ABSTRACT

The incidence of cervical cancer in the world remains high. In

2012, 528,000 new cases of cervical cancer were recorded. The
therapy of cervical cancer has been changing from time to time
including the addition of radiosensitizer to radiation therapy. As a
result, metastasis and progression has reported to be reduced and life
expectancy

has

increased,

but

unfortunately

an

increase

of

nephrotoxicity and myelotoxicity has obtained. Various studies have

conducted to evaluate the effectiveness by considering the mixed
results of radiosensitizers toxicity. The aim of this study is to analyze
the differences between radiation and chemoradiation therapys
effectiveness,

myelotoxicity

and

nephrotoxicity

in

patients

with

advanced stage of cervical cancer.

This study was a retrospective cohort study, comparing result of
radiation and chemoradiation treatment in patients, based on their
medical record. This study is conducted

in Hasan Sadikin General

Hospital, from September 2014 to February 2015. Total subjects were

53 and subjects were divided into 2 different groups, consist of 23 in
radiation group and 30 in chemoradiation group. The effectiveness of
therapy was analyzed by comparing clinically measurement of the
mass; hemoglobin levels, leukocyte count and platelets as markers
myelotoxicity; urea and creatinine levels as a marker myelotoxicity,
before treatment and six months after treatment.

The results of this study showed that full response was reported
to be 95.7% in the radiation group and 100% in the chemoradiation
group with p = 0.249 indicated that the response of that both groups
were comparable. It was obtained that increased levels of urea and
creatinine was greater in chemoradiation therapy compared to
radiation therapy (8.00 vs. 5.00; p = 0.015 and 0.11 vs 0.05; p =
0.037). Decreased levels of hemoglobin and leukocyte count were also
greater in chemoradiation therapy compared to radiation therapy (1.10
vs. 0.50; p = 0.003 and 4600.00 vs 3500.00; p = 0.033). Comparison
of platelet count decreased was insignificant in both groups (32000.00
vs 55500.00; p = 0.172).
As conclusions, there was an insignificant difference between the
effectiveness of radiation therapy and chemoradiation therapy, but
there was lower incidence of nephrotoxicity and myelotoxicity in the
radiation therapy compared to chemoradiation therapy. Based on this
study, radiation therapy may become standard procedure of advanced
stage cervical cancer therapy.
Keywords: radiation, chemoradiation, effectiveness, nephrotoxicity,
myelotoxicity

Background
The incidence of cervical cancer in the world has been not decreasing
significantly from year to year. In 2008, new cases of cervical cancer in

the world were 530,000, while in 2012 it was estimated that new cases
were at 528,000. The mortality rate of cervical cancer in the world
were 266 000 in 2012.
Cervical cancer ranks on fourth position as most frequent cancer in
women and ranks on seventh as most frequent existing cancer. In
Southeast Asia there are 175,000 new cases, with a mortality rate of
94,000 in 2012.

1,2

High Risk Human Papilloma Virus (HPV) assumed as the cause of

cervical cancer. Deoxyribonucleic acid (DNA) of HPV has found on 90%
in patients with intraepithelial neoplasia. HPV types 16 and 18 have the
highest percentage in cervical cancer patients, 47% and 23%,
respectively.3,4
Surgical operation is an effective management in treating early stage
of cervical cancer, whereas radiation can be carried out at all stages of
cervical cancer. To increase the success rate of cervical cancer therapy,
chemotherapy is given as neoadjuvant, which is simultaneously given
with radiation, or as an adjuvant. Combination of external radiation and
internal radiation is an effective treatment in advanced cervical cancer.
5.6

Radiation therapy can be used in treating all stages of cervical cancer,

with a recovery rate of 70% in stage I, 60% stage II, 45% in stage III
and 18% in stage IV. Radiation therapy generally consists of external
radiation combination, which is directed to regional lymph nodes and

shrink the tumor mass and brachytherapy, which is pointed at the

center of the tumor mass using intracavitary applicator or interstitial
implants. 7
By

giving

radiosensitizer,

it

was

conducted

to

improve

the

effectiveness of radiation that works, by reducing the size of the tumor,

thus oxygen can be easier to get into the rest of the tumor tissue and
facilitate the break-rays and inhibits ribonucleoside diphosphate
reductase enzyme for DNA replication. The cell cycle is inhibited prior
to S phase, which is known as the most radioresistant phases.

