Introduction
The liver is the second most common site for the
metastatic spread of cancer, mostly originating from
colorectal, pancreas, and breast cancers.[,] Surgical
resection is first treatment of choice for local treatment of liver metastasis (LM).[,] However, only few
patients are amenable to surgical resection because of
tumor size, location, and close proximity to major intrahepatic
vascular structures.[,] Although the treatment
option for LM has been considered palliative
previously, different local treatment modalities, including surgery, transcatheter arterial chemoembolization
(TACE), radiofrequency ablation, and radiotherapy
(RT) have been applied in selected patients.[,] These
local treatments could be applied alone or as an adjunct
to systemic chemotherapeutic agents to improve outcomes.[,,]
Over the past two decades, the role of RT in the
management of LM has evolving with the increase in RT
delivery techniques. Stereotactic body RT (SBRT), also
known by stereotactic ablative body radiation, is a high
precision RT technique that allows higher radiation
doses to the target with a steep dose gradient. In other
words, higher radiation doses could be delivered safely
to the liver without causing functional compromise with
new RT technics.[] There are strong evidences that
SBRT could be an effective treatment option for patients
with LM that are unresectable or not amenable to RFA
or TACE.[,] The local control rate is satisfactory
with reports of being 90% or higher in selected patients,
and with acceptable toxicity rates.[,]
Various technics have been used for hepatic SBRT,
and the planning modalities for each RT technic may
vary. Furthermore, the precise doses to the target volumes
and dose constraints for both liver and organs at
risk (OARs) have not yet been standardized. Although
it has been previously demonstrated that volumetric
arc therapy (VMAT) is advantageous for SBRT delivery
in various cancer types,[-] it remains to be determined
which rotational volumetric IMRT is advantageous
for LM treatment.
We aim to compare VMAT to HT, both rotational
techniques with different forms of implementation
and requiring dedicated helical tomotherapy (HT)
versus general purpose (VMAT) machines. The dosimetric
data for target volumes and OARs were assessed;
also target volume homogeneity and conformity
were analyzed.
Methods
Patients
We analyzed the dosimetric data of 18 consecutive patients
with LM that are unresectable and not amenable
for other local treatment modalities, and have been
previously treated with liver SBRT at our department.
Patient selection criteria included: ≤3 LM, maximum
tumor diameter <6 cm, Karnofsky Performance Status
≥70, normal coagulation function, Child Pugh Status
A-B, controlled primary disease, and life expectancy
more than 3 months.
Simulation, Delineation, and Image Registration
Patients underwent 1.25 mm multi-slice contrast enhanced
planning computed tomography (CT) from
tracheal bifurcation to the lower border of the kidneys
for simulation (Optima 580, (GE Healthcare, Waukesha,
WI, USA). Patients were positioned supine with
arms above the head and immobilized using a Body-
FIX® bluebag with vacuum wrap (Elekta, Stockholm,
Sweden). An abdominal compress was also used to
minimize the target volume motion.
Magnetic resonance imaging and 18-Fluorodeoxyglucose
positron emission tomography CT were fused
with planning CTs to help clinicians localize the target
volume precisely, where appropriate. Gross tumor
volume (GTV) included the visible tumor in imaging;
however, no clinical tumor volume was defined. Planning
tumor volume (PTV) was expanded with a 7 mm
in all directions except for 12 mm craniocaudal margin.[,,] No fiducial markers were implanted before
treatment planning.
Treatment Planning
Three different plans were generated with same CT
images including the same GTV, PTV, and OARS.
The prescribed dose was 54 Gy delivered in three
fractions, and the dose was prescribed to 90% isodose
line. Treatment was delivered every other day. First
VMAT plan (VMATM) was calculated with the Monaco
Treatment Planning System (TPS) version 5.10
(Elekta Ltd, Crawley, UK) using the Monte Carlo photon
algorithm and a sliding window multileaf collimator
(MLC) delivery technique. All treatment plans
were performed for delivery with an Axesse® linear
accelerator (Elekta AB, Stockholm, Sweden). VMAT
plans consisted of double or triple 358° arcs.
