Clinical Outcomes of Sanshen Fuzheng Decoction in Preventing Chemotherapy-induced Neutropenia in Ovarian Cancer

Summary

Sanshen Fuzheng Decoction, as an adjuvant to paclitaxel-carboplatin chemotherapy for ovarian cancer, reduces chemotherapy-induced neutropenia and recombinant human granulocyte colony-stimulating factor dosage, improves immune indices, and demonstrates safety without hepatic or renal toxicity. These preliminary findings warrant confirmation in larger multicenter studies.

Abstract

This study aimed to explore the clinical value of Sanshen Fuzheng Decoction in the secondary prevention of chemotherapy-induced neutropenia in patients with malignant ovarian tumors. Sixty patients with primary ovarian cancer who received postoperative chemotherapy between January 2022 and January 2023 were enrolled. Using a random number table, they were equally divided into a treatment group and a control group (n = 30 each). The control group received standard paclitaxel plus carboplatin (TP) chemotherapy (paclitaxel + carboplatin), while the treatment group received TP combined with Sanshen Fuzheng Decoction. Baseline indicators were not significantly different between groups before chemotherapy (P > 0.05). On days 3, 7, 10, 14, and 20 post chemotherapy, both groups showed increased hemoglobin (Hb), red blood cell (RBC), neutrophil (NE) counts, interleukin-2 (IL-2), and interleukin-6 (IL-6), and decreased white blood cell (WBC), lymphocyte (LYM), and platelet (PLT) counts. Compared to the control group, the treatment group showed significantly greater increases in Hb, RBC, NE, interleukin-2 (IL-2), and interleukin-6 (IL-6), and the decrease in LYM was more obvious, while the decrease in WBC and PLT was smaller (all P < 0.05). The total dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and the duration of leukopenia were significantly lower in the treatment group (P < 0.05). Additionally, more improvement in Traditional Chinese Medicine (TCM) symptom scores (fatigue, weakness, sweating, dizziness, pale complexion) was observed in the treatment group. The incidence of chemotherapy-related toxic side effects was significantly lower in the treatment group (P < 0.05). No significant differences were observed in liver/kidney function, febrile neutropenia, or absolute neutrophil count (ANC) reduction (P > 0.05). San shen Fu zheng Decoction, as an adjunct to chemotherapy in ovarian cancer, showed potential benefits in improving hematological recovery, reducing rhG-CSF use, and alleviating treatment-related symptoms.

Introduction

Ovarian cancer is the third most common gynecologic malignancy worldwide. It is often diagnosed at an advanced stage, with a high recurrence and mortality rate, and a low survival rate, posing a serious health threat to women¹. Globally, the incidence of ovarian cancer is approximately 5.0 per 100,000 in developing countries and 9.1 per 100,000 in developed countries². The primary treatment for ovarian cancer is surgery, supplemented by chemotherapy, with the goal of reducing residual tumor cells and improving survival outcomes³. Despite advancements in surgical techniques and chemotherapy regimens, long-term prognosis remains suboptimal. One of the major challenges is ensuring adequate dose-dense chemotherapy postoperatively to improve survival and prognosis, which is often hindered by chemotherapy-related adverse effects.

Myelosuppression, particularly the reduction in hemoglobin, neutrophils, and white blood cells, is a common adverse effect of chemotherapy. Among these, leukopenia typically occurs earliest and is one of the most severe hematologic toxicities. It can lead to neutropenic fever, impair cellular metabolism, damage the bone marrow microenvironment, and result in persistent leukopenia^4,5. Currently, Granulocyte Colony-Stimulating Factor (G-CSF) is an effective treatment for chemotherapy-induced neutropenia. However, its use is associated with adverse reactions such as bone pain and, in severe cases, splenic rupture, hemoptysis, and alveolar hemorrhage. Therefore, finding effective interventions to alleviate myelosuppression and reduce the dosage of G-CSF is critical to ensuring the continuity of dose-dense chemotherapy⁶.

From the perspective of traditional Chinese medicine (TCM), both radiotherapy and chemotherapy are considered forms of "heat toxin" that lead to "deficiency and damage" of the internal organs. Treatment principles include nourishing the blood and replenishing qi, strengthening the spleen and kidney, enriching yin and clearing heat, and warming yang to tonify the kidney, in order to mitigate chemotherapy-induced myelosuppressive adverse effects⁷. Traditional herbal medicines have been shown to enhance human immune function, particularly in cases where immune impairment is induced by disease in patients⁸. Composed of a variety of bioactive compounds, herbal medicines can modulate the tumor microenvironment; when used in combination with anticancer therapies, they can yield more pronounced clinical benefits⁹. Accordingly, this study aims to evaluate the clinical application of Sanshen Fuzheng Decoction in the secondary prevention of chemotherapy-induced neutropenia in patients undergoing treatment for malignant ovarian tumors.

