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Abstract

Objective

To compare the efficacy of paclitaxel liposomes combined with carboplatin and paclitaxel combined with carboplatin in the treatment of advanced ovarian cancer and assess their effects on serum human epididymis protein 4 (HE4), CA125, CA199, matrix metalloproteinase-2 (MMP2), MMP-7, and MMP-9 levels.

Methods

In this observational study, 102 patients with advanced ovarian cancer were assigned to receive paclitaxel liposomes combined with carboplatin (Group A) or paclitaxel combined with carboplatin (Group B). Clinical efficacy; serum HE4, CA125, CA199, MMP-2, MMP-7, and MMP-9 levels; and the occurrence of adverse reactions were compared between the groups.

Results

The overall response rate was significantly higher in Group A than in Group B. After chemotherapy, serum HE4, CA125, CA199, MMP-2, MMP-7, and MMP-9 levels were lower in Group A than in Group B. The incidence of myalgia, dyspnea, nausea and vomiting, facial flushing, peripheral neuropathy, and skin rash was lower in Group A than in Group B.

Conclusion

Paclitaxel liposomes combined with carboplatin displayed better efficacy in the treatment of advanced ovarian cancer than paclitaxel combined with carboplatin, which might be attributable to reductions in serum marker levels and the occurrence of adverse events.

Keywords

Ovarian cancer chemotherapy paclitaxel liposome carboplatin biochemical marker adverse event

Introduction

Ovarian cancer is a malignant tumor that poses a serious threat to women’s health. Specifically, 90% of ovarian cancers are of an epithelial cell type, and they comprise multiple histologic types featuring various specific molecular changes, clinical behaviors, and treatment outcomes. The remaining 10% are non-epithelial ovarian cancers, which mainly include germ cell tumors, sex cord-stromal tumors, and some extremely rare tumors such as small cell carcinomas.¹ BRCA1/2 germline mutations are the strongest known genetic risk factors for epithelial ovarian cancer, and they are present in 6% to 15% of patients. The BRCA1/2 status can be used to counsel patients regarding expected survival, as BRCA1/2 carriers with epithelial ovarian cancer respond better to platinum-based chemotherapies than non-carriers. This yields greater survival even though the disease is generally diagnosed at a later stage and higher grade.²

With research progress, additional methods have been applied to the clinical treatment of ovarian cancer. Among them, paclitaxel liposomes combined with carboplatin and paclitaxel combined with carboplatin are widely used regimens for ovarian cancer in recent years.³^,⁴ Paclitaxel exerts an anti-tumor effect mainly by inhibiting cell division through its action on the microtubule system.⁵ The use of injectable paclitaxel liposomes solved the water insolubility of paclitaxel.⁶

Research has revealed that paclitaxel liposomes combined with carboplatin have similar efficacy as paclitaxel combined with carboplatin in ovarian cancer, and the regimen is relatively safe.⁴ However, some studies found that paclitaxel liposomes combined with carboplatin produce better short-term efficacy in the treatment of advanced ovarian cancer than paclitaxel injection combined with carboplatin, and the former regimen can potentially reduce the levels of serum biochemical markers CA125 and CA199 and the incidence of adverse reactions.⁷ Therefore, the efficacy of paclitaxel liposomes combined with carboplatin and paclitaxel combined with carboplatin is unclear.

Human epididymis protein 4 (HE4) levels have certain utility in the early diagnosis, differential diagnosis, and therapeutic monitoring of ovarian cancer.⁸^,⁹ CA125, a tumor-associated antigen on the surface of ovarian tumor cells, is important in the diagnosis of ovarian cancer.¹⁰ CA199 is a tumor marker with potential value in the diagnosis of ovarian tumors because of its abnormal expression in ovarian tumors.¹¹ Tumor metastasis and matrix metalloproteinase-2 (MMP-2) are closely related, as MMP-2 can degrade the basement membrane and extracellular matrix, resulting in endothelial cell migration.¹² MMP-7 plays a role in human cancer.¹³ MMP-9 promotes angiogenesis and tumor growth and regulates cell migration.¹⁴ HE4, CA125, CA199, MMP-2, MMP-7, MMP-9, and other markers play important roles in the diagnosis, treatment, and prognosis of ovarian cancer. Understanding the effects of serum biochemical markers in patients with advanced ovarian cancer during treatment process can facilitate the identification of optimal treatment options for patients.

