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Journal of International Medical
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DOI: 10.1177/030006051204000633
2012 40: 2346 Journal of International Medical Research
Z Liu, Y Gao, YL Soong, X Chen, F Gao, W Luo, W Sheng, J Ren, L Zhang and J Wang
Cervical Cancer: A Retrospective Study
Intraoperative Electron Beam Radiotherapy for Primary Treatment of Stage IIB

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The Journal of International Medical Research
2012; 40: 2346 2354
2346
Intraoperative Electron Beam
Radiotherapy for Primary Treatment of
Stage IIB Cervical Cancer: a Retrospective
Study
Z LIU
1,a
, Y GAO
1,a
, YL SOONG
2
, X CHEN
3
, F GAO
3
, W LUO
1
, W SHENG
1
, J REN
1
,
L ZHANG
1
AND J WANG
1
1
Department of Radiation Oncology, First Affiliated Hospital, Medical College of Xian
Jiaotong University, Xian, China;
2
Department of Radiation Oncology, National Cancer
Centre of Singapore, Singapore;
3
Department of Oncology, Second Affiliated Hospital,
Medical College of Xian Jiaotong University, Xian, China
Introduction
Cervical cancer is the second most common
cancer in women, with 80% of cases
occurring in developing countries.
1
Approximately 25% of patients relapse after
5 years, and locoregional failure accounts for
> 50% of these relapses.
2
The 2-year survival
rate following local recurrence of cervical
cancer is poor, at ~22% regardless of
treatment.
3
Recurrent cervical cancer is
associated with pain, anorexia, vaginal
bleeding, cachexia and psychological
sequelae.
4
It is therefore important to
improve the local control rate during
primary treatment, to reduce the risk of
recurrence or distal metastasis.
Cisplatin-based concomitant chemo -
radiotherapy has been shown to be more
OBJECTIVE: A retrospective study to
evaluate intraoperative electron beam
radiotherapy (IOERT) as a primary
treatment modality for stage IIB cervical
squamous cell carcinoma. METHODS:
Patients underwent treatment with IOERT
(n = 78) or radical radiotherapy (RT; n =
89). Patients in the IOERT group received
20 Gy external beam radiotherapy (EBRT)
in 10 fractions, intracavitary brachy -
therapy (7 14 Gy, in patients with
tumours 4 cm in diameter) and simple
hysterectomy/selective lymphadenectomy
with 18 20 Gy IOERT. Patients in the RT
group received 50 Gy EBRT in 25 fractions
followed by intracavitary brachytherapy
(35 40 Gy). RESULTS: Median duration
of follow-up was 92 months. IOERT
resulted in significantly better 5- and 10-
year overall survival, disease-free
survival and local control rates, as well
as fewer rectal and bladder
complications, compared with RT.
CONCLUSION: IOERT is an effective
primary treatment for stage IIB cervical
squamous cell carcinoma.
a
Z Liu and Y Gao contributed equally to this work.
KEY WORDS: CERVICAL CANCER; INTRAOPERATIVE ELECTRON BEAM RADIOTHERAPY; RECURRENCE;
SURVIVAL
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Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
effective than radiotherapy alone for locally
advanced cervical cancer,
5 8
and is the
standard treatment for this disease.
9
It is
thought that concurrent chemotherapy
improves local control by enhancing the
effects of radiation.
10 12
Chemoradiotherapy
is associated with increased acute toxicities
and may therefore result in undesirable
radiotherapy treatment breaks.
9
The benefit
over radiotherapy alone is small,
particularly in developing countries where
ancillary medical care is poor.
13
Alternative
methods for improving local control are
therefore required.
Intraoperative electron beam
radiotherapy (IOERT) is used for the
treatment of cancers at various sites,
14,15
including salvage of recurrent cervical
cancer.
11
As a primary treatment modality, a
combination of preoperative chemo -
radiation, surgery and IOERT resulted in
92% local control after 10 years.
16
The aim of
the current retrospective study was to
evaluate the use of IOERT versus radical
radiotherapy (RT) in patients with stage IIB
cervical squamous cell carcinoma, in terms
of survival, recurrence, metastasis and
adverse effects.
Patients and methods
STUDY POPULATION
All patients with cervical cancer who were
undergoing radiation treatment at the
Department of Radiation Oncology, First
Affiliated Hospital, Medical College of Xian
Jiaotong University, Xian, China, between
June 2001 and May 2007, were considered
for inclusion in this retrospective study.
