Journal of Cancer Therapy, 2013, 4, 18-24
Published Online December 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.411A003
Open Access JCT
Dosimetric Improvements Utilising Intensity Modulated
Radiation Therapy for Patients with Glioblastoma
Multiforme
Michael Back1,2*, Shaun Clifford1, Helen Wheeler1,2, Thomas Eade1,2
1Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia; 2Northern Clinical School, University of Sydney,
Sydney, Australia.
Received September 29th, 2013; revised October 26th, 2013; accepted November 4th, 2013
Copyright © 2013 Michael Back et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Aims: The EORTC-NCI study investigating the addition of temozolomide trial to standard radiation therapy has dem-
onstrated improved duration of survival in patients with Glioblastoma multiforme (GBM). With longer survival dura-
tion, there is the potential for latent RT morbidity, not previously seen in historical patients. This study evaluates the
potential dosimetric advantages of utilising IMRT over 3D-conformal RT in such patients. Methods: 10 consecutive
patients with GBM formally screened for a clinical study over a two-month period were planned and treated with IMRT
utilising daily on-board imaging (OBI). The EORTC protocol dosimetric criteria and constraints were used in target
delineation and planning. For each patient, a 3DCRT plan was also produced. Endpoints for dosimetric evaluation ana-
lysed related to tumour dose: mean PTV60 dose (mPTV60Dose), Conformity Index (CI); and normal tissue dose: mean
normal brain do se (mBrainDose) and V4 0 Brain (Brainv40). IGRT endpoints w ere the median isocentre shifts r equired
in 3 axes measured in one direction. The variation between the IMRT and 3DCRT dosimetric endpoints was examined
using Wilcoxon analysis. Results: The 10 patients had tumours located in temporal (3), parietal (3), occipital (2) and
callosal (2) regions. The median PTV and normal brain volumes were 308.1 cm3 and 1077.5 cm3 respectively. The
IMRT dosimetry was significantly improved in all endpoints specifically CI (p = 0.002), mPTV60Dose (p = 0.004),
mBrainDose (p = 0.002) and Brainv40 (p = 0.019). OBI directed isocentre measurements in the patient group were
available for 230 treatments. The median shifts (and 95% C.I.s) were 0.1 cm vertical (0.1 - 0.2), 0.1 cm longitudinal
(0.1 - 0.2) and 0.2 cm lateral ( 0.2 - 0.2). At a minimum foll ow-up of 2 years’ post d iagnosis, the median survival of the
group is 18.0 months (95% CI: 13.4 - 22.6 months). Conclusion: IMRT for GBM produces significant dosimetric ad-
vantages in relation to planning target volume and normal tissue dose compared with 3D conformal plans. The data also
confirm the accuracy of IMRT technique for CNS with IGRT delivery utilising OBI demonstrating minimal deviation
from planned to treated isocentre.
Keywords: Intensity Modulated Radiation Therapy; Glioblastoma; Dosimetry
1. Introduction
The addition of temozolomide to radiation therapy in the
adjuvant therapy of glioblastoma multiforme (GBM) has
resulted in an era in which the median survival of pa-
tients has doubled, and a small proportion of patients are
alive at 5 years’ post diagnosis [1]. The EORTC-NCI Pro-
tocol demonstrated a 5-year survival of 9.8% w ith a good
prognostic subgroup of patients having a 5-year survival
of 28% [2].
The impact of intensified therapy and pr esence of lon-
ger term survival increases the emphasis on treatment
techniques to optimise outcome by consolidating the tu-
mour control and minimise poten tial late morbidity [2,3 ].
Specifically for radiation therapy this would involve te-
chniques that produce adequate target coverage with re-
duction of normal tissue dose. Concurrent improvements
in RT techniques utilizing intensity modulated radiation
therapy (IMRT) and image guided radiation therapy
(IGRT) have been shown to demonstrate improved tar-
geting and reduced morbidity in tumour sites such as
*Corresponding a uthor.