Second VMAT plan (VMATE) was generated with
an Eclipse version 13.7 (Varian Medical Systems, Palo
Alto, CA, USA) with using Acuros algorithm with 6MV
energy (MLC; Varian RapidArc, Varian Medical Systems,
Palo Alto, California, USA). Similar to VMATM
plan, VMATE plans also consisted of double or triple
arcs that included 179° as the starting angle, and 359°
as the end angle. All VMAT plans were generated in the
same manner, including same arc numbers and angles to
provide adequate target coverage and dose constraints.
The HT plans were generated using a Hi-Art Tomotherapy
system (TomoTherapy Inc., Madison, WI,
USA), a helical fan-beam IMRT using 6-MV photon
with inverse planning software. The HT plans were made
for the TomoEdge™ Dynamic Jaws system of the Tomo-
HDA™ series. A collimator aperture of 2.5 cm, pitch of 0.287, and modulation factor of 2.5 were used, which
has been previously defined.[,] Dose calculations
were performed using the fine-dose calculation grid (1
mm in the craniocaudal direction over a 256×256 matrix
in the axial plane from the original CT scan).
Dose Constraints
The OARs, including kidneys, liver, bowel, and spinal
cord, were contoured by the same physician. The dose
volume histograms generated from three different TPSs
were analyzed, and comparison was made between
plans. We adopted the constraint that at least 700 cm³
of healthy liver (entire liver volume minus cumulative
GTV) should receive <15 Gy in three fractions. Other
dose constraints of OARs included: total kidney volumes
V35 <15 Gy (volume receiving 15Gy should be
less than 35%), maximum dose (D1cm³) of spinal cord
<18 Gy, D1cc for duodenum <21 Gy, D1cm³ for small
bowel <21 Gy, D1cm³ for esophagus< 21 Gy, D1cm³ for
stomach <21 Gy, D1cm³ for heart <30 Gy, and D30 cm³
for the ribs <30 Gy.
Plan Evaluation
For all patients, cumulative dose-volume histograms
and dosimetric parameters were calculated and compared
for the PTV and OARs. Target volume coverage
was compared in terms of the minimal (Dmin), maximal
(Dmax), and mean doses (Dmean). Dxx was defined as the
minimum dose in the most irradiated XX cm³ tissue
volume. D2 and D98, the minimal doses to 2% and 98%
of the target volume, respectively, were used as surrogates
for the maximum and minimum doses. Target
homogeneity and conformity indices (HI and CI, respectively)
were compared. The HI was calculated as
HI=([D2-D98]/D50), where a greater HI value indicated
poorer uniformity of dose distribution.[] The CI was
calculated as VT,ref/VT×VT,ref/Vref, where VT,ref was the volume of the target covered by the reference isodose line,
VT was PTV, and Vref was the volume of tissue covered
by the reference isodose line. The reference isodose was
selected as 95% of the prescribed dose. The value of CI
varied between 0 and 1, with a value closer to 1 indicating
better conformity of the dose to PTV.[]
Statistical Analysis
Statistical analysis was performed using SPSS software
v. 21.0 (SPSS Inc., Chicago, IL). The Wilcoxon's
matched-pairs test was used to determine statistical
differences between volumes and doses in VMATM,
VMATE, and HT plans. The dose-volume parameters
of PTV and OARs for each planning system were measured
and compared to each other. The mean liver
doses (Dmean) and doses of 700 cc healthy liver (D700cc)
according to PTV subgroups (<50 cm³ vs. >50 cm³)
was compared according plans. The Mann-Whitney
U-test was used to compare volumes or dose values
in independent patient groups. All p-values reported
were two-sided, and p<0.05 was considered significant.
