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Physics Contribution
4p Noncoplanar Stereotactic Body Radiation
Therapy for Head-and-Neck Cancer: Potential to
Improve Tumor Control and Late Toxicity
Jean-Claude M. Rwigema, MD,* Dan Nguyen, BS,*
Dwight E. Heron, MD,y Allen M. Chen, MD,* Percy Lee, MD,*
Pin-Chieh Wang, PhD,* John A. Vargo, MD,y Daniel A. Low, PhD,*
M. Saiful Huq, PhD,y Stephen Tenn, PhD,* Michael L. Steinberg, MD,*
Patrick Kupelian, MD,* and Ke Sheng, PhD*
*Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California;
and yDepartment of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania
Received May 27, 2014, and in revised form Aug 27, 2014. Accepted for publication Sep 30, 2014.
Summary
Stereotactic body radiation
therapy is increasingly used
in head-and-neck cancer,
mainly for recurrent previously irradiated head-andneck cancer. Recent data on
reirradiation using SBRT
suggest the potential to
reduce severe late toxicity,
while maintaining similar
local control relative to
conventionally fractionated
radiation therapy. We tested
4p radiation therapy in
recurrent, primary unresectable, and metastatic headand-neck cancer. Our results
Purpose: To evaluate the potential benefit of 4p radiation therapy in recurrent, locally
advanced, or metastatic head-and-neck cancer treated with stereotactic body radiation
therapy (SBRT).
Methods and Materials: Twenty-seven patients with 29 tumors who were treated using SBRT were included. In recurrent disease (nZ26), SBRT was delivered with a median 44 Gy (range, 35-44 Gy) in 5 fractions. Three patients with sinonasal mucosal
melanoma, metastatic breast cancer, and primary undifferentiated carcinoma received
35 Gy, 22.5 Gy, and 40 Gy in 5 fractions, respectively. Novel 4p treatment plans were
created for each patient to meet the objective that 95% of the planning target volume
was covered by 100% of the prescription dose. Doses to organs at risk (OARs) and
50% dose spillage volumes were compared against the delivered clinical SBRT plans.
Local control (LC), late toxicity, tumor control probability (TCP), and normal tissue
complication probability were determined.
Results: Using 4p plans, mean/maximum doses to all OARs were reduced by 22% to
89%/10% to 86%. With 4p plans, the 50% dose spillage volume was decreased by
33%. Planning target volume prescription dose escalation by 10 Gy and 20 Gy were
achieved while keeping doses to OARs significantly improved or unchanged from clinical plans, except for the carotid artery maximum dose at 20-Gy escalation. At a
Reprint requests to: Ke Sheng, PhD, Department of Radiation
Oncology, 200 Medical Plaza, B265, University of California, Los
Angeles, Los Angeles, CA 90095. Tel: (310) 853-1533; E-mail: ksheng@
mednet.ucla.edu
Presented at the 56th Annual Meeting of the American Society for
Radiation Oncology, September 14-17, 2014, San Francisco, CA.
Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e9, 2014
0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2014.09.043
Conflict of interest: none.
Supplementary material for this article can be found at
www.redjournal.org.
AcknowledgmentsdThe study was supported in part by Varian Medical Systems. The authors thank Karen Holeva for her support with data
management.
2
International Journal of Radiation Oncology Biology Physics
Rwigema et al.
show improved organ
sparing and the potential to
safely enhance tumor control
with dose escalation.
median follow-up of 10 months (range, 1-41 months), crude LC was 52%. The 2-year
LC of 39.2% approximated the predicted mean TCP of 42.2%, which increased to
45.9% with 4p plans. For 10-Gy and 20-Gy dose escalation, 4p plans increased
TCP from 80.1% and 88.1% to 85.5% and 91.4%, respectively. The 7.4% rate of grade
3 late toxicity was comparable to the predicted 5.6% mean normal tissue complication probability for OARs, which was significantly reduced by 4p planning at the prescribed and escalated doses.
Conclusions: 4p plans may allow dose escalation with significant and consistent improvements in critical organ sparing, tumor control, and coverage. Ó 2014 Elsevier Inc.
