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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
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