1. health and fitness
2. disease
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Chiang Mai Med J 2009;48(4):125-133.
Original article
RADIOTHERAPY IN CERVICAL CARCINOMA
Ekkasit Tharavichitkul, M.D., Vicharn Lorvidhaya, M.D., Vimol Sukthomya, M.D.,
Pimkhuan Kamnerdsupaphon, M.D., Imjai Chitapanaraux, M.D.
Division of Therapeutic Radiology and Oncology, Department of Radiology,
Faculty of Medicine, Chiang Mai University
Abstract
Cervical cancer is one of the most common cancers in females in developing countries.
Radiation therapy plays a major role in the treatment of early and advanced stages.
Concurrent chemoradiation has improved treatment outcome in locally advanced cervical
cancer. The implementation of intensity-modulated radiotherapy (IMRT) and imageguided brachytherapy (IGBT) is waiting to be proved. Chiang Mai Medical Journal
2009;48(4):125-133.
Keywords: radiotherapy, cervical carcinoma
Cervical cancer is one of the most
common female cancers in Thailand and
many developing countries, with an incidence
of 24.5/100,000.(1) The treatment of cervical
cancer depends on the stage of disease. The
treatment of cervical carcinoma is shown in
Table 1.
Role of radiation therapy in cervical cancer
In the early stage (stage I-IIA by FIGO
staging), the roles of radiotherapy are postoperative radiotherapy, and radical treatment
when a patient has inoperable status.(2) In
the advanced stage (stage IIB-IVA by FIGO
staging), concurrent chemo-radiation with
a cisplatin-based regimen is standard.(3-7)
Radio-therapeutic management in cervical cancer is composed of external beam
radiotherapy (EBRT) and brachytherapy
(BT). EBRT is the use of a high energy
photon, which irradiates from outside to
the tumor, while BT is an application of
the radioisotope source, close or inside the
tumor. In the treatment of cervical cancer,
radiation oncologists use both methods
in giving irradiation to a patient, with the
goal of increasing radiation dose to the
tumor and decreasing it to normal tissue
(bladder and rectum). Moreover, in a pos-
Address requests for reprints: Ananchanok Saringcarinkul, M.D., Department of Anesthesiology, Faculty of
Medicine, Chiang Mai University, Chiang Mai 50200, Thailand: E-mail:[email protected]
Received 15 July, 2009 and in revised form 19 August, 2009.
126
Tharavichitkul E, et al.
Table 1. The treatment guidelines of cervical
cancer according to stage.(2)
Stage
Treatment
IA1
IA1, IA2
IB1
IB2, IIA
IIB
III
IVA
IVB
Simple hysterectomy, RT
Radical hysterectomy, RT
Radical hysterectomy, RT
CCRT, radical hysterectomy
CCRT
CCRT
CCRT, Exenteration
Palliation
toperative setting, post-operative radiotherapy is indicated as follows:(8)
o Major risks: positive margin (surgical
margin, vaginal margin or parametrial
margin), positive lymph node.
o Minor risks: size > 4 cm, lymphovascular invasion (LVSI), deep stromal invasion.
If patients have one major risk or two
minor risks, postoperative radiotherapy would
be prescribed. Concurrent chemo-radiation is
recommended in a major risk indication.
Treatment fields of EBRT(9)
Whole pelvic radiotherapy: two or fourfield box technique
Antero-posterior (AP) field & Posteroanterior (PA) field
Upper border: L4-L5 interspace
Lower border: Obturator foramina
Lateral border: 1.5-2 cm outer pelvic rim
Lateral field (in the case of the four-field
box technique)
Upper and lower border: the same as
the AP & PA field
Anterior border: cover pubic symphysis
Posterior border: S2-S3 interspace
The prescribed dose of post-operative
setting depends on pathological status.
Normally, the dose of EBRT is prescribed in
conventional fractionation (1.8-2.0 Gray per
fraction, five fractions per week) to the total
dose of 45-50 Gray. If the pathological
status shows a close or positive margin at
the parametrial side, an additional boost can
be prescribed to 56-60 Gray in conventional
fractionation.
