Assessment of normal tissue complications following prostate cancer
irradiation: Comparison of radiation treatment modalities
using NTCP models
Rungdham Takam and Eva Bezaka兲
School of Chemistry and Physics, The University of Adelaide, Adelaide SA 5000, Australia
and Department of Medical Physics, Royal Adelaide Hospital, Adelaide SA 5000, Australia
Eric E. Yeoh
School of Medicine, The University of Adelaide, Adelaide SA 5000, Australia and Department of Radiation
Oncology, Royal Adelaide Hospital, Adelaide SA 5000, Australia
Loredana Marcu
School of Chemistry and Physics, The University of Adelaide, Adelaide SA 5000, Australia and Faculty of
Science, University of Oradea, Oradea 410086, Romania
共Received 13 August 2009; revised 20 July 2010; accepted for publication 21 July 2010;
published 31 August 2010兲
Purpose: Normal tissue complication probability 共NTCP兲 of the rectum, bladder, urethra, and
femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models.
Methods: Model parameters from literature were used in this evaluation. The treatment techniques
included external 共standard fractionated, hypofractionated, and dose-escalated兲 three-dimensional
conformal radiotherapy 共3D-CRT兲, low-dose-rate 共LDR兲 brachytherapy 共I-125 seeds兲, and highdose-rate 共HDR兲 brachytherapy 共Ir-192 source兲. Dose-volume histograms 共DVHs兲 of the rectum,
bladder, and urethra retrieved from corresponding treatment planning systems were converted to
biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account
for differences in radiation treatment modality and fractionation schedule.
Results: Results indicated that with hypofractionated 3D-CRT 共20 fractions of 2.75 Gy/fraction
delivered five times/week to total dose of 55 Gy兲, NTCP of the rectum, bladder, and urethra were
less than those for standard fractionated 3D-CRT using a four-field technique 共32 fractions of 2
Gy/fraction delivered five times/week to total dose of 64 Gy兲 and dose-escalated 3D-CRT. Rectal
and bladder NTCPs 共5.2% and 6.6%, respectively兲 following the dose-escalated four-field 3D-CRT
共2 Gy/fraction to total dose of 74 Gy兲 were the highest among analyzed treatment techniques. The
average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2%
for HDR-BT.
Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to
normal tissues, the corresponding NTCPs were lower than those of external beam techniques other
than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed
normal tissues, the femoral heads were found to have the lowest probability of complications as
most of their volume was irradiated to lower equivalent doses compared to other tissues. © 2010
American Association of Physicists in Medicine. 关DOI: 10.1118/1.3481514兴
Key words: NTCP models, prostate radiotherapy
I. INTRODUCTION
The main therapeutic aim of all radiotherapy treatment techniques including those for prostate cancer is to maximize
damage to the tumor while, at the same time, keeping damage to the surrounding normal tissues as small as possible.
During treatment planning, normal tissue complication probability 共NTCP兲 as well as tumor control probability 共TCP兲
should be assessed, so as to optimize the therapeutic ratio of
any particular radiotherapy modality. Among plans which
have similar TCP, the one with the lowest NTCP should be
considered superior.
Many groups have published tumor control results following various radiotherapy techniques 共external beam and
5126
Med. Phys. 37 „9…, September 2010
brachytherapy兲 based on biochemical and other clinical outcomes. For instance, Livsey et al.1 reported 5 yr overall survival and disease-specific survival rate in patients with prostate cancer who received hypofractionated 共3.13 Gy/fraction兲
four-field conformal radiotherapy of 83.1% and 91%, respectively. Kupelian et al.2 analyzed the long term relapse-free
survival rates in the patients treated with hypofractionated
共2.5 Gy/fraction for 70 Gy兲 radiotherapy using the intensity
modulated radiation therapy technique and observed 5 yr
overall American Society for Therapeutic Radiology and Oncology biochemical relapse-free survival and Houston
共nadir+ 2兲 biochemical relapse-free survival rates of 85%
and 88%, respectively.
0094-2405/2010/37„9…/5126/12/$30.00
© 2010 Am. Assoc. Phys. Med.
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Takam et al.: Normal tissue complications following prostate cancer irradiation
Blasko et al.3 reported the 9 yr overall biochemical control rate of 83.5% in a group of patients treated with lowdose-rate brachytherapy 共LDR-BT兲 using palladium-103
共Pd-103兲 for a minimum dose of 115 Gy. Twelve-year overall
and disease-specific survival rates of 84% and 93%, respectively, were observed among patients treated with LDR-BT
using I-125 or Pd-103.4 Similarly, Zelefsky et al.5 reported
the 8 yr nadir+ 2 prostate specific antigen-disease-free survival 共PSA-DFS兲 rates of 73%, 60%, and 41% for low, intermediate, and high-risk prostate cancer patients, respectively, treated with I-125 LDR-BT 共median dose of 160 Gy兲.
In addition, for those patients who received Pd-103 LDR-BT
共median dose of 120 Gy兲, the 8 yr nadir+ 2 PSA-DFS rates
for low, intermediate, and high-risk patients were 73%, 64%,
and 38%, respectively. Poor implant quality as reflected by
D90 value 共the dose received by 90% of target volume兲 may
have contributed to slightly lower tumor control rates in this
study compared with previous reports.3,4
Mark et al.6 investigated the treatment outcomes of Ir-192
high-dose-rate brachytherapy 共HDR-BT兲 共45 Gy in six fractions兲 in localized prostate cancer patients and found that the
PSA disease-free survival rate was 90.3%. For a comprehensive list of studies, see the review by Nilsson et al.7
For the treatment of prostate cancer, while TCP increases
with increasing dose, the total radiation dose which can be
given to the prostate is limited by the tolerance of surrounding normal tissues such as the bladder, rectum, urethra, and
bowel. As shown above, although differences in dose levels,
fractionation, and quality of treatment delivery can affect the
efficacy of radiation treatment, clinical studies indicate that
currently used treatment techniques generally report similar
tumor control.7 As a result, assessment of NTCP values for
organs-at-risk 共OARs兲 in association with each treatment
plan or technique would assist clinicians and patients in the
selection of suitable treatment modality and dose per fraction
for a given treatment.
