Research Article

Austin J Radiat Oncol & Cancer. 2016; 2(1): 1019.

# Inter-Fraction Variations of D_{2cc} Brachytherapy Dose
Received By Bladder and Rectum in Patients with
Inoperable Cervical Cancer

Marosevic G¹*, Butler EB² and Mileusnic D¹

¹Center for Radiotherapy, International Medical Centers, City of Banja Luka, Bosnia and Herzegovina

²Department of Radiation Oncology, The Methodist Hospital, Houston, Texas, USA

***Corresponding author: **Goran Marosevic, Center
for Radiotherapy, International Medical Centers, City of
Banja Luka, Bosnia and Herzegovina

**Received: **May 17, 2016; **Accepted: **June 20, 2016; **Published: **June 22, 2016

## Abstract

**Purpose:** To examine the inter-fraction variations of the D_{2cc} of the
brachytherapy dose applied to bladder and rectum in patients with inoperable
cervical cancer on the CT basis. Methods and Materials. This prospective
study included 30 patients with cervical cancer FIGO IIb-IVa stage who were
treated with concomitant chemo-radiotherapy. Intracavitary brachytherapy was
performed with applicators type Fletcher tandem and ovoids, once a week at
the HDR regime (high dose rate). Computer tomography was made after every
application. The analysis was made whether there is a statistically significant
difference in the inter-fraction variations of the D_{2cc} of the brachytherapy dose to
bladder and rectum. Statistical significance of differences among the examined
groups was tested with ANOVA test as well as the Tukey post-hoc analysis. The
difference among the groups analyzed was considered significant if P<0.05.

**Results:** Statistical significance has been found neither in the change of the
dose for all fractions in relation to the first one nor by the post-hoc analysis by
Tukey method for the differences in the dose for all fractions mutually for bladder
(p=0.45) and for rectum (p=0.73). One standard deviation of the brachytherapy
dose for bladder is 1.09Gy and for rectum it is 1.045Gy (15.6% and 15% of the
prescribed dose).

**Conclusion:** There is no significant inter-fraction change of the
brachytherapy dose D_{2cc} of the bladder and rectum during the inoperable
cervical cancer brachytherapy. However, two standard deviations need to be
included while calculating the total EQD_{2cc} of the bladder and rectum.

**Keywords:** Inter-fraction variations; Brachytherapy; Inoperable cervical
cancer

## Introduction

Intracavitary brachytherapy has been an obligatory type of the
treatment of the locally advanced cervical cancer for decades. The
main principles of brachytherapy are based on traditional schools
(Paris, Manchester, Stockholm, Fletcher, etc.), that are still dominant
in planning brachytherapy for cervical cancer [1]. Verification of the
applicator position and organs at risk (bladder and rectum, as well as
the sigmoid for 3D brachytherapy) is done with the aim to optimize
brachytherapy dose in order to achieve complete dose distribution
around the target volume, while sparing organs at risk as much as
possible. Prescription of dose is done according to the standard
Manchester system of the dose into the point A [2]. Nowadays,
CT (computer tomography) and MR (magnetic resonance) based
brachytherapy are becoming a standard treatment of locally advanced
gynecological tumors [3-6]. Intracavitary brachytherapy of cervical
cancer consists of multiple applications, usually four to five. As
recommended by the GEC-ESTRO working group, it is important
for the 3D image guided brachytherapy of cervical cancer to verify
what is the dose received by 0,1 cm^{3}, 1 cm^{3} and 2 cm^{3} (D0,1_{cc}, D1_{cc}
and D_{2cc}, respectively) of bladder and rectum volume [7]. Doses
received by organs at risk for all brachytherapy applications are summed up together with the external dose, and the total cumulative
dose is determined by using the linear-quadratic model [8]. In
planning brachytherapy, CT does not give us the possibility to
precisely delineate tumor and plan the distribution of the therapy
dose to the tumor (as is the case with MR planning). However, it is
possible to obtain precise data on contribution of the brachytherapy
dose to the organs at risk [9,10]. Georg P. et al. correlated the level
of complications with the dose received by the abovementioned
referential volumes of the organs at risk [11]. Recently, Hollowey et
al. published the results including the application related variation of
the dose received by the sigmoid, under the conditions that the same
volume of sigma always receives the brachytherapy dose [12].

