] 2) Cervix is an organ with high internal organ
motion with change in its position caused by some
factors such as filling of urinary bladder, etc. 3) Local
control is low in large tumors using 2-dimensional
brachytherapy. 4) Local control rises above 90% when
D90 is greater than 87 Gy in target volume with external
radiotherapy + IGABT.
In the last 20 years, there has been an increase in
the success of treatment of cervix cancer with the developments
related to concomitant chemoradiotherapy and beginning of the application and widespread use of
IGABT. Since survival gets longer due to this increase,
the late side effects of radiotherapy have been gaining
more importance in time.
Table 1 shows the list of radiotherapy related side
effects for organs at risk (OAR) (rectum, sigmoid, urinary
bladder, bowel, vagina, and urethra) according to
the classification in CTCAE v 4.03.
Table 1: Radiotherapy related side effects in organs at risk (rectum, sigmoid, urinary bladder, bowel, urethra, and vagina)
according to the nomenclature in CTCAE v 4.03
Clinical results of IGABT studies
The clinical results of the studies including more than
30 patients on IGABT in cervix cancer are seen in Table
2. According to the results of these series, the incidence of serious side effects is lower than 10% while local
control is in the range of 79%-95%.[-] In the study
of Pötter et al., from the Medical University of Vienna
presenting clinical results of 3-D conformal radiotherapy
± concomitant chemotherapy + IGABT in cervix
cancer, favorable results have been reached for both local
control and morbidity with IGABT in which MRI
is used systematically.[] In this series of 156 patients
with stage IB-IVA cervix cancer, 3-year local control is
85-90% in locally advanced stage while it is 95-100%
for early stage. Besides, the frequency of serious (LENTSOMA
grade 3 and 4) side effects is 7%. Compared to
the results of historical 2-dimensional brachytherapy series of Vienna, these results display a statistically significant
increase in overall survival and pelvic control
rates and a statistically significant decrease in distant
metastasis rate. Additionally, using IGABT has caused
a threefold decrease in the rate of serious side effects
(21% vs. 7%) and the rate of 3-year actuarial serious
toxicity has declined from 15% to 8% (p=0.06).[]
Table 2: Clinical results obtained in cervical cancer patients receiving external radiotherapy ± concomitant chemotherapy
+ IGABT
In a French multicentric non-randomized prospective
study including 235 patients with cervix cancer
treated with concomitant chemotherapy and external
radiotherapy + brachytherapy, while the incidence of
grade 3-4 toxicity is 22.7% in 2-dimensional brachytherapy,
it decreases to 2.6% in 3-dimensional brachytherapy.[] In a retrospective study from Leiden
University including a total of 126 patients with cervix
cancer, compared to 2-dimensional brachytherapy,
IGABT has provided a statistically significant increase
in both complete response (99% vs. 84%) and overall
survival (86% vs. 51%), together with a decrease in the
frequency of grade 3-4 side effects from 15% to 8%
(p=0.06).[] In a retrospective study from Aarhus University
performed in a total of 239 patients with cervix
cancer, the cohort of patients applied 2-dimensional
brachytherapy was compared with the cohort of patients
applied IGABT.[] In this study, overall survival
has increased (79% vs. 63%; p=0.005) and also grade
3-4 combined urological and gastrointestinal morbidity
has decreased (3% vs. 10%; p=0.01) with IGABT
compared to 2-dimensional brachytherapy.[]
The positive results obtained with IGABT are aimed
to be confirmed repetitively through multicentric prospective
studies in which this modality is applied systematically
in the light of GEC-ESTRO recommendations.
In 2008, an international study on MRI-guided
brachytherapy in locally advanced stage cervix cancer (EMBRACE) has been designed with this aim. It is
thought that the correlation between local control and
target dose-volume parameters and late morbidity and
OAR dose-volume parameters can be demonstrated in
the perspective of EMBRACE data.
