BJR
Published by the British Institute of Radiology
Received: Revised: Accepted:
04 October 2019 05 December 2019 23 December 2019
Cite this article as:
Wang T, Zhou J, Tian S, Wang Y, Patel P, Jani AB, et al. A planning study of focal dose escalations to multiparametric MRI-­defined
dominant intraprostatic lesions in prostate proton radiation therapy. Br J Radiol 2020; 93: 20190845.
Proton Therapy special feature: Full Paper
A planning study of focal dose escalations to
multiparametric MRI-­defined dominant intraprostatic
lesions in prostate proton radiation therapy
Tonghe Wang, PhD, Jun Zhou, PhD, Sibo Tian, MD, Yinan Wang, MS, Pretesh Patel, MD, Ashesh B. Jani, MD,
Katja M. Langen, PhD, Walter J. Curran, MD, Tian Liu, PhD and Xiaofeng Yang, PhD
Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta 30322, Georgia
Address correspondence to: Dr Xiaofeng Yang
E-mail: ​xiaofeng.​yang@​emory.​edu
Objectives: The purpose of this study is to investigate
the dosimetric effect and clinical impact of delivering a
focal radiotherapy boost dose to multiparametric MRI
(mp-­MRI)-­defined dominant intraprostatic lesions (DILs)
in prostate cancer using proton therapy.
Methods: We retrospectively investigated 36 patients
with pre-­treatment mp-­MRI and CT images who were
treated using pencil beam scanning (PBS) proton radia-
tion therapy to the whole prostate. DILs were contoured
on co-­ registered mp-­ MRIs. Simultaneous integrated
boost (SIB) plans using intensity-­ modulated proton
therapy (IMPT) were created based on conventional
whole-­prostate-­irradiation for each patient and opti-
mized with additional DIL coverage goals and urethral
constraints. DIL dose coverage and organ-­at-­risk (OAR)
sparing were compared between conventional and SIB
plans. Tumor control probability (TCP) and normal tissue
Introduction
Radiation therapy for localized prostate cancer, as delivered
using external beam radiotherapy (EBRT), brachytherapy,
or a combination thereof, treats the entire prostate gland
to a single prescribed dose level since prostate cancer is
presumed to be multifocal.1–5 However, histopathological
studies have commonly identified dominant intraprostatic
lesions (DILs) in prostate cancer.6 DIL is the area within
the prostate containing the largest and/or highest grade of
cancer lesion.7 One or a few DILs are responsible for the
majority of the tumor burden despite typically representing
less than 10% of the total gland volume,6 and are the most
common sites of recurrence after radiation therapy.8,9
Studies have shown that escalating the dose to DILs
when irradiating the whole prostate has the potential to
increase tumor control probability (TCP) with acceptable
toxicity.10–13 Thus, dose escalation to DILs during radiation
© 2020 The Authors.
https://​doi.​org/​10.​1259/​bjr.​20190845
complication probability (NTCP) were estimated to eval-
uate the clinical impact of the SIB plans.
Results: Optimized SIB plans significantly escalated the
dose to DILs while meeting OAR constraints. SIB plans
were able to achieve 125, 150 and 175% of prescription
dose coverage in 74, 54 and 17% of 36 patients, respec-
tively. This was modeled to result in an increase in DIL
TCP by 7.3–13.3% depending on ‍α/β ‍and DIL risk level.
Conclusion: The proposed mp-­ MRI-­guided DIL boost
using proton radiation therapy is feasible without
violating OAR constraints and demonstrates a potential
clinical benefit by improving DIL TCP. This retrospective
study suggested the use of IMPT-­ based DIL SIB may
represent a strategy to improve tumor control.
Advances in knowledge: This study investigated the
planning of mp-­MRI-­guided DIL boost in prostate proton
radiation therapy and estimated its clinical impact with
respect to TCP and NTCP.