5,7,8

The effectiveness of a cytostatic is not only specified by the chemical

properties of the drug and biochemical characteristics of tumor cells,
but also affected by the ability of cells to recognize and repair DNA
damage and the time needed for repairs, which is the speed of tumor
growth. But due to its complexity, the results are mostly unpredictable.
9
The effectiveness of radiation and chemoradiation can be seen from
the assessment of tumor mass changes, which is an important part of
the

clinical

evaluation

in

cancer

therapies.

In

the

mid-90s,

standardization and simplification for clinical response of cancer

therapy criteria was carried out. Response Evaluation Criteria in Solid
Tumors (RECIST) was published in 2000. 10,11
Evaluation on a target lesion is divided into complete response, namely
the loss of the entire target lesion and partial response, which indicates

a reduction of 30% of target lesions diameter. Progressive condition

shows the increased by more than 20% of target lesions diameter.
Stable condition shows there are no significant changes. 11
Radiations side effects are divided into acute and chronic. The acute
effects of radiation are diarrhea, abdominal cramps, nausea, frequent
urination and bleeding from the bladder or colon mucosa. Chronic
effects usually occur months to years after radiation has completed.
Fistula colon and bladder, bleeding, stricture, stenosis and large bowel
obstruction occurs as chronic effects of radiation.7
Cytostatic drug has an effect on the normal cells of the body. The effect
is noticed mainly on rapidly growing cells, such as liver cells,
gastrointestinal mucosa, and the bone marrow. Cytostatic that is
widely used in gynecological cancer is cisplatin because of its
effectiveness, but it has the potential to cause toxicity. The most
common side effect of its toxicity is kidney damage that reducing
glomerular filtration rate. Sensory neuropathy, tinnitus, and highfrequency hearing loss are also reported to be common. Mild and
reversible bone marrow suppression; alopecia; acute nausea, or
vomiting reported to be complained. 9.12 Toxicity which occur in
Hematologic

myelotoxic

are

anemia,

leukopenia,

and

thrombocytopenia and nonhematologik form of nephrotoxic and

ototoxic. 13

Myelotoxicity on platinum chemotherapy can be occured due to its

ability to cause damage, and even death to myeloid progenitor cells in
the bone marrow, which resulting in diminished production of
erythrocytes, leukocytes granulocytes and platelets. The outcome of
myelotoxicity

is

the

occurrence

of

anemia,

leukopenia,

and

thrombocytopenia. 12.14
Moreover, cisplatin, will also cause a reduction in glomerular filtration
rate and lead to an increase of urea and creatinine in plasma, because
the increased production of reactive oxygen species can induced
damage on mesangial cells and causes contraction of the glomerular
capillary

surface

area,

thereby

reducing

the

surface

area

of

glomerulus. 14
National Cancer Institute (NCI) Common Toxicity Criteria (CTC) is widely
used in evaluating new cancer therapies. The term toxicity began to be
replaced by the term adverse events on the revision of second CTC.
The adverse events are defined as symptoms and signs, which are not
expected to be seen and have association with the use of therapeutic
or medical procedures. Toxicity generally used on the possible adverse
events or adverse events that definitely relate to the drug or therapy.
15
For any side effects, there is a scale of 0 to 5. 0 represent normal, 1
represents that the side effects are mild, 2 represents moderate side

effects, 3 represents severe side effects and unwanted, 4 represents

life-threatening side effects and 5 represents mortality. 15
A meta-analysis study published by cochcrane stated that there is
reduction in distant metastases, progressivity, and increased life
expectancy on the use of chemoradiation compared to radiation
therapy. On the other hand, there was an increase in haematological
and gastrointestinal toxicity in the chemoradiation therapy group
compared to radiation. 16.17
While the research conducted at the Cipto Mangunkusumo General
Hospital, Jakarta failed to show the superiority of radiosensitizer, when
both radiation and chemoradiation group were obtained complete
response 100%. 17 One study stated tahta there was a decrease in
superiority of chemoradiation compared to radiation, in accordance to
increase of cervical cancer stage. From the study, it was also noted
that

