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 radiosensitizer’s toxicity. The aim

of this study is to analyze the differences between radiation and chemoradiation

therapy’s 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 lesion’s diameter. Progressive condition shows the increased by more than

20% of target lesion’s diameter. Stable condition shows there are no significant

changes. 11

Radiation’s 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 high-frequency 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 urea, creatinine levels before and after

chemoradiation.

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 p-value 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 subject’s characteristic of

both groups are homogeneous so it can be compared and tested statistically in

further.

Results of Effectiveness Comparison Between Radiation and Chemoradiation

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 chemoradiation 55500.00), with a p value of

0.172 (p <0.05 significant)

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 p-value 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 patient’s 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 in nephrotoxicity between radiation and chemoradiation.

Choudhary said in his research that cisplatin nephrotoxicity is stereospecifically cis

bonds, not transisomer bond, such as carboplatin or oxaloplatin, even a platinum

compound is not a nephrotoxic agent. Cisplatin’s 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 in chemoradiation therapy and 0% patients in radiation

therapy. 17,18

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.

EfektivitasRadiasi Kemoradiasi

Nilai pn (%) n (%)

Tabel 1 Karakteristik Subjek Penelitian

Keterangan : nilai p dihitung berdasarkan uji

Tabel 2 Hasil Respons Klinis Kanker Serviks Setelah Perlakuan sebagai Tolok Ukur Efektivitas

KarakteristikRadiasi Kemoradiasi

Nilai pn (%) 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%)

b. Squamous cell 10 (43,5%) 14 (46,7%)

c. Adenokarsinoma 3 (13%) 4 (13,3%)

d. Clear cell 0 (0%) 0 (0%)

3. Stadium 0,383

a. II B 11 (47,8%) 20 (66,7%)

b. III A 1 (4,3%) 1 (3,3%)

c. III B 11 (47,8%) 9 (30%)

d.

Respon klinis 0,434

Respon Komplit 22 (95,7%) 30 (100%)

Respon Parsial 0 0 (0%)

Progresif

Stabil

1 (4,3%)

0

0 (0%)

0 (0%)

ToksisitasTerapi

Nilai pRadiasi Kemoradiasi

Hb

X (SD)

Median

Rentang

0,66 (0,64)

0,50

0,10 – 2,60

1,49 (1,20)

1,10

0,10 – 4,40

0,003

L

X (SD)

Median

3521,74 (2962,79)

3500,00

5683,33 (4160,25)

4600,0

0,033

Rentang 300,00 – 10800,00 200,00 – 20800,00

Tr

X (SD)

Median

Rentang

50652,17 (56316,97)

32000,00

5000 - 246000

89233,33 (88193,63)

55500,00

5000 - 350000

0,172

ToksisitasTerapi

Nilai pRadiasi Kemoradiasi

Ureum

X (SD)

Median

Rentang

5,70 (3,44)

5,00

1 - 13

12,83 (24,20)

8,00

1 - 137

0,015

Kreatinin

X (SD)

Median

Rentang

0,12 (0,15)

0,05

0,01 – 0,43

0,45 (1,60)

0,11

0,01 – 8,90

0,037

DAFTAR PUSTAKA

1. Cervical Cancer: Estimated Incidence, Mortality, and Prevalance Worldwide in

2012. In: GLOBOCAN, editor.: IARC WHO; 2012.

2. Arbyn M, Castellsague X, de Sanjose S, Bruni L, Saraiya M, Bray F, et al.

Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011;22(12):2675-86.

3. Motoyama S, Ladines-Llave CA, Luis Villanueva S, Maruo T. The role of human

papilloma virus in the molecular biology of cervical carcinogenesis. Kobe J Med Sci.

2004;50(1-2):9-19.

4. Addis IB, Hatch KD, Berek JS. Intraepithelial Disease of the Cervix, Vagina, and

Vulva. Dalam: Berek JS. Berek & Novak's Gynecology. Philadelphia: Lippincott

Williams & Wilkins; 2007. h. 561 - 99.

5. Eifel PJ. Concurrent chemotherapy and radiation therapy as the standard of care for

cervical cancer. Nat Clin Pract Oncol. 2006;3(5):248-55.

6. Chi DS, Abu-Rustum NR, Plante M, Roy M. Cancer of the Cervix. Dalam: Rock JA,

Jones HW. Te Linde's Operative Gynecology. Edisi ke-10. Philadelphia: Lippincott

Williams & Wilkins; 2008. h. 1227 - 90.

7. Bidus MA, Elkas JC. Cervical and Vaginal Cancer. Dalam: Berek JS. Berek &

Novak's Gynecology. Edisi ke-14. Philadelphia: Lippincott Williams & Wilkins;

2007. h. 1403 - 56.

8. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm--

general principles. Nat Clin Pract Oncol. 2007;4(2):86-100.

9. Sonoda Y, Barakat RR. Management of Complication of Chemotherapy. Dalam:

Rubin SC. Chemotherapy of Gynecologic Cancers: Society of Gynecologic

Oncologists Handbook. Edisi ke-2. Philadelphia: Lippincot William & Wilkins;

2004.

10. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al.

New guidelines to evaluate the response to treatment in solid tumors. European

Organization for Research and Treatment of Cancer, National Cancer Institute of the

United States, National Cancer Institute of Canada. J Natl Cancer Inst.

2000;92(3):205-16.

11. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New

response evaluation criteria in solid tumours: revised RECIST guideline (version

1.1). Eur J Cancer. 2009;45(2):228-47.

12. Candelaria M, Garcia-Arias A, Cetina L, Dueñas-Gonzalez A. Radiosensitizers in

cervical cancer. Cisplatin and beyond. Radiat Oncol. 2006;1:15.

13. Common Terminology Criteria for Adverse Events (CTCAE). In: Institute NC,

editor. 4 ed. Duarte: U.S.DEPARTMENT OF HEALTH AND HUMAN

SERVICES; 2010.

14. Choudhary R, Poonia S, Punia DP, Maheshwar R, Mathur KC. Platinum

Compounds-Induced renal and Bone Marrow Toxicity: a Review. J Phys Pharm

Adv. 2012;2(3):145-9.

15. Common Toxicity Criteria Manual. In: Institute NC, editor. 2 ed. Duarte:

U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES; 1999.

16. Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al. Concomitant

chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane

Database Syst Rev. 2005(3):Cd002225.

17. Gunawan R, Nuranna L, Supriana N, Sutrisna B, Nuryanto KH. Acute Toxicity and

Outcomes of Radiation Alone Versus Concurrent Chemoradiation for Locoregional

Advanced Stage Cervical Cancer. Indonesian J Obstet Gynecol. 2012;36(1).

18. Zuliani AC, Esteves SCB, Teixeira LC, Teixeira JC, Souza GAd, Sarian LO.

Concomitant Cisplatin Plus Radiotherapy and High–Dose-Rate Brachytherapy

Versus Radiotherapy Alone for Stage IIIB Epidermoid Cervical Cancer: A

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

Terapi

Tabel 4 Perbandingan Hasil sebagai Tolok Ukur Efektivitas Kadar