Recommended OAR dose parameters
to be reported and OAR dose limitations
Table 3 shows the OAR dose parameters recommended
for reporting routinely (excluding research) in the recent
report of ICRU (No: 89) related with cervix cancer
brachytherapy.[] OAR dose limitations in IGABT
advised by cooperative study groups in the USA and
Europe are given in Table 4.[]
Table 3: Organ at risk dose parameters recommended for reporting routinely (excluding research) in ICRU 89[]
Table 4: Dose limitations for organs at risk in IGABT recommended by the cooperative study groups in the USA and Europe[]
Rectal side effects
The frequency of serious rectal side effects for IGABT
is declared as 1-5%.[5,8,16-18] In the study of Georg
et al., from the Medical University of Vienna, the frequency
of grade 1-4 late side effects in rectum is13.8%
and the most frequent one is bleeding (10.7%).[]
Five-year actuarial incidence of late rectal side effects
has been calculated as19% in that study and all late side
effects have emerged in the first 3 years following radiotherapy.
Mean time for occurrence of late side effects
was 14 (3-34) months, whereas their mean duration
period was 19 (1-75) months.[]
In the study performed by Mazeron et al., from
Gustave Roussy Cancer Center, it has been shown that
grade 1-4 and grade 2-4 morbidities of rectum have
a relation with D2cc parameter of rectum.[] In a
study made in Leuven Cancer Institute, a correlation
has been determined between rectal D2cc >65 Gy and
occurrence of > grade 3 late rectal morbidity.[]
Sigmoid side effects
Generally, the documentation of sigmoid side effects
is insufficient for brachytherapy applied patients. In a
limited number of studies offering data on this subject
for IGABT applied patients, the frequency of sigmoid
serious side effects is reported as 0-2%.[,,]
Sigmoid D0.1cc and D2cc parameters have not been
shown to play any role to predict radiotherapy related
sigmoid side effects. The reasons of not being able to
determine any dose-volume parameters related with
sigmoid morbidity are as follows: 1) Sigmoid is a mobile
organ. 2) The frequency of side effects is low for
sigmoid. 3) There is a clinical misunderstanding that
the side effects originate from r rectum instead of sigmoid.
4) It is necessary to perform sigmoidoscopy,
which is not a routine procedure, in order to determine
sigmoid side effects.[]
At present, D2cc, D1cc, and D0.1cc are evaluated
for sigmoid, similar to the situation for rectum. Besides,
in case of any sigmoid loop being adjacent to the
applicator, this situation certainly must be paid attention
during dose optimization in computerized treatment
planning.
Urinary bladder side effects
The incidence of serious urinary bladder side effects
has been reported as 3-6% for IGABT.[,-,]
The incidence of grade 1-4 urinary bladder late side effects
is 21.8%, urinary incontinence (13.8%) being the
most frequent one, in the study of Georg et al., from
the Medical University of Vienna.[] In Georg et al."s
study, in which the 5-year actuarial incidence of late
urinary bladder side effects has been measured as 28%,
all side effects have occurred within the first 3 years
following radiotherapy. The mean time period for the
occurrence of late side effects was 27 (3-94) months
while the mean duration period was 20 (1-62) months.
[] In this study, it has been demonstrated that urinary bladder side effects emerge later and heal more
slowly than rectal side effects in patients receiving external
radiotherapy + IGABT.[]
In the study of Mazeron et al., from Gustave Roussy
Cancer Center, it has been shown that grade 2-4 and
grade 3-4 morbidities of urinary bladder are in relation
with urinary bladder parameters D0.1cc and
D2cc.[] In another study by the same author, it has
been displayed that the mean position of urinary bladder
D2cc differs from the position of ICRU urinary
bladder point, being located at 1.7 cm. cranial and 0.6
cm. posterior of the urinary bladder ICRU point.[]
According to the study, if D2cc/DICRU is >1.1, D2cc
volume will be located at the cranial of ICRU urinary
bladder point, and if the ratio is <1.1, it will be located
at the caudal of ICRU urinary bladder point. For the
patients with the ratio D2cc/DICRU is <1.1, it has been
determined that urinary bladder D2cc correlates with
the risk of grade 2-4 incontinence (p=0.017).[]
Bowel side effects
The incidence of serious bowel side effects for IGABT
has been reported as 0-4.8%.[,,] There are problems
in comparison of studies with respect to bowel side effects
related to radiotherapy. One of the most important
reasons for that is the variability in bowel contouring.
