Traditional Chinese medicine composition for treating recurrent ovarian cancer

Abstract

The invention belongs to the field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for treating platinum refractory or platinum drug-resistant recurrent ovarian cancer and application thereof. On the basis of an ancient prescription, a traditional Chinese medicine and western medicine combined treatment scheme is created by combining the clinical practical characteristics of the ovarian cancer phlegm and blood stasis toxin. The scheme is mainly directed at middle and advanced ovarian cancer second-line treatment patients, and clinical practice and early-stage single-arm tests preliminarily prove that the combined chemotherapy of the modified Huanhuang decoction is superior to pure chemotherapy in the aspect of reducing the tumor marker level, and has unique advantages in the aspects of improving the traditional Chinese medicine syndromes, KPS scores and life quality of the patients; the degree of inhibition of chemotherapy on hemoglobin and leukocytes can be reduced, the maintenance time of middle and advanced ovarian cancer patients is prolonged, and the scheme is low in toxicity and efficient.

Description

Technical Field

[0001] The present invention belongs to the field of traditional Chinese medicine, and specifically relates to a traditional Chinese medicine composition for treating platinum-refractory or platinum-resistant recurrent ovarian cancer and an application thereof. Background Art

[0002] The number of new cases of ovarian cancer each year ranks third among the three major gynecological malignancies, but the mortality rate ranks first. Ovarian cancer is one of the leading causes of death in women of all ages. According to the American Cancer Society, in 2022, there will be 19,880 new cases of ovarian cancer and 12,810 women will die from ovarian cancer, including 2,488 women aged 40 to 59 and 7,482 women aged 60 to 79 (SIEGEL RL, MILLER KD, FUCHS HE, et al. Cancer statistics, 2022[J]. CA Cancer J Clin, 2022, 72(1):7-3). In 2004, Kurman et al. proposed a dualistic classification of ovarian cancer based on the pathogenesis and progression of ovarian cancer, dividing ovarian cancer into type I and type II. Type I ovarian cancer includes: low-grade serous carcinoma, mucinous cystadenocarcinoma, clear cell carcinoma, low-grade endometrioid adenocarcinoma, and malignant Brenner tumor, and type II ovarian cancer includes high-grade serous carcinoma, high-grade endometrioid carcinoma, and carcinosarcoma. The two types of ovarian cancer differ in disease progression, sensitivity to chemotherapy, and prognosis. Type II ovarian cancer is sensitive to chemotherapy but has a poor prognosis, while type I ovarian cancer is the opposite (The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory [M]. 2010.). Due to the special anatomical location of the ovary, which is located deep in the pelvic cavity, the disease is hidden. Most patients seek medical treatment due to abdominal pain and bloating, and 70% of ovarian cancer patients are already in the late stage when diagnosed. Currently, the standard first-line treatment for ovarian cancer is cytoreductive surgery (CRS) combined with platinum-based chemotherapy, mainly paclitaxel and carboplatin. Despite this, about 70% of patients still experience cancer recurrence within 2-3 years, and 70% of patients survive no more than 5 years (Chang Xin, Han Lu. Research progress in maintenance treatment drugs for platinum-sensitive recurrent ovarian cancer [J]. International Journal of Obstetrics and Gynecology, 2022, 49(04): 382-7.).

[0003] The time from the end of the last first-line platinum-containing treatment for ovarian cancer patients to recurrence or disease progression is called the progression-free interval (PFI). PFI affects the response rate of patients to platinum retreatment after recurrence. It is also one of the indicators for evaluating the prognosis of patients and one of the most important factors affecting the prognosis of patients (DOCKERYLE, RUBENSTEINAR, DING K, et al. Extending the platinum-free interval: The impact of omitting 2ndline platinum chemotherapy in intermediate platinum-sensitive ovarian cancer[J]. Gynecol Oncol, 2019, 155(2): 201-6.). Based on the patient's progression-free interval, disease progression during treatment or within PFI ≤ 4 weeks was defined as platinum-refractory relapse, patients with relapse within 4 weeks ≤ PFI ≤ 6 months were considered platinum-resistant relapse, ovarian cancer patients with relapse within 6 months ≤ PFI ≤ 12 months were identified as platinum-partially sensitive relapse, and ovarian cancer patients with relapse within PFI > 12 months were identified as platinum-sensitive relapse (BEREK JS, RENZ M, KEHOE S, et al. Cancer of the ovary, fallopian tube, and peritoneum: 2021 update [J]. Int J Gynaecol Obstet, 2021, 155 Suppl 1 (Suppl 1): 61-85.).Patients with platinum-sensitive recurrence should first be evaluated for suitability for re-reduction surgery. Patients who are not suitable for surgery or who have undergone re-reduction surgery still need to receive platinum-containing combination chemotherapy. These patients generally respond well to platinum-containing chemotherapy, with a response rate of 30% to 90% and a median survival of 2 years (Davis A, Tinker AV, Friedlander M. "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit?" [J]. Gynecol Oncol, 2014, 133(3): 624-631.). Patients with long-term PFI (>12 months) have the highest response rate to platinum retreatment and the best prognosis (Wilson MK, Pujade-Lauraine E, Aoki D, et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer Inter-Group: recurrent disease [J]. Ann Oncol, 2017, 28(4): 727-732.). Da Costa et al. pointed out that platinum-sensitive recurrence is associated with prolonged OS compared with platinum-resistant recurrence (da Costa AABA, Dos Santos ES, Cotrim DP, et al. Prognostic impact of platinum sensitivity in ovarian carcinoma patients with brain metastasis [J]. BMC Cancer, 2019, 19 (1): 1194.). Although patients with platinum-sensitive recurrence respond better to platinum-based, non-platinum-based chemotherapy and other treatments than platinum-resistant patients (Baert T, Ferrero A, Sehouli J, et al. The systemic treatment of recurrent ovarian cancer revisited [J]. Ann Oncol, 2021, 32 (6): 710-725.), most patients will relapse multiple times and receive multiple lines of treatment over time, with a gradually shortened progression-free survival, and eventually develop platinum-resistant disease, and very few patients can be cured.For patients with platinum-resistant recurrence, it is generally believed that their response rate to subsequent treatment is low, treatment options and efficacy are limited (St Laurent J, Liu JF. Treatment Approaches for Platinum-Resistant Ovarian Cancer[J]. J Clin Oncol, 2024, 42(2): 127-133.), and their progression-free survival is short, averaging only 9 to 12 months (Pejovic T, Fitch K, Mills G. Ovarian cancer recurrence: “is the definition of platinum resistance modified by PARP inhibitors and other intervening treatments?” [J]. Cancer Drug Resist, 2022, 5(2): 451-458.).

[0004] Treatment options for platinum-resistant ovarian cancer are very limited, and there is a lack of guidance on the order of medication for this type of patient. The NCCN guidelines recommend sequential single-agent non-platinum chemotherapy (including paclitaxel, topotecan, liposomal doxorubicin, gemcitabine, etc.) or combined with bevacizumab or bevacizumab monotherapy as the first choice. Other recommended options include secondary tumor cell reduction surgery, anti-angiogenic drugs, and poly-ADP Ribose Polymerase (PARP) inhibitors. Chemotherapy drugs not only cannot completely eliminate cancer cells, but also cause a large number of normal tissue cells to apoptosis, which can cause side effects in mild cases and damage the body in severe cases, delaying treatment. Ovarian cancer is not sensitive to radiotherapy, and its treatment has certain limitations. It has not yet become the main means. Biological therapy and immunotherapy are just beginning. Studies have found that although anti-angiogenic drugs and PARP inhibitors have achieved significant benefits in both first-line and second-line maintenance treatments, their objective response rate (ORR) is low, PFS and OS are short, adverse reactions are obvious and affect the quality of life (Richardson DL, Eskander RN, O'Malley DM. Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance: A Narrative Review [J]. JAMA Oncol, 2023, 9 (6): 851-859.).