Introduction
Despite improvements in the multimodality treatment of
primary head-and-neck cancer, local recurrence after primary treatment remains significant and accounts for more
than 50% of disease-related mortality (1). Stereotactic body
radiation therapy (SBRT) has emerged as a salvage treatment strategy with many clinical applications in patients
with head-and-neck cancer. In particular, for those with
unresectable recurrent previously irradiated head-and-neck
cancer, a number of studies, including a single-institution
phase 1 and multi-institution phase 2 trials, have demonstrated the feasibility of SBRT, with efficacy similar to that
of intensity modulated radiation therapy (IMRT) and
3-dimensional conformal radiation therapy (2-6). Others
have investigated the use of SBRT in the primary setting of
locally advanced unresectable primary or metastatic headand-neck cancers, or to overcome radioresistance among
other cancers (7-9).
The rates of severe late toxicities pose a major concern
when contemplating head-and-neck cancer reirradiation,
mainly owing to the poor tolerance of critical structures
surrounding the previously irradiated treatment target.
Current SBRT data, although not randomized, suggest the
possibility of reducing severe late complications when
compared with conventionally fractionated radiation therapy, owing to the highly precise delivery of radiation dose to
the target volume with minimal dose to surrounding organsat-risk (OARs) (10). The most common SBRT regimen,
consisting of 5 fractions delivered on alternating days
(QOD), has been shown to be generally safer than treatment
delivered on consecutive days (QD). Specifically, the rates of
grade 3 late toxicities with QOD seem to be on average
10% (4, 5, 7) and seem to increase to approximately 20%
with QD (11, 12). Studies have also evaluated radiosensitization with concurrent cetuximab, image guidance,
optimal treatment target definition, and treatment duration,
as well as quality of life after SBRT, to further demonstrate
the feasibility and improved outcomes of SBRT (3, 13-17).
Although the improved local tumor control and treatment safety of SBRT seem promising, the limited 2-year
local control (LC) rates of 30 to 52% (4-7) and the potential
for severe toxicities with SBRT make SBRT a challenging
salvage option for patients who cannot afford a second local
failure coupled with added toxicity. Therefore, in the
present study, we sought to investigate whether 4p planning
could improve the dosimetry and quality of SBRT plans
delivered using a variety of standard techniques, to determine whether the risk of severe late complications can be
further reduced without causing a decline in LC.
The 4p system has already been shown to potentially
provide improved dose conformality, reduced dose spillage
to normal OARs, and lower integral dose when compared
with volumetric modulated arc therapy (VMAT) in SBRT
for central lung tumors, liver tumors, and prostate cancer
(18-20). For central lung tumors, dose escalation was also
safely achieved (19). In this work we tested whether dose
escalation was feasible in previously irradiated or advanced
head-and-neck cancer.
Methods and Materials
Twenty-seven patients (median age 66 [range, 42-87] years;
14 male) with 29 malignant tumors previously treated using
SBRT at the University of California Los Angeles (nZ8)
and at the University of Pittsburgh Cancer Institute (nZ19)
from February 2007 to October 2013 were included in the
study. Details of patient and previous treatment characteristics are shown in Table 1.
For recurrent previously irradiated tumors (nZ26),
SBRT was delivered with a median 44 Gy (range, 35-44 Gy)
in 5 fractions QOD at a median interval of 20 months from
the initial radiation therapy course of a median 70 Gy
(range, 45-131.2 Gy) for primary disease. Four patients had
previously received multiple courses of radiation therapy
with cumulative doses >110 Gy and required SBRT for
focal recurrences in the neck (nZ3) and maxillary sinus
(nZ1) (Table 1). Seven patients (25.9%) had concurrent
cetuximab with SBRT reirradiation at 400 mg/m2 on day 7
then 250 mg/m2 on day 0 and þ8. Three patients with
sinonasal mucosal melanoma, metastatic breast cancer,
and unresectable primary undifferentiated carcinoma had
received 35 Gy, 22.5 Gy, and 40 Gy in 5 fractions QOD,
respectively. Different radiosurgery systems were utilized to
deliver SBRT, including CyberKnife (nZ6) (Accuray,
Sunnyvale CA), Novalis Tx (nZ9) (Varian Medical Systems, Palo Alto, CA; and BrainLAB, Feldkirchen, Germany), Trilogy (nZ8), and TrueBeam STx (nZ6) (Varian
Medical Systems). The clinical plans used static IMRT
(nZ24), noncoplanar VMAT (nZ1), and coplanar VMAT
4p SBRT for head-and-neck cancer
Volume - Number - 2014
Table 1
Patient and treatment characteristics
Patient Age
Prior RT
no.
