Impact of volume of irradiation on survival and quality of life in glioblastoma: a prospective, phase 2, randomized comparison of RTOG and MDACC protocols

Abstract

Background
Though conformal partial-brain irradiation is the standard adjuvant treatment for glioblastoma, there is no consensus regarding the optimal volume that needs to be irradiated. European Organisation for Research and Treatment of Cancer (EORTC) and The University of Texas MD Anderson Cancer Center (MDACC) guidelines differ from the Radiation Therapy Oncology Group (RTOG) in their approach toward peritumoral edema, whereas RTOG and MDACC guidelines differ from EORTC in the concept of boost phase. A scarcity of randomized comparisons has resulted in remarkable variance in practice among institutions.

Methods
Fifty glioblastoma patients were randomized to receive adjuvant radiotherapy using RTOG or MDACC protocols. Apart from dosimetric and volumetric analysis, acute toxicities, recurrence patterns, progression-free survival (PFS), overall survival (OS), and quality of life (QoL) were compared using appropriate statistical tests.

Results
Both groups were comparable with respect to demographic characteristics. Dosimetric analysis revealed significantly lower boost-phase planning treatment volumes and V60 Gy in the MDACC arm (chi-squared, P = .001 and .013, respectively). No significant differences were observed in doses with respect to organs at risk, acute toxicity, or recurrence patterns (chi-squared, P > .05). On the log-rank test, median PFS (8.8 months vs 6.1 months, P = .043) and OS (17 months vs 12 months, P = .015) were statistically superior in the MDACC group.
Age, extent of resection, and proportion of whole brain receiving prescription dose were associated with improved PFS and OS on regression analysis. QoL of patients was significantly better in the MDACC group in all domains except cognitive, as assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) and Brain Cancer Module (QLQ-BN20) (general linear model, P < .05).

Conclusions
Use of limited-margin MDACC protocol can potentially improve survival outcomes apart from QoL of glioblastoma patients, as compared with the RTOG protocol.

Full text

Neuro-Oncology Practice
XX(XX), 1–8, 2019 | doi:10.1093/nop/npz024 | Advance Access date 18 July 2019
Impact of volume of irradiation on survival and
quality of life in glioblastoma: a prospective, phase 2,
randomized comparison of RTOG and MDACC protocols
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European
Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
NarendraKumar, RiduKumar, SureshC.Sharma, AnindyaMukherjee, NiranjanKhandelwal,
ManjulTripathi, RavitejaMiriyala , ArunS.Oinam, RenuMadan, BudhiS.Yadav, DivyaKhosla, and
RakeshKapoor
Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh,
India (N.K., R.K., S.C.S., A.M., A.S.O., R.Ma., B.S.Y., D.K., R.Ka.); Department of Radiodiagnosis, PGIMER, Chandigarh,
India (N.Kh.); Department of Neurosurgery, PGIMER, Chandigarh, India (M.T.); Department of Radiotherapy, PGIMER,
Chandigarh, India (R.M.)
Corresponding Author: Raviteja Miriyala, MD, PGIMER, Department of Radiotherapy, Sector 12, Chandigarh, 160012 India
(ravitejamiriyala@yahoo.com).
Abstract
Background. Though conformal partial-brain irradiation is the standard adjuvant treatment for glioblastoma, there
is no consensus regarding the optimal volume that needs to be irradiated. European Organisation for Research and
Treatment of Cancer (EORTC) and The University of Texas MD Anderson Cancer Center (MDACC) guidelines differ
from the Radiation Therapy Oncology Group (RTOG) in their approach toward peritumoral edema, whereas RTOG
and MDACC guidelines differ from EORTC in the concept of boost phase. Ascarcity of randomized comparisons
has resulted in remarkable variance in practice among institutions.
Methods. Fifty glioblastoma patients were randomized to receive adjuvant radiotherapy using RTOG or MDACC
protocols. Apart from dosimetric and volumetric analysis, acute toxicities, recurrence patterns, progression-free
survival (PFS), overall survival (OS), and quality of life (QoL) were compared using appropriate statistical tests.
Results. Both groups were comparable with respect to demographic characteristics. Dosimetric analysis revealed
significantly lower boost-phase planning treatment volumes and V60 Gy in the MDACC arm (chi-squared, P=.001
and .013, respectively). No significant differences were observed in doses with respect to organs at risk, acute tox-
icity, or recurrence patterns (chi-squared, P>.05). On the log-rank test, median PFS (8.8months vs 6.1 months,
P=.043) and OS (17months vs 12months, P=.015) were statistically superior in the MDACCgroup.
Age, extent of resection, and proportion of whole brain receiving prescription dose were associated with improved
PFS and OS on regression analysis. QoL of patients was significantly better in the MDACC group in all domains
except cognitive, as assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) and Brain Cancer Module
(QLQ-BN20) (general linear model, P<.05).