This study compared the efficacy of paclitaxel liposomes combined with carboplatin and paclitaxel combined with carboplatin in patients with advanced ovarian cancer and their effects on serum marker levels to provide accurate data and recommendations for clinical treatment.

Materials and methods

Study population

This observational study was approved by the Research Ethical Committee of The 909th Hospital, School of Medicine, Xiamen University (No. LL2019216). The reporting of this study conforms to the STROBE guidelines.¹⁵

Inclusion criteria

The eligibility criteria were as follows: women older than 18 years with a confirmed diagnosis of late-stage ovarian cancer by postoperative pathological examination; no prior receipt of interventions such as radiotherapy, chemotherapy, or targeted therapy before surgery; prior complete debulking surgery (no residual disease); a requirement for chemotherapy after surgery; FIGO stage III or IV; expected survival exceeding 6 months; and the provision of written informed consent by the patients or their families.

Exclusion criteria

The exclusion criteria were as follows: severe cardiovascular, liver, kidney, pulmonary, or other organ diseases; other malignant tumors; chemotherapy-related contraindications such as severe infections, coagulation disorders, or bone marrow suppression; neurological, cardiovascular, hematological, or immune system diseases; poorly controlled metabolic diseases such as diabetes or hypertension; and an inability to tolerate the study drugs.

Chemotherapy regimen

Patients were divided into two groups. Those in Group A received paclitaxel liposomes combined with carboplatin. In this regimen, paclitaxel liposomes were administered on day 1 via an intravenous infusion at a dose of 175 mg/m² added to 500 mL of 5% glucose over 3 hours. A carboplatin injection was administered on day 2 at a dose of 300 mg/m², which was calculated according to the area under the plasma drug concentration–time curve of 5, added to 500 mL of 5% glucose and infused over 2 hours.

Patients in Group B received paclitaxel combined with carboplatin. In this regimen, an intravenous infusion of conventional paclitaxel injection was administered on day 1 at a dose of 175 mg/m² added to 500 mL of 5% glucose and infused over 3 hours. On day 2, a carboplatin injection was administered as described for Group A.

Both groups received symptomatic supportive treatments such as anti-inflammatory, white blood cell-boosting, and antiemetic drugs during chemotherapy. Both groups were treated once every 7 days, with each cycle lasting for 21 days, for six cycles.

Efficacy evaluation

After chemotherapy (end of six cycles), clinical efficacy was evaluated in both groups according to the tumor response evaluation criteria in solid tumors in the Chinese guidelines for the diagnosis and treatment of common malignant tumors as follows: complete response (CR), disappearance of all lesions; partial response (PR), reduction of lesion the volume by at least 50%; stable disease, reduction of lesion volume by at least 25% but less than 50%; and disease progression, increase of the lesion volume by more than 25% or the appearance of new lesions.¹⁶ The overall response rate was calculated as (number of CR + PR cases)/total cases × 100%.

Observation indicators

Before and after chemotherapy, 5 mL of venous blood were extracted from each patient to assess serum biochemical markers including HE4, CA125, CA199, MMP-2, MMP-7, and MMP-9 using enzyme-linked immunosorbent assay. During treatment, adverse reactions such as leukopenia, thrombocytopenia, decreased hemoglobin, renal dysfunction, muscle and joint pain, and breathing difficulty were observed and recorded.

