Radiotherapy and Oncology 81 (2006) 151–157

www.thegreenjournal.com

Head and neck IMRT

Dynamic intensity-modulated non-coplanar arc

radiotherapy (INCA) for head and neck cancer
Jerôme Krayenbuehl, J. Bernard Davis, I. Frank Ciernik*
Radiation Oncology, Zurich University Hospital, Switzerland

Abstract
Background and purpose: To define the potential advantages of intensity-modulated radiotherapy (IMRT) applied using
a non-coplanar dynamic arc technique for the treatment of head and neck cancer.
Materials and methods: External beam radiotherapy (EBRT) was planned in ten patients with head and neck cancer
using coplanar IMRT and non-coplanar arc techniques, termed intensity modulated non-coplanar arc EBRT (INCA).
Planning target volumes (PTV1) of first order covered the gross tumor volume and surrounding clinical target volume
treated with 68–70 Gy, whereas PTV2 covered the elective lymph nodes with 54–55 Gy using a simultaneous internal
boost. Treatment plan comparison between IMRT and INCA was carried out using dose–volume histogram and
‘‘equivalent uniform dose’’ (EUD).
Results: INCA resulted in better dose coverage and homogeneity of the PTV1, PTV2, and reduced dose delivered to
most of the organs at risk (OAR). For the parotid glands, a reduction of the mean dose of 2.9 (±2.0) Gy was observed
(p = 0.002), the mean dose to the larynx was reduced by 6.9 (±2.9) Gy (p = 0.003), the oral mucosa by 2.4 (±1.1) Gy
(p < 0.001), and the maximal dose to the spinal cord by 3.2 (±1.7) Gy (p = 0.004). The mean dose to the brain was
increased by 3.0 (±1.4) Gy (p = 0.002) and the mean lung dose increased by 0.2 (±0.4) Gy (p = 0.87). The EUD suggested
better avoidance of the OAR, except for the lung, and better coverage and dose uniformity were achieved with INCA
compared to IMRT.
Conclusion: Dose delivery accuracy with IMRT using a non-coplanar dynamic arc beam geometry potentially improves
treatment of head and neck cancer.
c 2006 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 81 (2006) 151–157.

Keywords: Intensity-modulated radiotherapy; Non-coplanar arc therapy; External beam radiotherapy; Head and neck cancer; Toxicity;
Xerostomia; IMRT

Optimal dose conformity is critical for high standard
radiotherapy treatment with curative intent. Intensity mod-
ulated radiotherapy (IMRT) uses non-uniform beam intensity
to deliver highly conformal radiation and minimizes the
dose delivered to organs at risk (OAR) [1]. IMRT is an optimal
technical approach for treating head and neck cancer be-
cause of the anatomical complexity of the region with many
critical and radiation-sensitive tissue structures in close
proximity to the targeted cancer tissue [2,3].
The primary target volume is represented by the clinical
target volume (CTV) including the gross tumor volume (GTV)
and regions of suspected microscopic disease. In advanced
stage disease, these regions usually surround the spinal
cord. The need to spare the spinal cord from excessive radi-
ation doses results in concave-shaped clinical and planning
target volumes (PTV). IMRT allows to increase the dose ap-
plied to the GTV and reduces the risk of local relapse within
high dose zones [4].
Besides the spinal cord, the salivary glands representing
the non-target structures are of major interest and should
be spared as best as possible in order to avoid xerostomia
after completion of the external beam radiotherapy (EBRT)
[5]. The parotid glands can be more easily spared with IMRT
compared to the 3D-conformal RT (3D-CRT) [6,7]. A broad
experience and studies in a variety of anatomical sites have
been published comparing the plan quality of IMRT and 3D-
CRT, generally finding that IMRT produced superior treat-
ment plans [8–11]. For head and neck cancer patients,
the loss of salivary gland function can dramatically reduce
the quality of life and impact on social activity for long-term
survivors [12,13]. Several groups have reported that IMRT
allows adequate coverage of cancer tissue while sparing
the parotids, if compared to 3D-CRT [5,10,14–19]. Further-
more, non-coplanar beam geometry in 3D-CRT planning of
head and neck cancer patients seems beneficial [20].
We hypothesized that the dose distribution may improve
if additional degrees of freedom for the purpose of dose
delivery could be implemented. Therefore, we evaluated
the possibility of using dynamic arc beams that are intensity
modulated combined with a non-coplanar beam


0167-8140/$ - see front matter c 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2006.09.004
152 Intensity-modulated non-coplanar arc radiotherapy (INCA) for head and neck cancer

arrangement while maintaining the arc-like dose delivery.