Inclusion criteria were: (i) histologically
proven squamous cell carcinoma; (ii)
tumours classified as International
Federation of Gynecology and Obstetrics
stage IIB
17
; (iii) aged < 75 years; (iv) no
evidence of pelvic or para-aortic lymph node
metastasis on computed tomography (CT)
scan; (v) no evidence of metastasis on chest
X-radiography; (vi) normal liver and kidney
function; (vii) normal blood count; (viii)
haemoglobin level > 9 g/l. Patients with
nonsquamous cell carcinoma or previous
radiotherapy to the pelvis were excluded
from this analysis.
All patients underwent pretreatment
investigations including Eastern Cooperative
Oncology Group performance status,
18
gynaecological examination under general
anaesthesia, cystoscopy and biopsy.
Tumours were graded according to American
Joint Committee on Cancer criteria.
19
The study was approved by the Ethics
Committee of the Medical College of Xian
Jiaotong University, Xian, China, and all
patients provided written informed consent
for treatment.
TREATMENT
A radiation oncologist and gynaecological
surgeon provided each patient with identical
information regarding treatment options;
the patient was then allowed to choose
between IOERT (with hysterectomy) and RT
(without hysterectomy).
Radical radiotherapy comprised a total
dose of D
EQD2
(equivalent dose in 2 Gy
fractions) 50 Gy external beam radiotherapy
(EBRT), delivered in 2 Gy fractions five times
a week for 5 weeks, using 6 10 MV parallel
opposed anteriorposterior fields. The initial
30 Gy of radiotherapy was delivered to the
entire pelvis, with central shielding
(minimum width, 4 cm) applied for the
remaining 20 Gy. The borders of the
radiation field were the L4/L5 junction
(superior), 1 cm below the obturator foramen
(inferior) and 2 cm beyond the pelvic brim
(lateral). Intracavitary temporary
brachytherapy was performed weekly,
beginning 28 days after initiation of EBRT,
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Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
and twice weekly after completion of EBRT
until week 7. Tandem and ovoid applicators
(Nucletron, Veenendaal, Netherlands) were
used to deliver a total dose of D
EQD2
35 40
Gy high dose rate iridium-192 in 5 6
insertions, to International Commission on
Radiation Units and Measurements (ICRU)
reference point A.
20
Calculations of dwell
times and ICRU bladder and rectal point
doses were performed via orthogonal X-
radiography after each insertion. Bladder
and rectal point doses were limited to
D
EQD2
80 and D
EQD2
75 Gy, respectively.
Treatment was completed within 7 weeks.
Patients in the IOERT group received a
total dose of D
EQD2
20 Gy EBRT, delivered in
10 fractions of 2 Gy five times a week for 2
weeks, as described above. In addition,
intracavitary temporary brachytherapy (one
or two insertions of 7 Gy each, as described
above) was performed 1 week after the
initiation of EBRT, in cases where the tumour
was 4cm in diameter. Simple hysterectomy
with dissection of palpable pelvic lymph
nodes was performed in all patients 1 2
weeks after EBRT. A 12 MeV electron beam
(Clinac 1800; Varian Medical Systems, Palo
Alto, CA, USA) and applicator
21
were used to
deliver 18 20 Gy of radiation (D
EQD2
36 50
Gy) to the pelvic cavity during surgery, with
the field borders at the bifurcation of
common iliac vessels (superior), 2 cm inferior
to the vaginal vault (inferior), and 1 cm
beyond the lateral margin of external and
common iliac vessels (lateral). The bladder,
intestines and sigmoid colon were shifted out
of the radiation field, and the rectum was
shielded with 6-mm thick lead.
FOLLOW-UP
After completion of treatment, patients were
followed-up at 3-month intervals for 1 year,
6-month intervals for 3 years and annually
thereafter. Investigations included complete
blood count, chest X-radiography,
abdominopelvic CT, gynaecological
examination and biopsy where necessary.
Overall survival was defined as the time
from the end of treatment until death from
any cause. Disease-free survival was defined
as the time from the end of treatment until
recurrence or metastasis. Local control was
defined as the time from the end of
treatment until recurrence.
STATISTICAL ANALYSES
Between-group differences in recurrence,
metastasis and complications were made
using the
2
-test. Survival times were
calculated using the KaplanMeier method
and compared using the log-rank test.
Statistical analyses were performed using
SPSS