Statistical analysis

The data were statistically analyzed using SPSS 26 (IBM Corp., Armonk, NY, USA). Normally distributed metric data were expressed as the mean ± standard deviation and compared between the groups using an independent-samples t-test. Count data were expressed as n (%) and compared between the groups using the chi-square test or Fisher’s exact test. P < 0.05 was considered statistically significant.

Results

Demographic characteristics

In total, 102 patients with advanced ovarian cancer admitted to our hospital from January 2019 to June 2022 were selected as the study population, and no patients withdrew from the study. Among these patients, 9.80% were aged 40 to 50 years, 31.37% were aged 51 to 60 years, and 58.82% were aged ≥61 years. Meanwhile, 65.69% and 34.31% of patients had serous adenocarcinoma and mucinous adenocarcinoma, respectively. Meanwhile, 39.22% and 60.78% of patients had moderate and high differentiation, respectively. The FIGO stage was III in 55.88% of patients and IV in 44.12% of patients. The Eastern Cooperative Oncology Group (ECOG) performance status was 0, 1, and 2 in 54.90%, 38.24%, and 6.86% of patients, respectively (Table 1). A flowchart of this study is presented in Figure 1.

Table 1.

Demographic characteristics of the patients.

Variable	Category	n (%)
Age	40–50 years	10 (9.80)
	51–60 years	32 (31.37)
	≥61 years	60 (58.82)
Pathologic types	Serous adenocarcinoma	67 (65.69)
Pathologic types	Mucinous adenocarcinoma	35 (34.31)
Degree of differentiation	Moderate differentiation	40 (39.22)
Degree of differentiation	High differentiation	62 (60.78)
FIGO stage	III	57 (55.88)
FIGO stage	IV	45 (44.12)
ECOG performance status	0	56 (54.90)
	1	39 (38.24)
	2	7 (6.86)

ECOG, Eastern Cooperative Oncology Group.

Figure 1.

Flowchart of this study.

Efficacy evaluation

The overall response rate was 76.47% (39/51) in Group A, versus 56.86% (29/51) in Group B (P = 0.036, Table 2).

Table 2.

Efficacy evaluation.

Parameter	Group A (n = 51)	Group B (n = 51)	P
CR [n (%)]	16 (31.37)	12 (23.53)	–
PR [n (%)]	23 (45.10)	17 (33.33)	–
SD [n (%)]	7 (13.73)	11 (21.57)	–
PD [n (%)]	5 (9.80)	11 (21.57)	–
Overall response [n (%)]	39 (76.47)	29 (56.86)	0.036

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Comparison of serum HE4, CA125, and CA199 levels

Before chemotherapy, serum HE4, CA125, and CA199 levels did not differ between the groups, whereas after chemotherapy, serum HE4, CA125, and CA199 levels were significantly lower in Group A than in Group B (all P < 0.05, Table 3).

Table 3.

Comparison of serum HE4, CA125, and CA199 levels.

Parameter	Group A (n = 51)	Group B (n = 51)	P
Serum HE4 before chemotherapy (pmol/L)	162.60 ± 21.14	160.80 ± 18.53	0.647
Serum HE4 after chemotherapy (pmol/L)	53.85 ± 7.26	57.03 ± 6.57	0.023
Serum CA125 before chemotherapy (U/mL)	150.42 ± 20.29	151.28 ± 17.43	0.819
Serum CA125 after chemotherapy (U/mL)	50.11 ± 6.78	52.95 ± 6.06	0.028
Serum CA199 before chemotherapy (U/mL)	115.06 ± 15.52	113.72 ± 13.01	0.638
Serum CA199 after chemotherapy (U/mL)	32.71 ± 4.41	36.20 ± 4.16	<0.001

HE4, human epididymis protein 4.

Comparison of serum MMP-2, MMP-7, and MMP-9 levels

Although serum MMP-2, MMP-7, and MMP-9 levels did not differ between the groups, all of their levels were lower in Group A than in Group B after chemotherapy (all P < 0.05, Table 4).

Table 4.

