Hypo-fractionated radiation schemes may be used for
patients with a poor prognosis and limited survival without
compromising response.
Hyper-fractionation and accelerated fractionation have
not been shown to be superior to conventional fractionation
and are not recommended.
Brachytherapy or stereotactic radiosurgery as a boost to
external beam radiotherapy have not been shown to be
beneficial and are not recommended in the routine man-
agement of newly diagnosed malignant glioma.
Level 2
It is recommended that radiation therapy planning include a
1–2 cm margin around the radiographically defined T1
contrast-enhancing tumor volume or the T2 weighted
abnormality on MR imaging.
Rationale
Although radiation therapy has been a standard therapy for the
treatment of malignant glioma for more than 25 years there
remains controversy as to the optimal way to deliver this ther-
apy. Because of several randomized trials in the late 1970s and
early 1980s that showed a benefit with radiation treatment along
with retrospective series showing that there was a high rate of
local recurrence; the stage was set for dose escalation to be
studied. Dose escalation in conventional, hyper-fractionated,
accelerated and hypo-fractionated radiotherapy was evaluated.
Increased local dose was also evaluated including stereotactic
radiosurgery and brachytherapy. Generally survival has been
used as the endpoint for clinical trials, but increasing interest in
quality of life issues has yielded additional information par-
ticularly in the older patients and poor prognostic groups.
J. Buatti
Department of Radiation Oncology, University of Iowa, Iowa
City, IA, USA
T. C. Ryken
Department of Neurosurgery, University of Iowa College
of Medicine, Iowa City, IA, USA
M. C. Smith
Department of Radiation Oncology, University of Iowa
Hospitals and Clinics, Iowa City, IA, USA
P. Sneed
Department of Radiation Oncology, University of California,
San Francisco, CA, USA
J. H. Suh
Department of Radiation Oncology, Cleveland Clinic
Foundation, Cleveland, OH, USA
M. Mehta
Department of Radiation Oncology, University of Wisconsin,
Madison, WI, USA
J. J. Olson (&)
Department of Neurosurgery, Emory University School
of Medicine, 1365B Clifton Rd., NE, Ste. 6200,
Atlanta, GA 30322, USA
e-mail: jeffrey.olson@emoryhealthcare.org
123
J Neurooncol (2008) 89:313–337
DOI 10.1007/s11060-008-9617-2
This review focused on the issue of whether radiation
therapy is of benefit in the management of patients diagnosed
with malignant glioma. In addition, issues relating to the
delivery of this therapy are reviewed, with emphasis on
issues relevant to neurosurgeons involved in the treatment of
patients diagnosed with malignant glioma, including
brachytherapy and radiosurgery. The literature on radiation
sensitizers and proton beam radiotherapy was deferred but is
reviewed thoroughly in the excellent systematic review of
radiation therapy for malignant glioma by Laperriere et al.
for the Neuro-oncology Disease Site Group of the Cancer
Care Ontario Program available through the National
Guideline Clearinghouse (www.guideline.gov) [1].
Search criteria
A National Library of Medicine literature search was
undertaken including the period from 1966 through 2005
initially using the MESH subject heading astrocytoma gen-
erating a broad base of studies. Titles and abstracts were
reviewed with attention to those titles including radiation
therapy, radiosurgery, or radioactive implant. Secondary
searches crossing astrocytoma with radiation and radiation
therapy were undertaken. Bibliographies of selected papers
were reviewed for additional references of relevance.
Articles were selected if they addressed issues of radi-
ation therapy of malignant gliomas, dose considerations,
volume considerations or dose escalation techniques such
as radiosurgery or brachytherapy. Articles were preferen-
tially reviewed if they contained randomized or prospective
data. Randomized controlled trials were given preference
as Class I data. Cohort-matched or case–control studies
were given secondary consideration as Class II information
and institutional reviews with comparisons to historical
controls were categorized as Class III data.
Scientific foundation
Role of postoperative radiation therapy
Interest in radiation therapy for primary brain tumors led to
a series of randomized, multi-institutional studies, includ-
ing the widely quoted studies by the Brain Tumor Study
Group (BTSG) in the late 1970s and early 1980s. In some
instances these studies provide Class I data addressing the
role of radiation therapy in the management of newly
diagnosed malignant glioma and demonstrate that it is
effective at prolonging the life of patients with malignant
glioma compared to no treatment. In general, these trials
compared surgery, radiation therapy and chemotherapy
alone or in various combinations.
The first randomized study was reported by Shapiro in
1976 and randomized patients to surgery followed by
carmustine (BCNU) and vincristine chemotherapy versus
surgery followed by identical chemotherapy along with
45 Gy whole brain radiotherapy and 15 Gy boost dose to
the side ipsilateral to the lesion [2]. The results showed a
median survival of 11.1 months in the radiotherapy arm
compared to 7.5 months in the chemotherapy only arm.
Despite the apparent survival advantage the difference was
not statistically significant possibly because only 33
patients were randomized, three of whom withdrew prior to
completing therapy. In addition, the groups were not
evenly matched in terms of Karnofsky Performance Status
(KPS) with a mean KPS of 71 in the chemotherapy group
compared to 57 in the radiation therapy group, which
further supports the role of radiation therapy. The report
also noted that five patients in the radiotherapy group had
multi-centric or bilateral involvement versus only 2 in the
chemotherapy alone group.
In 1978, the first of the BTSG studies addressing these
issues was reported by Walker et al. [3]. There were 303
patients with malignant glioma randomized to one of four
study arms after surgical management. These included a
control of best supportive care alone after surgery, che-
motherapy alone with BCNU, radiation therapy alone with
whole brain radiotherapy to a dose of 50–60 Gy, and a
combination of BCNU with radiotherapy (identical doses
and delivery). Of the entire study group 73% were felt to
have been valid for analysis (valid study group), including
pathological confirmation and treatment according to the
protocol. The authors also reported an ‘‘adequately treated’’
group that received at least the prescribed dose of radiation
and at least two of the planned courses of BCNU chemo-
therapy. Analysis showed a significant advantage for those
groups receiving radiation therapy compared to those
receiving best supportive care or chemotherapy alone, with
a median survival of 4.3 months for the best supportive
care arm, 6.3 months in the chemotherapy alone group,
9.4 months in the radiotherapy alone group and 10.1 month
in the group receiving both chemotherapy and radiation.
The results of the later three were all statistically signifi-
cant when compared to the surgery alone group. This
provides Class I data supporting a role for radiation
therapy.
The follow-up BTSG study reported in 1980 random-
ized 467 patients with malignant glioma to semustine
(CCNU) chemotherapy alone, radiotherapy alone, radio-
therapy plus CCNU or radiotherapy plus BCNU [4]. This
study again confirmed a significant advantage for the
groups receiving radiotherapy. The radiotherapy in this
trial was better controlled and included specification of
60 Gy in 6–7 weeks. The results in the ‘‘valid study’’ group
that fulfilled protocol criteria indicated a median survival
314 J Neurooncol (2008) 89:313–337
123
of 6 months in the CCNU alone arm, 9 months with
radiotherapy alone, 12.8 months with BCNU plus radio-
therapy and 10.5 months with CCNU plus radiotherapy.
Statistical analysis indicated a significant survival advan-
tage in radiotherapy containing arms over chemotherapy
alone. This provided additional Class I data supporting the
role for radiotherapy.
A randomized study in Europe was reported in 1981 by
Kristiansen, et al. [5]. The study was a three arm ran-
domized, placebo controlled trial following surgical
management comparing best supportive care, radiotherapy
alone (with placebo) and radiotherapy combined with
concomitant bleomycin. The radiation in this trial was
45 Gy to the whole brain. Over the course of the study, 118
patients were randomized into the three arms with reported
median survivals of 5.2 months for the best supportive care
and 10.8 months for both the combined bleomycin/radio-
therapy and radiotherapy alone groups. The authors
indicate this was statistically significant but do not provide
statistical detail for review.
The randomized trial published by Sandberg-Wolheim
et al. was conducted in Sweden and included 171 patients
that were randomized to receive procarbazine, CCNU and
vincristine (PCV) alone or in combination with 50 Gy to
the whole brain and an additional 8 Gy to the ipsilateral
hemisphere for a total of 58 Gy [6]. The analysis included
139 patients in the ‘‘valid study’’ group. In this group the
median survival for the chemotherapy only group was
11.8 months versus 16.5 months with the addition of
radiotherapy (P = 0.01). The trial showed that the addition
of radiotherapy was advantageous and particularly so in
those younger than 50 years of age (median survival
19.3 months versus 30.5 months, P = 0.037).
Finally, in a systematic review of these six randomized
studies addressing the issue of survival advantage created
by postsurgical external beam radiotherapy, Laperriere
et al., detected a significant survival benefit [7]. The risk
ratio of 0.81 (P \ 0.00001) indicates a reduction in risk of
dying over the course of the studies in patients receiving
radiotherapy as opposed to not receiving it. Thus, even
though some of the studies contained smaller numbers and
did not achieve individual statistical significance, the
combined data favors a definite survival advantage with
external beam radiotherapy (see Evidentiary Table 1 for
further details on the role of postoperative radiation ther-
apy) [8].
Dose
Review of the literature reveals several randomized trials
addressing the optimal dose of radiotherapy for patients
with malignant glioma. Following the initial success of the
BTCG studies, trials using higher total radiotherapy doses
were undertaken. However, no clear benefit to escalation
has been demonstrated.
A randomized trial of 443 patients reported by the
Medical Research Council in the United Kingdom com-
pared whole brain radiotherapy dosage of 45 Gy in 20
fractions to 60 Gy in 30 fractions for patients with newly
diagnosed malignant glioma, as described by Bleehen et al.
[9]. A two to one randomization scheme placed more
patients in the higher dosage scheme. The 1-year survival
rates were 29% for the 45 Gy arm and 39% for the 60 Gy
arm. The 18 month-survival rates were 11% and 18%,
respectively and both comparisons were statistically sig-
nificant (P = 0.04). This study provides Class I data
supporting a dose of 60 Gy compared to 45 Gy.
In the combined Radiation Therapy Oncology Group
(RTOG) and Eastern Cooperative Group (ECOG) trial
reported by Nelson et al., 626 patients with newly diag-
nosed malignant glioma were randomized to four arms that
included 60 Gy to the whole brain (141 patients), 60 Gy to
the whole brain with a 10 Gy boost to the tumor (103
patients), 60 Gy with carmustine (156 patients) and 60 Gy
with semustine and dacarbazine (138 patients) [10]. The
median survival for the 60 and 70 Gy arms was reported as
9.3 and 8.2 months. No significant difference in median
survival was found between any of the treatment arms. This
provides Class I data that a dose above 60 Gy is not ben-
eficial (see Evidentiary Table 2 for further particulars on
the dosage of radiation) [11–13].
