METHODS
This prospective cohort study recruited nasopharyngeal cancer patients aged 18 or older. Radiation
planning adjustment was performed if at least one normal organ at-risk or target volume deviated from
the criteria.
RESULTS
A total of 11 patients were included as study subjects. After completing up to the 30th fraction of radiation,
8 of 11 patients lost more than 10% of their weight and required adjustments in their radiation
plan. The analysis of the relationship between the fractionation time and planning adjustment showed
the greatest increase in fractions 11 to 16, RR: 2.83 (1.74-4.61) and 4.76 (2.35-9.65), with a statistically
significant result (p=0.000). The widest neck separation demonstrated the highest sensitivity of plan adjustment
need (93.3%) and specificity (87.5%) at 1.21 cm with an area under the curve (AUC) of 0.951
and a 95% CI of 0.905-0.996 (p<0.001). The mastoid tip separation showed the highest plan adjustment
need sensitivity of 93.3% and specificity of 40.6% at 0.435 cm with an AUC of 0.741, 95% CI 0.631-0.852
(p<0.001). The Δ body weight percentage showed the plan adjustment needs a sensitivity of 91.1% and
specificity of 81.2% at 4.49 with an AUC of 0.911, 95% CI 0.844-0978 (p<0.001).
CONCLUSION
The radiation planning adjustment in patients with locally advanced nasopharyngeal cancer is suggested
at the 16th fraction, the 3rd week. It is recommended at the widest lymph node area separation of 1.21 cm
or a weight loss percentage of 4.49%.
Keywords: Nasopharyngeal cancer; radiation dosimetry; radiotherapy
Several studies reported that patients with headand-
neck cancer experienced significant body contour
changes in the radiation area in the 6-7th week of radiation,
one of which was due to a reduction in tumor size.
[
The dosimetry changes may cause a decreased
therapeutic ratio due to body contour changes that
occur during radiation, manifested as the loosening
of the head-and-neck thermoplastic mask. Stauch et
al.[
Hansen et al.[
The subjects were patients aged 18 years or more who were diagnosed with nasopharyngeal cancer. The inclusion criteria were patients subjected to kilovoltage cone beam CT (kV-CBCT) with a thickness of 2 mm by scanning the area from the vertex to below the clavicle, radiation planning carried out at TPS Monaco, and radiation at Versa using kV-CBCT every 5 fractions. Patients who did not complete the planned radiation, who had previously undergone external radiation, and patients with a radiation gap of >5 consecutive days or a total of 10 days were excluded.
The patients underwent a CT simulator with a
thickness of 2 mm per slice, which includes the head
vertex up to 2 cm below the sternoclavicular joint, to
calculate the radiation dose exposed to the brain that
may receive further toxic effects due to radiation. In the
delineation, the images produced by the CT simulator
were fused with previous images, either in the form of
magnetic resonance imaging (MRI) or positron emission
CT (PET-CT) scans. In nasopharyngeal cancer,
MRI was used to determine the target delineation of
the primary tumor (GTVp) more accurately and was
done within 2-3 weeks before the simulation, while
PET-CT is more used as a guide in identifying tumors,
especially in small lymph nodes that can be missed on
CT and MRI scans. It is recommended to make clinical
target volume (CTV) adjustments based on the nature
of tumor invasion and its anatomical relationship with
surrounding soft tissue. The cranial base is not considered
a strong barrier like other cortical bones, so delin eation adjustments were not necessary after 5 mm of
expansion into the cranial base.[
The following are delineation recommendations for
nasopharyngeal cancer CTV:[
a. High Dose CTVp1
• Margin of GTVp: GTVp + 5 mm (± Whole Nasopharynx)
• Minimum margin if near a critical organ: GTVp
+ 1 mm.
b. High Dose CTVn1
• Margin of nodal GTV (GTVn): GTVn+5 mm
(consider 1 cm if there is extracapsular extension).
c. Intermediate Dose CTVp2
• Margin of GTV: GTVp + 10 mm + Whole Nasopharynx
• Nasal cavity, the posterior part: At least covers
the anterior 5 mm of the choana
• Maxillary sinus, posteriorly: Extends at least 5
mm anteriorly from the posterior wall of the
maxilla
• Posterior ethmoid sinuses: Covers the vomer
area
• Base cranial: Includes the foramen ovale, rotundum,
lacerum, and the petrous edge
• Sinus cavernous: Included area of T3-T4 tumor
on the involved side
• Pterygoid fossa: Insert the entire fossa into the
CTV area
• Parapharyngeal space: Inserted into the CTV
area
• Sphenoid sinus: Inserted ½ inferior parts if the
tumor is T1-T2, and the entire sphenoid is inserted
if it is T3-T4
• Clivus: Insert 1/3 of the area if there is no clivus
invasion and insert the whole if there is clivus
invasion
• Minimum margin if the tumor is close to critical
organs: GTVp + 2 mm.
d. Intermediate dose CTVn2
• Margin of GTVn: CTVn1+5 mm
• Bilateral negative lymph nodes: Include levels II,
III, Va, VIIa, VIIb, and at least 1 level below the
level of the involved lymph nodes
• Level Ib: Included if lymph nodes are positive
at level Ib, submandibular nodes are involved,
there is the extracapsular extension at level II,
and there is the involvement of structures with
major drainage at level Ib
• If there is no involvement, the level Ib ipsilateral
area can be excluded.
e. Low dose CTVn3
• IV and Vb levels up to the clavicle are included
if cervical lymph nodes are involved.