The purpose of the current study is to assess NTCP of the
rectum, bladder, urethra, and femoral heads, following radiation treatment of prostate carcinoma using the relative seriality and Lyman models. Real patient plans for external
beam radiotherapy 共EBRT兲, LDR, and HDR brachytherapy
techniques, which had evolved approximately over a 7 yr
period at our center, were evaluated. Currently, EBRT and
LDR brachytherapy are used as monotherapy but HDR is
combined with EBRT.
II. MATERIALS AND METHODS
II.A. Prostate treatment techniques and differential
dose-volume histograms
Contouring of normal tissues in all plans was carried out
by one radiation oncologist only to ensure that all organs
were contoured consistently for all patients and treatment
techniques analyzed. While this does not eliminate intraobserver variability in contouring, this variability is minimized
by using absolute rather than percent volumes of the contoured OARs in the dose-volume histograms 共DVHs兲.8 The
full extent of the rectum and bladder were contoured based
Medical Physics, Vol. 37, No. 9, September 2010
5127
on CT slices of the entire pelvis obtained at 2–3 mm intervals in the axial plane. The rectum was defined as extending
from the anal canal to the rectosigmoid junction. Intravenous
contrast was used to assist in the definition of the bladder for
contouring purposes. The urethra was not contoured for the
EBRT techniques as this normal tissue would have received
the same homogenous radiation dose as the prostate. Following the dose calculation, DVHs of the rectum, bladder, and
urethra were exported from the corresponding treatment
planning systems.
In total, 215 DVHs from 101 patients were analyzed in
this study. Real treatment plans of treated patients were used
in the current study. As a result, different groups of patients
are compared when analyzing individual radiotherapy techniques. While acknowledging that this introduces another
variable into the study, it allows our risk estimates to be
correlated with patient data in the future. Details about each
treatment technique are briefly described in Table I. While
the heterogeneity of the techniques is acknowledged, this has
resulted from the development and validation of treatment
techniques reported in the medical literature. For example,
HDR-BT is now acknowledged to have an emerging role in
the management of prostate cancer.9
Although HDR-BT as monotherapy is currently not yet
available at our center, the promising results in terms of
treatment efficacy and low normal tissue toxicities of
HDR-BT as monotherapy 共often prescribed as four fractions
of 9.5 Gy兲 for prostate cancer have been recently
reported.10–16 In order to simulate the effect on NTCP using
HDR-BT as monotherapy, the original HDR-BT live treatment plans used for the combined modality treatment were
used as monotherapy plans by increasing the number of fractions 共of 9.5 Gy兲 from two to four 共same dose distribution
was assumed for each fraction兲.
II.B. Biologically effective dose and equivalent dose
conversion techniques
The probabilities of normal tissue complications were calculated from differential DVHs of organs-at-risk. The physical dose-based differential DVHs from hypofractionated
three-dimensional conformal radiotherapy 共3D-CRT兲,
HDR-BT 共live planning兲, and LDR-BT 共live planning兲 were
first converted to biologically effective dose 共BEffD兲-based
differential DVHs 共BEffDVHs兲 in order to normalize the
doses in the DVHs to the same biological end-point. This
conversion was performed using the formalism developed by
Dale17
BEffD = DⴱRE,
共1兲
where D is the delivered physical dose 共Gy兲 and RE is a
function of dose called relative effectiveness as defined in
Eqs. 共2兲–共4兲 in the following sections.
II.B.1. Dose conversion for hypofractionated 3DCRT, HDR-BT, and LDR-BT
Relative effectiveness for hypofractionated 3D-CRT with
dose per fraction d can be written as17
Same as 共1兲
Nucletron SPOT-PRO™
共live planning兲
Nucletron SWIFT™
共live planning兲
The prostate gland with a
275.0⫾ 24.5 共249.1–314.6兲
1.5 cm 95% isodose margina
Same as 共1兲
297.9⫾ 55.6 共253.6–429.2兲
Same as 共1兲
198.0⫾ 55.7 共112.9–283.8兲
Same as 共1兲 for the first 64 Gy,
then prostate gland with no margin 201.3⫾ 85.7 共93.0–396.9兲
d
,
共␣/兲
共2兲
冋 冉 冊册
2R0 
− ␣
ⴱ 关1 − e−共T兲兴−1 ⴱ
冎
1
关1 − e−T共+兲兴 ,
+
再
1
关1 − e−共2T兲兴
2
共3兲
N/A
冉冊
R0 
,
+ ␣
共4兲
9.5
Nucletron MicroSelectron HDR
where, R0 is the initial dose rate 共0.0704 Gy/h兲, is the
source decay constant 共0.000 48 h−1兲, and is the rate of
sublethal damage repair.18
Following the BEffD conversion of DVHs, in order to
account for the differences in dose fractionation schemes
such as between standard fractionated 共2 Gy/fraction for 64
Gy兲 and hypofractionated 共2.75 Gy/fraction for 55 Gy兲, and
also between HDR-BT and LDR-BT, BEffDVHs were subsequently converted to equivalent dose 共Deq兲-based differential DVHs 共DeqVHs兲. Equivalent dose Deq for a particular
dose delivering scheme is the dose which would be given
using conventionally fractionated 共2 Gy/fraction兲 irradiation
for the same biological effect. It can be calculated using the
formalism developed by Nag and Gupta19
Deq =
Reference 8.
38
7 cGy h−1
145
2
70
RE = 1 +
a
N/A
where R0 is the initial dose rate 共⬃94.86 Gy/ h兲, is the
source decay constant 共0.000 39 h−1兲, is the rate of sublethal damage repair 共0.46 h−1兲,18 and T is the total treatment
time 共⬃25 min per fraction兲.