Brachytherapy was designed to increase
the dose to the tumor, while decreasing it
to normal tissue. According to dose rate,
brachytherapy was divided into a Low Dose
Rate (LDR; less than 2 Gy/hour) and High
Dose Rate (HDR; more than 12 Gy/hour).
Nowadays, HDR with remote afterloading
can be used to avoid radiation exposure to the
officers, lessen hospitalization and allow
optimization.(10) Therefore, HDR is commonly used in Thailand.
In the patient whose pathologic results
show positive vaginal margin, intracavitary brachytherapy is applied to the vaginal
stump to increase the tumoricidal dose. The
dose schedule is performed depending on the
treatment center, and the volume of treatment
depends on disease status. Two colpostats or
vaginal cylinders are used to treat the disease
in the vaginal stump and its vaginal involvement. The American Brachytherapy Society
(ABS) recommendations were published in
the year 2000 to guide the dose schedule in
treatment of cervical cancer.(11)
In a medically inoperable setting, radical
radiotherapy alone is applied. The treatment
schedule is composed of EBRT plus BT. The
dose of 45-50 Gy in conventional fractionation is applied in whole pelvis irradiation,
while early central shielding reduces the dose
to the bladder and rectum.(11)
Radiotherapy in cervical carcinoma
127
BT is used to increase the dose to the tumor and reduce it to normal tissue. The dose
schedule in early-stage cervical cancer as well
as our dose schedule is shown in Table 2.
Radiotherapy of locally advanced cervical carcinoma
The treatment of locally advanced cervical
cancer is concurrent chemo-radiation with a
cisplatin-based regimen.(3-7) In the radiotherapeutic aspect, the treatment schedule is composed of EBRT plus BT. The dose of 45-50
Gy in conventional fractionation is applied to
cover microscopic disease, and an additional
boost of 5-10 Gy to the parametrial is added
to increase the dose to macroscopic disease
in the parametrium or pelvic side wall (stage
IIB-IIIB). Supporting data of cisplatin-based
chemoradiation in locally advanced cervical
cancer are shown in Table 3.
BT is used for escalating the dose to a
primary tumor at a curative level (85-90 Gy),
while it spares the dose to normal organ tissue
(bladder and rectum). Intracavitary brachytherapy is most commonly used as treatment.
Interstitial brachytherapy is used when the
tumour has bulky parametrial invasion, bulky
primary disease, narrow vagina or poor
geometry, and a suboptimal dose distribution
of intracavitary brachytherapy is utilized.(12)
The ABS dose schedule of the treatment in
locally advanced cervical carcinoma is shown
in Table 4.
Prescription point of ICBT
The prescription point of brachytherapy is
identified by orthogonal x-ray and divided to
the two main categories as follows:(13)
1. The dose of brachytherapy is prescribed at point A and B, which have the
following definitions;
• Point A: 2 cm lateral to the midline,
and 2 cm above the surface of the ovoid in the
lateral vaginal fornix.
• Point B: 3 cm lateral to point A.
2. According to the International Commission on Radiological Unit and Measurement (ICRU), the dose of normal tissue is
evaluated from the bladder and rectum points,
which have definitions the following;
• ICRU bladder reference point,
which is at the inferior part of the bladder
catheter balloon.
• ICRU rectal reference point, which
is on the anterior rectal wall at a point perpendicular from the cervical os or lowest vaginal
source.
Generally, the dose at ICRU points should
be less than 80% of point A.
Table 2. The dose schedule of radiotherapy in early stage cervical cancer form ABS recommendations.
Studies
ABS
recommendations
Chiang Mai schedule
EBRT dose (Gy)
BT dose
No. of HDR fractions
20
20
20
45
45
50
7.5
6.5
6.0
6.0
5.3
7
6
7
8
5
6
4
128
Tharavichitkul E, et al.