Conclusions. Use of limited-margin MDACC protocol can potentially improve survival outcomes apart from QoL
of glioblastoma patients, as compared with the RTOG protocol.
Keywords
1
glioblastoma | limited-margin radiotherapy | MDACC guidelines | RTOG guidelines |
randomized trial
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2 Kumar etal. RTOG vs MDACC guidelines for glioblastoma
Glioblastomas are highly aggressive malignant neoplasms
arising from the glial cells, constituting about 14.9% of all
brain tumors diagnosed in the United States between 2004
and 2014.1 Though the incidence rate of glioblastomas
has been relatively stable in developed countries over the
past decade, developing countries are experiencing an
increasing trend.1,2
Though maximal surgical resection is the primary treat-
ment of choice for glioblastomas and has prognostic value,
the infiltrating nature of these tumors and proximity to
vital structures often precludes complete surgical resec-
tion, resulting in almost universal recurrences and making
adjuvant radiotherapy indispensable for achieving local
control and overall survival (OS).3 Unfortunately, even
the addition of concurrent and adjuvant chemotherapy
has resulted in only modest improvements in survival
outcomes for glioblastomas, with poor 2- and 5-year sur-
vival rates of 17.2% and 5.5%, respectively.1,4,5 Most of the
failures in these studies were observed to be local and
within the irradiated volume, thus reiterating the impor-
tance of accurate target delineation in improving local con-
trol and survival in these patients.
Landmark randomized studies like the Brain Tumor
Cooperative Group80-01 have unequivocally substantiated
the therapeutic benefits of partial-brain irradiation as
compared with the historically practiced whole-brain ir-
radiation for glioblastomas, eventually establishing 3-di-
mensional (3D) conformal radiation (3D-CRT) as the global
standard of care in these patients.6,7 However, there is an
unfortunate ambiguity in achieving a uniform consensus
regarding the delineation of the clinical target volume (CTV)
for planning adjuvant radiotherapy for glioblastomas,
as evident from the proposal and practice of different
guidelines by different international bodies of repute.8
This ambiguity is largely attributed to 2 different schools
of thought concerning the etiology of peritumoral edema,
with deliberations concerning whether it is a physical re-
sponse to mass effect and vascular permeability factors
secreted by the gross tumor, or a pathological consequence
of microscopic infiltration by malignant cells.9 Whereas The
University of Texas MD Anderson Cancer Center (MDACC)
and European Organisation for Research and Treatment of
Cancer (EORTC) guidelines disregard the peritumoral edema
during treatment planning, the Radiation Therapy Oncology
Group (RTOG) recommends its inclusion in generating
CTV margins.8 Since the volume of brain irradiated is often
considered an accurate surrogate for delayed neurotox-
icity, multiple retrospective and dosimetric studies have
evaluated the feasibility of limited-margin radiotherapy.8,10
However, there is no prospective, randomized evidence
analyzing the impact of these margins on the survival of
glioblastoma patients. The purposes of this study are to
prospectively compare the recurrence patterns in patients
treated with the RTOG protocol and a limited-margin
MDACC protocol, and to analyze the impact of treatment
volume on their survival and quality of life(QoL).
Material and Methods
This study was an investigator-initiated, partially blinded,
phase 2, randomized, controlled trial with 2 arms,
comparing the outcomes using 2 different guidelines for
target delineation: RTOG (Arm A) and MDACC (Arm B).
Sample sizes were estimated based on a superiority de-
sign to identify an improvement in the median OS from
14 months (with standard margins) to 16 months (with
limited margins). It was calculated that 42 patients would
be required to have an 80% power of detecting an im-
provement of 2months in OS, and 56patients would be
required to have a 90% power. Assuming 20% attrition due
to drop-outs or losses to follow-up, the required sample
sizes increased to 52 and 70, for a power of 80% and 90%,
respectively. Being a phase 2 study, a limited sample size
of 50 was decided on so that subsequent phase 3 studies
could be planned according to the results obtained.
Approval was obtained from the institute ethics committee
before initiation of the trial, and informed consent was
obtained from all patients at the time of enrollment.
Accrual was performed between July 2009 and December
2011, in accordance with the specified inclusion and ex-
clusion criteria, and randomization was conducted using
computer-generated random tables.
Inclusion Criteria
i) Histopathologically proven primary glioblastoma
ii) Age ≥18years and ≤70years
iii) KPS scores ≥70
iv) Willingness to consent to treatment and follow-up
as per trial specifications
Exclusion Criteria
i) Prior history of any other malignancy
ii) Prior history of chemotherapy or radiotherapy
iii) Uncontrolled comorbidities such as diabetes or
hypertension interfering with the delivery of che-
motherapy or radiotherapy or steroid as per trial
protocol
Apart from history and physical examination and baseline
hematological and biochemical investigations, initial evalu-
ation included preoperative and postoperative MRI with T1
contrast and fluid-attenuated inversion recovery sequences.
