Radiation therapy of pathologically conﬁrmed newly diagnosed ...

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: [email protected]

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

http://www.guideline.gov

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


Most significant advantage in the Valid Study Group

in patients under 50 years of age

Median survival

PCV 19.3 months


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


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


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


First author/

Reference


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


First author/

Reference


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


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


First author/

Reference


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


First author/

Reference


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


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


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:


Accelerated hyper-fractionated 10.2 months

P = 0.08

Overall median survival for AA


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


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


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)



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


First author/

Reference


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].


First author/

Reference


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.


First author/

Reference


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


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




Median survival SRS ineligible

RTOG RPA Class 3 16.8 months (P = NS)

RTOG RPA Class 4 10.8 months (P = 0.042)



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


First author/

Reference


Nwokedi, E. C.,

et al.

Neurosurgery

2002 [65]


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]


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]


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]


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


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 5/6 13.1 months

RTOG RPA Historical Control



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


First author/

Reference


Masciopinto, J. E.,

et al. J Neurosurg

1995 [57]



GBM treated with EBRT plus

SRS

Follow report of Mehta et al. 1994

below


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]


patients including 17 newly

diagnosed GBM and 10 AA

III Overall median survival 13.9 months

One year survival 57%


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


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]



GBM treated with EBRT and

SRS (of a total of 53 newly

diagnosed GBM patients in

same time period)


One year survival 38%


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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