Dear Editor,
Intensity-modulated radiotherapy (IMRT) has a distinct advantage of high conformity
and is an appropriate technique for treating nasopharyngeal carcinoma (NPC). Previous
studies have demonstrated that anatomical changes in the external contour, shape,
and location of the target and critical structures are significant and result in dosimetric
changes [1, 2]. Patients’ quality of life and clinical outcomes might be improved
by IMRT replanning [3]. Therefore, replanning strategies should be considered instead
of single-planning strategies throughout the entire course of radiotherapy. However,
there are substantial controversies on (1) the appropriate time for target redelineation,
(2) how to modify the target volumes, and (3) how to evaluate the modified plans.
The present study provides a new perspective in replanning with regard to these three
aspects.
We analyzed the data of 54 patients with newly diagnosed NPC between October 2013
and June 2016. The mean age was 45.5 years (range 18–67 years). All patients had undifferentiated
non-keratinized carcinoma. According to the 7th edition of the Union for International
Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) staging system, 6
(11.1%), 17 (31.5%), 29 (53.7%), and 2 (3.7%) patients had stage IVb, IVa, III, and
II diseases, respectively. Twenty-four (44.4%) patients received induction chemotherapy
and concurrent chemoradiotherapy, 29 (53.7%) received concurrent chemoradiotherapy,
and 1 (1.9%) received radiotherapy alone. The median duration of radiotherapy was
47 days (range 41–71 days). The median duration of interruption between two plans
was 2 days (range 1–24 days). The baseline clinical characteristics are shown in Table 1.
Table 1
Baseline clinical characteristics of 54 patients with nasopharyngeal carcinoma
Characteristics
No of patients [cases (%)]
Sex
Female
14 (25.9)
Male
40 (74.1)
Treatment
Induction and concurrent chemoradiotherapy
24 (44.4)
Concurrent chemoradiotherapy
29 (53.7)
Radiotherapy alone
1 (1.9)
Staging (AJCC/UICC 2010)
T stage
T4
14 (25.9)
T3
24 (44.4)
T2
9 (16.7)
T1
7 (13.0)
N stage
N3b
2 (3.7)
N3a
6 (11.1)
N2
34 (62.9)
N1
11 (20.4)
N0
1 (1.9)
M stage
M0
54 (100)
M1
0 (0)
TNM stage
IVb
6 (11.1)
IVa
17 (31.5)
III
29 (53.7)
II
2 (3.7)
UICC the Union for International Cancer Control, AJCC the American Joint Committee
on Cancer
In plan-I radiotherapy, computed tomography simulation (CT-I) was performed for target
delineation. The gross target volume of the nasopharynx (GTVnx)-I was defined as all
gross lesions determined with clinical and imaging examinations. The high-risk clinical
target volume (CTV1-I) was delineated with a 1-cm margin surrounding the GTVnx-I area.
The low-risk clinical target volume (CTV2-I) was delineated with a 0.5-cm margin surrounding
the CTV1-I. Any metastatic retropharyngeal lymph nodes and cervical lymph nodes were
delineated as GTVrpn-I and GTVnd-I [4]. CTVrpn1-I and CTVnd1-I were delineated with
a 0.5- and 1.0-cm expansion from the GTVrpn-I and GTVnd-I. CTVrpn2-I and CTVnd2-I
were delineated with a 0.5-cm margin surrounding CTVrpn1 and CTVnd1-I, which included
the bilateral prophylactically irradiated lymphatic drainage areas. In patients undergoing
induction chemotherapy, target volumes were delineated according to the tumor appearance
after induction chemotherapy [5].
On the basis of results of previous studies [1, 2], we chose to perform a second CT
simulation (CT-II) after the 22nd fraction of radiotherapy, leaving 3 days for radiophysicists
to make plan-II. For the first 11 patients, considering the inadequate time for determining
adaptive plans, we implemented the plan-II radiotherapy after the 26th fraction. For
the following patients, we implemented the plan-II radiotherapy after the 25th fraction.