Contrast-enhanced (CE) treatment planning CT scan with
3mm slice thickness was obtained using thermoplastic cast
for immobilization, and coregistered with appropriate MR
sequences using the Eclipse treatment planning system,
version 11 (Varian Medical Systems Inc, Palo Alto, CA, USA).
Target Volumes and Dosimetric Analysis
Radiotherapy target volumes in the 2 arms are described
in Table 1. Patients in both arms were treated with a total
dose of 60Gy in 30 fractions at 2 Gy per fraction, 5days
per week over 6 weeks, in 2 phases using 3D-CRT. Adose of
40Gy was delivered in the initial phase, followed by a se-
quential boost of 20Gy with volume reduction, according
to the departmental protocol at the time of enrollment. All
patients received concurrent and adjuvant chemotherapy
with temozolomide according to established protocols, un-
less absolutely contraindicated or tolerated poorly.4,5
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3
Kumar etal. RTOG vs MDACC guidelines for glioblastoma
Neuro-Oncology
Practice
Dosimetric analysis was performed by comparing the
planning target volume (PTV) in each of the phases along
with doses to the organs at risk and proportion of whole
brain receiving prescription doses, in both treatment
groups, using the t-test. SPSS version 22 was used for all
statistical analyses.
Treatment-Related Toxicity
During the course of treatment, all patients were evaluated
weekly (during concurrent chemoradiation) and monthly
(during adjuvant chemotherapy) with a thorough clinical
examination and appropriate laboratory investigations.
All acute treatment-related toxicities were graded using
the Common Terminology Criteria for Adverse Events, ver-
sion 3.0.11 The chi-squared test was used to analyze the
differences in proportion of low-grade (grades 1 to 2)and
high-grade (grades 3 to 4)toxicities in both groups.
Patterns of Failure and Survival Analysis
After treatment completion, response assessment was
conducted at 3months using CE MRI of the brain, and repeated
at 6-month intervals or suspicion of clinical progression. MR
spectroscopy was used to differentiate pseudoprogression in
all cases with suspected radiological progression.12
In patients with evaluable recurrences, appropriate
MR sequences were coregistered with the initial plan-
ning images, and recurrent tumor volumes (RTVs) were
delineated for classification in relation to the prescription
isodose volumes of the treatment plan as defined in the lit-
erature.13 Accordingly, recurrences were classified as cen-
tral (>95% of RTV inside 95% isodose volume), infield (>95%
of RTV between 95% and 80% isodose volumes), marginal
(>95% of RTV between 80% and 20% isodose volumes), and
distant (>95% of RTV beyond 20% isodose volume).
Patterns of failure were compared between the treat-
ment groups using the chi-squared test. Progression-free
survival (PFS) and OS were analyzed using Kaplan–Meier
methods and the log-rank test. Regression analysis was
used to identify various factors correlating with survival,
toxicity, and QoL.
QoL Analysis
QoL assessment was performed before the start of treat-
ment by a blinded observer, using the EORTC Quality of
Life questionnaire (QLQ C30) and Brain Cancer Module
(QLQ-BN20), which have been validated as efficient tools
in various international trials.14,15 This evaluation was re-
peated 1 month after completion of radiation, and at
3-month intervals thereafter for 9months. Ageneral linear
model was used to estimate the differences in various
domains of QoL, such as global health status, functional
scores, and symptom scales in the QLQ C30 and QLQ-BN20
questionnaires at various points during the course of treat-
ment and follow-up.
Results
Demographics characteristics of all patients are presented
in Table 2, and no significant differences were observed be-
tween the arms on 2-way ANOVA. About 36% of patients
did not receive concurrent chemotherapy, largely be-
cause of poor affordability (30%) and poor tolerance (6%).
However, the distribution of these patients was uniform
among both groups.
In Arm A, the temporal lobe was the most common site
(n=8 patients) followed by the frontal lobe (n=4 patients)
and parietal lobe (n=4 patients); in Arm B, the frontal lobe
was the most common site (n = 8 patients) followed by
the temporal lobe (n=5 patients) and parietal lobe (n=3
patients). Dosimetric and volumetric data are presented in
Table 3. There was no significant difference in the mean PTV
among the groups in the initial phase (P=.24), whereas
a significant reduction in mean PTV was observed in the
boost phase with the MDACC protocol compared with the
RTOG protocol (P= .001). Though the mean doses to the
organs at risk (brainstem, optic apparatus, temporal lobes)
were lesser in Arm B, the difference did not reach statistical
significance.
