International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Clinical Investigation

Multi-institutional Observational Study

of Prophylactic Extended-Field Concurrent
Chemoradiation Therapy Using Weekly Cisplatin
for Patients With Pelvic Node-Positive Cervical
Cancer in East and Southeast Asia
Masaru Wakatsuki, MD, PhD,* Shingo Kato, MD,y Tatsuya Ohno, MD,z
Parvin Akhter Banu, MD,x Nguyen Cong Hoang, MD,k
Erdenetuya Yadamsuren, MD,{ Nana Supriana, MD,**
Jianping Cao, MD,yy C.R. Beena Devi, MD,zz Miriam Joy Calaguas, MD,xx
Yaowalak Chansilpa, MD,kk Chul-Koo Cho, MD,{{
Tasbolat Adylkhanov, MD,*** Noriyuki Okonogi, MD,yyy
Takashi Nakano, MD,z and Hirohiko Tsujii, MDyyy
*Department of Radiology, Jichi Medical University, Tochigi, Japan; yDepartment of Radiation
Oncology, Saitama Medical University International Medical Center, Saitama, Japan; zDepartment
of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan; xDepartment
of Radiation Oncology, Delta Hospitals Limited, Dhaka, Bangladesh; kDepartment of General
Radiation Oncology, National Cancer Hospital, Hanoi, Vietnam; {Department of Radiation Oncology,
National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; **Department of Radiotherapy, Dr.
Cipto Mangunkusumo General Hospital - Faculty of Medicine, Universitas Indonesia, Jakarta,
Indonesia; yyDepartment of Radiation Oncology, First Affiliated Hospital of Soochow University,
Suzhou, China; zzDepartment of Radiation Oncology, Sarawak General Hospital, Kuching, Malaysia;
xx
Department of Radiation Oncology, St Luke’s Medical Center, Quezon City, Philippines;
kk
Department of Radiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok,
Thailand; {{Department of Radiation Oncology, Korea Institute of Radiological and Medical
Sciences, Seoul, Korea; ***Department of Oncology and Visual Diagnostics, Semey State Medical
University, Semey, Kazakhstan; and yyyNational Institute of Radiological Sciences Hospital, National
Institutes for Quantum and Radiological Science and Technology, Chiba, Japan

Received Jan 17, 2019. Accepted for publication Apr 27, 2019.

Corresponding author: Masaru Wakatsuki, MD, PhD; E-mail:
wakkun100@yahoo.co.jp
This work was supported by the project of the Forum for Nuclear
Cooperation in Asia and the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
Disclosures: none.
Supplementary material for this article can be found at https://doi.org/
10.1016/j.ijrobp.2019.04.039.
AcknowledgmentsdThe authors thank the members of the Radiation
Oncology projects in the Forum for Nuclear Cooperation in Asia for their
constructive discussion and precious advice.

Int J Radiation Oncol Biol Phys, Vol. 105, No. 1, pp. 183e189, 2019
0360-3016/$ - see front matter Ó 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ijrobp.2019.04.039
184 Wakatsuki et al. International Journal of Radiation Oncology  Biology  Physics

Summary Purpose: This multi-institutional observational study conducted among 11 countries

