Evaluation of CA 125, BUN, and Creatinine Serum in Ovarian

Cancer Patients Receiving Paclitaxel-Cisplatin Chemotherapy

Treatment

Rini Noviyani

, P. A. Indrayathi

, I. N. G. Budiana

, Rasmaya Niruri

, K. Tunas

, Tamara Candra

Paramitha

1Department of Pharmacy, Faculty of Mathematics and Sciences, Udayana University, Jalan Raya Kampus UNUD, Bukit

Jimbaran Bali, Indonesia

2Department of Public Health, Faculty of Medicine, Udayana University, Jalan P.B. Sudirman, Denpasar, Indonesia

3Department of Obstetrics and Gynecology, Faculty of Medicine, Udayana University, Jalan PB. Sudirman, Denpasar,

Indonesia

4Department of Pharmacy, Faculty of Mathematics and Sciences, Sebelas Maret University, Jalan Ir. Sutami, Surakarta,

Indonesia

5Department of Public Health, Faculty of Health, Sciences, and Technology, Dhyana Pura University, Jalan Raya Padang

Luwih Tegaljaya, Kuta Utara, Indonesia

Keywords: Chemotherapy, Paclitaxel-cisplatin, Ovarian Cancer, CA 125, BUN, Creatinine Serum.

Abstract: The effectiveness and side effects of paclitaxel-cisplatin chemotherapy were assessed from the patient’s

treatment progress and toxicity level. The objective was to evaluate these two criteria through the

assessment of CA 125, BUN, and creatinine serum in patients as an approach to overcome the data

limitation at Sanglah General Hospital. Observational retrospective research with patients who had

epithelial ovarian cancer (EOC) at Stages I, II, III, and IV was conducted from February-March 2018.

Patients’ blood samples were checked before the first and after the sixth cycle of chemotherapy. The data

were processed with the Shapiro-Wilks normality test. As for the abnormally distributed data, they were

analyzed statistically using the Wilcoxon test in SPSS. The mean values of CA 125 before the first and after

the sixth chemotherapy cycles were 9,429.6 ± 1,5978.7 U/ml and 31.65 ± 36.07 U/ml, respectively (p-

value= 0109). The mean values of BUN parameter were 10.63 ± 2.95 mg/dl and 14.83 ± 7.176 mg/dl (p-

value= 0.315), respectively. The creatinine serums were averagely 0.693 ± 0.0929 mg/dl and 0.78 ± 0.2053

mg/dl (p-value= 0.417), respectively. There were differences in the levels of CA 125, BUN, and creatinine

serum before the first and after the sixth cycles.

1 INTRODUCTION

Indonesia had the third highest incidence of ovarian

cancer cases in Asia in 2012 (Raezi et al., 2016). In

2014, ovarian cancer was the second most common

gynecological cancer in women at Sanglah Hospital

(Dhitayoni and Budiana, 2017). Chemotherapy is a

therapy given to ovarian cancer patients by

administering cytotoxic drugs either in single or in

combination regimens (Braybrooke, 2011).

According to PERMENKES RI No. 72 in 2016 on

the Standards of Pharmaceutical Services in

Indonesian Hospitals, a pharmacist is obliged to

monitor the effectiveness and safety of the

chemotherapy given to the patients by preparing the

cytostatic compound and calculating the accurate

dosage according to the chemotherapy protocol

(Direktorat Jenderal Bina Kefarmasian dan Alat

Kesehatan, 2016). Paclitaxel combined with a

platinum-based regimen is known to be the most

frequently used chemotherapy regimen for epithelial

ovarian cancer (EOC) patients. The paclitaxel-

cisplatin combination is currently the first-line

regimen for ovarian cancer patients. Three trials

have established the paclitaxel-cisplatin combination

therapy as the standard regimen in advanced EOC

patients. Therefore, this regimen is used at Sanglah

Noviyani, R., Indrayathi, P., Budiana, I., Niruri, R., Tunas, K. and Paramitha, T.

Evaluation of CA 125, BUN, and Creatinine Serum in Ovarian Cancer Patients Receiving Paclitaxel-Cisplatin Chemotherapy Treatment.