treatment is an approach of particular clinical and research
interest.14
Although radiotherapy boost to DIL may improve disease
control, it may come at the cost of increased toxicity of
surrounding normal tissue such as bladder, urethra, and
rectum. The dosimetric effect and potential clinical impact
of different treatment schemes for prostate DIL dose esca-
lation has been reported for both photon EBRT and high-­
dose rate (HDR) brachytherapy.12,14,15 For photon EBRT,
intensity-­modulated radiation therapy (IMRT)/volumetric-­
modulated arc therapy (VMAT) techniques for conventional
fractionation, moderate hypofractionation, and stereotactic
ablative radiation therapy (ultra-­hypofractionation) have
been proposed.12,15–20 The boost dose can be escalated to
approximately 125% of the whole prostate prescription
dose, covering 95% of DIL volume, before organs-­at-­risk
 BJR
(OARs) constraints are violated. DIL dose escalation can also
be implemented in HDR brachytherapy. Recent studies have
demonstrated the potential of multiparametric MRI (mp-­MRI)-­
guided DIL focal boost HDR brachytherapy based on CT or tran-
srectal ultrasound (TRUS) images.14,18 Coverage to 150% of the
prescription dose can be achieved for the DIL without violating
dose constraints by standard peripheral loading with additional
needle(s) within the DIL. The relatively higher boost dose can
be attributed to the interstitial property of brachytherapy that
avoids entrance dose and provides more conformal dose distri-
bution when compared with photon EBRT.21,22 Using HDR for
focal boost may be technically challenging when implanting
individual needles. The mp-­MRI images need to be deformably
registered with real-­time TRUS images in the operating room in
order to propagate the mp-­MRI-­defined DIL contour to TRUS
images for needle guidance. Such deformable registration is chal-
lenging in that it involves two imaging modalities with different
contrast information and it is required to have high-­ speed
performance to enable real-­time guidance.23
Proton radiation therapy has been an emerging treatment
modality for prostate cancer. Due to favorable dosimetric prop-
erties related to the Bragg Peak, and virtually no exit dose, it
may have better clinical outcomes when compared with photon
EBRT.24,25 DIL dose escalation using proton radiation therapy is
promising by utilizing its sharp dose gradient at the distal end of
beam. Intensity modulatedproton therapy (IMPT) using pencil
beam scanning (PBS) has the ability to selectively boost DIL dose
by applying more weight to the spots contributing to it. Recent
studies comparing photon and proton radiation therapy in DIL
simultaneous integrated boost (SIB) plan have demonstrated
that passive scatter proton therapy and IMPT have comparable
or superior DIL boost dose distributions over IMRT/VMAT/
helical tomotherapy, respectively, with both having better OAR
sparing.26–28 However, the dosimetric differences between
proton DIL SIB plans and conventional non-­boost whole pros-
tate proton plans, which is important for clinicians in predicting
disease control and toxicity, have not been studied.
In this study, we investigated the planning of IMPT-­based boost
to the DIL, and compared it to conventional whole-­prostate
proton irradiation. The purpose of this study was to determine
the achievable level of DIL dose escalation, its estimated impact
on tumor coverage and dose to OARs, and its modeled clinical
impact. In a cohort of 36 patients, we retrospectively evaluated
the dose coverage of mp-­MRI-­defined DILs in IMPT-­based SIB
treatment plans, and compared its OAR sparing and prostate
coverage against conventional plans. TCP and normal tissue
complication probability (NTCP) were estimated to further eval-