Volume
Despite the propensity of early whole brain radiotherapy
studies, the choice for volume of radiation delivery has
evolved to a more limited field based primarily on natural
history studies demonstrating a tendency for local recur-
rence [14–16] and Class II data suggesting a lack of benefit
for whole brain radiotherapy compared to more limited
fields. A high percentage of progressive disease is found
within 1–2 cm of the initial treatment region. Early studies
utilized whole brain radiotherapy; however, given this
information and the advances in neuroimaging, recent
years have seen a shift away from utilizing whole brain
fields to the use of regional fields with margins around
enhancing disease, generally on the order of 1–2 cm.
Randomized studies addressing the volume of radio-
therapy delivery have been limited. Shapiro et al. described
the BTCG 8001 study in which 571 patients were ran-
domized into three chemotherapy regimens [17]. In the
early phase of the trial, patients received 60 Gy whole
brain radiotherapy. In the later phases, the protocol was
modified and patients received 43 Gy whole brain radio-
therapy and an additional 17 Gy focused on the enhancing
volume plus a 2 cm margin. After analysis there was no
J Neurooncol (2008) 89:313–337 315
123
difference in survival between the two different radio-
therapy regimens. Although this was a randomized study, it
was not specifically designed to address the issue of
radiotherapy delivery. Therefore there is only Class II data
supporting the role of limited field therapy.
Kita et al. published the results of their randomized trial
in which patients received either 40 Gy whole brain
radiotherapy in 20 fractions followed with a local boost of
18 Gy in nine fractions, giving a total dose of 58 Gy, or
56 Gy in 28 fractions targeted to the enhancing tumor
Evidentiary Table 1 Postoperative external beam radiation
First author/
Reference
Study description Data class Conclusion
Laperriere et al./[7] Systematic review of randomized trials
Six randomized studies identified
addressing the role of postoperative
external beam radiotherapy in newly
diagnosed malignant glioma following a
surgical procedure
I Meta-analysis Pooled data detected a significant survival benefit
favoring postoperative radiotherapy compared to
no radiotherapy (risk ratio 0.81, 95% CI 0.74–
0.88, P \ 0.00001). No significant heterogeneity
(v2 = 6.73, P [ 0.10)
Two randomized trials showed no difference in
survival rates for whole brain radiotherapy versus
the enhancing margin plus 2 cm margin. A
randomized trial detected a small improvement in
survival with 60 Gy in 30 fractions versus 45 Gy
in 20 fractions
This excellent systematic review supports the role of
external beam radiotherapy in patients with newly
diagnosed malignant glioma. The data supports
inclusion of the enhancing volume plus a margin
to a dose of 50 to 60 Gy but is primarily based on
studies utilizing whole brain radiotherapy for at
least a portion of the treatment regimen
Sandberg-Wollheim
et al./[6]
Randomized study of PCV with and
without EBRT (58 Gy total 50 WBRT
plus 8 additional to hemisphere) for
malignant glioma
Overall 171 patients
Valid study group 139 due to protocol
violations
PCV (n = 71)
PCV plus EBRT (n = 68)
I Overall median survival (n = 171):
PCV 10.5 months
PCV plus EBRT 15.5 months (P = 0.03)
Valid Study Group (n = 139): PCV 11.8 months
PCV plus EBRT 16.5 months (P = 0.01)
Most significant advantage in the Valid Study Group
in patients under 50 years of age
Median survival
PCV 19.3 months
PCV plus EBRT 30.5 months (P = 0.037)
Median Time to Progression
PCV 7 months, PCV plus EBRT 19.8 months
(P = 0.08)
The authors concluded that EBRT added a
significant survival advantage overall which
appeared most significant in patients under age 50
Kristiansen et al./[5] Randomized study of surgery, surgery
plus EBRT (45 Gray whole brain) or
surgery, EBRT and bleomycin
118 patients with Grade 3 and 4
astrocytoma
Group 1 Surgery, EBRT and bleomycin
(n = 45)
Group 2 Surgery plus EBRT (n = 35)
Group 3 Surgery alone (n = 38)
II Median survival:
Surgery 5.2 months
Surgery plus EBRT 10.8 months
Surgery plus EBRT and bleomycin 10.8 months (no
P-value reported but authors state it was
statistically significant between surgery alone and
the two groups with EBRT)
No data on extent of resection and no detail on
statistical analysis
Authors concluded that the addition of radiotherapy
doubles survival in patients with malignant
glioma over surgery alone
316 J Neurooncol (2008) 89:313–337
123
Evidentiary Table 1 continued
First author/
Reference
Study description Data class Conclusion
Walker et al./[4] Randomized comparison of EBRT (60
Gray whole brain) and nitrosoureas for
the treatment of malignant glioma
following surgery
Randomized 467 patients. 358 completed
study and formed valid study group
Four arms:
CCNU, EBRT, EBRT plus BCNU, EBRT
plus CCNU
I Median survival:
CCNU 6 months
EBRT 9 months
EBRT plus BCNU 12.8 months
EBRT plus CCNU 10.5 months
Statistical analysis indicated that all groups
receiving radiotherapy were significant versus
CCNU alone (P-values from\0.001 to 0.016). No
significant difference between any of the groups
receiving radiotherapy (P-values from 0.11 to
0.67)
The authors concluded that the addition of
radiotherapy increased median survival in a
statistically significant fashion and should be a
part of the treatment regimen for malignant
glioma
Walker et al./[3] Evaluation of BCNU and/or radiotherapy
in the treatment of malignant glioma
Randomized 303 patients to best
supportive care, BCNU, EBRT, EBRT
plus BCNU
EBRT 50 to 60 Gray whole brain
I Median survival:
Surgery alone 4.25 months
BCNU 6.3 months (P \ 0.002),
EBRT 9.4 months (P \ 0.001),
EBRT plus BCNU 10.1 months (P \ 0.006)
The authors concluded that the addition of external
beam radiotherapy resulted in significant
improvement in survival (increasing
approximately 150% in this study)
Andersen et al. Acta
Radiologica:
Oncology,
Radiation,
Physics, Biology
1978 [8]
Randomized trial of 108 patients with
GBM to surgery or surgery plus EBRT
(45 Gy whole brain)
57 patients surgery only
51 patients surgery plus EBRT
II Six month survival rates:
Surgery alone 25%
Surgery plus EBRT 64% (P \ 0.05)
One year survival rates:
Surgery alone 0%
Surgery plus EBRT 19% (P \ 0.05)
Suggests that EBRT has a significant impact on
survival
Randomized data but not clear if groups well-
matched and lacks sufficient details to consider
Class I evidence
Shapiro and Young/
[2]
Randomized study of BCNU and
Vincristine alone (n = 17) or with
EBRT (n = 16) (60 Gy–4500 whole
brain plus 1500 boost ipsilateral)
II Median survival–no statistically significant
difference demonstrated
7.5 months versus 11.1 months (favors the addition
of radiotherapy)
No statistical analysis
Incomplete follow-up. Pathology groups are
combined
Not clear if groups are well matched. Unable to
determine extent of resection
Survival using combination of radiotherapy and
chemotherapy following surgery was significantly
better than other studies at that time and the
authors encouraged continued investigation of
combination radiation and chemotherapy
J Neurooncol (2008) 89:313–337 317
123
volume [18]. The authors reported no significant difference
in survival between the two groups. The 2-year survival
was 43% for the whole brain group versus 39% for the
local field group and 17% versus 27% at 4 years. The study
consisted of a small number of patients (23 and 26 patients
respectively). This is additional Class II data supporting
more limited fields.
Although using an accelerated fractionation scheme, the
study of Phillips et al. randomized 68 older patients
(median age 58–59 years) with newly diagnosed glioblas-
toma to either conventional fractionated therapy of 60 Gy
in 30 fractions over 6 weeks or to 35 Gy in 10 fractions of
whole brain radiotherapy [19]. This study also demon-
strated no significant difference in survival comparing
10.3 months for conventional fractionation versus
8.7 months for the 35 Gy whole brain radiotherapy group
(P = 0.37). See Evidentiary Table 3 for further details on
the volume of tissue radiated.
Altered fractionation schedules
A variety of altered fractionation schemes have been descri-
bed in attempting to optimize fractionated radiotherapy
treatment. Terminology has developed in attempt to describe
these alterations and can be somewhat confusing as the
techniques invariably have some overlap. The comparison is
typically made to what may be loosely defined as a con-
ventional dose of approximately 60 Gy given in 30 fractions
of 2 Gy over 6 weeks. Compared with conventional radio-
therapy, hyper-fractionated radiotherapy is generally given
to a higher total dose over a similar overall treatment time
using multiple small fractions daily. The theoretical advan-
tage is the ability to deliver a higher dose without increased
toxicity, because of the smaller fraction size. The theoretical
advantage of hypo-fractionation is that a shorter overall
treatment time should enable better control of the tumor. In
the most extreme case of hypo-fractionation, single fraction
radiosurgery, toxicity is limited by treating a smaller volume.
Accelerated radiotherapy refers to a reduction in overall
treatment time by delivering multiple daily doses closer to
the usual size fraction to a similar overall dose. The basic
advantage of accelerated treatments is to reduce overall
treatment time, again assuming that acceptable efficacy and
toxicity are obtained.
A series of studies are reviewed below using various
combinations of altered therapy. These include hyper-
Evidentiary Table 2 Dose
First author/Reference Study description Data class Conclusion
Bleehen and Stenning/[8] Randomized 443 patients to 45 Gy in 20
fractions or 60 Gy in 30 fractions.
Patients were randomized in a 2:1 ratio
I Statistically significant difference correlating
to an improvement in median survival
of 2 months in the 60 Gy arm (P = 0.04)
Nelson et al. NCI Monogr.
1988 [12]
626 patients randomized to 4 study arms:
60 Gy to whole brain;
60 Gy to whole brain plus a 10 Gy boost;
60 Gy plus carmustine
60 Gy plus semustine and dacarbazine
I No statistically significant differences in
survival for any of the 4 arms
Chang et al. Cancer 1983
[11]
Randomized controlled trial of RTOG and
ECOG. Four study groups
60 Gy whole brain radiotherapy,
60 Gy whole brain radiotherapy plus
10 Gy local boost (total 70 Gy),
60 Gy whole brain radiotherapy plus
BCNU 60 Gy whole brain
radiotherapy plus CCNU and
dacarbazine,
I No significant improvement in survival
with the 10 Gy boost when compared
to 60 Gy whole brain alone
Walker MD Int J Radiat
Oncol Biol Phys 1979 [13]
Pooled data from randomized BTSG
studies 66-01, 69-01 and 72-01
II Re-analysis of BTSG studies with EBRT
doses from 4500 to 6000 showing best
survival using 6000 at 10.5 months survival.
