CLINICAL STUDY OF THE NECESSITY OF REPLANNING BEFORE THE 25TH
FRACTION DURING THE COURSE OF INTENSITY-MODULATED RADIOTHERAPY
FOR PATIENTS WITH NASOPHARYNGEAL CARCINOMA
WEI WANG, B.S.,* HAIHUA YANG, M.D.,* WEI HU, M.D.,* GUOPING SHAN, B.S.,* WEIJUN DING, M.D.,*
CHANGHUI YU, B.S.,* BIYUN WANG, M.D.,* XUFENG WANG, B.S.,* AND QIANYI XU, PH.D.y
*Department of Radiation Oncology, Taizhou Hospital, Wenzhou Medical College, Taizhou, Zhejiang, China; andyDepartment of
Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
Purpose: To quantify the target and normal structures on dose distributing variations during intensity-modulated
radiotherapy (IMRT) and to assess the value of replanning for nasopharyngeal carcinoma (NPC) patients.
33 fractions, to 70 to 76Gy, to the gross tumor volume (GTV). Before the 25th fraction of IMRT, a new simulation
computed tomography (CT) scan was acquired for all patients. According to the dose constraint criterion in the
Radiation Therapy Oncology Group (RTOG) 0225 protocol, the replanning was generated on the new simulation
CT. With the Quality Assessment Center of a CORVUS 6.3 treatment planning system, a phantom plan was gen-
CT. The dose–volume histograms of the phantom plan were compared with the replanning.
Results: The percentage of prescription dose delivered to the clinical target volume (CTV1) was significantly
increased by 4.91% ± 10.89%, whereas the maximum dose to the spinal cord, mean dose to the left parotid, and
V30 to the right parotid were significantly decreased by 5.00 ± 9.23Gy, 4.23 ± 10.03Gy, and 11.47% ± 18.89%
respectively in the replanning, compared with the phantom plan (p < 0.05). Based on the dose constraint criterion
tures, whereas no plan was out of limit in replanning (p < 0.001).
Conclusion: Replanning for patients with NPC before the 25th fraction during IMRT helps to ensure adequate
dose to the target volumes and safe doses to critical normal structures.
? 2010 Elsevier Inc.
Nasopharyngeal carcinoma, Intensity-modulated radiotherapy, Replanning.
Nasopharyngeal carcinoma (NPC) is one of the most
common head-and-neck cancers in Asia and Africa. Radio-
therapy (RT) has been the main treatment option for patients
with NPC for several decades because of the anatomically
challenging location and a demonstrated favorable response
to irradiation and chemotherapy (1–4). Over the past decade,
intensity-modulated radiation therapy (IMRT) has gained
popularity in the treatment of NPC because of its excellent
local control with decreased normal tissues effects. In
comparison with conventional radiotherapy, IMRT provided
ing of sensitive normal tissue structures in the treatment of
NPC (5–8). The sharp dose gradient common to IMRT plans
requires accurate dose delivery to the target volume. With
daily image guidance techniques becoming more widely
However, it was reported in several previous studies that
many patients undergoing RT for head-and-neck cancer
had significant anatomic changes during their course of treat-
ment, including shrinking of the primary tumor or nodal
masses and in overall body weight loss (9–15). A recent
study (9) has also demonstrated that anatomic changes in
ical structures appeared to be significant during the second
half of treatment and could potentially have a dosimetric
impact when highly conformal treatment techniques are
used. The IMRT technique is an example of of a highly con-
formal treatment approach; however, the dosimetric effect of
anatomic changes has not been extensively studied. In the
Oncology, Taizhou Hospital, Wenzhou Medical College, Taizhou,
317000, Zhejiang, China. Tel: +86-138-19639006; Fax: +86-576-
85199876; E-mail: email@example.com
The first and second authors contributed equally to this article.
This study was supported by Zhejiang Provincial Medical and
Health science Foundation of China (2008B198).
Conflict of interest: none.
Acknowledgment—The authors gratefully acknowledge Dr. Venka-
Received May 19, 2009, and in revised form Aug 17, 2009.
Accepted for publication Aug 17, 2009.
Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 2, pp. 617–621, 2010
Copyright ? 2010 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$–see front matter
present study, we focused on quantifying dose distribution
variations of the target and nearby critical structures caused
by anatomy shape and location changes for a group of
28 patients during the course of IMRT.