there

were

differences

in

disease

free

interval

between

chemoradiation and radiation, but the overall life expectancy cannot

be compared. 18
From the previous explanation, it was obtained that the central theme
in this study is: Numbers of cervical cancer incidence has not been
changed significantly. Proper treatment to improve survival in patients
with cervical cancer is needed. The modalities of therapy for cervical
cancer have developed over time. The main treatment of cervical
cancer, especially in advanced stages cervical acncer is radiation

therapy. By giving radiosesitizer, it is expected to improve the

effectiveness of cervical cancer therapy. Radiation therapy has side
effects on the gastrointestinal and genitourinary. Radiosensitizer has
side effects that affect the bone marrow (myelotoxic) and kidneys
(nephrotoxicity) that are not reported in radiation therapy. Myelotoxic
occur due to bone marrow suppression, which can lead to conditions,
such as anemia, leukopenia and thrombocytopenia. Nephrotoxicity due
to reduced glomerular filtration rate, which can be seen through the
increase of urea and creatinine. Controversy over the use of
chemoradiation occurred due to conducted researches, which found
that the effectiveness of radiation and chemoradiation is not much
different,

while

chemotherapy

can

causes

myelotoxicity

and

nephrotoxicity, which reported to be significantly higher compared to

radiation therapy. One technique that can be used to see clinical
response to a therapy is by using RECIST criteria. CTC is used to assess
the toxicity caused by radiosensitizer.

Method
This study is a correlation analytic study with retrospective cohort
design. The subjects were all patients with advanced stage of cervical
cancer,

who

received

radiation

or

chemoradiation

therapy

in

Gynaecological Oncology Subdivision, Department of Obstetrics and

Gynecology, Hasan Sadikin General Hospital, Bandung. The inclusion

criteria for subjects were including: patients with advanced stage of

cervical cancer who had received radiation or chemoradiation therapy,
no multiple primary tumors reported, and had no hematologic
disorders and renal function prior to radiation or chemoradiation
therapy. Exclusion criteria for subjects were including: incomplete data
in medical record.

Effectiveness, Myelotoxicity, and Nephrotoxicity

The effectiveness of chemotherapy is considered by seeing the size
changed of the tumor mass clinically after 6 months following the
radiation or chemoradiation therapy. Complete response means that
the tumor mass is disappeared entirely. Partial response means that
the diameter of the tumor mass was reduced at least 30%. Progressive
will be reported if the diameter of the tumor mass to grow at least
20%. Stable will be reported if the change in tumor mass is smaller
than the above criteria.
Myelotoxicity were assessed, by comparing the laboratory tests of
hemoglobin,

leukocytes

and

platelets

levels

before

and

after

chemoradiation. Nephrotoxicity was assessed, by comparing the

laboratory

tests

chemoradiation.

urea,

creatinine

levels

before

and

after

Statistical Analysis
The data obtained in this study was processed, by using SPSS version
21.0 for windows.

Result
Characteristics of Subjects
This research was conducted in September 2014, by collecting cervical
cancer patients medical records who were in advanced stage, who
underwent radiation and chemoradiation therapy from 1 September
2014 to 28 February 2015. During that period, 89 research subjects
were obtained and 82 patients met the inclusion and exclusion criteria.
Ten patients did not come to the hospital to be observed after
complete radiation or complete chemoradiation therapy, and 19
patients could not be included in the study because they only received
2-3 cycles of chemotherapy during radiation cycle, thus total of 53
research subjects were involved. Based on radiosensitizer given, the
study subjects were divided into two groups, 23 subjects as radiation
therapy group and 30 subjects as chemoradiation therapy group. Data
recording of patients age, histopathology, stage, size of the mass,
hemoglobin,

leukocytes,

platelets,

urea,

and

creatinine

were

performed.
Based on Table 1, it shows that age distribution in radiation group were
mostly at 50 years old or 16 people (69.6 %) in total, and 40-49