The authors suggest that a dose response
is demonstrated within this study
Dose (Gy) Median survival (months)
60 10.5
55 9.0
50 7.0
45 or less 3.4
318 J Neurooncol (2008) 89:313–337
123
fractionation, hypo-fractionation and accelerated tech-
niques. From the review, it would appear that hyper-
fractionation has perhaps received the most interest.
Hyper-fractionation
Summaries of the reported randomized trials and two meta-
analyses are included in the evidentiary tables.
Prados et al. reported a trial of 231 patients with newly
diagnosed malignant glioma randomized into two radio-
therapy treatments, accelerated hyper-fractionation with a
total dose of 70.4 Gy at 1.6 Gy twice daily versus con-
ventional fractionation to a total dose of 59.4 Gy at 1.8 Gy
daily[20]. Comparison of the two groups demonstrated
similar median survivals (10.5 vs. 10.2 months, respec-
tively, P = 0.75).
The Phase I/II dose escalation study described by Nelson
et al. randomized 435 patients using local fields and 1.2 Gy
in twice daily fractions to a total doses of 64.8 Gy, 72.0 Gy,
76.8 Gy and 81.6 Gy with median survivals of 11.4, 12.8,
12.0, 11.7 months, respectively [10]. The authors were
unable to demonstrate a statistically significant survival
advantage between any of these groups, but noted a trend
towards increased survival with 72 Gy given in twice-daily
fractions. This dose is approximately biologically equivalent
to the most standard conventional dose of 60 Gy.
Deutsch et al. randomized 603 patients into a trial that
included randomization to groups receiving conventional
fractionation with either BCNU, steptozotocin or misoni-
dazole or hyper-fractionated radiotherapy plus BCNU [21].
No significant difference in survival was identified.
The trial by Ludgate et al. randomized 76 patients to
either receive whole brain radiotherapy (40 Gy) plus local
boost therapy (10 Gy) with daily treatments or hyper-
fractionation to a total dose of 47.6 Gy in three times daily
fractions, hence also accelerated [22]. This study is com-
paratively small but also demonstrated no significant
differences in survival were identified.
Shin et al’s trial published in 1985 compared two frac-
tionation schemes: conventional fractionation of 58 Gy in
30 once-daily fractions over 6 weeks versus 61.4 Gy in
three times daily fractions [23]. An additional arm included
hyper-fractionation plus midonidazole and showed no
advantage. The authors found an improvement in 1-year
survival comparing 41% for the hyper-fractionated group
versus 20% for the conventional fractionation group with a
P-value of 0.07 which the authors concluded was signifi-
cant. This paper updated the paper by Fulton et al. [24]
which was used in the first of the two meta-analyses noted
below.
An earlier trial by Shin et al. compared conventionally
fractionated whole brain radiotherapy of 34 Gy in 17
fractions plus a 16 Gy local boost with hyper-fractionated
(superfractionated) treatments of 40 Gy whole brain in 45
fractions plus 10 Gy local boost [25]. The authors found no
significant difference between the treatment arms and
noted some imbalances between the two groups.
Payne et al. randomized 157 patients into two groups
comparing hyper-fractionated radiotherapy to 36–40 Gy in
four times daily fractions with conventional radiotherapy
of 50 Gy in 25 fractions with both groups also receiving
CCNU and hydrea [26]. No significant difference in med-
ian survival was noted.
Two meta-analyses of radiation therapy in newly diag-
nosed malignant glioma were identified and reviewed.
Stuschke and Thames analyzed the pooled data from the
trials of Deutsch et al., Fulton et al. and Shin et al. [21] and
reported a significant survival benefit for patients treated
Evidentiary Table 3 Radiation volume
First author/Reference Study description Data class Conclusion
Kita et al./[18] Randomly assigned 49 patients to receive
40 Gy in 20 fractions to whole brain
followed by a boost of 18 Gy in nine
fractions; or 56 Gy in 28 fractions via local
fields
II Survival rates for whole brain group versus local
field were 43% versus 39% at 2 years and
17% vs. 27% at 4 years (respectively). No
statistical analysis reported
Despite the randomized design the study is
limited in size and the details of the
randomization are not clear
Shapiro et al./[17] Randomized trial of 571 patients with
malignant glioma evaluating three
chemotherapy regimens BTCG Trial 8001
In the early portion of the study all patients
received 60.2 Gy whole brain radiotherapy. In
later portions they were randomized to either
whole brain radiotherapy or 43 Gy whole brain
radiotherapy plus 17.2 Gy to the tumor plus a
2 cm margin.
II No statistically significant differences in survival
based on altering the radiation volume
Class II because it was not clear that comparing
the radiation treatment volume was the initial
intent of the study
J Neurooncol (2008) 89:313–337 319
123
with hyper-fractionated therapy with an odds ratio of 0.67
(95% confidence interval 0.48–0.93, P = 0.02). This report
did not include the study by Ludgate et al. or, the updated
report on the Fulton trial published as Shin et al. in 1985
and it excluded the report by Payne et al.
A subsequent meta-analysis by Laperiere et al. pooled
data from the studies by Payne 1982, Shin 1983 Shin 1985
and Deutsch 1989 [7]. The data from Fulton et al. included
in the Stuschke and Thames review was included in the
updated report by Shin et al. With the inclusion of these
additional larger studies, the authors concluded that no
significant survival benefit for hyper-fractionated radio-
therapy could be identified when compared with
conventionally fractionated radiotherapy (RR, 0.89; 95%
CI, 0.73–1.09; P = 0.27). The analysis indicated no sta-
tistically significant heterogeneity (v2 = 6.27, P = 0.10).
The trial by Ludgate et al. was not included because the
survival curves were not available for the total study group
(see Evidentiary Table 4 for further details on hyper-frac-
tionation) [27].
Hypo-fractionation
There have been a series of single-arm prospective non-
randomized trials using hypo-fractionation in a variety of
regimens, generally in patients felt to have poor prognostic
factors (older age and poorer performance scores). These
regimens have generally been attempted to demonstrate
equivalent palliative results to conventional fractionation
but shorten the overall treatment time, which could have an
impact on the quality of life in individuals with a short life
expectancy. Several of the papers conclude that caution
should be used in utilizing these regimens in patients with a
better prognosis because long term cognitive follow-up was
not available [28] and elderly patients who have main-
tained a KPS greater than 50 may benefit from the standard
conventional fractionated therapies [29].
Sultanem et al. reported a prospective non-randomized
study of 25 patients with glioblastoma treated with a hypo-
fractionated regimen of 60 Gy in 20 daily fractions of 3 Gy
given over 4 weeks [30]. The median survival was
9.5 months. The authors concluded that although no sur-
vival advantage seemed to result, the 2 week shorter
treatment time appeared safe and feasible and could be
advantageous in selected situations.
Roa et al. randomized 100 older patients with newly
diagnosed glioblastoma to either conventional fractionation
of 60 Gy in 30 fractions over 6 weeks or hypo-fraction-
ation of 40 Gy in 15 fractions over 3 weeks [31]. The
median survivals were 5.1 versus 5.6 months, respectively,
and were not significantly different (P = 0.57). The
authors concluded that in the population over age 60, this
hypo-fractionated regimen could be considered.
Phillips et al. randomized 68 older patients (84% over
40 years of age, median age 58–59 years) with newly
diagnosed glioblastoma to either conventional fractionated
therapy of 60 Gy in 30 fractions over 6 weeks or to 35 Gy
in 10 fractions of whole brain radiotherapy [19]. The study
was closed prematurely due to poor accrual and was unable
to demonstrate a significant difference, although the med-
ian survival for the conventional group was longer,
comparing 10.3 months for conventional fractionation
versus 8.7 months for the 35 Gy group (P = 0.37).
Hulshof et al. described a prospective non-randomized
study examining aggressive hypo-fractionation in a group
of 155 patients with glioblastoma [32]. The schemes
included 33 fractions of 2 Gy, 8 fractions of 5 Gy and
four fractions of 7 Gy. The authors found that the period
of neurological stabilization was similar between the
groups receiving four fractions of 7 Gy versus the con-
ventional 33 fractions of 2 Gy and concluded that an
aggressive hypo-fractionation scheme in patients with
poor prognostic indicators was well tolerated and had
similar survival results compared with conventional
fractionation.
Kleinberg et al. retrospectively reviewed 219 patients
with malignant glioma treated with 51 Gy given as 30 Gy
in 10 fractions to either large local fields or whole brain,
followed 2 weeks later with 21 Gy in seven fractions to
local fields and stratified the outcomes by RTOG recursive
partitioning analysis groups [28]. The authors concluded
that for RTOG groups 4–6 the hypo-fractionated regimen
gave similar survival results when compared to previous
RTOG trials for malignant glioma treated with conven-
tional fractionation.
Ford et al. performed a matched-pair analysis compar-
ing 27 poor prognosis patients treated with 36 Gy in 12
fractions to 27 matched patients treated with 60 Gy in 30
fractions [33]. Comparison of the groups indicated no
difference in outcome (Hazard ratio of 1.0, 95% CI 0.57–
1.74) and the authors concluded that for poor prognosis
patients the shorter hypo-fractionated regimen was at least
no worse than conventional fractionation.
Hoegler et al. published a prospective non-randomized
study of 25 patients with a median age of 73 treated with
37.5 Gy in 15 fractions [34]. Median survival was
8.0 months overall and 10.4 months in the group with
KPS [ 70. The authors concluded for this group that sur-
vival was similar to that achieved with conventional
radiotherapy regimens and that a Phase III trial was
warranted.
Slotman et al. treated a group of 30 patients with GBM
in a non-randomized prospective trial with 42 Gy in 14
fractions using local fields [35]. The regimen had accept-
able toxicity and was well tolerated. Factors indicative of
improved survival included age under 50, KPS of 80% to
320 J Neurooncol (2008) 89:313–337
123
Evidentiary Table 4 Hyper-fractionation
First author/
Reference
Study description Data class Conclusion
Laperriere et al./[7] Systematic review of previous randomized
studies involving hyper-fractionated
radiotherapy for malignant glioma
Studies included:
Payne 1982
Shin 1983
Shin 1985
Deutsch 1989
Not including
Scott 1998 (Abstract Only–1 year survival
and number per group not reported),
Ludgate1988 (no overall survival
reported)
I Meta-analysis Pooled analysis included four randomized
studies. Two were identified but excluded as
data reporting not consistent
No significant survival benefit for hyper-
fractionated radiotherapy was identified when
compared with conventional radiotherapy
(RR, 0.89; 95% CI, 0.73–1.09; P = 0.27)
No statistically significant heterogeneity
(v2 = 6.27, P = 0.10).