Table 1
Arc beams are an alternative to fixed gantry radiotherapy, Patients’ characteristics
where the gantry continuously rotates meanwhile the radia-
Patient Gender Age (years) PTV2 (cm3) PTV1 (cm3)
tion source remains active [21]. A dynamic arc is an arc
where a multi-leaf collimated beam is delivered with the 1 M 78 269 167
MLC leaves moving continuously as the gantry rotates [22]. 2 F 68 263 155
It therefore seems to be a logical next step from 3D-CRT 3 M 79 239 253
4 M 53 229 64
to exploit coplanar IMRT, arc-IMRT and eventually intensity
5 F 46 294 353
modulated non-coplanar arc (INCA).
6 M 45 476 315
The present study aims to compare IMRT and INCA for 7 M 61 224 212
head and neck patients and to investigate the potential of 8 M 62 280 163
INCA to deliver improved dose distribution. An intra-individ- 9 M 59 273 145
ual comparison of two plans for each patients was per- 10 M 52 129 71
formed, where identical dose constraints for IMRT and
INCA plans were used. We assessed the ability of INCA to re- Mean 60 268 190
duce the dose to the OAR and to keep a high conformity and SD 12 87 95
homogeneity in the target in comparison with IMRT. The PTV1 (respectively, PTV2) includes the CTV1 (respectively,
CTV2 without CTV1) with a margin of 0.5 cm.

delivered by a 6 MV linear accelerator (Clinac 6EX, Varian

Materials and methods
Patients
Ten consecutive patients with advanced carcinoma of
the meso- or hypopharynx or base of tongue all presenting
with stage III or stage IVa disease treated during 2005 at
the University Hospital of Zürich, Switzerland, with IMRT
were included in this analysis. The patient’s group consisted
of 2 female and 8 male patients. At diagnosis, the average
age was 60 years, ranging from 45 to 79 years. The selected
patients were planned to receive a dose of 54–55 Gy to the
elective lymph nodes with a simultaneous integrated boost
of 69–70 Gy to the primary tumor and metastatic lymph
nodes in 33 fractions over a period of 45 days.
Target volumes were delineated in accordance with ICRU
guidelines [23]. The clinical target volume of first order
(CTV1) is defined as the GTV with an additional margin of
5 mm. CTV1 defines lymph nodes and tissue with macro-
scopically visible tumor tissue. The clinical target volume
of second order (CTV2) includes CTV1 with a further margin
considering subclinical tumor spread. CTV2 receives dose
sufficient to treat microscopic disease, being an elective
treatment of nodes without macroscopically involved lymph
nodes. CTV1 is treated to high doses exceeding 68 Gy. The
PTV1 (respectively PTV2) was constructed using the auto-
mated region growing tools from CTV1 (respectively CTV2
without CTV1) by adding an additional margin of 5–10 mm
in the three spatial directions. Target volumes for IMRT
and INCA were the same. OAR were defined, such as the
spinal cord, larynx, parotids, lung, oral mucosa and brain
were contoured by a physician in accordance with ICRU-50
recommendations. For comparison purpose, all plans were
normalized to 100% of the high dose PTV mean dose. Table
1 summarizes treatment data of the ten patients used in the
present study. All volumes, CT data, targets and OAR for
each patients were identical for INCA or IMRT.
Treatment technique
All patients were immobilized during the treatment with
a head and shoulder mask (Sinmed PosifixÒ), resulting in a
repositioning accuracy less than 2 mm. Treatments were
Medical Systems, 120 leaf Millennium MLC).
Treatment planning
Intensity modulated treatment plans were created using
an inverse treatment planning system, (HELIOS, Eclipse
V6.5, Varian Medical System) using conventional planning
CT scans. Three mm CT slices with no gap were taken from
the level of the skull to approximately the end of the lung.
The 3D dose distributions and the dose–volume histogram
(DVH) were generated by Eclipse (V6.5). Five radiation
beams were used in the optimized IMRT plans for each pa-
tient. The beams were equally weighted and arranged in
equi-angular steps of 72° around the isocenter. INCA was
simulated by a simultaneous gantry and table rotation for
each beam. Splitting an aperture modulated arc in a single
IMRT field has been described by Crook et al. [22]. In con-
trast to Crook et al., we hypothesized that an intensity mod-
ulated arc could be split into a number of IMRT fields. Each
plan was calculated with a single 360° intensity modulated
non-coplanar rotation. Each rotation consisted of eight seg-
ments and these segments were divided into two static IMRT
fields. Table 2 shows the angles for the first and last position
of the table and gantry rotation for the eight segments for a
representative patient from our study (patient number 3).
The field sizes for INCA, as for IMRT, were optimized by
Eclipse. According to the geometry of the target structure,
table angle, and beam position, a variability in field length is
observed up to 5% for either field size reduction or increase.
The choice of the gantry and table motion between each
beam had been decided by the planner to avoid the OAR
and to avoid collision between gantry and patient.
Plan optimization
The optimization of the IMRT and the INCA plans was per-
formed with the same initial constraints and the same goals.
To eliminate interoperator variations, the same operator
computed all the treatment plans. To achieve the goals pre-
scribed by the physician, the following dose constraints
were followed: The constraints to the targets were those
from the ICRU 50, the dose in the target was within 5%
 J. Krayenbuehl et al. / Radiotherapy and Oncology 81 (2006) 151–157 153

