Radiotherapy and Oncology 98 (2011) 23–27
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Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com
Treatment planning of NPC
The role of replanning in fractionated intensity modulated radiotherapy
for nasopharyngeal carcinoma
Liang Zhao, Qiuyan Wan, Yongqiang Zhou, Xia Deng, Congyin Xie, Shixiu Wu ⇑
Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical College, China
a r t i c l e
i n f o
Article history:
Received 18 May 2010
Received in revised form 9 September 2010
Accepted 3 October 2010
Available online 30 October 2010
Keywords:
IMRT
Nasopharyngeal carcinoma
Replanning
Adaptive
Clinical outcome
a b s t r a c t
Background and purpose: Anatomic changing frequently occurred during fractionated radiotherapy. The
aims of this study were to model the potential benefit of adaptive IMRT replanning during fractionated
radiotherapy and its potential advantage over clinical outcome in patients with nasopharyngeal carcinoma.
Materials and methods: Thirty-three patients with repeat CT imaging and replanning were retrospectively
analyzed. 66 case-matched control patients without replanning were identified by matching for AJCC
stage, gender, and age. Hybrid IMRT plans were generated to evaluate the dosimetric changing. Mann–
Whitney–Wilcoxon tests were used to evaluate the effect of replanning on volumetric and dosimetric
outcomes within individuals. Kaplan–Meier estimators were used to estimate the survival function of
patients with or without replanning.
Results: The mean volume of the ipsilateral and contralateral parotid glands decreased during the treatment. The hybrid IMRT plans showed decreased doses to target volumes and increased doses to normal
structures in replanning. The clinical outcome comparison indicated that the IMRT replanning improved
the 3 years local progression–free survival for patients who had AJCC staged more than T3 (T3,4Nx) and
ease the late effects for patients who had large lymph nodes (AJCC stage TxN2,3).
Conclusion: Repeat CT imaging and IMRT replanning were recommendatory for specific nasopharyngeal
carcinoma patients.
Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) 23–37
Anatomic changes were common response during radiotherapy
[1]. Generally, the nasopharyngeal carcinoma (NPC) is believed to
be sensitive to radiotherapy, both in lymph nodes and original tumors. Therefore, most of NPC patients were found to have changes
in anatomical structures during the course of treatment due to tumor shrinkage and/or weight loss, and/or parotid shrinkage. Barker
et al. have previously reported, using repeated CT scans throughout
a 7-week radiotherapy course, a 70% reduction of the gross tumor
volumes (GTV), together with the substantial changes in the anatomical structures including external neck contour modifications,
medial shift of normal structures due to tumor shrinkage and
weight loss, and parotid shrinkage [2]. Hansen et al. reported similar findings. They evaluated the effects of anatomical structure
changes on dosimetry by using ‘‘hybrid technique” [3]. Similar
findings also have been reported by Geets et al. who demonstrated
the theoretical gain that could be achieved from recalculating the
dose distribution throughout the course of radiotherapy, i.e. using
adaptive radiotherapy (ART) [4,5]. Therefore, methods of deformable registration (DR) algorithms were developed to evaluate more
⇑ Corresponding author. Address: Department of Radiation Oncology, The First
Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
E-mail address: [email protected] (S. Wu).
0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.radonc.2010.10.009
precisely the real impact of re-imaging during an adaptive planning [6–12] and various in-room image systems were applied to
patient repositioning and online re-optimization or off-line replanning [13–15].
However, adaptive strategies indicate both additional cost to
patients and workload to clinical staffs. Though the general impact
of replanning on dosimetric changes is well-reported, Haasbeek
et al. questioned the necessity of adaptive planning for stereotactic
radiotherapy of stage I non-small-cell lung cancer and showed a
negative result [16]. Such issues led to some clinicians’ hesitating
to adopt adaptive planning. The aims of this study were to model
the potential benefit of adaptive IMRT replanning during a course
of fractionated radiotherapy for NPC patients and to investigate
whether the dosimetric benefits from replanning could lead to estimable clinical outcome.