The aim of this research is to examine the inter-fraction variations
of the D_{2cc} of the brachytherapy dose applied to bladder and rectum
in patients with inoperable cervical cancer on the CT basis. If the
statistical significance does not exist, is it necessary to do computer
tomography for every application?

## Patients and Methods

## Patients

This prospective study included patients with cervical cancer, FIGO IIb-IVa stage, who were treated with concomitant chemoradiotherapy at the University Clinical Centre Tuzla, at the Department for radiotherapy of the Clinic for oncology, hematology and radiotherapy. The study was conducted on a consecutive sample of 30 patients treated in the period April 2010 – May 2012. Inclusion criteria were non-operated patients, brachytherapy was performed with an intra-uterine applicator and two vaginal ovoids.

## Methods

Patients were treated with external conformal radiotherapy
with the dose of 45Gy in 25 fractions to the tumor, parametria and
regional lymph nodes along with the concomitant chemotherapy
with Cisplatin with the dose of 40 mg/m^{2}. External radiotherapy was
performed on the linear accelerator Elekta Sinergy^{®} and with the
energy of 15 MV. Intracavitary brachytherapy was started after 10 to
13 fractions of external radiotherapy. Intracavitary brachytherapy was
performed with applicators type Fletcher tandem and ovoids, once a
week at the HDR regime (high dose rate) with radioactive Iridium
(^{192}Ir) on Flexitron^{®}. Rectum and bladder filling protocols required
that a patient takes 20mg bisacodyl laxative suppositories (Dulcolax^{®})
12 hours prior to every brachytherapy application and urinates
immediately before every brachytherapy application. During every
application, bladder and rectum were tamponed by same radiation
oncologist with gauze soaked in the lopromid (Ultravist^{®}) contrast
liquid which was in 4 to 1 ratio with the physiological solution. The
therapy dose (TD) of 7Gy was prescribed to the A point according to
the Manchester system.

After each brachytherapy application (five in total), computer
tomography of pelvis was made. Bladder and rectum were delineated
during each CT scan. Bladder and rectum delineation was made
on every CT slice: rectum at 1cm from anus to the recto-sigmoid
transition through the entire thickness of the organ wall, and bladder
following the outer contour of the entire organ volume. Planning of
brachytherapy dose distribution for each application was made on
the basis of computer tomography with the planning software system
Flexiplan Isodose Control^{®}

The quantity of the D2cc of the brachytherapy dose to bladder
and rectum for each application was defined. The analysis was made
whether there is a statistically significant difference in the interfraction
variations of the D^{2cc} of the brachytherapy dose to bladder
and rectum between the planning for all applications in relation to
the first application. A post-hoc analysis of the variations of the D^{2cc}
of the brachytherapy dose was made between applications.

## Statistical analysis

In statistical processing of the results, standard methods of descriptive statistics were used (arithmetic mean with the standard deviation and the numerical range from minimum to maximum value). Statistical significance of differences among the examined groups was tested with ANOVA test as well as the Tukey post-hoc analysis. Statistical hypotheses were tested at the significance level of α = 0.05, i.e. the difference P<0.05 was considered statistically significant. SPSS 17.0 (SPSS Inc, Chicago, IL) statistics software was used for the data analysis.

## Results

The study included thirty patients. A total of 150 brachytherapy applications were performed. Table 1 shows the patient demographics. The average age of patients at the time of the treatment was 52, and most of them were at FIGO IIb stage of planocellular cervical cancer.

**Table 1:**Patient Demographics.

Characteristics

AS ± SD*Age

Cancer stage FIGO

52 ± 11

IIb

24 (80%)

IIIb

5 (16,7%)

IVa

1 (3,3%)

*AS – Mean; SD – Standard deviation

Table 1:Patient Demographics.