The Eq. (1) can be derived from the power-law relation-

Table 2
Table and gantry positions ship that describes the dose–volume effect [27]. a can be
determined empirically by fitting published dose–volume
Segment Starting position Finishing position
data [24,34]. In the present study, the values for the param-
Gantry (°) Table (°) Gantry (°) Table (°) eter a for the spinal cord (a = 7.4), parotids (a = 5.0), larynx
1 180 0 225 5 (a = 7.4) have been taken from Wu et al. [34]. We used For-
2 225 5 270 0 mula 1 to derive the parameter for the brain (a = 4), the
3 270 0 315 345 lung (a = 1.4) and for the oral mucosa (a = 5) by using the
4 315 345 0 0 values from previous reports [7,24].
5 0 0 45 15
6 45 15 90 0
7 90 0 135 355
Statistics
8 135 355 180 0 Statistical analysis was performed using a paired t-test.
The t-test and the p-value were calculated with the soft-
Each patient planned with the INCA technique was treated with a
ware StatView (Version 5.0.1). A p-value of <0.05 was
single 360° intensity modulated non-coplanar rotation. Each
accepted as significant.
rotation consisted of eight segments. The first and last position
of each segments are listed in the table.

to +7% of the prescribed dose. The dose to the OAR was kept
lower than the minimal tolerance dose TD 5/5. TD 5/5 re-
fers to a severe complication rate of 5% within 5 years of
RT completion [24].
Evaluation of plans
For the comparison of the treatment plans, the DVHs
were normalized, so that the mean dose of PTV1 of the pri-
mary tumor was equal to 69.6 Gy (2.11 Gy for 33 fractions).
IMRT and INCA were compared using DVH and the equivalent
uniform dose (EUD), for tumors and normal tissues, intro-
duced by Niemierko
!1a
1 X a
EUD ¼ Di ; ð1Þ
N i
where N represents the number of voxels in the target or
OAR, Di is the dose in the ith voxel of the structure of inter-
est, and a is a tissue or tumor specific parameter [25,26].
Results
Planning target volume
The percentage of the PTVs receiving less than 95% and
the percentage receiving more than 105% of the prescribed
dose were assessed for IMRT and INCA. The mean dose and
EUD for all structures were assessed. Percentage of the par-
otids receiving more than 30 Gy and the maximal dose to the
spinal cord were evaluated. These values are summarized in
Tables 3 and 4. The reported values were averaged for the
10 head and neck cancer patients from the present study.
Dose delivery to the PTV was improved using the INCA tech-
nique: The difference of homogeneity was significant and
the volume covered by the 95% was increased by 3.1%
(respectively, 0.6%) for the PTV1 volume (respectively,
PTV2) (p = 0.002, respectively, p = 0.29). The volume cov-
ered by the 105% isodose was reduced by 6.9% (14.2%) for
PTV1 (respectively, PTV2) with INCA in comparison to IMRT
(p = 0,001; respectively, 0.019).
To provide an example of simulated INCA dose distribu-
tion, isodose distributions from IMRT and INCA plans are