Methods and materials
Patients
We retrospectively reviewed the database of 175 patients with
NPC treated with IMRT by using BrainLAB’s IMRT system (BrainLAB
AG, Heimstetten, Germany) between December 2002 and August
2007. There were 158 patients observed with obvious anatomic
24
IMRT replanning for nasopharyngeal carcinoma
changes (including tumor shrinkage, nodal shrinkage and/or
weight loss) before 20 fractions irradiation of 2.0 Gy per fraction.
All patients had NPC with AJCC stage II-IV. Thirty-three of those patients who had repeat CT imaging and replanning during their
courses of treatment (9 of patients had third CT imaging and second replanning) were selected as group ‘‘replanning”. The reason
why re-imaging and replanning were performed were due to tumor and/or nodal shrinkage (16 patients), weight loss (10 patients), or both (7 patients). Sixty-six control patients without
replanning were selected as group ‘‘no replanning” by matching
for AJCC stage and type of anatomic changes. All patients in these
two groups did not develop distant metastases. All the early and
late side effect scoring followed the RTOG/EOTRC radiation morbidity scoring.
Treatment planning
Before treatment, all the patients were immobilized with BrainLAB’s noninvasive thermoplastic mask and localizer frame system,
and CT simulation according to standard procedures. All CT scans
were obtained on a spiral CT scanner using 3-mm slice spacing.
Magnetic resonance scans and fusion with simulation CT images
were performed to assist the targets delineation. Based on the optimized CT images, two principal oncologists were responsible for
delineating the target volume and critical organs for all NPC patients treated in our center.
Gross tumor volume (GTV) was defined as the mass shown in
the enhanced CT images, including the nasopharyngeal tumor, retropharyngeal lymphadenopathy, and enlarged neck nodes. The
clinical tumor volume (CTV) was usually defined as the GTV plus
a margin of potential microscopic spread, and including the nasopharynx, retropharyngeal nodes, clivus, skull base, pterygoid fossae, parapharyngeal space, inferior sphenoid sinus, posterior
third of the nasal cavity, and maxillary sinuses. Two CTV volumes
were often used: CTV1 was designed differently to encompass the
inferior sphenoid sinus, clivus, skull base, nasopharynx, ipsilateral
parapharyngeal space, and posterior third of the nasal cavity and
maxillary sinuses. The ipsilateral neck nodes of level 1,2,3,5 were
also included. CTV2 contained the contralateral parapharyngeal
space and neck nodes of level 1,2,3,5. The middle and/or lower
neck fields were treated with a single anterior field jointed by conventional radiotherapy and matched to the IMRT field using a splitbeam technique. Organs at risk, such as brainstem, spinal cord, parotid glands, optic nerves, chiasm, pituitary, temporomandibular
joints, and middle and inner ears were also outlined. However,
only the brainstem, spinal cord, parotid glands, and lens were specified as organs at risk for inverse planning with different weights
[17].
Simultaneous modulated accelerated radiotherapy technique
was adopted in our center. The dose prescribed to GTV was
2.5 Gy per fraction and to CTV1 and CTV 2 was 2.0 Gy per fraction,
respectively, with a total dose of 70 Gy and 56 Gy delivered in 28
fractions within 6 weeks. The prophylactic irradiation dose to neck
field was 45–46 Gy at a depth of 3 cm from the anterior surface, given in 23–25 fractions at 1.8–2.0 Gy/fraction. The clinically involved neck nodes were boosted to 70 Gy using electron beam.
All treatment plans were generated with BrainLAB’s inverse planning system (with 7 equally spaced coplanar beams positioned
every 40° from the posterior and lateral directions).
CT re-scanning and IMRT replanning
A second planning CT scan was acquired for the 33 patients, due
to clinically observed changes in patient anatomy (by inspection,
palpation, and/or direct endoscopy) or measured weight loss by
the attending physician during the course of treatment, The first
thermoplastic mask no longer fit tightly for 23 patients, and new
masks were made for immobilization. No attempts were made to
restore patient positioning to exactly the same as it had been in
the first CT scan. Of nine patients, by applied ‘‘hybrid technique”,
the evaluated cumulative doses to critical organs might be higher
than the dose limit caused by the anatomic change after the second
replanning, therefore, a third planning CT scan was indicated. The
new CT scan was used to generate a new IMRT plan for the remaining fractions of treatment. Attempts were made to maintain the
original CTVs with modification that adapt to the changes in anatomic structure displayed in the second CT scans. GTVs were recontoured according to the shrinkage or/and distortion of primary
tumor or lymph nodes shown in the new CT scans by the same
physician. Normal structures and critical organs were contoured
as planned. All patients were seen and examined by a physician
at least once per week during the course of treatment, and monitoring diagnosis CT were applied judged by the oncologist.