[0005] Traditional Chinese medicine is an important part of traditional Chinese medicine. It plays a pivotal role in the treatment of ovarian cancer due to its unique syndrome differentiation and treatment, three-factor treatment and holistic concept. Traditional Chinese medicine can improve the patient's immune function, reduce the adverse reactions of radiotherapy and chemotherapy, and at the same time increase the sensitivity of tumor cells to chemotherapy, thereby improving the patient's prognosis and the quality of life after radiotherapy and chemotherapy. Ovarian cancer belongs to the category of diseases such as "stone masses", "lumps", and "intestinal mushrooms" recorded in traditional Chinese medicine. With the continuous development of traditional Chinese medicine, a large number of basic and clinical studies have proved that traditional Chinese medicine intervention in the recurrence stage of ovarian cancer has good results and is gradually gaining attention from scholars. Clinical studies have found that moxibustion combined with TP chemotherapy (acupoints: Mingmen, Pishu, Shenshu, Shenque, Guanyuan, Uterus, Zhongwan, Shuifen, Qihai, Zhongji) can significantly improve the treatment efficacy and autophagy gene levels of patients with ovarian cancer and peritoneal effusion (Chen Xiaoxiao, Yu Huixian. Effect of moxibustion on peritoneal effusion and quality of life in patients with extensive pelvic metastasis of ovarian cancer after surgery [J]. Chinese Journal of Maternal and Child Health, 2022, 37(2): 237-240.). Other studies have shown that Shenqi Fuzheng injection combined with TC chemotherapy for advanced ovarian cancer can effectively reduce tumor marker levels, inhibit tumor angiogenesis, regulate anti-tumor immune response, and reduce the occurrence of chemotherapy toxicity and side effects (Yang Li, Sun Mengxiong, Chen Lihua. Effect of Shenqi Fuzheng injection combined with TC chemotherapy on tumor markers, tumor angiogenesis factors and immune-related factors in advanced ovarian cancer [J]. Journal of PLA Medicine, 2020, 32(10): 79-83.). Fang Ying et al. found that the combination of Wenyang Yiqi Jianpi Decoction (Astragalus, Curcuma, Trillium, Codonopsis, Atractylodes, Poria, Ginger, White Peony, Sophora flavescens, Aconite, and Hedyotis diffusa) with TC chemotherapy can improve RR and DCR of patients and reduce CD3 + 、CD4 + 、CD8 + and NK cell levels, and improve the 1- and 3-year survival rates of patients (Fang Ying, Xing Wei, Wang Wuliang. Effects of Wenyang Yiqi Jianpi Decoction combined with chemotherapy on immune function and serum HE4 and CA125 levels in patients with advanced ovarian cancer [J]. Chinese Journal of Traditional Chinese Medicine, 2019, 34(6): 2819-2822.). Wu Yongjun et al. found that Qiyu Liujun Decoction (raw sun-dried ginseng, astragalus, angelica, donkey-hide gelatin, stir-fried white atractylodes, Poria, roasted licorice, tangerine peel, ginger pinellia, wolfberry, cornus officinalis, Jianqu) combined with chemotherapy on the basis of chemotherapy can effectively prevent and treat post-chemotherapy bone marrow suppression, among which the therapeutic effect on white blood cells and neutrophils is the most significant (Wu Yongjun. Clinical study of Qiyu Liujun Decoction in preventing and treating bone marrow suppression after TC chemotherapy for ovarian cancer [D]. Chengdu: Chengdu University of Traditional Chinese Medicine, 2019.). Summary of the invention

[0006] The present invention is a combination of traditional Chinese and western medicine treatment scheme created on the basis of ancient prescriptions and in combination with the actual clinical characteristics of ovarian cancer with phlegm, blood stasis and toxins. The scheme has been preliminarily confirmed in clinical practice and early single-arm trials that combined chemotherapy has a certain effect of reducing tumor markers and controlling tumor growth trends, and can prolong the maintenance time of patients with advanced ovarian cancer, with low toxicity and high efficiency. Based on this, the present invention was completed.

[0007] In a first aspect, the present invention provides a traditional Chinese medicine composition, wherein the traditional Chinese medicine composition is made of the following traditional Chinese medicines in parts by weight:

[0008] The main medicine is made of 1-12 parts of wine rhubarb and 0.1-1 part of vinegar kansui;

[0009] The auxiliary medicine is prepared from 20-45 parts of processed turtle shell and 0.1-1 part of realgar;

[0010] The adjuvant is prepared from 1-10 parts of Sichuan pepper and 1-12 parts of donkey hide gelatin beads;

[0011] The adjuvant is prepared from 1-10 parts of Indigo Naturalis and 1-12 parts of Cimicifuga Herba.

[0012] Preferably, the Chinese medicine composition is made of the following Chinese medicines in parts by weight:

[0013] The main medicine is made of 3-10 parts of wine rhubarb and 0.1-0.8 parts of vinegar kansui;

[0014] The auxiliary medicine is prepared from 20-40 parts of processed turtle shell and 0.1-0.8 parts of realgar;

[0015] The adjuvant is made of 1-6 parts of Sichuan pepper and 3-10 parts of donkey hide gelatin beads;

[0016] The adjuvant is prepared from 1-6 parts of Indigo Naturalis and 3-10 parts of Cimicifuga Herba.

[0017] More preferably, the Chinese medicine composition is made of the following Chinese medicines in parts by weight:

[0018] The main medicine is made of 5-8 parts of wine rhubarb and 0.1-0.4 parts of vinegar kansui;

[0019] The auxiliary medicine is prepared from 20-35 parts of processed turtle shell and 0.1-0.4 parts of realgar;

[0020] The adjuvant is made of 1-4 parts of Sichuan pepper and 5-8 parts of donkey hide gelatin beads;

[0021] The adjuvant is made of 1-4 parts of Indigo Naturalis and 5-8 parts of Cimicifuga Herba.

[0022] In some specific embodiments of the present invention, the Chinese medicine composition is made of the following Chinese medicines: 1-12 parts of wine rhubarb, 0.1-1 parts of vinegar kansui, 20-45 parts of processed turtle shell, 0.1-1 parts of realgar, 1-10 parts of Sichuan pepper, 1-12 parts of donkey-hide gelatin beads, 1-10 parts of indigo and 1-12 parts of cimicifuga.

[0023] Preferably, in some specific embodiments of the present invention, the Chinese medicine composition is made of the following Chinese medicines: 3-10 parts of wine rhubarb, 0.1-0.8 parts of vinegar kansui, 20-40 parts of processed turtle shell, 0.1-0.8 parts of realgar, 1-6 parts of Sichuan pepper, 3-10 parts of donkey-hide gelatin beads, 1-6 parts of indigo, and 3-10 parts of cimicifuga.

[0024] More preferably, in some specific embodiments of the present invention, the Chinese medicine composition is made of the following Chinese medicines: 5-8 parts of wine rhubarb, 0.1-0.4 parts of vinegar kansui, 20-35 parts of processed turtle shell, 0.1-0.4 parts of realgar, 1-4 parts of Sichuan pepper, 5-8 parts of donkey-hide gelatin beads, 1-4 parts of indigo and 5-8 parts of cimicifuga.

[0025] In a second aspect, the present invention provides a traditional Chinese medicine preparation, which is made of 1-12 parts of wine rhubarb, 0.1-1 parts of vinegar kansui, 20-45 parts of processed turtle shell, 0.1-1 parts of realgar, 1-10 parts of Sichuan pepper, 1-12 parts of donkey-hide gelatin beads, 1-10 parts of indigo and 1-12 parts of cimicifuga.

[0026] Furthermore, the traditional Chinese medicine preparation also contains pharmaceutically acceptable excipients required for the corresponding preparation.

