Oktavianus 165 *Center for The Study of Oncology, Faculty of Medicine, Universitas Padjadjaran **Department of Pathology, Faculty of Medicine, Universitas Padjadjaran/ Dr. Hasan Sadikin General Hospital, Bandung ***Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran ****Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran/ Dr. Hasan Sadikin General Hospital, Bandung Corresponding: Afandi Charles Center for The Study of Oncology Faculty of Medicine, Universitas Padjadjaran Jl. Raya Bandung Sumedang Km.21, Jatinangor, West Java, Indonesia. Phone and fax number: +6282297446690 Email: afandi.charles@gmail.com Univ Med 2016;35:165-70 DOI: 10.18051/UnivMed.2016.v35.165-170 pISSN: 1907-3062 / eISSN: 2407-2230 This open access article is distributed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License ABSTRACT UNIVERSA MEDICINA September-December, 2016September-December, 2016September-December, 2016September-December, 2016September-December, 2016 Vol.35 - No.3 Vol.35 - No.3 Vol.35 - No.3 Vol.35 - No.3 Vol.35 - No.3 Paclitaxel-carboplatin chemotherapy induced hematologic toxicities among epithelial ovarian cancer patients Afandi Charles*, Birgitta M. Dewayani**, Edhyana Sahiratmadja***, Gatot N.A. Winarno****, and Herman Susanto**** BACKGROUND Epithelial ovarian cancer (EOC) is one of the most common cancers diagnosed in Indonesian women. A combination of paclitaxel and carboplatin is used to treat EOC as standard chemotherapy which is known to have hematologic toxicities. This study aimed to investigate the effect of combined paclitaxel-carboplatin chemotherapy on hematologic status in EOC patients managed at Dr. Hasan Sadikin General Hospital, Bandung, West Java. METHODS All patients with confirmed pathological diagnosis of EOC at Dr. Hasan Sadikin General Hospital in the period of 2013 to 2014 were registered. Only patients with complete hematologic data before and after chemotherapy were collected and compared using the paired non- parametric Wilcoxon and McNemar tests. RESULTS In total there were 147 patients with EOC (median age 46 ± 12 years), with the most dominant pathological diagnosis of mucinous (32.7%) and serous (29.3%) types. Only 33 patients had hematologic data before the initiation of chemotherapy. There was a significant decrease after chemotherapy including hemoglobin level (12.0 vs 10.9 g/dL, p=0.013), erythrocyte count (4.53 vs 3.74 million/µL, p<0.001), leukocyte count (7,700 vs 4,000/mm3 p<0.001) and platelet count (343,000 vs 215,000/ mm3, p<0.001). Interestingly, anemia cases after chemotherapy were predominant (87.9%) compared with erythopenia, leukopenia, thrombocytopenia i.e. 39.4%, 57.6%, and 27.3% respectively. CONCLUSIONS This study confirmed the hematologic toxicities after paclitaxel- carboplatin chemotherapy in EOC patients treated in Hasan Sadikin General Hospital, West Java. The hemoglobin concentration may serve as prognostic factor. Further studies directed to other factors such as genetic factor for polymorphisms may be encouraged to explore the decrease of the hematologic indices. Keywords: Anemia, erythropenia, leukopenia, thrombocytopenia, epithelial ovarian cancer, paclitaxel-carboplatin DOI: http://dx.doi.org/10.18051/UnivMed.2016.v35.165-170 166 Charles, Dewayani, Sahiratmadja, et al Hematologic toxicities by paclitaxel-carboplatin chemotherapy INTRODUCTION Epithelial ovarian cancers (EOC) are still burdening female health nowadays. The World Health Organization estimated that this type of cancer accounted for 151,905 female deaths worldwide in 2012.(1) In Indonesia, EOC, together with other ovarian cancers are placed in the third rank of the most prevalent gynecologic cancers, next to breast and cervical cancers.(2) There are several risk factors associated with EOC, for example age older than 50 years, no pregnancy and lactation history and family history of breast and ovarian cancers.(3) Management of EOC consists of explorative surgery and chemotherapy.(3) The standard regimen for EOC is intravenous paclitaxel 175 mg/m2 and carboplatin area under curve is 7.5 for six cycles.(3) These regimen components, especially carboplatin have several side effects in bone marrow, resulting in suppression of hematopoiesis. Common hematologic toxicities developing in patients include anemia, thrombocytopenia, and leukopenia.(4) These side effects are mediated by the formation of DNA- protein cross-linking that further disrupts cell- cycle regulation and suppresses cell growth.