(y) Gender Histology dose (Gy)*
1
2
3
4
5
6
7a
7b
8
9
10
11
12
13
14
15
16
17a
17b
18
19
20
21
22
23
24
25
26
27
3
59
77
86
71
67
71
78
78
83
75
62
54
80
61
85
72
50
61
61
42
54
75
79
70
65
46
60
70
70
M
F
M
M
M
M
M
M
F
M
M
M
F
F
F
M
M
F
F
F
M
F
M
F
F
M
M
F
F
SCC
SCC
UC
SCC
SCC
SCC
AC
SCC
SNMM
SCC
SCC
UC
PCT
SCC
AC
SCC
SCC
UC
UC
SCC
AC
SCC
SCC
MC
MC
ACC
SCC
SCC
SCC
131
45
NA
45
Unknown
86.4
NA
129
NA
66.6
71.3
70
70.2
70
68.4
63
70
112
112
70
64
70
68.8
61.2
Unknown
66
70
70
64
Primary
site
SBRT
dose (Gy)y
Oropharynx
Oral tongue
Pterygoid
Base of tongue
Larynx
Tongue
Breast
Oropharynx
Nasal cavity
Parotid
Larynx
Nasopharynx
Thyroid
Nasopharynx
Parotid
Larynx
Base of tongue
Sinonasal
Sinonasal
Nasopharynx
Oropharynx
Base of tongue
Larynx
Palate
Parotid
Parotid
BOT/FOM
Oropharynx
Oral cavity
40
40
40
40
40
35
22.5
40
35
44
35
44
44
44
44
44
40
44
44
44
44
40
44
44
44
44
44
40
44
SBRT
site
TV
(cm3)
Machine
Neck
18.9 Novalis-Tx
Base of tongue
83.4 Novalis-Tx
Pterygoid
32.3 Novalis-Tx
Base of tongue 209.4 Novalis-Tx
Larynx
5.9 Novalis-Tx
Neck
202.8 Novalis-Tx
Neck
41.6 Novalis-Tx
Neck
6.2 Novalis-Tx
Nasal cavity
78.5 Novalis-Tx
Cervical spine
41.9 Cyberknife
Neck
15.7 Cyberknife
Base of skull
83.9 Cyberknife
Retrostyloid
75
Cyberknife
Base of skull
38
Cyberknife
Parotid
22.4 Cyberknife
Hypopharynx
50.6 TrilogyTM
Oropharynx
12.7 TrilogyTM
Maxillary sinus
2.8 TrilogyTM
Neck
3.7 TrilogyTM
Nasopharynx
89
TrilogyTM
Oropharynx
25.8 TrilogyTM
Base of tongue
13.6 TrilogyTM
Larynx
63.3 TrilogyTM
Maxillary sinus
9.7 TrueBeam-STX
Parotid
74.4 TrueBeam-STX
Submandibular
63.3 TrueBeam-STX
Base of tongue 195
TrueBeam-STX
Oropharynx
16.5 TrueBeam-STX
Palate
40.5 TrueBeam-STX
Technique
C-VMAT
S-IMRT
S-IMRT
C-VMAT
S-IMRT
S-IMRT
C-VMAT
C-VMAT
NC-VMAT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
S-IMRT
Abbreviations: AC Z adenocarcinoma; ACC Z acinic cell carcinoma; BOT/FOM Z base of tongue/floor of mouth; MC Z myeloepithelial carcinoma; C-VMAT Z coplanar volumetricemodulated arc therapy; NC-VMAT Z noncoplanar volumetricemodulated arc therapy; PCT Z papillary
carcinoma of thyroid; SNMM Z sinonasal mucosal melanoma; SCC Z squamous cell carcinoma; S-IMRT Z static intensity modulated radiation
therapy; TV Z tumor volume; UC Z undifferentiated carcinoma.
a, b denote patients with 2 lesions.