Prados et al./[20] Randomized controlled trial of 231 patients
with newly diagnosed GBM in four
groups comparing accelerated
hyperfractionated radiotherapy (70.4 Gy
using two fractions per day) versus
standard fractionated irradiation
(59.4 Gy using daily fractions) with or
without DFMO as a radiosensitizer
Groups balanced with respect to age, KPS,
extent of resection
I No difference in groups with or without DMFO
Accelerated Hyper-fractionated (2 arms):
Overall Survival 10.5 months, Standard
Radiation Therapy (2 arms): Overall Survival
10.25 months (P = 0.75)
The authors concluded that there was no survival
benefit observed with accelerated hyper-
fractionated therapy
Stuschke M et al.,
Int J Radiat Oncol
Biol Phys 1997
[27]
Meta-analysis including three previously
reported randomized trials including
hyper-fractionation in newly diagnosed
malignant glioma
Studies included:
Deutsch 1989
Fulton 1984
Shin 1983
II Meta-analysis The authors reported a trend in favor of hyper-
fractionation with O.R. of 0.67 (95% CI 0.48–
0.93, P = 0.02).
Small number of studies limits interpretation
Nelson et al./[10] Randomized controlled trial of 435
analyzed patients with newly diagnosed
malignant glioma initially into three arms
receiving 1.2 Gy fractions twice daily;
64.8 Gy
72.0 Gy
76.8 Gy, and subsequently into two arms:
72.0 Gy
81.6 Gy All patients also received BCNU
Local field radiotherapy used and defined as
edema on imaging plus 2.5 cm margin
II Complicated study to interpret due to the change
in the radiation doses used over the sequence
Median survival:
64.8 Gy 11.4 months
72.0 Gy 12.8 months
76.8 Gy 12.0 months
81.6 Gy 11.7 months
The authors report no significant differences
between any of the groups but note the trend
towards increased survival at the 72.0 Gy dose
given in twice daily fractions and note similar
survival for this group to the survival in
previous studies of 60 Gy in daily fractions
This trial led to the subsequent RTOG 9006 trial
comparing hyper-fractionated radiotherapy to
72.0 Gy in 1.2 Gy fractions twice daily to
60 Gy daily fractions of 2 Gy as reported in
abstract form by Scott et al. The results of the
subsequent trial involving 712 adults with
newly diagnosed malignant glioma did not
indicate an advantage to hyper-fractionation
over daily fractionation (10.2 months vs.
11.2 months, P = 0.44)
J Neurooncol (2008) 89:313–337 321
123
Evidentiary Table 4 continued
First author/
Reference
Study description Data class Conclusion
Deutsch et al./[21] Randomized controlled trial of 603 patients
with newly diagnosed malignant glioma
in four groups:
Standard radiotherapy plus BCNU
Standard radiotherapy (60 Gy in 30–35
fractions) plus streptozotocin
Hyper-fractionated radiotherapy (66 Gy in
60 fractions–twice daily) plus BCNU
Standard radiotherapy plus misonidazole
and BCNU
I Median survivals:
Standard radiotherapy plus BCNU 9.9 months
Standard radiotherapy plus streptozotocin
9.9 months
Hyper-fractionated radiotherapy plus BCNU
10.4 months
Standard radiotherapy plus misonidazole and
BCNU 9.2 months
No statistically significant difference between
any of the groups and no advantage to hyper-
fractionation
Ludgate et al./[22] Randomized controlled trial of 76 patients
with newly diagnosed GBM comparing
whole brain radiotherapy plus 10 Gy
local boost delivered daily treatments to
40 Gy versus three fractions per day to a
dose of 47.6 Gy
I Median survival:
Daily fraction group 8 months
Hyper-fractionated group 11.5 months (P-value
reported as not significant)
No significant difference in survival was
identified. An increase in early radiation reaction
and a decrease in late radiation reaction was
identified in the hyper-fractionated group. The
age of the daily fractionated group was older
than the hyper-fractionated group
This trial was not included in the Laperiere et al.
meta-analysis as the survival curves were
reported for three different age groups but not
for the total group. It was not included in the
meta-analysis by Stuschke et al. for unknown
reasons
Shin et al./[23] Randomized controlled trial in newly
diagnosed malignant astrocytoma
comparing two fractionation schemes
with misonidazole (124 patients):
Conventional fractionation (58 Gy in 30
fractions over 6 weeks) 38 patients versus
Multiple daily fractions (61.4 Gy three
daily fractions over 4.5 weeks) 43 patients
versus Multiple daily fractions plus
midonidazole 43 patients
I One year survival rate:
Coventional fractionation 20%
Multiple daily fractionation 41%
Multiple daily plus midonidazole 45%
No significant difference between fractionation
schemes favoring multiple daily fractions
(P = 0.07). No effect of midonidazole
Shin et al./[25] Randomized controlled trial for newly
diagnosed malignant astrocytoma
comparing:
Superfractionated radiotherapy (40 Gy in
45 fractions whole brain with 10 local
boost) 34 patients versus conventional
fractionated radiotherapy (34 Gy in 17
fractions whole brain with 16 Gy local
boost) 35 patients
I One year survival:
Conventional fractionated therapy 10%
Superfractionated therapy 32%
Two year survival:
Conventional fractionated therapy 21%
Superfractionated therapy 54%
Median survival:
Conventional fractionated therapy 9 months
Superfractionated therapy 13 months
The authors note a trend in favor of
superfractionation but note that it was not
statistically significant and may have been
explained by differences between the two
groups (primarily age was younger in the
superfractionated group)
322 J Neurooncol (2008) 89:313–337
123
100% and 75% or greater resection. If none of those factors
were present the median survival dropped to 6.25 months.
Bauman et al. treated 29 patients with GBM with poor
prognostic factors (age greater than 64 and KPS less than
50) with 30 Gy whole brain radiotherapy in 10 fractions
over 2 weeks [29]. They compared their median survival of
6 months with historical controls of 35 similar patients
treated with 50 Gy (median survival of 10.1 months) and
28 patients receiving supportive care only (median survival
of 1 month). The authors concluded that the hypo-frac-
tionated course could be used in elderly patients with poor
prognosis and that conventional therapy should be con-
sidered in the elderly patient with a higher KPS.
Thomas et al. used a scheme of 30 Gy in six fractions
using local fields over 2 weeks in 38 patients with malig-
nant glioma and poor prognostic indicators and found a
median survival of 6 months [36]. They felt the regimen
was well tolerated and provided effective palliation but
indicated definitive conclusions would require randomized
data.
Glinski et al. published a randomized controlled trial of
108 patients including 44 with glioblastoma and 64 with
anaplastic astrocytoma with two arms: conventional frac-
tionation (50 Gy whole brain plus 10 Gy in five fractions to
the tumor) or hypo-fractionation (two courses of 20 Gy in
five fractions separated by a month and followed a month
later by 10 Gy in 5 as a boost to the tumor) [37]. The
groups appeared to be well balanced. Reporting on the 2-
year survival there was no survival advantage for the
anaplastic astrocytoma groups (22% vs. 18%, P [ 0.05),
However, they found a survival advantage in the subgroup
of 44 glioblastoma patients treated with hypo-fractionated
split regimen of 23% versus 10% (P \ 0.05). See
Evidentiary Table 5 for further particulars on hypo-
fractionation.
Accelerated radiotherapy
Brada et al. described a single arm non-randomized study
described the treatment of 211 patients with malignant
glioma treated with 55 Gy in 34 twice daily fractions [38].
The median survival was 10 months. In comparing to a
historical control group treated with 60 Gy in 30 fractions
the authors concluded their results were nearly identical.
They added the opinion that given the lack of clear survival
advantage, the logistics of administering multiple fractions
per day appeared to be an unnecessary complication.
Werner-Wasik et al. published their randomized con-
trolled trial evaluating dose escalation, hyper-fractionation
and accelerated dosing in 747 evaluable patients (RTOG
83-02) [39]. The accelerated group received 1.6 Gy twice
daily to doses up to 54 Gy. Although they found low
toxicity with the accelerated regimen, the median survival
of 10. 2 months for glioblastoma and 40.3 months for
anaplastic astrocytoma was not significantly different than
the hyper-fractionated regimen or from historical conven-
tionally fractionated controls (10.2 vs. 10.8 months,
P = 0.08 for glioblastoma and 42.3 versus 40.3 months,
P = 0.67 for anaplastic astrocytoma).
Horiot et al. reported on the results of an EORTC ran-
domized controlled trial of 340 malignant glioma patients
[40]. The study involved three arms: 60 Gy in 30 fractions
over 6 weeks (conventional fractionation), 60 Gy total but
given in 2 Gy fractions three times daily for 1 week
(30 Gy) and then repeated after 2 week interval (acceler-
ated fractionation). The third group consisted of the
Evidentiary Table 4 continued
First author/
Reference
Study description Data class Conclusion
Payne et al./[26] Randomized controlled trial comparing 157
patients with newly diagnosed malignant
astrocytoma treated with
Hyper-fractionated (36–40 Gy given four
fractions per day) versus Standard
radiotherapy (50 Gy in 25 fractions) Both
groups received CCNU and hydrea
I Median survival:
Hyper-fractionated 10.6 months
Standard radiotherapy 10.2 months (P = NS)
No significant survival or toxicity differences
were seen between the two groups
Scott et al.
Proceedings of the
Annual Meeting
of ASCO 1998
Randomized comparison of hyper-
fractionated rad iotherapy to 72.0 Gy
versus standard radiotherapy
RTOG 9006
712 patients with malignant glioma
Patients also received BCNU
Not Graded Presented as an abstract only. It is included here
for reference because it is a large trial that is
referred to in the literature with some
frequency
Authors reported no significant difference in
median survival between the two groups
Limited data available precluded this large
negative study from being included in
subsequent meta-analysis
J Neurooncol (2008) 89:313–337 323
123
accelerated fractionated regimen plus misonidazole.
Although the detail provided in this paper is minimal, the
authors reported no significant difference between any of
the groups (P-value not reported). They did not describe an
increase in toxicity with the accelerated regimen.
Keim et al. described a non-randomized comparison of
38 patients with GBM treated with an accelerated radio-
therapy regimen of 1.6 Gy three times daily to a total dose
of 60 Gy [41]. They found a median survival of
10.5 months. Comparison to similar group of 26 patients
treated with conventional fractionation found no significant
difference (P-value not reported). The authors concluded
that there were no increased problems with the accelerated
regimen but it did not improve survival.