(5) Chemotherapy is a standardized process performed at Dr. Hasan Sadikin Hospital, Bandung. There is a need for research on the hematologic impact of the paclitaxel- carboplatin combined therapy in EOC patients. Therefore, the aim of this study was to explore EOC patients treated in Dr. Hasan Sadikin General Hospital, Bandung and to investigate the effect of the paclitaxel-carboplatin regimen. METHODS Research design This study employed an analytical retrospective cohort study design conducted using medical records of patients treated in Dr. Hasan Sadikin General Hospital, Bandung. The medical records were collected in the period of January 2013 to December 2014. Research subjects All subjects with a pathological diagnosis of EOC were recruited for this study. Other types of ovarian cancer including malignant granulosa cell tumor and teratoma were excluded. Clinical, laboratory and chemotherapy data including the number of chemotherapy cycles were recorded. Laboratory analysis As for laboratory data, hematologic findings were collected before the initiation of chemotherapy and after chemotherapy of 6 cycles. Anemia was defined at a Hb concentration of <12.0 g/dL, erythropenia at an erythrocyte count of <3.6 million/µL, leukopenia at a leukocyte count of <4400/mm3 and thrombocytopenia at a platelet count of <150,000/mm3. Only patients with complete hematologic data and number of chemotherapy cycles were included. Statistical analysis Descriptive statistics for clinical data and histopathological category of EOC were shown as frequencies. McNemar and Wilcoxon tests were used to determine the association of the h e m a t o l o g i c s t a t u s b e f o r e a n d a f t e r chemotherapy. For the statistical analyses, the SPSS 22.0 software package (SPSS Inc. Chicago. IL) was used. Ethical clearance The ethical clearance required for this study was granted by the Health Research Ethics Committee, Faculty of Medicine, Universitas Padjadjaran - Dr. Hasan Sadikin General Hospital, Bandung (No. 3010/UN6.C.C1/PP/ 2015). RESULTS In total, there were 147 women with a median age of 46 years and an age range of 14 to 81 years, among whom more than half (59.2%) were younger than 50 years, i.e. the cut-off point of menopausal age in Indonesia. The most common histopathological types found in these 167 Univ Med Vol. 35 No.3 Table 1. Characteristics of epithelial ovarian cancer patients with complete hematologic data (n=33) *FIGO=International Federation of Gynecology and Obstetrics Table 2. Difference of hematologic findings between pre- and post-chemotherapy *p values were statistically significant. Analysis conducted using Wilcoxon test. Significance level p=0.05 **Values were x1.000 patients were the mucinous and serous types, comprising 32.7% and 29.3%, respectively. Many of the subjects were lost to follow up; some of them refused to undergo chemotherapy m a n a g e m e n t o r d i d n o t h a v e c o m p l e t e hematologic laboratory data, resulting in only 33 patients with complete laboratory and chemotherapy data who were further analyzed in this study. Of these EOC patients, most (54.5%) were diagnosed before the age of 50 years and were already in stage III (51.5%). Only 12 of 33 patients completed the six cycles of chemotherapy, while others underwent only three t o f i v e c y c l e s ( Ta b l e 1 ) . T h e r e w a s n o documentation in the medical records regarding t h e c a u s e o f e a r l y t e r m i n a t i o n o f t h e chemotherapy. The hematologic findings were not normally distributed, except for erythrocyte counts. Therefore the hemoglobin, leukocyte and platelet counts were presented as mean and standard deviation, whereas the erythrocyte count was presented as median and range. The hemoglobin level and the erythrocyte, leukocyte and platelet c o u n t s d e c r e a s e d s i g n i f i c a n t l y a f t e r chemotherapy as depicted in Table 2. Using categorical laboratory references, the distribution of patients with anemia, erythropenia, leukopenia, and thrombocytopenia also decreased significantly as shown in Table 3. Interestingly, after chemotherapy there was a predominant increase in anemia in 20 of 33 patients (60.6%), while erythropenia, leukopenia, and thrombocytopenia increased only in 13/33 (39.4%), 19/33 (57.6%), and 9/33 (27.3%) of patients, respectively (Table 3). The age at clinical presentation of EOC was analyzed to determine whether it was associated with the decrease in all post-chemotherapy hematologic findings, but the results showed no association (data not shown). 168 Charles, Dewayani, Sahiratmadja, et al Hematologic toxicities by paclitaxel-carboplatin chemotherapy Table 3. Chemotherapy induced anemia, erythropenia, leukopenia and thrombocytopenia in adults *p values were statistically different. Analysis conducted using McNemar test. Significance level p=0.05 **Low hematologic counts after chemotherapy DISCUSSION Our study explored the hematologic findings before and after paclitaxel-carboplatin chemotherapy among patients with epithelial ovarian cancer (EOC) and confirmed that there was a significant decrease in hematologic findings such as anemia, erythropenia, leukopenia, and thrombocytopenia. These findings are coherent with studies in advanced EOC cases, either using conventional or dose-dense paclitaxel-carboplatin regimen.