* Total prior prescription dose.
y
SBRT dose in 5 fractions.
(nZ4). Figure 1a shows typical beam orientation patterns of
4p planning compared with static IMRT, coplanar VMAT,
and noncoplanar VMAT. All clinical plans were initially
generated and optimized using treatment planning systems
corresponding to the different techniques used clinically.
All clinical and 4p plans were then imported into CERR
(Computational Environment for Radiotherapy Research,
Washington University, St. Louis, MO) and dose distributions evaluated using identical settings.
The novel 4p treatment planning process has been
previously described (17-19). Briefly, the 4p method is a
highly noncoplanar and nonisocentric planning system
developed on C-arm gantry linear accelerators. For each
patient a candidate pool was created consisting of 1162
beams evenly distributed throughout the 4p solid sphere
angle space, with approximately 6 of separation between
adjacent beams. A beam geometry solution space was
initially created using the 3-dimensional surface images of
a human subject and the treatment machine to determine
the minimal distances between the x-ray source and the
tumor for each beam angle. A collision buffer of 4 cm was
added to the distances. If the resultant distance was
>100 cm, extended source-to-tumor distances were used.
Beams that still resulted in collision of the gantry and
couch or patient due to reaching the couch movement
limits were excluded. Of the remaining candidate beams,
30 intensity modulated beams were automatically selected
to meet the objective of 95% of the planning target volume
(PTV) covered by 100% of the prescription dose. The
candidate beams were segmented into 5 5-mm2 beamlets. This was followed by the calculation of
2.5 2.5 2.5-mm3 resolution dose matrices using an inhouse convolution/superposition code with 6-MV polyenergetic kernels. A column generation algorithm (21)
was used to iteratively select and optimize the beams
until the desired number of 30 beams was reached.
In addition to the plans adhering to their original prescription doses, dose escalation plans of 10 Gy and 20 Gy
4
Rwigema et al.
International Journal of Radiation Oncology Biology Physics
maintain a consistent correlation between R50 and normal
tissue toxicity, V50 was defined according to the original
prescription dose in the dose-escalated plans.
Planning target volume coverage was determined and
compared with the clinical plans by evaluating the dose that
covered 95%, 98%, and 99% of the PTV, as well as the PTV
minimum and maximum doses (ie lowest and highest point
doses in the PTV corresponding to the volume of 1 voxel).
Crude and actuarial LC and late toxicity rates, as well as tumor
control probability (TCP) and normal tissue complication
probability (NTCP) were determined. Local control was
defined as any reduction in tumor volume and/or metabolic
activity as assessed with follow-up positron emission tomography/CT and/or MRI as well as clinical examination.
Kaplan-Meier analysis was used to determine actuarial LC
rates. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3 (22).
TCP was calculated as:
TCPZexpð Dc V expðaBEDÞÞ
ð2Þ
where Dc is the clonogens density Z 107/cm3, V is the
tumor GTV volume, and BED is the biological equivalent
dose calculated assuming a/b Z 10 Gy for the tumor (22).
The TCP was determined at tumor radiosensitivities (a) of
0.15/Gy, 0.25/Gy, and 0.35/Gy (23, 24).