The absolute volume of whole brain receiving 60 Gy
was significantly less in Arm B as compared with Arm
A(P=.013). Since the volume of whole brain is an inde-
pendent variable, the relative percentage of the whole
brain receiving 95% of the prescription dose (57Gy) was
evaluated, and a significant difference was observed be-
tween Arm A(mean proportion, 40.21%; SD, 11.67) and Arm
B (mean proportion, 30.41%; SD 12.05) with a P value less
than .005. However, no statistically significant differences
were observed in treatment-related acute toxicities and
steroid requirements between both arms (P>.05).
About 36% of patients in each group succumbed to
progression of their illness at home, and radiological
classification of their recurrence patterns could not be
performed. Hence, they were excluded from the patterns
Table 1 Radiotherapy Target Volumes in Both TreatmentGroups
Target Volumes Arm A(RTOG) Arm B (MD Anderson)
Initial phase GTV=gross disease GTV=gross disease
CTV=GTV + peritumoral edema + 2cm isotropic margin CTV=GTV + 2cm isotropic margin
Boost phase CTV=GTV + 2.5cm margin CTV=GTV + 0.5cm
Abbreviations: CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume; RTOG, Radiation Therapy Oncology Group.
5mm PTV margin for setup errors was used for all phases, as per institutional protocol.
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4 Kumar etal. RTOG vs MDACC guidelines for glioblastoma
of failure analysis, and the results of evaluable patients in
both groups are presented in Table 4. Central recurrences
were the most common in both groups, and no signif-
icant differences were observed in the proportions of
recurrences on chi-squaredtest.
Recurrences were managed with salvage surgery,
reirradiation, chemotherapy, or best supportive care, ac-
cording to the performance status of the patient at the time
of recurrence, and no significant differences were observed
between the modalities used among both groups on chi-
squared test (P>.05).
Kaplan–Meier survival curves for PFS and OS are
presented in Fig. 1. A statistically significant difference
was observed between both groups in PFS (6.1months vs
8.7months) as well as OS (12months vs 17months), with
P values of .043 and .015, respectively, on log-ranktest.
Multivariate regression analysis was performed to identify
the factors correlating with PFS and OS. Age of the patient,
extent of initial surgery, and percentage of whole brain re-
ceiving 57 Gy were found to be significant independent
factors correlating with PFS and OS, as presented in Table 5.
QoL analysis is presented in Fig. 2, A and B. Statistically
significant differences favoring Arm B were observed
in various QLQ C30 domains such as global (P = .008),
Table 3 Dosimetric and Volumetric Analysis of Patients in Both TreatmentGroups
Arm A(Mean±2 SD) Arm B (Mean±2 SD) P Value
PTV (Initial Phase) 539.20±142.85 593.81±184.97 .249
PTV (Boost Phase) 436.10±126.19 246.92±116.02 .0 01
Brain V 60 Gy 356.79±137.57 255.47±141.06 .013
V 40 Gy 806.06±218.99 764.76±238.31 .526
Ipsilateral temporal lobe V 60 Gy 47.29±39.00 32.34±30.31 .137
V 54 Gy 57.43±42.60 43.78±33.70 .215
Contralateral temporal
lobe
V 60 Gy 0.69±1.24 0.73±2.41 .936
V 54 Gy 9.35±8.87 7.74±13.63 .622
Brainstem V 60 Gy 5.92±8.84 2.47±5.18 .098
V 54 Gy 13.37±11.29 8.09±8.44 .067
Optic apparatus D max 55.6±3.2 54.7±2.1 .622
Abbreviation: Dmax,dose maximum;PTV, planning target volume;SD, standard deviation;V,volume.
Statistically significant difference (in bold) in boost phase PTVs and volume of brain receiving 60 Gy between the arms.
Table 4 Patterns of Recurrence in Evaluable Patients in Both
TreatmentGroups
Arm A Arm B P Value
Central 12 (75%) 11 (68.75%) P=.81
Infield 2 (12.5%) 3 (18.5%)
Marginal 2 (12.5%) 1 (6.25%)
Distant 0 1 (6.25%)
Table 2 Demographic Characteristics of Patients in Both TreatmentGroups
Arm A(RTOG) Arm B (MD Anderson) P Value
Number 25 25 >.05
Sex (M:F) 15:10 16:9
Age, mean (range) 52 (18-70) 48 (20-68)
KPS, median (range) 70 (70-100) 70 (70-100)
Extent of Surgery
GTR 11 (44%) 14 (56%) .55
NTR 07 (28%) 07 (28%)
STR 07(28%) 04 (16%)
Concurrent chemotherapy 15 (60%) 17 (68%) .55
Adjuvant chemotherapy 13 (52%) 14 (56%) .77
Abbreviations: F, female; GTR, gross total resection; KPS, Karnofsky’s Performance Score;M, male; NTR, near total resection; RTOG, Radiation
Therapy Oncology Group; STR, subtotal resection.
