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Application of Nonstandard Radiotherapy Techniques in Glioblastoma Multiforme: A Case

Study
Authors: Sharan Swenski, A.A.S., B.A., RT(T), Shands James B.S., RT(T), Yinan Wang, M.S.,
Ashley Hunzeker, M.S. CMD, Nishele Lenards, M.S., CMD, R.T.(R)(T), FAAMD
Medical Dosimetry Program at the University of Wisconsin - La Crosse, WI
Abstract:
Introduction: The purpose of this case study was to evaluate the varying dosimetric outcomes of
glioblastoma multiforme (GBM) plans using volumetric modulated arc therapy (VMAT), VMAT
utilizing flattening filter free (FFF), and proton therapy.
Case Description: A previously treated GBM patient was randomly selected and a plan was
created with each technique. The photon plans used 2 arcs, while the proton plan used 5 beam
angles to achieve a dose distribution that would contribute to an overall 95% of the volume
receiving 100% of the dose (V100).
Conclusion: The plans were all studied to ensure they were deliverable plans by comparing V100,
conformity index (CI), homogeneity index (HI) and how well the organs at risk (OR) constraints
were met. The goal was to explore alternatives to the standard of care which would compare and
contrast the quality of each technique. Protons outperformed the other two plans by producing
consistently lower OR doses. Interestingly, there was no advantage for the integral dose,
conformity, and homogeneity indices for the proton plan over the VMAT and VMAT FFF plans.
However, the VMAT FFF plan demonstrated marginally more desirable values for these indices
over the VMAT plan.
Key words: Glioblastoma, protons, flattening filter free, VMAT
Introduction
Cancer of the brain and central nervous system affects nearly 23,000 individuals a year,
with roughly 20% of these patient receiving a GBM diagnosis.1 With recent advances of
targeting specific DNA structures, GBM survival rates have increased. The median survival rate
for patients diagnosed with GBM, is around 12 months.2 Grade IV astrocytoma tumors, or GBM
tumors are a class of tumors difficult to keep in remission requiring a multidisciplinary GBM

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treatment approach. Trying to achieve a greater mean survival time has led to new combinations
of therapeutic agents. Trials boasting the success of concurrent radiation therapy and
chemotherapy in the form of an oral pill called temozolomide are increasing survival rates.3
A major aspect of local control for GBM tumors, involves irradiating the tumor or tumor
bed following a resection. Radiation therapy is the standard of care for GBM tumors, but there
are many varying techniques that can be utilized. Current practices include but are not limited to
intensity modulated radiation therapy (IMRT), VMAT, gamma knife and stereotactic
radiosurgery (SRS). Nonstandard practices of radiation therapy need to be evaluated to supersede
the stagnant conditions of the current dosimetric outcomes for these patients. Utilizing either
VMAT, VMAT FFF or protons for these patients is evident in the literature. Though
combinations of IMRT, VMAT, FFF VMAT, and protons have been performed, no study has
compared VMAT, FFF VMAT and protons.4 Currently VMAT is the best practice for GBM
tumors due to the high degree of conformality and variability in limiting dose to OR. Due to the
special beam characteristics of VMAT FFF, it was a great choice to utilize in this application.
The pencil-like beam has a high dose rate and altered mean energy.5 Protons for GBM tumors are
not completely new either, with some studies analyzing dose escalation of the tumor volume to
extinguish any chances of central recurrence.6 These techniques are a well-rounded
representation of the current standard of care including the new promising techniques not widely
used in practice. This study analyzed VMAT, VMAT FFF and protons for a GBM case to better
grasp the limitation and advantages posed by each technique.
Case Description
Patient Selection and Setup
A recently treated GBM patient was selected at random for this case study comparison. A
CT scan was performed using 3 mm axial slices. The patient was placed supine in a U-frame
with an Aquaplast mask for immobilization. A 3 point was placed on the mask for localizing.
Target Delineation
A GBM was located in the right parietal lobe of the brain, without crossing midline or
destroying any bony anatomical structures. The tumor was resected, leaving no air in the pocket
only soft tissue. The CT image was registered to the patients MRI scans. The gross tumor
volume (GTV) consisted of the tumor bed, drawn from MRI T1-post and the planning target