Dosimetric Improvements Utilising Intensity Modulated Radiation
Therapy for Patients with Glioblastoma Multiforme 19
prostate and nasopharyngeal cancer [4,5].
This study aims to demonstrate the potential dosimet-
ric benefits of utilising IMRT in management of GBM
over the standard 3DCRT as used in the EORTC-NCI
Protocol.
2. Methods
Consecutive adult patients diagnosed with GBM and re-
ferred to The Department of Radiation Oncology at the
Northern Sydney Cancer Centre are entered into a pro-
spective database, approved by Institutional Ethics Re-
view Board. 10 consecutive patients with GBM formally
screened for a clinical study investigating an anti-angi-
ogenesis agent over a two month period from February
2009 to March 2009 were included in this dosimetric
study. These patients wer e part of a cohort of 100 conse-
cutive patients with glioblastoma multiforme formally
managed with adjuvant radiation therapy between 1st
July 2007 and 31st December 2011 under the dosimetric
criteria and constraints specified as per the standard
EORTC-NCI Protocol [1,6]. Patients proceeded to be
managed with IMRT and IGRT utilising daily on-board
imaging (OBI). For these 10 patients at an additional
plan was produced using an optimal 3D conformal RT
technique. The IMRT and 3DCRT plans were then util-
ised for formal comparison.
2.1. Radiation Therapy Planning
The patients had CT simulation with immobilization by
an individual Perspex mask system. Pre and post opera-
tive MRI scans were fused with the non-contrast CT scan
and entered into the Varian Eclipse Planning system. A
single clinician and dosimetrist were used for the plan-
ning proce ss.
Target volume segmentation was undertaken using the
EORTC-NCIC Protocol with Clinical Target Volume be-
ing based on the enhancing tissue on postoperative im-
aging and an expansion of 1.5 cm to anatomical bounda-
ries. The CTV was expanded uniformly by 5 mm to cre-
ate the Planning Target Volume or PTV. The dose pre-
scription was 60 Gy in 30 fractions as a single-phase
treatment. Normal tissue dose constraints were specified
as optic chiasm and brainstem to receive less than 55 Gy,
and lens less than 6 Gy.
An IMRT plan was created with inverse planning lim-
ited by a maximum of 6 fields and dose constraints with
highest priority on PTV, optic chiasm and brainstem. At
sites where PTV involved a dose limiting structure, a se-
parate high priority PTV was created for the overlap re-
gion and optimisations performed to control the dose at
that region. Fluence painting was undertaken on each
field to remove areas of high dose gradient. This plan
was used for treatment delivery.
A second plan was subsequ ently produced by the same
dosimetrist using a forward planned four to five field
3DCRT beam arrangement. Non-coplanar beams were
utilised as required to optimize the dose distribution.
2.2. Radiation Therapy Delivery
Treatment was delivered with IMRT using 6 MV pho-
tons on a Varian Trilogy Linear Accelerator. Daily IGRT
was performed with the on-board imager (OBI) verifying
position based on middle cranial fossa and orbital bone
landmarks.
2.3. Systemic Therapy Management
Concurrent and adjuvant temozolomide was used as per
the EORTC-NCIC Protocol. Of the ten patients screened
for the prospective clinical study, three were eligible for
randomisation and one allocated the study drug in addi-
tion to temozolomide. Thus the remaining nine patients
were managed under the standard protocol.
2.4. Dosimetric Endpoints
The volumes that formed the basis of the analysis, PTV
(measured in cm3) and Brain (defined as Whole brain mi-
nus PTV) were calculated for each patient.
The study related dosimetric endpoin ts evaluated were
calculated from the Eclipse Planning System. These were
related to Tumour Dose (mean PTV dose and Confor-
mity Index); and Normal Tissue Dose (mean Brain dose,
percentage volume of brain receiving 40 Gy and volume
of Brain receiving 20 Gy). The conformity index (CI)
was defined as the volume of tissue encompassed by the
95% isodose as a proportion of the volume of the PTV
(CI = V95% / VPTV).