The group of patients who are not allowed oral intake for
being under anesthesia cannot be given contrast agent
orally during imaging in CT-simulation for IGABT. Such
a situation makes it difficult to view bowel loops during
contouring on CT sectional images and also prevents
the distinction between small and large bowel loops being
made easily. In cases of being unable to make such a
distinction, the whole of small and large bowels above
sigmoid are contoured as bowel. Besides, in some centers,
it may be preferred to contour not only bowel segments,
but also the bowel including peritoneal cavity in
order to reduce uncertainty due to bowel motility.
In the study of Petit et al., from Gustave Roussy Cancer
Center performed in patients with locally advanced
stage cervix center receiving concomitant chemoradiotherapy
+ IGABT, it has been found that the incidence
of > grade 3 late small bowel side effects was 2.6% and
parameters of D2cc and D0.1cc did not influence late
small bowel toxicity.[] In recent years, small bowel
is claimed to be a complex model formed by organization
of mucosal, mesenchymal, vascular, immune
and inflammatory components, in addition to being a
serial organ.[] For this reason, it is thought that the
parameters like D2cc and D0.1cc which are more valid
for serial organs may have not been significantly correlated
with small bowel morbidity of radiotherapy.[]
It has been suggested by some authors that "moderate
doses to large volumes" stemming from external radiotherapy
could play a greater role than "high doses
to small volumes" originating from brachytherapy for
the occurrence of radiotherapy related late small bowel
toxicity.[,] However, bowel D2cc and D0.1cc may
still be important especially for side effects like fistula,
stricture and obstruction, gaining more importance in
the presence of a small bowel segment adjacent to the
applicator. This must be absolutely paid attention during
dose optimization in computerized treatment planning
of IGABT.
Vaginal side effects
The incidence of serious vaginal side effects with IGABT
has been reported as 3-5.7%.[,,,,,] In
EMBRACE study, vaginal stenosis, vaginal dryness
and vaginal bleeding/mucositis, respectively, were the
most frequent ones among vaginal morbidity types
encountered in external radiotherapy + IGABT.[]
In general, the incidence of vaginal morbidity due to
radiotherapy reaches its peak in the 2nd year starting
from the end of the radiotherapy. Compared to the
other vaginal side effects, vaginal stenosis (shortening
and/or narrowing) and vaginal dryness tend more to
be permanent.[]
According to some studies, vagina D2cc does not
have a role to predict radiotherapy related vaginal
morbidity.[,] In a series of 34 patients with cervix
cancer from the Medical University of Vienna, mean
vagina D2cc was 95.2 Gy with only IGABT and 141 Gy
totally with the combination of external radiotherapy
and IGABT.[] Rai et al., from Chandigargh Research
Institute, India have not observed any relation between
vagina D0.1cc, D2cc, D5cc, D10cc and vaginal toxicity
(telangiectasia, shortening of vagina, dyspareunia)
within the 1st year after the end of the external radiotherapy + IGABT.[] The reasons of being unable to
show such a relation are as follows: 1) There is inherent
difficulty in contouring vagina (alteration of organ
thickness due to personal anatomical differences, probability
of getting too much thin at some parts depending
on the diameter of the applicator used). 2) Different
approaches exist in contouring of vagina (inclusion of
distal surface of cervix also into vagina by some researchers,
etc.). 3) Vagina is both a target volume and
OAR totally or partially. 4) There is an increase in uncertainty
with regard to high doses formed in vaginal
mucosa due to closeness of especially vaginal surface
to the radioactive sources during brachytherapy. 5) It
is difficult to determine the total dose (external radiotherapy
+ IGABT) received by the portion of vagina
included within the external radiotherapy fields. On
the other hand, in a study held at Duke Cancer Center
in the USA, which is the biggest cohort investigating
vaginal morbidity with IGABT, both vagina D2cc and
vagina D1cc have been displayed as independent prognostic
factors affecting ≥ grade 2 vaginal morbidity.
[] In this study, where vagina is contoured without
including the mucosa covering distal part of cervix, it is
recommended that vagina D2cc should not exceed 108
Gy totally with external radiotherapy + IGABT.[] In
a recent study from the Medical University of Vienna,
rectovaginal reference point total dose >65 Gy, external
radiotherapy dose >45 Gy/25 fx and extension of tumor
to vagina have been determined as risk factors for
vaginal stenosis.[]
Also it is known that the radiotherapy tolerance
of distal vagina is lower than that of proximal vagina.