NTCP was calculated according to the Lyman model
(23), defined as:
2
Zt
1
x
NTCPZpffiffiffiffiffiffi
exp
dx
ð3Þ
2
2p
N
where
½D TD50 ðvÞ
ð4Þ
½m TD50 ðvÞ
V
vZ
ð5Þ
Vref
TD v ZTD 1 )vn
ð6Þ
and TD50 is the dose that led to a 50% complication rate, n
is the volume dependence parameter, m is the slope of the
complication probability dose curve, Vref is the reference
volume, V is the actual volume irradiated, and v is the
fractional volume irradiated (25). Statistical comparisons
for between groups were performed with a paired t test for
data with a normal distribution, otherwise a nonparametric
Wilcoxon rank test was used to compare means all with a
statistical significance of PZ.05 (2-tailed).
tZ
Fig. 1. (a) Typical entrance patterns of 4p beams versus
volumetric modulated arc therapy (VMAT) (coplanar and
noncoplanar) beams and static intensity modulated radiation therapy (IMRT) beams. (b) Axial, coronal, and sagittal
CT views with dose wash of the clinical case and the 4p
plans at prescription and escalated planning target volume
doses for a single patient. The color bar was adjusted to be
uniform between all cases. All 4p plans spare the carotid
artery (axial view) compared with the clinical plan. A color
version of this figure is available at www.redjournal.org.
additional dose to the PTV were also created on the clinical
and 4p planning systems and evaluated using CERR. Doses
to OARs and 50% dose spillage volume index (R50) were
compared against the delivered clinical SBRT plans. R50
was used as a measure of the high dose gradient outside the
PTV. R50 was defined as:
V50
ð1Þ
R50 Z
VPTV
where V50 is the total volume receiving 50% or more of the
prescription dose, and VPTV is the volume of the PTV. To
Results
At the same prescription dose (4pPD), the mean and
maximum (Dmax) doses to OARs were reduced with 4p
plans compared with clinical plans. Significant reductions
(P<.05) were observed for the spinal cord, the brainstem,
pharyngeal constrictor muscles, parotid glands, the larynx,
the mandible, the cochlea, and the optic apparatus (ie
chiasm, eye, lens, and optic nerves), whereas statistically
nonsignificant (P>.05) reductions were obtained for the
4p SBRT for head-and-neck cancer
Volume - Number - 2014
brachial plexus, the carotid artery, and the cervical esophagus (Table 2). Dose spillage outside the PTV, as measured
by R50, was reduced by 33% (P<.001) (Table 3). Coverage
of the PTV was improved according to respective increases
in PTV maximum and mean doses, D95, D98, and D99 by
4.4%, 5.5%, 2.4%, 4.7%, and 6.5%, respectively (P<.01).
The 1.7% increase in PTV minimum dose was not statistically significant (PZ.69). Planning target volume prescription dose escalations by 10 Gy (4pPD þ 10 Gy) in 5
fractions were achieved with a simultaneous reduction in
R50 by 5.7% (PZ.07, Table 3), and doses to OARs
significantly improved or were unchanged from clinical
plans (Table 2). For 20-Gy escalation (4pPD þ 20 Gy) in 5
fractions, R50 was increased by 24.2% (PZ.001, Table 3);
however, doses to OARs were still significantly improved
or unchanged from clinical plans, except for a significant
increase in Dmax for the carotid artery (Table 2). When
patients with tumors partially or completely wrapping the
carotid artery were excluded (nZ9), the reductions in
carotid artery mean dose and Dmax were maintained with
dose escalation at both levels (Table 2).
Figure 1b shows a planning CT with a dose color wash
for a typical 4p case in axial, coronal, and sagittal projections. The dose spillage reduction with 4p plans, as
demonstrated with improved R50, was consistent with the
observed steep dose fall-off outside the PTV that resulted in
reduced volume receiving 50% of the original prescription
Table 2
5
dose even in the 10-Gy dose-escalated plan. Figure 2a and b
show example doseevolume histograms, which demonstrate the improved dosimetry with 4p plans compared with
clinical plans. At escalated doses, doseevolume histograms
still indicated OAR doses lower with 4p plans than was
observed in nonescalated clinical plans (Fig. 2b).
At a median follow-up of 10 months (range, 141 months), the crude LC of our cohort was 52%. The
median overall survival (OS) was 12 months with a corresponding 2-year LC of 39.2% (actuarial data not shown).