The results of the minimum brachytherapy dose expressed in
Gy, received by the most exposed 2cm^{3} (D_{2cc}) of bladder for each
application are presented as arithmetic means with standard deviation
in Table 2. The lowest value of D_{2cc} of bladder was measured in the
second application on average (4.3±1.4), while the highest value was
measured in the fifth application (4.6±1.3). The total (TRT + BHT)
biologically equivalent dose in 2Gy by application (EQD_{2}) for bladder
was on average 76.7 ± 5.6 Gy.

**Table 2:**D

_{2cc}of bladder for each application, given in Gy.

Applications

AS ± SD*Application I

4,4 ±1,4

Application II

4,3 ±1,4

Application III

4,7 ±1,2

Application IV

4,4 ±1,2

Application V

4,6 ±1,3

*AS – Mean; SD – Standard deviation

Table 2:D_{2cc}of bladder for each application, given in Gy.

The results of the minimum brachytherapy dose expressed
in Gy, received by the most exposed 2cm^{3} (D_{2cc}) of rectum for
each application are presented as arithmetic means with standard
deviation in Table 3. The lowest value of D_{2cc} of rectum was measured
in the fifth application on average (4.7 ±0.7), while the highest value
was measured in the second and fourth application (5.0 ±1.0). The
total (TRT + BHT) biologically equivalent dose in 2Gy by application
(EQD_{2}) for rectum was on average 81.9 ± 3.4 Gy.

**Table 3:**D

_{2cc}of rectum for each fraction given in Gy.

Applications

AS ± SD*Application I

4,9 ±1,0

Application II

5,0 ±0,8

Application III

4,9 ±0,9

Application IV

5,0 ±1,0

Application V

4,7 ±0,7

*AS – Mean; SD – Standard deviation

Table 3:D_{2cc}of rectum for each fraction given in Gy.

Inter-fraction variations, the change in the D2cc of the brachytherapy
dose received by 2cm^{3} of bladder during each application in relation
to the first application, are shown in Table 4 and Figure 1. All values
are given in Gray (Gy). The mean value of change of D_{2cc} of bladder
ranged from 0.23Gy in the fourth application to 0.56Gy in the third
application, with the total standard deviation of 1.09Gy (15.6% of
the prescribed dose). The analysis of variance did not show statistical
significance in the dose change for all fractions in relation to the
first one. The same can be said for the Tukey post-hoc analysis of the differences in the dose for all applications in correlation (p=0.45).
The range of change in the D_{2cc} of the brachytherapy dose of bladder
ranged from the decrease of the dose by 2.2Gy (31.4%) to the increase
by 2.7Gy (38.5 %). The range of the change in the brachytherapy
biologically equivalent dose in 2 Gy per application (EQD^{2}) at D_{2cc} of
bladder among the patients ranged from 2.6Gy to 14.6Gy.

**Table 4:**Change in the D

_{2cc}of brachytherapy dose given in Gy for bladder for each application in relation to the first one.

**Dose change at2ccD

AS*

SD¶

Minimum

Maximum

II-I application0.55

1.08

-1.90

2.70

III-I application0.56

0.66

-1.00

1.50

IV-I application0.23

0.84

-2.20

1.50

V-I application0.37

0.06

-2.10

2.70

*AS – Mean; ¶SD – Standard deviation; **ANOVA; p= 0.45

Table 4:Change in the D_{2cc}of brachytherapy dose given in Gy for bladder for each application in relation to the first one.

**Figure 1:**Change in the D

_{2cc}of brachytherapy dose given in Gy for bladder for each application in relation to the first one.

Figure 1:Change in the D_{2cc}of brachytherapy dose given in Gy for bladder for each application in relation to the first one.