DOI: 10.5220/0008238900330038

In Proceedings of the 1st Muhammadiyah International Conference on Health and Pharmaceutical Development (MICH-PhD 2018), pages 33-38

ISBN: 978-989-758-349-0

General Hospital (Ozols et al., 2000). The regimen

efficacy can be evaluated by CA 125, i.e., an ideal

tumor marker of epithelial ovarian cancer (Gupta

and Lis, 2009). Aside from its therapeutic effects,

chemotherapy triggers various side effects,

particularly on renal function. The use of paclitaxel-

cisplatin for cervix cancer at Sanglah General

Hospital has been proved to elevate BUN level and

decreases creatinine serum after the third cycle of

chemotherapy (Noviyani et al., 2016). However, the

data of the therapeutic effect and side effect of a

paclitaxel-cisplatin regimen for ovarian cancer

treatment at Sanglah General Hospital remain

limited. Hence, this research aimed to evaluate the

difference in the levels of CA 125, BUN, and

creatinine serum of EOC patients before the first

cycle and after the sixth cycle of chemotherapy.

2 MATERIALS AND METHODS

2.1 Materials

The source of the research material was patients’

medical records from January 2017 to May 2018.

All data were obtained from a collecting form and

summarized using a data summary form. This

research used a set of computer unit containing

SPSS software.

2.2 Methods

This observational retrospective research was

located at Sanglah General Hospital, Denpasar, Bali

and conducted from January to March 2018. The

research subject was selected with consecutive

sampling. The research commenced following the

approval granted by the Research and Development

Ethics Commission, Faculty of Medicine/Sanglah

General Hospital, Denpasar [Ethical Clearance

number: 87/UN.14.2/KEP/2017].

The inclusion criterion was EOC patients at

Stage I, II, III, or IV who had consented to the

collection of their CA 125, BUN, and creatinine

serum data for research purposes. The exclusion

criterion was patients with renal dysfunction before

the chemotherapy started. The information obtained

from the data collecting form was summarized and

analyzed afterward.

2.3 Data Analysis

The summarized data were analyzed statistically in

SPSS. The data were processed with the Shapiro-

Wilks normality test. The data with normal

distribution were analyzed with a dependent t-test,

while the abnormally distributed ones were later

examined using the Wilcoxon test with a 95%

confidence level (*p= 0.05). The conditions before

the first and after the sixth cycle were concluded as

significantly different if the *p-value of the collected

data was <0.05.

3 RESULTS AND DISCUSSION

3.1 Patients’ Characteristics

The number of samples collected from February to

May 2018 was three. All samples fulfilled the

inclusion criterion. Their characteristics are

described in Table 1.

Ovarian cancer risk increases sharply after the

age of 40 years old and tends to reach its peak at the

age of 50-60 years old (Arania and Indri, 2015). The

ovarian cancer risk elevates as the age increases

until around 70 years old (Goodman et al., 2003).

According to Table 1, the samples involved in this

research are mostly of 41-60 years old.

Women need to receive education and

information about gynecological health from the age

of adolescence. The lack of knowledge and

information about the risk factors and symptoms

leads to limited awareness of ovarian cancer. The

latest formal education of one of the three samples

involved in this research was primary school.

Meanwhile, the rest had never received any formal

education at school. The low educational level of the

Table 1: Patients’ Characteristics

Characteristics

Number

(N=3)

Percentage

(%)

Age 20-40 y.o. 1 33.3

41-60

.o. 2 66.7

Educational

Level

No formal

education

2 66.7

Elementary

school

1 33.3

Occupational

Status

Farme

1 33.3

Employee 1 33.3

Unemploy-

1 33.3

Marital

Status

Married 1 33.3

Single 2 66.7

Cancer

Classification

Serous 2 66.7

Mucinous 1 33.3

Cancer Stage I 1 33.3

III 2 66.7

= Number of total sam

les

MICH-PhD 2018 - 1st Muhammadiyah International Conference on Health and Pharmaceutical Development

samples suggests that education and information

about ovarian cancer are highly needed since

adolescence (Rachmani et al., 2012).

One of the three samples was married and had

more than one child, while the other two were single

and had no children. Patients who have not given

birth to any children have a higher risk of

developing ovarian cancer (Permuth-Wey and

Sellers, 2009). One of the three samples was

diagnosed with Stage I ovarian cancer and the rests

were diagnosed with Stage III ovarian cancer. This

condition shows that ovarian cancer is most likely

diagnosed at later stages due to its ambiguous and

non-specific symptoms at the early stage. Patients

probably confuse them with other less severe

diseases (Roett and Evans, 2009). Also, there is

currently no routine and accurate test to detect early-

stage ovarian cancer in general population;

therefore, most women are not diagnosed until the

tumors grow and metastasize to other vital parts of

the body (Badgewell and Bast, 2007).