For a permanent implant with a 共infinite兲 decaying source
as used in LDR-BT, assuming that repair rates never exceed
rates of double-strand break induction and without cell proliferation, the relative effectiveness in this case is defined
as17
共6兲 HDR-BT monotherapy 共Ir-192兲 共n = 19兲
共2兲 Hypofractionated 3D-CRT 共n = 30兲
共3兲 Dose-escalated 3D-CRT 共n = 44兲
共4兲 Five-field 3D-CRT 共n = 42兲
5128
where ␣ /  is the dose when the linear and quadratic components of cell killing are equal 共using the linear-quadratic
dose-response model兲.
Relative effectiveness for a nonpermanent implant with a
decaying radioactive source as used in HDR-BT is defined
as17
−
共5兲 LDR-BT monotherapy 共I-125兲 共n = 73兲
2
2.75
2
64
55
70 or 74
共1兲 Standard fractionated 3D-CRT 共n = 21兲
RE = 1 +
RE = 1 +
18 MV photons 共Varian 2100EX兲,
four-field 共AP/PA, laterals兲
Same as 共1兲
Same as 共1兲
18 MV photons 共Varian 2100EX兲,
five-field 共AP/two laterals, two obliques兲
Average needles used: 24;
average seeds implanted: 70
Margin
Average
planning treatment
volume 共PTV兲
in cm3 共range兲
Beams
arrangement or
implantation
Dose/fraction
Prescription or dose rate
共Gy兲
dose 共Gy兲
Treatment
technique
共n = no. of DVH兲
TABLE I. Radiation treatment techniques for prostate carcinoma at Royal Adelaide Hospital, Radiation Oncology Department, South Australia, which were involved in this study.
Pinnacle3 6.2b
共Phillips Medical System兲
Same as 共1兲
Same as 共1兲
Takam et al.: Normal tissue complications following prostate cancer irradiation
Treatment
planning
system
5128
Medical Physics, Vol. 37, No. 9, September 2010
BEffD
,
共1 + dref/␣/兲
共5兲
where dref is the reference dose per fraction for a conventionally fractionated EBRT. In this study, the dref was 2 Gy/
fraction.
The aim of conversion of physical doses in DVHs to
BEffD and Deq in this study was to normalize the physical
dose from individual radiation treatment techniques to the
dose which would produce the same biological end-point
共BEffD兲 as that of the standard fractionated 共2 Gy/fraction兲
dose schedule 共Deq兲.
For standard fractionated 3D-CRT or other EBRT techniques based on 2 Gy fraction delivering scheme, these dose
conversions were not needed because the final Deq obtained
from BEffD conversions will be equal to the original physical
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Takam et al.: Normal tissue complications following prostate cancer irradiation
5129
TABLE II. The default parameter values of the relative seriality and the Lyman models for organs-at-risk
involved in this study.
Default values
Parameters
共1兲
共2兲
共3兲
共4兲
共5兲
␣ /  ratio
s
k
m
n
Rectum
Bladder
a
a
5.4 Gy
0.75c
10.64e
–
–
7.5 Gy
1.3d
14.5e
–
–
80 Gy for
symptomatic
bladder contracture
and volume lossb
80 Gy for severe
proctitis/necrosis/
stenosis/fistulab
共6兲 D50
Urethra
Femoral heads
7.5 Gy关estimated兴
1.0关estimated兴
14.5e
–
–
6 Gyb
–
–
0.12b
0.25b
68 Gy for
clinical stricture/
perforationb
65 Gy for
Necrosisb
a
Reference 25.
Reference 26.
c
Reference 24.
d
Reference 27.
e
Reference 28.
b
doses. The original differential DVHs obtained from treatment planning system were used directly in these cases.
II.C. NTCP calculations
The relative seriality model was applied to most of the
DeqVHs in this study, with the model parameters of the organs of interest for specified end points obtained from literature. This model was chosen mainly because it accounts for
the architecture of the organ through parameter “s,” which is
derived from the ratio of serial subunits to all subunits in the
organ.20 In this scheme, an organ where the substructures are
organized in series becomes nonfunctional when one substructure is damaged, while for a parallel organ, the probability of complication depends on the fraction of substructures
damaged.21 Hence, the magnitude of volume irradiated to a
certain radiation dose will strongly affect the final outcome
of irradiated normal organ. This is particularly important for
brachytherapy techniques where small volumes are exposed
to high doses.
The following logistic function was used to estimate the
NTCP:22–24
再
冋 冉
NTCP = 1 − 兿 1 −
i
1
1 + 共D50/Deq,i兲k
冊册
s i/V
冎
1/s
.
共6兲
D50 in the above equation represents the dose required to
produce 50% probability of specific tissue complications, i
is the normal organ subvolume which received the equivalent
dose Deq,i. Parameters s and “k” are empirically determined
NTCP parameters which dictate the seriality of the organ
structural architecture and steepness of dose-response curve,
respectively.
Model parameters used for calculations of NTCP for each
OAR are summarized in Table II.
The model parameters for calculation of the NTCP of the
urethra are not readily available despite extensive reports of
urethral toxicity following various prostate cancer radiotherapy techniques. For example, Burman et al.26 lists sevMedical Physics, Vol. 37, No. 9, September 2010
eral OARs end points and tolerance parameters for use in
estimating NTCP following radiotherapy but not the urethra.
As the urethra has similar anatomical structures to OARs
such as the colon, esophagus, and small intestine, and strictures leading to the obstruction of the passage of the luminal
contents are common end points following radiotherapy, it
was decided to use the end points and tolerance parameters
of the esophagus 共Table II兲 to estimate the urethral NTCP in
this work. In addition, in case of standard fractionated and
hypofractionated 3D-CRT techniques, the urethra was not
contoured and, as a result, differential DVHs of urethra for
these techniques were not available. However, assuming that
equivalent doses, Deq,i are the same as the target dose and
were uniformly delivered to the urethral volume within the
prostate, urethral NTCP was calculated using the following
equation:23
NTCP =
1
1 + 共D50/Deq,i兲k
共7兲
,
where D50 and k have the same definition as described previously.