Uterine cervical cancer is
among the most common
cancers in East and South-
east Asia, and it is necessary
to develop new treatment
methods suitable for devel-
oping countries. This multi-
institutional observational
study conducted among 11
East and Southeast Asian
countries aimed to evaluate
the clinical outcomes of
prophylactic extended-field
concurrent chemoradiation
therapy with locally
advanced cervical cancer.
The results indicated that
extended-field concurrent
chemoradiation therapy is
feasible and effective for
locally advanced cervical
cancer in developing
countries.
in East and Southeast Asia aimed to assess the clinical outcomes of prophylactic
extended-field concurrent chemoradiation therapy using weekly cisplatin for patients
with locally advanced cervical cancer.
Methods and Materials: Between October 2007 and May 2016, 106 patients with un-
treated squamous cell carcinoma of the cervix were enrolled in the present study. Ra-
diation therapy consisted of pelvic irradiation (total dose, 50 Gy in 25 fractions
including central shielding), prophylactic paraortic regional irradiation (36-40 Gy in
20 fractions), and either high- or low-dose-rate intracavitary brachytherapy (ICBT) ac-
cording to institutional practice. The planned point A dose was 21 to 28 Gy in 3 to 4
fractions for high-dose-rate ICBT and 40 to 41 Gy in 1 to 2 fractions for low-dose-rate
ICBT. Five cycles of weekly cisplatin (40 mg/m2) were administered during the radi-
ation therapy course.
Results: A total of 106 patients were enrolled. Of these, 9 had major protocol viola-
tions and 2 did not receive treatment because of worsened general condition. Thus, 95
patients were evaluable. The median follow-up was 56 months. Of the 95 patients, 76
(80%) received 4 or 5 cycles of chemotherapy. Acute grade 3 leukopenia was observed
in 20 of the patients (21%), and late grade 3 gastrointestinal toxicity was observed in
3%. The 2-year local control, progression-free survival, and overall survival rate for all
patients were 96%, 78%, and 90%, respectively.
Conclusions: The results indicated that prophylactic extended-field concurrent che-
moradiation therapy using weekly cisplatin is feasible and effective for patients with
locally advanced cervical cancer in East and Southeast Asia. Ó 2019 Elsevier Inc. All
rights reserved.