3.2 CA 125

CA 125 is a tumor marker used to diagnose ovarian

cancer in women. It has the highest specificity

(80%) compared to other tumor markers, such as CA

19-9 (36.4%) and CEA (8.1%) (Malati, 2007). CA

125 is secreted by abnormal epithelial cells and

found in 83% of epithelial ovarian cancer patients

(Liao et al., 2014).

In this research, CA 125 data were collected

before the first and after the sixth cycle of

chemotherapy. These data showed an abnormal

distribution. The results of the Wilcoxon test are

shown in Table 2.

According to Table 2, there is no significant

difference between the CA 125 values before the

first and after the sixth cycle of chemotherapy (p*-

value>0.05). A larger sample is, however, required

for the next stage of this research to get a more

accurate result. On the other hand, clinically, the

mean values of the samples show a decreasing CA

125 before the first and after the sixth cycle of

chemotherapy, i.e., 9,429.6 U/ml and 31.65 U/ml,

respectively The CA 125 value of a normal

individual is lower than 35 U/ml (Agarwal and

Kehoe, 2010). The reduction of CA 125 value to the

normal range after the sixth cycle suggests that the

paclitaxel-cisplatin chemotherapy contributes to

good therapeutic response in ovarian cancer patients

at Sanglah General Hospital. Based on the

information collected from 223 patients, Lee et al.

(2016) explain that the CA 125 values decrease to

the normal range after the first cycle of paclitaxel-

cisplatin chemotherapy and normalize within three

cycles of chemotherapy.

Paclitaxel works by interrupting the production

of microtubules, stabilizing the existing

microtubules, and inhibiting their destruction (Lacy

et al., 2004). It arrests the cell cycle at the G2/M

phase and leads to apoptosis (Barbuti and Chen,

2015). Meanwhile, cisplatin works by binding to

DNA―leading to the formation of interstrand and

intrastrand crosslinks―and interrupting DNA

synthesis and replication in cell proliferation (Miller

et al., 2010). The reduction of CA 125 value

compared to the previous cycle of chemotherapy

indicates good treatment response, whereas an

elevated CA 125 value signifies the possibility of

chemo-resistance, which prompts the replacement of

ongoing regimen with another therapeutic one

(Agarwal and Kehoe, 2010).

3.3 BUN

The decomposition process of protein produces a

waste product called urea. A renal function

evaluation was conducted by examining the BUN

value of the samples. An elevated BUN is a

characteristic identified in the plasma of patients

with severe renal dysfunction (Sherwood, 1996).

The BUN value increases along with the

Table 2: The Results of the Wilcoxon Test of CA

125 Before the First and After the Sixth Cycle of

Chemotherapy

CA 125

Mean SD

Before

first c

cle

3 9429.6 15978.74066

0.10

9 NS

After

sixth

cle

3 31.6467 36.06815

Table 3: The Results of the Dependent T-Test of

BUN Values Before the Firstnd After the Sixth

Cycle of Chemotherapy

BUN

Mean SD

Before the

first c

cle

3 10.6333 2.94845

0.315

After the

sixth c

cle

3 14.8333 7.17658

N= number of samples,

SD = standard deviation,

P= significant value.

Evaluation of CA 125, BUN, and Creatinine Serum in Ovarian Cancer Patients Receiving Paclitaxel-Cisplatin Chemotherapy Treatment

deterioration of renal function. Therefore, the

evaluation of BUN value decides whether an ovarian

cancer patient experiences renal dysfunction (Duong

and Jin-Yew, 2006). Since the collected BUN data

before the first and after the sixth cycle of

chemotherapy showed a normal distribution, they

were analyzed with a dependent t-test. The results

are summarized in Table 3.

The kidneys receive approximately 25% of

cardiac output and have a crucial role in absorbing

drugs. The high rate of drug uptake and delivery

results in a high intracellular concentration of

substances. These substances are then processed in

an extensive metabolism that leads to the production

of reactive oxygen species and toxic metabolites

(Perazella, 2009). Another study with 18 cervical

cancer patients who undergo cisplatin chemotherapy

shows an elevated BUN value and creatinine serum

after the fifth cycle of chemotherapy (Arankumar et

al., 2012).