Results
Target Volume Doses
The mean GTV and PTV volumes were 11.1 cm3
(range, 0.7-55.2 cm3) and 52.8 cm3 (range, 13.4-164.0
cm3), respectively. The dosimetric parameters for target
volumes are summarized in Table 1. All plans met
the criteria for PTV coverage (Fig. 1). The average
maximum doses for PTV were significantly higher
in VMATM plans (56.9±1.0 Gy) compared to HT
(55.3±0.3 Gy; p<0.001) and VMATE plans (55.2±1.2
Gy; p<0.001); however, there was no significant difference
between VMATE and HT plans (p=0.51). Minimum
doses were significantly lower in VMATE plan compared to VMATM plan (p<0.001) and HT plan
(p<0.001), however no significant difference in minimum
doses between VMATE and HT plans. Mean PTV
doses were significantly higher in VMATM compared
to other plans.
Table 1: Dose volume histogram parameters for planning target volume according to radiotherapy techniques
Fig 1: Representative axial computed tomography slices showing 90% of prescribed dose distributions for (a) VMATM, (b)
HT, and (c) VMATE plans, and 50% of prescribed dose distributions for (d) VMATM, (e) HT, and (f) VMATE plans.
VMAT: Volumetric arc therapy; VMATM: VMAT with Monaco treatment planning system; VMATE: VMAT with Eclipse treatment planning
system; HT: Helical tomotherapy.
The HI was significantly higher in VMATM plan
(1.05±0.02) compared to HT plan (1.03±0.01; p<0.001)
and VMATE (1.01±0.01; p<0.001) plans, similarly the HI
was significantly higher in HT plan compared to VMATE
plan (p<0.001). VMATE plans achieved superior CI
compared to VMATM plan (p=0.003) and HT (p=0.001)
plans. The mean monitor units (MU) in VMATE plan
were significantly higher than those measured in
VMATM plan (5145±391 vs. 3874±1421; p=0.02).
OAR Doses
A comparison of the dosimetric parameters of OARs
for each of the plan types is listed in Table 2. The Dmean,
V20 and V30 of both kidneys did not differ significantly
for VMATM, HT, and VMATE plans. Maximum bowel dose was significantly higher in HT plan compared
to VMATM plan only (2.00±1.65 Gy vs. 1.21±1.06
Gy; p=0.03), but there was no significant difference in
bowel doses between VMATM and VMATE plans, and
HT and VMATE plans. Spinal cord mean maximum
doses did not differ significantly between techniques.
Table 2: The dosimetric parameters of organs at risk for three different radiotherapy plans
Liver Dosimetry
The dosimetric parameters for liver volumes are summarized
in Table 3. Although liver Dmean doses did not
differ significantly between VMAT plans and HT plan
(Fig. 2a), maximum doses were significantly higher
in VMATM plan (57.4±1.7 Gy) compared to HT plan
(55.7±0.4 Gy; p<0.001) and VMATE plan (54.5±0.3 Gy;
p<0.001). The mean liver D700cc for VMAT1, HT, and
VMAT plans was 5.6±4.0 Gy, 6.5±4.6 Gy and 6.5±4.9
Gy, respectively, and no significant difference was observed
between plans (Fig. 1b). The liver doses from
V10-V40 were significantly higher in VMATE plan
compared to VMATM and HT plans (Fig. 3). The liver dose volume parameters of VMATM and HT plans
were similar except for V10 values, which significantly
lower in VMATM plan.
Table 3: The dosimetric parameters for liver volumes for three different radiotherapy plans
Fig 2: Box plot graph demonstrating (a) mean liver doses and (b) mean doses of 700 cm³ of healthy liver for VMAT
and HT plans.
VMAT: Volumetric arc therapy; HT: Helical tomotherapy; VMATM: VMAT with Monaco treatment planning system; VMATE: VMAT
with Eclipse treatment planning system; Gy: Gray.
Fig 3: The mean dosimetric indices for the healthy
liver volume receiving 10-40 Gy with the three
techniques.
VMAT: Volumetric arc therapy; VMATM: VMAT with
Monaco treatment planning system; VMATE: VMAT with
Eclipse treatment planning system; HT: Helical tomotherapy;
Gy: Gray.