The dose prescription was conducted based on a
study conducted by Lee et al., specifically that ≥95%
of the prescription dose covers 100% of the volume of
the planning target volume (PTV), or ≥93% of the prescription
dose covers ≥99% of the volume of the PTV.
Meanwhile, for OAR in nasopharyngeal cancer, the
dose limits were given according to the recommendations
by Lee et al.[
The CT data sets were sent to the Eclipse TPS for
contouring. The contouring was carried out by medical
residents and reviewed separately by two radiation
oncologists based on international guidelines for the
delineation of the CTV for nasopharyngeal carcinoma.
Afterward, the patients were given a dose prescription.
Simultaneous Integrated boost with a dose of 70/60/54
Gy in 33 fractions, and constraints were determined
according to the Deviation Protocol on target organs
and OAR.
Radiation planning was made by two medical physicists
after receiving the dosage prescription and dose
limits to normal organs that had been previously determined.
The radiation planning was then reviewed separately
by two radiation oncologists. The positioning
was verified using kV-CBCT in the first fraction and
each of the next 5 fractions in each patient. The kVCBCT
images and the images used for radiation planning
or CT planning were verified through automatic
and manual co-registration based on the bone and soft
tissue anatomy with a displacement tolerance of 3 mm
from the isocenter. This was conducted by a radiation
oncology resident under the supervision of a radiation
oncologist. The radiation was then given to the Versa
HDlinear Accelerator (LINAC).
To compare the dosimetry, contouring was performed
on the kV-CBCT image in each fraction
against the target volume, and OAR was selected
based on clinical preference. Fusion was performed
between the kV-CBCT image on the Versa HD LINAC
and the CT simulator planning image carried out
previously by 2 radiation oncologists and 1 medical
physicist to reduce bias due to the selection of different bone landmarks. For each patient, all planning parameters
were recalculated using kV-CBCT images.
Using the kV-CBCT calibration curve, the simulated
dose distribution based on the kV-CBCT weekly fraction
image was evaluated. Dosimetry evaluation results
were recorded on the OAR and target volume for
each kV-CBCT. Radiation planning adjustment was
carried out in the presence of a deviation in at least
one normal OAR or target volume according to the
specified criteria. If the dosimetry deviation criteria
were met but occurred in fraction 31, the radiation
planning adjustment was unnecessary.
The dosimetry data were analyzed with the Statistical
Program for the Social Science version 23.0.
The analysis of the numerical data distribution was
carried out using Shapiro-Wilk. The relationship between
numerical variables and the radiation planning
adjustment criteria conducted with logistic regression
and sensitivity analysis as presented in the receiver
operating curve. Chi-square and Fischer exact
tests were carried out to determine the relationship
between categorical variables.
The mean age of the subjects was 50±15.14 years, and the mean body weight was 62.2±11.16 years.
After completing up to the 30th fraction of radiation,
8 of 11 patients lost more than 10% of their weight and
required adjustments in their radiation plan. For the
widest neck separation, 10 out of 11 patients were found
to have decreased neck separation of more than 1.5 cm
and required adjustment to radiation planning, while the
results for changes in mastoid tip separation were varied.
There were only 1 out of 11 patients who did not require
adjustment to radiation planning with a body weight decrease
of 1.52%, a widest lymph node separation of 0.67
cm, and a mastoid tip separation of 1.71 cm in the 30th
fraction. Changes in dosimetry of GTVn were the most
common cause of radiation planning adjustments. The
characteristics of study subjects who required radiation
planning adjustments are presented in Table
Periodic measurements of all study participants
during radiation included body weight, widest neck
separation, and mastoid tip separation. When compared
to before undergoing radiation, all three parameters
showed increased values after radiation, as
can be seen in Figure
The target volume of GTVn had a dosimetry change
at D100 that widens as the number of fractions received
increases, with a significant change at the 16th fraction,
while for the mean dosimetry of GTVp, target volume
changes tend to be unstable. For Target CTV, the
dosimetry changes were also wider, with changes of up
to 2-3 times in the 31st fraction when compared to the
first fraction. The largest increase in CTV dosimetry
changes occurred in the 16th fraction compared to the
11th fraction in V95 CTV70 and V95 CTV54. There was
an increase in PTV in dosimetry changes as the number
of fractions increased in V95 PTV70 and V95 PTV60,
but it tended to be unstable in V95 PTV54. Normal organs
at risk of the optic chiasma, spinal cord, and brainstem
showed an increase in dosimetry changes, but the
right optic nerve showed a decreasing trend of dosimetry
changes in the 20th fraction, and the left optic nerve
decreased after the 26th fraction as can be seen in Table
The bivariate analysis was conducted with Chisquare
and Fischer tests to investigate the relationship
between time of fractionation and radiation planning
adjustment, as can be seen in Table
The cutoffs of the three clinical parameters were
evaluated using the receiver operating characteristic.
