Effect of combination of Yiqi Jianpi Yangxue Decoction and chemotherapy on quality of life and adverse reactions of patients with recurrent ovarian cancer

Purpose: To investigate the effect of combined treatment with Yiqi Jianpi Yangxue Decoction and chemotherapy (carboplatin + paclitaxel) on quality of life (QOL) and adverse reactions of patients with recurrent ovarian cancer (ROC). Methods: One hundred and fourteen (114) ROC patients in The Second Children & Women’s Healthcare of Jinan City were split into chemotherapy group (n = 60) and combination group (n = 54), based on whether or not they were treated with Yiqi Jianpi Yangxue Decoction. Differences in clinical efficacy, adverse reactions, levels of tumor marker, levels of immune indexes, and scores on Karnofsky Performance Status (KPS) between the two groups were evaluated. Results: Treatment effectiveness was higher in the combination group than in the chemotherapy group (p < 0.05). Compared with the chemotherapy group, post-treatment levels of HE4 and CA125 in the combination group were lower, while the levels of CD3+, CD4+ and CD8+, and population of NK cells were higher (p < 0.05). After treatment, the KPS score in the combination group was higher than the corresponding score in the chemotherapy group (p < 0.05). Conclusion: Combination of Yiqi Jianpi Yangxue Decoction and chemotherapy (carboplatin + paclitaxel) produces significant enhancement of clinical efficacy in the treatment of ROC. The combination treatment is highly safe, and improves the health status and QOL of patients. Therefore, the combination treatment appears to be suitable for the management of ovarian cancer.


INTRODUCTION
Ovarian cancer (OC), a malignant tumor in the female reproductive organs, may occur at any age, but it is seen mostly in women over 50 years old [1][2][3]. Clinical medical statistics indicate that the incidence of OC ranks third, while its mortality ranks first among gynecological malignancies in China [4]. The early symptoms of OC are not easily noticeable, and the symptoms of advanced lesions are not typical. The major therapeutic strategies often used in clinical practice for OC are surgery, chemotherapy and targeted-drug therapy. However, these treatment methods often result in high levels of posttreatment recurrence. Moreover, recurrence during treatment is an important cause of death in OC patients [5][6][7][8].
Yiqi Jianpi Yangxue Decoction is a newly developed type of traditional Chinese medicine (TCM) which exerts an adjuvant effect on middle and advanced forms of ovarian cancer [9]. Nowadays, limited reports have been observed on the treatment of recurrent ovarian cancer (ROC) using combination of Yiqi Jianpi Yangxue Decoction and chemotherapy. Therefore, this paper was to explore the clinical effect of combined use of Yiqi Jianpi Yangxue Decoction and chemotherapy in the treatment of ROC. Moreover, the effects of this therapy on quality of life (QOL) and adverse reactions were determined, with a view to providing a new research direction for improved clinical treatment of ROC.

Patients
One hundred and fourteen (114) ROC patients admitted in The Second Children & Women's Healthcare of Jinan City (January 2019-January 2021) were chosen, and split into chemotherapy group (n = 60) and combination group (n = 54), based on whether or not they were given Yiqi Jianpi Yangxue Decoction. The study was approved by the institutional ethics committee, and conducted in accordance with the Declaration of Helsinki as revised in 2013 [10].

Inclusion criteria
Patients in the following categories were included in the study: those who were confirmed to have ovarian cancer after postoperative pathological examination, patients who were stable after undergoing six cycles of chemotherapy, those with increased serum levels of CA125, patients with lesions that were measurable with computed tomography (CT), ultrasound and magnetic resonance imaging (MRI) after chemotherapy, and patients with Eastern Cooperative Oncology Group (ECOG) score less than 2 points.

Exclusion criteria
Patients whose conditions were complicated with other malignant tumors or organic diseases, patients with expected survival times less than three months, and those who had communication or cognitive impairment, were excluded from the study. Moreover, patients who had incomplete clinical data were excluded.
This study obtained the approval of the Ethics Committee of The Second Children & Women's Healthcare of Jinan City (approval no. 20181119). The purpose and procedures involved in the study were explained to the patients and their families, and they signed informed consent forms to indicate their willingness to participate in the study.