Introduction Although CCRT has been established as the standard

treatment for locally advanced cervical cancer, the overall
survival rate is still unsatisfactory because these cases
Uterine cervical cancer is among the most common cancers
have a high rate of distant metastases, particularly para-
in developing countries in East and Southeast Asia,1 and
ortic lymph node (PALN) metastases. The pattern of
the mortality rate remains high in these countries because
spread in cervical cancer appears to be orderly, initially
many patients present at a relatively advanced stage.
involving the low pelvis and then progressing to high
Cisplatin-based concurrent chemoradiation therapy (CCRT)
has become the standard treatment for locally advanced pelvic lymph nodes (PLN) and PALN.13-15 In the previous
study, 44.4% of patients developed PALN failure for
cervical cancer on the basis of good outcomes reported
locally advanced cervical cancer with PLN metastases.16
from several randomized phase 3 clinical trials in the
To control occult PALN metastasis, extended-field radia-
1990s,2-6 and the previous clinical trial showed that CCRT
tion therapy (EFRT) including the paraortic region and
is also a feasible and effective treatment for cervical cancer
PLN region may be one of the effective treatments. There
in East and Southeast Asia.7,8
have been a few reports of concurrent chemotherapy and
The Forum for Nuclear Cooperation in Asia (FNCA) is a
EFRT for locally advanced cervical cancer. The Radiation
framework of regional cooperation among Asian countries
with the aim of peaceful and safe application of nuclear Therapy Oncology Group performed a prospective study
(RTOG 0116) of concurrent weekly cisplatin and EFRT,
science and technology. The FNCA medical project was
but this study reported very high rates of acute and late
launched in 1993 with 11 countries participating: the Peo-
toxicities.17
ple’s Republic of Bangladesh, the People’s Republic of
The FNCA clinical study group conducted a prospective
China, the Republic of Indonesia, Japan, the Republic of
observational study of CCRT to EFRT for locally advanced
Kazakhstan, the Republic of Korea, Malaysia, Mongolia, the
cervical cancer. In addition, our group planned delayed
Republic of the Philippines, the Kingdom of Thailand, and
prophylactic PALN radiation therapy (PALN-RT) to reduce
the Socialist Republic of Vietnam. As its first activity, the
project aimed to standardize radiation therapy (RT) and the acute and late toxicities. The purpose of this study was
to evaluate the toxicity and efficacy of the combination of
CCRT and to improve the treatment outcomes of predomi-
CCRT to the pelvis and prophylactic PALN-RT for patients
nant cancers in Asia, such as uterine cervical cancer, naso-
with locally advanced cervical cancer with PLN metastasis
pharyngeal cancer, and breast cancer.7-12 Since the project
and without PALN metastasis in East and Southeast Asian
started, we have conducted 3 multi-institutional clinical
countries.
studies of RT or CCRT for advanced cervical cancer.7,8,11,12
Volume 105  Number 1  2019
Methods and Materials
Patients
The target of this study was patients with locally advanced
cervical cancer with a high risk of PALN metastasis, that is,
stage IIB or IIIB with PLN enlargement. Patients were
enrolled from October 2007 to May 2016 from 13 facilities
in 11 countries, namely, the People’s Republic of
Bangladesh, the People’s Republic of China, the Republic
of Indonesia, Japan, the Republic of Kazakhstan, the Re-
public of Korea, Malaysia, Mongolia, the Republic of the
Philippines, the Kingdom of Thailand, and the Socialist
Republic of Vietnam (Supplementary Material E1, avail-
able online at https://doi.org/10.1016/j.ijrobp.2019.04.039).
All patients had (1) previously untreated squamous cell
carcinoma of the cervix, (2) International Federation of
Gynecology and Obstetrics stage IIB with a tumor size of
4 cm or stage IIIB disease, (3) enlarged PLN (>1 cm in
maximum diameter) on computed tomography (CT) or ul-
trasonography (US), and (4) no enlarged lymph node in the
abdominal paraortic region (>1 cm in maximum diameter)
on CT or US. Other eligibility criteria included age 20 to 70
years, World Health Organization performance status of
0 to 2, and estimated life expectancy of 6 months. Pa-
tients had to have adequate bone marrow, hepatic function,
and renal function with the following criteria: a leukocyte
count of 3000/mm3, a platelet count of 100,000/mm3,
hemoglobin of 10 g/dL (after transfusion, if necessary),
total bilirubin of <1.5 mg/dL, aspartate aminotransferase
and alanine aminotransferase of <2 times the upper limit of
normal, and serum creatinine <1.5 mg/dL. Patients with a
history of previous chemotherapy, pelvic surgery, or RT
were excluded from the studies. The patients were also
excluded if they had severe concomitant illness such as
uncontrolled cardiovascular disease, uncontrolled diabetes
mellitus, active peptide ulcer, severe pelvic infection, se-
vere psychological illness, or an active double cancer. The
standard treatment was explained to each participant, and
then written informed consent to participate was obtained.
Radiation therapy
External beam radiation therapy (EBRT) was delivered to
the whole pelvis and PALN regions through anterior and
posterior parallel-opposed portals or the 4-field box tech-
nique using 4- to 10-MV x-rays or 60Co g-rays. The clinical
target volume included the cervical tumor, uterus, para-
metrium, at least the upper half of the vagina, and the PLN
and PALN regions. EBRT was performed at 1.8-2.0 Gy per
fraction in 5 fractions per week. A central shield (CS),
which was 3 to 4 cm in width at the isocenter between
upper edge of the first sacral and lower border of radiation
field, was inserted in the radiation field after delivering 30
to 40 Gy to the whole pelvis according to tumor volume.
The total dose of pelvic irradiation was 50 Gy, and 36 to 40
Extended-field CCRT for cervical cancer 185
1 2 3 4 5 6 7 8
Weeks
EBRT
Pelvic RT WP CS
WP: 30-40Gy
CS: 20-10Gy
PALN RT
36-40Gy/20Fr or
ICBT
HDR-ICBT 24-28 Gy/4fr (21 Gy/3fr or 33 Gy/6fr)
or LDR-ICBT 40-45 Gy/1-2fr
Chemotherapy
Cisplatin
(40mg/m2 )
Fig. 1. Treatment regimen: radiation therapy consisted of
whole pelvic irradiation, central shielding, prophylactic
paraortic regional irradiation, and either high- or low-dose-
rate intracavitary brachytherapy. Prophylactic irradiation to
the PALN region was started concurrently with central
shield irradiation.
Gy of prophylactic PALN-RT was also performed. The
upper border of the PALN field was Th12/L1 or L1/L2
interspace. The method of the matching the PALN fields
with pelvic fields used the half-beam technique or set the
gap of both fields according to the dose distribution. Pro-
phylactic PALN-RT was started concurrently with CS
irradiation (Fig. 1) because our pilot study, which delivered
PALN-RT at the same timing as whole pelvic irradiation,
showed higher rate of acute toxicities.
Regarding intracavitary brachytherapy (ICBT), either
high-dose-rate (HDR) or low-dose-rate (LDR) treatment
was performed according to the institutional practice. A
192
Ir source was used for HDR treatment and a 137Cs source
was used for LDR treatment. HDR-ICBT was performed
weekly, with the prescribed dose to point A of 24 to 28 Gy
in 4 fractions (6-7 Gy per fraction) according to the tumor
volume. In LDR-ICBT, the prescribed dose to point A was
40 to 45 Gy in 1 to 2 fractions. ICBT was performed
concurrently with CS EBRT. To avoid the negative effect of
treatment prolongation, it was recommended that the
overall treatment time (OTT) not exceed 60 days. RT was
withheld if a patient developed grade 4 hematologic tox-
icities or grade 3 to 4 nonhematologic toxicity and was
resumed when the hematologic and nonhematologic tox-
icities recovered to grade 2.
Chemotherapy
Cisplatin at a dose of 40 mg/m2 was administered weekly
starting from week 1 for 5 consecutive weeks, concurrently
with EBRT. Cisplatin was given intravenously 2 to 2.5
hours before RT. Patients were hydrated with >2000 mL of
normal saline. Antiemetics, such as 5-HT3 receptor an-
tagonists, metoclopramide, and dexamethasone, were given
before and after cisplatin administration. Chemotherapy
was interrupted if a patient developed a leukocyte
count <3000/mm3, a platelet count <75,000/mm3, fever
>38.0 C, or grade 3 to 4 nonhematologic toxicity.
186 Wakatsuki et al. International Journal of Radiation Oncology  Biology  Physics