uate the clinical impact of the SIB plans.
Methods and materials
Patients
We retrospectively identified 36 patients who were treated using
PBS proton therapy at a single institution. Median age was 69.5
years (range 49–83), clinical T classification were T1c to T3b,
median PSA was 8.4 (range 3.1–40). Median MR-­based pros-
tate volume was 53.0 cc (range 24.1cc-214.0cc), and median
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Wang et al
Gleason score was 7 (range 6–9). The numbers of patients in
ISUP grade group from 1 to 5 are 5, 13, 10, 5, and 3. Among
the 36 patients, 24 patients had androgen deprivation (ADT).
All patients received 70 Gy RBE dose (assuming a proton RBE of
1.1) in 28 fractions to the prostate and proximal seminal vesicles
using pencil beam scanning proton beams. Institutional review
board approval was obtained; informed consent was not required
for this Health Insurance Portability and Accountability Act
(HIPAA) compliant retrospective analysis.
Image acquisition and contouring
Recent advances in mp-­MRI techniques have shown its efficacy
in identifying DILs,29–32 and its reliability, accuracy, and repro-
ducibility as validated against reference pathology.33–36 Multiple
studies have supported its use for image guidance in treatment
planning of EBRT and HDR brachytherapy for DIL boosts.37,38
In our study, mp-­MRI scans, which included T1W, T2W and
diffusion-­weighted MRI (DWI), were acquired on the same
day as the planning CT on an Aera (Siemens, Germany) 1.5T
scanner. T1W MRI used gradient recalled (GR) sequence with
10° flip angle, repetition time (TR) 6.9 ms, echo time (TE) 2.39
ms, echo train length 2, and 1.4 mm pixel size and slice thickness.
T2W MRI used spin echo (SE) sequence with 170° flip angle,
TR/TE = 1600 ms/166 ms, echo train length 76, 1.0 mm pixel
size, and slice thickness. DWI MRI used a single-­shot SE-­echo
planar imaging (EPI) with TR/TE = 5000 ms/61 ms, 1.8 mm pixel
size, and 3.5 mm slice thickness. Apparent diffusion coefficient
(ADC) maps were then generated with b-­value = 800 s/mm2 for
analysis. Planning CT images were acquired with a SOMATOM
Definition Edge (Siemens, Germany) with 120 kVp, 0.5 s rotation
time, 500 to 650 mA tube current, 1.0 mm pixel size, and 1.5 mm
slice thickness.
Each patient’s original approved clinical plan included a deform-
able registration between mp-­MRIs and CT images. The whole
prostate contour was delineated on MRs and propagated to CT
images. The bladder, rectum, left and right femoral heads were
contoured on CT images. Eleven of the 36 patients had large
bowel contours. For our dose escalation study, DILs contours
were based on the above MRI images to reach a consensus
between two radiation oncologists using VelocityAI 3.2.1 (Varian
Medical Systems, Palo Alto, CA). An example of DIL delineation
on T2W MRI and ADC map is shown in Figure 1. Each patient
has one DIL defined within the prostate. The average DIL volume
among the 36 patients was 0.63 ± 0.53 cc (range 0.09–2.27cc).
The urethra was also contoured on MRIs for each patient. Both
DIL and urethra contours were propagated from MRIs to plan-
ning CTs for SIB planning.
Treatment planning study
Two opposing lateral beams were used for both the conven-
tional whole-­prostate-­irradiation plans and the proposed DIL
SIB plans. While conventional plans were optimized with single
field optimization (SFO) technique, DIL SIB plans were opti-
mized with multifield optimization (MFO) technique to facilitate
DIL coverage and OAR sparing. Both the conventional whole-­
prostate-­irradiation plans and the proposed DIL SIB plans were
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 Multiparametric MRI-­guided Dose Boost in Prostate Proton Therapy BJR