version 12.0 (SPSS Inc., Chicago, IL,


USA) for Windows

. A P-value < 0.05 was


considered statistically significant.
Results
The study population comprised 167 patients
(IOERT n = 78; RT n = 89). Baseline
demographic, clinical and tumour
characteristics are shown in Table 1. There
were no significant between-group
differences in age, ECOG performance status,
anaemia (defined as a haemoglobin level
< 10 g/dl) or tumour characteristics. All
patients completed the planned course of
treatment. The median overall duration of
follow-up was 92 months (range 16 155
months). A total of 49 patients in the RT
group and 66 patients in the IOERT group
were recruited 10 years prior to the
conclusion of the study, and were included in
calculations of 10-year survival and
recurrence.
The 5- and 10-year overall survival,
disease-free survival and local control rates
were significantly higher in patients who
underwent IOERT compared with those who
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Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
received RT (P < 0.01 for all comparisons;
Table 2). KaplanMeier curves for disease-
free and overall survival are shown in Fig. 1.
The rates of local recurrence and distal
metastasis at 5 and 10 years after completion
of treatment are shown in Table 3. IOERT was
associated with better locoregional control
(cervix/vagina and pelvic lymph nodes) than
TABLE 1:
Baseline demographic, clinical and tumour characteristics of patients included in a study
to compare intraoperative electron beam radiotherapy (IOERT) with radical radiotherapy
(RT) for primary treatment of stage IIB
17
cervical squamous cell carcinoma
IOERT RT
Characteristic n = 78 n = 89
Age, years 46 (21 72) 47 (22 74)
ECOG performance status
18
0 43 (55.1) 50 (56.2)
1 32 (41.0) 36 (40.4)
2 3 (3.8) 3 (3.4)
Haemoglobin level
10 g/dl 48 (61.5) 57 (64.0)
< 10 g/dl 30 (38.5) 32 (36.0)
Cancer stage
17
IIB, < 4 cm 26 (33.3) 33 (37.1)
IIB, 4 cm 52 (66.7) 65 (73.0)
Tumour grade
19
1 2 40 (51.3) 53 (59.6)
3 38 (48.7) 36 (40.4)
Enlarged pelvic lymph nodes 8 (10.3) 8 (9.0)
Data presented as median (range) or n (%) of patients.
ECOG, Eastern Cooperative Oncology Group.
No statistically significant between-group differences (P 0.05);
2
-test.
TABLE 2:
Overall and disease free-survival and local control rates in patients with stage IIB
17
cervical
squamous cell carcinoma who underwent primary treatment with intraoperative electron
beam radiotherapy (IOERT) or radical radiotherapy (RT)
IOERT RT Statistical
Survival n = 78 n = 89 significance
a
5 years
OS 69 (88.5) 65 (73.0) P = 0.012
DFS 68 (87.2) 60 (67.4) P = 0.003
LC 75 (96.2) 65 (73.0) P < 0.001
10 years
OS 66 (84.6) 49 (55.1) P < 0.001
DFS 63 (80.5) 41 (46.1) P < 0.001
LC 73 (93.6) 58 (65.2) P < 0.001
Data presented as n (%) of patients.
OS, overall survival; DFS, disease-free survival; LC, local control.
a
Log-rank test
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2350
Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
radiotherapy at both 5 and 10 years (P < 0.05
for all comparisons). There were no
significant between-group differences in the
rates of metastasis (para-aortic lymph nodes,
lung or liver) at 5 or 10 years after the
completion of treatment.
The use of IOERT was associated with
significantly fewer cases of radiation-
induced rectal or bladder injury than RT
(P < 0.05 for both comparisons; Table 4).
There were no significant between-group
differences in the incidence of pelvic pain
and peripheral neuropathy, hydronephrosis
or oedema of the lower leg.
FIGURE 1: KaplanMeier survival analysis of patients with stage IIB
17
cervical
squamous cell carcinoma undergoing primary treatment with intraoperative electron
beam radiotherapy (IOERT) or radical radiotherapy (RT). (A) Disease-free survival; (B)
overall survival
1.0
A
0.8
0.6
C
u
m
u
l
a
t
i
v
e