[0027] Furthermore, the excipient is a pharmaceutical excipient that enhances the efficacy, reduces toxicity and / or alleviates side effects of the main drug.

[0028] Furthermore, the Chinese medicine preparation is one or more of paste prescriptions, pills, pills, decoctions, granules, capsules, powders and / or tablets.

[0029] In a third aspect, the present invention provides the use of the traditional Chinese medicine composition described in the first aspect in the preparation of a drug for treating recurrent ovarian cancer, wherein the traditional Chinese medicine composition is prepared from 1-12 parts of wine rhubarb, 0.1-1 parts of vinegar kansui, 20-45 parts of processed turtle shell, 0.1-1 parts of realgar, 1-10 parts of Sichuan pepper, 1-12 parts of donkey-hide gelatin beads, 1-10 parts of indigo and 1-12 parts of cimicifuga.

[0030] Furthermore, the recurrent ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

[0031] The medicinal properties and effects of each Chinese medicinal material in the present invention are as follows:

[0032] Wine rhubarb: bitter, cold in nature. It enters the spleen, stomach, large intestine, liver, and pericardium meridians. It has the effects of purging and attacking accumulation, clearing away heat and purging fire, cooling blood and detoxifying, removing blood stasis and promoting menstruation, and removing dampness and jaundice. It is used for constipation due to excess heat accumulation, vomiting and bleeding due to blood heat, red eyes and swollen throat, carbuncle, abdominal pain due to intestinal carbuncle, amenorrhea due to blood stasis, postpartum stasis, traumatic injury, damp-heat dysentery, jaundice and red urine, stranguria, edema; external treatment for burns and scalds. Wine rhubarb is good at clearing heat and toxicity in the upper Jiao blood, and is used for red eyes and swollen throat, and swollen and painful gums.

[0033] Indigo: salty, cold in nature. Enters the liver meridian. Has the effects of clearing away heat and detoxification, cooling blood and removing spots, purging fire and calming convulsions. Used for fever and toxic spots, vomiting and bleeding due to blood heat, chest pain and hemoptysis, mouth sores, mumps, throat paralysis, and epilepsy in children.

[0034] Sichuan pepper: spicy, warm, toxic. Enters the spleen, stomach, and kidney meridians. Has the effects of warming the middle and relieving pain, killing insects and relieving itching. Used for food stagnation, cold pain in the heart and abdomen, vomiting, belching, coughing and gas reversal, wind-cold-dampness arthralgia, diarrhea, dysentery, hernia pain, toothache, ascariasis, pinworm disease, vaginal itching, sores and scabies.

[0035] Processed turtle shell: salty, slightly cold. Enters the liver and kidney meridians. Has the effects of nourishing yin and suppressing yang, reducing fever and removing steaming, softening and dispersing nodules. Used for fever due to yin deficiency, bone steaming and fever due to fatigue, yin deficiency and yang hyperactivity, dizziness, internal movement of virtual wind, spasms in the hands and feet, amenorrhea, masses, and long-term malaria.

[0036] Donkey hide gelatin beads: sweet in taste, neutral in nature. Enter the lung, liver, and kidney meridians. It has the effects of nourishing blood and yin, moistening dryness, and stopping bleeding. It is used for blood deficiency and sallow complexion, dizziness and palpitations, muscle weakness, restlessness and insomnia, internal wind movement, dry cough, hemoptysis due to fatigue, hematemesis and hematuria, bloody stool and metrorrhagia, and fetal leakage during pregnancy.

[0037] Cimicifuga: Spicy, slightly sweet, slightly cold. Enters the lung, spleen, stomach, and large intestine meridians. Has the effects of relieving rashes, clearing away heat and detoxifying, and raising Yang Qi. Used for wind-heat headache, toothache, mouth sores, sore throat, measles that do not break out, Yang poison spots, rectal prolapse, and uterine prolapse.

[0038] Vinegar-Gan Sui: bitter, cold in nature; toxic. Enters the lung, kidney, and large intestine meridians. Has the effects of purging water and expelling fluid, reducing swelling and dispersing stagnation. Used for edema, chest and abdominal water accumulation, phlegm and fluid accumulation, qi reversal, cough and asthma, constipation, wind-phlegm epilepsy, carbuncle, swelling and sore.

[0039] Realgar: pungent, warm in nature; toxic. Enters the liver and large intestine meridians. Has the effects of detoxification, insecticide, dampness-drying, expectorant, and antimalarial. Used for carbuncle, furuncle, snake and insect bites, abdominal pain caused by insect accumulation, epilepsy, and malaria.

[0040] The treatment principle of the present invention is:

[0041] This recipe is derived from the combination of two ancient recipes, Shengma Biejia Decoction and Dahuang Gansui Decoction, in the Synopsis of the Golden Chamber. The Synopsis of the Golden Chamber, Chapter 3 on the Symptoms and Treatments of Yin-Yang Poisonous Diseases due to Lily and Fox, states: Yang poison is caused by red spots on the face like brocade, sore throat, and spitting of pus and blood. It can be cured in five days, but not in seven days. Shengma Biejia Decoction is the main treatment. The original recipe of Shengma Biejia Decoction is composed of Shengma, Angelica, Sichuan pepper, Licorice, Realgar, and Biejia. Synopsis of the Golden Chamber, Chapter 22 on the Pulse and Treatment of Miscellaneous Diseases in Women: Women with full lower abdomen, slight difficulty in urination but no thirst, and giving birth to a baby, this is because water and blood are both trapped in the blood chamber, and Dahuang Gansui Decoction is the main treatment. The original recipe of Dahuang Gansui Decoction is composed of raw rhubarb, donkey-hide gelatin, and gansui. The ovaries are located in the human pelvic cavity. Chinese medicine believes that they belong to the lower part of the human body. From the perspective of the three-burner syndrome differentiation, they belong to the liver and kidney. Symptoms of mid- to late-stage ovarian cancer include abdominal distension, abdominal pain, bloody ascites, and local tumor recurrence and metastasis. Traditional Chinese medicine believes that ovarian cancer is caused by liver and kidney deficiency, blood and water accumulation, and cancer toxins.

[0042] This prescription uses processed turtle shell to nourish the liver and kidney, soften and dissipate lumps, donkey-hide gelatin beads to nourish the liver and kidney, replenish essence and blood, and enter the lower part of the body. Sichuan pepper enters the liver and kidney meridians, can warm the yang energy of the lower part of the body, and is compatible with turtle shell and donkey-hide gelatin beads, yin and yang are mutually transformed, and can relieve pain, relieve the abdominal pain and bloating caused by the blood and water in the middle and late stages of ovarian cancer, and a large amount of ascites; Indigo enters the liver meridian to clear the liver and detoxify, Cimicifuga clears heat and detoxifies, Rhubarb in wine promotes blood circulation and menstruation, Ginseng is bitter, cold, and toxic, and enters the lung, spleen, and kidney meridians, and has the effects of purging water, expelling fluid, reducing swelling and dissipating lumps. For cancer toxins, realgar is used to attack poison with poison, dry dampness and resolve phlegm, and has a good effect on ovarian cancer with internal cancer toxins and internal phlegm and dampness.

[0043] Beneficial Effects

[0044] This prescription is mainly used for patients with advanced ovarian cancer who are receiving second-line treatment, especially for patients with refractory ovarian cancer who have relapsed after platinum-containing chemotherapy or relapsed after initial platinum-resistant chemotherapy. It has been proven to have the following advantages in clinical practice and early single-arm trials:

[0045] (1) Jiawei Suihuang decoction combined with chemotherapy is not only superior to chemotherapy alone in reducing tumor marker (CA125) levels, but also has unique advantages in improving patients' TCM symptoms, KPS scores, and quality of life;

[0046] (2) Jiawei Suihuang decoction combined with chemotherapy can reduce the degree of suppression of hemoglobin and leukocytes by chemotherapy;

[0047] (3) Jiawei Suihuang decoction combined with chemotherapy can prolong the maintenance time of patients with advanced ovarian cancer with low toxicity and high efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is the progression-free survival curve of the two groups of patients. Note: "1" represents the control group, and "2" represents the observation group. DETAILED DESCRIPTION

[0049] The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0050] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

[0051] Explanation of terms

[0052] The Chinese medicines of the present invention are all prepared according to the methods recorded in the "Pharmacopoeia of the People's Republic of China: 2020 Edition".