Paclitaxel likely leads to peripheral neuropathy

and hematological side effects, such as neutropenia

and leukopenia (Lawrenti, 2013). Meanwhile,

cisplatin tends to be dominant in causing renal side

effects. It accumulates in the kidneys and interacts

with sulfhydryl compounds, which, thereby,

increases renal membrane fragility and induces the

depletion of intracellular glutathione. Renal damage

is associated with acute focal tubular necrosis and

the dilatation of convoluted tubules and collecting

ducts. Clinically, the damage is manifested as an

increase in BUN, creatinine serum, and electrolyte

disturbance (Arankumar et al., 2012). However,

BUN values are not fully determined by patients’

renal function. The other influencing factors include

patients’ protein intake, muscle injury, necrosis, and

liver function (Duong and Jin-Yew, 2006).

3.4 Creatinine Serum

Creatinine serum is the most sensitive renal function

indicator because the human body constantly

produces this substance. Renal dysfunction causes

an increase in creatinine serum (Ignativicius and

Workman, 2006). The collected data before the first

and after the sixth cycle of chemotherapy had a

normal distributed. These data were then analyzed

with a dependent t-test. The results are shown in

Table 4.

The results showed that there was no significant

difference between the creatinine serum levels

before the first and after the sixth cycle of

chemotherapy (p> 0.05). However, clinically, there

was an elevated creatinine serum after the sixth

cycle of chemotherapy. This elevation was still

within the normal range of creatinine serum value

(0.6-1.3mg/dl) (Duong and Jin-Yew, 2006). Such

increase implies that paclitaxel-cisplatin causes a

renal side effect on patients receiving chemotherapy.

From the data of 18 patients who undergo cisplatin

chemotherapy, Arankumar et al. (2012) conclude

that the levels of the creatinine serum before the first

and after the fifth cycle of chemotherapy are

significantly different. They also state that the

creatinine serum of the patients increases by 44.87%

after the fifth cycle of the cisplatin chemotherapy

(Arankumar et al., 2012).

In addition to the effects of the chemotherapy,

several factors can contribute to the increase of

creatinine serum, such as muscular dystrophy,

malnutrition, the reduction of muscle mass, and the

use of several drugs like cimetidine and ascorbic

acid (Indrawati et al., 2011). Compared to another

platinum-based agent such as carboplatin, cisplatin

has a higher nephrotoxic effect caused by its lower

selectiveness to tumor cells. Besides, carboplatin is a

derivative of cisplatin. Therefore, carboplatin is

more stable than cisplatin; however, they exhibit an

equivalent activity against some types of cancer

(Anderson et al., 2002). To prevent any cisplatin-

induced nephrotoxicity, hydration and

supplementation are highly recommended for EOC

patients. For patients administered with ≤50 mg/m

cisplatin, 2-4 L NS and potassium supplementation

are required. In addition to this recommendation,

magnesium supplementation is necessary for

patients given with ≥50 mg/m

cisplatin. Meanwhile,

patients receiving ≥100 mg/m

cisplatin are

recommended to also take mannitol (Crona et al.,

2017).

Table 4: The Results of the Dependent T-Test of

Creatinine Serum Before the First and After the

Sixth Cycle of Chemotherapy

Creatinine Seru

Mean SD

Before the

first c

cle

3 0.6933 0.09292

0.417

After the

sixth c

cle

3 0.7767 0.20526

N= number of samples,

SD = standard deviation,

P = significant value

MICH-PhD 2018 - 1st Muhammadiyah International Conference on Health and Pharmaceutical Development

4 CONCLUSION

There are differences in the levels of CA 125, BUN,

and creatinine serum before the first and after the

sixth cycle of chemotherapy. There are a decrease in

CA 125 and elevations in BUN level and creatinine

serum after the sixth cycle of chemotherapy.

ACKNOWLEDGMENT

The authors would like to thank the Ministry of

Research, Technology, and Higher Education of the

Republic of Indonesia, I Wayan Megadhana,

SPOG(K) as the Head of Obstetric and Gynecology

Specialist Study, and all staffs at Sanglah General

Hospital Obstetric Polyclinic, Denpasar for all of

their cooperation.

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