Simpson and Platts published a randomized trial of 134
patients with glioblastoma initially with three treatment
Evidentiary Table 5 Hypo-fractionation
First author/
Reference
Study description Data class Conclusion
Sultanem et al./[30] Prospective trial of 25 patients with GBM
treated with a hypo-fractionated
radiotherapy. 60 Gy in 20 daily
fractions of 3 Gy to the tumor volume,
and 40 Gy in 20 fractions of 2 Gy over
4 weeks
III Median survival 9.5 months (range: 2.8–22.9 months)
One-year survival rate 40%
Median progression-free survival was 5.2 months
(range: 1.9–12.8 months)
The 2-week reduction in the treatment time may be a
valuable benefit for this group of patients. However,
despite this accelerated regimen, no survival
advantage has been observed
Roa et al./[31] Randomized controlled trial of 100
patients with newly diagnosed GBM
over age 60.
Two groups:
60 Gy in 30 fractions over 6 weeks versus
40 Gy in 15 fractions over 3 weeks
I Median survival:
60 Gy group 5.1 month
40 Gy group 5.6 month P = 0.57
6 month survival:
60 Gy group 44.7%
40 Gy group 41.7%
No significant difference could be demonstrated. The
abbreviated regimen may be reasonable to consider
in patients over the age of 60
Phillips et al./[19] Randomized controlled trial in newly
diagnosed GBM (closed early for slow
accrual)
84% of all patients were over 40 years of
age.
Two groups:
60 Gy in 30 fractions over 6 weeks–Local
field (n = 36) versus 35 Gy in 10
fractions–Whole Brain Radiotherapy
(n = 32)
I Median survival:
60 Gy group 10.3 month
35 Gy group 8.7 month P = 0.37
Risk of dying over course of the study appeared
increased in the whole brain radiotherapy with RR of
1.47 (95% CI 0.89–2.42) but was not significant
Hulshof et al./[32] Prospective non-randomized comparison
of conventional and hypo-fractionated
radiotherapy in GBM
155 patients Three different radiation
schemes were used;
33 9 2 Gy
8 9 5 Gy
4 9 7 Gy
III Median survival:
33 9 2 Gy 7 months
8 9 5 Gy 5.6 months
4 9 7 Gy 6.6 months
In general, patients in the hypo-fractionation group had
far worse prognostic factors compared with patients
treated with the conventional scheme
The period of neurological improvement or
stabilisation was similar between the 4 9 7 Gy and
33 9 2 Gy group
An extreme hypo-fractionation scheme of 4 9 7 Gy
conformal irradiation in poor prognostic
glioblastoma patients is well tolerated, convenient
for the patient and provides equal palliation without
negative effects on survival compared with
conventional fractionation
324 J Neurooncol (2008) 89:313–337
123
Evidentiary Table 5 continued
First author/
Reference
Study description Data class Conclusion
Kleinberg et al./[28] Retrospective review and classification of
219 patients with malignant glioma
treated with 51 Gy delivered as 30 Gy
in 10 fractions to large field or whole
brain, followed 2 weeks later with
21 Gy in seven fractions
Outcomes stratified by RTOG RPA
classes
III The six RTOG prognostic groupings were significantly
predictive of outcome for patients treated with this
shortened regimen (log rank P \ 0.001)
Median
survival
(months)
Two-Year
Survival
(%)
RTOG Class 1 68 64
RTOG Class 2 57 67
RTOG Class 3 22 45
RTOG Class 4 13 8
RTOG Class 5 8 3
RTOG Class 6 5 3
The median and 2-year survival results for each
prognostic classes were similar to the results
achieved by aggressive treatment on RTOG
malignant glioma trials for selected patients
The authors concluded that this decreased regimen
could be considered an appropriate treatment option
for most malignant glioma patients (RTOG groups
4–6), as it resulted in similar survival as standard
regimens with reduced treatment time
However, they did not recommend this regimen for
RTOG classes 1–3 because long-term neuro-
cognitive effects are unknown using this hypo-
fractionation scheme
Ford et al./[33] Matched case–control 32 poor prognosis
patients with GBM treated with 36 Gy
in 12 fractions Compared with matched
patients receiving 60 Gy in 30 fractions
II 27 pairs were used
Median survival for the 36 Gy group was 4 months
Comparison with control group resulted in a Hazard
ratio of 1.0 (95% CI was 0.57–1.74)
For poor prognosis patients the shorter regimen was no
worse than the standard
Hoegler et al./[34] Prospective non-randomized study of 25
patients with GBM treated with
37.5 Gy in 15 fractions. Median age
73 years
III Median survival (overall group) 8.0 months
Median survival (if KPS [ 70) 10.4 months
The authors conclude that for this elderly group the
survival was similar to longer radiotherapy regimens
and that a Phase III study was warranted
Slotman et al./[35] Prospective non-randomized study of 30
patients with GBM treated with 42 Gy
in 14 fractions to the tumor plus 3 cm
III Median survival was 9 months for the overall group
Three prognostic factors were identified
Median survival:
Age under 50, KPS 80 to 100, 75% or greater
resection–12.5 months
One or two of the above factors–9.5 months
None of the above factors–6.25 months
Bauman et al./[29] Prospective single arm trial. 29 patients
with GBM poor prognosis (age greater
than 64 years or KPS less than 50)
treated with 30 Gy whole brain in 10
fractions over 2 weeks
III Median survival 6 months
Compared with historical cohorts, 35 similar patients
treated with greater than 50 Gy (Median survival
10.1 months) and 28 patients treated with supportive
care only (1 month)
The authors conclude that although this lower dose
regimen may be useful in poor prognosis older
patients, elderly patients with KPS greater than
50 my be considered for higher dose radiotherapy
regimens given the historical better outcome
J Neurooncol (2008) 89:313–337 325
123
arms [42]. These included whole brain radiotherapy to
30 Gy given either as three times daily over 1 week, three
times daily over 3 weeks or daily for 3 weeks. As the study
progressed (presumably based on the safety evaluation and
lack of efficacy) the doses were adjusted upwards to
include 40 Gy. The authors found no difference in survival
between any of the groups in this study (see Evidentiary
Table 6 for further points on accelerated radiotherapy).
Brachytherapy
Brachytherapy is a technique that utilizes the placement of
radioactive seeds in and around tumors to increase, or
boost, the delivery of local radiation. Both temporary and
permanent sources have been described and a variety of
radioactive sources have been utilized, with the majority of
more recent studies in malignant glioma describing the use
of I-(125). Theoretically this could offer an advantage in
malignant glioma when the tumors are unifocal at presen-
tation and because the majority of tumors progress or recur
within 2 cm of their original location. Two randomized
studies, one matched control study and a series of retro-
spective studies of interest are abstracted in the Evidentiary
Table 7.
Significant effort has gone into attempting to identify
patients with malignant glioma who would benefit from
this technique. Generally patients selected for brachyther-
apy have good KPS and smaller, more focal tumors. Wen
et al. described a series of matched control patients with a
median survival in the implant group of 18 months versus
11 months in the control group (P \ 0.0007) [43]. Similar
encouraging results in non-randomized fashion were
observed by Sneed et al. in two separate reports (median
survivals of 19 months) and Chang et al. (median survival
19.5 months with brachytherapy vs. 12.5 months without)
[44–46]. Effect of dose rate delivered by different isotopes
was studied by Koot et al. and did not appear to alter the
survival [47].
A number of investigators have applied the RTOG
recursive partitioning analysis to brachytherapy series.
Videtic et al. evaluated the effect of tumor volume on
survival, finding that the observed inverse relationship
between tumor volume implanted and survival disappeared
within each RPA class suggesting that even patients with
larger volumes may benefit from brachytherapy [48].
Chang et al. evaluated a series of 28 patients stratified by
RPA class finding an overall trend in favor of brachy-
therapy but due to the small numbers in each class only
found significance in RPA class 5 [46]. Lamborn et al.
evaluated 832 patients involved in eight different clinical
trials finding that in addition to extent of resection, che-
motherapy, age and KPS brachytherapy also had a
significant effect on survival [49].
Despite these thoughtful and promising results, there
have been two randomized trials of brachytherapy that
failed to demonstrate a survival advantage for brachyther-
apy when added to the treatment regimen for newly
diagnosed malignant glioma. Laperriere et al’s study pub-
lished in 1998 randomly assigned 140 patients to external
Evidentiary Table 5 continued
First author/
Reference
Study description Data class Conclusion
Thomas et al./[36] Prospective non-randomized study of 38
patients with malignant glioma and
poor prognosis treated with 30 Gy in
six fractions over 2 weeks to the
enhancement plus 2 cm
III Median survival 6 months
One year survival rate 23%
The authors conclude that this hypo-fractionated
regimen was well tolerated, convenient and provided
effective palliation. They indicated that comparison
with conventional radiotherapy or supportive care
only would require randomized studies
Glinski/[37] Randomized controlled trial of 108
patients with malignant glioma
(44 GBM, 64 AA). Randomized to two
arms: Conventional fractionation
(50 Gy Whole brain plus 10 Gy in 5
fraction local boost to the tumor) and
Hypo-fractionated (three courses
separated by one month interval 20 Gy
in 5 times two plus 10 Gy in 5 fraction
boost)
II An analysis of all 108 randomized patients
demonstrated no significant difference in survival
between the treatment arms
Non-significant difference in the 64 patients with AA
(22% vs. 18%, P [ 0.05)
Significant survival benefit favoring hypo-fractionated
radiation compared with conventional radiation in
the subgroup of 44 patients with glioblastoma (23%
vs. 10% at 2 years; P \ 0.05)
Long-term neuropsychological data is lacking in these
groups. The mixed groups limits the numbers and
limits interpretation
326 J Neurooncol (2008) 89:313–337
123
radiotherapy of 50 Gy in 25 fractions over 5 weeks (69
patients) versus the same external radiotherapy plus tem-
porary stereotactic iodine-125 implants with a minimum
peripheral tumor dose of 60 Gy (71 patients) [50]. Median
survival for the brachytherapy arm was 13.8 months versus
13.2 months for the non-brachytherapy arm (P = 0.49).
Improved survival was associated with either chemother-
apy or reoperation at progression (P = 0.004) or KPS
greater than or equal to 90 (P = 0.007). The authors
concluded that stereotactic radiation implants did not
demonstrate a statistically significant improvement in sur-
vival in the initial management of patients with malignant
glioma.
Although the initial report of the Brain Tumor Coop-
erative Group (BTCG Trial 87-01) randomized trial of
radiotherapy plus BCNU with and without interstitial
radiation for a total dose of 60 Gy at the tumor periphery
suggested a significant survival advantage, the subsequent
Evidentiary Table 6 Accelerated radiotherapy
First author/
Reference
Study description Data class Conclusion
Brada et al./[38] Single arm study of 211 patients with
malignant glioma treated with 55 Gy in
34 fractions (twice daily).