2.5. IGRT Delivery Endpoint
The discrepancy between clinical positioning of the pa-
tient in the immobilization mask and the subsequent ra-
diological verification of po sition using the OBI was cal-
culated each day. This provided a bidirectional measure-
ment in 3 axes: medial, lateral and vertical. For analysis
this daily isocentre shift was calculated as one direction
and the median shift calculated for each patient.
2.6. Clinical Endpoints
All patients were followed clinically until death or the
censure date of the study on August 1st 2013. The dura-
tion of survival from date of diagnosis was calculated for
the 10 patients. The site of relapse was recorded as in-
field (within 95% isodose or high dose RT); marginal
(within 20 mm from 95% isodose) or distant (>20 mm
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Dosimetric Improvements Utilising Intensity Modulated Radiation
Therapy for Patients with Glioblastoma Multiforme
Open Access JCT
20
from 95% isodose).
2.6. Statistical Considerations
All patients had clinical and dosimetric data entered on
an Excel database at Northern Sydney Cancer Centre and
updated for outcome events.
The variation between the IMRT and 3DCRT dosi-
metric endpoints was examined using Wilcoxon analysis.
The median survival of the patient group was calculated
using the Kaplan-Meier method.
3. Results
The 10 patients were managed with radiation therapy and
completed the planned treatment course. One patient had
an interruption to therapy delivery of 2 days due to ad-
mission with febrile neutopaenia secondary to marrow
suppression from temozolomide. All patients were avai-
lable for follow-up.
3.1. Target Volume Parameters
The 10 tumours were located in parietal (3), temporal (2),
occipital (2), splenium (1), frontal/callosal (1) and cere-
bellar (1) regions of the brain. The median PTV was
308.1 cm3 with a range of 216 cm3 to 516 cm3. The me-
dian normal brain volumes were 1077.5 cm3 with a range
of 930 cm3 to 1348 cm3.
3.2. Radiation Planning
The IMRT plans all reached the dosimetric requirement
of the EORTC-NCIC Protocol in regard to PTV coverage
and normal tissue avoidance. The beam arrangement for
IMRT involved either 4, 5 or 6 beams treated with a dy-
namic MLC.
The 3DCRT plans were of high conformal design with
8 patients receiving a non-coplanar beam procedure; and
patients receiving either a 4 portal (5 patients) or 5 portal
(5 patients) field arrangement.
3.3. Dosimetric Endpoints
The dosimetric endpoints were significantly improved
for all categories with the IMRT plans compared with the
3D CRT plans. The results are summarized in Table 1.
The IMRT Plans were able to deliv er more dose to the
tumour target as reflected by the Conformity Index being
lower in all 10 patients for IMRT; and the mean PTV
dose being higher in 9 patients (Figures 1 and 2). The
site of the tumour reflected the extent to which the mean
PTV dose varied from the 3DCRT, as demonstrated by
the inferior frontal lobe (Patient 6) and temporal lobe
IMRT plans (Patients 2,3,4) showing up to 7% higher
dose delivered to the PTV.
The normal brain dose was reduced or equivalent in all
patients at the 20 Gy and 40 Gy dose levels. The differ-
ence varied between patients and target volume size, but
the volume of normal brain receiving 20 Gy was reduced
by 15% - 20% in 4 patients (Figure 3 and 4). An exam-
ple of the reduced brain dose at the 20 Gy isodose level
is demonstrated in Figure 5.
3.4. IGRT Delivery
OBI directed isocentre measurements in the patient group
were available for 230 treatments. The accuracy of treat-
ment delivery was confirmed with median shifts (and
95% C.I.s) of 0.1 cm vertical (0.1 - 0.2), 0.1 cm longitu-
dinal (0.1 - 0.2) and 0.2 cm lateral (0.2 - 0.2).
