Introduction
Cancer remains one of the leading causes of death for
children all over the world.[] Leukemia, central nervous system (CNS) tumors and lymphomas are the
most commonly observed pediatric cancers.[] Primary
malignant tumors of CNS are the most common
solid organ tumors in children accounting for tolapproximately
25% of all cancers in those patients.
[,] A well-known treatment method for most of
these tumors is maximal surgical resection followed
by a local or craniospinal radiation therapy. However,
there are increasing concerns about the functional
status, quality of life and damages left in the tissues
and organs of the children undergoing these treatments.
In the early 2000s, a novel advance for 3D conformal
radiotherapy (3DCRT) has been developed as a
result of rapid technologic progress namely Intensity
Modulated Radiotherapy (IMRT). IMRT techniques
employ various intensities across multiple radiation
beams leading to the construction of highly conformal
dose distributions, achieved by subdividing each
radiation beam into smaller radiation beamlets and
varying the individual intensities of these beamlets.
[] After a decade, there has been attempt on arcbased
or rotational therapies to overcome some of the
limitations of fixed-field IMRT. The basic concept of
arc therapy is the delivery of radiation from a continuous
rotation of the radiation source and allows
the patient to be treated at a full 360° beam angle.
Arc therapies can achieve highly conformal dose distributions
and are essentially an alternative form of
IMRT.[] With efficient use of these techniques and
good physical planning, the control rate of tumor is
enhanced in tumor dose while the toxicity of the normal
tissues is not raised.[] However, the large field of
low dose regions leads to some concerns for OAR. Although
many studies have been done about the use of
IMRT and VMAT in head neck and pelvis tumors,[]
comparative studies for these two modalities in craniospinal
therapy are limited.
The purpose of our study is to compare the target
volumes and doses received by OARs by re-creating
VMAT and IMRT plans in patients who had previously
undergone a craniospinal 3D-CRT for curative
purposes.
Methods
Patients
Eleven patients treated with the conventional 3D-CRT
method for craniospinal radiotherapy were included in
the study. The computed tomography (CT) simulations
of the patients were re-loaded to the planning system,
and IMRT and VMAT plans were carried out by defining
OARs and target volumes.
CT Simulation and Treatment Planning
All patients were immobilized in a supine position
using a thermoplastic head and neck mask and with
the arms kept in a relaxed position at both sides of
the body. In CT simulation images of 2.5 mm thickness
from 2 cm above the cranial apex to 2 cm below
the termination of the sacrum were sent to the Varian
Eclipse treatment planning system (version 8.6) for recontouring
the organs at risk and target volumes.
The eyes, optic nerves, thyroid, esophagus, lungs,
heart, liver, kidneys, parotids and the oral cavity were
contoured as the OARs. Clinical target volume (CTV)
of the brain was contoured covering the whole brain
with the cribriform plate and the meninges, and CTV
of the spinal cord was contoured including the entire
spinal canal and subarachnoidal space as seen laterally
in T2 weighted magnetic resonance (MR) or CT
images from the foramen magnum to the thecal sac.
Planned target volume (PTV) was defined as the total
of the PTV spinal which is formed by extending the
CTV of the brain and spinal for 0.5 cm in all directions.
Dose definition was a total of 36 Gy in 1.8 Gy per fraction
for all patients. In target coverage, PTV volume
was meant to be at least 95% and at most 107% of the
prescribed dose. The intention was to protect the OARs
as much as possible.
Treatment plans were prepared using the Varian
Eclipse planning system (version 8.6) with a progressive
resolution optimizer (PRO) and anisotropic analytical
algorithm (AAA) so that treatment could be
delivered with 6 MV photon energy from Varian iX
model linear accelerator (Rapid Arc) which has 120
MLCs and can carry out kV imaging (CBCT).
VMAT Planning
Treatment regions were generated by using multiple
isocentric methods with 6 MV energy and a maximum
dose rate of 600 MU/min. To cover the whole PTV, two
full arcs, one between 181-179 degrees in clockwise
and the other one between 179-181 degrees counterclockwise
directions were used.