Figure 1. Example of DIL delineation on T2W MRI (left) and apparent diffusion coefficient map (right).

robustly optimized with 6 mm setup uncertainty in all directions
except for 0 mm laterally, which was covered by the 3.5% range
uncertainty. Both plans were normalized to achieve whole pros-
tate coverage at 100% of the prescribed dose to 98% of the CTV
(V100 = 98%), with hard OAR dose constraints based on RTOG
0415 Arm 2.39 Additional optimization goals for OAR doses were
used as constraints for both plans if further normal tissue sparing
was feasible (Table 1). DILs and urethra were not considered as
part of conventional plan optimization. DIL SIB plans were reop-
timized as simultaneous boosts to the conventional plan based
on additional DIL coverage. The goal for DIL dose coverage
was D95 ≥ 140% and D90 ≥200% of the prescribed dose while
meeting the above CTV/OAR constraints, as well as an addi-
tional urethra constraint (maximum dose ≤82 Gy (117%)).

In the following context, we refer to the above two scenarios

Table 1. Organ-­ at-­
risk dose constrains and additional opti-
mizing goals for both the conventional whole-­ prostate-­
as “conventional” and “SIB,” respectively. Treatment planning
irradiation plans and the proposed DIL SIB plans was performed using Raystation 8B (RaySearch, Stockholm,
Sweden). Clinically relevant dose-­ volume histogram (DVH)
CTV V100 = 98% metrics were selected for comparison between the two scenarios
Dose to 15% (D15) for prostate with DIL cropped, DIL, bladder, rectum, femoral
≤79 Gy heads, large bowel, and urethra. A student t-­test was performed
D25 ≤ 74 Gy between “Conventional” vs “Boost” to evaluate the significance
of corresponding DVH metric changes. A p-­value less than 0.05
D35 ≤69 Gy
was considered statistically significant.
Bladder D50 ≤64 Gy
D15 ≤74 Gy
TCP and NTCP modeling
D25 ≤ 69 Gy The clinical impact of SIB plans was evaluated in terms of TCP
D35 ≤64 Gy and NTCP. TCP was calculated using the LQ-­Poisson Marsden
model,40 and NTCP was calculated for bladder, rectum,
Rectum D50 ≤59 Gy
CTV/OAR and urethra by Lyman-­ Kutcher-­ Burman (LKB) model with
constraints Penile Bulb Mean ≤ 51 Gy Niemierko’s equivalent uniform dose model.41–43 Equations and
Additional DIL a
D95 ≥140% details of TCP and NTCP calculation were done as previously
optimizing goals
D90 ≥200%
reported.14 All doses used for DVHs were converted to equiva-
lent dose in 2 Gy/fraction (EQD2) based on the linear quadratic
Bladder Max <71.5 Gy model in our calculation.44,45 TCP calculations assume the
Rectum Max <71 Gy population of clonogenic cells (with initial cell density ‍ρclon‍ and
Femoral head Max <40 Gy constant ‍α/β ‍ ratio) with radiosensitivity (‍α‍) varies according
a
to a Gaussian distribution with mean ‍ᾱ‍and standard deviation
Urethra Max <82 Gy
‍σα‍. To evaluate the possibility of varying tumor radiation resis-
a
Used in SIB plan only tance, we investigated two different ‍α/β ‍ratios (1.5 Gy and 3 Gy)

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Table 2. Tumor control probability parameters

‍ρclon
‍ᾱ‍(Gy−1) −1
(‍ cc−1)
α
‍β (Gy)
‍ ‍σα‍(Gy )
1.5 Prostate-­DILa 0.155 0.058 4
‍6.2 × 10 ‍
DIL (high risk) 0.155 0.058
1‍ × 107‍
DIL (very high risk) 0.155 0.058 8
‍2.8 × 10 ‍
3 Prostate-­DIL 0.217 0.082 4
‍6.2 × 10 ‍
DIL (high risk) 0.217 0.082
1‍ × 107‍
DIL (very high risk) 0.217 0.082 8
‍2.8 × 10 ‍
Prostate-­DIL, Prostate with DIL cropped.