Protocol

Ethics approval for this study was obtained from the Ethics Committee of Jinhua Maternal and Child Health Hospital at Jinhua Maternal and Child Health Center (approval number: 2022KY014). All participants were provided with information regarding the study and gave their written informed consent prior to participation. This study was conducted in compliance with the Declaration of Helsinki and all applicable ethical guidelines.

Study subjects

A total of 60 patients with primary ovarian cancer who underwent postoperative chemotherapy at our hospital between January 2022 and January 2023 were enrolled in this study. Patients were randomly assigned to the treatment group or control group (30 cases each) using a random number table method, and the specific grouping workflow is presented in Figure 1.

Inclusion criteria included patients aged 18-75 years; a diagnosis of ovarian cancer confirmed by surgical pathology in accordance with the 2021 Ovarian Cancer Diagnosis and Treatment Guidelines; newly diagnosed patients who had received radical surgery followed by postoperative chemotherapy primarily based on the paclitaxel-carboplatin (TP) regimen; a Karnofsky Performance Status (KPS) score greater than 60; prior leukopenia (WBC < 4.0 × 10⁹/L) and Absolute Neutrophil Count (ANC) < 2.0 × 10⁹/L during chemotherapy (with G-CSF support) and normal hepatic and renal function indices; and provision of informed consent by patients and families.

Exclusion criteria included concurrent other malignancies or recurrent ovarian cancer; fasting status or gastrointestinal bleeding; active hepatitis B infection or concomitant cardiac, hepatic, or renal dysfunction; history of drug abuse or poor treatment compliance; other conditions deemed unsuitable by investigators; and infectious hematologic diseases. Case exclusion criteria were withdrawal of informed consent; incomplete data affecting safety or efficacy evaluation; poor compliance or failure to adhere to treatment protocol; occurrence of severe adverse reactions; disease progression requiring treatment modification; or any other circumstance deemed unsuitable for continuation by investigators.

Treatment protocol

The control group received TP combination chemotherapy consisting of paclitaxel 175 mg/m² administered intravenously over 3 h on day 1, followed by carboplatin dosed to an area under the curve (AUC) of 5-6 intravenously on day 1. The regimen was repeated every 3 weeks. During chemotherapy, patients who developed neutropenia were treated with subcutaneous rhG-CSF (5 µg/kg daily) until ANC ≥ 1.0 × 10⁹/L. The treatment group received the same TP chemotherapy regimen as the control group. In addition to G-CSF during neutropenic periods, patients were administered Sanshen Fuzheng decoction.

All herbal materials were obtained from a GMP-certified manufacturer and verified by the hospital pharmacy before use. The prescription consisted of Astragalus membranaceus (Huangqi) 30 g, Salvia miltiorrhiza (Danshen) 15 g, Codonopsis pilosula (Dangshen) 30 g, Scrophularia ningpoensis (Xuanshen) 10 g, stir-fried Paeonia lactiflora (Baishao) 15 g, Angelica sinensis (Danggui) 15 g, Poria cocos (Fuling) 15 g, Saposhnikovia divaricata (Fangfeng) 10 g, honey-fried Glycyrrhiza uralensis (Zhigancao) 3 g, stir-fried Atractylodes macrocephala (Baizhu) 15 g, Ziziphus jujuba (Dazao) 15 g, and wheat grain from the Huai region (Huai Xiaomai) 30 g, totaling approximately 203 g of crude herbs.

Herbs were soaked in cold water for 30 min and decocted twice. The combined filtrate was cooled and adjusted to approximately 200 mL. One dose was taken daily in two 100 mL portions (morning and afternoon, ~6 h apart), 30 min after meals. Each course lasted 21 days. The decoction was freshly prepared and consumed the same day; if not taken immediately, it was stored in a refrigerator. The final preparation was a clear brownish liquid with a mild aroma and slightly bitter taste, without abnormal odor or visible precipitate. All decoctions were prepared centrally in the hospital pharmacy and dispensed uniformly.

Indicator measurements

Peripheral venous blood (6 mL) was collected from the antecubital vein after overnight fasting on day 1 before chemotherapy and on days 3, 7, 10, 14, and 20 after cessation of chemotherapy. Samples were placed into heparinized and EDTA anticoagulant tubes. After centrifugation, serum and plasma were separated and stored at -20 °C until analysis. Routine blood examinations were performed using an automated hematology analyzer calibrated daily according to the manufacturer's instructions.

Plasma IL-2 and IL-6 levels were measured using ELISA kits in accordance with manufacturer protocols¹⁰. Plasma samples were equilibrated at 37 °C for 20 min, and optical density was measured at 430 nm. Concentrations were calculated using standard curves.