3.5. Clinical Outcome
A minimum of 50 months follow-up from diagnosis was
available for the 10 patien ts included in surviv al duration
analysis. All patients are deceased from relapse of glio-
blastoma. The relapse occurred infield in 7, marginal
alone in no patients and distant (>2 cm from 95% iso-
Table 1. Dosimetric endpoints for IM RT and 3D CRT plans.
Endpoint IMRT (mean score and range) 3D Conforma l (mean score and range) P value
Mean dose to PTV 61.4 Gy (60.4 - 62. 5 ) 60.0 Gy (58.8 - 61. 9 ) p = 0.004
Conformity ind e x 1.14 (1.05 - 1.27) 1.31 (1.15 - 1.47) p = 0.002
V40 (volume of brain receiving 40 Gy) 14.8% (7.4% - 28.3%) 17.9% (10.9% - 27.1%) p = 0.019
V20 (volume of brain receiving 20 Gy) 47.4% (31.3% - 70.2%) 55.3% (39.6% - 75.9%) p = 0.015
Mean dose to brain 22.3 Gy (16.3 - 29. 9 ) 24.5 Gy (19.3 - 30. 9 ) p = 0.002

Dosimetric Improvements Utilising Intensity Modulated Radiation
Therapy for Patients with Glioblastoma Multiforme 21
Figure 1. Mean PTV dose (Gy): Comparison of IMRT and 3D CRT plans for each patient.
Figure 2. Conformity index: Comparison of IMRT and 3D CRT plans for each patient.
dose) in 3. The median survival of patients was 18.0
months (95% CI: 13.4 - 22.6 months). This is consistent
with the reported outcome of 17.0 months (95% CI: 13.2
- 20.7 months) from the larger cohort of 100 patients
managed with IMRT [6].
4. Discussion
This study confirms that the use of IMRT as a radiation
technique for adjuvant therapy of GBM results in im-
proved dose distribution compared with standard 3DCRT.
Dose to the tumour target can be increased with less dose
delivered to surrounding normal brain tissue. This im-
provement is significant with potential increases of tu-
mour dose by 5% - 7% and reductions in volumes of nor-
mal brain dose receiving 20 Gy by 15% - 20%.
Whilst an aim of radiation therapy is to deliver an op-
timal dose distribution it is uncertain whether these do-
simetric improvements translate to clinical advantage. In
this study the use of IMRT was not planned to have a
major direct effect on tumour control because the treat-
ment prescription is kept unaltered without any dose es-
calation or treatment acceleration. However at certain
neuroanatomical sites adjacent to dose limiting structures
such as tumours based in medial temporal lobe, there
may be an impact on tumour control because of an im-
proved dose to PTV. Similarly the clinical impact of re-
duction in normal brain dose is uncertain as the associa-
tion between brain do se and risk of n eurocognitive effect
is not well defined [7].
In this small cohort of patients the median survival
was 18 months with three patients surviving into the
fourth year after diagnosis. This is consistent with the
survival from recently reported clinical trials [8-10], and
our report of 100 patients consecutively managed with
IMRT [5]. Optimising radiation therapy dosimetry
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Dosimetric Improvements Utilising Intensity Modulated Radiation
Therapy for Patients with Glioblastoma Multiforme
22
Figure 3. Brain v40 (%brain receiving >40 Gy): Comparison of IMRT and 3D CRT plans for each patient.
Figure 4. Brain v20 (%brain receiving >20 Gy): Comparison of IMRT and 3D CRT plans for each patient.
should not be neglected as the effect of enhancing both
surgery and systemic therapies may result in a potential
exacerbation of RT morbidity. More aggressive neuro-
surgical debulking into eloquent areas of brain may result
in small vessel effects which could subsequently increase
the risk of later ischaemic events from radiation therapy.
Similarly the addition of further agents to temozolomide
with either cytotoxic or molecular agents may accentuate
a risk of delayed leukoencephalopathy. Waiting for cli-
nical evidence to provide a reason to implement an im-
proved radiation therapy technique may not be warranted
in this era of managing a cancer in which th e median sur-
vival has double d .