for prostate and DIL, each of which corresponds to a different
set of parameters (‍ᾱ‍ and ‍σα‍) as previously reported.12,46 Note
that EQD2 was also calculated separately for each ‍α/β ‍ratio. For
all ‍α/β ‍ ratios, ‍ρclon‍ in non-­DIL was assumed to be ‍6.2 × 104‍ /
cc, and in DIL was assumed to be 1‍ × 107‍ /cc and ‍2.8 × 108‍ /cc
to represent lesions of high and very high risk, respectively, as
previously reported.12,47,48
NTCP calculations involve OAR-­dependent parameters T ‍ D50‍, m
‍ ‍
and n‍ ‍ chosen according to existing studies. The ‍α/β ‍ ratios were
only used in EQD2 conversion, and were assumed to be three if
not explicitly listed.12,49,50Parameters for TCP and NTCP calcu-
lation are listed in Tables  2 and 3. The calculation was imple-
mented by Biosuite software.46 NTCPs of left and right femoral
heads were averaged.
Results
The dose distributions of conventional and SIB plans were
compared side-­by-­side-­for a representative patient (Figure  2).
In conventional plan, the DIL received essentially the stan-
dard prescription dose (Figure 2(a)). The SIB plan successfully
achieved the DIL V175 coverage (V175 = 98.5%) with increased
dose on femoral heads (Figure 2(b) and (c)). The DVH compar-
ison of this patient is shown in Figure 3. The DVH of DIL in the
conventional plan overlapped with that of prostate in the conven-
tional plan. The dose deposited to the DIL in the SIB plan was
significantly higher than that of the conventional plan, with an
increased hotspot in the non-­DIL prostate region. Qualitatively,
DVH curves of the SIB plan were similar to that of the conven-
tional plan for OARs, with exception of the femoral heads.
Comparative DVH metrics for prostate and DIL between the
two plans among 36 patients are summarized in Table 4. For the
non-­DIL prostate, although minimal differences were found in
prescription dose coverage, the volume of high dose (>110% of
prescription dose) spill was about 20% in the SIB plans. Figure 4
shows the percentage of patients receiving various levels of
coverage to the DIL in the SIB plan. 74, 54, and 17% of patients
had escalated doses to V125 > 95%, V150 > 95%, V175 >95%
of DIL, respectively. These results are consistent with the above
qualitative findings and quantitatively demonstrate the dose
coverage improvement to the DIL in SIB plans.
Similarly, comparison of OARs is summarized in Table  5. All
the SIB plans met OAR constraints and urethra V90Gy = 0. The
largest discrepancy was found in maximum dose to the femoral
heads. Increases in DVH metrics of bladder and rectum received
were within 3% of prescription dose. There was no statistically
significant difference between the two plans for large bowel
D0.03cc and penile bulb Dmean.
The TCP and NTCP results are summarized in Table  6.
Overall, the SIB plans significantly increased the TCP of DILs
compared to the conventional plans, while maintaining the
TCP of non-­DIL prostate region. The greatest TCP improve-
ment was seen for very high risk DILs with ‍α/β = ‍ 3 (13.3%),
and the least was for high risk DILs with ‍α/β = ‍ 1.5 (7.3%).
NTCP results for bladder and rectum had no significant differ-
ences between the two plans. For urethra and femoral heads,
the SIB plans showed 2.3% (p < 0.05) and 0.6% (p < 0.05)
higher NTCP, respectively.

Table 3. Normal tissue complication probability parameters

α
‍β (Gy)
‍ ‍ D50‍(Gy)
T ‍ ‍
m ‍‍
n Source
Bladder Contracture/volume loss 3 80 0.11 0.5 Burman, et al.51
Rectum Grade 2 + late toxicity or rectal 3 76.9 0.13 0.09 Michalski, et al.52
bleeding
Urethra Stricture requiring urethrotomy 5 70.7 0.37 0.3 Panettieri et al.53
within 4 years after RT completion
Femoral Heads Necrosis 3 65 0.12 0.25 Burman, et al.51