Compared to historical control of similar
group treated with 60 Gy in 30 fractions
over 6 weeks
III Median survival 10 months,
The authors state that their results are similar to a
matched cohort of patients who had received
60 Gy in 30 fractions over 6 weeks in a previous
MRC study and felt that a matched comparison
would yield similar results
Overall conclusion was that accelerated treatments
complicated the logistics for delivery of
radiotherapy and added nothing to survival
Werner-Wasik et al./
[39]
Randomized controlled dose escalation
study randomized to hyper-fractionated
(1.2 Gy twice daily to 64.8, 72, 76.8,
81.8 Gy) or accelerated radiotherapy
(1.6 Gy twice daily to doses of 48 or
54.4 Gy)
RTOG 83-02
786 patients (747 eligible and evaluable)
81% GBM and 19% AA)
All patients recieved BCNU
I Overall median survival for GBM:
Hyper-fractionated 10.8 months
Accelerated hyper-fractionated 10.2 months
P = 0.08
Overall median survival for AA
Hyper-fractionated 42.3 months
Accelerated hyper-fractionated 40.3 months
P = 0.67
Overall analysis indicated no significant survival
difference among any of the dose schemes
(P = 0.598). There was low toxicity with
accelerated fractionation
Horiot et al./[40] Randomized controlled trial (EORTC
Protocol 22803.
340 patients with malignant glioma into
three arms.
60 Gy in 30 fractions over 3 weeks
30 Gy in 15 fractions in three daily
fractions, interval of 2 weeks then repeat
(one group with and one group without
misonidazole)
II Minimal details reported but the authors concluded
that there was no difference in survival between
the three treatment groups (P-value not
reported). No increased toxicity with
accelerated radiation
Keim et al./[41] Non-randomized comparison of 38 patients
with GBM treated with accelerated
radiotherapy (1.6 Gy three times daily to
total dose of 60 Gy) compared to 26
patients treated with 60 Gy in 30
fractions over 6 weeks
III Median survival 10. 5 months. No difference
between these two treatment groups. P-value
not reported
The authors concluded that the tolerance of the
accelerated schedule was as good as the
conventional but that survival was not improved
Simpson and Platts/
[42]
Randomized trial of 134 patients with GBM
with three treatment groups
Total whole brain dose of 30 Gy (in initial
group three times daily for 1 week, three
times daily for 3 weeks or daily for
3 weeks) Doses were escalated to 40 Gy
in later portions of the study)
II No significant difference noted between any of the
groups. All P-values greater than 0.05
Although reported as a randomized study, the
detail included makes evaluation difficult
J Neurooncol (2008) 89:313–337 327
123
published report did not. The final report of Selker et al.
described this randomized multi-center comparison of
surgery, EBRT and BCNU (n = 137) versus surgery,
EBRT, BCNU and I-125 brachytherapy boost (n = 133) in
newly diagnosed malignant glioma (299 total patients, with
270 (90%) in the valid study group) [51]. The median
survival, with all pathologies included, for surgery, EBRT
and BCNU (control) was 14.7 months compared to
17.0 months for surgery, EBRT, BCNU and (125)-I
brachytherapy (P = 0.101). In the GBM only group
(n = 230) the median survival was 14.5 for control
(n = 107) and 16.0 months for the brachytherapy group
(n = 123), (P = 0.169). As in most previous studies, age,
KPS, and pathology were all independent predictors of
mortality. Incorporating an adjustment for these variables
in both stratified and Cox proportional hazard models
failed to demonstrate any statistically significant differ-
ences in survival between these two treatment groups. The
authors concluded that no long-term survival advantage
was demonstrated with the addition of (125)-I brachy-
therapy to surgery, EBRT and BCNU in patients with
newly diagnosed malignant glioma (see Evidentiary
Table 7 for further details on brachytherapy) [52, 53].
Stereotactic radiosurgery
Stereotactic radiosurgery is used to provide a single
fraction of radiation utilizing computer assisted stereo-
tactic technique. A series of encouraging reports initially
described the use of radiosurgery as a focal radiation
dose boost in conjunction with fractionated external
beam radiotherapy. Selected studies are detailed in the
Evidentiary Table 8 (Stereotactic Radiosurgery). These
studies represented early trials in determining the safety
and feasibility of this technique and generally compared
study outcome to historical controls from the RTOG
RPA data. Reported median survivals for GBM ranged
from 10 to 20 months and 2-year survivals ranged from
20% to 40%. Reoperation following these combined
radiotherapy technique ranged from 10 to 30%. Essen-
tially all of these authors acknowledged the limitations of
their studies and given the limited toxicity observed,
indicated the need for a randomized prospective study to
evaluate the role of SRS in newly diagnosed malignant
glioma.
The question of selection bias is of concern as noted for
brachytherapy trials and has been addressed. Initially,
Curran et al. applied previously used selection criteria for
SRS (KPS [ 60, tumor diameter of 4.0 cm or less, and
superficial location) to patients entered in a separate trial
not involving SRS [54]. They found that the median sur-
vival for SRS eligible patients was 14.4 months versus
11.7 months for SRS ineligible patients (P = 0.047)
suggesting that there appeared to be a survival advantage
favoring patients eligible for stereotactic radiosurgery,
primarily based on the inclusion of a subgroup with a
higher KPS. Subsequently, Lustig et al. applied the entry
criteria for the RTOG 93-05 randomized trial of EBRT plus
SRS versus EBRT alone, to a previous randomized RTOG
trial not involving SRS using RTOG RPA analysis [55].
They reported that no significant difference could be
demonstrated between the two groups comparing the SRS
eligible versus the SRS ineligible groups, supporting the
outcome of the trial subsequently reported by Souhmai
et al. [56]. These reports highlight the importance of
careful interpretation of individual studies and the need to
avoid extrapolation of the results to patient groups not
specifically studied in a given trial.
The results of the RTOG 93-05 trial were reported by
Souhami et al. and are outlined in the evidentiary table for
stereotactic radiosurgery [56]. This prospective multi-cen-
ter randomized trial recruited 203 patients. Seventeen
patients were excluded from final analysis including seven
who were randomized to SRS but had tumor treatment
diameters greater than 40 mm at the time of SRS. Ten
additional patients were excluded based on histology
(n = 3), refusal or withdrawal (n = 4), multifocal tumor
(n = 1), prior chemotherapy (n = 1) and failure to record
KPS (n = 1), leaving 186 patients for evaluation. Ninety-
seven were randomized to EBRT alone and eighty-nine to
EBRT plus SRS. Both groups received IV BCNU. Median
survival was 13.6 in the EBRT group and 13.5 in EBRT
plus SRS (P = 0.57) with no significant difference in two
and three survival rates or quality of life measures. The
authors conclude that stereotactic radiosurgery followed by
EBRT and BCNU does not improve outcome in patients
with newly diagnosed GBM.
Despite a relatively large number of preliminary trials
suggesting a survival benefit, currently randomized data
does not support the use of stereotactic radiosurgery as a
routine addition to the initial management of glioblastoma.
Selected patients may benefit but the specific characteris-
tics of this group have yet to be identified (see Evidentiary
Table 8 for further particulars on stereotactic radiosurgery)
[57–66].
Summary and key issues for future investigation
Review of the literature published to date provides clear
and consistent class I data supporting the role of adjuvant
radiation therapy in the treatment of glioblastoma. Early
studies provide evidence comparing radiation therapy to
supportive care, chemotherapy and combinations of ther-
apy and virtually all conclude that arms that included
radiation therapy had enhanced survival.
328 J Neurooncol (2008) 89:313–337
123
Data supporting the most common conventional dose of
approximately 60 Gy in 30 fractions of 2 Gy each are
ubiquitous. Studies looking at lower doses in conventional
fashion and higher doses in conventional fashion appeared
either inferior or of no additional benefit.
Several attempts to utilize altered fractionation schemes
have been studied. Hyper-fractionated radiotherapy, with-
out significant acceleration in terms of delivery duration,
has been explored in class I studies and failed to show a
significant benefit. A roughly equivalent biological dose to
Evidentiary Table 7 Brachytherapy
First author/
Reference
Study description Data class Conclusion
Lamborn et al./ [49] Survival analysis of single institution data
accumulated from eight clinical
prospective trials on 832 newly
diagnosed GBM (based on 776 with
complete data)
Analysis using Cox proportional hazards
modeling and recursive partitioning
analyses
II Multivariate analysis (Cox) indicated significant effect of:
Chemotherapy Hazard Ratio 0.60 P \ 0.001
Extent of resection Hazard Ratio 0.75 P \ 0.001
KPS Hazard Ratio 0.97 P \ 0.001
Age Hazard Ratio 1.03 P \ 0.001
Brachytherapy Hazard Ratio 0.60 P \ 0.001
The inclusion of brachytherapy in the overall treatment had
a significant effect on survival and altered the results of
the recursive partitioning analysis
This is a retrospective analysis of previous reported
randomized data
Chang CN et al., J
Neurooncol 2003
[52]
Comparative study of 28 newly diagnosed
GBM treated postop with EBRT and
brachytherapy (high dose rate HDR)
and 28 controls treated without the
addition of brachytherapy
Selection based on patient or physician
preference
All deemed eligible for brachytherapy:
Unilateral, supratentorial, less than 6 cm,
KPS over 60 without subependymal
spread
III Median survival:
EBRT plus brachytherapy 19.5 months
EBRT 12.5 months (P-value not stated)
Two year survival:
EBRT plus brachytherapy 61%
EBRT 28% (P = 0.12)
Median survival by RTOG RPA Class:
Class 3: 41.6 versus 21.2 months (P = 0.39)
Class 4: 16.7 versus 12.1 months (P = 0.37)
Class 5: 18.7 versus 10.6 months (P = 0.02)
The authors felt that a trend in favor of brachytherapy was
demonstrated but due to the small numbers only the
comparison within RTOG Class 5 reached significance.