The calculated individual patient TCP for clinical plans
and 4p plans is shown in Table E1 (available online at
www.redjournal.com). Figure 3 shows the mean TCP
curves for both clinical and 4p plans at a of 0.35. The
clinical TCP of 42.2% at initial prescription dose approximated the patient cohort’s LC at 39.2%, suggesting that the
radiosensitivity of tumors in the study cohort is closer to
0.35. Predicted TCP results using a of 0.25 and 0.15 were
<10%, significantly different from the clinical observation,
thus not shown here. Using 4p planning, clinical TCP
increased to 45.9% (PZ.02). The slight increase was due to
reduced cold spots by 4p as seen in Figure 2a. At 10-Gy
and 20-Gy escalation, the clinical TCP was respectively
increased from 80.5% and 88.1% to 85.5% (PZ.24) and
91.4% (PZ.32) with 4p plans.
There were 3 late toxicities (11.1%), consisting of grade
2 dysphagia, grade 3 dysphagia, and grade 3
Reductions in mean and maximum doses to organs at risk from clinical plans in comparison with 4p planning
4pPD
4pPD þ 10 Gy
4pPD þ 20 Gy
Organ at risk
Mean (%)
P*
Dmax (%)
P*
Mean (%)
P*
Dmax (%)
P*
Spinal cord
Brainstem
Mandible
Ipsilateral parotid
Contralateral parotid
Pharyngeal constrictor
muscles
Larynx
Cervical esophagus
Ipsilateral carotid
Ipsilateral carotidz
Contralateral carotid
Brachial plexus
Ipsilateral cochlea
Contralateral cochlea
Ipsilateral lens
Contralateral lens
Ipsilateral eye
Contralateral eye
Ipsilateral optic nerve
Contralateral optic nerve
Chiasm
60
53
45
66
66
55
<.001
.017
<.001
.002
.004
<.001
53
46
22
60
60
40
<.001
.006
.001
<.001
<.001
<.001
50
40
33
54
57
40
<.001
.066
.001
.007
.009
<.001
40
34
4
48
48
24
<.001
.022
.714
.001
.001
.010
57
74
22
58
55
48
82
86
82
89
72
70
68
77
81
.004
.067
.014
.080
.003
.203
.002
.004
.090
.126
.041
.023
.006
.015
.010
35
49
10
41
57
32
65
77
74
86
43
41
28
56
67
.038
.336
.096
.121
.001
.383
.004
.005
.064
.106
.051
.028
.220
.014
.017
47
66
2
49
41
33
78
82
76
78
56
60
54
70
74
.006
.110
.845
.163
.008
.401
.003
.004
.081
.117
.025
.016
.007
.015
.013
Abbreviation: PD Z prescription dose.
* Paired t test P values.
y
Negative values reflect increased doses to organs at risk.
z
With patients with tumors partially or completely wrapping the carotid excluded.
18
31
11y
26
33
13
56
72
70
71
38
24
9
48
59
.404
.570
.230
.431
.006
.877
.011
.005
.060
.106
.048
.268
.748
.027
.034
Mean (%) P* Dmax (%) P*
40
30
26
42
45
33
.001
.164
.016
.030
.025
.001
30
5
9y
36
38
14
.008
.827
.289
.014
.014
.187
43
61
19y
41
28
19
65
59
53
67
33
50
39
67
67
.042
.141
.086
.272
.020
.619
.004
.008
.030
.228
.061
.033
.009
.014
.023
7
26
26y
14
18
6y
39
52
48
64
23
15
2
41
57
.953
.684
.041
.786
.040
.772
.041
.009
.061
.113
.373
.442
.954
.068
.055
6
International Journal of Radiation Oncology Biology Physics
Rwigema et al.