Volume comparisons
Target volumes and normal tissue volumes were compared between the different CT scans with a paired samples analysis. Only
risk organs, such as spinal cord, brainstem, and parotid gland were
included in analysis. The generous treatment volume was also outlined from the posterior clinoid bone superiorly to a fixed distance
inferiorly that covered all gross disease in the neck with at least
5 mm margin and was included in comparison for each patient.
Dosimetry comparisons
The ‘‘hybrid technique” reported by Hansen et al. [3] was used
to evaluate the dosimetric difference between replanning and no
replanning. For each IMRT plan, dose–volume histograms (DVHs)
were calculated for target volumes and normal structures. The replanned one was then compared to the corresponding original plan
without replanning to investigate the effects of anatomic changes
on dosimetric outcomes. The comparison accounted for only the
number of fractions delivered by the replanned IMRT plan. In this
setting, the DVHs for the portion of treatment can be directly compared with and without replanning.
QA for re-scanning and replanning
To eliminate the setup errors between two CT scan simulations,
the spatial relationship of the isocenters of the two CT scans was
established by using CT–CT fusion based on bony landmarks for
each patient.
To ensure that the replanned plans were consistent in their
quality and dosimetric outcomes, the 2D film dosimetry verifications were performed.
Statistics
Descriptive statistics were calculated to characterize the dose
and volume parameters for normal tissues and target volumes.
Comparisons between the paired CT volume measurements and
between dosimetric parameters with and without replanning were
analyzed using analysis of variance methods for repeated measures. Mann–Whitney–Wilcoxon tests were used to evaluate the
effect of replanning on dosimetric outcomes within individuals.
Kaplan–Meier estimators were used to estimate the survival function of patients with or without replanning. A probability value less
than 0.05 was considered significant. No adjustments for multiple
comparisons in determining significance were made. All statistics
were calculated by using SPSS 13.0 statistical software (SPSS Inc.,
Chicago, USA).
25
L. Zhao et al. / Radiotherapy and Oncology 98 (2011) 23–27
Results
Table 1
Volume comparisons between original plans and first replans.
Patient characteristics
The average number of radiation fractions delivered between
first and second CT scans was 15 (±5) fractions. The mean time span
between the first and second CT scans was 21 (±8) days. For patients
who had third CT scans, the average number of radiation fractions
delivered between the second and third CT scans was 12 (±4) fractions. The mean time span between the second and third CT scans
was 15 (±5) days. For all 99 patients, the mean PTV volume was
370.30 ± 95.45 cc, the mean contoured tumor volume was
31.95 ± 24.69 cc, and the mean contoured lymph nodes volume
was 19.96 ± 30.53 cc. For 33 patients who had replanning, the mean
PTV volume was 377.54 ± 93.04 cc, the mean contoured tumor volume was 37.65 ± 24.32 cc, and the contoured lymph nodes volume
was 19.83 ± 36.20 cc for the initial CT scans. For 66 patients without
replanning, the mean PTV volume was 367.40 ± 96.79 cc, the mean
contoured tumor volume was 29.10 ± 24.39 cc, and the contoured
lymph nodes volume was 20.03 ± 27.25 cc.
Tumor and nodal shrinkage were observed in all the 33 replanning patients and 66 no replanning patients by the monitoring
diagnosis CT. In replanning patients, the mean tumor shrinkage
volume was 4.14 ± 2.23 cc after 10 fractions and 32.51 ± 10.75 cc
after 20 fractions, the mean nodal shrinkage was 15.33 ± 21.74 cc
after 10 fractions and 17.27 ± 22.46 cc after 20 fractions. In no
replanning patients, the mean tumor shrinkage volume was
3.86 ± 2.42 cc after 10 fractions and 30.12 ± 11.82 cc after 20 fractions, the mean nodal shrinkage was 15.54 ± 20.81 cc after 10 fractions and 18.13 ± 21.57 cc. after 20 fractions.