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volume (PTV) consisted of the edema noted from the MRI T2 fluid attenuated inversion
recovery (flair) images. While the planning volumes were drawn from the MRI images, the
brainstem, chiasm, optic nerves, lens and cochlea were drawn with the information from the CT
scan within radiation oncology.
Treatment Planning
A single phase treatment regimen of 2 Gy per fraction for 30 fractions was the chosen
dose scheme. For all plans, the isocenter was placed in the middle of the GTV. Using the Eclipse
treatment planning system (TPS), the photon plans were designed with 2 full arcs with an energy
of 6 MV, one clockwise and the other counterclockwise. The VMAT and FFF VMAT plans used
an optimized collimator rotation of 30 degrees and 330 degrees.
The proton machine characteristics used for treatment planning are from IBA ProteusOne
that provides the latest advanced precise dose delivery of pencil beam scanning. The RayStation
4.8 software was utilized to set up 5 proton beams to encompass the size of the GBM volume. In
intensity modulated proton therapy (IMPT), the conventional PTV concept does not work well,
due to IMPTs high sensitive to range uncertainty. As a result, RayStation implements a robust
optimization scheme to take all the uncertainties into account and a worst case scenario is
considered.7, 8 In the current IMPT planning, a uniform 3 mm setup uncertainty and 3.5% range
uncertainty for both the clinical target volume (CTV) and brainstem were used for robust
optimization and 98% of CTV to receive 60 Gy. Utilizing IMPT delivers dose by scanning the
target volume layer-by-layer. By switching energies the proton beams penetrate the target volume
at different depths so that the bragg peaks stop at different layers.7,9
Plan Analysis and Evaluation
The transverse, sagittal and coronal views of isodose distribution for the three plans are
shown in Figure 1-3. The coverage on all 3 plans was above the minimum requirement of V100
greater than 95%. All plans met the minimum requirements as gained from the qualitative
analysis of normal tissue effects in the clinic (QUANTEC) reviews.10 As shown in Table 1, the
dose to the OR is best executed with protons. While the VMAT and VMAT FFF plans are quite
comparable, the most differentiation occurs between dose in the anatomical structures on the
ipsilateral side. For example, the right lens dose for the VMAT was 12.89 Gy and the VMAT FFF
plan had a dose of 17.70 Gy. While both photon plans were unable to meet the set lens

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constraints, the proton plans right lens dose of 0.06 Gy is well below required tolerance for
toxicities related to long term effects. The plan using protons has multiple lower normal structure
doses listed and achieves the required target coverage.
In addition to comparing the three modalities ability to spare normal tissue in the vicinity
of the target volume, plan quality was assessed using the HI, CI, and integral dose (ID). Ideally,
the maximum dose in a treatment plan will be the prescription dose, but this not possible in real
life scenarios. The HI is a ratio of the maximum and minimum doses within the target volume.
This index quantifies how well a plan can achieve a homogenous dose across the volume,
excessive dose gradients interspersed in target area makes the plan less homogenous. To
calculate HI the dose at 5% of the volume (D5) is divided by the dose at 95% of the volume (D95).
The CI is a ratio between the prescription dose volume divided by the target volume. The goal of
a treatment plan is to obtain a CI value as close to 1 as possible. This value indicates how closely
the prescription isodose line conforms to the treatment volume. Lastly, integral dose is the
measurement of intermediate dose spillage to normal tissue. As plan conformity decreases the
integral dose increases. Ideally, a treatment plan will limit integral dose as much as possible to
reduce the risk of normal tissue side effects. To assess the intermediate dose spillage the 50%
isodose line(IDL) is divided by the PTV volume referred to as R50%.
The most homogeneous treatment plan proved to be the VMAT FFF plan indicating a
more uniform isodose distribution and a lower hotspot. However, the values of the HI for each
plan were very similar (Table 2). In regards to the conformity index, the VMAT FFF plan had the
most ideal value at 1.016. The VMAT plan had the least conformal plan where the prescription
dose volume was larger than the treatment volume. In contrast, the proton plan had a CI below 1
(0.978) indicating a slight lack of coverage of the target. Although the VMAT FFF plan had the
lowest R50% value, the proton plan used the CTV volume instead of PTV volume to calculate the
index. The actual 50% dose volume is the smallest among the three plans, indicating a lower
intermediate dose to the normal tissue of the proton plan.
The dosimetry improvement from conventional VMAT to FFF VMAT was minimal,
although the FFF VMAT does have significantly less treatment time. On the other hand,
treatment plans from IMPT have an incredible advantage of normal organ sparing.9 The dose to
the lenses, optical nerves, and optic chiasm are much lower than those from the photon plans