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5
Kumar etal. RTOG vs MDACC guidelines for glioblastoma
Neuro-Oncology
Practice
physical (P = .005), role functional (P = .009), emotional
(P =.006), and social (P= .003), but not in the cognitive
domain (P=.393). However, overall QoL assessed with the
QLQ C30 as well as the site-specific QLQ-BN20 module was
significantly better in Arm B compared with Arm A, with P
values of .007 and .005, respectively.
Discussion
Beginning with the seminal work of Hochberg and Pruitt,
multiple studies have demonstrated that local recurrences
were the predominant pattern of failure after treatment of
glioblastomas, and that most local recurrences occur within
2cm to 3cm of the primary tumor.16–19 Further substantiated
by multiple prospective trials, conformal partial-brain irradi-
ation has replaced whole-brain radiotherapy as the standard
of care for adjuvant treatment of glioblastomas.7,20,21
Although treatment protocols for management of glio-
blastoma have undergone considerable transformation in
the past few decades with evolution of surgical and radia-
tion techniques and newer chemotherapeutic agents, the
prognosis for these patients still remains dismal, with re-
ported median survival in the range of 9 to 12months and
2-year survival in the range of 8% to 12%.4,5
Furthermore, the observation that nearly 90% of all
recurrences occurred within the treatment fields in
spite of dose escalation to 70Gy to 90Gy reiterated the
radioresistance of glioblastomas and insinuated the futility
of giving larger margins around the primary tumor.22,23
Simultaneously, the impact of larger volumes of irradia-
tion on performance status, QoL, and delayed toxicity was
realized.8,10,24
Though these studies answered important questions,
they simultaneously generated new clinically rele-
vant conundrums regarding the optimal volume to be
irradiated for maintaining adequate local control while
reducing treatment-related toxicity. A large part of this
debate could be attributed to the etiology of peritumoral
edema. Halperin and colleagues have analyzed post-
mortem topography of recurrent glioblastomas and
observed that a 3 cm margin around the preoperative
tumor and the peritumoral edema would be necessary
to encompass all the tumor cells during radiation plan-
ning.25 Other studies by Kelly etal and Lu and colleagues
have demonstrated that infiltrating tumor cells may
have a considerable contribution to peritumoral edema
apart from the vasogenic component.26,27 Whereas
some studies reported the prognostic significance of
peritumoral edema, its unreliability as a prognostic
1.0
Survival functions
Treatment arm
Arm A (RTOG)
Arm B (MD Anderson)
Arm A (RTOG)-censored
Arm B (MD Anderson)-
censored
0.8
0.6
0.4
Cum survival
0.2
0.0
0.0 20.00 40.00 60.00
PFS (months)
1.0
Survival functions
Treatment arm
Arm A (RTOG)
Arm B (MD Anderson)
Arm A (RT
OG)-censored
Arm B (MD Anderson)-
censored
0.8
0.6
0.4
Cum survival
0.2
0.0
0.0 20.00 40.00 60.00
PFS (months)
Fig. 1 Kaplan–Meier Survival Curves for Progression-Free Survival (PFS) and Overall Survival (OS) RTOG indicates Radiation Therapy Oncology
Group.
Table 5 Factors Associated With Progression-Free Survival (PFS) and Overall Survival(OS)
PFS OS
Factor Standardized Coefficient P Value Standardized coefficient P Value
Age –0.423 .0001 –0.462 .0001
Extent of resection 0.295 .008 0.283 .007
Percentage of whole brain receiving 57 Gy –0.434 .0001 –0.484 .0001
Abbreviation: OS, Overall Survival; PFS, Progression Free Survival.
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6 Kumar etal. RTOG vs MDACC guidelines for glioblastoma
180.00
A
B
160.00
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
140.00
Pre RT Post
RT_1M
Post
RT_3M
Global_Health
Post
RT_6M
Post
RT_9M
Estimated marginal means
120.00
–25.00
–50.00
–75.00
–100.00
–125.00
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
RT_GROUP
ARM_A_RTO
G
ARM_B_MD
ANDERSON
RT_GROUP
ARM_A_RTOG
ARM_B_MD
ANDERSON
Pre RT Post
RT_1M
Post
RT_3M
Post
RT_6M
Post
RT_9M
Pre RT Post
RT_1M
Post
RT_3M
Social
Post
RT_6M
Post
RT_9M
Pre RT Post
RT_1M
Post
RT_3M
Overall_Symptoms
Post
RT_6M
Post
RT_9M
Pre RT Post
RT_1M
Post
RT_3M
Overall_BN20 SCORE
Post
RT_6M
Post
RT_9M
Pre RT Post
RT_1M
Post
RT_3M
Post
RT_6M
Post
RT_9M
Estimated marginal means
Estimated marginal means
Estimated marginal means
40.00
20.00
0.00
–20.00
–40.00
–60.00
–80.00
Estimated marginal means
Pre RT Post
RT_1M
Post
RT_3M
Cognitive
Post
RT_6M
Post
RT_9M
20.00
0.00
–20.00
0.00
–10.00
–20.00
–30.00
–40.00
550.00
500.00
450.00
400.00
350.00
300.00
Estimated marginal means
40.00
37.50
35.00
32.50
30.00
27.50
–40.00
–60.00
–80.00
–100.00
Estimated marginal means
–150.00
–120.00
RT_GR
OUP
ARM_A_RTO
G
ARM_B_MD
ANDERSON
–250.00
–300.00
Pre RT Post
RT_1M
Post
RT_3M
Physical
Post
RT_6M
Post
RT_9M
Estimated marginal means
–350.00
Fig. 2 A and B, Quality of Life Domain Analysis Using AGeneral Linear Model BN20 indicates European Organisation for Research and Treatment
of Cancer brain cancer module; M, months; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group.