METHODS AND MATERIALS
From August 2007 to December 2008, a total of 28 patients
(median, 46 years; range, 28–73 years) with NPC treated with
IMRT who underwent repeat CT scanning and replanning before
the 25th fraction of IMRT were selected for this study. Of the 28
patients, 19 were male and 9 were female (male:female ratio,
2.1:1). Tumor biopsy specimens were obtained from all the patients
for histological examination. Pretreatment evaluation included
a complete medical history and physical examination, complete
blood count and chemistry profile determination, contrast-enhanced
computed tomography (CT) or/and magnetic resonance imaging
(MRI) of the head-and-neck region, Type B ultrasound of the ab-
dominal and cervix, and emission computed tomography bone
scan. The disease was staged according to the 2002 American Joint
Committee on Cancer (AJCC) staging classifications (16). Of the
patients, 1 was in pathologic Stage I disease, 12 were in Stage II,
6 were in Stage III, 7 were in Stage IVa, and 2 were in Stage IVb.
The specific characteristics of the patients were shown in Table 1.
All subjects gave their informed consent, and the study was
approved by the local ethics committee.
Simulation CT procedures
Before CT scanning, each patient was in the supine position and
was immobilized with a thermoplastic head-and-shoulder mask and
a head-and-shoulder board. The same patient position and orienta-
tion were maintained for two CT scans. All patients underwent
scanning through the head-and neck region (from the skull vertex
to 2 cm below the clavicles), and all scans were acquired on a GE
spiral CT (GE LightSpeed 16, Hinoshi, Tokyo, Japan) with 2.5-mm
2 days before the treatment that was used to generate an initial plan.
The second simulation CT scan was performed before the 25th
fraction of IMRT for replanning. Those simulation CT images
were transferred to the CORVUS inverse planning system (version
6.3, NOMOS Corporation, Cranberry Township, PA).
Delineation of target volume
The gross tumor volume (GTV) included the primary nasopha-
ryngeal tumor (GTVnx) and involved lymph nodes (GTVnd) as
shown by clinical information and endoscopic and radiologic
examinations (including CT and MRI). The clinical target volume
(CTV) included the high-risk regions (CTV1) and the low-risk
regions (CTV2). The planning target volume (PTV) covered the
CTV and 3-mm margins needed for systemic and random setup
were manually outlined slice by slice on the simulation CT images
by the same attending physician.
Treatment planning and delivery
Target prescription doses and critical structures limit doses were
according to the RTOG 0225 trial (17). The nasopharyngeal regions
and upper neck with IMRT plans were generated and approved for
each patient using a commercial inverse planning system (Cor-
vus6.3, NOMOS Corporation). The IMRT plan was delivered using
a sequential helical tomotherapy technique with special MLC
(MINIC, NOMOS), whereas a conventional anterior field was
used for the low-neck and supraclavicular regions.
Based on dose constraint criteria in the RTOG 0225 protocol, the
replanning was generated on the new simulation CT. To correct
patient setup error between the two CT scans, CT–CT fusion was
used. By using the Quality Assessment Center of CORVUS 6.3
treatment planning system, after the phantom shift was eliminated,
a phantom plan was generated for each patient by applying the
beam configurations of the initial plan to the anatomy of new simu-
lation CT. Thephantom planswere generated for eachpatient inthis
study to represent the actual dose distributing in which no replan-
ning would have occurred before the 25th fraction of IMRT.
A total of 70 to 76Gy at 2.12 to 2.3 Gy/fraction per day was
delivered to the GTVnx; the GTVnd received 66 to 70 Gy at 2.0
to 2.12 Gy/fraction per day; the CTV1 received 60 to 66 Gy at 1.8
to 1.8 Gy/fraction per day with IMRT. The low-neck and supracla-
vicular regions received 50 to 60 Gy at 2.0-Gy/fraction per day with
conventional radiotherapy. The replanning wasgenerated before the
25th fraction of IMRT and was used to complete the planned course
Dose–volume histograms (DVHs) were calculated for target
volumes and normal structures for each IMRT plan. For each
patient, the target volumes and normal structures on dose distribut-
ing variations between the phantom plan and replanning were
compared. This comparison included the prescription dose to
GTVnx and CTV1, the maximum dose to the spinal cord and brain-
stem, the mean dose of the parotid gland, and the percentage of the
volume of the parotid gland receiving $30 Gy and so forth in the
Table 1. Patient characteristics and tumor stage
Median 46 (range, 28–73)
Abbreviations: KPS = Karnofsky performance status score.