Volume comparisons
Table 1 lists the volumes of the normal tissues and target volumes in the original plans and the first replans for the patients
with replanning. The mean volume of ipsilateral parotid glands
was significantly decreased during the treatment (p = 0.05). The
mean volume of contralateral parotid glands variations was not
significant (p = 0.06). There were no significant differences observed in the volumes of other contoured normal structures among
the consecutive CT scans including the spinal cord, brainstem, and
lens. There was no significant difference in the volume of the GTVs
for original tumor between the first and second CT scans (p = 0.83),
whereas GTVs decreased significantly in the third CT scans for
those 9 patients who had second replans (p = 0.003). The volume
of lymph nodes decreased during the first and second CT scans
(p < 0.001), but it showed no significant difference between the
second and third CT scans for those 9 patients who had second replans (p = 0.09).
Dosimetry comparisons
There were no significant qualitative dosimetric differences
among the different IMRT plans (based on their corresponding CT
scans) that might have accounted for the differences seen when
compared to the hybrid plans. However, when comparing the dosimetric results of replanning vs. no replanning, the hybrid IMRT
plans (without replanning) demonstrated both decreased doses
to target volumes and increased doses to normal structures. Table
2 showed the dosimetric differences between replanning and no
replanning. For CTV the mean dose to 99% of the volume (D99),
the mean dose to 95% of the volume (D95), and the mean percent
of the volume receiving =95% of the prescribed dose (V95) all decreased without replanning. The doses to target volumes decreased
in the plans without replanning, whereas the doses to normal
structures without replanning increased. The mean maximum dose
(Dmax) and the mean dose to 1 cc (D1 cc) of the spinal cord both
Mean volume (cc)
Out line
GTV(t)
GTV(l)
CTV
Brainstem
Cord
Iparotid
Cparotid
Original plan on 1st CT
1st Replan on 2nd CT
P value
4875
37.65
19.83
377.54
27.01
16.46
32.77
34.91
4663
32.41
5.56
364.32
29.66
17.37
30.58
34.48
0.79
0.83
<0.001
0.66
0.47
0.49
0.05
0.06
Out line = defined external skin surface volume; GTV(t) = planned target volume of
tumor; GTV(l) = planned target volume of lymph nodes; CTV = planned target volume of clinical target volume; I parotid = ipsilateral parotid; C parotid = contralateral parotid.
Table 2
Dosimetry comparisons for 33 replanned patients by using ‘‘hybrid technique”.
1st CT
GTV
D99 (Gy)
D95 (Gy)
V95
CTV
D99 (Gy)
D95 (Gy)
V95
Spinal cord
Dmax (Gy)
D1 cc (Gy)
Brainstem
Dmax (Gy)
D1 cc (Gy)
D1% (Gy)
Iparotid
Dmean (Gy)
D50 (Gy)
V57
Cparotid
Dmean (Gy)
D50 (Gy)
V46
2nd CT
1st plan
2nd plan
1st plan
P value
2.44
2.48
99.30%
2.43
2.46
99.50%
2.48
2.52
100%
0.307
0.305
0.671
1.88
1.92
98.40%
1.84
1.91
97.40%
1.14
1.64
84.79%
0.034
0.052
0.047
1.38
1.33
1.26
1.24
1.58
1.36
0.063
0.057
1.40
1.32
1.35
1.54
1.50
1.52
1.64
1.36
1.44
0.12
0.27
0.22
1.20
1.00
28.30%
1.22
0.98
26.83%
1.30
1.06
39.29%
0.08
0.11
0.04
0.87
0.83
38.26%
0.77
0.74
28.51%
1.12
0.94
52.72%
0.03
0.04
0.03
GTV and CTV = planning target volumes of gross tumor volume and clinical tumor
volume, respectively; Dmax = maximum dose per fraction; D99 = dose to 99% of the
volume per fraction; D95 = dose to 95% of the volume per fraction; V95 = percent of
volume receiving P93% of the prescribed dose; D1 cc = dose to 1 cc of the volume
per fraction; D1% = dose to 1% of the volume per fraction; Dmean = mean dose per
fraction; D50 = dose to 50% of the volume per fraction; V57 and V46 = percent of
volume receiving 57% and 46% prescribed dose (2 Gy), respectively.