The issues surrounding high-dose versus low-dose
brachytherapy were discussed and a prospective study
was proposed
Mayr, M. et al. Int J
Oncol 2002 [53]
Retrospective review of 73 patients (67
evaluable) treated with brachytherapy
Includes 17 newly diagnosed GBM and
28 recurrent
III Median survival for newly diagnosed GBM was
9.02 months
For patients with a glioblastoma multiforme, median
survival from diagnosis and implant was 15.7 and
9.3 months respectively
For patients with an anaplastic astrocytoma, median
survival from diagnosis and implant was 39.5 and
9.2 months respectively
Eleven patients (16%) developed radiation necrosis. Six
patients (9%) developed infections
Age and histologic diagnosis were significant predictors of
survival from diagnosis
Age and KPS were independent predictors of time to
failure after implant
Certain characteristics, specifically younger age (\55), and
a higher KPS (C70), appear to be associated with longer
survival after brachytherapy. Complication rate
significant and must be taken into consideration when
adding brachytherapy to other treatment regimens
J Neurooncol (2008) 89:313–337 329
123
the conventional fractionated dose of 60 Gy (72 Gy in 60
fractions) appeared the best choice in large hyper-frac-
tionated series that looked at both higher and lower doses
[10]. The additional effort in delivering twice or three times
daily treatment is generally felt to increase the difficulty of
treatment and hence without a clear benefit in survival is not
recommended. Hypo-fractionated radiotherapy has been
studied in several class I level studies in selected older or
more poorly performing patients and has appeared to do as
well as conventional fractionation [19, 31]. Despite this a
Evidentiary Table 7 continued
First author/
Reference
Study description Data class Conclusion
Selker et al./[51] Randomized multicenter comparison.
Newly diagnosed malignant glioma
(299 patients, 270 (90%) in valid study
group). Surgery, EBRT and BCNU
(n = 137) versus Surgery, EBRT,
BCNU and (125)-I brachytherapy boost
(n = 133)
I Brain Tumor Cooperative Group NIH Trial 87-01 trial to
investigate the effect of implanted radiation therapy in
addition to surgery, EBRT and BCNU in newly
diagnosed GBM
Median survival (all pathologies included): Surgery,
EBRT, BCNU (control) 14.7 months
Surgery, EBRT, BCNU and (125)-I brachytherapy
17.0 months (P = 0.101)
Median survival (GBM only, 230 patients):
Surgery EBRT, BCNU (control) (n = 107) 14.5 months
Surgery, EBRT, BCNU and (125)-I brachytherapy
(n = 123) 16 months (P = 0.169)
Age, KPS, and pathology were predictors of mortality
Analysis incorporating an adjustment for these prognostic
variables, using both stratified analysis and Cox
proportional hazards models, failed to demonstrate any
statistically significant differences in the cumulative
proportion of patients surviving between the two
treatment groups
The authors concluded that no long-term survival
advantage was demonstrated with the addition of I-(125)
brachytherapy to surgery, EBRT and BCNU in patients
with newly diagnosed malignant glioma
Koot et al./[47] Comparative study of two methods of
brachytherapy applied to 84 patients
with newly diagnosed GBM treated in
two different centers. All treated with
EBRT.
Biopsy plus I-(125) implant (n = 45) and
Resection plus Ir-(192) implant compared
with Surgery plus EBRT (n = 18)
III Median survival (for Age [ 50, KPS [ or = 70, non-
midline):
I-(125) group 17 months
Ir-(192) group 16 months
Control 10 months (no p value reported)
Volume:
I-(125) group–average volume 23 cm3
Ir-(192) group–average volume 48 cm3
Dose Rate:
I-(125) group dose rate–permanent implants 2.5–2.9
cGy/h, temporary implants 4.6 cGy/h
Ir-(192) group dose rate–temporary implants 44–100
cGy/h
Reoperation (necrosis, tumor or both):
I-(125) group–4 (9%)
Ir-(192) group–7 (33%)
The authors conclude that given the similar survival
observed regardless of methodology of brachytherapy
that dose rate does not play a significant role in the effect
of brachytherapy in the treatment of malignant glioma.
The uncontrolled nature of this study complicates the
interpretation of the results but there does appear to be a
higher rate of necrosis observed in the higher dose rate
delivery group
330 J Neurooncol (2008) 89:313–337
123
large and inclusive trial with a hypo-fractionated arm has
not been performed. Concerns regarding long term sequelae
with very limited fractionation schemes has lead to poor
accrual and concerns for a more inclusive population
[19, 28]. Accelerated fractionation has also failed to show a
significant benefit in class I studies [39, 40].
Evidentiary Table 7 continued
First author/
Reference
Study description Data class Conclusion
Videtic et al./[48] Single center stratification of GBM
patients treated with surgery, EBRT
and I-(125) brachytherapy at initial
diagnosis by RPA survival class
focusing on the relationship between
implant volume and survival and
whether volume acted as a prognostic
variable within each RPA class
Review of 52 (of 53) GBM patients
Class III–12, Class IV–26
Class V–13
Class VI–1. Mean age 57.5 years (range
14–79).
Median KPS 90 (range 50–100)
Median follow-up 11 months
III Two-year survivals and median survival for implanted
GBM patients compared to the RTOG database:
Class III 74% versus 35% and 28 months versus
17.9 months
Class IV 32% versus 15% and 16 months versus
11.1 months
Class V/VI 29% versus 6% and 11 months versus
8.9 months
Mean implanted tumor volume was 15.5 cc (range 0.8–78)
Plotting survival as a function of 5-cc TV increments
suggested a trend toward poorer survival as the
implanted volume increases
Effect of implanted volume on survival by RPA class:
Class III no significant difference observed
Class IV, marginally significant difference at 10 cc
(P = 0.05)
Class V/VI, marginally significant difference at 20 cc
(P = 0.06)
The authors concluded that for GBM patients, an inverse
relationship between implanted tumor volume and
median survival was suggested but the prognostic effect
disappeared within each RPA class suggesting that any
patient meeting size criteria for brachytherapy be
considered for implantation
Laperriere et al./[50] Randomized prospective trial of 140
patients with newly diagnosed GBM
Two Groups:
EBRT 50 Gy in 25 fractions (n = 69)
EBRT 50 Gy in 25 plus I 125
brachytherapy to 60 Gy (n = 71)
I Median survival:
EBRT 13.2 months
EBRT plus brachytherapy 13.8 months (P = 0.49)
Improved survival associated with either chemotherapy or
reoperation at progression (P = 0.004) or KPS greater
than or equal to 90 (P = 0.007)
The authors concluded that the addition of brachytherapy
did not demonstrate a statistically significant
improvement in survival over EBRT alone in the initial
management of newly diagnosed GBM
Sneed et al./[44] Randomized single-institution study of
hyper-thermia in addition to surgery,
EBRT, brachytherapy in newly-
diagnosed GBM
35 patients treated with hyper-thermia
versus 33 without
III for
brachytherapy
data
Evaluation of effect of adjuvant interstitial hyper-thermia
(HT) in patients with glioblastoma undergoing
brachytherapy boost after conventional radiotherapy
Median survival:
Surgery, EBRT and brachytherapy 19.0 months
Surgery, EBRT, brachytherapy and hyper-thermia
21.2 months (P = 0.02)
Two-year Survival:
Surgery, EBRT and brachytherapy 15%
Surgery, EBRT, brachytherapy and hyper-thermia 31%
(P = 0.045)
The authors concluded that adjuvant interstitial brain HT,
used with brachytherapy boost significantly improved
survival of patients with focal glioblastoma. This study
did not randomize patients to brachytherapy
J Neurooncol (2008) 89:313–337 331
123
The treatment volume for external beam radiotherapy is
perhaps the most incompletely studied question despite
clear patterns of care being established. Most studies sup-
porting the role of adjuvant radiation therapy used whole
brain radiotherapy, a technique that is not recommended as
a standard approach today. One class I/II study compared a
whole brain dose of 40 Gy plus a boost of 18 Gy to an
approach using local fields for 56 Gy and found no dif-
ference in outcome at 2 years [18]. In addition BTCG trial
8001 allowed a change during the protocol accrual to limit
the whole brain dose to 43 Gy followed by a boost and
found no difference compared to the traditional whole
brain dose of 60 Gy [17]. This taken along with class III
data showing that more than 80% of recurrences occurred
within 2 cm of the resection and enhancing volume bed
support the strategy of deleting whole brain radiotherapy.
Despite this generally accepted practice of treating the
edema volume with an approximately 2 cm margin fol-
lowed by a boost to the enhancing volume with 1–2 cm
margin––there is little class I data addressing the issue of
appropriate volume in glioblastoma or malignant glioma.
The addition of boost doses of radiation therapy and in
particular both brachytherapy and stereotactic radiosurgery
have been extensively studied in recent years. Large
institutional class III trials suggested potential benefit for
brachytherapy and lead to class I randomized trials [43–
46]. Unfortunately, class I trials did not show the promising
results of the previous more selected and uniform institu-
tional series and failed to show a benefit to brachytherapy
[50, 51]. Similarly, several large and controlled institu-
tional and non-randomized multi-institutional trials
suggested the potential of benefit for stereotactic radio-
surgery. Despite this promise the test of a randomized trial
via the RTOG 93-05 failed to show a survival benefit for
dose escalation achieved through stereotactic radiosurgery
[56]. These techniques are therefore not recommended as a
standard component of therapy for glioblastoma or malig-
nant glioma.
Evidentiary Table 7 continued
First author/
Reference
Study description Data class Conclusion
Sneed et al./[45] Retrospective review of newly diagnosed
GBM treated with EBRT and I-(125)
brachytherapy (n = 159)
III Retrospective review undertaken to examine the influence
of age on the survival of patients undergoing
brachytherapy in newly diagnosed GBM
Brachytherapy doses ranged from 35.7 to 66.5 Gy
(median, 55.0 Gy) at 0.30 to 0.70 Gy per hour (median,
0.43 Gy/h)
Median survival 19 months
Reoperations were performed in 81 patients (51%)
Univariate and multivariate analyses showed that age was
the most important parameter influencing survival
(P \ 0.0005)
Wen et al./[43] Prospective non-randomized protocol and
review of 56 newly-diagnosed
glioblastoma patients
Surgery, EBRT, and (125)-I
brachytherapy (additional 50 Gy to the
tumor bed). Compared to 40 matched
controls
II Median survival:
Brachytherapy 18 months
Control 11 months (P \ 0.0007)
Two-year survival:
Brachytherapy 34%
Control 12.5% (P \ 0.0004)
Thirty-six patients (64%) re-operation for symptomatic
radiation necrosis (median interval 11 months 3 to
42 months).