[0053] Wine Rhubarb: Take clean rhubarb slices and fry them until dry according to the wine roasting method.

[0054] Donkey hide gelatin beads: Take donkey hide gelatin, bake it until soft, cut it into dices about 1 cm in size, and blanch it with clam powder as in the frying method until it becomes beads. When there is no runny core inside, take it out, sieve out the clam powder, and let it cool.

[0055] Vinegar-Gansui: Take clean Gansui and fry it dry according to the vinegar-roasting method. For every 100kg of Gansui, use 30kg of vinegar.

[0056] Progression Free Survival (PFS): PFS is defined as the time from the start of treatment to the observation of tumor progression or death due to any cause.

[0057] Example 1 Clinical Study

[0058] 1. Research Methods

[0059] This study adopted a randomized controlled clinical study.

[0060] 1.1 Sample size calculation

[0061] The sample content is calculated using the formula: n = (Uα + Uβ)2 × 2 × P × (1-P) / (P1-P0)2

[0062] Where n is the sample size of a single group. This study randomized the groups according to a 1:1 ratio, so the sample sizes of the control group and the observation group were equal. Taking the test level α = 0.05, the test power 1-β = 0.8, and referring to the quantile table of the normal distribution, we can get U α (0.05) = 1.65, U β(0.2)=0.84; P0 and P1 are the total effective rates of the control group and the observation group, respectively. Consult previous similar research literature (DOI:10.15887 / j.cnki.13-1389 / r.2021.23.060.), take P0=60%, P1=82.9%, P=(P1+P0) / 2=(0.829+0.6) / 2=0.7145, substitute the above parameters into the formula to get:

[0063] n=(1.65+0.84)2×2×0.7145×(1-0.7145) / (0.829-0.6)2≈47

[0064] That is, the required sample size for each group is 47. Considering that there may be a certain dropout rate in the study, the sample size is increased by 10%, and finally 52 subjects are required in the control group and observation group, for a total of 104 subjects.

[0065] 1.2 Grouping method

[0066] According to the principle of randomization and control, the 104 patients who met the inclusion criteria were numbered in chronological order of their admission time and divided into a control group and an observation group using a random number table, with 52 cases in each group.

[0067] 2. Research subjects

[0068] 2.1 Case Source

[0069] All patients were from the Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University. The time span was from July 2021 to January 2024, and a total of 104 patients were enrolled.

[0070] 2.2 Diagnostic criteria:

[0071] 2.2.1 Western medicine diagnostic criteria:

[0072] Refer to the pathological diagnostic criteria for ovarian cancer in the "CSCO Ovarian Cancer Diagnosis and Treatment Guidelines" (2021 edition) developed by the Chinese Society of Clinical Oncology (CSCO), and clarify the diagnosis and pathological type based on the patient's imaging evidence, pathological results, and tumor markers.

[0073] Clinical staging standards: refer to the 2014 FIGO staging standards for gynecological tumors developed by the Federation International of Gynecology and Obstetrics (FIGO).

[0074] Diagnostic criteria for platinum-resistant recurrent ovarian cancer: Refer to the "CSCO Ovarian Cancer Diagnosis and Treatment Guidelines" (2021 edition) Diagnostic criteria for platinum-resistant recurrent ovarian cancer.

[0075] 2.2.2 TCM diagnostic criteria:

[0076] Referring to the "Cancer Disease" section of "Chinese Medicine Internal Medicine" (Edited by Wu Mianhua) and the "Ovarian Cancer Syndrome Differentiation and Classification" section of "Guidelines for Diagnosis and Treatment of Malignant Tumors in Chinese Medicine" (Edited by Lin Hongsheng), the syndrome differentiation criteria for ovarian cancer with phlegm and blood stasis are formulated as follows (Table 1):

[0077] Table 1 Syndrome differentiation criteria for phlegm and blood stasis syndrome in ovarian cancer

[0078]

[0079] This syndrome can be diagnosed if the patient has ≥2 main symptoms and ≥2 secondary symptoms, combined with tongue and pulse.

[0080] 2.3 Inclusion and Exclusion Criteria

[0081] 2.3.1 Inclusion criteria

[0082] (1) Cases of platinum-sensitive recurrent ovarian cancer:

[0083] ① Primary ovarian cancer confirmed by pathological tissue;

[0084] ②Received initial tumor cell reduction surgery and platinum-based postoperative chemotherapy;

[0085] ③ The time from the end of initial platinum-containing chemotherapy to tumor recurrence is ≥ 6 months;

[0086] ④ The recurrence has at least one measurable objective lesion or elevated CA125 or the presence of pleural effusion and ascites.

[0087] Platinum-refractory cases:

[0088] Patients with primary ovarian cancer confirmed by pathological tissue, whose initial treatment is ineffective with platinum-based chemotherapy, or whose disease progresses during treatment;

[0089] Cases of platinum-resistant recurrent ovarian cancer:

[0090] ① Primary ovarian cancer confirmed by pathological tissue;

[0091] ②Received initial tumor cell reduction surgery and platinum-based postoperative chemotherapy;

[0092] ③ The time from the end of initial platinum-containing chemotherapy to tumor recurrence is less than 6 months;

[0093] ④ The recurrence has at least one measurable objective lesion or elevated CA125 or pleural effusion and ascites;

[0094] (2) the patient's FIGO stage ranged from IC to IV;

[0095] (3) Patients who had previously received platinum-based chemotherapy but progressed or relapsed within 6 months after completing chemotherapy, or had no response to initial chemotherapy or progressed within 4 weeks after chemotherapy and were clinically diagnosed with platinum-resistant relapse;

[0096] (4) at least one lesion measurable by CT, MRI, or PET / CT;

[0097] (5) KPS score ≥ 60 points and expected survival time > 3 months;

[0098] (6) The functions of major organs and bone marrow are basically normal, and they meet the indications and basic requirements for chemotherapy and targeted therapy;

[0099] (7) Age 25-75 years old;

[0100] (8) Those who were informed of this study and signed the informed consent.

[0101] 2.3.2 Exclusion criteria

[0102] (1) Patients with two or more primary malignant tumors;

[0103] (2) Those who suffer from severe organ dysfunction or blood system diseases and whose conditions cannot be effectively controlled;

[0104] (3) Those who are allergic to the Chinese medicine in this study.

[0105] 2.4 Falling off and rejection criteria:

[0106] (1) If a case is found not to meet the inclusion criteria after inclusion, it must be excluded;

[0107] (2) Subjects with poor compliance, serious adverse events, and other reasons that make them unsuitable to continue the trial, or those who withdraw on their own are all considered dropouts;

[0108] (3) Handling of dropout cases: When a subject drops out, the researcher should take active measures to complete the last test as much as possible in preparation for the analysis of its efficacy and safety. For all dropout cases, the trial conclusion table and the reason for the case dropout should be filled in the case report form.

[0109] 3. Treatment options

[0110] 3.1 Control group

[0111] Standard Western medicine treatment, irinotecan, paclitaxel (weekly treatment), liposomal doxorubicin, gemcitabine combined with bevacizumab treatment is a level I recommended regimen in the guidelines of the Chinese Society of Clinical Oncology (CSCO) and the National Comprehensive Cancer Network (NCCN) guidelines of the United States.