s
u
r
v
i
v
a
l
0.4
0.2
0
25 50 75
Survival time (months)
100 125 150
Log-rank P < 0.01
IOERT
RT
IOERT
RT
1.0
B
0.8
0.6
C
u
m
u
l
a
t
i
v
e

s
u
r
v
i
v
a
l
0.4
0.2
0
25 50 75
Survival time (months)
100 125 150
Log-rank P < 0.01
TABLE 3:
Rates of recurrence or distal metastasis in patients with stage IIB
17
cervical squamous cell
carcinoma 5 and 10 years after primary treatment with intraoperative electron beam
radiotherapy (IOERT) or radical radiotherapy (RT)
5 years 10 years
IOERT RT Statistical IOERT RT Statistical
Location n = 78 n = 89 significance
a
n = 66 n = 49 significance
a
Cervix or vagina 1 (1.3) 14 (15.7) P = 0.001 1 (1.3) 15 (16.9) P = 0.001
Pelvic lymph nodes 2 (2.6) 10 (11.2) P = 0.03 4 (5.1) 16 (18.0) P = 0.011
Para-aortic lymph nodes 2 (2.6) 3 (3.4) NS 3 (3.8) 5 (5.6) NS
Lung 2 (2.6) 3 (3.4) NS 4 (5.1) 6 (6.7) NS
Liver 1 (1.3) 1 (1.1) NS 2 (2.6) 2 (2.2) NS
Total 8 (10.3) 29 (32.6) P = 0.001 14 (17.9) 39 (43.8) P < 0.001
Data presented as n (%) of patients.
NS, not statistically significant (P 0.05).
a

2
-test.
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Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
Discussion
This retrospective study of IOERT as primary
treatment for cervical cancer indicated
significantly improved overall survival,
disease-free survival and local control
compared with RT. The 5-year overall
survival and disease-free survival rates for
cervical cancer have been reported as 72.2%
and 65.8%, respectively,
2
which are
comparable with to the findings in the RT
group, in the current study. Overall and
disease-free survival rates were significantly
higher in the IOERT group than in the RT
group (Table 2), but further studies in a
clinical trial setting are required in order to
confirm this finding. Locoregional control
rates at 5 and 10 years were significantly
higher following IOERT compared with
radiotherapy. There was no between-group
difference in the rate of distal metastasis in
the present study, which was expected due to
the local nature of IOERT.
Intraoperative electron bean radiotherapy
delivers a single high dose of radiation (18 20
Gy; D
EQD2
36 50 Gy). Studies have revealed
that stereotactic body radiotherapy provides
greater than expected efficacy than can be
predicted from clonogenic cell inactivation
alone.
22
A single high dose of radiation allows
delivery of a large equivalent dose of radiation
to the tumour, such that a single dose of IOERT
is 1.5 2.5 times more effective than the same
total dose of fractionated EBRT.
23 25
In
addition, IOERT is applied during surgery,
rather than at a much later time point (as is
required with conventional EBRT), in order to
avoid interfering with wound healing.
26
An
additional advantage of IOERT is that the risk
area can be assessed intraoperatively,
allowing tailoring of the radiation field. The
fact that the patient is unconscious and
immobile during surgery further increases the
accuracy of IOERT.
27,28
Both treatment methods in the present
study resulted in approximately the same
dose of radiation being delivered to ICRU
point A. The total dose delivered to point A by
RT was D
EQD2
80 Gy, comprising D
EQD2
30 Gy
EBRT and D
EQD2
50 Gy brachytherapy. IOERT
delivered a total dose of D
EQD2
76 80 Gy
(EBRT D
EQD2
20 Gy + IOERT D
EQD2
36 50 Gy).
It is possible that the improved local control in
IOERT was a result of surgical removal of the
tumour and the ability to deliver radiation
accurately to areas at risk of microscopic
disease. The rates of bowel and bladder injury
TABLE 4:
Complications in patients with stage IIB
17
cervical squamous cell carcinoma following
primary treatment with intraoperative electron beam radiotherapy (IOERT) or radical
radiotherapy (RT)
IOERT RT Statistical
Complication n = 78 n = 89 significance
a
Rectal injury 4 (5.1) 27 (30.3) P < 0.05
Bladder injury 1 (1.3) 9 (10.1) P < 0.05
Pelvic pain and peripheral neuropathy 9 (11.5) 10 (11.2) NS
Hydronephrosis 10 (12.8) 5 (5.6) NS
Lower leg oedema 1 (1.3) 2 (2.2) NS
Total 25 (32.1) 53 (59.6) P < 0.05
Data presented as n (%) of patients.
NS, not statistically significant (P 0.05).
a