Inverse planning module was used with the 5-phase
PRO algorithm that calculates the dose rate, leaf position
and gantry rotation rate in a total of 177 control
points with ~2 degree angles to optimize the results
Ring control volumes were formed in order to achieve
maximum dose conformity and the control dose distribution
outside PTV. PTV and OAR dose constraints
and dose volume limitations were used as the dose tolerances defined by Radiation Therapy and Oncology
Group (RTOG).[]
IMRT Planning
Before planning, various gantry angles were examined
in order to obtain the most effective dose distribution
in the entire craniospinal volume. The best
scenario was achieved with 6 MV photon energy by
using gantry angles of 90° and 270° (two laterals) with
forwarding IMRT (field-in-field) technique for the
cranial field and five gantry angles (140°, 160°, 180°,
200°, 220°) with inverse IMRT technique (sliding window)
for the spinal field. The Maximum dose rate was
300 MU/min. Optimal fluencies were converted into
real fluency distributions with an anisotropic analytical
algorithm (AAA) by using Leaf Motion Calculator
(LMC). The dose calculation range was determined
as 2.5 mm.
Evaluation of Treatment Plans
IMRT and VMAT plans were performed in all patients
by defining a total dose of 36 Gy at 1.8 Gy/fraction.
Both treatment methods were compared by using the
following definitions: Plans were normalized so that
PTV receives at least 95% of the prescribed dose intending
to protect OARs. Each OAR and target volume
was evaluated using a dosevolume histogram (DVH).
Dosimetric parameters determined for PTV evaluation
were PTV mean, D2, D98, V95, V107, V110 in
which Vx defined PTV volume including x% of the defined
dose and Dy dose defined the receiving y% of the
volume.
Plan compatibilities and PTV heterogeneity were
calculated with the conformity index (CI) and homogeneity
index (HI) formulae determined by RTOG.
[] CI and HI are defined as the ratio of defined dose
volume to PTV volume and the ratio of maximum dose
to the defined dose, respectively. Mean dose (Dmean)
and maximum dose (Dmax) values were separately determined
for the OARs. Low dose volume (low dose
bath) was also defined in our study using V2, V5, V10,
V15, and V20 volumes of the body. MUs of all plans
were calculated and the duration of treatment was determined.
The ethical approval was obtained from the Ethical
Committee for Clinical Researches of Cerrahpasa
Medical Faculty, Istanbul University, by the decision
numbered B.30.2.İST.0.30.90.00719045.
Results
Demographic Characteristics
Eleven cases with brain tumors were included in this
study. The mean age of the cases at the onset of radiation
therapy was 10±2 years. Seven of eleven cases
(63.6%) were male. Diagnostic distribution of the patients
was medulloblastoma in 6 cases (54.5%), anaplastic
ependymoma in 2 cases (18.2%), craniospinal
extension in 2 cases (18.2%) and highgrade glioma in
1 case (9.1%). A craniospinal radiation therapy of 36
Gy was planned in all cases which had completed their
treatments before the study.
Analyses of Dose-volume Histograms
In all cases, OAR and target volume coverage were
compared regarding previously defined criteria.
Dmean and Dmax received by the OARs were compared.
VMAT was found to be significantly superior
to IMRT regarding the optic nerve (p=0.0008), thyroid
(p<0.0001), esophagus (p<0.0001), heart (p<0.0001)
and oral cavity (p=0.0004). IMRT was better at Dmean
of the lungs (p<0.0001) and kidneys (p<0.0001) than
VMAT (Table 1). Dmax of VMAT plan was kept at low
limits in all OARs. Doses at all OARs were within the
range of clinically acceptable criteria.
When two plans were compared regarding the low
dose values received by the body, it was found that
IMRT plans were significantly better in V2 and V5,
while VMAT plans were significantly better in V15
and V20 (p<0.0001). No significant result was found
for V10. Integral doses were determined by the calculation
of the ratio of Body-PTV volume to Body-PTV
Dmean, hence, IMRT plans were found to be significantly
better than VMAT plan (p=0.0011) (Table 2).