Table 3
Planning target volume (PTV) statistics for clinical planning as compared with 4p planning at different dose levels
4pPD
Parameter
PTV mean dose (Gy)
PTV max dose (Gy)
PTV min dose (Gy)
D95 (Gy)
D98 (Gy)
D99 (Gy)
R50
Clinical, mean SD
41.5
45.8
29.7
40.3
38.8
37.2
5.3
5.3
6.6
10.3
5.0
5.3
6.2
2.1
4pPD þ 10 Gy
Mean SD
P*
.005
.003
.69
<.001
.001
.006
<.001
43.9
47.9
30.2
41.3
40.7
39.8
3.5
5.4
6.6
10.1
5.1
5.1
5.4
1.6
Mean SD
P*
<.001
<.001
<.001
<.001
<.001
<.001
.07
54.6
59.1
42.1
51.4
50.5
49.2
5.0
5.5
6.7
14.7
5.2
5.3
5.9
1.9
4pPD þ 20 Gy
Mean SD
P*
<.001
<.001
<.001
<.001
<.001
<.001
.001
63.4
68.0
40.6
60.1
58.9
57.1
6.6
4.4
5.5
15
3.9
4.2
5.7
2.9
Abbreviation as in Table 2.
* Paired t test P values.
osteoradionecrosis. Individual OAR NTCP data are shown
in Table E2 (available online at www.redjournal.com). The
NTCP for structures corresponding to observed late toxicities, namely pharyngeal constrictor muscles, cervical
esophagus, and larynx and the mandible, were respectively
reduced by 14.6%, 3.8%, 4.9%, and 17.6% from clinical
plans to 4p plans at the original prescription dose (Table
E2). Overall, 4p planning reduced the mean NTCP at the
all dose levels by approximately a factor of 3 at all dose
levels (P<.0001) (Fig. 3b, Table E2).
Fig. 2. Doseevolume histogram with fractional volume
plotted against dose, with a clinical plan compared with (a)
4pPD plan, and (b) 4pPD þ 10 Gy plan and 4pPD þ 20 Gy
plan. PCM Z pharyngeal constrictor muscles; PD Z
prescription dose; PTV Z planning target volume.
Discussion
The prognosis of recurrent head-and-neck cancer after
salvage reirradiation is poor, and management of these patients remains challenging. The Radiation Therapy Oncology
Group (RTOG) 96-10 and RTOG 99-11 prospective trials
and others reported 2-year LC of 11%-37% and median OS
at 8.2-12.5 months (26-32) in patients reirradiated using
3-dimensional techniques with concurrent chemotherapy.
Grade 3 late toxicities ranged from 8% to 33% (26-32).
With the advent of IMRT, reirradiation with chemotherapy
saw further improvements in LC, with 2-year rates of
19%-67%, which translated into a median OS benefit of 1527.6 months (33-35). Yet the observed severe late complications rate of 12%-32% remained largely unchanged (33-35),
and notably treatment-related deaths occurred in approximately 10% of patients with either IMRT or 3-dimensional
conformal radiation therapy (26, 35). Emerging SBRT data
suggested an opportunity to preserve LC gains registered with
IMRT, while potentially reducing severe late toxicities (36).
The 2-year LC of 39.2%, a median OS of 12 months, and a
7.4% rate of grade 3 late complications were consistent with
results from other SBRT series (4-7, 10-12).
Whereas a randomized, phase 3 trial is ultimately warranted to compare results of SBRT and conventionally
fractionated radiation therapy, efforts are clearly needed to
carefully augment LC in the salvage of recurrent head-andneck cancer to improve patient survival. Herein, we purposed
to ameliorate SBRT outcomes with 4p planning, with the
goal to reduce late toxicities while attempting to improve
local tumor control. We demonstrated that better dosimetry is
achievable with reduction in doses to OARs obtained (Fig. 2,
Table 2) and dose spillage outside the PTV, while improving
PTV coverage (Fig. 1b, Table 3). Improvements were
observed in all previously treated patients regardless of planning technique and treatment machine selection. We also
found that even with a 10-Gy total PTV dose escalation, the
reduction in dose spillage was maintained with a corresponding reduction in OAR doses. Although dose spillage was
increased for 4pPD þ 20 Gy, doses to OARs were still reduced
or unchanged, except for the carotid artery when patients with
tumors wrapping the carotid artery were included.