In case of femoral heads, the relative seriality model parameters were not available. Therefore, the Lyman NTCP
model with effective volume DVH reduction scheme29–31
was used instead. The Lyman NTCP model may be defined
as follows:
NTCP共D,V兲 =
1
冑2
冕
t
e−共t⬘
2/2兲
dt⬘ ,
共8兲
⬁
where
t=
Dmax − D50共eff兲
.
mⴱD50共eff兲
共9兲
The normal deviate t represents the number of standard deviations the point 共Dmax , eff兲 is away from D50共eff兲, the 50%
tolerance dose for the effective volume 共eff兲. D50共eff兲 is
taken to vary with eff as32
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Takam et al.: Normal tissue complications following prostate cancer irradiation
D50共eff兲 = D50共1兲/共eff兲n .
5130
共10兲
The effective volume 共eff兲 is calculated using the following
equation:
eff =
冉 冊
1
D
兺 i Dmaxi
ref i
1/n
,
共11兲
where ref can be either a volume of the whole organ or
reference volume of that organ and n is the volume dependence of the complication probability.26
Model parameters used for femoral heads are shown in
Table II.
II.D. Assessment of NTCP values dependence on the
relative seriality model parameters
It is clear from Eq. 共6兲 described above that the relative
seriality NTCP model contains several variable parameters
such as Deq,i, s, and k. The dose Deq,i 共derived in this study
by first converting physical dose to BEffD and then to Deq as
described earlier兲 depends on the ␣ /  ratio of the OAR. To
investigate the sensitivity of the NTCP values obtained depending on the model parameters, values of ␣ /  ratio, as
well as s and k parameters were varied and rectal NTCPs for
hypofractionated 3D-CRT and HDR-BT treatment plans
were calculated. The parameter k was calculated applying the
following equation:
k=
4
冑2m ,
共12兲
showing that it is related to the value of parameter “m” 共the
slope of the complication probability vs dose curve兲. Hence,
testing of sensitivity on the NTCP model associated with the
parameter k can be done either by varying the value of parameter k directly or by varying the value of parameter m.
The latter approach was used in this study by varying the
value of one parameter at a time while keeping others constant by using their default value. Typical rectal BEffDVHs
FIG. 1. A plot shows differential DVHs of rectum obtained from a four-field
hypofractionated 3D-CRT treatment plan for prostate. Differential volume
共cm3兲 of rectum was plotted against original physical doses and corresponding converted biological effective doses and equivalent doses.
Medical Physics, Vol. 37, No. 9, September 2010
FIG. 2. A plot shows differential DVHs of rectum obtained from a HDR-BT
as monotherapy treatment plan for prostate.
for the various treatment modalities were used to demonstrate the results of this sensitivity testing in the following
subsections.
III. RESULTS
III.A. DVHs of organs-at-risk
Changes in OAR DVHs as a result of physical doses conversion are demonstrated in Figs. 1–3, showing examples of
typical differential DVHs of the rectum obtained from fourfield hypofractionated 3D-CRT, HDR-BT, and LDR-BT as
monotherapy treatment plans for the prostate. In these figures, the normalized cumulative volume 共%兲 of rectum was
plotted against the original physical doses.
Calculated NTCP values were statistically analyzed using
one-way ANOVA and t-tests for their significance. NTCP for
standard four-field 3D-CRT technique and 64 Gy total dose
was used as reference.
FIG. 3. A plot shows differential DVHs of rectum obtained from a LDR-BT
as monotherapy treatment plan for prostate.
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Takam et al.: Normal tissue complications following prostate cancer irradiation
5131
TABLE III. Average calculated rectal NTCP following various prostate cancer treatment techniques calculated with relative seriality model and dosimetric
parameters 共equivalent dose was used in calculation兲.
No. of
DVH/patient
Average of mean
equivalent dose in
Gy⫾ S.D 共range兲
Average irradiated
volume in
cm3 ⫾ S.D 共range兲
Average
NTCP in
% ⫾ S.D 共range兲
P-value
t-value
Statistical
significance
7
48.5⫾ 4.1
共41.6–53.6兲
93.9⫾ 44.4
共54.6–186.6兲
2.8⫾ 1.0
共1.1–4.1兲
Reference
10
43.9⫾ 2.0
共39.6–46.2兲
83.8⫾ 29.6
共45.9–142.5兲
1.3⫾ 0.2
共1.1–1.6兲
⬍0.0001
31.32
Yes
Dose-escalated 3D-CRT
A. Total dose of 70 Gy
13
46.6⫾ 5.5
共38.1–55.8兲
72.0⫾ 31.1
共25.3–141.7兲
3.3⫾ 1.6
共1.2–5.5兲
B. Total dose of 74 Gy
3
51.6⫾ 0.6
共50.8–52.0兲
62.7⫾ 9.8
共51.8–70.9兲
5.2⫾ 1.0
共4.1–6.1兲
Five-field 3D-CRT
共70 Gy at 2 Gy/fraction兲
14
38.6⫾ 5.7
共30.2–51.6兲
98.5⫾ 51.9
共36.6–204.5兲
2.7⫾ 0.9
共1.3–4.1兲
HDR-BT 共Ir-192兲
monotherapy 共4 ⫻ 9.5 Gy兲
9
59.8⫾ 8.3
共49.6–78.5兲
5.4⫾ 2.6
共2.1–8.1兲
0.5⫾ 0.4
共0.0–1.1兲
LDR-BT 共I-125兲
37
61.9⫾ 5.8
共50.5–73.3兲
3.4⫾ 1.0
共1.5–5.3兲
0.6⫾ 0.4
共0.0–1.8兲
0.2637
1.173
No
0.0553
4.072
No
0.5632
0.5932
No
⬍0.0001
17.55
Yes
⬍0.0001
29.27
Yes
Treatment technique
Standard fractionated 3D-CRT
共64 Gy at 2 Gy/fraction兲
Hypofractionated 3D-CRT
共55 Gy at 2.75 Gy/fraction兲
III.B. NTCP of OARs
III.B.1. Rectal NTCP
Table III shows the volumetric, radiation dosimetric data,
and NTCP of rectum for prostate radiation treatment techniques investigated. Calculations based on the relative seriality model indicate that the risk of rectal complications was
the highest following dose-escalated 3D-CRT to a total dose
of 74 Gy being approximately 5.2⫾ 1.0%. Average rectal
NTCP were smaller for HDR-BT 共0.5⫾ 0.4%兲 and LDR-BT
共0.6⫾ 0.4%兲 treatment plans.