Treatments
Patients in the chemotherapy group were given paclitaxel (Yunnan Handle Bio-Tech Co. Ltd, specification: 30 mg; SFDA approval no. H10960322) at a dose range of 135-175 mg/m 2 solubilized in 500 mL of 0.9 % NaCl and administered via intravenous drip for no less than 3 h. In addition, the patients were given carboplatin (Qilu Pharmaceutical Co. Ltd.; SFDA approval no. H20020181; specification: 50 mg) at a dose of 350 mg/m 2 or AUC of 5.0 -7.5 mg/mL/min, dissolved in 250 mL of 5 % glucose solution and administered via intravenous drip for 1 h, once every 3 weeks. The patients received 6 cycles of chemotherapy. During chemotherapy, the patients' symptoms were closely monitored. Before chemotherapy, the patients received 20 mg of dexamethasone (specification: 5 mg; manufacturer: Shanghai Xiandai Hasen Pharmaceutical Co. Ltd; SFDA approval no. H41021924) via intravenous injection; 30 mg of cimetidine (specification: 0.2 g; manufacturer: Guangzhou Baiyunshan Mingxing Pharmaceutical Co. Ltd.; SFDA approval No: H44024199) via intramuscular injection, and 40 mg of diphenhydramine (specification: 20 mg; manufacturer: Beijing Yookon Pharmaceutical Co. Ltd; SFDA approval no. H11020523) via intramuscular injection, in order to prevent adverse reactions [11]. Patients in the combination group were given Yiqi Jianpi Yangxue Decoction obtained from 30 g of Astragalus membranaceus, 20 g of poria cocos, 15 g of oldenlandia, 10 g of curcuma zedoary, 10 g of dangshen, 10 g of kuh-seng, 10 g of ginger, 10 g of bighead atractylodes rhizome, 10 g of Paeonia lactiflora, 8 g of rhizoma sparganii and 8 g of monkshood. This resulted in 400 mL of Yiqi Jianpi Yangxue Decoction which was administered every morning and evening. Chemotherapy treatment was same as that in the chemotherapy group.

Evaluation of treatment effectiveness
Treatment effectiveness was categorized into three, based on CA125 level: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Patients were said to have CR if CA125 level was less than 35 U/mL, while PR was used for patients whose CA125 levels decreased by more than 50 % for more than 4 weeks. Stable disease (SD) was used for patients whose CA125 levels decreased by 25 -50 % for more than 4 weeks, while PD was used for patients whose CA125 levels decreased by less than 25 %, or whose CA125 levels were increased. Total treatment effectiveness (TTE) was calculated as shown in Eq. 1:

Adverse reactions
Adverse reactions were categorized based on the classification of adverse reactions in American Adverse Reaction Evaluation System for Generic Chemotherapy Drugs (Fourth Edition) [12]. Mild adverse reactions without symptoms or treatment, in addition to white blood cell (WBC) count of 3.0-3.9 ×10 9 /L, hemoglobin (Hb) level of 95-100 g/L, and platelet (PLT) count of 75-99 ×10 9/ L, were classified as level 1. Moderate adverse reactions, with patients having WBC count of 2.0-2.9 ×10 9 /L, Hb level of 80-94 g/L, and PLT count of 50-74 ×10 9 /L (without effect on life) were classified as level 2. Severe adverse reactions requiring active intervention in patients with WBC count of 1.0-1.9 ×10 9 /L, Hb level of 65-79 g/L, and PLT count of 25-49 ×10 9 /L, were categorized as level 3. Adverse reactions which caused organ failure and disabled or threatened life, with WBC count of < 1.0×10 9 /L, Hb < 65 g/L, and PLT count < 25×10 9/ L, were classified as level 4. Adverse reactions that led to death were classified as level 5.

Serum tumor markers
Fasting peripheral venous blood samples were obtained from patients in the morning, before and after treatment, and serum samples were obtained after centrifugation. Chemiluminescence immunoassay was used to determine the contents of serum human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125). In these assays, HE4 > 150 pmol/L or CA125 > 35 U / mL indicated that the patients were positive.

Immune function
The T cell markers i.e., T cell subsets such as CD3 + , CD4 + , CD8 + and NK cells, and their proportions, were determined directly or indirectly using immunofluorescence.

Karnofsky Performance Status (KPS) scores
The KPS score of patients were determined before and after treatment. The maximum score was 100 points. A higher score indicated that patients had better health status and could tolerate side effects caused by the treatment. Scores above 50-70 points were classified as non-dependency, suggesting that the patients could take care of themselves. Scores of 50-70 points indicated semi-dependency which implied that the patients could basically take care of themselves. Scores below 50 points were indicative of dependency, meaning that the patients needed much help from others. Patients with scores above 80 points had good postoperative status and long survival time.

Statistical analysis
In this study, SPSS20.0 was used as data processing software, while GraphPad Prism 7 (GraphPad Software, San Diego, USA) was used for graphics. Count data and measurement data obtained in this study were subjected to statistical analyses using ꭓ 2 , t-test and normality test. Differences were considered statistically significant at p < 0.05.

Comparison of general data on patients
No marked differences in general patient profiles were observed between the two groups (p > 0.05; Table 1).

Clinical efficacy
There was markedly higher total treatment effectiveness in the combination group than in the chemotherapy group (p < 0.05, Table 2). Table 3 shows no statistic differences in incidence of adverse reactions between the two groups (p > 0.05).

Serum levels of tumor markers
In the chemotherapy group, the levels of HE4 before and after treatment were 274.35 ± 51.32 and 59.45 ± 9.06, respectively, while the corresponding levels in the combination group were 275.34 ± 50.82 and 25.36 ± 8.72, respectively.