The liver Dmean according to tumor volume is presented
in Figure 4a. The Dmean of liver was significantly
higher in PTV larger than 50 cm³ compared to PTV <50
cm³ in VMATM plan (11.54±1.49 Gy vs. 7.42±2.27 Gy;
p<0.001), VMATE plan (12.18±1.90 Gy vs. 7.51±2.25 Gy; p<0.001), and HT plan 12.03±2.01 vs. 7.11±2.19
Gy; p<0.001) (Fig. 5a). Liver Dmean in PTV >50 cm³
was significantly less in VMATM plan compared to HT
(p=0.04) and VMATE plans (p=0.04).
Fig 4: (a) Mean liver doses and (b) mean doses of 700 cm³ of healthy liver according to tumor volume in three techniques.
VMAT: Volumetric arc therapy; VMATM: VMAT with Monaco treatment planning system; VMATE: VMAT with Eclipse treatment planning
system; HT: Helical tomotherapy; Gy: Gray.
Fig 5: Box-plot graphs demonstrating the (a) mean liver doses and (b) mean doses of 700 cm³ of healthy liver according
to planning tumor volume <50 cc and >50 cc.
PTV: Planning target volume; VMAT: Volumetric arc therapy; VMATM: VMAT with Monaco treatment planning system; VMATE:
VMAT with Eclipse treatment planning system; HT: Helical tomotherapy; Gy: Gray.
There were no significant difference in mean liver
D700cc between PTV <50 cm³ and PTV >50 cm³ in
VMATM (4.52±2.63 Gy vs. 7.41±5.24 Gy; p=0.21) and
HT plans (5.59±3.49 Gy vs. 7.93±5.95 Gy; p=0.37) (Fig. 5b). However, mean liver D700cc was significantly higher
in larger PTV compared to small PTV in VMATE plan
only (9.64±5.89 Gy vs. 4.51±2.93 Gy; p=0.03). The
liver D700cc was significantly higher in PTV >50 cm³
with VMATE plan compared to HT plan (p=0.001) and
VMATM plan (p=0.03).
Discussion
To the best of our knowledge, our study was the first
dosimetric study comparing two modern VMAT techniques
and HT for patients with LM. Although all three
SBRT plans met the criteria for PTV coverage, VMATE plan yielded better HI and CI compared to other plans.
There was no significant difference in terms of kidney,
bowel, and spinal cord doses. Mean liver doses were not
significantly different in the plans; however, liver doses
from V10 to V40 were significantly higher in VMATM
plan compared to VMATE and HT plans. We also
found that VMATM plan better spared liver in larger tumors
compared to small tumors, and the liver doses increased
with the increasing tumor size in VMATE plan.
The SBRT is gaining importance as a non-invasive
and effective treatment method for patients with LM.
Although surgery still remains the treatment of choice
in LM, most patients cannot undergo surgery because
of comorbidity, poor performance status, or tumor related
factors such as size, location, and relationship with
vascular structures.[,] SBRT offers non-invasive, effective,
and safe local treatment in patients with LM.
The feasibility of SBRT for LM was demonstrated by
numerous studies with 1-and 2-year local control rates
ranging from 70% to 100% and 60% to 90%, respectively.[] Toxicity profile of SBRT compared to other
invasive/minimally invasive local therapies is quite better.
The reported Grade III or higher toxicity rates were
1-10%, and the incidence of radiation induced liver
disease (RILD) ranged between 1% and 5%.[,,]
The feasibility and efficiency of VMAT in SBRT for
liver tumors were shown in various dosimetric and
clinical studies.[,,] Recently, Qui et al.[] demonstrated
an acceptable target volume coverage with
VMAT technique in nine patients with liver tumors.