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7
Kumar etal. RTOG vs MDACC guidelines for glioblastoma
Neuro-Oncology
Practice
factor because of steroid-induced variations was
highlighted by others.28–31
This disparity in the interpretation of these studies led
to an unfortunate lack of consensus regarding the optimal
margins for irradiation. It is aptly reflected in the results of
an audit among radiation oncologists of Canada, in which
it was observed that 54% of responders follow institute-
specific protocols for target delineation, whereas published
guidelines by the EORTC and RTOG were followed by a
dismal 14% and 32%, respectively.32
EORTC and MDACC guidelines differ from RTOG
guidelines in their approach toward inclusion of peritumoral
edema in the treatment volume, whereas RTOG and MDACC
guidelines differ from EORTC in the concept of boost phase.8
Though there are limited retrospective and prospective
studies comparing RTOG and EORTC protocols, there have
been no prospective studies comparing MDACC and RTOG
protocols, to the best of our knowledge. In their retrospective
dosimetric reviews, Chang and colleagues and Minnitti etal
observed no significant differences in patterns of recurrence
between RTOG and EORTC delineation protocols.10,33 Similar
outcomes were reported in 2prospective multicentric trials
in which both EORTC and RTOG protocols were allowed for
radiation planning.34,35
In our study comparing RTOG and MDACC protocols,
the patterns of recurrence among both groups were statis-
tically similar and comparable to those reported in the lit-
erature. In their retrospective study of patients treated with
the EORTC protocol, Sherriff etal reported that 77% of all
recurrences were central, though their definition for classifi-
cation of recurrences was slightly different from that used in
our study.36 Using the same definitions as in our study, Ogura
and colleagues observed central, infield, marginal, and dis-
tant recurrences in 66.7%, 19%, 0%, and 9.5% of patients, re-
spectively.37 However, it should be noted that the definitions
used for classifying recurrences are based on prescription
isodose lines rather than their distance from the initial tumor
location, and hence could be subject to potential confounding
when target volumes for irradiation are different. This might
result in a spuriously higher proportion of central recurrences
when larger margins are given around the tumor (RTOG)
as compared with smaller margins (MDACC) as has been
observed in our study, albeit without statistical significance.
Though recurrence patterns were similar in both groups,
we observed a statistically significant improvement in
the PFS and OS with the MDACC protocol compared with
the RTOG protocol. As reported in our regression anal-
ysis, this improvement in survival outcomes may largely
be attributed to the difference in the percentage of whole
brain irradiated at the prescription dose. Our findings are
in concordance with the study by Gebhardt etal, in which
margins smaller than RTOG and EORTC were used ac-
cording to Adult Brain Tumor Consortium guidelines. They
reported a median PFS of 8months, which is comparable
to that of the MDACC arm (8.7 months) in our study.38
However, similar improvement in survival outcomes was
not observed in the studies comparing RTOG and EORTC
protocols.10,33–35 A possible explanation for this could be
that the benefit of volume reduction in the EORTC protocol
might have been offset by the absence of a boost phase,
thereby increasing the proportion of whole brain receiving
the prescription dose in those patients.
Apart from improvements in the PFS and OS, a signif-
icantly better QoL was observed in the MDACC arm of
our study compared with the RTOG arm. This difference
was consistent throughout the period of evaluation, and
substantiates the importance of treatment volume reduc-
tion in reducing treatment-related late toxicity.
Notwithstanding a phase 2 design, our study is limited
by a relatively smaller sample size and lack of informa-
tion regarding molecular and genetic markers that carry
important prognostic value. Moreover, the dose schedule
followed (40 Gy + 20 Gy) in our study is different from that
of current standard practice (46 Gy + 14 Gy) and might
have influenced the outcomes in our analysis.