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Figure 2. Dose distributions of (a) conventional, (b) simultaneous integrated boost plans and (c) dose difference map = (b)-(a).
Prostate and dominant intraprostatic lesion are indicated by red and blue contours.
Discussion
In this study, we investigated the planning of mp-­MRI-­defined
DIL dose escalation using IMPT-­based proton radiation therapy,
and estimated its clinical impact in terms of TCP and NTCP. SIB
plans significantly escalated the dose to DILs while respecting
prostate coverage and OAR constraints. DIL dose boost to 125,
150, and 175% of prescription dose could be achieved in 74, 54,
and 17% of 36 patients, respectively. This resulted in an increase
from conventional plan in DIL TCP by 7.3–13.3% depending on
‍α/β ‍and risk level.
DIL dose escalation using proton beam was first proposed by
Schulte et al.54 A number of follow-­up studies have since been
published.26–28,55 These studies focused on comparing proton
to photon-­based plans (EBRT or HDR brachytherapy) in terms
of achievable escalated dose and OAR sparing. DIL boost dose
coverage varied from study to study, but generally was able to
be pushed up to about 130% of prescription dose. However,
these studies differ from our study in several ways, such that a
direct comparison in feasible boost dose is not possible. Only
bladder and rectum were considered in plan design/optimiza-
tion in several studies.26,27,55 Others28 did include other common
OARs (penile bulb, femoral head, etc.) in planning, but used a
less common five-­oblique-­field setup. Neither of these dosi-
metric studies was closely based on the clinical workflow for
prostate cancer proton treatment planning. Additionally, the
urethra was not contoured, and thus unable to be used as a dose
limiting structure in these prostate DIL boost studies (except
Figure 3. The DVHs of patient in Figure 1 of conventional and
simultaneous integrated boost plans. Prostate-­DIL = Prostate
with DIL cropped.
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BJR
for reference28 which assumed it to be the center of prostate on
each slice). In conventional planning, it was widely assumed that
the prostatic urethra received the uniform prescription dose;56
however, the urethra in SIB plans is likely to have substantial
changes in the volume receiving more than 100% of the prescrip-
tion dose, depending on boost dose and distance from DIL.
Urethral hotspots are directly related to late urinary toxicity,
including urethral strictures.57 Moreover, the limited patient
sample sizes (ranging from 7 to 12) of prior studies also weakens
the validity of their conclusions.
In this study, our purpose was to determine the feasible DIL dose
boost and the resulting dosimetric changes to OARs. SIB plans
were largely based on the conventional plan with the DIL and
urethra added as additional optimizing constraints. The compar-
ison between boost and conventional plans demonstrated both
the dosimetric benefits for DIL coverage and also the dose
increase to OARs, which provides a benchmark to clinicians
about the relative advantage and risks of treating using a proton-­
based boost. To overcome other limitations discussed above, we
included all common OARs (including urethra) in planning and
evaluation, and an intermediate size of patients was involved in
this study.
A potential tradeoff of SIB plans is the high dose spill from the
DIL, and the increased high dose (≥110% of prescription dose)
volume in the non-­DIL prostate. However, the necessities of
enforcement on dose homogeneity in target volume in conven-
tional fractionated EBRT are debatable.58 Ablative doses have
proven effective for prostate tumor control,59 and studies have
shown that dose heterogeneity may be beneficial in localized
prostate cancer for its improvement in OAR sparing.60 Thus, the
hotspot in non-­DIL prostate can be accepted or even preferred.
Another consequence from the hotspot in non-­DIL prostate
region is the increased urethral dose. Reducing the urethra dose
is an important optimization goal in our treatment planning. In
HDR brachytherapy, a commonly used urethra tolerance dose is
<125% of prescription dose (13.5 Gy ×2).61 For the fractionation
scheme in our study, it is equivalent to 90 Gy, assuming ‍α/β =
‍ 5 in
biological effective dose conversion.60 Table 4 shows that all the
patients in our SIB plan met this constraint (V90Gy = 0). Notably,
the absolute urethra NTCP values are overestimated using the
current parameters. They are much higher than previously
reported rates of urethral stricture after EBRT (2%–3%).62–64 As
discussed previously, one potential reason is the lack supporting
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 BJR Wang et al