Inter-fraction variations, the change in the D_{2cc} of the
brachytherapy dose received by 2cm^{3} of rectum during each
application in relation to the first application are shown in Table
5 and Figure 2. All values are also given in Gy. The mean value of
change of D_{2cc} of rectum ranged from -0.17Gy in the fifth application
to 0.10Gy in the second application, with the total standard deviation
of 1.045Gy (15% of the presrcibed dose). The analysis of variance did
not show statistical significance in the dose change for all fractions
in relation to the first one. The same can be said for the Tukey
post-hoc analysis of the differences in the dose for all applications
in correlation (p=0.73). The range of the change in the D_{2cc} of the
brachytherapy dose of rectum ranged from the decrease of the dose
by 2.2Gy (31.4%) to the increase by 2.0Gy (28.6 %). The range of
change in the brachytherapy biologically equivalent dose in 2Gy per
application (EQD_{2}) at D_{2cc} of rectum among the patients ranged from
3.1Gy to 13.7Gy.

**Table 5:**Change in the D

_{2cc}of brachytherapy dose given in Gy for rectum for each application in relation to the first one.

**

Dose change at2ccD

AS*

SD¶

Minimum

Maximum

II-I application0.1

1.01

-1.8

1.6

III-I application0.01

0.97

-1.7

2

IV-I application0.07

1.08

-2.2

2

V-I application-0.17

1.03

-2

1.9

*AS – Mean; ¶SD – Standard deviation; **ANOVA; p= 0.73

Table 5:Change in the D_{2cc}of brachytherapy dose given in Gy for rectum for each application in relation to the first one.

**Figure 2:**Change in the D

_{2cc}of brachytherapy dose given in Gy for rectum for each application in relation to the first one.

Figure 2:Change in the D_{2cc}of brachytherapy dose given in Gy for rectum for each application in relation to the first one.

## Discussion

It is recommended to monitor and report the dose received by
small volumes of organs at risk in the gynaecological brachytherapy
[13,14]. This study examined the dose received by 2cm^{3} (D_{2cc}) of
bladder and rectum and it was shown how the brachytherapy dose
received by 2 cm^{3} of bladder changed from one application to another on average from 4.3 ±1.4 Gy to 4.7 ±1.2 Gy (Table 2), while
for the rectum the dose ranged from 4.7 ±0.7 Gy do 5.0 ±1.0 Gy
(Table 3). An average total (TRT + BHT) biologically equivalent dose
in 2Gy per application (EQD_{2}) is calculated by linear-square model
based algorithm, and it includes the dose, its speed, and the number
of applications during the entire radiotherapy [8]. This model is
implemented into the routine practice by the model α/β = 3 Gy for
the organs at risk and T1/2 = 1.5h for all tissues [15,16].

In a multi-centric research published in the study by Jurgenliemk-
Schulz et al. [1], variations were examined in the planning of MRI
based brachytherapy treatment of cervical cancer, and a comparative
analysis of DVH parameters of 3D plans recommended by GECESTRO
was made. One of the goals was to keep D_{2cc} of bladder and
rectum below EQD_{2} 90Gy and 75Gy respectively. The results of this
multi-centric research showed that in the MRI brachytherapy nonoptimized
planning without interstitial needles an average dose of
EQD_{2cc} for bladder was 92 ± 8 Gy, while for rectum the dose was 64 ±
3Gy. Comparing this with the results in this study (76.7 ± 5.6Gy for
bladder and 81.9 ± 3.4Gy for rectum) it can be said that in this study
the contribution of the dose on bladder was even lower, but rectum
received somewhat higher dose on average. Lower EQD_{2cc} in this
study, when compared to the abovementioned study, can be explained
by the fact that this study included the front vaginal packing, which
made bladder more distant from the radio-active source. Also, in this
study the contrast liquid was not applied on the bladder, so it had a
small volume during each application and was more distant from the
radio-active source than when filled with the contrast. Higher EQD_{2cc}
in this study, when compared to the abovementioned one, can be
explained by the fact that, in this study, one application more was prescribed, which, according to the LQ model, is 14 Gy. Therefore,
while comparing the results, it is evident that there was no difference
in the EQD_{2cc} dose of rectum. Although this was not an MRI based
study, it has been proved that CT scanning is equally valid in the
evaluation of DVH parameters of the organs at risk [10].