2
-test.
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2352
Z Liu, Y Gao, YL Soong et al.
IOERT in cervical cancer
were lower in the IOERT group than in the RT
group, probably due to the careful shielding
employed during irradiation. In addition,
some patients in the IOERT group received
brachytherapy after a comparatively low dose
of EBRT (8 16 Gy, compared with 30 Gy in
the RT group), with the result that most of the
high-dose region was likely to fall within the
gross tumour. This is compared with the RT
group, where the tumour would have shrunk
significantly by the time that brachytherapy
was delivered.
The use of combined surgery and RT is not
recommended for the treatment of early
stage cervical cancer
29
because of the
increased risk of severe toxicities.
30
Data
regarding the rate of complications after
IOERT are inconclusive, with some showing
no difference in complications
31
and others
finding an increase in adverse effects.
32
The
reduced rate of adverse effects with IOERT
compared with radiotherapy in the present
study may be due to the use of simple
hysterectomy with limited nodal dissection,
rather than radical hysterectomy and
complete pelvic lymph node dissection, thus
reducing the duration of surgery and
limiting the extent of injury to healthy
tissue. In the IOERT group in the present
study, the radiation dose to the bowel and
bladder was limited by moving the organs
away from the applicator during irradiation,
and the known low level of radiation
leakage (5%) from the applicator itself.
21
In the present study, the incidence of pelvic
pain and peripheral neuropathy was similar
in both treatment groups. The rates of
chronic pelvic pain and peripheral
neuropathy following IOERT have been
shown to range between 10 and 30%.
16,33,34
Rates of other complications, including
hydronephrosis and oedema of the lower leg,
were also similar between the groups. All
cases of toxicity were managed using
conservative treatment.
This study has several limitations. First, its
retrospective and nonrandomized nature
may have resulted in selection bias: fitter
patients could have chosen surgery and
patients with more comorbidities could have
chosen radiation alone, leading to differences
in overall survival. Secondly, chemo radio -
therapy is recommended for treatment of
locally advanced cervical cancer, but none of
the patients in the current study received
concurrent chemotherapy. It is therefore
unclear what impact, if any, this would have
had on the outcome. Thirdly, the grading of
toxicities was not performed consistently and
it was therefore not possible to report any
data regarding the severity of adverse events.
Finally, the optimal IOERT dose is not known.
Doses ranging from 10 30 Gy have been
reported.
31,35,36
Whether a lower dose would
reduce toxicities, or a higher dose would
further improve local control, is not known.
In conclusion, the present study findings
indicate that IOERT is an effective treatment for
stage IIB cervical squamous cell carcinoma,
resulting in enhanced local control and
improvements in disease-free and overall
survival compared with RT, without an increase
in complications. IOERT does not prevent
distant metastasis, however, and more effective
systemic therapies should be evaluated.
Conflicts of interest
The authors have no conflicts of interest to
declare in relation to this article.
Acknowledgements
This work was supported by grants from the
National Natural Science Foundation of
China (No. 81071838), Shaanxi Province
Department of Health Key Program (No.
2010A02) and the Foundation of the First
Affiliated Hospital of Medical College of
Xian Jiao Tong University (No. 2010YK3).
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SAGE Publications Ltd 2012
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IOERT in cervical cancer
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Authors address for correspondence
Dr Zi Liu
Department of Radiation Oncology, First Affiliated Hospital, Medical College of Xian
Jiaotong University, 277 Yanta West Road, Xian 710061, China.
E-mail: liuzmail@163.com
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IOERT in cervical cancer
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