The incidence of ovarian cancer has been steadily increasing, leading to approximately 140,000 women worldwide succumbing to this disease annually (1). Ovarian cancer ranks has the highest mortality rate among malignant tumors affecting the female reproductive system, representing a significant threat to women’s health (2, 3). Due to the ovaries’ deep location in the pelvis, ovarian cancer typically presents insidiously and is often difficult to detect in its early stages. Consequently, about 70% of patients are diagnosed at an advanced stage (4, 5). For these advanced cases, although targeted therapies have been incorporated into the treatment strategy for first-diagnosed ovarian cancer, the conventional treatment approach involves primary debulking surgery (PDS) followed by postoperative adjuvant chemotherapy (6–8). Additionally, for patients with multiple high-risk preoperative factors and where achieving optimal surgical outcomes is challenging, the combination of preoperative neoadjuvant chemotherapy (NACT), interval debulking surgery (IDS), and postoperative adjuvant chemotherapy is being explored (9, 10).

The role of NACT in treating advanced ovarian cancer remains controversial. A meta-analysis encompassing 835 ovarian cancer cases suggested that NACT is linked to a poorer prognosis (11). However, the prospective randomized controlled study (EORTC 55971) by Vergote et al. suggested that NACT-IDS is considered noninferior to PDS in individuals facing stage IIIC-IV ovarian cancer and is associated with fewer perioperative complications. Furthermore, the CHORUS study confirmed similar overall survival rate between NACT-IDS and PDS, with better prognoses reported in individuals facing stage IV ovarian cancer (12, 13). Despite ongoing debates regarding the efficacy of NACT-IDS, it has proven to enhance the likelihood of significant tumor reduction and reduce perioperative complication risks. Therefore, NACT-IDS should be considered a viable alternative treatment for individuals with The International Federation of Gynecology and Obstetrics (FIGO) stage III-IV ovarian cancer when satisfactory tumor reduction is not feasible with PDS alone (14, 15).

The neutrophil/lymphocyte ratio (NLR) in peripheral blood is recognized as an indicator of the body’s inflammatory and immune responses, with several studies highlighting its correlation with the prognosis of individuals suffering from ovarian cancer (16, 17). Moreover, studies have revealed that serum tumor markers, including carbohydrate antigen 153 (CA153), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), and human epididymal protein 4 (HE4), are linked to ovarian cancer prognosis. However, the sensitivity and specificity of these single-marker tests often fall short of ideal standards (18–23). To enhance tumor reduction rate, minimize perioperative complications, decrease postoperative chemotherapy resistance, and accurately select patients suitable for NACT, this study utilizes dynamic testing of NLR and tumor markers including CA125, CA199, CEA, CA153, and HE4 before and after NACT. The ability to accurately predict NACT’s effectiveness in individuals facing advanced ovarian cancer is crucial for developing personalized and precise treatment plans, ultimately aiming to improve the quality of life for these individuals.

Ovarian cancer typically presents insidiously and is difficult to detect in its early stages, with nearly 70% of patients being diagnosed at an advanced stage (4, 5). Numerous investigations have demonstrated that surgical thoroughness significantly correlates with survival rates in patients with advanced ovarian cancer. Achieving satisfactory tumor reduction during PDS is a prerequisite for successful postoperative maintenance therapy. Moreover, attaining R0 resection is linked to a considerable enhancement in overall survival for those facing advanced stages of the disease (25–27). Patients facing advanced ovarian cancer often have metastases to multiple sites such as the peritoneum, greater omentum, intestines, liver, spleen, diaphragm, and lymph nodes. This multifocal spread complicates the direct application of PDS and significantly increases the risk of perioperative complications and mortality (27–29). NACT-IDS can increase the feasibility of minimally invasive surgery, potentially improving tumor reduction and reducing risks of postoperative complications and perioperative mortality. However, this approach might not extend postoperative survival, and could increase the risks associated with chemotherapeutic drug resistance and tumor recurrence (14, 15, 30–32).

The choice between PDS and NACT-IDS for patients with advanced ovarian cancer necessitates a careful evaluation and requires a multidisciplinary approach, incorporating insights from gynecological oncologists, pathologists, and the analysis of clinical indicators and imaging results. This collaborative effort aims to provide tailored and precise treatment to achieve the best therapeutic outcome (33, 34). Predicting the efficacy of NACT represents a crucial clinical inquiry for future research endeavors.

Research has reported a connection between chronic inflammation and the progression of ovarian cancer, highlighting the critical role of the inflammatory response in tumor proliferation, invasion, and migration by upregulating inflammation to promote tumor angiogenesis and inhibit antitumor activity (35, 36). Neutrophils, produced in the bone marrow, possess phagocytic, chemotactic, and bactericidal effects. They can also synthesize vascular endothelial growth factor (VEGF), which promotes abnormal neovascularization and accelerates the growth and metastasis of malignant tumor cells (37, 38). Lymphocytes, produced in lymphoid organs, are crucial for immune recognition and constitute the main cellular components of the immune response. A decrease in lymphocyte counts can diminish immune-mediated tumor antagonism, thereby facilitating the proliferation and metastasis of malignant tumor cells (39, 40). NLR is a leukocyte-associated inflammatory marker suggestive of the body’s immune homeostasis. An increased NLR disrupts the immune homeostasis, resulting in an imbalance between antitumor immune response and protumor inflammatory response, which promotes tumor cell growth and metastasis, and bears a strong correlation with the progression and prognosis of ovarian cancer (16, 17, 41, 42).

