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\begin{document}

\title{Improved Organ Sparing Using Auto-Planned Stanford Volumetric Modulated
Arc Therapy for Total Body Irradiation (VMAT-TBI) Technique}



\author[1]{Nataliya Kovalchuk}%
\author[1]{Nicholas Ngo}%
\author[1]{Erik Blomain}%
\author[1]{Eric Simiele}%
\author[1]{Ignacio Romero}%
\author[1]{Richard Hoppe}%
\author[1]{Susan Hiniker}%
\affil[1]{Stanford University School of Medicine}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Purpose/Objectives:} To evaluate dosimetric differences between
auto-planned Volumetric Modulated Arc Therapy (VMAT) Total Body
Irradiation (TBI) technique and 2D AP/PA TBI technique.
\textbf{Methods:} Ten pediatric patients treated with VMAT-TBI on Varian
c-arm linac were included in this study. VMAT-TBI plans were generated
using our in-house developed and publicly shared auto-planning scripts.
For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the
institution's clinical setup with the patient positioned at extended SSD
with a compensator to account for differences in patient thickness,
50\%-transmission daily lung blocks and electron chest-wall boosts
prescribed to 50\% of the photon prescription. Clinically relevant
metrics were analyzed and compared between the VMAT and 2D plans.
\textbf{Results:} All VMAT-TBI plans achieved PTV D90\%[?]100\% of
prescription. VMAT-TBI PTV D90\% significantly increased (6.2\%\selectlanguage{ngerman}±2.4\%,
p\textless{}0.001) compared to the 2D technique, whereas no differences
were observed in global Dmax (p\textless{}0.2) and PTV V110\%
(p\textless{}0.4). Compared to the 2D plans, significant decreases in
the Dmean to the lungs (-25.6\%±11.5\%, p\textless{}0.001) and lungs-1cm
(-34.1\%±10.1\%, p\textless{}0.001) were observed with the VMAT plans.
The VMAT technique also provided additional sparing to other organs: for
12Gy prescription, kidneys Dmean of 64.7\%±3.3\%; for 2Gy prescription,
testes/ovaries (Dmean of 31.6\%±10.7\%), brain (Dmean of 74.8\%±1.6\%)
and thyroid (Dmean of 72.5±3.5\%). \textbf{Conclusions}: Superior lung
sparing with improved target coverage and similar global Dmax were
observed with the VMAT plans as compared to 2D plans. In addition,
VMAT-TBI plans provided greater dose reductions in gonads, kidneys,
brain, and thyroid.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\section*{INTRODUCTION}

{\label{introduction}}

Total body irradiation (TBI) is a well-established conditioning regimen
used in bone marrow or stem cell transplantation during which the whole
body is irradiated with the intention of eliminating malignant cells and
preventing the rejection of donor cells through immunosuppression. Even
though this regimen is effective\textsuperscript{1}, it is associated
with significant side effects including pulmonary toxicity
(approximately 25\% of patients),\textsuperscript{2,3} cataracts
(30-40\% of patients)\textsuperscript{4}, gonadal
failure\textsuperscript{5}, thyroid and kidney
dysfunction\textsuperscript{6,7} and decreased bone mineral
density\textsuperscript{8}. Based on the most recent Children Oncology
Group (COG) survey on TBI techniques\textsuperscript{9}, most
conventional AP/PA TBI techniques use partial transmission lung blocks
of non-patient-specific thickness to limit the lung toxicity. However,
lateral TBI techniques rarely incorporate lung blocks, resulting in lung
dose that is equal to or higher than the prescription dose. In addition,
inconsistent lung dose reporting, and manual monitor unit calculation in
a homogenous medium based on patient thickness measurements limit
accuracy in lung dose determination. The importance of reduction of lung
dose in decreasing the risks of pneumonitis and potentially lethal
pulmonary toxicity has been demonstrated, with recent studies have
demonstrated that mean lung doses below 8 Gy are needed to decrease lung
toxicity risks and improve overall survival\textsuperscript{10}.

The Children's Oncology Group survey of 152 COG institutions on the
practice patterns in pediatric TBI in 2020-21 found that 100\% of
physician respondents were interested in refining the conventional TBI
techniques to lower lung dose and 75\% of physicians were interested in
implementing VMAT or Tomotherapy TBI\textsuperscript{9}. But, as shown
by the survey, the supply does not meet the demand: only 14\% of
institutions adapted VMAT-TBI and Tomotherapy TBI.

Several studies showed the benefit of modern treatment planning and
treatment delivery approaches to TBI, including helical
tomotherapy\textsuperscript{11-12} or volumetric modulated radiation
therapy (VMAT)\textsuperscript{13-15} allowing for superior organ
sparing and more comfortable patient positioning during treatment.
However, these treatment techniques require expertise and special
equipment, which has limited their accessibility, and relatively little
data regarding dosimetric comparisons has been reported. We have
developed the Stanford auto-planned VMAT-TBI
technique\textsuperscript{13,16-17} and shared the auto-planning scripts
with the public to make VMAT-TBI more wide-spread
(https://github.com/esimiele/VMAT-TBI). Our technique was also included
as a basis for VMAT-TBI methodology among 2D and Tomotherapy TBI
techniques on the Children Oncology Group (COG) ASCT2031 trial. In this
work, we report the comparison between our auto-planned VMAT-TBI for
myeloablative and nonmyeloablative regimens and our 2D-conventional TBI
technique. These results are relevant for institutions intending to
switch from 2D to VMAT-TBI technique and can be beneficial for creation
of future analysis and dosimetric correlatives for Children Oncology
Group (COG) ASCT2031 trial.