Volume - Number - 2014
4p SBRT for head-and-neck cancer
7
Fig. 3. (a) Mean tumor control probability (TCP) and (b) mean normal tissue control probability (NTCP) for the entire
patient cohort for both clinical (dashed) and 4p plans; (c) 4p planning may enhance the therapeutic index by increasing the
separation between TCP and NTCP curves. PD Z prescription dose.
Carotid artery blowout syndrome (CBS) is a serious and
often fatal complication in reirradiation. Published data
reveal that CBS rates can be high in reirradiation with
SBRT, especially in patients with tumors wrapping the
carotid artery, nearby skin involvement, or necrosis at time
of recurrence (37, 38). Cengiz et al (12) reported a 17.8%
rate CBS in patients with tumors wrapping around the
carotid artery among 46 patients reirradiated with CyberKnife. They found that CBS occurred when the tumor
encompassed 180 of the carotid artery while receiving
100% of the prescription dose under a QD regimen, but
when they adopted QOD, CBS rates were significantly
reduced (12, 39). Our results suggest that 4p SBRT can
add to the benefit of a QOD regimen and render patients
who were otherwise relatively contraindicated suitable for
reirradiation with SBRT.
The optimized noncoplanar SBRT (4p) allowed for
improvement in TCP at all dose levels, while simultaneously keeping NTCP lower when compared with clinical
plans. Thus, our results suggest that 4p may enhance the
therapeutic ratio, because TCP and NTCP curves are
separated further relative to clinical planning (Fig. 3c).
Patients with radioresistant, previously irradiated tumors or
primary radioresistant tumors, such as sinonasal mucosal
melanoma (8) as in this study, might benefit from the higher
prescription dose. Conversely, 2 patients had a decrement in
TCP when the dose was further increased from 10 Gy to
20 Gy with 4p planning (Table E1). This finding may be
explained by the fact that during 4p optimization, PTV
coverage may be compromised to preserve high-priority
OAR constraints. Thus, dose escalation should be considered within the context of an individual patient’s anatomic
and clinical factors.
To implement 4p delivery in the clinic using C-arm linear
accelerators, practical considerations such as avoidance of
couch and gantry collision, as well as achieving optimal
treatment delivery time, must be evaluated. We created a
beam geometry solution space based on the computer-aided
design (CAD) model of the machine and patients. Collisions
were predicted and prevented using this model. To eliminate
the risk of collision and maintain targeting accuracy, the
patients would need to be well immobilized. Increasing
the collision buffer might further improve the safety, but
it would lead to an increased number of beams using
extended source-to-tumor distances, slightly degrading the
multileaf collimator resolution and dosimetry. Positioning
the couch and gantry manually for such a large number of
noncoplanar, nonisocentric beams would be impractical and
likely unsafe. However, this task would be feasible with
robotized couch and gantry maneuvering. According to our
measurement of a delivered 4p plan, the total time used for
couch and gantry traversing through 30 static beams would
be <200 seconds.
As with all studies involving TCP and NTCP modeling,
there can be significant uncertainties stemming from inaccuracies in estimated radiobiological parameter values. The
8
Rwigema et al.
LC rate predicted by the TCP model is close to the
observation (42.2% vs 39.2%), indicating that the estimated
tumor radiobiological parameters are reasonable. Similarly,
the predicted mean NTCP rate of 5.6% approximated the
actual 7.4% rate of severe (grade 3) late toxicities. The
validity of linear quadratic cell survival in the SBRT dose
range has also been questioned, particularly for fractional
dose over 10 Gy, which would be the upper limit of the
dose escalated plans. Nevertheless, this uncertainty is unlikely to influence the significant changes in TCP and
NTCP observed in this study and overall conclusions.
Conclusions
Using C-arm linear accelerators, 4p radiation therapy may
allow head-and-neck cancer SBRT dose escalation, with
significant and consistent improvements in tumor control,
tumor coverage, and critical organ sparing. These findings
should be evaluated in a prospective feasibility trial to
validate whether 4p radiation therapy can enhance LC
while reducing late toxicity.
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