Based on this concept, Georg et al. [11] correlated the dose received
by 2 cm^{3} of rectum during the definite radiotherapy (including the
MR based brachytherapy) for the patients with inoperable cervical
cancer. The results of the DVH parameters in correlation with the
clinical symptoms measured by the LENT/SOMA scale showed the
complications of LENT/SOMA 0 for D_{2cc} = 63 ± 8Gy and LENT/
SOMA 1-4 for D_{2cc} = 72 ± 6Gy. Taking into consideration D_{2cc} of
rectum in this study, we can expect a higher number of our patients
with complications of higher grade.

By using the 3D imaging, this study examined not only the
contribution of the dose on bladder and rectum, but also the interfraction
variations, that is the change in the D_{2cc} brachytherapy dose
of bladder and rectum as the organs at risk during the brachytherapy
treatment. Statistical significance was not found in the change of
the dose for all applications in relation to the first one, as well as
the differences in the change of the dose for all the applications in
correlation. However, it is important to notice a large range of
minimum and maximum changes of the dose at D_{2cc} of bladder - min.
2.2Gy (31.4% of the dose per brachytherapy application) and max.
2.7Gy (38.5% of the dose per brachytherapy application), and for the
rectum - min. 2.2Gy (31.4% of the dose per brachytherapy application)
to the increase by 2.0Gy (28.6% of the dose per brachytherapy
application). Regarding such extreme variations which can occur
from one application to another, it is necessary to do computer
tomography for each application, and use it as the basis for planning
and optimizing the dose to the organs at risk. It is very important
to notice the total standard deviation of inter-fraction variations of
the brachytherapy dose, which was 1.09Gy (15.6%) for bladder and
1.05Gy (15%) for rectum. These results correspond to those of the
multi-centric study in which one standard deviation was ranged from
12% to 24.7% for bladder and from 15.1% to 24.8% for rectum. The
effect of these variations on the total biologically equivalent dose is
around 20% [17]. Basically, provided that we want to predict the total
dose received by D_{2cc} of the organs at risk in 95% of the cases, we need
to calculate the inter-fraction variations of the brachytherapy dose
and include two standard deviations in both directions.

Holloway et al. [12] monitored the proximity distance of the
sigmoid from applicators, their variance, the predictor of the change
in the brachytherapy dose, as well as the level of complications on
the sigma in the brachytherapy of cervical cancer, using computer
tomography as the planning basis. Around 20% of HDR applications
required the manipulation of the proximity “dwell” positions in order
to decrease the dose on the sigma. Also, the proximity distance of the
most exposed point of the sigma from the tandem had a significant
correlation to the sigmoid dose (p<0.0001). The brachytherapy dose
during the HDR treatment (27.5Gy in 5 applications to the A point)
in their study for D_{2cc} of the bladder ranged from 11.6Gy to 52.3Gy
and 7.2Gy to 40.8Gy for rectum. All this shows that the extreme
variations of the brachytherapy dose to the organs at risk were present
in their study as well, which corresponds to the results of this study.

However, all the things mentioned are valid provided that the same
2cm^{3} volume of the organs at risk for each application received the
minimum brachytherapy dose. This is the presumption on which all
the previous reports in the studies were based. Basically, the worst
case scenario is reported. The question is: “What if there are interfraction
displacements of 2cm^{3} volume of the organ that receives the
minimum brachytherapy dose?” Is the worst case scenario feasible?

To conclude, during the brachytherapy of inoperable cervical
cancer there is no significant inter-fraction change in D_{2cc} of the
brachytherapy dose to bladder and rectum. One standard deviation
of inter-fraction variations of the D_{2cc} of the brachytherapy dose
for bladder was 15.6% and 15% for rectum of the prescribed
brachytherapy dose. The values of two standard deviations need to
be included in the calculation of the total biologically equivalent dose
received by 2 most exposed cm^{3} of the bladder and rectum volume.
Computer-based planning of brachytherapy for inoperable cervical
cancer is necessary for every application during the brachytherapy
treatment.

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