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145]

Original Article

Volume changes during head‑and‑neck

radiotherapy and its impact on the parotid
dose – A single‑institution observational
study
ABSTRACT Bhargavi
Aims: This study aims at assessing the volume changes that occur in the targets (gross tumor volume and planning target Ilangovan,
volume [PTV]) and the organs at risk in squamous cell carcinoma of the head and neck during radiotherapy and assessing the dose Murali
changes that occur as a result of them. Venkatraman,
Subathira
Settings and Design: This was a prospective observational study in a tertiary care center after obtaining the appropriate scientific
Balasundaram
and ethics committee clearance.
Subjects and Methods: Forty‑five patients diagnosed with squamous cell carcinoma of the head and neck, who were treated with Department of
intensity‑modulated radiotherapy in the time period from March 2018 to May 2019, were enrolled in the study. A planning computed Radiotherapy, Apollo
Cancer Institute,
tomography (CT) scan (CTplan) was done for all patients, followed by scans after 15 fractions (CT15) and after 25 fractions (CT25). The Chennai, Tamil Nadu,
volume changes and the subsequent dose changes were assessed and recorded. India
Statistical Analysis Used: Data entry was done in MS Excel spreadsheet. The continuous variables were expressed as
For correspondence:
mean + standard deviation. The comparison of normally distributed continuous variables was done by paired t‑test. Data analysis Dr. Bhargavi
was done by SPSS (Statistical Package for the Social Sciences) version 16.0. P < 0.05 was considered statistically significant. Ilangovan,
A multivariate linear regression model was constructed to study the correlation between mean dose to the parotid glands and the 64 G, SR Dream
other variables. All statistical modeling and analysis were done using SAS (Statistical Analysis Software) version 9.4. Bungalow, Gowri
Nagar, Mugalivakkam,
Results: Of the 45 patients, 25 were male and 20 were female. The majority of the patients had malignancies in the oral cavity (16) and Chennai ‑ 600 125,
hypopharynx (14). Most of them had Stage III/IV (AJCC v 8) disease (41). There were a 36% decrease in the PTV‑high risk (PTV‑HR) Tamil Nadu, India.
volume and a 6.05% decrease in the PTV‑intermediate risk (PTV‑IR) volume CT15. In CT25, the volume decrease in the PTV‑HR E‑mail: bhargavi.
and the PTV‑IR was 47% and 9.06%, respectively. The parotid glands also underwent a reduction in their volume which has been ilangovan@gmail.com
quantified as 21.7% and 20.9% in the ipsilateral and contralateral parotids in CT15 and 36% and 33.6% in CT25, respectively. The
D2 (dose received by 2% of the volume) and D98 (dose received by 98% of the volume) of the PTV‑IR showed changes of +3.5%
and –0.2% in CT15 and + 4.6% and –0.31% in CT25, respectively. The homogeneity index and conformity number of the PTV‑IR
changes by 0.03 and 0.08 in CT15 and by 0.04 and 0.12 in CT25, respectively. The mean dose to the ipsilateral parotid gland increased
by 14% in CT15 and 19% in CT25. The mean dose to the contralateral parotid gland increased by 17% in CT15 and 25% in CT25.
Submitted: 12-Aug-2019
Conclusion: The dose to the parotid glands increases as a result of the changes that occur during the course of radiation. The Revised: 17-Oct-2019
changes are significant after 15 fractions of radiation. A replanning at this juncture might be considered to reduce the dose to the Accepted: 30-Dec-2019
parotid glands. Published: 18-Jul-2020

KEY WORDS: Head‑and‑neck radiotherapy, intensity‑modulated radiotherapy, parotid glands, volume changes

INTRODUCTION
Head‑and‑neck malignancies constitute the third
most common tumors in India.[1] Radiation therapy
forms an important modality in the management
of head‑and‑neck malignancies. The increased
rate of organ preservation has made radiotherapy
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Cite this article as: Ilangovan B, Venkatraman M, Balasundaram S. Volume changes during head-and-neck radiotherapy and
its impact on the parotid dose – A single-institution observational study. J Can Res Ther 2020;16:575-80.

