A predictive mathematical model for the calculation of the final mass of Graves' disease

thyroids treated with

131
I
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Phys. Med. Biol. 50 (2005) 21812191 doi:10.1088/0031-9155/50/9/018
A predictive mathematical model for the calculation
of the nal mass of Graves disease thyroids treated
with
131
I
Antonio C Traino
1
, Fabio Di Martino
1
, Mariano Grosso
3
,
Fabio Monzani
4
, Angela Dardano
4
, Nadia Caraccio
4
,
Giuliano Mariani
3
and Mauro Lazzeri
2
1
Sezione di Fisica MedicaU.O. Fisica Sanitaria, Azienda Ospedaliera Universitaria Pisana,
via Roma 67, 56125 Pisa, Italy
2
U.O. Fisica Sanitaria, Azienda Ospedaliera Universitaria Pisana, via Roma 67, 56125 Pisa, Italy
3
Centro Regionale di Medicina Nucleare, Azienda Ospedaliera Universitaria Pisana e Universit` a
di Pisa, via Roma 67, 56125 Pisa, Italy
4
Dipartimento di Medicina Interna, Universit` a di Pisa, via Roma 67, 56125 Pisa, Italy
E-mail: c.traino@ao-pisa.toscana.it
Received 13 January 2005, in nal form 14 February 2005
Published 20 April 2005
Online at stacks.iop.org/PMB/50/2181
Abstract
Substantial reductions in thyroid volume (up to 7080%) after radioiodine
therapy of Graves hyperthyroidism are common and have been reported in
the literature. A relationship between thyroid volume reduction and outcome
of
131
I therapy of Graves disease has been reported by some authors. This
important result could be used to decide individually the optimal radioiodine
activity A
0
(MBq) to administer to the patient, but a predictive model relating
the change in gland volume to A
0
is required. Recently, a mathematical
model of thyroid mass reduction during the clearance phase (3035 days)
after
131
I administration to patients with Graves disease has been published
and used as the basis for prescribing the therapeutic thyroid absorbed dose.
It is well known that the thyroid volume reduction goes on until 1 year after
therapy. In this paper, a mathematical model to predict the nal mass of
Graves diseased thyroids submitted to
131
I therapy is presented. This model
represents a tentative explanation of what occurs macroscopically after the
end of the clearance phase of radioiodine in the gland (the so-called second-
order effects). It is shown that the nal thyroid mass depends on its basal
mass, on the radiation dose absorbed by the gland and on a constant value
typical of thyroid tissue. has been evaluated based on a set of measurements
made in 15 reference patients affected by Graves disease and submitted to
131
I
therapy. A predictive equation for the calculation of the nal mass of thyroid is
presented. It is based on macroscopic parameters measurable after a diagnostic
131
I capsule administration (0.371.85 MBq), before giving the therapy. The
nal mass calculated using this equation is compared to the nal mass of thyroid
0031-9155/05/092181+11$30.00 2005 IOP Publishing Ltd Printed in the UK 2181
2182 A C Traino et al
measured 1 year after therapy administration in 22 Graves diseased patients.
The nal masses calculated and measured 1 year after therapy are in fairly
good agreement (R = 0.81). The possibility, for the physician, to decide a
therapeutic activity based on the desired decrease of thyroid mass instead of
on a xed thyroid absorbed dose could be a new opportunity to cure Graves
disease.
1. Introduction
The use of
131
I in the therapy of Graves disease has a long history, dating back to the
early 1940s. It has largely replaced surgery and is nowadays commonly used for denitive
treatment of Graves disease. It is convenient and has proven to be effective in the treatment
of hyperthyroidism. Nevertheless, there is no consensus regarding the most appropriate
dosimetric approach for radioiodine therapy. Traditionally, the amount of
131
I therapeutic
activity is decided based on one of two different approaches:
1. the administration of a xed radioiodine activity (MBq);
2. the administration of a radioiodine activity individually calculated on the basis of a
prescribed thyroid absorbed dose (Gy).
Many papers have been published in order to decide which of these two approaches is better
(Catargi et al 1999, Peters et al 1997, J onsson and Mattsson 2003). Others were published to
establish an optimum value of therapeutic activity (Jarlov et al 1995) or target absorbed dose
(Reinhardt et al 2002, Bajnok et al 1999, Howarth et al 2001). The results of these studies