Comparison of serum MMP-2, MMP-7, and MMP-9 levels.

Parameter	Group A (n = 51)	Group B (n = 51)	P
Serum MMP-2 before chemotherapy (ng/mL)	308.12 ± 45.81	306.91 ± 47.01	0.896
Serum MMP-2 after chemotherapy (ng/mL)	186.07 ± 27.66	198.43 ± 30.98	0.036
Serum MMP-7 before chemotherapy (ng/mL)	0.82 ± 0.12	0.80 ± 0.13	0.514
Serum MMP-7 after chemotherapy (ng/mL)	0.31 ± 0.05	0.37 ± 0.06	<0.001
Serum MMP-9 before chemotherapy (ng/mL)	426.75 ± 63.27	428.39 ± 66.96	0.899
Serum MMP-9 after chemotherapy (ng/mL)	251.73 ± 37.32	267.61 ± 41.27	0.047

MMP, matrix metalloproteinase.

Comparative analysis of adverse reactions

The incidence rates of leukopenia, thrombocytopenia, decreased hemoglobin, renal dysfunction, diarrhea, alopecia, and anorexia were not significantly different between the groups (Table 5). The incidence rates of muscle and joint pain, dyspnea, nausea and vomiting, facial flushing, peripheral neuropathy, and rash were significantly lower in Group A than in Group B (all P < 0.05, Table 5).

Table 5.

Comparative analysis of adverse reactions.

Adverse reaction	Group A (n = 51)	Group B (n = 51)	P
Leukopenia [n (%)]	13 (25.49)	14 (27.45)	0.822
Thrombocytopenia [n (%)]	3 (5.88)	1 (1.96)	0.617
Decreased hemoglobin [n (%)]	15 (29.41)	18 (35.29)	0.525
Renal dysfunction [n (%)]	1 (1.96)	3 (5.88)	0.617
Muscle and joint pain [n (%)]	3 (5.88)	10 (19.61)	0.038
Dyspnea [n (%)]	1 (1.96)	6 (11.76)	0.112
Nausea and vomiting [n (%)]	4 (7.84)	12 (23.53)	0.029
Facial flushing [n (%)]	5 (9.80)	14 (27.45)	0.022
Peripheral neuropathy [n (%)]	3 (5.88)	13 (25.49)	0.006
Rash [n (%)]	1 (1.96)	11 (21.57)	0.002
Diarrhea [n (%)]	12 (23.53)	20 (39.22)	0.088
Alopecia [n (%)]	31 (60.78)	32 (62.75)	0.839
Anorexia [n (%)]	16 (31.37)	18 (35.29)	0.674

Discussion

Paclitaxel combined with carboplatin is the first-line chemotherapy regimen for advanced ovarian cancer. Its main mechanism of action is inhibiting DNA synthesis and cell division in tumor cells, thereby exerting an anti-tumor effect.¹⁷ The results of this study revealed that the short-term efficacy of paclitaxel liposomes combined with carboplatin was higher than that of paclitaxel combined with carboplatin in the treatment of advanced ovarian cancer, and the former regimen significantly reduced the incidence of some adverse reactions. This was consistent with the conclusions of other studies.⁷ The reasons might be that compared with paclitaxel combined with carboplatin, paclitaxel liposomes combined with carboplatin has several advantages. First, paclitaxel liposomes can accumulate in tumor cells in large quantities, thereby increasing the therapeutic effect of the drug.¹⁸ Second, paclitaxel liposomes release drugs only in tumor tissues without affecting affect the function of normal tissue cells. Therefore, paclitaxel liposomes combined with carboplatin can effectively reduce the incidence of certain adverse reactions.

Some studies suggested that although the paclitaxel liposomes combined with carboplatin treatment achieved better therapeutic effects, it also has more adverse reactions on the hematopoietic system, such as decreases in platelet counts.⁷ However, the current study found no significant difference in platelet counts between the groups, possibly attributable to the smaller sample size. Therefore, individualized treatment must be conducted according to the specific conditions of different patients to maximize the balance between treatment effectiveness and adverse reactions.