618I. J. Radiation Oncology d Biology d PhysicsVolume 77, Number 2, 2010
The Statistical Package for the Social Science (SPSS for
ysis. Values were expressed as mean ? SD, except for age, which
was expressed as median and range. Categorical variables are
presented as frequencies and percentages. The Chi-square test was
used for categorical variables. Comparisons between two plans
were performed by analysis of paired samples t test. All p values
are two-sided. A value of p < 0.05 was considered statistically
In the present study, in phantom plan and replanning, the
average of percentage of prescription dose of CTV1 were
86.71% ? 12.81% and 91.62% ? 7.78% respectively, the
average of percentage of prescription dose of GTVnx were
83.64% ? 22.77% and 91.39% ? 12.51%, respectively;
the average of maximum dose of the brain stem were 59.10
? 11.35 Gy and 55.05 ? 5.35 Gy; the average of brainstem
V50 were 3.82% ? 5.27% and 2.28% ? 3.29%; the average
of the left parotid gland V30 were 44.32% ? 21.89% and
36.26% ? 16.85%; the average of mean dose of the left
parotid gland were 32.16 ? 8.20 Gy and 27.93 ? 5.17 Gy;
the average of the right parotid gland V30 were 49.49% ?
22.37% and 38.02% ? 16.95%; the average of mean dose
of the right parotid gland were 32.42 ? 9.94 Gy and 29.26
? 7.17 Gy; the average of maximum dose of spinal cord
were the average of 48.68 ? 8.43 Gy and 43.68 ? 4.46
Gy; and the average of spinal cord V40 were 13.20% ?
19.85% and 5.07% ? 7.39%, respectively. The comparison
between these two plans showed better dose coverage for
the target and better sparing of the critical structures after
replanning. Overall doses to targets were increased in the
replanning and the doses to the surrounded normal structures
were decreased (Fig. 1).
In our study, a significant increase in the percentage of
prescription dose to CTV1 was observed in replanning
compared with that in the phantom plan. The mean
increment was 4.91% ? 10.89% (95% CI, 0.68–9.13Gy;
p = 0.024). The maximum dose of the spinal cord, mean
dose of the left parotid gland and right parotid gland V30
were decreased significantly in replanning (p < 0.01) by
5.00 ? 9.23 Gy (95% CI, 1.42–8.58Gy, p = 0.008), 4.23
? 10.03 Gy (95% CI, 0.35–8.12 Gy, p = 0.034), and
11.47% ? 18.89% (95% CI, 4.15–18.80%, p = 0.003)
respectively (Table 2).
Based on the dose constraint criteria in RTOG0225 proto-
col, comparison of conformity indices for two plans, the dose
of the normal critical structures for 50% (14/28) of the phan-
tom plan were out of limit compared with 0% (0/28) of the
replanning (p = 0.000) (Table 3).
Radiotherapy is the primary treatment for NPC because
of the anatomical proximity of critical structures and the
high degree of radiosensitivity. In external beam radiother-
apy, treatment goals have always aimed at treating the
tumor to an adequate dose while protecting the surrounding
normal tissues. Use of IMRT to achieve the goal is
a milestone for radiotherapy in the 21st century. There is re-
cent increasing interest in dosimetric effect changes during
the course of IMRT. In this study, we evaluated the dosi-
metric variations of the target volumes and normal organs
during IMRT for NPC. This study demonstrated the impor-
tance of repeat CT scan and replanning before the 25th
treatment fraction during the course of IMRT for patients
Local control is directly related to the dose delivered to the
target volume for NPC. Limited published data are available
on target volume dose variations for NPC patients
undergoing IMRT (18–22). Hansen et al. (10) performed
a study in 13 locally advanced head-and-neck cancer patients
receiving IMRT, in which all patients underwent a repeat CT
scan and replanning with an average interval of 39 days
(average, 19 treatment fractions delivered) between the first
treatmentfractionandthesecond CTimaging. The investiga-
tors found that the doses to 95% of the planning target
Fig. 1. Average of the percentage and the dose in two plans. In this histogram, the target doses (CTV1 and GTVnx) were
increased in the replanning, the doses to the surrounded normal structures (two parotid glands, spinal cord and brain stem)
Replanning during IMRT for nasopharyngeal carcinoma d W. WANG et al. 619
volume of GTV and the CTV were increased in 92% patients
Gy, respectively. Similarly, our study found that in
replanning, the doses to the planning target volume of
GTVnx and CTV1 were increased by 0.48–15.98 Gy and
0.68–9.12 Gy, respectively. Moreover, there were significant
differences of the percentage of prescription doses of CTV1
between these two plans.