Table 4. Mean ± Std of DVH metrics of prostate and dominant intraprostatic lesion for both plans among 36 patients

Prostate-­DIL DIL
D90(%) V100(%) V110(%) D90(%) D95(%) V100(%) V125(%) V150(%) V175(%)
Conventional 100.7±0.1 98.2±0.4 0 101.3±0.7 101.1±0.7 98.6±6.1 0 0 0
SIB 100.4±0.1 98.0±0.1 20.4±8.5 155.2±24.6 147.3±25.2 99.9±0.3 93.0±17.2 81.8±28.5 64.0±33.9
P-­values <0.001 0.023 <0.001 <0.001 <0.001 0.203 <0.001 <0.001 <0.001

Prostate-­DIL, Prostate with DIL cropped.

clinical evidence for urethral NTCP LKB modeling parame-
ters.14 The parameters of urethra used in this study and refer-
ence14 were cited from Panettieri et al, where the clinical studies
of these parameters are not provided.53 Another set of NTCP
parameters of urethra was provided in another study without
additional sources.65 To the best of our knowledge, these are the
only two publications presenting urethra NTCP LKB modeling
parameters. Thus, the reliability of the NTCP calculation may be
affected and therefore should be viewed with caution.
The largest DVH change among OARs was seen in Dmax of
femoral heads (about 12 Gy), which was directly caused by the
increased entrance dose from the two opposing lateral beams as
shown in Figure 2. Considering only an absolute NTCP increase
of 0.6%, it may be clinically acceptable after careful judgment.
Future studies would investigate the dependence of OAR toxicity,
especially femoral heads Dmax, on the size and location of DIL.
The closest OAR to the DIL would be usually more affected by the
dose spilled out from DIL. Considering that two opposing lateral
beams were used for both the conventional whole-­ prostate-­
irradiation plans and the proposed DIL SIB plans as well as more
dose uncertainty at the end of beam than the lateral, femoral
head would be more sensitive to DIL location than other OARs.
Such study may predict the upper limit of dose escalation and
the toxicity of femoral heads before plan optimization. Moreover,
the use of non-­lateral proton beams in treating prostate has been
shown feasible with dosimetric advantage especially for hip.66
Such benefit is expected for DIL SIB plan, while dose sparing
in other OARs may be compromised by the larger range uncer-
tainty caused by bladder/rectum filling.
TCP/NTCP models are used to estimate the clinical impact of the
SIB plans. TCP/NTCP models serve as a surrogate to reflect the
potential treatment outcome/toxicity from the change of DVHs.
The limitations of using TCP/NTCP models have been presented
in several studies.67–69 In this study, specifically, the choice of the
model parameters may change the TCP/NTCP scores. Thus the
absolute values of TCP/NTCP are not proper to be applied for
planning and decision-­making due to the uncertainty of model
parameters.
Among the 36 patients in this study, 24 patients had ADT.
ADT has been shown to reduce the conspicuity of lesion in
mp-­MRI,18,70,71 which may affect the accuracy of DIL target
delineation. In order to have an accurate DIL contour for escala-
tion planning, it may be more appropriate to contour DIL based
on the diagnostic mp-­MRI before ADT. Image registration then
would be required to propagate the DIL contour from diagnostic
mp-­MRI to planning CT, and its accuracy becomes essential to
the treatment planning accuracy. Recently, sophisticated image
registration methods between MRI and CT has been proposed
and validated in accuracies,72,73 which may address this difficulty
in clinical application.
In this study, we evaluated the planning of a DIL boost only for
patients with a single DIL. Boosting two anatomically distinct

Figure 4. Percentage of patients receiving different dominant intraprostatic lesion dose coverage (125%, 150% and 175% prescrip-
tion dose covering >95%, 90–95%, 80–90%, or 0–80% of DIL volume) in simultaneous integrated boost plan.