CA125 is currently the most commonly used adjuvant indicator for the diagnosis, efficacy observation, and prognostic assessment of ovarian cancer, and kinetic changes for the prediction of satisfactory subtractive tumors have been widely studied (18, 19, 43, 44). Normalization of pre-IDS CA125 levels is an accurate predictor of satisfactory tumor-reducing surgery and is significantly associated with better survival rates. However, the CALYPSO and ICON-8 studies demonstrated that CA125 levels do not accurately assess patient sensitivity to chemotherapy (45–47). CA199 is a tumor marker associated with pancreatic, gallbladder, gastric, and colon cancers. In patients with ovarian cancer, CA199 is highly expressed and can be shed in large quantities from the cell membranes of the ovarian cancer cells into the bloodstream, showing remarkable sensitivity for ovarian cancer detection (20, 48, 49). CEA, a soluble glycoprotein with complex structure and embryonic antigenic properties, is mostly found in the fetal liver and gastrointestinal tract during the embryonic period, and is present in minimal quantities in tissues. Abnormally elevated levels of CEA may affect the differentiation of tumors and increase the risk of tumor infiltration and metastasis, which in turn affects the clinical regression of patients with ovarian cancer (21, 50, 51). CA153 was first found in breast cancer epithelial cells and can cause changes in cell surface glycans due to activation of glycosyltransferases during carcinogenesis. This marker is present in a variety of adenocarcinomas and has increasingly been used as an adjunctive indicator for the diagnosis and differentiation of ovarian cancer in recent years (22, 52, 53). HE4 is an acidic inhibitory protein that exacerbates ovarian cancer by facilitating early infiltration and metastasis, thereby accelerating the disease’s progression. Elevated expression levels of HE4 may signal poor clinical regression in patients with ovarian cancer, reflecting the disease’s progression and prognosis to a certain extent (19, 23, 48, 54).

In this study, NACT demonstrated effectiveness when the HE4 level exceeded 422.95 pmol/L. NLR exhibited a remarkable sensitivity of 93.3% in predicting the effectiveness of NACT in individuals facing advanced ovarian cancer, while CA199 displayed a high specificity of 92.3% in the same regard. In individuals facing advanced ovarian cancer, HE4 was the best predictor of NACT efficacy, boasting a sensitivity of 75.3% and a specificity of 84.6%, whereas CEA and CA153 were poor predictors of NACT efficacy in these patients, displaying low sensitivity and specificity. The combined HE4 and CA125 test exhibited an area under the curve of 0.825 for predicting the ineffectiveness of NACT in individuals facing advanced ovarian cancer, demonstrating a sensitivity of 84.6% and a specificity of 74.2%. Among the indicators of NLR, CA125, CA199, CEA, CA153, and HE4 in advanced ovarian cancer, the single tests had some degree of defects, thus affecting their value, whereas the combined tests made up for each other’s defects, thereby improving the prediction of the effectiveness of NACT in individuals facing advanced ovarian cancer and accurately selecting the patients suitable for NACT, avoiding unnecessary excessive NACT.

This study does have some limitations. First, the investigation was a prospective clinical study with participants recruited from the same hospital, and no multicenter study was conducted, thereby resulting in geographical differences. Second, in this study, the distribution of participants included 54 patients at stage IIIC, 36 at stage IVB, and 12 at stage IVA, while stage IIIA and stage IIIB had no representation, and therefore, the results of the study may be biased. Third, the sample size was insufficient. Collaboration with other centers is required to reduce the incidence of error bias. Fourth, the use of cisplatin instead of carboplatin in the chemotherapy regimen may have increased nephrotoxicity, potentially affecting efficacy. Fifth, the relationship between types of pathology and chemotherapy efficacy was not considered, and mixed histopathology types may have biased the results. Certain types of pathology do not respond to NACT, and analysis of high-grade serous adenocarcinoma alone may be more clinically relevant. Sixth, the study was limited to a single chemotherapy regimen. The potential for combining polymerase (PARP) inhibitors with chemotherapy, antiangiogenic therapy, immune checkpoint inhibitors, and other DNA damage response modifying drugs for NACT deserves further exploration (6). NLR, CA125, CA199, and HE4 dynamic testing can provide valuable insights into forecasting the effectiveness of NACT for individuals facing advanced ovarian cancer, and in our future clinical works, we should continue to improve our surgical skills and apply a variety of new technologies (55, 56), so that more patients can achieve a true R0 resection by receiving individualized and precise treatment plans, thereby improving their quality of life and maximizing therapeutic outcomes.

Ovarian cancer, often diagnosed at advanced stages due to its insidious early symptoms, remains the leading cause of death from gynecological malignancies. The predictive accuracy of NACT’s efficacy in advanced ovarian cancer is significantly enhanced by NLR’s high sensitivity and CA199’s high specificity. Furthermore, the synergistic analysis of CA125 and HE4 demonstrates an improved predictive effect, which can accurately select patients suitable for NACT, determine the appropriate timing of the IDS surgery, achieve a satisfactory effect of tumor reduction, avoid unnecessary excessive NACT, reduce the occurrence of perioperative complications, reduce the postoperative chemotherapy resistance and toxic side effects, and carry out the individualized precision treatment to achieve the best therapeutic effect. To further improve patient outcomes, ongoing enhancement of surgical techniques and integration of innovative technologies are essential. These advancements enable more patients to achieve a true R0 resection, providing a solid foundation for subsequent chemotherapy, targeted therapies, and immunotherapy, ultimately elevating survival rates and quality of life for individuals facing advanced ovarian cancer.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethical Committee of Ganzhou Cancer Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

JH: Writing – review & editing, Writing – original draft, Project administration, Conceptualization. DD: Writing – original draft, Investigation, Data curation. HC: Writing – original draft, Investigation. DL: Writing – original draft, Investigation. QW: Writing – original draft, Investigation. CL: Writing – original draft, Data curation. YL: Writing – original draft, Investigation, Data curation. YY: Writing – original draft, Conceptualization.