Table 3
Comparison of INCA and IMRT: mean dose, PTV volume receiving less than 95% and more than 105% of the prescribed dose, maximal dose to
the spinal cord, mean dose and parotid volume receiving more than 30 Gy, mean dose to the larynx, brain and lung
INCA SD IMRT SD Mean Diff. Paired t-test, p-value
INCA vs. IMRT*
PTV1 mean dose (Gy) 69.7 0.1 69.7 0.1 0 0.2
PTV2 mean dose (Gy) 54.6 0.4 55 0.9 0.4 0.22
% PTV1 receiving 95% of the prescribed dose 97.7 1.6 94.6 2 3.1 0.002
% PTV1 receiving 105% of the prescribed dose 0.4 1 7.3 4.5 6.9 <0.001
% PTV2 receiving 95% of the prescribed dose 97.9 2 97.3 1.5 0.6 0.29
% PTV2 receiving 105% of the prescribed dose 9 5.5 23.2 15.8 14.2 0.013
Maximum dose to the spinal cord (Gy) 39.1 2.4 42.3 2.4 3.2 0.004
Mean dose to the parotid (Gy) 19.3 5.9 22.2 4.4 2.9 0.002
% parotid receiving > 30 (Gy) 28.6 13.6 36.8 10.5 8.2 <0.001
Mean dose to the larynx (Gy) 29.4 5.1 36.3 2.6 6.9 0.003
Mean dose to the oral mucosa (Gy) 31 4.7 33.4 3.6 2.4 <0.001
Mean dose to the brain (Gy) 5.4 2.3 2.4 1.4 3 0.002
Mean dose to the lung (Gy) 3.6 1.5 3.4 1.5 0.2 0.87
*
Bold entries indicate significance of p < 0.05.
154 Intensity-modulated non-coplanar arc radiotherapy (INCA) for head and neck cancer

Table 4
Mean EUD for the targets and OAR for INCA and IMRT
EUD (Gy) Paired t-test, p value
INCA IMRT INCA vs. IMRT

PTV1 68.8 ± 0.2 68.6 ± 0.2 <0.001

PTV2 55.5 ± 0.3 56.0 ± 0.8 NS
Parotid 23.1 ± 2.1 28.0 ± 1.4 <0.001
Spinal cord 29.9 ± 2.1 31.4 ± 1.6 0.02
Oral mucosa 34.6 ± 2.3 37.0 ± 2.0 <0.001
Larynx 31.7 ± 4.0 38.8 ± 2.2 0.002
Lung 4.3 ± 0.8 3.5 ± 0.5 0.003
Brain 11.4 ± 3.0 9.0 ± 4.8 0.06

shown at the level of the isocenter (Fig. 1). On these two
slices, INCA displays a better coverage of the PTV1 (red
structure) and a better avoidance of the spinal cords in com-
parison with IMRT.
Fig. 2. DVH of the PTV1 (69.6 Gy) (blue), PTV2 (54 Gy) (orange),
spinal cord (green), parotids (black) and brain (red) averaged over
the 10 studied patients. The DVHs have been normalized to 69.6 Gy
at 100% of the mean dose to the PTV1. Solid lines represent the
INCA plans and the doted lines represent the IMRT plans.

OAR
The dose delivered to the parotid glands is lower with the
Both techniques were able to keep the EUD and the max-
INCA technique by 2.9 Gy (p = 0.002) in comparison to IMRT.
imum spinal cord dose below its tolerance dose. A signifi-
The parotid glands volume receiving more than 30 Gy was
cant reduction of 3.2 Gy (respectively, 1.5 Gy) to the
reduced by 8% (p < 0.001). The EUD is reduced from 28.0
maximum dose (respectively EUD) is achieved with INCA in
(±2.1) Gy with IMRT to 23.1 (±2.1) Gy with INCA (Fig. 2,
comparison to IMRT (p = 0.004, respectively, p = 0.02)
Tables 3 and 4).
(Fig. 2, Tables 3 and 4).
Monitor units (MU) for IMRT and INCA were evaluated.
The mean lung dose was increased by 0.2 Gy (p = 0.2) and
The mean MU per treatment for IMRT and INCA was 1204
the EUD increases from 3.5 (±0.5) Gy with IMRT to 4.3 (±0.8)
(±178) and 1900 (±422), respectively. The increase by 58%
Gy with INCA (p = 0.003). The brain mean dose increased
of the number of MU will impact on the delivery time. Thus,
with INCA in comparison to IMRT by 3 Gy, from 2.4 (±1.4)
the beam on time will increase from 4 minutes to 6–7 min.
Gy to 5.4 (±2.3) Gy (p = 0.002). The increase of the EUD
was not significant with a difference of 2.4 Gy and a p-value
of 0.06 and (Fig. 3, Tables 3 and 4).
The oral mucosa and the larynx are simulated with a sig-
nificant reduction of the mean dose by 2.4 Gy for the oral Discussion
mucosa and 6.9 Gy for the larynx with INCA in comparison In the present study, we investigated the potentials of
to IMRT (p < 0.003), summarized in Table 3. The oral mucosa maximizing the geometric degree of freedom of the gantry
and larynx DVH are both displayed in Fig. 3. for dose delivery for EBRT for head and neck cancer patients.