Chemotherapy was resumed when the hematologic and Table 1 Characteristics of the patients (n Z 95)
nonhematologic toxicities recovered to grade 1. Gran-
Age in y, median (range) 49 (24-69)
ulocyte colony-stimulating factor was used if patients had a
PS, n (%)
neutrophil count <1000/mm3; however, its prophylactic use 0 47 (50)
was not accepted. 1 46 (48)
2 2 (2)
Assessment and follow-up Stage, n (%)
IIB 51 (54)
IIIB 44 (46)
The patients underwent complete blood cell counts, blood Tumor size, n (%)
chemistry testing, pelvic examinations, and clinical as- <40 mm 17 (18)
sessments weekly during treatment. Although follow-up 40-60 mm 55 (58)
timing after treatment depends on the institutional prac- >60 mm 23 (24)
tices, it is recommended that patients be evaluated at least EBRT, n (%)
every 3 months for the first 2 years, every 4 months during 60
Co g-rays 13 (14)
the third year, every 6 months during the fourth and fifth 4MV x-rays 5 (5)
years, and then annually thereafter. Disease status and late 10MV x-rays 77 (81)
toxicities were assessed through history taking, physical ICBT dose rate, n (%)
examinations, appropriate laboratory examinations, intra- Low dose rate 15 (16)
Medium dose rate 7 (7)
venous urography, and chest radiography. US, CT of the
High dose rate 73 (77)
abdomen and pelvis, and magnetic resonance imaging of EBRT to pelvis, median Gy (range)
the pelvis were optionally used for assessment. The imag- Total dose 50.0 (48-60)
ing follow-up was performed with acceptable variability Whole pelvis 36.0 (30-50)
per institutional practice. Suspected cases of persistent or Central shielding 16.0 (9-20)
recurrent disease were confirmed via biopsy whenever EBRT to PALN region, 36.0 (12.6-41.4)
possible. Treatment failures were classified as pelvic fail- median Gy (range)
ure, PALN failure, or distant failure (outside the RT fields). ICBT point A dose 81.9 (68.3-107.6)
Acute hematologic and nonhematologic toxicities were (BED: a/bZ 10),
graded according to the National Cancer Institute Common median Gy (range)
Terminology Criteria for Adverse Events, version 3.0. Late Cycles of chemotherapy, 5 (2-6)
median no. times (range)
toxicities were graded according to the Radiation Therapy
Treatment period, median d (range) 57 (34-194)
Oncology Group and European Organization for Research
and Treatment for Cancer late radiation morbidity scoring Abbreviations: BED Z biological effective dose; EBRT Z external
scheme.18 beam radiation therapy; ICBT Z intracavitary brachytherapy; PALN
Z paraortic lymph node; PS Z performance status.