Table 1: Comparison of target volume doses at organs at
risk between two different planning treatments
Table 2: Comparison of body doses, integral doses and target volume doses between two different planning treatments
Target volume coverages were evaluated by obtaining
the desired limits in OARs. For PTV, Dmean was
102.7% in IMRT and 102.3% in VMAT plan. V95 was
higher than the clinically acceptable criteria in both
methods, namely 99.7% in IMRT and 97% in VMAT
plan (p=0.002). V107 was found to be 2.6% in IMRT
and 4% in VMAT plans. D2 and D98 targets, defined
by International Commission on Radiation Units and
Measurement (ICRU) criteria,[] were achieved in
both VMAT and IMRT plans (Table 2) (Figs. 1, 2).
Fig 1: Isodose distribution of VMAT plan.
Fig 2: Isodose distribution of IMRT plan.
CI and HI values were found to be significantly superior
in IMRT plans compared to VMAT (p<0.05).
The number of MU in VMAT was found to be significantly
less than IMRT with (p=0.001) (Table 3).
Table 3: Comparison of conformity index (CI), homogeneity index (HI), monitor unit (MU) and treatment time between
two different planning treatments
Discussion
The main purpose of the treatment for many CNS tumors
in childhood is providing the maximum chance
for the cure as well as limiting long term toxicities.
CSRT means irradiation of the entire neural axis, including
the whole cranium and whole spinal cord until
the third sacral vertebra. 3D-CRT is currently a method
of choice in CSRT to make better plans by protecting
the OARs and minimizing the complication rates
with the use of IMRT and VMAT techniques. On the
other hand, the greatest advantage of using modern radiotherapy
techniques such as VMAT and IMRT is the
capability of adjusting high dose areas formed in the
overlapping zones with automatic optimization.[,]
Therefore, in the present study, the target volumes in
dosimetric plans and doses received by OARs were
compared between IMRT and VMAT, planned in patients
who had undergone craniospinal 3D-CRT.
In the study by Fogliata et al., the craniospinal radiotherapy
was carried out in 5 cases and VMAT was
shown to be superior to conformal radiotherapy regarding
the target volume coverage and protection of
OAR.[] Their results VMAT with 36 Gy prescription
dose were comparable with our PTV in the mean dose
and coverage of target volumes except for V107 being
higher than the value in our study.
In the study by Chen et al., VMAT was carried out
in the supine position with the rapid arc device and dosimetric
results revealed homogenous and conformal
dose distribution in the craniospinal field and better
protection was acquired for the OAR. They planned
CSRT with the VMAT technique for two patients and
found that CI value was 1, HI value was 12.7% with
D5-D95/Dmean calculation, while D5 was 108% and
D95 was 95%.[] In our study, when CI and HI formulae
defined by RTOG were used whereas D5 was
106%, D95 was 99%, CI was 1.21 and HI was 1.13 for
IMRT treatment. In VMAT plans, D5 was 106%, D95
was 97%, CI was 0.9 and HI was 1.19. Thus, our findings
were consistent with the literature when the dose
coverage of target volumes was compared taking into
account the defined doses.
Al-Wassia et al. performed a comparative analysis
of target volume coverage, homogeneity and OAR
doses between IMRT and VMAT plans for CSRT.
[] They found that V95 values for PTV in CNS
were 98.97% for VMAT and 99.19% for IMRT, which
were comparable with our results as 97% for VMAT
and 99% for IMRT, with the coverage in IMRT being
slightly higher than Al-Wassia et al. The doses to OARs were also found to be slightly lower with
VMAT than IMRT,[] consistent with our findings
and most of the literature.[-,]
According to Lee et al., the use of VMAT in CSRT
provided protection of radiosensitive organs. However,
they claimed that in small organs close to PTV or within PTV (cochlea, coronary artery and lens,
etc.), low doses could not be obtained in VMAT plans
compared with conventional radiotherapy, carrying a
potentially increased risk of secondary malignancies.
[] Similarly in our study, the mean doses on optic
nerve and eyes doses could not be kept at low limits
in both VMAT and IMRT. Lee et al. found that the
kidney and liver doses were higher in VMAT plans
than conventional methods.[] In our study, lower
doses on kidney and liver were obtained in IMRT
plans compared with VMAT. However, for the organs
in which doses are critical, optimization can be obtained
in lower doses more by reducing the coverage
in PTV.