[0112] Paclitaxel 60 mg / m IV 2 , infused for 1 hour, used on days 1, 8, and 15. Liposomal doxorubicin, intravenous infusion 40-50 mg / m 2 , once every 4 weeks. Gemcitabine 1000 mg / m 2 , used on days 1, 8, and 21, with 21 days as one cycle. Bevacizumab was intravenously infused at 10 mg / kg, once every 2 weeks.

[0113] 3.2 Experimental Group

[0114] On the basis of the control group, the patients were given modified Suihuang decoction orally.

[0115] Modified Suihuang Decoction: wine rhubarb 6g, indigo 3g (wrapped and decocted), Sichuan pepper 3g, processed turtle shell 30g (decocted first), donkey-hide gelatin beads 6g, cimicifuga 6g, vinegar gansui 0.1g (infused), realgar 0.1g (infused).

[0116] Usage: Except for Gan Sui and Realgar, the remaining medicines are decocted in water for 200mL, and then taken with Gan Sui powder and Realgar powder. One dose per day, decocted in water for 400mL, and 200mL is taken orally 30 minutes after breakfast and dinner respectively. Patients start taking Chinese medicine from the first day of chemotherapy, and take it for 14 consecutive days and then stop for 7 days as one course of treatment. A total of 6 courses of treatment are taken along with the chemotherapy cycle.

[0117] 4. Observation indicators

[0118] 4.1 Main indicators

[0119] Objective Response Rate (ORR)

[0120] According to RECIST criteria [2] To conduct an assessment:

[0121] (1) Complete remission, complete disappearance of the tumor, and maintained for at least 4 weeks;

[0122] (2) Partial remission: the product of the maximum diameter of the tumor and its maximum perpendicular diameter decreases by more than 50% and lasts for at least 4 weeks;

[0123] (3) stable disease, between partial response and progressive disease;

[0124] (4) Disease progression: the product of the maximum diameter of the tumor and its maximum perpendicular diameter increases by more than 25%, or new lesions appear.

[0125] Objective response rate = [(number of complete response cases + number of partial response cases) / total number of cases] × 100%.

[0126] 4.2 Secondary indicators

[0127] (1) Tumor markers such as CA125, duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0128] During the study, patients in both groups were followed up regularly (once every 2 months) to inquire about their tumor progression and survival until tumor progression, death, or the end of this clinical trial (the follow-up deadline is January 31, 2024). Patients who had no tumor progression, were lost to follow-up, or died of other diseases as of the last follow-up date were considered censored data.

[0129] (2) Evaluation criteria for clinical efficacy of traditional Chinese medicine

[0130] The comparison of the total efficacy and symptom efficacy after treatment was formulated in accordance with the "Guidelines for Clinical Research of New Chinese Medicines (Trial)":

[0131] ① Significant improvement: the integral value decreased by ≥70%;

[0132] ② Partial improvement: the integral value decreased by ≥30% and <70%;

[0133] ③ No improvement: The integral value has no change, or the change is less than 30%;

[0134] ④Aggravated: The integral value increases by ≥30%.

[0135] Total effective rate (%) = (number of cases with significant improvement + number of cases with partial improvement) / total number of cases × 100%.

[0136] (3) Quality of life assessment

[0137] The FACT-O scale for quality of life of patients with ovarian cancer was used to evaluate the quality of life of patients. The quality of life score was obtained from five aspects: physical condition, social condition, emotional condition, functional condition and other items of concern. Each item was scored on a 5-level scale: "not at all" was level 0, "a little" was level 1, "normal" was level 2, "quite a lot" was level 3, and "very much" was level 4. Level 0 was scored as 0 points, level 1 was scored as 1 point, and so on. The higher the score, the worse the quality of life.

[0138] 5. Statistical analysis

[0139] All raw data were summarized in the Excel table and statistically analyzed using SPSS28.0 software. For measurement data, the Shapiro-Wilk (SW) method was first used for normality test. If the data conformed to normal distribution and the variance was equal, it was expressed as mean ± standard deviation (X ± S), and the two groups were compared by t test; if the data conformed to normal distribution but the variance was not equal, it was expressed as mean ± standard deviation (X ± S), and the two groups were compared by corrected t test; if the data did not conform to normal distribution, it was expressed as median M (P25, P75), and the two groups were compared by nonparametric rank sum test. For count data, χ 2 Test or Fisher's exact probability method. For ranked data, the rank sum test was used to compare the two groups. The Kaplan-Meier method was used to draw the survival curve, and the Log-rank test was used to compare whether there was a statistical difference between the two groups. P < 0.05 indicated that the difference was statistically significant.

[0140] 6. Research Results

[0141] 6.1 Study Enrollment

[0142] According to the inclusion and exclusion criteria, a total of 104 patients were initially enrolled in this study, including 52 in the control group and 52 in the observation group. During the study, 2 patients in the control group lost contact and could not be followed up, 1 patient requested to withdraw from the study, 3 patients were excluded for taking anti-tumor Chinese patent medicines on their own, and 2 patients were excluded for not completing chemotherapy according to the prescribed course of treatment; 3 patients in the observation group lost contact and could not be followed up, 2 patients requested to withdraw from the study, 4 patients were excluded for not taking Chinese medicines according to the prescribed course of treatment, and 1 patient was excluded for not completing chemotherapy according to the prescribed course of treatment. A total of 86 patients finally completed the clinical trial, including 44 in the control group and 42 in the observation group.

[0143] 6.2 General Data Comparison

[0144] 6.2.1 Comparison of age between the two groups

[0145] As shown in Table 2, the average age of the patients in the control group was 53.48±12.42 years old, and the average age of the patients in the observation group was 56.19±11.29 years old. After two independent sample t-test analysis, there was no statistical difference in the age of the two groups of patients (t=-1.058, P=0.293>0.05), and they were comparable.

[0146] Table 2 Comparison of age between the two groups of patients (years, X±S)

[0147]

[0148] 6.2.2 Comparison of pathological types between the two groups

[0149] As shown in Table 3, Fisher's exact probability test showed that there was no statistical difference in the pathological types of the two groups of patients (P = 0.959 > 0.05), and they were comparable.

[0150] Table 3 Comparison of pathological types between the two groups of patients [cases (%)]

[0151]

[0152] 6.2.3 Comparison of clinical stages between the two groups

[0153] As shown in Table 4, the chi-square test showed that there was no statistical difference in the clinical stages of the two groups of patients (P = 0.921 > 0.05), and they were comparable.

[0154] Table 4 Comparison of clinical stages of the two groups of patients [cases (%)]

[0155]

[0156] 6.3 Clinical efficacy evaluation

[0157] 6.3.1 Tumor marker CA125 level

[0158] Due to the skewed distribution of data, the rank sum test was used to compare the CA125 levels of the two groups of patients before and after treatment. There was no statistical difference in the CA125 levels of the two groups of patients before treatment (Z=0.112, P=0.911>0.05), which was comparable.

[0159] Intra-group comparison: The paired rank-sum test was used to compare the CA125 levels of the two groups of patients before and after treatment. The results showed that the CA125 levels of the two groups of patients after treatment were significantly decreased compared with those before treatment, and the differences were statistically significant (P < 0.05).

[0160] Comparison between groups: After treatment, there was a statistically significant difference in the CA125 levels between the two groups (Z=2.778, P=0.005<0.05). The CA125 level of the observation group was significantly lower than that of the control group, as shown in Table 5.

[0161] Table 5 Comparison of CA125 levels between the two groups of patients [U / mL, M (P 25 , P 75 )]

[0162]

[0163] 6.3.2 Evaluation of TCM Syndrome Efficacy

[0164] As shown in Table 6, due to the skewed distribution of the data, the TCM syndrome scores of the two groups of patients before and after treatment were compared using the grouped two-sample rank sum test. There was no statistical difference in the TCM syndrome scores of the two groups of patients before treatment (Z=0.804, P=0.421>0.05), which was comparable.