The combination of large irradiated volume and high radiation dose exposure led to higher probability of rectal complications in standard fractionated and dose-escalated 3DCRT compared to other techniques. The NTCP in four-field
3D-CRT increases with the increasing total dose and dose
escalation can only be recommended if PTV margin can be
reduced.
With five-field 3D-CRT, radiation beams were arranged in
such a way that irradiation of critical organs such as rectum
and bladder was minimized. Therefore, the average rectal
NTCP following five-field 3D-CRT was smaller than that of
dose-escalated four-field 3D-CRT with the same total dose.
For HDR-BT and LDR-BT monotherapy, only approximately 1% and 0.1% of rectal tissues were exposed to the
prescribed doses, hence, calculated probabilities of rectal
complications for these techniques were the lowest. These
techniques offer better dose conformality and less peripheral
Medical Physics, Vol. 37, No. 9, September 2010
radiation dose exposure of surrounding normal tissues. The
lower NTCP values for LDR and HDR brachytherapy were
found to be statistically significant.
III.B.2. Bladder NTCP
Table IV shows the volumetric, radiation dosimetric data,
and NTCP of the bladder for various prostate radiation treatment techniques. Similar to rectal complications, it was observed that severe bladder complications are most likely following dose-escalated four-field 3D-CRT 共to a total dose of
74 Gy兲 for prostate cancer. Average bladder NTCP following
this technique was 6.6% 共range 5.8%–7.4%兲. Following the
same technique with a smaller total dose of 70 Gy delivered
to the prostate, the average bladder NTCP was reduced to
5.0% despite a larger irradiated volume.
For standard fractionated four-field 3D-CRT, the maximum bladder irradiated volume receiving equivalent dose
around 63 Gy was approximately 10%, resulting in an average 1.9% NTCP for bladder. Similar fractions of bladder
共9%兲 were irradiated to lower equivalent dose of 59 Gy from
hypofractionated 3D-CRT which led to smaller average bladder NTCP at 0.7%.
Similar to the discussion for rectal DVHs analysis, bladder NTCP for hypofractionated four-field 3D-CRT technique
resulted in lesser equivalent dose given and smaller volume
of bladder irradiated, thus the probability of severe bladder
complications was able to be reduced.
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Takam et al.: Normal tissue complications following prostate cancer irradiation
5132
TABLE IV. Average calculated bladder NTCP following various prostate cancer treatment techniques calculated with relative seriality model and dosimetric
parameters 共equivalent dose was used in calculation兲.
Treatment technique
Standard fractionated 3D-CRT
共64 Gy at 2 Gy/fraction兲
No. of
DVH/patient
Average of
mean equivalent
dose in
Gy⫾ S.D 共range兲
Average
irradiated
volume in
cm3 ⫾ S.D 共range兲
Average
NTCP in
% ⫾ S.D 共range兲
P-value
t-value
Statistical
significance
7
53.4⫾ 4.1
共44.6–56.4兲
133.4⫾ 32.9
共90.7–181.0兲
1.9⫾ 0.2
共1.6–2.3兲
Reference
Hypofractionated 3D-CRT
共55 Gy at 2.75 Gy/fraction兲
10
50.8⫾ 4.3
共42.8–54.9兲
119.6⫾ 42.3
共56.0–184.6兲
0.7⫾ 0.2
共0.4–0.9兲
Five-field 3D-CRT
共70 Gy at 2 Gy/fraction兲
14
43.0⫾ 12.2
共20.4–63.7兲
162.4⫾ 99.2
共46.6–456.8兲
3.3⫾ 1.0
共1.4–4.8兲
Dose-escalated 3D-CRT
A. Total dose of 70 Gy
13
48.3⫾ 13.3
共20.6–65.5兲
161.7⫾ 72.6
共81.5–306.0兲
5.0⫾ 2.4
共1.3–9.1兲
B. Total dose of 74 Gy
3
44.2⫾ 6.3
共37.9–50.5兲
199.4⫾ 147.9
共72.4–361.8兲
6.6⫾ 0.8
共5.8–7.4兲
III.B.3. Urethral NTCP
⬍0.0001
23.24
Yes
0.0002
5.146
Yes
⬍0.0001
5.784
Yes
0.0095
10.18
Yes
Table V shows the volumetric, radiation dosimetric data,
and NTCP of urethra for radiation treatment techniques discussed. As expected, urethral NTCPs following standard
fractionated and hypofractionated four-field 3D-CRT techniques were higher than those for other organs due to uniform high-dose exposure. Following standard fractionated
3D-CRT, average urethral NTCP was found to be approximately 9% 共range 8.2%–11.2%兲. Similar high average urethral NTCP was also predicted for HDR-BT 共18.4%, range
12.2%–31.1%兲 as well as LDR-BT 共24.7%, range 12.0%–
55.1%兲. The corresponding average urethral NTCP for hypofractionated four-field 3D-CRT was lower at 3.6%.
are shown in Table VI. Necrosis of femoral heads may be a
consequence of excessive exposure to radiation from prostate
radiotherapy. Assessment of femoral heads DVHs retrieved
from treatment plans for dose-escalated four-field 3D-CRT
treatment for prostate cancer indicated that approximately
11% and 14% of the femoral heads volume was irradiated to
doses of 70 and 74 Gy, respectively. The mean equivalent
dose received was lower than other OARs partly because of
their distance from the treated volume. Accordingly, an average NTCP for femoral heads was observed to be as low as
0.02% for dose-escalated four-field 3D-CRT 共to total dose of
70 Gy兲 and 0.06% for dose-escalated four-field 3D-CRT 共to
total dose of 74 Gy兲.