Statistical design
This study was prospective, single-arm, multi-institutional,
and observational with variability acceptable per institu-
tional practice. The primary endpoint was the 2-year
progression-free survival (PFS) rate. The secondary end-
points included 2-year overall survival (OS) rate and acute
and late toxicities. The sample size, which was calculated
via the 2-year PFS rate, was determined to be 100 patients.
One hundred patients is 50% of the 2-year PFS rate for N1
cases in the previous reports on CCRT for locally advanced
cervical cancer,7,8 with 20% of cases developing PALN
failure. We chose 70% of the 2-year PFS rate as a desirable
target level and 50% of that as uninteresting when using the
protocol treatment (CCRT to the pelvis plus prophylactic
PALN-RT). Our design has a power in excess of 80% and
less than 5% of type I error. Considering the decrease of
power (eg, lost to follow-up and entry of ineligible cases),
this trial was designed to enroll 100 patients.
Local control (LC), PFS, and OS curves were plotted
using the Kaplan-Meier method using the Statistical
Package for JMP 12 (SAS Institute Inc, Cary, NC).
Results
Patient characteristics
A total of 106 patients were enrolled in the study. One pa-
tient had PALN metastases before treatment and was thus
excluded. Of the 106 remaining patients, 2 patients received
no treatment owing to worsened general condition, 2 pa-
tients had incomplete treatment, and 7 patients received a
different dose of chemotherapy. Thus, 95 patients were
evaluable. The follow-up rate at 2 years and 5 years was
98% and 93%, respectively. The median follow-up duration
was 56 months (range, 2-120 months) for all patients. The
characteristics of the patients are listed in Table 1. All pa-
tients underwent CT scans or magnetic resonance imaging
of the pelvis at diagnosis, and 91 patients (97%) underwent
CT of the abdomen at diagnosis. The remaining 3 patients
underwent US of the abdomen for the diagnosis of PALN
metastases. Only 8 of 95 patients (8.4%) received positron
emission tomography imaging for staging because most fa-
cilities did not have positron emission tomography imaging.
Volume 105  Number 1  2019 Extended-field CCRT for cervical cancer 187

1.0 96%
91% Table 2 Toxicities (n Z 95)
90% 77%
0.8 Acute hematological toxicities, n Grade
78%
probability

70%
0.6 Toxicity G0 G1 G2 G3 G4
0.4 Leukopenia 24 25 26 20 0
Neutropenia 39 20 20 15 1
0.2
Anemia 23 37 33 2 0
0.0 Median follow-up duration: 56 months (2-130 months) Thrombocytopenia 70 20 4 1 0
0 12 24 36 48 60 Acute hematological toxicity total 12 26 31 25 1
No. at risk Months after treatment
LC 95 88 72 64 53 43
Acute nonhematological toxicities, n Grade
OS 95 93 82 67 56 44
PFS 95 82 70 59 50 40 Toxicity G0 G1 G2 G3 G4