© 2020 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow 575
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Ilangovan, et al.: Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study
an inevitable treatment modality in these cancers.[2,3] During
radiotherapy, the patient’s anatomy undergoes changes in
the form of decrease in the tumor volume, nodal volume,
weight loss, and the changes in parotid volume.[4] As a result
of these, the mean dose to the parotid is generally more
than what is calculated based on the treatment planning
computed tomography (CT). This study aims to quantify
the abovementioned volume changes, the subsequent dose
changes, and their effect on the parotid gland dose.
SUBJECTS AND METHODS
This is a prospective nonrandomized observational clinical
study. This was conducted in a tertiary care oncology hospital.
The study was commenced after clearance from the hospital’s
scientific and ethics committee.
The study involved 45 patients diagnosed with squamous
cell carcinoma of the head and neck undergoing radiotherapy
with intensity‑modulated radiotherapy with a Karnofsky
Performance Status  ≥70 and with Stage T 2a–T 4, N 0–N3,
and M0. Early‑stage diseases which would warrant small
fields or ipsilateral neck fields were excluded. Radiotherapy
preparation consisted of immobilization using a neck
rest and thermoplastic mask. A CT scan (CT plan) of the
head‑and‑neck region from the base of the skull to the
superior mediastinum was obtained in 3 mm slice thickness.
The CT scan images were transferred to the Oncentra
treatment planning system. The images were imported,
and the gross tumor volumes (GTVs) and clinical target
volumes (CTVs, comprising CTV primary and the nodal
volumes) were contoured in axial images. A planning
target volume (PTV) expansion of the GTV and the CTV was
created (GTV with a 3 mm margin to create the PTV‑HR and
CTV with a 5 mm margin to create the PTV‑IR). The organs at
risk (OARs such as the parotids, spinal canal, and mandible)
were also contoured.
The patient images and contours were then given for
radiotherapy planning. A dose of 66 Gy in 33 fractions was
delivered to the PTVHR and a dose of 59.4 Gy in 33 fractions was
delivered to the PTVIR. Dose constraints of mean dose <26 Gy
to the bilateral parotids and <20 Gy if only one parotid can be
spared and a Dmax of 45 Gy to the spinal canal were imposed.
The plans were evaluated by visual analysis of the isodose lines
and evaluation of the dose‑volume histograms. Once the plan
was acceptable, it was approved, and the details were exported
for treatment delivery. All patients received concurrent weekly
cisplatin (40 mg/m2).
A follow‑up CT was done at the end of 15 fractions (CT15) and at
the end of 25 fractions (CT25) using the same abovementioned
protocols. The follow‑up CT images were registered with the
planning CT images by the mutual information method. The
structure sets in the CTplan were transferred to the CT15 and CT25.
576
The structures including the GTV, CTV, and OARs were
manually modified in all axial slices, by the same physician
according to the changes in the body, primary tumor,
nodes, nodal volumes, and the parotids, thereby reducing
the interobserver variations. PTV‑HR and PTV‑IR were
generated based on the same expansion margins as for
the CTplan. The volume changes in the PTV‑HR, PTV‑IR, and
ipsilateral (iParotid) and contralateral (cParotid) parotids
were measured and documented. By transferring the
primary structure sets, and then modifying them rather
than recontouring, the subjective errors while contouring
were minimized. The optimized beam setup of the original
plans done on CTplan was then imported onto CT15 and CT25
which then had the modified structure sets. In CT15 and
CT25, reference marks were kept indicating the isocenter
position. Hence, it was possible to align the isocenter to
match that in the original plan using the beam modeling
tool and recalculate the dose for the structure sets in CT15
and CT25. This plan depicted the doses the structures would
receive if the same primary plan was to be executed over
the modified volume.
The D2 (dose received by 2% of the volume) and D98 (dose
received by 98% of the volume) were measured for the tumor
volumes; Dmean (mean dose) for the parotids and Dmax
(maximum dose), D2cc (Dose to 2cc of the spinal canal) for
the spinal canal and Dmax for the mandible were observed
and documented in each of the plans. The changes in the
low‑dose volumes and the high‑dose volumes were derived in
each follow‑up scan. The homogeneity and conformity indices
were calculated. Homogeneity index (HI) was calculated using
the following formula:
HI= (D2‑D98/D50) × 100[5]
D2 = dose received by 2% of the volume,
D98 = dose received by 98% of the volume,
D50 = dose received by 50% of the volume.
The conformity number (CN) was calculated using the
following formula:
CN= (VTD/V) × (VTD/VD)[6]
CN = Conformity number,
VTD = Volume of the target covered by the isodose line,
VD = total volume covered by the isodose line,
V = Volume of the target.
Data entry was done in MS Excel spreadsheet. The continuous
variables were expressed as mean + standard deviation. The
comparison of normally distributed continuous variables
was done by paired t‑test. Data analysis was done by IBM
SPSS Statistics for Windows, version 16 (IBM Corp., Armonk,
N.Y., USA). P < 0.05 was considered statistically significant.
A multivariate linear regression model was constructed to
study the correlation between mean dose to the parotid glands
and the other variables. All statistical modeling and analysis
were done using SAS Institute Inc 2013. SAS/ACCESS® 9.4.
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Ilangovan, et al.: Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study