In plan-II radiotherapy, GTVnx/rpn/nd-II was defined as all residual diseases; CTV1/rpn1/nd1-II
was the same as CTV1/rpn1/nd1-I; and CTV2/rpn2/nd2-II was not delineated (Fig. 1).
Fig. 1
Illustration of target delineation in plan-I and plan-II. Magnetic resonance imaging
(MRI)-I acquired before plan-I radiotherapy with cross-sectional T2-weighted images,
T1-weighted images, and contrast-enhanced T1-weighted (T1 + C) images shows the primary
tumor, which locates on the left side of the upper wall and extends into the nasal
cavity, left medial pterygoid plate, and navicular fossa. In plan-I radiotherapy,
the gross target volume of primary tumor (GTVnx-I) was outlined (red line). Clinical
target volume 1-I (CTV1-I) (green line) is delineated with a 1.0-cm margin surrounding
GTVnx-I. Clinical target volume 2-I (CTV2-I) (blue line) is delineated with a 0.5-cm
margin surrounding CTV1-I. MRI-II acquired after 22 fractions of irradiation shows
that the tumor greatly regressed. In plan-II radiotherapy, the residual tumor is delineated
as GTVnx-II (red line). The regressing areas of the intracavitary area, the left medial
pterygoid plate, and the navicular fossa lesion are included not in GTVnx-II but in
CTV1-II (green line), which maintains the same as CTV1-I. CTV2-II is not delineated.
GTVnx-I was copied to the CT-II for comparison (purple line)
A 3- to 5-mm margin surrounding the above targets was required for the delineation
of the planning target volumes (PGTVnx, PGTVrpn, PGTVnd, PCTV1, and PCTV2).
Before June 2014, the doses prescribed were as follows: GTVnx/rpn/nd-I, 57 Gy in 26
fractions at 2.19 Gy/fraction; PCTV1/rpn1/nd1-I, 50 Gy in 26 fractions at 1.92 Gy/fraction;
PCTV2/rpn2/nd2-I, 46–47 Gy in 26 fractions at 1.77–1.81 Gy/fraction; PGTVnx/rpn/nd-II,
11 Gy in 5 fractions at 2.2 Gy/fraction; PCTV1/rpn1/nd1-II, 10 Gy in 5 fractions at
2.0 Gy/fraction.
After June 2014, the doses prescribed were as follows: PGTVnx/rpn/nd-I, 53–54 Gy in
25 fractions at 2.12–2.16 Gy/fraction; PCTV1/rpn1/nd1-I, 47.5 Gy in 25 fractions at
1.90 Gy/fraction; PCTV2/rpn2/nd2-I, 45 Gy in 25 fractions at 1.8 Gy/fraction; PGTVnx/rpn/nd-II,
15–15.5 Gy in 7 fractions at 2.14–2.21 Gy/fraction; PCTV1/rpn1/nd1-II, 13.5 Gy in
7 fractions at 1.93 Gy/fraction.
The target delineation and dose prescription of organs at risk (OARs), including the
brain stem, spinal cord, and optic chiasm, were performed according to Radiation Therapy
Oncology Group (RTOG) 0225 protocol [4]. Under the dose tolerance limit requirements
of the RTOG 0225 protocol [4], the dose constraints for OARs were calculated via multiplying
the dose tolerance limit (Dtolerance limit) by the percentage of dose of each plan
in total dose.
The average weights of the patients were 61.2 ± 9.3 kg before radiotherapy and 58.2 ± 9.0 kg
after the 22nd fraction of irradiation, without significant weight reduction (P > 0.05).
GTVnx, GTVnd-R, volumes of bilateral parotids, and volumes of bilateral submandibular
glands showed significant reductions after 22 fractions of irradiation (all P < 0.05),
whereas other volume changes were not significant (Additional file 1: Table S1).
Nearly 100% of PGTV was irradiated with 95% of the prescription dose of PGTVnx in
the two plans. No significant differences in the percentage of the mean dose (Dmean)
in the total dose (Dmean%) of PGTVnx, bilateral PGTVrpn, or bilateral PGTVnd were
observed between the two plans. Among the evaluated OARs, Dmean% values of the brain
stem, spinal cord, optic chiasm, pituitary, oral cavity, oropharynx, hypopharynx,
and thyroid gland were significantly different between plan-I and plan-II (P < 0.05)
(Additional file 1: Table S2).