Conclusion
Disregarding peritumoral edema during target delinea-
tion does not influence the patterns of failure in glioblas-
toma. Reducing the volume of irradiation by following the
limited-margin MDACC protocol has the potential to im-
prove survival outcomes apart from QoL of glioblastoma
patients, as compared with the RTOG protocol.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement. None declared.
References
1. OstromQT, GittlemanH, LiaoP, etal. CBTRUS statistical report: primary
brain and other central nervous system tumors diagnosed in the United
States in 2010-2014. Neuro Oncol. 2017;19(suppl5):v1–v88.
2. DasguptaA, GuptaT, JalaliR. Indian data on central nervous tumors: a
summary of published work. South Asian J Cancer. 2016;5(3):147–153.
3. SimpsonJR, HortonJ, ScottC, etal. Influence of location and extent of
surgical resection on survival of patients with glioblastoma multiforme:
results of three consecutive Radiation Therapy Oncology Group (RTOG)
clinical trials. Int J Radiat Oncol Biol Phys. 1993;26(2):239–244.
4. Stupp R, MasonWP, vanden BentMJ, et al. Radiotherapy plus con-
comitant and adjuvant temozolomide for glioblastoma. NEngl J Med.
2005;352(10):987–996.
5. Stupp R, HegiME, MasonWP, etal. Effects of radiotherapy with con-
comitant and adjuvant temozolomide versus radiotherapy alone on sur-
vival in glioblastoma in a randomised phase III study: 5-year analysis of
the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466.
6. ShapiroWR, GreenSB, BurgerPC, etal. Randomized trial of three che-
motherapy regimens and two radiotherapy regimens and two radio-
therapy regimens in postoperative treatment of malignant glioma. Brain
Tumor Cooperative Group Trial 8001. JNeurosurg. 1989;71(1):1–9.
Downloaded from https://academic.oup.com/nop/advance-article-abstract/doi/10.1093/nop/npz024/5535731 by University of Sussex Library user on 22 July 2019

8 Kumar etal. RTOG vs MDACC guidelines for glioblastoma
7. Nabors LB, PortnowJ, Ammirati M, et al. NCCN guidelines insights:
central nervous system cancers, version 1.2017. J Natl Compr Canc
Netw. 2017;15(11):1331–1345.
8. Zhao F, Li M, KongL, Zhang G, YuJ. Delineation of radiation therapy
target volumes for patients with postoperative glioblastoma: a review.
Onco Targets Ther. 2016;9:3197–3204.
9. Price SJ, GillardJH. Imaging biomarkers of brain tumour margin and
tumour invasion. Br J Radiol. 2011;84(Spec No 2):S159–S167.
10. ChangEL, AkyurekS, AvalosT, etal. Evaluation of peritumoral edema in
the delineation of radiotherapy clinical target volumes for glioblastoma.
Int J Radiat Oncol Biol Phys. 2007;68(1):144–150.
11. Colevas AD, Setser A. The NCI Common Terminology Criteria for
Adverse Events (CTCAE) v 3.0 is the new standard for oncology clinical
trials. JClin Oncol. 2004;22(14suppl):6098.
12. Brandes AA, Tosoni A, Spagnolli F, et al. Disease progression or
pseudoprogression after concomitant radiochemotherapy treatment:
pitfalls in neurooncology. Neuro Oncol. 2008;10(3):361–367.
13. MilanoMT, OkunieffP, DonatelloRS, etal. Patterns and timing of recur-
rence after temozolomide-based chemoradiation for glioblastoma. Int J
Radiat Oncol Biol Phys. 2010;78(4):1147–1155.
14. AaronsonNK, AhmedzaiS, BergmanB, etal. The European Organization
for Research and Treatment of Cancer QLQ-C30: a quality-of-life instru-
ment for use in international clinical trials in oncology. JNatl Cancer
Inst. 1993;85(5):365–376.
15. Taphoorn MJ, ClaassensL, AaronsonNK, et al. An international vali-
dation study of the EORTC brain cancer module (EORTC QLQ-BN20) for
assessing health-related quality of life and symptoms in brain cancer
patients. Eur J Cancer. 2010;46(6):1033–1040.
16. HochbergFH, PruittA. Assumptions in the radiotherapy of glioblastoma.
Neurology. 1980;30(9):907–911.
17. GardenAS, MaorMH, YungWK, etal. Outcome and patterns of failure
following limited-volume irradiation for malignant astrocytomas.
Radiother Oncol. 1991;20(2):99–110.
18. WallnerKE, GalicichJH, KrolG, ArbitE, MalkinMG. Patterns of failure
following treatment for glioblastoma multiforme and anaplastic
astrocytoma. Int J Radiat Oncol Biol Phys. 1989;16(6):1405–1409.
19. HessCF, SchaafJC, Kortmann RD, SchabetM, BambergM. Malignant
glioma: patterns of failure following individually tailored limited volume
irradiation. Radiother Oncol. 1994;30(2):146–149.