HE4 levels have certain utility in the differential diagnosis and treatment monitoring in ovarian cancer.¹⁹^,²⁰ CA125 is a widely used and relatively specific tumor marker for the diagnosis of ovarian cancer.²¹ CA199 is mucin glycoprotein that is abnormally expressed in the sera of patients with malignant tumor.²² The present study observed lower serum HE4, CA125, and CA199 levels in patients treated with paclitaxel liposomes combined with carboplatin than in those treated with paclitaxel combined with carboplatin, in line with prior findings.²³ MMP-2 is important in the process of tumor angiogenesis.²⁴ MMP-7 and MMP-9 participate in physiological and pathological processes such as tumor metastasis and invasion.²⁵

This study found that compared with paclitaxel combined with carboplatin treatment, paclitaxel liposomes combined with carboplatin treatment can effectively reduce the serum levels of MMP-2, MMP-7, and MMP-9 in patients with advanced ovarian cancer.

This study had several limitations, such as a small sample size and a lack of diversity in treatment options. Further large-scale, multicenter, randomized double-blind controlled studies can better validate the efficacy of this treatment regimen and provide a more comprehensive evaluation of its safety and tolerability. In the future, more large-scale, multicenter, randomized double-blind controlled studies are needed to verify the effectiveness and reliability of this treatment regimen. In addition, resistance to chemotherapy is increased in mucinous and low-grade ovarian cancer. The subjects of this study included epithelial tumors (serous adenocarcinoma, mucinous adenocarcinoma) with modal to high differentiation. Therefore, there could be biases in this study. In the future, only one histological type should be used to analyze the efficacy of chemotherapy to avoid bias.

Conclusion

Compared with paclitaxel and carboplatin combination therapy, paclitaxel liposomes and carboplatin combination therapy exhibited better efficacy in patients with advanced ovarian cancer, and this regimen reduced serum HE4, CA125, and CA199, MMP-2, MMP-7, and MMP-9 levels and the incidence of adverse reactions.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231200267 - Supplemental material for Comparison of paclitaxel liposomes combined with carboplatin versus paclitaxel combined with carboplatin in the treatment of advanced ovarian cancer

Supplemental material, sj-pdf-1-imr-10.1177_03000605231200267 for Comparison of paclitaxel liposomes combined with carboplatin versus paclitaxel combined with carboplatin in the treatment of advanced ovarian cancer by Xiangbin Tan, Shuangyou Zou, Hui Chen and Dachao Chen in Journal of International Medical Research

Footnotes

Authors’ contributions

Xiangbin Tan and Shuangyou Zou conceived the project, designed the study, analyzed the data, and wrote the paper. Hui Chen analyzed the data. Dachao Chen critically reviewed the manuscript.

Data availability statement

The dataset of this article is not openly available. However, it can be accessed upon reasonable request from the corresponding author.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This study received no external funding.

ORCID iD

Dachao Chen

References

Cheung

Shah

Parker

et al. Non-Epithelial Ovarian Cancers: How Much Do We Really Know? Int J Environ Res Public Health 2022; 19: 1106–1123.

Shah

Cheung

Kutka

et al. Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes. Int J Environ Res Public Health 2022; 19: 8113–8126.

Mahner

Meier

Du Bois

et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a subset analysis of the CALYPSO phase III trial. Eur J Cancer 2015; 51: 352–358.

Yang

et al. Effectiveness and safety of paclitaxel liposomes and carboplatin for ovarian cancer: A systematic review. Chinese J Evidence-Based Med 2012; 12: 42–48.

Sharifi-Rad

Quispe

Patra

et al. Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy. Oxid Med Cell Longev 2021; 2021: 3687700.