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Table 5. Mean ± Std of DVH metrics of OARs in different plans among all 36 patients

Bladder Rectum
D15(Gy) D25(Gy) D35(Gy) D50(Gy) D15(Gy) D25(Gy) D35(Gy) D50(Gy)
Conventional 29.7 ± 20.4 13.4 ± 15.0 5.9 ± 9.0 1.8 ± 3.3 36.0 ± 18.0 21.8 ± 14.5 12.1 ± 9.3 4.7 ± 3.9
SIB 32.0 ± 21.4 14.9 ± 16.5 6.8 ± 10.5 2.0 ± 4.0 35.6 ± 19.4 22.8 ± 16.3 13.2 ± 10.7 5.2 ± 4.3
P-­values <0.001 <0.001 0.008 0.053 0.525 0.017 0.006 0.008
Urethra Large Bowel Penile Bulb Femoral head (L) Femoral head (R)
V90Gy(cc) D10(Gy) D0.03cc (Gy) Dmean Dmax Dmax
Conventional 0 71.8 ± 0.1 35.6 ± 30.4 8.6 ± 7.1 32.0 ± 1.3 31.5 ± 0.9
SIB 0 75.3 ± 2.6 35.8 ± 30.1 8.6 ± 5.6 44.2 ± 2.2 44.2 ± 2.2
P-­values N/A <0.001 0.911 0.991 <0.001 <0.001

Table 6. Mean ± Std of tumor control probability and normal tissue complication probability of different plans among all 36
patients

TCP (%), ‍α/β ‍=1.5 TCP (%), ‍α/β ‍=3

DIL (very high DIL (very
Prostate-­DIL DIL (high risk) risk) Prostate-­DIL DIL (high risk) high risk)
Conventional 89.6 ± 0.9 89.1 ± 1.4 82.6 ± 1.9 88.2 ± 0.9 87.7 ± 1.56 80.4 ± 2.1
SIB 89.7 ± 1.7 96.4 ± 2.3 94.4 ± 4.0 88.5 ± 1.6 95.8 ± 2.57 93.7 ± 4.2
P-­value 0.927 <0.001 <0.001 0.228 <0.001 <0.001
NTCP (%)
Bladder Rectum Urethra Femoral heads
Conventional 0 2.9 ± 3.7 57.9 ± 2.2 0.3 ± 0.1
SIB 0 3.0 ± 4.0 60.2 ± 2.3 0.9 ± 0.2
P-­value N/A 0.446 <0.001 <0.001
Prostate-­DIL, Prostate with DIL cropped.

DIL sites can be technically challenging for photon EBRT.74
Proton-­based therapy could outperform photon-­ based plans
by reducing the degree of overlap between the two lesions. The
planning of delivering focal boosts to more than a single DIL
is worth further examination. A comprehensive evaluation with
a larger population of patients representing diverse pathological
abnormalities would aid in revealing any potential limitations of
the current SIB planning method and also proposing novel treat-
ment techniques for future study.
Conclusions
We investigated the planning of mp-­MRI-­defined DIL dose esca-
lation in proton radiation therapy, and reported the potential clin-
ical impact of this technique using TCP and NTCP estimation.
Overall, while respecting all OAR constraints, SIB plans were
able to achieve 125, 150, and 175% of prescription dose coverage
in 74, 54, and 17% of 36 patients, respectively. This was modeled
to result in an increase in DIL TCP by 7.3–13.3% depending on
‍α/β ‍ and DIL risk level. This retrospective study suggested the
use of IMPT-­based DIL SIB may represent a strategy to improve
tumor control.
Acknowledgment
This research was supported in part by the National Cancer Insti-
tute of the National Institutes of Health under Award Number
R01CA215718 (XY), the Department of Defense (DoD) Prostate
Cancer Research Program (PCRP) Award DoD W81XWH-17-
1-0438 (TL) and W81XWH-17-1-0439 (AJ) and Dunwoody Golf
Club Prostate Cancer Research Award (XY), a philanthropic
award provided by the Winship Cancer Institute of Emory
University.

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