III.B.4. Femoral heads NTCP
III.C. Assessment of NTCP values dependence on the
relative seriality model parameters
The volumetric, radiation dosimetric data, and NTCP of
femoral heads for individual treatment techniques discussed
Figure 4 shows the effect of varying ␣ /  ratio on rectal
NTCP calculated with the relative seriality model. For hy-
TABLE V. Average urethral NTCP in various prostate cancer treatment techniques calculated with relative seriality model 共equivalent dose was used in
calculation兲.
Treatment technique
Standard fractionated 3D-CRT
共64 Gy at 2 Gy/fraction兲
Hypofractionated 3D-CRT
共55 Gy at 2.75 Gy/fraction兲
HDR-BT 共Ir-192兲 monotherapy
共4 ⫻ 9.5 Gy兲
LDR-BT 共I-125兲
No. of
DVH/patient
7
10
10
36
Medical Physics, Vol. 37, No. 9, September 2010
Average of
mean equivalent
dose in
Gy⫾ S.D 共range兲
Average
irradiated volume in
cm3 ⫾ S.D 共range兲
Average
NTCP in
% ⫾ S.D 共range兲
64.2⫾ 0.6
共63.8–65.3兲
59.3⫾ 0.1
共59.2–59.4兲
93.5⫾ 5.7
共83.7–103.4兲
130.4⫾ 5.1
共118.0–139.2兲
5.2⫾ 0.5
共4.6–5.9兲
5.5⫾ 1.1
共4.3–7.5兲
0.8⫾ 0.3
共0.5–1.5兲
0.6⫾ 0.2
共0.2–1.6兲
9.4⫾ 1.1
共8.2–11.2兲
3.6⫾ 0.7
共2.8–5.0兲
11.2⫾ 3.9
共6.5–19.3兲
24.7⫾ 8.0
共12.0–55.1兲
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Takam et al.: Normal tissue complications following prostate cancer irradiation
5133
TABLE VI. Average femoral heads NTCP and in various treatment techniques for prostate cancer 共equivalent dose was used in calculation兲.
Treatment technique
Five-field 3D-CRT
共70 Gy at 2 Gy/fraction兲
No. of
DVH/patient
Average of
mean equivalent
dose in
Gy⫾ S.D 共range兲
Average
irradiated
volume in
cm3 ⫾ S.D 共range兲
Average
NTCP in
% ⫾ S.D 共range兲
14
30.2⫾ 7.2
共20.4–44.0兲
204.0⫾ 68.9
共101.5–372.8兲
0.2⫾ 0.4
共0.0–1.3兲
33.5⫾ 7.1
共17.3–39.0兲
39.4⫾ 1.4
共38.4–40.3兲
121.9⫾ 55.7
共38.6–217.2兲
117.7⫾ 7.3
共112.6–122.8兲
0.02⫾ 0.02
共0.0–0.05兲
0.06⫾ 0.04
共0.04–0.09兲
Dose-escalated 3D-CRT
A. Total dose of 70 Gy
10
B. Total dose of 74 Gy
2
pofractionated 3D-CRT, variation of ␣ /  ratio from 1 to 10
Gy causes around 5% change in rectal NTCP. However, a
smaller change 共ⱕ2%兲 in rectal NTCP was observed either
for hypofractionated 3D-CRT and HDR-BT considering ␣ / 
ratio for rectum ⱖ5 Gy 共typically assumed for normal tissues兲. If ␣ /  is less than 3 Gy then the NTCP difference
between the techniques will only be greater, with EBRT resulting in worse NTCP.
In case of varying the value of the s parameter, the rectal
NTCP for hypofractionated 3D-CRT appears to have a linear
relationship with the s parameter. The rectal NTCP varies
from approximately 0.3%–1.6%, i.e., around 1.3% change,
for the whole range of the s parameter values from 0 to 1
共Fig. 5兲. The relationship between the s parameter and the
rectal NTCP appears to be exponential for HDR-BT. However, small changes only in rectal NTCP 共⬍1.2%兲 were observed with increasing of the s parameter value from 0.1 to
1.0. This full extent of the s parameter values is unrealistic as
rectum is considered a serial organ 共s values closer to 1兲
rather than parallel 共s values closer to 0兲. The variations in
NTCPs between s values of 0.5 and 1 are less then 0.5% for
FIG. 4. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT
共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value
of rectal ␣ /  ratio.
Medical Physics, Vol. 37, No. 9, September 2010
hypofractionated EBRT and less than a percent for HDR-BT,
therefore not contributing to the final error bar significantly.
Finally, Fig. 6 shows the relationship between value of
parameter k and rectal NTCP as predicted by the relative
seriality model. Variation of the value of this parameter from
1 to 20 causes considerable change in rectal NTCP for hypofractionated 3D-CRT especially when the value of parameter k is smaller than 10. Contrarily, varying the value of
parameter k in the same range has a much smaller effect in
rectal NTCP for HDR-BT with approximately 1%–2%
change. For values of k less than 10, the difference in NTCPs
between HDR-BT and hypofractionated EBRT will only be
accentuated/increased. As a result, we believe that the NTCP
differences between modalities 共EBRT and BT兲 are valid
even within the model uncertainties.