The improvements in conformity index have increased
the potential for dose escalation or treatment acceleration
to be considered as a technique to improve outcome [11].
Previous attempts at dose escalation have been unsuc-
cessful, though most were involved with the addition of
dose at the completion of standard therapy, either with an
external beam boost, stereotactic boost or brachytherapy
[12-14]. All these prior studies were performed in the era
before temozolomide. Combined with the improvements
in tumour delineation with MRI and PET imaging, IMRT
now allows the potential for alteration to standard dose
fractionation regimens with smaller better defined target
volumes. This principally allows the dose escalation to
be delivered via an integrated boost technique without
extending the radiation treatment duration [11,15,16]; or
via hypofractionation with a high dose of RT to a smaller
target over shorter treatment duration [17,18]. Both of
these approaches have potential radiobiological advan-
tages, especially in tumours with a high proliferative rate.
An IMRT integrated boost approach allows a limited
volume target to be treated to a higher dose whilst main-
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Dosimetric Improvements Utilising Intensity Modulated Radiation
Therapy for Patients with Glioblastoma Multiforme 23
Figure 5. Brain v20 (%brain receiving >20 Gy): Comparison of IMRT and 3D CRT plans for patient #4.
taining similar doses that h ave been used historically to a
larger volume. The higher dose volume should be a re-
gion that is perceived to be of higher risk for relapse such
as the site of residual tumour, or more biologically resis-
tant tumour. This may be determined by postoperative
MRI imaging or PET imaging utilizing a tracer that de-
termines a specific high biological risk feature such as
amino acid for residual disease, hypoxic cells. The region
of high risk is then dose-painted as a separate target vo-
lume which receives an escalated dose per fraction over
the same time period. This provides a potentially more
effective dose to the high-risk region without increasing
dose to the surrounding normal brain tissue. Early fa-
vourable Phase II data is being reported utilizing this
approach in selected patients with such regimens as 72
Gy in 30 fractions to a region defined by FET PET with a
standard 60 Gy to a larger volume [15].
A more radical approach is to reduce the IMRT treat-
ment duration by hypofractionation, in which a six-week
course of therapy is delivered in a shorter period to a
reduced volume. This higher dose per fraction may in-
crease the risk of late morbidity, but is minimized through
the reduction in volume expansion. An example is a re-
gimen of 60 Gy being delivered in 10 fractions over 2
weeks to a highly defined volume with a lower dose of
30 Gy to surrounding tissues [17]. The IMRT dose de-
livery is thus accelerated to the limited volume which
may be defined by MRI, or PET tracers such as C-me-
thionine. The data is limited at presen t but there does not
appear to be an increased risk of treatment related necro-
sis in selected patients. These approaches allow the po-
tential technological advances in imaging and radiation
therapy to potential enhance outcome.
The implementation of IMRT in brain tumour man-
agement may be limited by potential barriers including
high departmental workload, concern over geographical
target miss and uncertainty with the target volume deli-
neation. These appear to be addressed with improve-
ments in patient immobilization, RT Planning software
including image fusion and target volume autosegmenta-
tion; and improved linear accelerator hardware with daily
treatment image verification. As demonstrated in this co-
hort with median isocentre displacements of 1 - 2 mm at
setup the treatment may not only be planned more accu-
rately but the delivery is confirmed and precise. This pro-
vides more clinician and therapist confidence in sophis-
ticated therapy design. Overcoming these barriers allows
a pathway that makes the planning and implementation
of IMRT more efficient and logistically feasible, espe-
cially in departments with high workload.
5. Conclusion
IMRT for glioblastoma multiforme can achieve signifi-
cant dosimetric improvements over 3D CRT. The poten-
tial for clinical benefit with standard therapy remains un-
certain and the impact of novel techniques of integrated
boost dose escalation is yet to be explored. However,
optimisation of radiation technique using IMRT will al-
low for a minimisation of future late tissue morbidity
whilst other modalities of surgery and systemic therapy
are enhanced.
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