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(Table 1). The dose to the brainstem or organs adjacent to the target is still high in the IMPT plan
due to the large spot size when utilizing pencil beam scanning in IMPT, which causes large
lateral penumbra.7 In addition, the proton beam range uncertainties were large and the beam
angle number was limited to ensure the efficiency of treatment delivery. As the proton beam spot
size continually gets smaller, the conformity and uniformity of the IMPT plans become more
comparable to photon plans. However, the range uncertainty in proton therapy is still challenging
as seen with organs proximal to the PTV such as the brainstem where the maximum dose is still
close to the prescription dose. By adding more beams, the range uncertainty can be reduced.
Conclusion
Treatment plan evaluation largely evaluates the tumor dose and the dose to normal
structures near the target. Sparing normal tissue is essential in maintaining quality of life for a
patient receiving treatment for a GBM. The plan with the greatest normal tissue sparing potential
is the proton plan. In regard to all of the OR, the proton plan was able to drastically reduce dose
to the surrounding normal tissue. In the cases of the left optic nerve, left cochlea, and left lens
there was no measurable dose delivered. In regards to the CI, HI, and ID, the VMAT FFF plan
was marginally superior compared to the VMAT and proton plans. Therefore, the IMPT plan is
the superior plan because of its ability to greatly spare normal tissue and by extension, quality of
life. To explore the feasibility of protons for GBM tumors, serious thought must be given to the
benefits of utilizing this subatomic particle and the drastic reduction in dose to the critical
structures that envelope GBM tumors. Additional research should focus not only on studying the
long term effects of treatment but also the feasibility of protons being delivered within the
designated volume. With the uncertainty of protons and robustness build in to deliver dose within
a volume it is yet to be determined how this will affect retreating a previously irradiated tumor
bed. When further studies are performed to study the feasibility of GBM tumors, it will be
necessary to include a larger patient study set to ensure accurate results with a large patient
population to represent the GBM responses. In addition, including recurrences or having a
completely separate study specifically for recurrences could be beneficial given the risk of
additional toxicities. Protons were shown to be the best plan for this GBM case, however the use
of a CTV for planning and the paradigm shift required when treating with protons would
necessitate a comparative study amongst protons only.

References
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Glioblastoma Multiforme. National

Association of Neurological Surgeons Website. http://www.aans.org/patient

%20information/conditions%20and%20treatments/glioblasto ma%20multiforme.aspx.
Updated October 2015. Accessed June 1, 2016.

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MacDonald S, Ahmad S, Kachris S,

et al. Intensity modulated radiation therapy versus three-dimensional conformal radiation

therapy for the treatment of high grade glioma: a dosimetric comparison. J Appl Clin Med
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Stupp R, Mason WP, van den Bent
MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N
Engl J Med. 2005;352(10):987-996. http://dx.doi:10.1056/NEJMoa043330
4.
Gasic D, Ohlhues L, Brodin NP, et
al. A treatment planning and delivery comparison of volumetric modulated arc therapy with
or without flattening filter for gliomas, brain metastases, prostate, head/neck and early stage
lung cancer. Acta Oncol Stockh Swed. 2014;53(8):1005-1011.
http://dx.doi:10.3109/0284186X.2014.925578
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Lohse I, Feng J, Lang S, et al. Effect

of high dose per pulse flattening filter-free beams on cancer cell survival. Radiother Oncol.
2011;101(1):226-232. http://dx.doi:10.1016/j.radonc.2011.05.072
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Fitzek MM, Thornton AF, Rabinov
JD, et al. Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for
glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg. 1999;91(2):251260. http://dx.doi:10.3171/jns.1999.91.2.0251
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Liu W, Zhang X, Li Y, Mohan R.

Robust optimization of intensity modulated proton therapy. Med Phys. 2012;39(2):1079

1091. http://doi.org/10.1118/1.3679340
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Liu W, Frank SJ, Li X, et al. PTV-

based IMPT optimization incorporating planning risk volumes vs robust optimization. Med
Phys. 2013;40(2):1-8. http://doi.org/10.1118/1.4774363
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Brown, P. Glioblastoma Multiforme
(GBM) Proton vs. Intensity Modulated Radiotherapy (IMRT). MD Anderson Cancer Center.
https://clinicaltrials.gov/ct2/show/nct01854554. Updated August, 2016. Accessed November
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Figures

Figure 1. VMAT plan isodose transverse, coronal, and sagittal views.

Figure 2. FFF VMAT plan isodose transverse, coronal, and sagittal views.

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Figure 3. Proton plan isodose transverse, sagittal and coronal views. Proton beams are shown in
dash lines.

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Tables
Table 1. Cumulative dose at a glance from all three plans.
Organ
R Lens
L Lens
R Optic Nerve
L Optic Nerve
Optic Chiasm
Brain Stem
R Cochlea
L Cochlea

Statistic
Maximum
Maximum
Maximum
Maximum
Maximum
V60
Maximum
Maximum

Quantec
2 Gy
2 Gy
55 Gy
55 Gy
55 Gy
<0.03 cc
<=35 Gy
<=35 Gy

VMAT
12.89 Gy
16.06 Gy
24.93 Gy
22.59 Gy
33.25 Gy
0
14.37 Gy
7.64 Gy

VMAT FFF
17.70 Gy
16.32 Gy
27.60 Gy
21.13 Gy
24.68 Gy
0
18.30 Gy
7.89 Gy

PROTON
0.06 Gy
0 Gy
.59 Gy
0 Gy
1.20 Gy
0
7.13 Gy
0 Gy

Table 2. Indices comparing each plan side by side.

Conformity Index

Homogeneity Index

Integral Index

VMAT

1.024

1.028

2.51

VMAT FFF

1.016

1.027

2.48

Proton

0.978

1.030

2.54