[0165] Intra-group comparison: The paired rank sum test was used to compare the TCM syndrome scores of the two groups of patients before and after treatment. The results showed that there was no statistical difference in the scores of the control group before and after treatment (Z=0.905, P=0.365>0.05), and the scores of the observation group after treatment were significantly lower than those before treatment (Z=4.274, P=0.000<0.05).

[0166] Comparison between groups: After treatment, the TCM syndrome score of the observation group was significantly lower than that of the control group (Z=3.137, P=0.002<0.05).

[0167] Table 6 Comparison of TCM syndrome scores between the two groups of patients (points, M (P 25 , P 75 ))

[0168]

[0169] The efficacy of TCM syndrome in the two groups of patients was evaluated. As shown in Table 7, the total effective rates of the control group and the observation group were 11.36% and 59.52%, respectively. According to the rank sum test, the difference in the efficacy of TCM syndrome between the two groups was statistically significant (Z=4.384, P=0.000<0.05), and the efficacy of the observation group was significantly better than that of the control group.

[0170] Table 7 Comparison of TCM syndrome efficacy between two groups of patients (cases)

[0171]

[0172] 6.3.3 KPS Rating

[0173] Due to the skewed distribution of the data, the KPS scores of the two groups of patients before and after treatment were compared using the grouped two-sample rank sum test. As shown in Table 8, there was no statistical difference in the KPS scores of the two groups of patients before treatment (Z=1.201, P=0.230>0.05), which was comparable.

[0174] Intra-group comparison: The KPS scores of the two groups of patients before and after treatment were compared using the paired rank sum test. There was no statistically significant difference in the scores of the control group before and after treatment (Z=1.633, P=0.102>0.05), and the scores of the observation group after treatment were significantly higher than those before treatment (Z=4.213, P=0.000<0.05).

[0175] Comparison between groups: After treatment, the KPS score of the observation group was significantly higher than that of the control group (Z=2.578, P=0.010<0.05).

[0176] Table 8 Comparison of KPS scores between the two groups of patients (points, M (P 25 , P 75 ))

[0177]

[0178] The KPS score of the two groups of patients was evaluated for efficacy. As shown in Table 9, the total effective rates of the control group and the observation group were 63.64% and 78.57%, respectively. According to the rank sum test, the difference in the KPS score efficacy between the two groups was statistically significant (Z=2.670, P=0.008<0.05), and the efficacy of the observation group was significantly better than that of the control group.

[0179] Table 9 Comparison of KPS score efficacy between the two groups of patients (cases)

[0180]

[0181] 6.3.4 Quality of life assessment

[0182] Since the two groups of data conformed to normal distribution but had unequal variances, the adjusted t-test was used to compare the quality of life scores of the two groups of patients before and after treatment. There was no statistical difference in the quality of life scores of the two groups of patients before treatment (t=0.143, P=0.887>0.05), which showed comparability.

[0183] Intra-group comparison: Due to the skewed distribution of the difference before and after treatment, the paired rank sum test was used to compare the quality of life scores of the two groups of patients before and after treatment. There was no statistical difference in the scores of the control group before and after treatment (Z=1.574, P=0.115>0.05), and the score of the observation group after treatment was significantly higher than that before treatment (Z=5.528, P=0.000<0.05).

[0184] Inter-group comparison: After treatment, the quality of life score of the observation group was significantly higher than that of the control group (t=-2.599, P=0.011<0.05), see Table 10 for details.

[0185] Table 10 Comparison of quality of life scores between the two groups of patients (points, X±S)

[0186]

[0187] 6.3.5 Evaluation of myelosuppression

[0188] As shown in Table 11, the t-test showed that there was no statistical difference in the levels of hemoglobin, white blood cells, neutrophils and platelets between the two groups of patients before treatment (all P>0.05), which showed comparability.

[0189] Table 11 Comparison of blood indicators between the two groups of patients before treatment (X±S)

[0190]

[0191] The results in Table 12 showed that after treatment, there were 32 cases in the control group and 26 cases in the observation group with hemoglobin suppression of degree I or above, and there were 24 cases in the control group and 16 cases in the observation group with leukocyte suppression of degree I or above.

[0192] According to the rank sum test, there were statistically significant differences in hemoglobin and leukocyte inhibition between the two groups of patients after treatment (P < 0.05), but no statistically significant differences in neutrophil and platelet inhibition (P > 0.05), indicating that Jiawei Suihuang Decoction combined with chemotherapy can significantly reduce the degree of chemotherapy-induced inhibition of hemoglobin and leukocytes.

[0193] Table 12 Comparison of bone marrow suppression between the two groups of patients after treatment (cases)

[0194]

[0195]

[0196] 6.3.6 Progression-free survival (PFS)

[0197] The follow-up ended on January 31, 2023, with a follow-up period of 7-28 months. There were 22 censored data in the control group and 23 censored data in the observation group.

[0198] The PFS analysis of the two groups of patients showed that the average PFS of the control group was (15.83±1.08) months, and the median PFS was (15.00±0.54) months; the average PFS of the observation group was (16.87±1.06) months, and the median PFS was (17.00±1.48) months. There was no significant statistical difference in PFS between the two groups (χ 2 =1.059, P=0.303>0.05), but the mean PFS and median PFS of the observation group were slightly better than those of the control group, as shown in Table 13 and Figure 1 .

[0199] Table 13 Comparison of PFS between the two groups of patients (months, X±S)

[0200]

[0201] 7. Conclusion

[0202] (1) Jiawei Suihuang decoction combined with chemotherapy is not only superior to chemotherapy alone in reducing CA125 levels in patients after ovarian cancer surgery, but also has unique advantages in improving patients' TCM symptoms, KPS scores, and quality of life;

[0203] (2) Jiawei Suihuang decoction combined with chemotherapy can reduce the degree of suppression of hemoglobin and leukocytes by chemotherapy, but has no significant effect on neutrophils and platelets;

[0204] (3) Although there was no significant statistical difference in PFS between the two groups, the mean and median PFS of the patients in the Jiawei Suihuang Decoction combined with chemotherapy group were numerically slightly better than those in the chemotherapy alone group.

[0205] Example 2 Clinical typical

[0206] Case 1

[0207] Patient: Zhao, age: 57

[0208] First visit time

[0209] July 20, 2021

[0210] Chief complaint

[0211] The patient was diagnosed with ovarian malignancy in the past 5 years, and the neck mass had been progressively increasing in size for 1 month.

[0212] History of present illness:

[0213] A lump appeared in the neck on August 30, 2016.

[0214] On September 12, 2016, a puncture of the neck mass was performed in a local hospital, which showed that inflammatory cells and a small amount of lymphocytes were found. Anti-inflammatory treatment was recommended, and the mass did not shrink significantly after treatment.

[0215] On September 20, 2016, the pathological results of the second puncture biopsy showed: right cervical lymph node puncture, metastatic adenocarcinoma. Immunohistochemistry of right cervical lymph node puncture: CK7+; CK20-; Villin-, CD×-2-, PA×-8+, ER+80%, PR+10%; Her-2-; WT-1+, P53++90%, GCDFP15-; mTTF-1-; NapsinA-, right cervical lymph node metastatic carcinoma, poorly differentiated carcinoma. Please first examine the female reproductive system (such as ovaries, etc.) clinically.

[0216] On September 28, 2016, she received three rounds of neoadjuvant chemotherapy, with the regimen of paclitaxel 180mg ivgtt D1 + carboplatin 400mg ivgtt D1. On November 30, 2016, she underwent total hysterectomy + bilateral salpingo-oophorectomy + omentectomy + implant removal in another hospital. Postoperative pathology: high-grade serous papillary carcinoma of the left and right ovaries, with cell degeneration, consistent with chemotherapy reaction grade I. Left and right fallopian tubes (-), vaginal stump (-), omentum (-).