\textbf{METHODS AND MATERIALS}

Ten pediatric patients (age range, 3 -- 17 y.o.) treated with the
VMAT-TBI technique on the Varian TrueBeam from November 2019 to August
2020 were included in this IRB approved study. Patients were treated
with either non-myeloablative (2 Gy in one fraction) or myeloablative
(12 Gy in six fractions) regimens. Corresponding 2D plans replicating
our current clinical setup with lung blocks and chest-wall boost were
created for all ten patients for dosimetric comparison between the 2D
and VMAT techniques.

For VMAT-TBI, patients were simulated head-first supine (HFS) position
in a CIVCO long vac-lok bag positioned on the in-house developed
rotational platform. Patients' necks were extended resting on the
AccuForm cushion (CIVCO) neck support, arms tightly clasped straight
alongside the body, and the CIVCO knee fix and/or feet fix were placed
under patient's knees for comfort and leg position reproducibility. The
in-house-developed auto-planning script within Eclipse v15.6 Application
Programming Interface (API) was used for treatment
planning\textsuperscript{16}. The VMAT plans were auto-generated with
three isocenters (head, chest/abdomen, pevis/legs) in HFS position.
Additional AP/PA plans with 1 to 2 isocenters in the feet-first supine
(FFS) position were used if patient height exceeded 115 cm (due to the
longitudinal table limit in HFS position). Upper-body VMAT plans using 6
MV or 10 MV were optimized with all isocenters included in one plan with
at least~2 cm overlap between the fields. The AP/PA Upper Leg plan was
used a baseline dose in the optimization to homogenize the dose
distribution near the matchline area. The auto-feathering optimization
option was turned on to create smooth dose gradients in the
fields'~overlapping areas and to prevent extreme dose heterogeneity in
the event of larger setup variations.~ The VMAT plans were optimized
and normalized to achieve at least 90\% coverage of the whole body PTV
with the prescription dose. The PTV volume was created by cropping 3 mm
from skin and critical normal tissues.

For each VMAT-TBI plan, a simulated 2D plan was developed in Eclipse
based on the VMAT-TBI CT scan. The 2D plan fields were setup for AP/PA
technique at an extended SSD (\textasciitilde{}608 cm), collimators at
45\selectlanguage{ngerman}° and 135°, field sizes set to 40 x 40 and 15 MV energy. Umbilicus was
used as the isocenter. Screen-to-skin distance, separation and off-axis
measurements that are typically acquired during clinical setup were
measured based on the CT scan. The compensator layers were re-created on
the CT scan to homogenize dose distribution based on the following
midline points: head, chin, neck, suprasternal notch (SSN), xiphoid,
umbilicus, hip/pubis, thigh, knee, calf, and ankle. Lung blocks were
generated using the lung contour contracted by 1 cm (lungs-1cm) and 1 cm
below clavicle with the constant thickness of 2.5 cm of Cerrobend for
every patient. The block transmission measurements in the middle of 10
cm thick lung slab sandwiched in-between two 4-cm thick solid water
slabs was 50\% for 15 MV beam. Electron chest wall (CW) boost fields
were created for all patients prescribed to 50\% of TBI photon
prescription to depth of maximum dose. The accuracy of the dose
calculation was verified using the ion chamber measurement in the
phantom composed of the lung slab sandwiched between the solid water
slabs.

The clinically relevant metrics in this study, including plan global
Dmax, PTV D90\%, PTV V110\%, lungs and lungs-1cm Dmean, were analyzed
and compared between the VMAT-TBI and simulated 2D plans. For gonadal
sparing comparison, the VMAT-TBI plans were compared to 2D plans for a
girl (Patient 4) and a boy (Patient 3) assuming 5 cm lead shield for
testes/ovaries in front of the patient with 5 mm margin. All dosimetric
comparisons between the VMAT and 2D plans were made with the dose
expressed as a percentage of the prescription dose and the volume
expressed as a percentage of the PTV volume. Paired t-test was used to
compare the dosimetric indices between the VMAT and 2D TBI plans with
p-values less than 0.05 considered to be statistically significant.

\textbf{RESULTS}

Table 1 shows the patient and dosimetric characteristics for VMAT-TBI
plans. The mean global Dmax was 118.8\%±4.0\% and the PTV V110\% ranged
from 0.1\% to 5.3\%. All lung Dmean values were below 7.2 Gy and
lungs-1cm Dmean was 36.5\%±4.8\%. For patients that required kidney
sparing, the average kidney Dmean was 67.5\%±4.0\% of the prescription
dose. Achieved testes/ovaries Dmean and Dmax were 0.66±0.07Gy and
0.90±0.03Gy, respectively. The average brain-1 cm Dmean was
55.9\%±3.7\%. Thyroid sparing was performed for two patients with Dmean
= 1.45Gy±0.07Gy. Lenses were spared to 90\% of prescription for all
patients.