are in poor agreement.
Recently, an empirical relationship between post-therapeutic thyroid volume and therapy
outcome has been demonstrated by a number of authors, with a smaller change in thyroid
volume occurring in persisting hyperthyroidismthan in either euthyroidismor hypothyroidism
(Muratami et al 1996, Chiovato et al 1998, Haase et al 2000, Gomez-Arnaiz et al 2003). The
relationship between reduction of thyroid volume and outcome of radioiodine therapy of
Graves disease suggests the possibility of deciding the optimal
131
I activity (A
0
) to administer
to the patient based on the desired therapy-induced reduction in thyroid volume.
To date, the foregoing results have not been applied clinically, mainly because prediction
of the reduction in thyroid volume as a result of radioiodine therapy of Graves disease has
been considered an intractable problem. This is because the thyroid volume reduction depends
on a number of patient-specic generally non-measurable parameters.
Recently, a mathematical model of thyroid mass reduction during the clearance phase
(3035 days) after
131
I therapy administration to patients with Graves disease has been
published. It has been used to improve the accuracy of the traditional algorithms for thyroid
absorbed-dose calculation (Traino et al 2001, 2004).
In this paper, a new mathematical model which describes the thyroid mass reduction also
after the end of the clearance phase of
131
I in thyroid (i.e., after the rst month post-therapy
administration) is presented. This model allows prediction of the nal mass of the thyroid as
a function of the
131
I administered activity A
0
. The possibility, for the physician, of giving a
therapeutic
131
I activity based on the desired decrease of thyroid mass instead of on a xed
thyroid absorbed-dose value could be a new chance to cure Graves disease.
A predictive mathematical model for the calculation of the nal mass of Graves disease thyroids 2183
2. Materials and methods
2.1. Thyroid mass reduction model
The model for the reduction of Graves diseased thyroid mass after
131
I therapy administration
is based on the hypothesis that the thyroid mass reduction is due to a dose-dependent
inactivation of thyroid cells. The inactivation of thyroid cells occurs in two distinct time
frames and is therefore divided into so-called rst- and second-order effects:
1. During the radioiodine clearance phase after therapy administration (3035 days), the
inactivation of thyroid cells depends directly on the
131
I present in the thyroid (direct
rst-order effect). This is an immediate effect occurring in the rst 3035 days after
therapy administration.
2. After the
131
I clearance phase (from 3035 days to 1 year after therapy administration),
the inactivation of thyroid cells depends on the irreparable damage due to the dose
absorbed by the gland during the clearance phase (indirect second-order effect). This is
a time-delayed effect.
The total number of thyroid cells irreparably damaged (rst- and second-order effects) by
ionizing radiation can be mathematically described by the following (well-known) simple
model for the survival of cells irradiated by ionizing radiation (Tubiana et al 1990):
N
n
= N
0
exp(D
T
) (1)
where N
n
is the number of surviving (i.e., still functional) thyroid cells; N
0
is the basal
number of thyroid cells; D
T
is the thyroid absorbed dose and (Gy
1
) is a constant. Under
the reasonable hypothesis that the thyroid mass m
T
is linearly related to the number N
T
of cells
in the tissue (i.e., m
T
= N
T
, where is a constant), the nal mass of a Graves disease
thyroid submitted to
131
I therapy could be described by the same model presented in equation
(1). It follows
m
n
= m
0
exp(D
T
). (2)
Note that in this paper we refer to thyroid mass taking into account that it can be easily
calculated by thyroid volume measurements (thyroid tissue density = 1 g ml
1
). (Gy
1
) is
a constant which represents the dose value needed to reduce m
0
to 0.37m
0
. It is characteristic
of the thyroid and represents the response of Graves diseased thyroid tissue to the absorbed
dose D
T
.
2.2. Validation of the model
Fifteen reference patients were followed after
131
I therapy administration to measure m
n
and
to calculate and D
T
. In practice, m
n
corresponds to the mass of the thyroid 1 year after
radioiodine therapy. D
T
has been calculated using the equation (Traino et al 2001, 2004)
D
T
=