years old patients were four people (17.4%). Age distribution in

chemoradiation group were mostly between 40-49 years, as many as
14 people (46.7%), and followed by 50 years old, 13 people (43.3%).
The p-value was 0.081 (p> 0.05), which it was not statistically
significant.
For

histopathology,

radiation

group

had

the

same

number

of

epidermoid ca and squamous cell, which both types reported in 10

people (43.5%), while in the chemoradiation group, the most common
histopathology type was squamous cell, 14 people (46.7%). The pvalue was 0.967 (p> 0.05), which it was not statistically significant.
Based on cervical cancer stage in radiation therapy group in this study,
stage IIB and IIIB reported to have same number of patients, which was
11 people (47.8%). In cisplatin group, most of subjects were on stage
IIB, with total 20 people (66.7%), and stage IIIB reported in 9 people
(30%). The p-value was 0.383 (p> 0.05), which it was not statistically
significant.
Based on the above characteristics, all the characteristics that included
in this study, has p value greater than 0.05, which indicated that the
subjects characteristic of both groups are homogeneous so it can be
compared and tested statistically in further.

Results

of

Effectiveness

Chemoradiation

Comparison

Between

Radiation

and

From table 2, it shows that good clinical response were moderately

numerous in both groups, although the radiation showed a tendency to
be inferior compared to chemoradiation (radiation chemoradiation
95.7% vs 100%). Progressive clinical response was only found in
radiation therapy group, happened to 1 patient (4.3%). Both groups
were then tested statistically and it showed that the p value was 0.434
(p> 0.05), which is insignificant. This result suggested that the clinical
response of patients in both groups, after chemoradiation, were
comparable.
Myelotoxicity Comparison
Parameter of myelotoxicity is based on hemoglobin levels, leukocytes,
and platelets examination. Blood tests were conducted before and
after chemoradiation.
Table 3 represents the data of hemoglobin decreased levels difference,
which shows significant differences between two groups (0.50 for
radiation vs. 1.10 for chemoradiation), with a p-value of 0.003 (p <0.05
significant).
Mean of leukocytes number decrease between the two groups showed
insignificant

results

(radiation

3500.00

versus

chemoradiation

4600.00), with a p value of 0.033 (p <0.05 significant).

Platelets number decrease difference between the two groups showed
insignificant

results

(radiation

32000.00

versus

55500.00), with a p value of 0.172 (p <0.05 significant)

chemoradiation

Nephrotoxicity Comparison
Nephrotoxicity parameters were based on the examination of the urea
and creatinine. Blood tests were performed before and after radiation
or chemoradiation.
From Table 4 it showed that there was increase urea levels differences
in both groups (radiation 5.00 vs. chemoradiation 8.00), with the pvalue of 0.015 (p <0.05), which means a significant or statistically
significant.
An elevated creatinine level in Table 4 indicates that there were
significant

differences

between

the

two

groups

(0.05

vs.

chemoradiation radiation 0.11), with p value of 0.037 (p <0.05

significant).
The conclusions that can be drawn from the analysis of nephrotoxicity,
which are including levels of urea and creatinine from mean difference
of the all data, is that there were significant differences in term of
nephrotoxicity between radiation and chemoradiation therapy.

DISCUSSION
Characteristics of Research Subjects
Characteristics distributions of the patients in this study were analyzed
based on their of age, histopathology, and stadium of cancer. Most
patients in the radiation group were 50 years old (69.6%), followed
by patients age ranged from 40-49 years (17.4%). Most patients in