Han

Yang

Chen

et al. Preparation, Characterization, and Pharmacokinetic Study of a Novel Long-Acting Targeted Paclitaxel Liposome with Antitumor Activity. Int J Nanomed 2020; 15: 553–571.

Zhou

Yuan

Zhu

et al. Influence of paclitaxel liposome for injection on serum tumor markersand immune functionin patients with advanced ovarian cancer. Chin J Clin Obstet Gynecol 2022; 23: 42–45.

Nalini

Kumar

Sharma

et al. The Diagnostic Accuracy of Serum and Urine Human Epididymis Protein 4 (HE4) in Ovarian Cancer in 15,394 Subjects: An Updated Meta-Analysis. Cureus 2022; 14: e30457.

Bilgi Kamaç

Altun

Yilmaz

et al. A label-free dual immunosensor for the simultaneous electrochemical determination of CA125 and HE4 biomarkers for the early diagnosis of ovarian cancer. Anal Bioanal Chem 2023; 415; 1709–1718.

10.

Omer

Abdelbar

El-Kemary

et al. Cancer antigen 125 assessment using carbon quantum dots for optical biosensing for the early diagnosis of ovarian cancer. RSC Adv 2021; 11: 31047–31057.

11.

Lertkhachonsuk

Buranawongtrakoon

Lekskul

et al. Serum CA19‐9, CA‐125 and CEA as tumor markers for mucinous ovarian tumors. J Obstet Gynaecol Res 2020; 46(11): 2287–2291.

12.

Liao

Huang

et al. Association of Matrix Metalloproteinase-2 Genotypes With Prostate Cancer Risk. Anticancer Res 2023; 43: 343–349.

13.

Liao

et al. Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem 2021; 92: 9–18.

14.

Mondal

Adhikari

Banerjee

et al. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem 2020; 194: 112260.

15.

Von Elm

Altman

Egger

et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147: 573–577.

16.

Wang

Ding

Yang

et al. Effect of different dosage forms of paclitaxel combined with carboplatin in patients with advanced ovarian cancer and its impact on serum human epi-didymal protein 4, carbohydrate antigen 125 and T lymphocyte subsets. Oncology Progress 2021; 19: 844–855.

17.

Ngoi

Syn

Goh

et al. Weekly versus tri‐weekly paclitaxel with carboplatin for first‐line treatment in women with epithelial ovarian cancer. Cochrane Database Syst Rev 2022; 2: CD012007.

18.

Vahed

Salehi

Davaran

et al. Liposome-based drug co-delivery systems in cancer cells. Mater Sci Eng C Mater Biol Appl 2017; 71: 1327–1341.

19.

Lycke

Ulfenborg

Lauesgaard

et al. Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics. Clin Chem Lab Med 2021; 59: 1954–1962.

20.

Barr

Funston

Jeevan

et al. The Performance of HE4 Alone and in Combination with CA125 for the Detection of Ovarian Cancer in an Enriched Primary Care Population. Cancers (Basel) 2022; 14: 2124.

21.

Talaat

Helmy

Saadawy

SF.

Evaluation of miRNA-21 and CA-125 as a promising diagnostic biomarker in patients with ovarian cancer. Egypt J Med Hum Genet 2022; 23: 123–129.

22.

Wang

Sun

et al. Relationship between clinicopathological features of ovarian cancer with CA125, 199 and FIGO staging. Int J Clin Exp Med 2020; 13: 8700–8706.

23.

Liu

Zhang

Wang

et al. Efficacy of paclitaxel liposome combined with cisplatin for patients with advanced ovarian cancer and analysis of serum tumor markers. International Medicine and Health Guidance News 2022; 23: 3260–3263.

24.

Webb

Gao

Goldsmith

et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer 2017; 17: 434.

25.

Brun

Cortez

Commo

et al. Serous and mucinous ovarian tumors express different profiles of MMP-2, -7, -9, MT1-MMP, and TIMP-1 and -2. Int J Oncol 2008; 33: 1239–1246.

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