Median survival after reoperation 22 months versus
13 months without (P \ 0.02)
Radiographic progression in brachytherapy group: Local
35%
Marginal or Distant progression 65%
The authors conclude that brachytherapy may prolong
survival and improve local tumor control in the initial
treatment of selected patients with glioblastoma. The
study represents prospective data collected and
compared with a matched control group
332 J Neurooncol (2008) 89:313–337
123
Evidentiary Table 8 Stereotactic radiosurgery
First author/
Reference
Study description Data class Conclusion
Souhami et al./[7] Randomized prospective trial of
203 patients with newly
diagnosed supratentorial GBM
(tumor less than or equal to
40 mm maximum cross section
after surgery) Postop SRS plus
EBRT (60 Gy) plus BCNU
(n = 89) versus EBRT plus
BCNU (n = 97) SRS dose
volume dependent (range 15 to
24 Gy) Median followup
61 months
17 patients excluded consisting of
10 for path, patient refusal or
protocol violation and 7 for tumor
size greater than 40 mm at time of
SRS
I This study investigated the effect of stereotactic radiosurgery
(SRS) added to conventional external beam radiation therapy
(EBRT) with carmustine (BCNU) on the survival of patients
with newly diagnosed GBM
Median survival:
SRS plus EBRT/BCNU 13.5 months (95% CI
11.0–14.8 months)
EBRT/BCNU 13.6 months (95% CI
11.2–15.2 months) P = 0.57
There were also no significant differences in 2- and 3-year
survival rates and in patterns of failure between the two arms
Quality of life deterioration and cognitive decline equivalent. No
difference in quality-adjusted survival between the arms
The authors concluded that stereotactic radiosurgery followed by
EBRT and BCNU did not improve the outcome, quality of life
or cognitive function in patients with newly diagnosed GBM
Cho, K. H. et al.
Technol Cancer
Res Treat 2004
[64]
Retrospective review of 24
patients with newly diagnosed
GBM treated with EBRT plus a
stereotactic boosted therapy
Fourteen patients (58%) were
treated with stereotactic
radiosurgery (SRS) and 10 patients
(42%) with fractionated
stereotactic radiotherapy (FSRT)
III This study compared single dose or fractionated stereotactic
boosted therapy plus EBRT in newly diagnosed GBM
Overall median survival 16 months
Overall 1 year survival rate 63%
Overall 2 year survival rate 34%
Median survival:
RTOG Class 3 28.3 months (expected 11.1)
RTOG Class 4 10.3 months (expected 8.9)
RTOG Class 5/6 6.0 months (expected 4.6)
Survival predicted by age, extent of surgery, re-operation and the
RTOG RPA class
The authors concluded in this non-randomized retrospective study
that the observed median survival of 16 months was superior to
that expected by historical RTOG RPA controls with similar
results with either SRS or FSRT (possibly with less
complication in the FSRT group) and that further study is
warranted
Lustig et al./ [55] Study applying the entry criteria of
the RTOG 93-05 trial (Souhami
et al 2004) to the patient
enrolled in the RTOG 90-06
trial comparing 60 Gray versus
72 Gray in patients with GBM
to evaluate possible selection
bias of the SRS entry criteria
599 total patients. 137 Eligible and
372 Ineligible for 93-05 Radiation
Therapy Oncology Group (RTOG)
Recursive partitioning analysis
(RPA) was used to evaluate for
differences
II Comparison of Median survival by RTOG RPA Class for patient
either eligible or ineligible for SRS trial:
Median survival SRS eligible
RTOG RPA Class 3 16.8 months
RTOG RPA Class 4 12.0 months
RTOG RPA Class 5 8.3 months
RTOG RPA Class 6 1.7 months
Median survival SRS ineligible
RTOG RPA Class 3 16.8 months (P = NS)
RTOG RPA Class 4 10.8 months (P = 0.042)
RTOG RPA Class 5 7.2 months (P = 0.09)
RTOG RPA Class 6 2.7 months (P = 0.2)
The authors conclude that there does not appear to be a selection
bias performing a randomized study on patients eligible for
stereotactic radiosurgery, supporting the validity of a
randomized study of the effects of stereotactic radiosurgery in
newly diagnosed GBM
This is review of previous reported randomized data
J Neurooncol (2008) 89:313–337 333
123
Evidentiary Table 8 continued
First author/
Reference
Study description Data class Conclusion
Nwokedi, E. C.,
et al.
Neurosurgery
2002 [65]
Retrospective review of 82
patients with GBM. 64 included
in review
33 treated with EBRT and 31
treated with EBRT plus SRS (10–
28 Gray)
Miniumum followup of 1 month
reported
III Retrospective review of the impact of SRS on patients treated for
GBM
Median survival:
EBRT 13 months
EBRT plus SRS 25 months (P = 0.03)
Predictors of overall survival by Cox regression analysis included:
age, KPS and SRS
No acute Grade 3 or Grade 4 toxicity was encountered
The authors conclude that SRS in conjunction with surgery and
EBRT significantly improved survival but deferred to
forthcoming randomized study
Shrieve, D. C., et al.
J of Neurosurg
1999 [66]
Retrospective review of 78
patients treated with EBRT and
SRS boost
III Median survival 19.9 months
One year survival 88.5%
Two year survival 35.9%
Age, RPA class significant in univariate analysis
Age significant in multivariate analysis
Reoperation rate 54.8%
The authors conclude that SRS appears to add a significant
survival advantage and support a randomized trial
Kondziolka, D., et al
Neurosurgery
1997 [61]
Retrospective review of 109
patients involving SRS in
additional to EBRT in malignant
glioma management
Included n = 45 newly diagnosed
GBM and n = 21 AA
III For newly diagnosed (SRS plus EBRT):
Median survival: GBM 20 months (s.d. 2.6) range 5 to 76 months,
AA 56 months (s.d. 8.9) range 9 to 93 months
Two year survival: GBM 41%, AA 88%
Reoperation rate: GBM 19%, AA 23%
The authors conclude that SRS appears promising and call for a
randomized tria
Larson, D. A., et al.
Int J Radiat Biol
Phys 1996 [62]
Retrospective review of 189
patients either primary or
recurrent malignant glial tumor
patients treated with SRS as a
portion of their overall
treatment. Includes 41 newly
diagnosed GBM and 16 AA
Patients stratified by whether they
would be eligible for
brachytherapy in previous
protocols
III Median survival:
GBM
Brachytherapy eligible 21.5 months
Brachytherapy ineligible 10 months (P = 0.01)
AA
Brachytherapy eligible 24 months
Brachytherapy ineligible 24 months (P = NS)
Tumor grade, age, KPS, smaller volume, unifocal tumor all
correlated with prolonged survival
The authors conclude that bias in patient selection is concerning
and support need for randomized trial
Sarkaria, J. N., et al.
Int J Radiat Biol
Phys 1995 [63]
Combined retrospective analysis
of data from three centers
(Masciopinto et al., Buatti et al.,
Shrieve et al.)
115 patients with newly diagnosed
malignant glioma (96 GBM and
19 AA)
III Stratified by and Compared to RTOG RPA analysis:
SRS boost
RTOG RPA Class 3 38.1 months
RTOG RPA Class 4 19.6 months
RTOG RPA Class 5/6 13.1 months
RTOG RPA Historical Control
RTOG RPA Class 3 17.9 months
RTOG RPA Class 4 11.1 months
RTOG RPA Class 5/6 8.9 months
Overall P-value \ 0.001.
The authors conclude that the addition of SRS to EBRT in
patients treated with malignant glioma appears to improve
survival and support a randomized trial
334 J Neurooncol (2008) 89:313–337
123
Review of this data leads to the conclusion that radiation
therapy should be recommended as standard therapy for
glioblastoma and malignant glioma as supported by con-
sistent class I data. Patients with good prognosis can
confidently be treated with conventional doses of 60 Gy in
30 fractions as supported by the body of the literature.
Consideration for hypo-fractionated regimens especially in
the setting of poor prognosis is very reasonable and is
supported by the literature in class I data. Other altered
fractionation schemes are not supported outside a study
setting. Local fields are generally used to treat the tumor
volume as identified on imaging with a 1–2 cm margin.
Although there is minimal Class I support for this, the
preponderance of evidence supports this approach and
there is no clear benefit of larger whole brain fields. Studies
addressing the appropriate volume in systematic fashion
are needed. The role of dose escalation with brachytherapy
and radiosurgery is limited and not supported as a standard
approach.
Acknowledgements We wish to acknowledge Stephen Haines,
MD, Jack Rock, MD, and Tom Mikkelson, MD for their review and
consultations regarding on this work. The authors also wish to express
Evidentiary Table 8 continued
First author/
Reference
Study description Data class Conclusion
Masciopinto, J. E.,
et al. J Neurosurg
1995 [57]
Retrospective review of 31
patients with newly diagnosed
GBM treated with EBRT plus
SRS
Follow report of Mehta et al. 1994
below
III Median survival 9.5 months
Two year survival 37%
The authors conclude that due to limited response and local
recurrence that the role of SRS in malignant glioma be
carefully considered in selected patients until further study
Gannett, D., B. et al.
Int J Radiat Biol
Phys 1995 [58]
Retrospective review of 30
patients including 17 newly
diagnosed GBM and 10 AA
III Overall median survival 13.9 months
One year survival 57%
Two year survival 25%
No significant toxicity reported
Reoperation rate 10%
The authors concluded that SRS could be used to provide safe and
feasible technique for dose escalation in the primary
management of unselected malignant glioma and call for a
randomized study
Buatti, J. M., et al.
Int J Radiat Biol
Phys 1995 [59]
Retrospective review of 11 newly
diagnosed patients (6 GBM and
5 AA) treated with EBRT and
SRS
III Median survival 17 months
Maximum radiosurgical volume 22.5 cm3
All patients had local progression within one year of treatment
The authors note the need to define appropriate patients for boost
technique
Mehta, M. P., J.
et al. Int J Radiat
Biol Phys 1994
[60]
Retrospective review of 31
patients with newly diagnosed
GBM treated with EBRT and
SRS (of a total of 53 newly
diagnosed GBM patients in
same time period)
III Median survival 10.5 months
One year survival 38%
Two year survival 28%
Authors suggest that this may demonstrate improved 2 year
survival compared to RTOG RPA 2 year survival of 9.7%
(P \ 0.05) but that the improvement in broadly selected GBM
is difficult to determine
Reported 13% symptomatic necrosis
Curran et al./[54] Study applying SRS treatment
criteria (KPS [ 60, 4.0 cm or
less, and superficial) to the
patients enrolled in RTOG 83-
02 trial (Phase I/II dose
escalation)
778 total patients 89 (11%)
determined to be eligible for SRS
II Comparison of Median Survival by RTOG RPA Class for patient
either eligible or ineligible for SRS trial:
Median Survival Eligible 14.4 months Median Survival Ineligible
11.7 months (P = 0.047)
Multivariate analysis indicated age, KPS, path and SRS eligibility
all predictive of increased survival
The authors conclude that there appeared to be a survival
advantage favoring patients eligible for stereotactic
radiosurgery, primarily based on inclusion of a subgroup of
higher KPS
This is a review of previously reported randomized data
J Neurooncol (2008) 89:313–337 335
123
appreciation to the AANS/CNS Joint Guidelines Committee for their
review, comments and suggestions. We also thank Linda Phillips for
meeting organization and collection of materials and Emily Feinstein
for her assistance in editing the material for publication.
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