np
UA
0
m
0
_
T
max
2
+
1
A
0
_
1
_
1 2
A
0
T
eff
ln(2)
_1
2
__
(3)
where
np
=0.032 mGy g MBq
1
s
1
is the
131
I equilibriumdose constant for non-penetrating
radiations (Stabin 1996); A
0
(MBq) is the
131
I activity administered to the patient; T
eff
(h) is
the effective half-life of radioiodine in thyroid; U = A
m
/A
0
is the fractional uptake in thyroid
(A
m
is the maximum activity in the gland, expressed in MBq); T
max
(h) is the time to maximum
uptake and m
0
(g) is the pre-therapy mass of the gland. is a dimensional constant whose
value is 2.2 10
6
. Equation (3) is a predictive equation which allows the calculation of
2184 A C Traino et al
the radiation dose to the thyroid taking into account the change of thyroid mass during the
clearance phase of
131
I in the gland (ICRU-67 2002). The thyroid masses have been evaluated
from measured (by ultrasonography) thyroid volumes, considering a thyroid density of
1 g ml
1
. U, T
max
and T
eff
were evaluated for each patient by serial measurements of activity in
thyroid after therapy administration. The experimental procedure has been already described
(Traino et al 2004). It was as follows:
1. The
131
I activity A
0
to be administered to the patient was determined on an empirical basis.
2. The activity of the
131
I capsule was measured in a thyroid phantom before being given
to the patient. A Victoreen 660 5/DE 400 cm
3
ionization chamber was used to obtain a
reference dose rate value corresponding to the activity of the capsule (treated as a point
source).
3. Measurements were made from 0 to 840 h after the administration, placing the ionization
chamber close to the neck of the patient. The ionization chamber is a thin cylinder
(4 cm in length) and this minimizes the contribution of the other body structures. In this
way, a number of dose rate values (A
tir
) were obtained. These values were corrected for
a geometrical factor depending on the thyroid volume which considers the thyroid to be
a point source. The measurements were normalized to the reference dose rate, obtaining
values of A
tir
/A
0
, where A
tir
is the activity present in thyroid.
4. A
tir
/A
0
values were tted to the following equation:
A(t ) =
_

_
A
m
t
T
max
t < T
max
A
m
exp
_

ln 2
T
eff
(t T
max
)
_
t > T
max
(4)
to estimate A
m
, T
max
and T
eff
. Equation (4) describes the
131
I kinetics. Note that U =
A
m
/A
0
.
3. Results
The measured and calculated thyroid parameters for the reference patients are shown in table 1.
has been calculated for each of 15 patients by equation (2). Its average value is =0.0038
0.0011 (standard deviation) Gy
1
. From equation (2), taking into account equation (3), it
follows that
m
n
= m
0
exp
_

np
UA
0
m
0
_
T
max
2
+
1
A
0
_
1
_
1 2
A
0
T
eff
ln(2)
_1
2
___
. (5)
Equation (5), like equation (3), is predictive because it depends on macroscopic parameters
measurable after a
131
I diagnostic capsule (0.371.85 MBq) administration. Thus, equation (5)
allows prediction of the nal mass of a Graves diseased thyroid before
131
I therapeutic activity
administration. Equation (5) can be solved giving
A
0
=
2
T
max
_
1
m
0

np
U
ln
_
m
n
m
0
_
+
1
T
max
ln 2

_
2T
eff
+
_
(2T
eff
+ T
max
ln 2)
2
+ 4 ln 2
m
0
T
max
T
eff

np
U
ln
_
m
n
m
0
__1
2
__
.
(6)
A
p
r
e
d
i
c
t
i
v
e
m
a
t
h
e
m
a
t
i
c
a
l
m
o
d
e
l
f
o
r
t
h
e
c
a
l
c
u
l
a
t
i
o
n
o
f
t
h
e