IV. DISCUSSION
From all rectal differential DVHs evaluated for standard
four-field 3D-CRT, it was observed that some DVHs contained a dose peak at the Deq around 30–40 Gy while some
of them had a peak at the Deq of 60–65 Gy. For those DVHs
FIG. 5. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT
共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value
of parameter s.
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Takam et al.: Normal tissue complications following prostate cancer irradiation
FIG. 6. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT
共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value
of parameter k.
which had the peak around intermediate Deq range, the average rectal NTCP was around 1%, while those rectal DVHs
which had the peak around the prescribed tumor doses have
average rectal NTCPs in a range of 2%–4%. Similarly, most
of the bladder DVHs for standard fractionated 3D-CRT had
the dose peak around the prescribed tumor doses of 60–65
Gy which resulted in a bladder NTCP of approximately 2%,
while those DVHs having a peak around 30–40 Gy resulted
in NTCP of less than 2%. In addition, reduction of normal
tissue complication risk following external beam radiotherapy can also be achieved by decreasing the normal tissue
volume that might be exposed to therapeutic radiation dose,
i.e., reducing the treatment margin.
With hypofractionated four-field 3D-CRT, dose-volume
distributions of the rectum, bladder, and urethra were similar
to that of standard fractionated four-field 3D-CRT, but the
irradiated volumes were approximately 11% smaller. Additionally, lower equivalent doses 共maximum of 55 Gy兲 were
used to irradiate the prostate which, accordingly, resulted in
lower dose exposure of the surrounding normal tissues,
which ultimately led to lower estimated probability of complications following the treatment. Since the prostate has
been observed to have lower ␣ /  ratio than normal tissues,
this gives some advantages to hypofractionated EBRT or
HDR-BT as treatment of choice for prostate cancer because
both techniques have a potential to yield increased tumor
control for a given level of late complications or decreased
late complications for a given level of tumor control.33 Results from this study partly confirmed this theory as the estimated NTCP for a particular organ from hypofractionated
3D-CRT was lower than that from standard fractionated 3DCRT. However, it should be noted that there are few reports
of higher values of ␣ /  ratio for prostate.34,35 Possible reasons for the lower NTCP estimated in this study include
lower average irradiated volumes particularly for the bladder
and the use of an ␣ /  ratio of 7.5 for bladder and of 5.4 for
rectum. Based on the ␣ /  ratio considerations, the linearMedical Physics, Vol. 37, No. 9, September 2010
5134
quadratic model would predict lower 2 Gy equivalent doses
for the hypofractionated schedule used in this study. Outcome analysis of latest randomized trials comparing hypofractionated schedules with conventional fractionation for
prostate show quite inconclusive results regarding NTCP.
While some trials show no difference between the two
schedules in regards to NTCP,36,37 others show better NTCP
with hypofractionation38 or only a small increase in certain
toxicities and not necessarily on genitourinary ones.39,40 Obviously, NTCP results depend on fraction size too, as really
large fraction sizes can induce toxicity. However, more studies and longer follow-up are needed, especially for the recent
trials, to fully validate the efficacy of hypofractionation both
NTCP and TCP wise.
HDR-BT, either as monotherapy or as a boost to EBRT,
has been reported to cause very low rates of severe late toxicity to surrounding normal tissues.41–43 Mean Deq received
by rectum from HDR-BT ranged between 50 and 78 Gy,
while the mean Deq for urethra ranged similarly between 50
and 73 Gy. DVHs obtained from prostate treatment plans
indicated that only small fractions 共approximately 1.5% of
total volume兲 of rectum were exposed to high therapeutic
doses during the treatment. Therefore, average rectal NTCP
following HDR-BT predicted was much smaller than that
following EBRT. This conclusion is in agreement with clinical findings.
Data based on a review of clinical results following
HDR-BT as a boost to EBRT indicate a small prevalence of
severe long term toxicity.7 Furthermore, chronic toxicities
after HDR-BT as monotherapy for prostate cancer have been
reported to less than LDR-BT after a median follow-up period of 35 months.11 Most complications observed in the
HDR monotherapy patients were low grade toxicity and
none of the patients experienced grade 4 toxicities. With a
median follow-up of 4 yr, the most severe late complication
observed in patients treated with HDR-BT was urethral stricture with a 5 yr actuarial risk of 7% and no patient experienced late severe rectal complications.41 The incidence of
urological complications observed in the previous report was
obvious when it is related to differential DVHs assessment
observed in this study where average Deq received by the
urethra from the treatment was as high as 120 Gy representing the highest received by all normal tissues.
For LDR-BT using I-125 permanent radioactive seeds, radiotherapy parameters such as average BEffD and Deq were
similar to HDR-BT although rectal and urethral irradiated
volume were slightly smaller. Dose-volume distribution of
LDR-BT in the rectum appeared to be more inhomogeneous
compared to other techniques and ranged widely from 30 to
130 Gy. Although a wide range of equivalent dose was delivered to rectum, only small fractions 共approximately 4% in
total兲 were irradiated to the prescription dose. Hence, a small
value of average rectal NTCP ensued.