Table 3. The studies that showed concurrent chemo-radiation benefit in locally advanced cervical cancer.
Refs
Study
FIGO
Pts in arms
Whitney, et al. (3)
GOG 85/SWOG
8695
IIB-IVA
177
191
Morris, et al.(4)
RTOG 9001
IB2-IVA*
195
193
Rose, et al.(5)
GOG 120
IIB-IVA
177
173
176
Peters, et al.(6)
GOG109/SWOG IA2-IIA
8797/RTOG 9112
GOG 123
IB2‡
127
116
183
186
Keys, et al.(7)
RT regimen
Pelvic
EBRT/IC
Pelvic
EBRT/IC
Pelvic
EBRT/IC
PA + Pelvic
EBRT/IC
Pelvic
EBRT/IC
Pelvic
EBRT/IC
Pelvic
EBRT/IC
Pelvic EBRT
Pelvic EBRT
Pelvic
EBRT/IC
Pelvic
EBRT/IC
Chemo
remimen
Cis/5Fu
HU
Cis/5Fu
none
Weekly cis
Cis/5Fu/HU
none
Cis/5Fu
none
Weekly cis
none
Table 4. The dose schedule in locally advanced cervical cancer.
Studies
ABS recommendations(8)
Our schedule
EBRT dose (Gy)
BT dose (Gy)
No. of HDR fractions
45
45
50.4
50.4
50.4
56
6.5
5.8
7.0
6.0
5.3
7
5
6
4
5
6
4
Radiation therapy in recurrent disease
Patients with an isolated pelvic recurrence
after initial treatment with radical hysterectomy can sometimes be treated with radiation
therapy. Those who have isolated central
recurrence without regional disease can be
handled in up to 60-70% of cases by EBRT
plus BT. The prognosis is poorer when the
pelvic wall is involved and only 10-20%
of patients survive 5 years after radiation
therapy.(14) Pelvic exenteration is the treatment of choice in patients who experience
local recurrence after radical radiotherapy
and have a 5-year over-all survival rate of
approximating 50 percent.(15) Re-irradiation
in patients who were previously irradiated is
Radiotherapy in cervical carcinoma
a serious issue. Normally, this is considered
in the case of inoperable recurrence. However, the dose of previous irradiation, late
complication status and patient issue should
be carefully considered before decision
making. More recent experiences have
provided encouraging results in selectively
re-irradiated patients with small central recurrences, in whom the use of brachytherapy
was emphasized. Despite these advances,
a higher complication rate than that seen
with primary radiation is to be expected, and
patients have to be appropriately counseled
prior to re-irradiation.(16)
Radiation therapy in palliative treatment
of cervical cancer
In the case of metastatic disease, and
poor performance status that is not ready
for radical treatment, radiotherapy can be
used as a palliative goal to relieve symptoms
(for example; bleeding, pain and respiratory
obstruction ) at the site of the lesion. The
dose of 3-10 Gy per fraction is prescribed
with this intention. EBRT or Brachytherapy
can be used according to the disease and
physician’s opinion.(17)
Results of treatment
The treatment of cervical cancer with
radiotherapy is dependent on the size of
tumor, and stage and performance status of
the patient. The results of overall treatment
and brachytherapy are shown in Table 5 and
Table 6, respectively.
Complications
The development of complications depends on multiple factors (age, performance
status, co-morbidities, dose of EBRT and the
use of chemotherapy). Complications direct-
129
ly attributable to brachytherapy relate to the
very high dose delivered around the cervix,
upper vagina, bladder base and anterior
rectal wall. The pattern of care study reported
that 8-15% of cervical cancer patients, who
were treated with radical radiotherapy,
required hospitalization due to severe complications.(25) These may be considered as
Follows:
• Vaginal side effects predominantly
relate to stenosis and shortening of the
vagina, which can be prevented to some
degree by the use of vaginal dilators.