20. Stupp R, Brada M, van denBentMJ, Tonn JC, PentheroudakisG;ES
MO Guidelines Working Group. High-grade glioma: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2014;25(suppl3):iii93–iii101.
21. CabreraAR, KirkpatrickJP, FiveashJB, etal. Radiation therapy for gli-
oblastoma: executive summary of an American Society for Radiation
Oncology evidence-based clinical practice guideline. Pract Radiat Oncol.
2016;6(4):217–225.
22. Lee SW, FraassBA, MarshLH, etal. Patterns of failure following high-
dose 3-D conformal radiotherapy for high-grade astrocytomas: a quanti-
tative dosimetric study. Int J Radiat Oncol Biol Phys. 1999;43(1):79–88.
23. ChanJL, LeeSW, FraassBA, etal. Survival and failure patterns of high-
grade gliomas after three-dimensional conformal radiotherapy. JClin
Oncol. 2002;20(6):1635–1642.
24. Sharma RR, Singh DP, Pathak A, et al. Local control of high-grade
gliomas with limited volume irradiation versus whole brain irradiation.
Neurol India. 2003;51(4):512–517.
25. HalperinEC, BentelG, HeinzER, BurgerPC. Radiation therapy treatment
planning in supratentorial glioblastoma multiforme: an analysis based
on post mortem topographic anatomy with CT correlations. Int J Radiat
Oncol Biol Phys. 1989;17(6):1347–1350.
26. KellyPJ, Daumas-DuportC, KispertDB, KallBA, ScheithauerBW,IlligJJ.
Imaging-based stereotaxic serial biopsies in untreated intracranial glial
neoplasms. JNeurosurg. 1987;66(6):865–874.
27. Lu S, Ahn D, JohnsonG, LawM, Zagzag D, Grossman RI. Diffusion-
tensor MR imaging of intracranial neoplasia and associated peritumoral
edema: introduction of the tumor infiltration index. Radiology.
2004;232(1):221–228.
28. Pope WB, SayreJ, PerlinaA, VillablancaJP, MischelPS, CloughesyTF.
MR imaging correlates of survival in patients with high-grade gliomas.
AJNR Am J Neuroradiol. 2005;26(10):2466–2474.
29. SchoeneggerK, OberndorferS, WuschitzB, etal. Peritumoral edema on
MRI at initial diagnosis: an independent prognostic factor for glioblas-
toma? Eur J Neurol. 2009;16(7):874–878.
30. RamakrishnaR, BarberJ, KennedyG, etal. Imaging features of inva-
sion and preoperative and postoperative tumor burden in previously
untreated glioblastoma: Correlation with survival. Surg Neurol Int.
2010;1.
31. Iliadis G, Kotoula V, Chatzisotiriou A, et al. Volumetric and MGMT
parameters in glioblastoma patients: survival analysis. BMC Cancer.
2012;12:3.
32. Ghose A, LimG, HusainS. Treatment for glioblastoma multiforme:
current guidelines and Canadian practice. Curr Oncol. 2010;
17(6):52–58.
33. MinnitiG, Amelio D, AmichettiM, et al. Patterns of failure and com-
parison of different target volume delineations in patients with glio-
blastoma treated with conformal radiotherapy plus concomitant and
adjuvant temozolomide. Radiother Oncol. 2010;97(3):377–381.
34. GilbertMR, Wang M, AldapeKD, etal. Dose-dense temozolomide for
newly diagnosed glioblastoma: a randomized phase III clinical trial.
JClin Oncol. 2013;31(32):4085–4091.
35. StuppR, Hegi ME, GorliaT, etal. Cilengitide combined with standard
treatment for patients with newly diagnosed glioblastoma with meth-
ylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a
multicentre, randomised, open-label, phase 3 trial. Lancet Oncol.
2014;15(10):1100–1108.
36. SherriffJ, TamanganiJ, SenthilL, etal. Patterns of relapse in glioblastoma
multiforme following concomitant chemoradiotherapy with temozolomide.
Br J Radiol. 2013;86(1022):20120414.
37. OguraK, MizowakiT, ArakawaY, etal. Initial and cumulative recurrence
patterns of glioblastoma after temozolomide-based chemoradiotherapy
and salvage treatment: a retrospective cohort study in a single institu-
tion. Radiat Oncol. 2013;8:97.
38. Gebhardt BJ, Dobelbower MC, Ennis WH, Bag AK, Markert JM,
Fiveash JB. Patterns of failure for glioblastoma multiforme following
limited-margin radiation and concurrent temozolomide. Radiat Oncol.
2014;9:130.
Downloaded from https://academic.oup.com/nop/advance-article-abstract/doi/10.1093/nop/npz024/5535731 by University of Sussex Library user on 22 July 2019