For urethra, during prostate irradiation, a part of the urethra located inside the prostate 共prostatic urethra兲 may receive the same dose which was given to the prostate especially with the EBRT. As a result, higher NTCP values were
observed from DVHs assessment for the urethra than other
5135
Takam et al.: Normal tissue complications following prostate cancer irradiation
irradiated organs. For brachytherapy, planning was done in
such a way that dose to the urethra was minimized. However,
some fractions of the urethra were still irradiated with the
equivalent doses in a range of 120–140 Gy for LDR-BT and
110–130 Gy for HDR-BT, which were considerably higher
than the doses that other organs received. Accordingly, it was
indicated by the NTCP model that severe complications of
urethra following prostate irradiation are more likely to be
observed than that of other surrounding healthy organs. With
LDR-BT, approximately 3% of urethral volume was irradiated to equivalent doses in the range of 100–150 Gy, clearly
the highest among the doses received by other OARs. The
average urethral NTCP of 24.7% predicted is higher than
severe complication rates reported clinically. The discrepancy is likely to be attributable to the lack of published urethral specific model parameters. The average urethral NTCP
of 24.7% predicted by this model is, however, consistent
with reports of low grade 共grade 0–grade 2兲 urinary toxicity
共incontinence兲 after I-125 LDR-BT range widely between
0%–40%.44,45
Dose-escalated four-field 3D-CRT to a total dose of 70
and 74 Gy is currently used at our center for treatment of low
and intermediate/high-risk prostate cancer. The planning target volume is reduced after 64 Gy to avoid exposure of surrounding normal tissues to the full prescription dose. Distribution of equivalent doses over the volume of rectum and
bladder was therefore similar to that of standard fractionated
and hypofractionated 3D-CRT. Although PTV was reduced
in order to minimize the healthy tissue damage, some portions of rectum and bladder volume were still exposed to
high doses resulting in a higher prediction of rectal and bladder NTCP.
Zelefsky et al.5 reported 5 yr actuarial likelihood of development of grade 2 and grade 3 late GI toxicities of 11%
and 0.75%, respectively, following the prostate treatment using dose-escalated 3D-CRT up to 81 Gy. In addition, the 5 yr
actuarial likelihood of development of grade 2 and grade 3
late GU toxicities was 10% and 3%, respectively. Our differential DVHs assessment showed NTCP ranges of 1.2%–
6.1% and 1.3%–9.1% for the rectum and bladder, respectively, which are consistent with the rates of severe late GI
and GU toxicities.
Michalski et al.46 recently investigated dose-volume effects in radiation induced rectal injury. They reviewed several published data on rectal injury and estimated parameters
for the Lyman–Kutcher–Burman NTCP model. While the s
value of the relative seriality model used in this study for
estimation of NTCP for rectal complications is slightly lower
than the n parameter of the Lyman–Kutcher–Burman model
in their work, it yields NTCPs within a similar range for
dose-escalated 3D-CRT.
Severe complications of femoral heads have been rarely
reported. Corresponding differential DVHs from our doseescalated 3D-CRT treatment plans indicated that they would
normally receive equivalent doses in a range of 30–40 Gy
explaining the lack of reports of severe complications. In
addition, the complication rates for femoral heads are lower
than those observed compared to other OARs because the
Medical Physics, Vol. 37, No. 9, September 2010
5135
DVHs show that only 11%–14% of the femoral head were
irradiated to the prescription doses, the remainder receiving
lower physical and therefore equivalent doses. While the
NTCP increases with the dose 共from 0.02% to 0.06% for 70
and 74 Gy, respectively兲, a larger increase in NTCP has been
observed for larger volumes of the femoral heads irradiated
to the prescribed dose of 70 Gy 共0.2% for 204 cm3 and
0.02% for 122 cm3兲.
Borghede and Hedelin47 reported the estimated femoral
heads dose of 49 Gy from 3D-CRT treatment technique 共total
dose of 70 Gy with standard fractionation兲 and 64.8 Gy with
hypofractionated 共2.4 Gy/fraction兲 for prostate cancer. Out of
184 patients involved in their study, only one patient 共0.5%兲
experienced osteonecrosis of the hip joint 18 months after
the treatment and was suspected as a result of three-field
treatment technique which increased the dose to femoral
heads compared to four-field technique. A range of mean
doses similar to ours, received by femur head and neck during prostate treatment, was reported by Gershkevitsh et al.48
For a dose prescribed to target of 64 Gy with different plans,
the mean doses to this OAR were in the range of 3–34 Gy,
the maximum mean dose falling within the range reported in
this study. Bedford et al.49 reported the use of the Lyman
model to estimate a complication probability of femoral
heads for different radiation treatment plans of conformal
radiotherapy for prostate cancer. In his report, the NTCP of
femoral heads was generally small 共⬍0.1%兲 except for a few
plans with NTCP of up to 5.5%. Luxton et al.50 also reported
very small NTCP probability 共up to 0.05%兲 of femoral heads
as a result of 3D-CRT for prostate carcinoma.
Testing for the sensitivity of NTCP predictions using the
relative seriality model, the values of ␣ /  ratio and s and k
parameters for the rectum were varied within the total range
and changes in estimated rectal NTCP in hypofractionated
3D-CRT and HDR-BT were investigated. In case of ␣ / 
ratio for rectum which is typically assumed to be larger than
that for the target organ 共prostate兲, increasing from its default
value 共5.4 Gy兲 to the maximum value 共10 Gy兲 had little
effect on estimated rectal NTCP in both hypofractionated
EBRT and HDR-BT. It may be assumed that within the typical range of ␣ /  ratio 共5–10 Gy兲 for rectum, the estimated
rectal NTCP is virtually independent to rectal ␣ /  ratio. The
magnitude of variation in rectal NTCP in both techniques as
a result of changes in the s parameter was not substantial as
only around a 1.2% increase in rectal NTCP was observed.
Variations of the k parameter within the expected range
共1–20兲 had greater effect on estimated rectal NTCPs in hypofractionated 3D-CRT than HDR-BT, especially for k ⱕ10.
The effect of this dependence on rectal NTCP in HDR-BT
was far less pronounced and seems to be virtually independent of the value. For values of k less than 10, the difference
in NTCPs between HDR-BT and hypofractionated EBRT
will only be increased.
V. SUMMARY
Results form this study are based on theoretical predictions using available radiobiological models and are intended
5136
Takam et al.: Normal tissue complications following prostate cancer irradiation
to provide clinicians with additional information to assist in
the selection of a radiation treatment technique and plan for
radiotherapy of prostate cancer. Validation of the predicted
NTCP awaits long term toxicity data of the different techniques and fractionation studies preferably from randomized
clinical trials.
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