increased without replanning (p = 0.002, p = 0.03, respectively),
and also the mean maximum dose (Dmax) and the mean dose to
1 cc (D1 cc) of the brainstem both increased without replanning
(p = 0.007, p = 0.04, respectively). All dosimetric end points for
the parotid gland increased without replanning, including the
mean dose (Dmean), the dose to 50% of the volume (D50), the percent of the volume of the contralateral parotid gland receiving
>26 Gy (V26) and the the percent of the volume of the ipsilateral
parotid gland receiving >32 Gy (V32). All these situations could induce unexpected results to the clinical prescription.
Clinical outcome
The median follow-up from the completion of radiotherapy was
38 months (range, 3–75 months) for patients with IMRT replanning and 40 months (range, 3–80 months) for patients without
IMRT replanning. Results of Kaplan–Meier estimator were shown
26
IMRT replanning for nasopharyngeal carcinoma
in Fig. 1. For patients with replanning: The 3-year local relapse–
free survival was 72.71%, and median local relapse–free survival
was 50 months. (95% CI, 43.18-58.46). For patients without replanning: The 3-year local relapse–free survival was 68.16% and median local relapse–free survival was 48 months. (95% CI, 44.03–
53.52). The replanning patients showed no significant difference
with the no replanning patients in survival (p = 0.34). For patients
who had AJCC stage more than T3 (T3,4Nx),there were significant
trends in improvement of the 3-year local relapse–free survival
in patients with replanning compared to patients without replanning (p = 0.03). There was no significant difference for both early
and late side effects of patients between replanning and no replanning (p = 0.35, p = 0.07, respectively). For patients who had large
lymph nodes volume (AJCC stage TxN2,3), the 3-year local relapse–free survival and early side effects of patients showed no significant difference between replanning and no replanning
(p = 0.58, p = 0.22, respectively). For the late side effects, there were
no significant difference with neuritis, skin and auditory damages
(p = 0.31, p = 0.52 and p = 037, respectively); the severity of injury
of mucosa and xerostomia in replanning patients was marginally
improved than in no replanning patients (p = 0.05 and p = 0.04,
respectively) (Fig. 2).
Discussion
Our dosimetric results showed that IMRT replanning based on
repeat CT imaging was beneficial to ensure adequate doses to target volumes and safe doses to normal structures for patients who
have clinically identified anatomic changes during the course of
IMRT in nasopharyngeal carcinoma. Without replanning during
treatment, the doses to normal structures were significantly increased and doses to target volume significantly decreased. It
was consistent with conclusions of previous published papers in
head and neck cancers [2–5]. Though the general effect of replanning on dosimetric changes is well-reported, previous works seldom evaluated the clinical outcome affected by such dosimetric
changes in head and neck cancer. Haasbeek et al. [16] reported a
study of adaptive treatment planning of stereotactic radiotherapy
for stage I non-small-cell lung cancer, and the results of their study
indicated that adaptive treatment planning was of limited value for
fractionated stereotactic radiotherapy. Even when using ‘‘hybrid
technique” or any other images registration algorithms, we still
could never fuse and get the exact treatment doses in the exact
same pixels between CT images and calculated the exact cumula-
Fig. 2. Comparison of late effects between NPC patients (AJCC staged TxN2,3) with
and without IMRT replanning: 8 patients in replanning group;20 patients in no
replanning group.
tive treatment doses for replanning. This raises the issue whether
the theoretical dosimetric effects would lead to significant clinical
outcome difference.
Our study showed that the IMRT replanning can improve 3-year
local relapse–free survival for patients who had AJCC stage more
than T3 (T3,4Nx) and significantly alleviated the late effects (injury
of mucosa and xerostomia) for patients who had large lymph
nodes (AJCC stage TxN2,3). One important issue was that most of
the replanning patients had early tumor response resulted in anatomical changes. This might bring the question to the credibility of
the clinical omtcome to this study. However, early tumor response
was common in NPC receiving radiotherapy and there was no clear
relationship between early tumor response and long term clinical
outcome [18]. In order to evaluate whether the comparison of
the two groups of patients was interfered by the early tumor response, the interfraction tumor regressions of all patients were
evaluated by reconstructing the diagnosis CT images during treatment. It showed no significant difference of tumor shrinkage rate
between two groups. Therefore, the effects of early tumor response
should be minimized in this study.