With the help of prospective IGABT studies, it will be
possible to determine dose-volume limitations differing
according to the upper-middle-lower anatomical
parts of vagina.
Urethral side effects
The reporting of urethral side effects related to radiotherapy
is very limited in IGABT applied patients with
gynecological tumors. As a result of this, organ tolerance
information that is present for prostatic urethra
is not available for female urethra. Currently, D2cc is
reported for urethra as being similar for urinary bladder.
The reasons of being unable to show dose-volume
parameters predictive of urethral morbidity are as follows:
1) There is difficulty in the contouring of urethra.
2) Female urethra usually is not exposed to a significant
dose level due to its relatively more distal location
while only the 1/3 upper part of vagina is included into
the target volume for the majority of gynecological tumors. 3) There is scarcity of series of patients with vaginal
tumors in which urethra receives significant dose.
In a series by Dimopoulos et al., from the Medical
University of Vienna including 13 patients with locally
advanced stage vagina cancer who received IGABT
after concomitant external radiotherapy and chemotherapy,
urethral necrosis has been detected following
radiotherapy in 1 patient who had extensive tumor
invasion into urethra. Mean urethra D2cc was 76 Gy
in this study, in which no urethral morbidity has been
reported except for that case.[]
Quality of life
Therapy related late morbidity is an important problem
for cancer patients receiving curative therapy. As
late morbidity may create problems which need to be
solved clinically, it also affects patients" quality of life
negatively. The studies on IGABT have to guide to develop
quality of life by evaluating it prospectively in addition
to evaluating treatment success and morbidity.
Fifty sequential patients with locally advanced stage
cervix carcinoma have been evaluated prospectively
and longitudinally in terms of quality of life in the
study of Kirchheiner et al., from the Medical University
of Vienna.[] In this study, EORTC QLQ C30 general
quality of life questionnaire and EORTC CX24 quality
of life questionnaire for patients with cervix cancer
have been applied to the patients prior to, and during
radiotherapy and also 1 week and 3 months after
IGABT. A comparison has been made in terms of quality
of life with the reference group taken from general
population and matched according to age. In the study,
it has been determined that the state of global health
and physical and role functioning of patients with cervix
cancer are apparently reduced (p<0.001), returning
to its base value in the 3rd month after therapy. Besides,
the state of global health and emotional and role functioning
of patients with cervix cancer have been found
lower compared to the reference group. The symptoms
expressed to have been experienced by patients "at an
important level" have been stated as fatigue (78%), diarrhea
(68%), urinary frequency (60%), and nausea
(54%) in the study. It has been expressed that these
symptoms recovered partially 3 months after the end
of radiotherapy, although fatigue (50%) continued and
hot flush (44%), sexual anxiety (38%), and leg edema
(22%) emerged.[]
In one of the recent EMBRACE studies, quality of
life of the 744 patients with locally advanced stage cervix
cancer applied concomitant chemoradiotherapy +
IGABT has been evaluated prospectively and longitudinally.[] Similar to the study mentioned in the
paragraph above, same questionnaires have been used
for the measurement of quality of life, this time, for a
longer period after IGABT (every 3 months in the 1st
year, every 6 months in the 2nd and 3rd years, then once
in a year for people who became disease-free). In EMBRACE
study, it is stated that while general quality of
life and emotional and social functioning of patients
with cervix cancer were insufficient prior to therapy,
they recovered in the first 6 months following therapy
and reached to the level of the reference group, although
cognitive functioning kept to be insufficient.
On the other hand, it has been detected that while social
and role functioning were at the lowest level prior
to therapy, they recovered after therapy (forming a plateau
at 6th month) and deteriorated slightly in the 3rd
and 4th years. It has been observed that while symptoms
of tumor (pain, loss of appetite, constipation) were severe
prior to therapy, they reduced apparently at the
first control after therapy. Also it has been detected
that therapy related symptoms appeared suddenly after
therapy and kept their level (diarrhea, menopausal
symptoms, peripheral neuropathy, sexual dysfunction)
or initiated slowly and increased gradually (lymph edema,
dyspnea).[]