RESULTS for the intercept and PTV‑IR VD were found to be statistically

A total of 45 patients with squamous cell carcinoma of the
head‑and‑neck region were enrolled in this study. Their
characteristics are shown in Table 1.
There was a statistically significant reduction observed
in the volumes of the PTV‑HR, PTV‑IR, and ipsilateral and
contralateral parotid glands. The change was significant even
after 15 fractions [Table 2].
The subsequent dose changes were assessed in the form of
minimum and maximum doses, HI, and conformity index.
The D2 of the PTV‑HR and PTV‑IR increases with statistical
significance. The D98 of the PTV‑IR and the PTV‑HR showed
a decrease in the dose without statistical significance. The
changes were significant even at the end of 15 fractions
[Table 3].
The volume of the PTV‑IR covered by the prescription isodose
line showed a statistically significant decrease. However, the
total volume covered by the prescription isodose line showed
a statistically significant increase, suggesting that more than
intended normal tissue was being irradiated [Table 4].
There was a significant increase in the mean dose to the
parotid glands, and the Dmax to the spinal canal and mandible
also showed a significant increase in CT15 and CT25 [Table 5].
A multivariate linear regression model was constructed to
study the correlation between cParotid mean dose, PTV‑IR VD,
PTV‑IR, and stage. The independent variables were chosen
based on the best fit for the model. The parameter estimates
Table 1: Patient characteristics
Characters Number of patients
Total number
Gender
Male
Female
Stage
II
III
IV
Subsite
Hypopharynx
Larynx
Oral cavity
Oropharynx
Others
significant. The model shows a positive correlation between
the dependent variable and PTV‑IR VD and stage and a negative
correlation between the dependent variable and PTV‑IR. Based
on the model, a 1% increase in PTV‑IR VD would cause an
increase of 0.20% in the cParotid Dmean value. To further study
the degree of dependence between the dependent variable
and the independent variables, a Pearson and Spearman
correlation tests were performed. The tests showed that
cParotid mean has the most dependence on PTV‑IR VD. The
Pearson and Spearman correlation coefficients are listed below.
Similarly, another regression model was built to study the
correlation between iParotid Dmean and the other variables
PTV‑IR, PTV‑IR VD, PTV‑IR VTD, gender, and age. The parameter
estimates were found to be statistically significant for
all of the independent variables, except age. The model
exhibits a positive correlation between iParotid Dmean and the
independent variable PTV‑IR VD. Based on the model, a 1%
increase in PTV‑IR VD would cause an increase of 0.10% in the
iParotid Dmean value.
DISCUSSION
The aim of IMRT is to achieve tumor control while sparing the
adjacent normal structures. In other words, it increases the
therapeutic index by lowering the normal tissue complication
probability. This has been tested and proven in studies which
have shown the positive effect of IMRT in reducing the rates
of Grade 2 xerostomia in patients with head‑and‑neck cancers
undergoing radiotherapy with IMRT.[7] However, the decrease
in the volume of the PTV‑HR, PTV‑IR, parotid glands, and the
other positional changes occurring throughout the course of
radiotherapy results in delivering more than planned dose to
the adjacent normal tissues.[8]
In our study, there were a 36% decrease in the PTV‑HR volume
45
and a 6.05% decrease in the PTV‑IR volume at the end of
25 15 fractions. After 25 fractions, the volume decrease in the
20 PTV‑HR and the PTV‑IR was 47% and 9.06%, respectively.
The PTV‑IR volume change in our study is less than that
4
17 reported in earlier studies.[9] This could be because majority
24 of the patients included in this study had laryngopharynx
and oral cavity malignancies. The PTV‑IR changes in most
14
4
of them were due to the reduction in the lateral separation
16 of the neck, rather than gross changes in the PTV‑HR. The
3 PTV‑HR changes did not alter the CTV or the PTV‑IR as the
8 regions harboring subclinical diseases, such as the neck