Despite the dosimetric comparison in early staged NPC patients
being significant our study showed that early staged NPC patients
could receive limited benefits from IMRT replanning. Similar to the
negative results reported on early staged non-small-cell lung cancer [14].The reasons of such a deviation might be due to: (1) the
Fig. 1. Kaplan–Meier estimators of local relapse–free survival for NPC patients with and without IMRT replanning: (a) AJCC staged T1,2N0,1 patients: 14 patients in replanning
group; 28 patients in no replanning group (b) AJCC staged T3,4Nx patients: 19 patients in replanning group; 38 patients in no replanning group.
L. Zhao et al. / Radiotherapy and Oncology 98 (2011) 23–27
registration algorithm we used to fuse the two sets of CT images
were not good enough and needed to be modified. (2) The overall
survival in early staged NPC patients after IMRT is excellent. Therefore, the benefit of such adaptive strategy was concealed.
The implementation of repeat CT imaging and IMRT replanning
include the increased workload for clinical staff, the increased use
of limited simulation and treatment machine time, the increased
workload for physicists and dosimetrists, and the increased physician time spent in recontouring target volumes and normal structures. Moreover, there may be a significant financial burden on the
treating institution, because of the increased cost of reimaging and
replanning, especially given that there may be no reimbursement
for these processes. In our study, those patients who had observable anatomic changes during fractionated radiotherapy can benefit
from replanning, suggesting that the volumes regression and
shape/position shift during the course of radiotherapy be monitored by on-line image system and CT based replanning be performed if the anatomic changes were observable.
Another important concern is how to delineate targets volumes
on repeat CT scans obtained during the course of IMRT. Since tumor composition was heterogeneous, tumor volumes were not
reflective of the amount of actively replicating cancerous tissue
[19]. It is not clear yet whether regressing tumors leave behind
nests of cells that should be treated further or whether smaller
fields adequately encompass sub-clinical disease. Hansen et al.
[3] chose to maintain the size of the original GTV when contouring
the GTV on the anatomy of the second CT scans. In our study, we
chose to adapt the GTV to the observed tumors or lymph nodes
volumes on the anatomy of the second CT scans, but maintain
the size of the original CTV. Excellent local-regional control had
been achieved in our NPC series treated by IMRT [17]. In addition,
smaller high dose treatment volume can alleviate the acute/late
toxicities.
At present, we acquire a repeat CT scan during the course of
IMRT for NPC patients who develop significant tumor shrinkage,
weight loss, and/or a loose-fitting mask that causes difficulty in
accurate repositioning. Clinician judgment plays the key role in
determining the need for a new CT scan. Ongoing studies in our
clinic will help to identify specific predictive factors that contribute
to reimaging and replanning. Since the technique of online imaging
was well applied in routine practice, the anatomy changing during
the treatment can be monitored more closely than before. It is
helpful to the applications of interfraction adaptive planning by
repeating CT scan and IMRT replanning. Future prospective studies
with larger sample sizes and better deformable registration algorithm will help to validate the criteria for repeat CT imaging and
IMRT replanning in NPC patients undergoing radiotherapy.
Conclusion
This study indicated that NPC patients (patients with AJCC
staged of late T or N) might potentially benefit from repeat CT
imaging and IMRT replanning, whereas NPC patients at early stage
(AJCC staged T1,2N0,1) could not benefit from IMRT replanning.
Therefore, repeat CT imaging and IMRT replanning were recommendatory for specific NPC patient population.
27
Acknowledgement
This study was supported by a grant from Science and Technology Department of Zhejiang Province of China: Major Program of
high incidence disease prevention and control (No. 2007C13054),
Major program of Wenzhou Science & Technology Bureau (No.
s20070026) and Natural Science Foundation of Zhejiang Province
(No. Y2110007).
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