The authors pointed that out that the main advantages
of VMAT plans were substantial decrease in beam on
time and lower MU. Thomas et al.[] demonstrated that inversely optimized IMRT plans were dosimetrically
superior to conventional IMRT plans with shorter
delivery times. Paik et al.[] analyzed the dosimetric
comparison of VMAT and robotic radiosurgery in 29
liver tumors. They reported better conformity in robotic
radiosurgery plans while VMAT plans had also good
dosimetric distribution, better sparing healthy liver, and
shorter beam on time. Our study supported the feasibility
of VMAT plans in liver SBRT with acceptable OARs
doses and good homogeneity even in large tumors.
HT based SBRT was investigated by Baisden et
al.[] in a phase I study. They hypothesized that the
maximum tolerable dose delivered to a lesion by HT
based SBRT could be predicted based on the PTV and
liver volume. The authors found that HT was capable of
performing SBRT for liver lesions with adequate target
dose while sparing normal tissues. Furthermore, Engels
et al.[] conducted a phase II study of HT in the multidisciplinary
treatment of oligometastatic colorectal
cancer. They treated a total of 53 metastasis of lung, liver,
and lymph nodes. They reported the actuarial 1-year
local control, progression-free survival, and overall survival
were 54%, 14%, and 78%, respectively, with only
4% Grade III toxicity. Lee et al.[] analyzed SBRT with
HT for patients with hepatic oligometastasis. 54 hepatic
lesions were treated, and 1-and 2-year local control
rates were 59.9 and 49.0%, respectively, without any
Grade 3 or higher toxicity. Our dosimetric study also
supported that HT was a feasible technique for liver
SBRT compared to with modern VMAT techniques.
Historically, the most common toxicity with liver
SBRT had been reported as RILD. In most of the recent
studies, the rates of RILD were reported <1%.
[] The generally-accepted dose constraint for the
healthy liver was 700 cm³ <15 Gy, for minimizing the
risk of RILD.[,] Although, in the current study,
the dose constraints for both OARs and healthy liver
were acquired, our dosimetric analysis indicated that
liver doses increased with the increased tumor size in
VMATE plan. However, VMATM was advantageous in
achieving lower liver mean doses and better sparing
healthy liver in larger tumors.
Our study had certain limitations. First, due to its
retrospective nature, we only compared the dosimetric
parameters of two different VMAT techniques and HT
in the management of LM in a limited cohort of patients.
Second, considering the fact that a comparison of
dosimetric parameters does not indicate a comparison
of clinical effectiveness, our results should be interpreted
carefully in the absence of clinical studies. Finally,
long follow-up periods are essential for better analyzing
the tolerance and/or toxicity profile of OARs. Nevertheless,
this study is important as it is the first dosimetric
study comparing two modern VMAT techniques and
HT technique in the treatment planning for LM.
Conclusion
Through the dosimetric comparison of SBRT plans
with two modern VMAT techniques and HT technique for LM, we found that all three SBRT plans met
the criteria for PTV coverage with no significant difference
in terms of OARs doses including mean liver
doses. VMATE plan yielded better HI and CI compared
to VMATM and HT, but liver doses from V10 to V40
were higher in VMATE plans compared to other plans.
Although liver doses were higher in patients with
larger tumors in all plans, VMATM plan better spared
liver in larger tumors compared to small tumors, and
the liver doses increased with the increasing tumor
size in VMATE plan. Because this study is a dosimetric
study, the clinical results of this study are required to
interpret these findings in clinical practice.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Baskent University Faculty of Medicine Ethics Committee
(no: KA18/148, date: 30/04/2018).
Financial Support: None declared.
Authorship contributions: Concept - E.O., O.C.G., C.Ö.;
Design - E.O., O.C.G., C.Ö.; Supervision - E.O., O.C.G.,
C.Ö.; Funding - None; Materials - E.O., O.C.G., C.Ö.; Data
collection and/or processing - E.O., O.C.G., C.Ö.; Data analysis
and/or interpretation - E.O., O.C.G., C.Ö.; Literature
search - O.C.G.; Writing - E.O., O.C.G.; Critical review -
E.O., O.C.G., C.Ö.
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