Table 2: Volumes with significant changes on CT15 and CT25 in relation to CTplan
PTV‑IR (cc), mean (SD) P PTV‑HR (cc), mean (SD) P iParotid (cc), mean (SD) P cParotid (cc), mean (SD) P
CTplan 591.27 (274.72) 52.67 (48.27) 16.46 (8.91) 18.98 (8.48)
CT15 555.46 (260.01) 0.0001 42.30 (37.45) 0.0094 12.87 (7.69) 0.0001 15.01 (7.47) 0.0001
CT25 537.67 (253.81) 0.0001 37.6 (33.23) 0.0029 10.53 (7.04) 0.0001 12.6 (6.88) 0.0001
The mean value is the average value of the 45 patients in cm3. P<0.05 is statistically significant. SD=Standard deviation, PTV=Planning target volume,
IR=Intermediate risk, HR=High risk

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Ilangovan, et al.: Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study

nodal regions, did not undergo much change. The PTV‑HR The maximum dose to the PTV‑HR and the PTV‑IR (as recorded
volume changes, however, are comparable with other earlier as the dose to 2% of the target volume) showed an increase
studies.[10,11] and the minimum dose (as recorded as the dose 98% of the
target volume) showed a nonsignificant decrease. The total
The parotid glands underwent a reduction in their volumes, volume irradiated by the prescription isodose line increased
which has been quantified as 21.7% and 20.9% in the as the volume of the PTV‑IR decreased. As a result of these
ipsilateral and contralateral parotids at the end of 15 fractions changes, the plans were more inhomogeneous and less
and 36% and 33.6% in the ipsilateral and contralateral parotids conformal. Similar results have been reported by studies
at the end of 25 fractions. As a result of these abovementioned earlier[12] [Figure 2].
changes in the PTV‑HR, PTV‑IR, and the parotid glands, there
occurred a change in the dose delivered to the target volumes This increases the volume irradiated by the prescription
and normal structures [Figure 1]. isodose line as a result of the PTV‑IR volume changes and
the movement of the parotid into this area coupled with the
Table 3: Averaged dose‑volume parameters on CTplan, parotid gland’s volume changes increases the dose to the
CT15, and CT25 for target volumes parotid glands. The rate of xerostomia might increase as
D2, mean (SD) P D98, mean (SD) P the mean doses increases. There are several studies which
PTV‑HR have applied NTCP (normal tissue complication probability)
CTplan 106.94 (2.90) 0.0001 96.38 (3.98) 0.5167 models to see the correlation between the two, suggesting
CT15 109.3 (3.52) 95.92 (3.87) that keeping the mean dose of the parotid as low as possible
PTV‑IR
CTplan 110.12 (3.45) 0.0001 97.78 (4.12) 0.4193 without compromising the target coverage is prudent.[13‑16]
CT25 114.92 (4.47) 94.16 (4.96)
All values are averaged percentages of Dpres for PTV‑HR and PTV‑IR and The quality of life will be better if we were to reduce the
SD. A value of P<0.05 is statistically significant. SD=Standard deviation,
PTV=Planning target volume, IR=Intermediate risk, HR=High risk
rate of incidence of xerostomia.[17,18] Although recovery of
salivary function has been reported, it is prudent to keep
the dose to the minimum without compromising on the
Table 4: Averaged volumes covered by the prescription
isodose line on CTplan, CT15, and CT25 for PTV‑IR tumor control.
VD, mean (SD) P VT, D, mean (SD) P
Studies assessing the role of weekly IMRT adaptive planning
CTplan 614.45 (273.05) 515.86 (229.94)
CT15 650.5 (259.74) 0.0004 489.92 (226.73) 0.0011
have been done and have concluded that these strategies
CT25 647.07 (254.12) 0.0023 467.71 (220.05) 0.0001 improve PTV coverage and reduce the normal tissue doses.[19]
All values are the volumes in cm3. VD is the total volume covered by the
prescription isodose line and VT,D is the volume of the PTV‑IR covered by While analyzing the kinetics of these changes, it has been
the prescription isodose line. A value of P<0.05 is statistically significant.
SD=Standard deviation found in this study, as has been shown in multiple other
studies, that the changes are statistically significant after
Table 5: The mean dose changes of organs at risk in CTplan, 15 fractions. This is shown by significant volume and dose
CT15, and CT25 changes CT15. This is similar to the studies in the literature.[9,20,21]
Mean (SD), Gy P
Bhide et al. analyzed weekly and concluded that the changes
iParotid Dmean
were significant in the second week. Beltran et al. and Bhandari
CTplan 24.29 (5.63) et al. also made similar assessments. In a study by Schwartz
CT15 28.62 (7.82) 0.0001 et al., they suggested that the changes were significant during
CT25 30.58 (8.24) 0.0001 the 3rd and 4th weeks of radiotherapy.[22]
cParotid Dmean
CTplan 24.27 (10.43)
CT15 27.79 (11.75) 0.0001
CT25 29.06 (11.96) 0.0001
Spinal canal Dmax
CTplan 36.34 (6.97)
CT15 39.56 (7.76) 0.0001
CT25 40.98 (7.29) 0.0001
Spinal canal D2CC
CTplan 31.17 (6.37)
CT15 33.53 (7.07) 0.0001
CT25 34.66 (7.13) 0.0001
Mandible Dmax
CTplan 60.88 (6.38)
CT15 64.23 (6.56) 0.0001
CT25 65.17 (6.76) 0.0001 a b c
The values are averaged doses of the Dmean of the parotid glands, Dmax of the
spine and the mandible, D2cc of spine in the CTplan, CT15, and CT25. A value of Figure 1: (a‑c) Coronal images of the CTplan, CT15, and CT25 showing
P<0.05 is statistically significant. SD=Standard deviation parotid volume changes and the VTD increase