Fig. 2. Kaplan-Meier curves of overall survival (blue), Rectum and sigmoid 24 52 19 0 0

local control (red), and progression-free survival (green) for Bladder 51 43 1 0 0
all 95 patients combined. Skin 59 35 1 0 0
Nausea or vomiting 18 51 23 3 0
Fatigue 25 47 20 3 0
Fifty-one patients had stage IIB disease, and 44 patients Weight loss 64 27 4 0 0
had stage IIIB disease. All patients had pelvic node Creatinine 83 9 0 2 0
enlargement and no PALN enlargement. The median
Grade (RTOG/
number of cisplatin administrations was 5 (range, 2-6), and
Late toxicities, n EORTC)
76 patients (80%) received 4 or more cycles of chemo-
therapy. The median OTT was 57 days (range, 34-147 Toxicity 0 1 2 3 4
days). Nine cases had an OTT of 100 days because of Rectum and sigmoid 69 11 13 2* 0
treatment machine issues. Small intestine 80 12 1 2* 0
Within 2 years, 9 patients had died, 82 were alive, and 4 Bladder 76 14 5 0 0
(4%) had been lost to follow-up. A total of 23 patients had
Abbreviations: EORTC Z European Organization for Research and
died by the time of last follow-up. Of the 23 patients who Treatment of Cancer; RTOG Z Radiation Therapy Oncology Group.
died, 17 died of cervical cancer, 5 died of other disease, and * One patients had G3 toxicities in rectum and small intestine.
1 died of unknown causes. Local failure developed in 7
patients (7%), and 19 (20%) developed distant metastasis.
The 2-year LC, PFS, and OS rates for all patients combined
PALN-RT for patients with locally advanced cervical can-
were 96%, 78%, and 90%, respectively, and the 5-year LC,
cer with PLN metastasis and without PALN metastasis in
PFS, and OS rates were 91%, 70%, and 77%, respectively
East and Southeast Asian countries. The delayed prophy-
(Fig. 2).
lactic PALN-RT decreased the rate of distant metastases
All of the observed acute and late toxicities are listed in
and improved PFS and OS without increasing toxicities.
Table 2. These 95 evaluable cases completed the scheduled
This regimen can lead to benefits for patients with PLN-
therapy. Regarding acute hematological toxicities, 1 patient
positive locally advanced cervical cancer in developing
developed grade 4 neutropenia, and 26 of the 95 patients
countries.
(27%) developed grade 3 or worse hematological toxicities.
Several studies on EFRT with concurrent chemotherapy
Meanwhile, 5 patients (5.3%) developed grade 3 acute
in locally advanced cervical cancer have been conducted;
nonhematological toxicities. Of these, 3 patients (3%) had
however, there is no high-level evidence for the efficacy of
grade 3 nausea and vomiting, 3 patients (3%) had grade 3
this treatment modality because most studies comprised
fatigue, and 2 patients (2%) had increased creatinine level.
only a small number of patients and were retrospective in
No grade 4 or worse toxicity was observed. All of these
design.17,19-24 In the present study, relatively higher rates of
patients were manageable and recovered from the toxicities
PFS and OS were found than those in previous studies,
after the treatment. Regarding late toxicities, 2 patients
although PLN involvement is known to be among the
(2%) developed grade 3 rectosigmoid late complications,
important adverse prognostic factors. Choi et al reported 2-
and 2 patients (2%) had grade 3 small intestine toxicities.
year and 5-year PFS rates of 64.6% and 61.0%, respec-
One patient had grade 3 toxicities both in the rectosigmoid
tively, and OS rates of 87% and 64%, respectively, after
and the small intestine. Only 3 patients (3%) had grade 3 or
conventional CCRT in the PLN-positive group.25 In a
worse late toxicity.
cohort study, Matsuo et al reported the survival of 6888
patients who were PLN-positive and had T1-3 disease and
Discussion showed a 5-year cause-specific survival rate of 62.1%.26 In
addition, our group’s previous study showed that 35% of
The present study revealed the toxicity and efficacy of the patients with stage IIB or IIIB cancer developed distant
combination of CCRT to the pelvis and prophylactic failure after CCRT regardless of PLN involvement.7,8 In the
188 Wakatsuki et al. International Journal of Radiation Oncology  Biology  Physics