n
a
l
m
a
s
s
o
f
G
r
a
v
e
s

d
i
s
e
a
s
e
t
h
y
r
o
i
d
s
2
1
8
5
Table 1. Thyroid parameters measured in 15 Graves diseased reference patients after
131
I therapy administration. The average value of = 0.0038 0.0011 Gy
1
.
Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
m
0
(g) 64 51 32 18 17 16 16 14 9 23 18 29 21 23 27
A
0
(MBq) 925 555 666 370 555 339 370 503 296 555 370 370 555 555 555
U 0.68 0.86 0.89 0.73 0.45 0.98 0.78 0.81 0.46 0.58 0.73 1 0.99 0.59 0.67
T
max
(h) 23 20 19 22 22 4 20 25 10 24 22 23 28 24 23
T
eff
(h) 117 108 98 90 120 141 131 139 139 104 90 115 141 103 117
D
T
(Gy) 258 199 362 257 352 535 450 812 385 289 256 280 759 289 320
m
n-meas
(g) 19 20 7 6 5 4 3 3 2 14 5 10 3 8 5
(Gy
1
) 0.0047 0.0047 0.0042 0.0046 0.0035 0.0028 0.0041 0.0019 0.0039 0.0018 0.0050 0.0038 0.0026 0.0036 0.0056
2186 A C Traino et al
Equation (6) depends on the same parameters as equation (5). Thus, equation (6) is a predictive
equation for the calculation of
131
I activity to administer A
0
as a function of the desired value
of m
n
.
To test the model, the nal thyroid masses calculated by equation (5) are compared to the
actual masses measured by ultrasonography 1 year after radioiodine therapy administration in
22 Graves diseased patients treated in the Nuclear Medicine Department of our hospital. The
results are shown in table 2.
The
131
I kinetics in these patients has been evaluated as follows:
1. a basal measurement of the diagnostic capsule (1.85 MBq) in a thyroid phantom has been
made before giving to the patient (reference measurement) using a NaI(Tl) probe properly
collimated and calibrated;
2. two measurements (4 and 24 h post-diagnostic capsule administration) have been made
in the neck of each patient using the same NaI(Tl) probe;
3. the fractional thyroid uptake after 4 (U
4
) and 24 h (U
24
) have been calculated. T
eff
(h),
T
max
(h) and the maximum fractional uptake in thyroid U for each patient was decided on
the basis of the ratio U
24
/U
4
(see table 3).
Following this method, the patients are usually divided into four groups (table 3): a normal-
kinetics group (T
max
= 24 h; T
eff
= 121 h; U = U
24
); a normal-kinetics group with a quick
uptake (T
max
= 4 h; T
eff
= 121 h; U = U
4
); a slow-kinetics group (T
max
= 4 h; T
eff
=
169 h; U = U
4
) and a quick-kinetics group (T
max
= 4 h; T
eff
= 107 h; U = U
4
). This is
the standard method to evaluate the
131
I kinetics in the thyroids of Graves diseased patients
treated in the Nuclear Medicine Department of our hospital. The predicted activity and dose to
the gland are usually calculated based on this procedure. This method has some disadvantages
because it does not follow precisely the radioiodine kinetics in a patients thyroid by serial
measurements during the uptake and clearance phase after diagnostic capsule administration.
Thus, the calculated predicted dose and activity are approximate (about 25%). On the other
hand, this method has also some advantages because it is not time consuming and it ts very
well the logistic requirements of the department (it should be very difcult to follow a great
number of patients making more than two measurements). The predicted absorbed dose and
activity can be considered acceptably accurate.
The differences between the nal mass calculated by equation (5) and the nal mass
evaluated by ultrasonography thyroid volumes are shown in gure 1. The uncertainty of
the evaluated thyroid volumes is approximately 20% (Szebeni and Beleznay 1992), that of the
calculated (by equation (5)) nal masses is approximately 35%(gure 1). This last uncertainty
is due to the inaccurate determination of T
eff
(three xed values T
eff
= 121 h; T
eff
= 169 h;
T
eff
=107 h instead of the exact T
eff
for each patient), A
0
, m
0
and U. The maximum uncertainty
of T
eff
is 15%; that of A
0
is 10%; that of m
0
is 20%; that of U is 10%.
The maximum uncertainties of thyroid absorbed dose D
T
and calculated nal mass of
thyroid are not so different.
4. Discussion
Some authors have asserted that the outcome of radioiodine therapy of Graves disease is
related to the therapy-induced reduction in thyroid volume (Muratami et al 1996, Chiovato
et al 1998, Haase et al 2000, Gomez-Arnaiz et al 2003). This seems to be reasonable if
one hypothesizes that the reduction in thyroid volume determines the reduction in thyroid
functionality (Di Martino et al 2002), i.e., the capability of the gland to extract iodine from
A
p
r
e
d
i
c
t
i
v
e
m
a
t
h
e
m
a
t
i
c
a
l
m
o
d
e
l
f
o
r
t
h
e
c
a
l
c
u
l
a
t
i
o
n
o
f
t
h
e