(4,7) The paclitaxel-carboplatin regimen is known to have a lower incidence of high-grade neutropenia in EOC chemotherapy compared to its alternative regimen, docetaxel and carboplatin.(8) In our study we did not perform neutrophil counts; however, the hemoglobin level was significantly reduced after chemotherapy. Hemoglobin levels before chemotherapy have proposed to have prognostic value in terms of progression-free survival time for EOC patients.(9) The paclitaxel-carboplatin regimen is also used in other neoplasm cases, notably non-small cell lung cancer (NSCLC) and urothelial cancer, and has been associated with febrile neutropenia.(10) Furthermore, anemia, neutropenia, and thrombocytopenia are the most frequently observed toxicities after paclitaxel-carboplatin chemotherapy in advanced urothelial cancer patients in Japan.(11) These hematologic toxicities are also observed in NSCLC, and in addition, the paclitaxel-carboplatin regimen has been revealed to produce more severe anemia and neutropenia in Asian than in non-Asian patients.(12) As hematopoietic stem cells undergo senescence, many lesions and mutations are accumulated in their DNA, producing exhaustion in stem cell division.(7) This underlying mechanism may be responsible for the more severe hematologic toxicities of cytotoxic chemotherapy regimens, for example cyclophosphamide- doxorubicin in breast cancer and bevacizumab- paclitaxel-carboplatin in NSCLC.(13,14) However, an association between age and severity was not documented in these studies, and another study in NSCLC cases with paclitaxel-carboplatin chemotherapy also yielded similar results.(15) The hematologic toxicities occurring in EOC patients after having received paclitaxel- carboplatin chemotherapy are influenced by several factors, i.e. from the regimen itself and patient background. Paclitaxel exerts its c y t o t o x i c e ff e c t s b y d e p o l y m e r i z i n g microtubules, thus arresting the cell cycle and inducing apoptosis.(16) However, paclitaxel only induces minimal hematologic toxicities when administered alone.(16) Carboplatin used in this regimen has a myelosuppressive effect via the mechanism of DNA-protein damage in bone marrow by means of crosslinking between them, t h u s r e s u l t i n g i n d e c r e a s e d n u m b e r s o f erythrocytes, leukocytes, and platelets, as well 169 Univ Med Vol. 35 No.3 as other toxic effects (neurotoxicity, ototoxicity, and nephrotoxicity).(17,18) It also seems that carboplatin may increase serum TNF-α, suppressing the development of hematologic progenitor cells.(19) Currently, genetic polymorphisms are being investigated to determine their association with paclitaxel-carboplatin hematologic toxicity, depending on race and ethnicity. The single nucleotide polymorphisms 2677G>T/A and 3435C>T of ABCB1 genes have been associated with neutropenia in paclitaxel chemotherapy in E O C c a s e s i n s o m e s t u d i e s , ( 2 0 , 2 1 ) b u t n o association has been found in others.(22,23) Some studies in NSCLC have demonstrated that polymorphisms in drug-transporter genes (ABCB1 and ABCG2), DNA-repair pathway genes ( ERCC4 and XCC ), and apoptosis pathway genes (CASP 8 and CASP10) are associated with thrombocytopenia, neutropenia, and severe hematologic toxicity, respectively, due to paclitaxel-carboplatin effects.(24-26) One limitation of this study is the small sample size which was not appropriate to the estimated sample size due to incomplete data. Another limitation is inadequate hematologic data in each of the chemotherapy cycles, which l i m i t s s t a t i s t i c a l a n a l y s i s ; h o w e v e r, t h e decreasing trend in the hematologic data might be used to generalize the findings. CONCLUSION In conclusion, the decrease in hematologic data such as anemia, leukopenia, and thrombocytopenia after paclitaxel-carboplatin chemotherapy were confirmed in EOC patients treated in Dr. Hasan Sadikin General Hospital. The hemoglobin concentration may serve as prognostic factor. In addition, further studies are needed on genetic background factors that may play a role in the decrease in hematologic data. CONFLICT OF INTEREST Competing interest: No relevant disclosures. ACKNOWLEDGEMENT This research is part of a Progress Grants 2014 study conducted under the Oncology Working Group, Faculty of Medicine, Universitas Padjadjaran. REFERENCES 1. Union for International Cancer Control. Epithelial ovarian cancer. Geneva: World Health Organization;2014. 2. Wahidin M, Noviani R, Hermawan S, et al. Population-based cancer registration in Indonesia. Asian Pac J Cancer Prev 2012;13: 1709-10. 3. Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. 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