Table 3 Clinical trials: extended-field RT for cervical cancer

Acute GI Late GI 5-y local Overall
Study or No. of toxicity toxicity control survival
reference Y patients EBRT Chemo (G3), % (G3), % rate, % (mo) rate, % (y)
Eifel et al23 2004 195 Conventional None 1.6 9.3 66 41 (8)
RTOG 90-01
Grigsby et al24 2001 30 Conventional CDDP þ 5-FU 56 21 50 29 (4)
RTOG 92-10
Small et al17 2007 26 Conventional CDDP 35 27 62 (18) 60 (1.5)
RTOG 0116
Jensen et al21 2013 21 IMRT CDDP 19 0 90.5 (22) 60 (1.8)
Beriwal et al22 2007 36 IMRT CDDP 3 3 80 (24) 65 (2)
Poorvu et al20 2013 46 IMRT CDDP 6.5 6.5 NR NR
Lee et al28 2018 80 IMRT CDDP 0 3.8 NR 93
Oh et al19 2017 52 Conventional CDDP 7.7 13.5 NR 77
Wakatsuki et al26 2015 26 C-ion RT None 0 0 84 (24) 73 (2)
Present study 2018 95 Conventional CDDP 3 3 91 77 (5)
Cervix-IV
Abbreviations: 5-FU Z 5-fluorouracil; CDDP Z cisplatin; C-ion Z carbon-ion radiation therapy; EBRT Z external beam radiation therapy; GI Z
gastrointestinal; IMRT Z intensity modulated radiation therapy; NR Z not reported; RT Z radiation therapy.

present study, only 19 patients (20%) developed distant
metastases, and the 5-year OS rate was 77%, although all
patients in this study have PLN-positive T2b and T3b dis-
ease. Prophylactic PALN-RT might decrease the rate of
distant metastasis for patients with PLN-positive cervical
cancer and might improve the PFS and OS rates.
In the RTOG 0116 study, which delivered EFRT with
concurrent cisplatin,17 Small et al reported an 81% rate of
acute grade 3 or higher toxicity, excluding grade 3 leuko-
penia, and 40% late grade 3 or 4 toxicity. Small et al
concluded that the use of EFRT and chemotherapy was
associated with high rates of acute and long-term toxicities.
In addition, the pilot study of this study in FNCA, which
delivered PALN-RT concurrently with whole pelvic irra-
diation, showed similar results. Therefore, our present
study was designed to delay prophylactic PALN-RT to
reduce the acute and late toxicities (Fig. 1). In this study,
27% of patients had hematological acute grade 3 or worse
toxicities, 5% of patients had nonhematological acute grade
3 toxicities, and 3% of patients had late grade 3 toxicities.
Several studies reported that extended-field intensity
modulated radiation therapy combined with concurrent
chemotherapy or extended-field carbon-ion radiation ther-
apy showed less acute and late toxicity compared with
previous conventional treatments (Table 3).17,20-24,27,28 Our
present study showed comparable toxicity to these other
studies even though we used conventional radiation
techniques.
Another strategy to improve survival by treating outside
the pelvic radiation field is adjuvant chemotherapy (ACT)
after CCRT; thus, there have been several clinical trials of
ACT after CCRT for locally advanced cervical cancer.29-31
Dueñas-González et al reported significant improvement in
PFS and OS among those who received CCRT plus ACT
compared with those who received CCRT monotherapy.29
However, the application of ACT is limited by several
social and economic problems in developing countries,32
including longer overall treatment duration and higher
costs of treatment. In the present study, treatment durations
were extended by only 1 to 2 weeks, and additional medical
costs were not high because only prophylactic PALN-RT
was conducted instead of radical CCRT. Thus, this treat-
ment strategy might be a suitable alternative treatment to
ACT for patients with PLN-positive locally advanced cer-
vical cancer in developing countries.
A limitation of this research is that this study allowed
various treatment methods based on the treatment situation
of each country rather than strict protocols. Further exam-
ination in phase 2 or 3 clinical trials is necessary to
determine whether the outcomes are reproducible in each
country.
Conclusions
In conclusion, the results of the present study indicate that
the combination of CCRT to the pelvis and prophylactic
PALN-RT is feasible and effective for patients with locally
advanced cervical cancer in East and Southeast Asian
countries. The delayed prophylactic PALN-RT decreased
the rate of distant metastases and improved PFS and OS
rates without increasing toxicities.
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