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Ilangovan, et al.: Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study
Figure 2: Dose‑volume histogram of the parotid gland dose in the three
computed tomography scans
This has been said to be because the more sensitive acinar
cells succumb to radiotherapy in the early weeks and the
less sensitive cells remain with smaller volume changes
thereafter.[23] In general, a replanning at this juncture might
lead to improved preservations of the critical structures and
thereby help us achieve the goal with which we started the
radiotherapy treatment planning. The changes in the dose to
the spinal canal and the mandible were similar to other studies
and were within their tolerance levels.[20]
CONCLUSION
It was observed that the target volumes and the normal
structures underwent changes during the course of
radiotherapy. There was a reduction in the volumes of the GTV,
CTV, and the parotid glands. The subsequent dose changes
were in the form of increase in the maximum dose to the
PTV‑HR and PTV‑IR and decrease in the minimum dose. The
total volume covered by the prescription isodose line also
increased leading to irradiation of more adjacent normal
tissue. The dose changes to the normal structures were in
the form of increase in the mean dose to the parotid glands
and the maximum dose to the mandible and spine. Of the
normal structures analyzed, the increase in the mean dose
to the parotid glands may reflect as an increase in the rate of
incidence of xerostomia. Although other variables also have
been studied, such as the mean dose to the soft palate and
submandibular glands, the mean dose to the parotid gland
remains a factor that can be controlled assessment of the
volume changes.[24] These changes are statistically significant
even after 15 fractions of radiation. Hence, a replan at this
juncture might be beneficial in reducing long‑term toxicities.
Furthermore, the use of models[25] to choose the patients who
might benefit from the replanning may help in optimal use
of the technique.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Journal of Cancer Research and Therapeutics - Volume 16 - Issue 3 - April-June 2020
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580 Journal of Cancer Research and Therapeutics - Volume 16 - Issue 3 - April-June 2020