KPS scores
In the chemotherapy group, the KPS scores before and after treatment were 63.18 ± 13.48 and 71.55 ± 12.67, respectively, while the corresponding scores in the combination group were 62.59 ± 12.35 and 78.81 ± 13.56, respectively. After treatment, KPS scores in both groups were increased, with higher KPS score in the combination group. See Figure 3. Table 4 shows notably higher levels of CD3 + , CD4 + , CD8 + and NK cells in the combination group than in the chemotherapy group (p < 0.05).    Values are presented as mean ± SD. *P < 0.001, KPS scores in the chemotherapy group and the combination group after treatment vs the corresponding scores before treatment; **p < 0.001, KPS score in the chemotherapy group after treatment vs KPS score in the combination group after treatment

DISCUSSION
Clinical research on recurrent ovarian cancer (ROC) has been gradually deepened in recent times. At present, the prognosis of ROC has been greatly improved, although many patients still suffer from varying degrees of recurrence within 1-2 years after treatment [13][14][15][16]. Medical research data show that secondary gene mutation is inevitable in ROC treatment: new gene mutations are the root causes of enhanced invasion and drug resistance of ROC. Indeed, patients who relapse within a short period of time have a high probability of carrying drug-resistant genes, leading to unsatisfactory inhibitory effect of chemotherapy on cancer. In recent years, great achievements have been made in clinical practice using TCM. Modern TCM has put forward the theories of blood stasis and toxins in summarizing the pathological features of various diseases. In a study by Wu et al [17], the etiology of ovarian diseases was attributed to blood stasis in the uterus and kidney yang deficiency, leading to entry of toxins and cold wind into the body. In addition, blood stasis in the body and deficiency of vital qi result in cold coagulation and qi stagnation, all of which accumulate and produce a mass in the uterus. It has been revealed that ROC patients often show qi deficiency and blood stasis, while Wenyang Yiqi Jianpi Decoction dissolves blood stasis, detoxifies the blood and supports body resistance, with significant benefits for treatment of ROC [18].
In the prescription of Yiqi Jianpi Yangxue Decoction, Astragalus membranaceus plays the role of promoting yang diuresis, and tonifying middle-jiao and qi; while Curcuma zedoary removes blood stasis, dissolves lumps and relieves pain by promoting qi circulation, thereby greatly enhancing blood stasis removal and alleviation of pain when it is combined with rhizoma sparganii. In addition, bighead atractylodes rhizome clears dampness, promotes diuresis, invigorates the spleen and supplements qi. Dangshen strengthens the spleen, nourishes the lung, and tonifies middle-Jiao and qi. Poria cocos strengthens the spleen, calms the heart, promotes diuresis and clears dampness. Kuhseng clears heat and dry dampness. Paeonia lactiflora nourishes the blood and regulates menstruation; it calms the liver and relieves pain. Oldenlandia clears heat and removes toxicity, while monkshood stops pain by eliminating cold; it tonifies fire and helps yang. Ginger stops cough by warming the lungs; it checks vomiting by warming the middle; it resolves the exterior and dissipates cold. The combined use of these drugs results in removal of blood stasis, detoxification, supplementation of qi and promotion of yang.
The present study has demonstrated that total treatment effectiveness was markedly higher in the combination group., and the HE4 and CA125 levels after treatment in the combination group were lower compared with the chemotherapy group. Serum human epididymis secretory protein 4 (HE4) protects the immune function, while CA125 is a tumor marker used for diagnosing ovarian cancer with high sensitivity, and it is highly expressed in the epithelial tissue of ovarian cancer. Thus, simultaneous assays of levels of HE4 and CA125 are beneficial in the diagnosis of ovarian cancer.
The levels of CD3 + , CD4 + , CD8 + and NK cells in the combination group were higher, indicating enhanced the immune function of patients caused by combined therapy. After treatment, the KPS score in the combination group was higher. In TCM, it is believed that Astragalus membranaceus exerts anticancer effect by inhibiting tumor cell proliferation, promoting apoptosis and inhibiting angiogenesis. Astragalus membranaceus contains a large number of saponins, flavones and polysaccharides which can restore red blood cells, white blood cells and megakaryocytes in bone marrow, thereby reducing the inhibitory effect of chemotherapy on bone marrow. In addition, Kuh-seng exerts strong anti-tumor effect: it inhibits angiogenesis and prevents proliferation. Bighead atractylodes rhizome exerts anti-inflammatory effects, increases the level of white blood cells, improves the synthesis of small intestinal protein and regulates intestinal activity. Dangshen enhances immune function, protects the gastric mucosa of patients, and reduces gastrointestinal reactions caused by chemotherapy.

Limitations of the study
This study was a single-center study with small number of patients. In order to further confirm the effect of Yiqi Jianpi Yangxue Decoction on ROC patients, multi-center studies with more patients are needed.

CONCLUSION
This study has demonstrated that the combination of Yiqi Jianpi Yangxue Decoction and chemotherapy significantly enhanced clinical efficacy in the treatment of ROC. The combined treatment has high safety, and improves the health status and life quality of patients.