Because the parotid glands are often in close proximity to
the target and often included in these high-dose regions, the
delivery dose to the parotid is associated with patient quality
of life (23–26). It has been reported previously that patients
undergoing RT for NPC have significant volume decrease
duringtheircourse oftreatment.In this study, themean doses
to both parotid glands were lower for replanning than for the
phantom plan. In addition, there was significant difference of
the left parotid gland mean dose between these two plans.
Both parotid glands V30 were lower for replanning than
for phantom plan. Since the change in the parotid glands
receiving the dose for each patient was related to the different
locations of primary tumors and nodal disease, degree of
shrinkage of primary tumors, and the asymmetric volume
studies should investigate the effects of the above factors by
multiple factors analysis.
In our present study, consistent with the previous reports
(10, 11), the maximum dose and V40 of the spinal cord
were lower for replanning than for the phantom plan.
Although there were no statistically significant differences
for the maximum dose and V50 of the brainstem between the
phantom plans and the replanning, 11 of 14 plans (78.57%)
were out of constraint criteria in the phantom plans based
on the RTOG 0225 trial protocol, as for the dose delivered
to the brainstem. The relationship between the planning
dose constraints and the resultant dose distributions was
dependent on several factors, such as variations in anatomic
relationship between the tumor and sensitive structures,
special clinical considerations from patient to patient, treat-
ment delivery method, and the characteristics of the inverse
planning system. The brainstem is immediately adjacent to
GTVnx, and the dose for brainstem is slightly closer to the
planning dose constraints. Hence, a slight change of anatomy
may render the brainstem dose out of the constraint criteria.
However, in our study, there was no significantly change
for the overall dose.
Based on the dose constraint criteria in the RTOG0225
protocol and the comparison of conformity indices for these
two plans, 14 of 28 phantom plans (50%) were out of limits
for the dose to the normal critical structures, whereas no
plan was out of limit in the replanning. In theory, these do-
simetric changes of replanning may increase rates of local
control and decrease the incidence of complications around
the normal critical structures. Unfortunately, the clinical
outcomes for these patients were not evaluated in our pres-
ent study, and it is unclear what the clinical outcomes might
have been if these patients had not received replanning.
There are several aspects of this study that require future
investigation. In this study, all repeat CT imaging and
replanning were performed only before the 25th fraction
of IMRT. In addition, there are several current limitations
to the implementation of repeat CT imaging and IMRT
Table 2. Changes of dose of the target/normal critical
structures in two plans (N = 28)
95% CI of the
phantom plan LowerUpper
dose of brain
dose of spinal
Spinal cord V40 (%)
gland V30 (%)
4.91* 10.890.68 9.13 0.024
?0.48 15.98 0.064
?8.80 0.71 0.092
?8.58 ?1.42 0.008
?8.12 ?0.35 0.034
18.89 ?18.80 ?4.15 0.003
?7.4511.05 1.13 0.142
Abbreviations:CI = confidence interval; SD = standard deviation.
* Increment in replanning.
yDecrement in replanning.
Table 3. Numbers of plans with dose contribution exceeding
normal critical structures criterion (N = 28)
Phantom plan (n) Replanning (n)
Dose of brain
stem >54 Gy and
V60 > 1%
Dose of spinal
cord >45 Gy and
With one of the above
620I. J. Radiation Oncology d Biology d PhysicsVolume 77, Number 2, 2010
replanning including the increased workload for clinical Download full-text
staff, the increased workload for physicists and dosimet-
rists, and the increased physician time spent recontouring
target volumes and normal structures. Finally, there might
be a significant financial burden on the patients because
of the increased cost of reimaging and replanning, espe-
cially given that there maybe no reimbursement for these
processes from many second-party payers and in develop-
ing countries such as China. Thus, future studies are needed
to identify specific predictive factors that might identify the
need for repeat CT scanning and replanning and so that
these dosimetric changes will translate into changes in
Patients with NPC undergoing external beam RT can have
significant dose variations to the target volume and the sur-
rounding normal tissue. Repeat CT scan and replanning be-
fore the 25th treatment fraction during the course of IMRT
to normal tissues. Future prospective studies with larger sam-
ple sizes will help to determine criteria for the appropriate
time to receive repeat CT scan and replanning during the
course of IMRT and what kind of patients need repeat
CT scan and replanning among NPC patients undergoing
1. Qin D, Hu Y, Yan J, et al. Analysis of 1379 patients with naso-
pharyngeal carcinoma treated by radiation. Cancer 1988;61:
2. Wang DC, Cai WM, Hu VC. Long term survival of 1035 cases
of nasopharyngeal carcinoma. Cancer 1988;61:2338–2341.
3. Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the naso-
pharynx. Eighteen years experience with megavoltage radiation
therapy. Cancer 1976;37:2605–2612.
4. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy
versus radiotherapy in patients with advanced nasopharyngeal.
5. Sultanem K, Shu HK, Xia P, et al. Three-dimensional intensity-
modulated radiotherapy in the treatment of nasopharyngeal
carcinoma: The University of California–San Francisco experi-
ence. Int J Radiat Oncol Biol Phys 2000;48:711–722.
6. Hunt MA, ZelefskyM,Wolden S,etal.Treatment planningand
delivery of intensity-modulated radiation therapy for primary
nasopharynx cancer. Int J Radiat Oncol Biol Phys 2001;49:
7. Kam M, Suen J, Choi PHK, et al. Intensity-modulated radio-
therapy in nasopharyngeal carcinoma: Dosimetric advantage
over conventional plans and feasibility of dose escalation. Int
J Radiat Oncol Biol Phys 2002;56:145–157.
8. Xia P, Fu K, Wong GW, et al. Comparison of treatment plans
involving intensity-modulated radiotherapy for nasopharyngeal
carcinoma. Int J Radiat Oncol Biol Phys 2000;48:329–337.
9. Barker JL, Garden AS, Ang KK, et al. Quantification of volu-
metric and geometric changes occurring during fractionated
radiotherapy for head-and-neck cancer using an integrated
CT/linear accelerator system. Int J Radiat Oncol Biol Phys
10. Hansen EK, Bucci MK, Quivey JM, et al. Repeat CT imaging
and replanning during the course of IMRT for head-and-neck
cancer. Int J Radiat Oncol Biol Phys 2006;64:355–362.
11. Han CH, Chen YJ, Liu AL, et al. Actual dose variation of pa-
rotid glands and spinal cord for nasopharyngeal cancer patients
during radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:
12. SuitHD,WalkerAM.Assessment oftheresponseoftumoursto
radiation: Clinical and experimental studies. Br Cancer J 1980;
13. Barkley HT, Fletcher GH. The significance of residual disease
after external irradiation of squamous-cell carcinoma of the
oropharynx. Radiology 1977;124:493–495.
14. Sobel S, Rubin P, Keller B, et al. Tumor persistence as
a predictor of outcome after radiation therapy of head and
neck cancers. Int J Radiat Oncol Biol Phys 1976;1:
15. Trott KR. Human tumour radiobiology: Clinical data. Strahlen-
16. Greene FL, Page DL, et al. 2002 AJCC Cancer Staging Hand-
book, 6th ed. New York, Springer-Verlag, 2002; p 50.
17. RTOGprotocol 0225:Aphase IIstudyof IMRT+/-chemother-
apy for nasopharyngeal cancer. Available at: www.rtog.org.
Accessed December 15, 2006.
18. Chao KS, Ozyigit G, Tran BN, et al. Patterns of failure in
patients receiving definitive and postoperative IMRT for
head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003;55:
19. Dawson LA, Anzai Y, Marsh L, et al. Patterns of localre-
gional recurrence following parotid-sparing conformal and
segmental intensity-modulated radiotherapy for head and
neck cancer. Int J Radiat Oncol Biol Phys 2000;46:
20. Teo PM, Leung SF, Tung SY, et al. Dose-response relation-
ship of nasopharyngeal carcinoma above conventional tumor-
icidal level: A study by the Hong Kong Nasopharyngeal
Carcinoma. Study Group (HKNPCSG). Radiother Oncol
21. Leibel SA, Kutcher GJ, Harrison LB, et al. Improved dose
distributions for 3D conformal boost treatments in carcinoma
of the nasopharynx. Int J Radiat Oncol Biol Phys 1991;20:
22. Marks JE, Bedwinek JM, Lee F, et al. Dose–response analysis
for nasopharyngeal carcinoma: An historical perspective. Can-
23. Chambers MS, Garden AS, Kies M, et al. Radiation-induced
impactonqualityoflife, andmanagement. HeadNeck2004;26:
and neck radiotherapy. Crit Rev Oral Biol 2003;14:199–212.
25. Epstein JB, Emerton S, Kolbinson DA, et al. Quality of life and
oral function following radiotherapy for head and neck cancer.
Head Neck 1999;21:1–11.
26. McMillan AS, Pow EHN, Leung WK, et al. Oral healthrelated
quality of life in disease-free survivors following radiotherapy
for nasopharyngeal carcinoma. J Oral Rehabil 2004;31:
Replanning during IMRT for nasopharyngeal carcinoma d W. WANG et al. 621