Table 2 shows the comparison between VMAT and 2D plans for target and
lung dosimetric indices. The target coverage, PTV D90\%, was
significantly superior for VMAT plans as compared to 2D plans with a
mean difference of 6.1\%±2.4\%, p\textless{}0.001. No significant
difference was observed between the VMAT and 2D plans for global Dmax
and PTV V110\% (mean differences of -2.0±6.7\% and 0.0±2.9\%,
respectively). With the 2D plans, lungs received an average of 80.6\% of
the prescription dose (range: 72.0\% - 90.0\%). The average lungs-1cm
Dmean for 2D TBI plans was 70.6\%±8.1\%.

The mean lungs and lungs-1cm dose for VMAT-TBI plans was significantly
lower as compared to the 2D plans: reductions of -25.6\%±11.5\% and
-34.1\%±10.1\%, respectively, were observed (p\textless{}0.001). In
addition, VMAT-TBI plans spared kidneys, brain, thyroid, testes/ovaries,
and lenses, while 2D plans delivered the prescribed dose to those
organs.

Gonadal sparing between 2D and VMAT-TBI plans was compared for two
patients (female - patient 4 and male -- patient 3). For patient 4,
Figure 1 shows the dose distribution comparison between the 2D and VMAT
plans. The ovaries were spared to mean dose of 65.8 cGy and maximum dose
of 87.8 cGy with the VMAT plan. Although gonadal sparing would not be
practical with the 2D approach due to difficulties in ovary localization
in the standing AP/PA treatment in the booth, the 2D plan was created
for dosimetric comparison. With the 2D plan, the ovaries received 147.1
cGy Dmean and 150.0 cGy Dmax (prescription dose of 2 Gy). Figure 2 shows
the DVH comparison between the VMAT and 2D Conventional TBI plans for
patient 3. The maximum and mean doses to the testes were 71.9 cGy and
44.7 cGy, respectively, for the VMAT plan compared to 156.4 cGy Dmax and
136.2 cGy Dmean with the 2D plan.

All ten patients tolerated treatment well. The image guidance included
CBCT at chest isocenter and MV portal images for the consequent
isocenters. The average treatment time was 44.4 min, range: 25.1 min to
57.4 min. Three patients were treated under anaesthesia, and seven
remaining patients were watching movies during radiotherapy.

\textbf{DISCUSSION}

VMAT-TBI is a promising modality with increasing clinical utilization.
In this study, we analyzed organ sparing using the VMAT technique in
comparison to the conventional 2D technique. 2D and VMAT plans were
generated for the same patients and directly compared. The VMAT-TBI
treatment was well tolerated and significant improvements in target
coverage and lung sparing were achieved with the VMAT technique versus
the 2D comparison plans. In addition, the VMAT technique provided the
opportunity to spare other organs, such as kidneys, gonads, brain,
thyroid, lenses when deemed appropriate. Other benefits of using
VMAT-TBI technique are more comfortable patient positioning lying down,
ability to treat TBI under anesthesia, more accurate dose calculation
and image-guided treatment delivery, and the ability to treat TBI
patients in a small vault.

The 2D conventional technique with lung blocks is the current standard
of care. At our institution, lung blocks are created to allow, on
average, 50\% transmission at mid-lung point for an average-size
patient. The size of the blocks are drawn to match the lungs--1cm
contour and 1 cm below clavicle to enable dose coverage to the bones
(clavicle and ribs). Therefore, a good portion of the lungs will still
receive significant dose (\textgreater{}50\% of the prescription dose).
In addition, there is a dose contribution from chest wall boosts, adding
up to a mean lung dose of 80.6\% of the prescription.

Although the study improves upon the kidneys, brain, thyroid, lenses
sparing, it is unclear that this benefit will be clinically meaningful,
although the early outcomes and toxicity report is
promising\textsuperscript{18}. Despite this possibility, our institution
generally abides by the ALARA (as low as reasonably achievable)
principle, which would argue that lower organ doses are desirable in and
of itself for patients without active disease; however, further studies
will be necessary to elucidate the exact dose response of this lung
toxicity at these lower observed doses.

\textbf{CONCLUSION}

VMAT-TBI is a modern alternative to conventional 2D-TBI treatment,
offering superior lung sparing with superior target coverage and similar
global Dmax. In addition, VMAT-TBI plans using auto-planning scripts
provided significant dose reductions in gonads, kidneys, brain, thyroid
and lenses.

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Figure 1: Dose distribution on the coronal view for patient 4 with
gonadal sparing for the 2D plan (left) and VMAT (right).

Figure 2: DVH comparison for the VMAT and 2D TBI treatment techniques
for patient 3.\selectlanguage{english}
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\textbf{Hosted file}

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