The widest neck separation demonstrated the highest
sensitivity (93.3%) and specificity (87.5%) at 1.21 cm
with an area under the curve (AUC) of 0.951 and a 95%
CI of 0.905-0.996. The results were statistically significant
(p<0.001). As can be seen in Figure
ROC: Receiver operating characteristic.
The majority of the patients in this study used a thermoplastic Orfit mask (72.7%), while the remaining (27.3%) used a clear thermoplastic mask. The difference between these two masks is that there are more fixation points on clarity, namely 9 points, while Orfit has only 4 points. The current Orfit mask is a recycled mask, while the Klarity mask is disposable or a maximum of one-time recycled.
The results of the dose-volume histogram CT planning
evaluation showed that the patients received a
mean of 66.5 Gy, indicating the minimum dose needed
to reduce the risk of local recurrence.[
As with other head-and-neck cancers, clinically
significant changes in the form of the reduced size of
the primary tumor and lymph nodes and weight loss
occurred in nasopharyngeal cancer when external radiation
was performed. Cheng et al. demonstrated a
mean reduction in tumor size in the lymph nodes and
primary tumor of 16.2% and 9.1% at 30 Gy and 28.7%
and 13.1% at 50 Gy, respectively. It was difficult to determine
the GTV in the kV-CBCT data set so that the
existing contours were the result of the registration of
the contours in CT planning, which was then adjusted
based on the area that exits the body contour. Nonetheless,
Cheng et al. showed a response to reduced tumor
size in accordance with the measurement of the widest
neck separation, which underwent a 3-fold change in
separation compared to the first fraction, where the Δ
of the widest lymph node separation in the first fraction
changed from 0.62±0.51 cm to 1.7±0.87 cm in the
16th fraction, which corresponds to week 3 or having
received a dose of 30 Gy. At the mastoid tip, the Δ separation
increased from 0.3±0.3 to 1.1±0.5 at week 3.[
Weight loss often occurs in cases of nasopharyngeal
cancer. Cheng et al.[
The distribution of doses to the target volume
and normal organs at risk may experience a shift or
change of doses along with the anatomical changes
that occur during radiation. Fung et al.[
There are no guidelines yet on the best time to
perform radiation planning adjustments. Gregoire
et al.[
In this study, the replanning was carried out based on
the determined criteria and when tolerance was interfered
with. Starting from the 6th fraction, there was a statistically
significant relative risk of 2.34 (1.52-3.61) for
replanning, with the most significant increase in the 16th
fraction (RR 4.76, 2.35-9.65). Among the three studied
clinical parameters, the widest separation had the highest
sensitivity and specificity at 1.21 cm with an AUC of
0.951, 95% CI 0.905-0.996. The widest separation parameter
was better than the separation on the mastoid
tip, which has the best sensitivity at 0.435 cm, namely
93.3%, but with a specificity of 40.6% and an AUC of
0.741 (95% CI 0.631-0.852). The weight loss body had
the highest sensitivity (91.1%) and specificity (81.2%) at
4.49% with an AUC of 0.911, 95% CI 0.844-0.978.
Advanced toxicity in nasopharyngeal cancer can reduce
the patient's quality of life. Radiation techniques
with IMRT are currently associated with reduced toxicity
compared to 2DRT. Several studies reported that
with the IMRT technique, toxicity to the neural system
has a low rate, such as the incidence of temporal lobe
radionecrosis, which is 0.2%. In the area of the chiasma
and optic nerve, the incidence of radiation-induced optic
neuropathy is quite low, with a Dmax of <55 Gy in radiation
and a fraction of 2 Gy. Lee et al. recommended
giving a dose of D0.03 cc at PRV <54 Gy and maximum
acceptance criteria (MAC) <60 Gy. In this brainstem
case, Lee et al.[
Limitations of the Study
This study has several limitations, including poor image
quality produced by kV-CBCT compared to CT
simulators, the use of partially recycled masks, and different
fixation points.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the Universitas Indonesia Faculty of Medicine Ethics Committee (no: KET-183/UN2.F1/ETIK/PPM.00.02/2022, date: 21/02/2022).
Financial Support: None declared.
Authorship contributions: Concept - A.R.B., S.M.S., H.K., H., N.N., E.H.; Design - A.R.B., S.M.S., H.K., H., N.N., E.H.; Supervision - A.R.B., S.M.S., H.K., H., N.N., E.H.; Materials - A.R.B., S.M.S., H., N.N.; Data collection and/or processing - A.R.B., S.M.S., H.K.; Data analysis and/or interpretation - A.R.B., S.M.S., H.K., H., N.N., E.H.; Literature search - A.R.B., N.N., E.H.; Writing - A.R.B.; Critical review - A.R.B., S.M.S., H.K., H., N.N., E.H.