Late-term adverse effects can be minimized by
keeping doses on the heart, esophagus, thyroid, liver,
and parotids at low limits. The most controversial toxicities
in CSRT are cardiac toxicity and a significant
amount of exit dose delivered to the heart. In the literature,
it is well established that, radiation-induced heart
disease and cardiac toxicity are common in children
who received craniospinal irradiation.[,] In our
study, significantly better protection was obtained in
the heart, esophagus, thyroid, and parotids with VMAT
plans in compliance with the literature.[-,]
The most controversial and unexplored topic in
intensity adjusted radiotherapy or in all other multiangled
treatments is about the regions receiving low
doses. Extension of the field receiving <10 Gy and the
biological effects of high integral doses are still not
clear.[] However, there are studies reporting that
IMRT increases the risk of secondary cancers and malignancies
due to extensive high MU in low dose areas.[] Parker et al. gave a mean of 455 MU in IMRT plans, however, by using the same plans, they calculated
a mean of 180 MU with standard techniques in a
patient treated with CSRT with a prescription dose of
23.4 Gy. Despite its superiority in protecting OAR, they
have stated that the risk of secondary cancer increases
with IMRT.[]
In the study by Miralbell et al., conventional treatments,
protons therapies and IMRT were compared
regarding the risk of secondary cancers in two patients
diagnosed with medulloblastoma and rhabdomyosarcoma
using International Commission on
Radiologic Protection Model 60. As expected, the
risk was least with proton therapy while IMRT was
found to be better than conventional therapy.[]
Moreover, in non-craniospinal studies comparing
VMAT and IMRT plans, although MU values were
found to be 50% lower in VMAT, they were lower in
the low dose receiving volume in IMRT.[] In our
study, VMAT was better than IMRT regarding both
protection of the normal tissues and number of MUs
delivered, suggesting that VMAT can be more reliable
in terms of the risk for secondary cancers in pediatric
patients.
While the duration of treatment was 10-15 min
for IMRT and tomotherapy in the study by Parker et
al., this was found to be a few minutes for VMAT in
the literature.[,] However, in our study, the mean
duration of treatment was 7-8 min with the 3-zone
double arc method and 4-5 min in five-area IMRT. The
reason for the shorter duration of treatment in IMRT
was that each arc determined as clockwise and counterclockwise
in VMAT plans lasted an average of 1.23
min (Clinac IX).
Conclusion
In conclusion, IMRT and VMAT are advantageous
treatment alternatives in pediatric patients receiving
a CSRT in order to achieve a more homogenous dose
distribution and decrease the late adverse effects. Although
doses of OARs are significantly lower in the
craniospinal axis in VMAT compared with IMRT
plan, it is known to increase the integral dose. IMRT is
claimed to increase the risk of secondary cancers in the
long- term in areas receiving low doses, no randomized
studies are showing this. Still, this risk should be taken
into consideration and cases should be treated regarding
risk-benefit ratios. Comparing VMAT and IMRT
plans of previously treated patients after re-structuring,
VMAT therapy may provide a better protection
in OARs in the CSRT. Randomized controlled phase 3
studies are needed to evaluate the clinical reflection of
this result.
Acknowledgement: The present study was presented as
publish-only abstract in 2014 ASCO (The American Society
of Clinical Oncology) Annual Meeting held in Chicago, Illinois.
Peer-review: Externally peer-reviewed.
Conflict of Interest: None declared.
Ethics Committee Approval: The ethical approval was obtained
from the Ethical Committee for Clinical Researches of
Cerrahpasa Medical Faculty, Istanbul University, by the decision
numbered B.30.2.İST.0.30.90.00719045.
Financial Support: None declared.
Authorship contributions: Concept - E.E.Ö.., T.S.T.; Design
- E.E.Ö., T.S.T., Ö.U.; Supervision - E.E.Ö.; Materials
- E.E.Ö., Y.Ç.; Data collection &/or processing - E.E.Ö.,
Y.Ç.; Analysis and/or interpretation - E.E.Ö., S.K.; Literature
search - E.E.Ö., Y.Ç., F.Ç.; Writing - E.E.Ö., F.Ç.; Critical review
- E.E.Ö., T.S.T., Ö.U., S.K.
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