[0217] On December 12, 2016, he received three postoperative adjuvant chemotherapy regimens: paclitaxel 180mg ivgtt D1 + cisplatin 90mg ivgtt D1. On October 9, 2019, B-ultrasound showed: multiple solid and mixed masses in the bilateral neck and bilateral supraclavicular areas, and metastasis was considered. There was a mixed mass above the right kidney, which may metastasize; no mass was found in the pelvic cavity after surgery.

[0218] Considering tumor recurrence, six chemotherapy sessions were started on December 10, 2019, with the regimen of paclitaxel + carboplatin.

[0219] In September 2020, the patient's disease progressed again, and the local hospital gave him 4 cycles of doxorubicin hydrochloride liposome + cisplatin chemotherapy. He then took niraparib for maintenance treatment, but the disease progressed after only 1 month of taking it.

[0220] In April 2021, he started oral etoposide + apatinib treatment, but the treatment was discontinued due to intolerance.

[0221] PET-CT on June 10, 2021 showed: ① Multiple nodules and masses in the right breast, increased FDG uptake, breast cancer is considered, multiple lymph node metastases in the submandibular, posterior cervical triangle, supraclavicular fossa, mediastinum and axillary fossa on both sides, multiple small nodules in both lungs, close follow-up is recommended. ② "After comprehensive treatment of ovarian cancer", no abnormal FDG uptake was found after surgery. ③ The density of the two lobes and isthmus of the thyroid gland is uneven, please combine ultrasound examination.

[0222] Breast puncture pathology on June 15, 2021: (right breast mass puncture specimen) Combined with tissue morphology, immunohistochemistry and test results, it is consistent with metastatic adenocarcinoma, ovarian origin. Because she is unwilling to undergo chemotherapy and requires simple Chinese medicine treatment, she is now seeking Chinese medicine diagnosis and treatment.

[0223] Grave disease

[0224] Fatigue, poor appetite, distending pain and discomfort in the neck, dry stool, only once every two days, dark red tongue, white fur, deep and stringy pulse.

[0225] past history

[0226] History of hypertension for 2 years.

[0227] diagnosis

[0228] Traditional Chinese Medicine: Ovarian cancer, liver and kidney deficiency, phlegm and blood stasis syndrome;

[0229] Western medicine: Postoperative FIGO stage IV high-grade serous carcinoma of the ovary - breast and multiple lymph node metastases.

[0230] Governing Law

[0231] Nourishes the liver and kidneys, promotes blood circulation and detoxifies

[0232] prescription

[0233] Wine rhubarb 6g, Indigo 3g (wrapped and decocted), Sichuan pepper 3g, processed turtle shell 30g (decocted first), donkey-hide gelatin beads 6g, Cimicifuga 6g, vinegar gansui 0.1g (washed), realgar 0.1g (washed).

[0234] usage

[0235] Except for gansui and realgar, the remaining medicines are decocted in water for 400mL, and taken with gansui powder and realgar powder. Take one dose daily, divided into 2 doses, orally for 5 days, and stop taking the medicine for 2 days.

[0236] The patient took 20 doses orally for the first time and did not complain of any special discomfort afterwards. He had regular checkups and the prescription remained unchanged.

[0237] The patient took the medicine until April 2022, reviewed the progress of the disease, received repeated psychological counseling, explained the importance of combining Chinese and Western medicine for diagnosis and treatment, and received chemotherapy combined with targeted therapy and modified Chinese medicine treatment.

[0238] Treatment Effects

[0239] The breast and neck ultrasound examination on July 30, 2021 showed that the mass was slightly smaller than before, and the cervical lymph nodes were larger (3×3.4cm). The patient's fatigue, dry stool and neck pain were better than before.

[0240] The follow-up ultrasound on August 22, 2021 showed that the patient's condition was stable.

[0241] On April 21, 2022, the cervical lymph nodes were found to be larger than before, and the larger one (5×4.3cm) was considered to be larger than before. The patient was treated with simple Chinese medicine maintenance treatment for advanced ovarian cancer, and her condition was stable for 10 months.

[0242] Case 2

[0243] Patient: Cai, age: 49

[0244] First visit time

[0245] September 13, 2023

[0246] Chief complaint

[0247] Ovarian cancer was diagnosed more than 2 years ago.

[0248] History of present illness

[0249] The patient developed dry cough without obvious cause in June 2020, and the local hospital's chest ultrasound showed bilateral pleural effusion. Pleural effusion cytology at the local hospital: (pleural effusion) Under the microscope, clusters of round or polygonal tumor cells were seen, and squamous cell carcinoma was considered.

[0250] 2021-06-18 CT scan of the neck, chest and abdomen in our hospital: 1. The soft tissue nodules in the left adnexa and uterine rectal fossa are considered to be malignant lesions, with metastases to the pelvic cavity and bilateral diaphragmatic surfaces. 2. A large amount of fluid in the chest, abdomen and pelvic cavity.

[0251] On June 20, 2020, a right inguinal lymph node puncture biopsy showed: malignant tumor cells were found (considered squamous cell carcinoma).

[0252] Cancer cells were found in ascites cytology on June 23, 2020. Tumor stage: IVB stage.

[0253] From 2020-06-24 to 2020-10-26, the patient received 6 cycles of TP chemotherapy combined with bevacizumab targeted therapy, specifically: albumin-bound paclitaxel 300 mgd1 + nedaplatin 40 mgd1-3 + bevacizumab 300 mgd1. The efficacy was evaluated as PR during the period.

[0254] Chemotherapy was performed on November 21 and December 21, 2020, with the regimen: albumin-bound paclitaxel 300 mgd1 + nedaplatin 40 mgd1-2 + bevacizumab 300 mgd1.

[0255] From 2021-01-14 to 9-7, 10 cycles of bevacizumab 300 mg maintenance treatment were received.

[0256] The patient's tumor markers CA125 and HE4 were elevated during a review on September 28, 2021.

[0257] Considering the possibility of biochemical recurrence of the tumor, 6 cycles of chemotherapy with albumin-paclitaxel 300 mg / d1 + nedaplatin 100 mg / d1 + bevacizumab 300 mg / d1 were performed from September 30, 2021 to February 27, 2022. After that, pamiparib was taken all the time, but pamiparib was discontinued for 21 days in July due to bone marrow suppression.

[0258] On October 5, 2022, the patient's abdominal CT scan showed that liver metastasis could not be ruled out, and the regimen was adjusted to: bevacizumab 300 mg + pamiparib 2 tablets bid.

[0259] 2023-2-13 Abdominal CT scan at the local hospital indicated disease progression.

[0260] From February 20 to June 12, 2023, 4 cycles of immunotherapy combined with chemotherapy were performed, with the regimen of: Sepalimab 240 mg / d1 + albumin-paclitaxel 300 mg / d1 + nedaplatin 100 mg / d1. Grade I thrombocytopenia occurred after chemotherapy. Sepalimab 240 mg immunotherapy was given on May 2.

[0261] On July 10 and August 4, the patient was treated with sepalimumab 240 mg + anlotinib 8 mg d1-14.

[0262] The multi-slice spiral CT chest and whole abdomen (enhanced) on August 2, 2023 showed: Compared with the film on April 27, 2023: 1. Scattered nodules in the liver, similar to the previous ones, metastasis is considered, please combine clinical follow-up for reexamination. 2. Enlarged lymph nodes in the mediastinum and retroperitoneum, nodular thickening in the abdominal and pelvic cavity, greater omentum, peritoneum, and mesentery, all of which are considered metastasis, and some are larger than before. Please combine clinical follow-up for reexamination. 3. Intrahepatic bile duct dilatation, bile stasis may be more obvious than before. 4. Perihepatic effusion; fluid accumulation in the original gallbladder fossa, absorbed more than before; gallbladder hypertonia, gallbladder wall thickening. 5. Mild atrophy of the left kidney, similar to the previous one. 6. Small nodules in both lungs, similar to the previous one. 7. Tracheal diverticulum, similar to the previous one. The patient's disease progressed during this reexamination, and the patient requested to come for treatment with traditional Chinese medicine alone.