Fig. 1. Isodose distributions at isocenter level for 1 representative patient (patient 3 in Table 1). Curves are shown for whole treatment (total
dose of 69.6 Gy to the PTV1, purple structure, and 54 Gy to the PTV2, red structure). The yellow structure corresponds to the parotids. Isodose
lines represent 34 (orange), 49 (cyan), 62 (blue) and 69 (green) Gy which correspond, respectively, to 40%, 70%, 80%, and 100% of the
prescribed dose.
 J. Krayenbuehl et al. / Radiotherapy and Oncology 81 (2006) 151–157
Fig. 3. DVH of the lung (blue), oral mucosa (red) and the larynx (green) averaged over the 10 patients of the present study for INCA and IMRT.
We showed that the combination of an arc technique inte-
grating with non-coplanar dose delivery technique bears
the potentials to improve RT of head and neck cancer pa-
tients. The present study demonstrates the potential utility
and the needs for further improvement of highly conformal
RT. The continuous technical evolution of highly conformal
dose delivery techniques is illustrated in Fig. 4. In a first step,
aperture modulation of conformal fields into an arc beam
geometry (AMAT) can be regarded as a major step significant-
ly improving dose conformity [22]. During AMAT, the MLC
leafs conform to the projection of the PTV. Going from
step-and-shoot conformal techniques, the ability to modu-
late a beam dynamically results in high dose conformity and
has been routinely used in clinical practice since the intro-
duction of reliable multi-leaf technology [28]. An additional
improvement has been suggested using arc therapy with con-
tinuously modulating the beam while changing the beam
direction, termed intensity-modulated arc treatment (IMAT)
[28–31]. The possibilities of using rotating beams being con-
tinuously modulated in respect of beam intensity have been
implemented and resulted in novel designs of linear acceler-
ators such as the tomotherapy unit [32,33]. In the present
study we show that modulated arc therapy may additionally
be improved, if non-coplanar beam geometry is ascertained.
In the present study, the PTV from INCA plans showed a
systematic and significant improvement in terms of target
coverage and homogeneity compared to IMRT plans. There-
fore, the main issue at this point is given by the need for
maximal conformity, because even if the differences be-
tween INCA and IMRT are significant, clinically evidence will
be required to test whether additional optimization steps
translate in better treatments. Improved conformity may
help to deliver higher doses to the GTV without delivering
more dose to OAR. Currently, the need for dose escalation
in the treatment of head and neck cancer has not been con-
3D-CRT >> AMAT >> IMRT >> IMAT >> INCA
(aperture modulation arc therapy)
(intensity modulation arc therapy)
Fig. 4. Development of highly conformal EBRT from 3D-CRT to
dynamic intensity modulated non-coplanar IMRT.
155
clusively shown. Doses around 70 Gy with additional cisplat-
in-based chemotherapy allow to reach high rates of local
disease control and the dose–response relation at doses
over 70 Gy is ‘‘flat’’ [4]. Steep dose gradients however
may allow to establish additional dose levels within the pri-
mary CTVs, such as target volumes delivering additional
dose to hypoxic tumor areas.
In respect of the non-target structures such as all OAR,
both, IMRT and INCA, were able to keep the larynx mean
dose and EUD below its tolerance level of 45 Gy, shown in
Fig. 3. However, further dose reduction in non-target struc-
tures without compromising the dose in the target volumes
could lead to additional clinical advantages, because side
effects during or following treatment might be reduced or
additional dose reserves obtained in case of later salvage
treatment. On the other hand, dose reduction in non-target
volumes could allow additional dose escalation in the target
structures. Therefore, additional dose modulation capabili-
ties exceeding the currently available IMRT-derived confor-
mity could be clinically beneficial.
In the present study, INCA and IMRT were both able to
keep spinal cord maximum dose and the EUD below its crit-