chemoradiation group were between 40-49 years (46.7%), then 50

years (43.3%), according to research conducted by Gunawan, et al.
stated that most patients with advance stage of cervical cancer
surveyed were 48-68 years old in radiation therapy group and its
numbers were nearly similar to 35-47 years old and 48-68 years old in
the chemoradiation. 17 Another study conducted by Zuliani, et al.,
majority of research subjects were >45 years old in radiation group
therapy and chemoradiation group therapy. 18 In this study, there were
no significant age differences between carboplatin and cisplatin
group(p = 0.081).
Based on histopathological examination, it was obtained that there
were same amount of numbers between squamous and epidermoid
types, ie 43.5% in the radiation group and the cisplatin group, it was
found that squamous type was the most frequent, 46.7%, p = 0.967.
which indicates that there was no significant difference between both
groups. These results were in accordance to study conducted
Gunawan. et al. which stated that 87.5% of the subject who received
radiation and 75% of subjects who received chemoradiation had
squamous cell type. 17
Based on stadium of cancer, cervical cancer who received radiation
therapy in this study, consisted 47.8% stage IIB, 4.3% stage IIIA and
47.8% of stage IIIB while patients who receivied chemoradiation in this
study consisted of 66.7% stage IIB, 3.3% stage IIIA and 30%, stage IIIB,

p = 0.383 which indicates there was no significant difference regarding

stage between both groups. According to study conducted by
Gunawan, et al. showed that 50% of subjects in radiation and
chemoradiation therapy group were in stage IIB and then followed by
stage IIB. 17

Effectiveness Comparison of Radiation and Chemoradiation

This study showed that clinical response in tumor size after radiation
was 95.7% for complete response and 4.3% were progressive, whereas
in chemoradiation therapy group, 100% showed complete response.
Both groups showed no significant difference in the results in terms of
clinical response (p = 0.434). Gunawan, et al on his research at the
University of Indonesia compared outcomes among patients with
cervical cancer who were given cisplatin chemoradiation with radiation
therapy only, and stated that clinical response after treatment of both
groups, with the last chemoradiation within 3 months, were similar, ie
100%. 17 Green, et al in their meta-analysis study has mentioned
superiority

of

disease

free

interval

in

chemoradiation

therapy

compared to radiation, 16 whereas Zuliani, et al stated that the

superiority decreases in accordance to the advancement of cancer
(stadium).18 It can be concluded that the effectiveness of radiation
and chemoradiation had a similar result, based on their capability to
decrease the tumor mass which found during physical examination.

Comparison of toxicity between radiation and Chemoradiation therapy

Analysis of nephrotoxicity in the chemoradiation group showed that the
mean of distinction was greater than the radiation group. Increase of
urea levels, which shown in chemoradiation therapy group was 8.00
whereas in radiation therapy group was 5.00, with a p value = 0.015,
and increase of creatinine levels which shown in chemoradiation
therapy group was 0.11 whereas in radiation therapy group was 0.05,
with a p value = 0.037. These findings indicate that there were
significant

differences

chemoradiation.

in

Choudhary

nephrotoxicity
said

in

his

between

radiation

research

that

and

cisplatin

nephrotoxicity is stereospecifically cis bonds, not transisomer bond,

such as carboplatin or oxaloplatin, even a platinum compound is not a
nephrotoxic agent. Cisplatins active metabolites, which is not bound
freely, filtered at the glomerulus, and uptake in the cells of renal
tubular through the Ctr1 and OCT2 transport medium, which then
cause damage to the glomeruli and tubules and caused glomeruli
filtration to be decreased, so that urea and creatinine increase and
cause tubular leakage and also cause an imbalance of electrolytes,
such as sodium, potassium (via transporter Na / K ATPase), and
magnesium. 14
Gunawan et al. on their study in Jakarta obtained the results that there
was no nephrotoxicity reported in patients with radiation while

nephrotoxicity at various levels seen in patients with chemoradiation (p

= 0.000). 17
Myelotoxicity in this study reported as levels of hemoglobin and
leukocytes which is decreased significantly in chemoradiation therapy
group compared to radiation therapy group (p = 0.003 and p = 0.033),
but there was no significant difference in reduction of platelet levels (p
= 0.172) between both groups.
Myelotoxicity

cisplatin

according

to

Choudary

will

continuously

accelerate after repeated administration and will cause anemia,

thrombocytopenia, and leukopenia. Severe anemia is thought to be a
result of changes in the pattern of erythropoiesis in the bone marrow
and kidney damage that causing production of erythropoietin in the
kidneys decreases, beside the hemolysis, which caused by antiglobulin
antibodies that attack erythrocyte that has cisplatin antigen on the cell
membrane. 14