n
a
l
m
a
s
s
o
f
G
r
a
v
e
s

d
i
s
e
a
s
e
t
h
y
r
o
i
d
s
2
1
8
7
Table 2. Comparison between the nal thyroid mass measured from ultrasonography-measured volume (m
n-meas
) and calculated by equation (5) (m
n-cal
) in 22 patients submitted to
131
I therapy for Graves disease. m
n-meas
and m
n-cal
are in fairly good agreement (R = 0.81).
Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
m
0
(g) 70 70 52 52 45 39 35 33 32 31 25 22 20 19 19 18 16 14 14 13 13 11
A
0
(MBq) 592 592 548 518 740 503 740 555 222 222 370 185 185 740 185 351 370 370 111 296 370 340
U 0.69 0.81 0.59 0.68 0.61 0.71 0.6 0.37 0.77 1 0.49 0.9 0.63 0.8 0.83 0.67 0.8 0.57 0.9 0.61 0.5 0.22
T
max
(h) 24 24 24 24 24 24 24 24 24 4 24 24 24 4 24 24 24 24 24 24 24 4
T
eff
(h) 121 121 121 121 121 121 121 121 121 169 121 121 121 107 121 121 121 121 121 121 121 169
D
T
(Gy) 143 168 151 163 257 219 326 151 120 216 168 169 130 657 180 301 429 349 157 317 330 214
m
n-meas
(g) 21 34 18 20 16 10 18 26 10 11 5 7 9 3 3 6 9 7 7 4 5 4
m
n-cal
(g) 40.6 37.0 29.3 28.0 16.9 17.0 10.2 18.6 20.3 13.6 13.2 11.6 12.2 1.6 9.6 5.7 3.1 3.7 7.7 3.9 3.7 4.9
2188 A C Traino et al
0 5 10 15 20 25 30 35
0
5
10
15
20
25
30
35
m
f
in
-
c
a
l (
g
)
m
fin-meas
(g)
0
10
20
30
40
50
60
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
PATIENT NUMBER
F
I
N
A
L