• Rectal complications are compounded
by the external beam dose delivered and
include rectal frequency and bleeding due to
telangiectasia. Severe rectal problems should
be seen in no more than 5% of patients, but
less troublesome grade I and II side effects
are seen in over 30%.
• Bladder side effects include frequency
and hematuria from bladder telangiectasia.
Occasionally, urethral stricture may also
develop requiring dilation. These are typically seen in less than 5% of patients.
Normally, rectal complications develop
sooner than bladder complications, with the
mean time to onset for rectal complications
Table 5. The overall treatment results of cervical
cancer.(2)
Stage
IA1
IA1, IA2
IB1
IB2, IIA
IIB
III
IVA
IVB
5 yr survival (%)
>95
>95
80-90
80
65-75
30-50
10-20
<5
130
Tharavichitkul E, et al.
Table 6. The treatment of cervical cancer with HDR brachytherapy.
Studies
No. of patients
Stage
Paremeters
Results
Grade 3, 4
complications
Han(18)
88
IB-IVA
5 yr SR
3.4%
Sarkaria(19)
Teshima(20)
40
259
IB-IIIB
I-III
3 yr SR
DFS
Petereit DG(21)
173
I-IIIB
3 yr SR
Patel FD(22)
236
I-III
5 yr SR
Orton(23)
Shigematsu(24)
7468
143
I-IV
IIB-III
5 yr SR
Cumulative SR
IB/IIA 88%
IIB/IIA69%
IIIB/IVA 56%
77%
I 85%
II 73%
III 53%
IB 86%
II 65%
IIIB 33%
I 78%
II 64%
III 42%
61%
55%
being two to three years, and bladder
problems developing a year or two later on
average.(26)
Development of radiotherapy in cervical cancer
Nowadays, with new imaging and
machines, the development of EBRT and
BT has been shifted into image-based treatment planning. In EBRT, the treatment with
Intensity- Modulated Radiotherapy (IMRT)
has been developed to replace conventional
whole pelvic radiotherapy (WPRT). Many
pilot studies have show the benefit of IMRT
in decreasing organ risk doses in the treatment of cervical cancer.(27,28) However, the
benefits of IMRT are controversial.(29)
The treatment of cervical cancer has
developed to image-based brachytherapy.
With the emergence of recommendations
from the Groupe Européen de CuriethérapieEuropean Society for Therapeutic Radiology
2.5%
10%
2.5%
0.4%
9.1%
36%
and Oncology (GEC-ESTRO) in the year
2005, volume-based parameters have been
used in many studies.(30) Studies from Vienna,
Paris and Leuven showed the benefit of
magnetic resonance image (MRI)-guided
brachytherapy in the treatment of cervical
cancer.(31) In the year of 2007, the study of the
clinical impact of MRI-guided brachytherapy
was published.(32) The development of imagebased brachytherapy still waits for further
study to confirm clinical benefits.
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เอกสิทธิ์ ธราวิจิตรกุล, พ.บ., วิชาญ หลอวิทยา, พ.บ., วิมล สุขถมยา, พ.บ.,
พิมพขวัญ กำเนิดศุภผล, พ.บ., อิ่มใจ ชิตาพนารักษ, พ.บ.
หนวยรังสีรักษาและมะเร็งวิทยา ภาควิชารังสีรักษา คณะแพทยศาสตร มหาวิทยาลัยเชียงใหม
บทคัดยอ
มะเร็งปากมดลูกเปนมะเร็งทีพ่ บบอยในประชากรสตรีในประเทศกำลังพัฒนา รังสีรกั ษาเปนการ
รักษาหลักอยางหนึง่ ในการรักษามะเร็งปากมดลูก ทัง้ ในระยะเริม่ ตนและระยะลุกลาม ในปจจุบนั
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ในรังสีรกั ษาระยะใกลกำลังไดรบั การพัฒนาและตรวจสอบ เพือ่ นำมาใชในการรักษา เชียงใหม
เวชสาร 2552;48(4):125-133.
คำสำคัญ: รังสีรกั ษา มะเร็งปากมดลูก