Adverse events were evaluated based on RTOG acute radiation morbidity scoring criteria.
Grade 1–2 adverse events were mainly observed in the skin, oral mucosa, and salivary
glands, whereas grade 0 adverse events were mainly observed in the hypopharynx mucosa
and larynx mucosa. Grade 3 leukopenia, neutropenia, and thrombocytopenia were observed
in 18 (33.30%), 13 (24.07%), and 5 (9.25%) patients, respectively; 1 (1.85%) developed
grade 4 neutropenia.
The median follow-up period was 30 months (range 3–44 months). Three patients developed
distant metastasis, and 4 developed locoregional failure, but none occurred in the
regression area. The 3-year overall survival, local recurrence-free survival, and
distant metastasis-free survival rates were 93.3%, 90.5%, and 91.4%, respectively.
Few studies have described the target redelineation in detail for replanning or modified
dose prescription for tumor regression areas. Hansen et al. [6] used the same GTV
in plan-II without extending it beyond the skin contour or into adjacent normal structures.
Chitapanarux et al. [7] recontoured the GTV-II by removing the air cavity formed due
to tumor shrinkage while maintaining the other dimensions of GTV-I. CTV-II was adapted
by excluding the air cavity and noninvolved tissues. According to basic research and
the results of definitive irradiation for NPC [8], a dose of 60 Gy delivered to subclinical
lesions achieved good treatment efficacy. In the present study, upon disappearance/dissolution
of tumor areas, the initial location of the tumor were included in CTV1-II, and the
total dose delivered to the disappeared part of GTVnx-I after radiotherapy was over
65 Gy. Our follow-up results showed that no recurrence occurred in the regression
areas of GTVnx/rpn/nd-I which were delineated as CTV1/rpn1/nd1-II, and the 3-year
survival rate was not decreased as compared with previously reported outcomes [9].
CTV2 was not prescribed any dose in plan-II, whereas a total dose of 45–47 Gy in 25–26
fractions was prescribed for CTV2 in plan-I. Historically, the suggested dose for
microscopic sterilization was 45–50 Gy at 1.8–2 Gy/fraction [10]. Zhang et al. [11]
analyzed prognostic factors of 1302 NPC patients based on a 10-year follow-up and
found that the 5- and 10-year survival rates of patients without cervical lymph node
metastasis who underwent 40–45 Gy irradiation were similar to those of patients with
clinical adenopathy who underwent 50–60 Gy irradiation. The present study showed no
recurrence in the CTV2 area. This outcome needs to be confirmed in long-term follow-up.
According to the principle of radiobiology, the tumor-killing effect of radiation
is related to not only the fractionated dose but also the total dose. Wang et al.
[2] and Yang et al. [3] used the same dose fractionation for each target volume in
plan-II as that in plan-I, which may facilitate a simple superposition assessment
of the doses between plans. Fung et al. [12] used the same dose fractionation, 2.1 Gy/fraction,
for plan-I and plan-II over 7 weeks and used a higher dose fractionation, 3.5–3.7 Gy/fraction,
for plan-III. The total dose for the three plans was as large as 80.9 Gy in 37 fractions
or 84 Gy in 38 fractions, but the efficacy or toxic adverse effects of radiotherapy
were not reported. The dose hyperfractionation in plan-II might increase the possibility
of late reaction tissue damage and may elicit serious sequelae. In the present study,
a higher dose per fraction was prescribed for GTVnx-II and CTV1-II with the intention
of increasing the biological effect of radiation and improving therapeutic effect.
In conclusion, our adaptive replanning IMRT for patients with NPC provides a new perspective
on target redelineation and dose prescription, as it would demonstrate a significant
dosimetric and clinical benefits without recurrence and reduction in survival.
Additional file
Additional file 1: Table S1. Changes in target volumes and volumes of OARs between
plan-I and plan-II. Table S2. Relative doses for targets and OARs between plan-I and
plan-II.