T
H
Y
R
O
I
D

M
A
S
S

m
f
i
n

(
g
)
mfin-meas (g)
mfin-cal (g)
(a)
(b)
Figure 1. (a) Comparison between nal thyroid masses evaluated by experimental volume
measurements (m
n-meas
) and nal thyroid masses calculated by equation (5) (m
n-cal
) for
22 Graves diseased patients submitted to
131
I therapy. The thyroid volume measurements have
been made 1 year after radioiodine administration. The m
n-meas
and m
n-cal
uncertainty is 20%
and 35%, respectively. (b) Scattergram: m
n-meas
and m
n-cal
are in fairly good agreement (R =
0.81).
Table 3. Kinetics parameters of
131
I for 22 control patients affected by Graves disease. T
max
(h),
T
eff
(h) and U depend on U
4
and U
24
values. U
4
and U
24
were measured using a NaI(Tl) probe.
U
24
< U
4
U
24
> U
4
U
24
/U
4
0.88 0.88 < U
24
/U
4
< 0.92 U
24
/U
4
0.92
T
max
(h) 24 4 4 4
T
eff
(h) 121 107 121 169
U U
24
U
4
U
4
U
4
the blood, synthesize it into thyroid hormone and release it into the circulation under feedback
control by pituitary-secreted hormones.
If validated, the correlation between thyroid mass reduction and
131
I therapy outcome
in Graves disease is an interesting result. It could be employed by physicians to choose
A predictive mathematical model for the calculation of the nal mass of Graves disease thyroids 2189
individually the optimal activity to cure Graves disease. Nevertheless, this new approach
cannot be tested nor used without a model which relates the nal volume of the gland (m
n
) to
the radioiodine activity administered to the patient (A
0
).
In this paper, a mathematical model to predict the nal mass of thyroid (equation (2)
and consequently equation (5)) is presented. The model is based on the hypothesis that the
reduction of thyroid mass (volume) due to
131
I therapy of Graves disease is macroscopically
described by equation (2).
The cell-survival model represented by equation (1) is very simple. Thus, equation (2)
is also an over-simplication of the real situation. More realistic models for the cell-survival
curve have a shoulder for low dose values (below 10 Gy) followed by a mono-exponential
curve. Thus, equation (1) and consequently equation (2) can be considered good models for
cell-survival curves at higher dose values.
The model represented by equation (1) assumes that the probabilities of hitting
intracellular radiation targets are the same. This obviously does not mean that there
is the same probability for each cell to be immediately inactivated during the clearance
phase after
131
I therapy administration (rst-order effect) or to be irreparably damaged
but not immediately inactivated (second-order effect). The post-therapy thyroid mass
change rate during the clearance phase of radioiodine in thyroid is higher than in the
remaining period (until 1 year) (Muratami et al 1996, Nygaard et al 1995, Peters et al
1996), but the absolute change in mass due to the rst-order effect is less than that
due to second-order effect. This means that probably there are fewer inside-cell targets
for the immediate inactivation of the cell than for the time-delayed inactivation of the
cell.
In this paper, we present a practical macroscopic model to calculate the nal thyroid
mass due to radioiodine therapy. The measurements of the parameters needed to calculate
the nal mass m
n
(equation (5)) are rather imprecise and a mono-exponential doseresponse
model (equation (2)) is therefore adequate to describe the overall radiation-induced reduction
in thyroid mass.
The nal mass of the Graves disease thyroid depends on parameters measurable after
a diagnostic capsule administration (0.371.85 MBq), prior to therapy (equation (5)). This
could allow the nuclear medicine specialist to decide a therapeutic
131
I activity based on the
desired thyroid mass reduction instead of the gland absorbed dose.
In equation (2) (and also equations (5) and (6)), the parameter (whose dimension
is Gy
1
) can be considered to be a constant value characteristic of the thyroid tissue
(0.0038 0.0011 Gy
1
).
This is an over-simplication in that it implies that the thyroids of all Graves disease
patients respond in the same way to radioiodine therapy after the end of the clearance phase.
At present, our data are such that a relationship between and measurable parameters (such as
m
0
and U) cannot be discerned (Traino et al 2001, 2004, Di Martino et al 2002). On the other
hand, using a constant value = 0.0038 Gy
1
, the agreement between predicted (calculated)
and measured nal masses of thyroid can be considered fairly good (R = 0.81), although
there are a number of large differences between the measured and corresponding tted data
(gure 1). Thus, equation (5) can be used to calculate the nal thyroid mass before therapy
administration and equation (6) can be used to calculate the
131
I activity needed to obtain a
desired nal thyroid mass value m
n
.
In this paper, the hypothesis that the thyroid anatomical mass is identical to the functional
mass has been made. This is an approximation usually made for Graves diseased patients
at a macroscopic level. It allows the evaluation of the functional mass by ultrasonography-
measured volumes of the gland.
2190 A C Traino et al
5. Conclusions
A new mathematical model for the evaluation of the nal mass of thyroid due to radioiodine
therapy of Graves disease is presented. This model is described by equation (5). It allows
prediction of the nal mass of the gland before therapy administration (after a diagnostic
activity) depending on the
131
I activity A
0
to be administered to the patient. Equation (5) can
be solved giving equation (6). Equation (6) can be solved using a spreadsheet, yielding the
therapeutic administered activity based on the desired nal thyroid mass.
The model presented is based on a set of idealized hypotheses (the uniform distribution
of
131
I in thyroid, the mono-exponential thyroid-cell-survival equation). Thus, it represents
only a starting point to try to relate the administered therapeutic activity to the thyroid mass
reduction due to
131
I therapy of Graves disease. The model presented is only a tentative
proposal to approach the Graves disease radioiodine therapy in a new way, trying to make
usable some results obtained fromothers, i.e., the relationship between the outcome of Graves
disease and the reduction of thyroid volume. It is not the best possible model and it can be
improved. Nevertheless, a model which relates the administered activity to the nal thyroid
mass can probably be useful at present.
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