Traditional Chinese Medicine symptom scores included fatigue, physical exhaustion, dizziness and blurred vision, spontaneous sweating, and facial and lip complexion. Each symptom was graded as severe (9 points), moderate (6 points), mild (3 points), or none (0 points).

Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0¹¹. Patients who experienced severe adverse reactions withdrew immediately from the study and received appropriate treatment. Safety follow-up was performed one month after therapy, and patients were followed up again at 1 year to monitor survival and recurrence.

Statistical analysis

Quantitative data were presented as mean ± standard deviation, with group comparisons conducted using independent sample t-tests. Ranked data were compared using rank-sum tests. Count data were expressed as percentages and analyzed with the Chi-square test. P-values < 0.05 were considered statistically significant.

Results

Comparison of baseline characteristics between the control and treatment groups

Table 1 presents the baseline characteristics of patients in both groups. There were no significant differences between the two groups across all baseline variables (all p > 0.05). This indicates that the two groups were comparable at the start of the study, eliminating the influence of potential confounding facto...

Discussion

Chemotherapy remains a cornerstone in the management of ovarian cancer, primarily through the cytotoxic effects of antineoplastic agents that inhibit the synthesis of functional proteins and suppress tumor cell proliferation, ultimately inducing apoptosis in malignant cells. However, due to the intrinsic toxicity of these agents, chemotherapy-induced leukopenia (CIN) has emerged as one of the most common dose-limiting toxicities. This condition directly compromises immune function, thereby increasing the susceptibility t...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Carboplatin for Injection (AUC 5–6)	Qilu Pharmaceutical Co., Ltd., Jinan, China	National Drug Approval No. H20093458	Administered intravenously on day 1, every 3 weeks
ELISA Kit for IL-2	Invitrogen, Thermo Fisher Scientific, USA	Cat. No. 88-7346-88	Quantitative detection of plasma IL-2 levels
ELISA Kit for IL-6	Invitrogen, Thermo Fisher Scientific, USA	Cat. No. EH2IL6	Quantitative detection of plasma IL-6 levels
Hematology Analyzer	Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China	BC-7500 CRP	Fully automated hematology analyzer; daily calibration; used for WBC, RBC, Hb, PLT, LYM, NE; RRID: SCR_021849
Microplate Reader	Shenzhen Huisong Technology Co., Ltd., China	Model MB-530	Optical density measured at 430 nm
Paclitaxel for Injection (175 mg/m²)	Bristol-Myers Squibb Co., Ltd., Shanghai, China	National Drug Approval No. H20030009	Used in TP chemotherapy regimen; intravenous infusion over 3 h, day 1, every 3 weeks
Recombinant Human G-CSF (rhG-CSF)	Kyowa Kirin China Pharmaceutical Co., Ltd., Shanghai, China	National Drug Approval No. J20180062	Subcutaneous injection, 5 μg/kg/day during neutropenia until ANC ≥ 1.0×109/L
Sanshen Fuzheng Decoction	Prepared by Hospital Pharmacy, Jinhua Maternal and Child Health Hospital	—	Prescription verified by hospital pharmacy; herbs obtained from GMP-certified manufacturer (Jinhua Intech Pharmaceutical Co., Ltd., Jinhua, China); decoction freshly prepared daily
— Angelica sinensis (Danggui)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220511	15 g; blood tonic
— Astragalus membranaceus (Huangqi)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220508	30 g; tonic herb for Qi reinforcement
— Codonopsis pilosula (Dangshen)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220510	30 g; supports spleen and lung Qi
— Honey-fried Glycyrrhiza uralensis (Zhigancao)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220520	3 g; harmonizing herb
— Jujube (Dazao)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220519	15 g; Qi tonic and harmonizing herb
— Poria cocos (Fuling)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220518	15 g; diuretic and spleen tonic
— Salvia miltiorrhiza (Danshen)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220512	15 g; promotes blood circulation
— Saposhnikovia divaricata (Fangfeng)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220517	10 g; dispels wind and relieves exterior
— Scrophularia ningpoensis (Xuanshen)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220509	10 g; nourishes Yin and clears heat
— Stir-fried Atractylodes macrocephala (Baizhu)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220513	15 g; strengthens spleen Qi
— Stir-fried Paeonia lactiflora (Baishao)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220515	15 g; nourishes blood and harmonizes Ying
— Wheat grain from Huai region (Huai Xiaomai)	Jinhua Intech Pharmaceutical Co., Ltd., China	Batch No. 20220516	30 g; calms the spirit
Vacuum Blood Collection Tubes (Heparin, EDTA)	Becton Dickinson (BD Vacutainer), Franklin Lakes, NJ, USA	—	Used for plasma and serum sample collection