ical level. There is a significant decrease of the maximum
dose with INCA in comparison to IMRT. Under stringent con-
dition, when steep dose gradients within a few millimetres
are desired, INCA could be superior to conventional IMRT
techniques.
One important goal for INCA was to deliver a minimal
mean dose with an EUD below the TD5/5 of 30 Gy to the par-
otids [34]. In this study, a reduction of the EUD of about
5 Gy between INCA and IMRT was observed. The mean
reduction of dose to the parotid seems important, since
the TD 5/5 for the parotid is close to the mean EUD
(28.0 ± 2.1 Gy) obtained with IMRT, compared to INCA
(23.1 ± 2.1 Gy). 30% of IMRT patients had an EUD of the
parotid higher than 30 Gy, whereas INCA resulted in a dose
reduction to the parotid glands in all patients, always
achieving an EUD below the TD5/5. Thus at low doses, addi-
tional dose reduction to the parotids may be relevant for pa-
tients treated with EUDs just lower than the TD5/5. In fact,
the normal tissue complication probability for the parotid
glands reported by Eisbruch et al. is described as a
156 Intensity-modulated non-coplanar arc radiotherapy (INCA) for head and neck cancer
continuous and monotonously increasing function of the
mean dose with a steep gradient between 20 and 30 Gy
[12]. Any significant reduction of the mean EUD in this range
may thus be of clinical benefice.
With INCA treatments, the mean dose to the oral mucosa
was reduced by 2.4 Gy. This decrease of dose seems small,
but potentially improves the patient’s quality of life, reduc-
ing complaints during the early phase of treatment such as
loss of taste or after treatment [35]. Loss of taste is not only
a result of the effect of irradiation on the taste buds, but is
also related to the reduction in salivary flow rate [36]. Usu-
ally, taste gradually returns to normal or near-normal levels
within one year of radiotherapy, although it can take as long
as 5 years. The degree of taste recovery and the recovery
time depend on the radiation dose received. Some patients
may retain a residual reduction in taste acuity (hypogeusia),
or even a permanent impairment in sensation (dysgeusia)
[37]. Conger reported that taste sensation decreases expo-
nentially with a cumulative dose of about 30 Gy (3 weeks),
2 Gy per fraction, after which it becomes virtually absent
[38]. INCA may improve treatment quality in respect of
deregulation of the taste in head and neck cancer patients.
The INCA technique is able to reduce the mean dose and
the EUD to the majority of the anatomical sites in head and
neck cancer cases. Reduction of these doses results from
the additional degree of freedom introduced with the non-co-
planar beam geometry. However, non-coplanarity will in-
crease the dose delivered to the lungs and the brain. The
variation of the lung and brain mean dose in INCA compared
to coplanar IMRT is small, but significant for the brain (varia-
tion of 0.2 Gy for the lung and 3 Gy for the brain). To our
knowledge, nobody has reported complications for these
two structures at such low doses. It remains to be shown,
whether dose constraints to the lungs or the brain must be
routinely defined for INCA treatment plans of the head and
neck region.
Conclusion
INCA technique increases the degrees of freedom for the
treatment in comparison with IMRT by the means of a non-
coplanar dynamic arc technique with intensity-modulated
dose delivery. Compared with IMRT, INCA achieves a more
conformal dose homogeneity in the PTVs while important
OARs can be better spared. In the head and neck cancer,
mean dose to the lung and to the brain may increase
slightly. Steeper dose gradients may allow dose escalation
and may improve tumor control.
Acknowledgement
Supported in part by the Radium Fund, University of Zurich,
Switzerland.
* Corresponding author. I. Frank Ciernik, Istituto Oncologico
della Svizzera Italiana, 6500 Bellinzona, Switzerland. E-mail
address: Ciernik@iosi.ch
Received 30 December 2005; received in revised form 26 June 2006;
accepted 15 September 2006; Available online 19 October 2006
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