Both Gunawan, et al and Zuliani, et al in their study stated that there

were significant differences in myelotoxicity between radiation therapy
group and chemoradiation therapy group in patients with cervical
cancer. In the study by Gunawan, et al. p = 0.002 was obtained for the
comparison of myelotoxicity, whereas in the study Zuliani et al. it was
found

that

25.6%

of

patients

had

haematological

toxicity

chemoradiation therapy and 0% patients in radiation therapy. 17,18

in

CONCLUSION
There was no difference in effectiveness (in the form of clinical
response in reduction size of the tumor mass) between radiation and
chemoradiation therapy in patients with advanced stage of cervical
cancer.
There was a myelotoxicity (in the form of reduced levels of
hemoglobin, leukocytes, and platelets) and nephrotoxicity (in the form
of increased levels of urea and creatinine) which were lower in patients
with advanced cervical cancer who received radiation compared to
chemoradiation.

Karakteristik
Kemoradiasi
Nilai p
Tabel 1 Karakteristik Subjek Radiasi
Penelitian
n (%)
n (%)
1. Umur (tahun)
0,081
a. > 50
16 (69,6%)
13 (43,3%)
b. 40 - 49
4 (17,4%)
14 (46,7%)
c. < 40
3 (13%)
3 (10%)
2. Histopatologi
0,967
a. Epidermoid ca
10 (43,5%)
12 (40%)
: nilai
p dihitung berdasarkan uji chi square
b. Squamous cell
10 Keterangan
(43,5%)
14 (46,7%)
c. Adenokarsinoma
3 (13%)
4 (13,3%)
d. Clear cell
0 (0%)
0 (0%)
3. Stadium
0,383Kanker Serviks Setelah Perlakuan
Tabel 2 Hasil Respons Klinis
a. II B
11 (47,8%) sebagai
20 (66,7%)
Tolok Ukur Efektivitas
b. III A
1 (4,3%)
1 (3,3%)
c. III B
11 (47,8%)
9 (30%)
d.

Efektivitas
Toksisitas Terapi
Nilai p
Respon klinis
Radiasi
Toksisitas
ResponTerapi
Komplit
Ureum
ResponRadiasi
Parsial
5,70 (3,44)
Progresif
Hb
X (SD)
5,00
1 - 13
Stabil 0,66 (0,64)
X (SD)
Median

Radiasi
n (%)

Kemoradiasi
Nilai p
n (%)
0,434
Kemoradiasi
22 (95,7%) 30 (100%)
0,015
0
Kemoradiasi
0 (0%)
1 (4,3%)
0 (0%)
12,83 (24,20)
0

Median 0,50
Rentang
Kreatinin
Rentang 0,10 2,60
L
X (SD)
0,12 (0,15)

8,00
1 - 137

1,10
0,10 4,40

0,037

0,45 (1,60)
0,11

Median 3500,00
Rentang
0,01 0,43

4600,0
0,01 8,90

300,00 10800,00

0,003

0 (0%)
1,49
(1,20)

X (SD) 3521,74 (2962,79)

Median
0,05

Rentang
Tr

Nilai p

0,033

5683,33 (4160,25)

200,00 20800,00
0,172

X (SD)

50652,17 (56316,97)

89233,33 (88193,63)

Median

32000,00

55500,00

Rentang

5000 - 246000

5000 - 350000

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Randomized Controlled Trial. J Clin Oncol. 2014;32(6):542-7.

Tabel 3

Perbandingan Hasil Rerata Penurunan Kadar Hemoglobin, Hitung

Leukosit dan Trombosit sebagai Tolok Ukur Myelotoxicity
Toksisitas
Terapi
Nilai p

Tabel 4

Perbandingan Hasil sebagai Tolok Ukur Efektivitas Kadar

Ureum dan Kreatinin sebagai Tolok Ukur Nefrotoksisitas

Keterangan: nilai p dihitung berdasarkan uji Mann Whitney

Keterangan: nilai p dihitung berdasarkan uji Mann Whitney

Keterangan: Nilai p dihitung berdasarkan uji Exact Fisher