[0263] Grave disease

[0264] Fatigue, poor appetite, occasional abdominal pain, more obvious at night, loose stools, twice a day. Dark red tongue, white fur, deep and stringy pulse.

[0265] past history

[0266] He was in good health.

[0267] diagnosis:

[0268] Traditional Chinese Medicine: Ovarian cancer, liver and kidney deficiency, phlegm and blood stasis syndrome;

[0269] Western medicine: Ovarian squamous cell carcinoma FIGO stage IVB - liver metastasis - multiple metastases to abdominal lymph nodes.

[0270] Governing Law

[0271] Nourishes the liver and kidneys, promotes blood circulation and detoxifies

[0272] prescription

[0273] Wine rhubarb 6g, Indigo 6g (wrapped and decocted), Sichuan pepper 6g, processed turtle shell 60g (decocted first), donkey-hide gelatin beads 6g, Cimicifuga 30g, vinegar gansui 0.2g (washed), realgar 0.1g (washed).

[0274] usage

[0275] Except for gansui and realgar, the remaining medicines are decocted in water for 400mL, and taken with gansui powder and realgar powder. Take one dose daily, divided into 2 doses, orally for 5 days, and stop taking the medicine for 2 days.

[0276] The patient took 20 doses orally for the first time, and did not complain of any special discomfort afterwards. He had bowel movements 3 times a day without obvious discomfort. He underwent regular checkups and the prescription remained unchanged.

[0277] The patient took the medicine until March 14, 2024, when the disease progress was reviewed, and was treated with anlotinib combined with sepamine. The Chinese medicine prescription reduced the realgar to 0.1g, and the cimicifuga was changed to 15g to continue the treatment.

[0278] On June 20, 2024, the condition progressed and the Chinese medicine prescription was changed.

[0279] Treatment Effects

[0280] The abdominal enhanced CT scan on October 15, 2023 showed no significant changes compared with that in August 2023.

[0281] Re-examination on November 29, 2023 indicated stable status.

[0282] The abdominal enhanced CT scan on March 14, 2024 showed that the liver mass was stable and the abdominal lymph nodes were larger than before. Considering the progression of the disease, the patient was treated with anlotinib combined with sepamine. The Chinese medicine prescription reduced the realgar to 0.1g and the cimicifuga to 15g to continue the treatment.

[0283] The disease progressed on June 20, 2024. The condition was stable for 5 months with Chinese medicine alone and for a total of 8 months with combined Chinese and Western medicine treatment.

[0284] Case 3

[0285] Patient: Wang, age: 42 years old

[0286] First visit time

[0287] August 4, 2023

[0288] Chief complaint

[0289] More than 11 years after ovarian cancer surgery, fatigue for more than 2 months.

[0290] History of present illness

[0291] In 2012, the patient underwent abdominal puncture in another hospital due to abdominal distension. Ascitic pathology showed some nuclear heterogeneous cells in the smear, which were considered to be consistent with adenocarcinoma.

[0292] On November 4 and December 5, 2012, PC chemotherapy was performed: paclitaxel 240 mg d1, carboplatin 400 mg d1.

[0293] On December 27, 2012, she underwent "abdominal total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and abdominal para-aortic lymph node dissection + clearance of intestinal metastatic lesions". Because the left retroperitoneum was hard and thickened, the left pelvic lymph nodes were not cleared. Postoperative pathology showed: (right) ovarian borderline mucinous cystoma, local transformation (low-grade serous carcinoma, and more psammoma bodies were seen, the tumor size was 8×8×4cm and 2.2×2.2×1.5cm, without involving the right fallopian tube and fimbria, the tumor invaded the subserous fibrous tissue and smooth muscle of the right side of the uterus, (left) ovarian borderline mucinous cystadenoma with psammoma bodies, local canceration, partly micropapillary, the tumor size was 4×2.5×1.5cm, and invaded the left fallopian tube serosa and Mesentery, epithelial dysplasia at the end of the left fallopian tube, tumor invaded the serosa and deep muscle layer of the left wall of the uterus. No cancer was found in the lymph nodes sent for examination (right pelvic and para-aortic, left pelvic cavity), (0 / 10, 0 / 3 respectively). Tumor tissue infiltration was seen in the fibrous and adipose tissue (greater omentum). Immunohistochemistry: HER-1(-), HER-2(-), P53(-), ER(+), Ki-67(+1-10%), PR(-), VEGF(-), TOP-IIa(-), PDGFR-β(-), PDGFR-α(-).

[0294] PC chemotherapy was performed on 2013-1-5 and 2013-1-30: paclitaxel 210mg d1 + carboplatin 400mg d1.

[0295] On March 11, 2013, he visited the local hospital and received 4 cycles of PC chemotherapy on March 11, April 6, April 28 and May 25. CA125 was 23U / m1 on March 11 and 13.9U / m1 on May 25. On April 27, 2016, CA125 was 36.5U / m1 in the same hospital and no abnormality was found in the abdominal CT scan.

[0296] On June 19, 2018, CA125 was 67.5U / ml, HPV52 type (-), semi-quantitative: 415.85. On May 5, 2019, CA125 was 98.9U / ml, and abdominal CT showed a nodule at the left posterior edge of the vaginal stump, which was considered a tumor recurrence. One cycle of paclitaxel 270mg + nedaplatin 150mg chemotherapy was performed, but the side effects were severe and the chemotherapy was not performed on time.

[0297] 2022-2-27 CA125: 431.8U / ml, abdominal plain scan CT: After ovarian cancer surgery, peritoneum thickened, peritoneal metastasis possible, multiple calcified nodules in the left posterior cervical space and left clavicle area, the largest of which was about 0.9×0.7cm, considered metastasis, larger and more numerous than before; multiple calcified nodules in the abdominal cavity, retroperitoneum, around the intestines, and beside bilateral blood vessels, the largest of which was about 1.4×1cm, located in the portal area, considered metastasis, larger and more numerous than before.

[0298] On March 4, 2022 and April 1, 2022, chemotherapy with Lipusu 270mg and Nedaplatin 150mg was performed. The patient reported that CA125 did not decrease significantly. From April 24 to 2022-8, Bevacizumab 400mg was combined. On July 2022, CA125 was 79.3U / m1. The patient reported that the symptoms improved but no regular follow-up was performed.

[0299] On May 2023, the patient went to another hospital for chest tightness. On May 4, a thoracentesis was performed. The pathological results of the pleural effusion showed papillary adenocarcinoma cells. CA125: 684.4 U / m1. During this period, BRCA1 / 2 gene testing did not show pathogenic mutations (no report). The patient was afraid of chemotherapy and has been taking oral Chinese medicine for treatment so far.

[0300] 2023-7The patient was admitted to another hospital due to severe chest tightness and abdominal distension and underwent thoracentesis and drainage. The chest tightness and wheezing improved slightly compared with before.

[0301] He visited our department on 2023-8-4.

[0302] Grave disease

[0303] General weakness, occasional pain in legs, numbness in hands and feet, occasional upper abdominal pain, no acid reflux, heartburn, nausea and vomiting, no abdominal distension, occasional nose and gum bleeding, no abdominal pain and vomiting, good appetite, poor sleep, 2-3 nocturia, 1-2 days of bowel movements, occasionally unformed. No significant weight change in the past month.

[0304] past history

[0305] He was in good health.

[0306] diagnosis

[0307] Traditional Chinese Medicine: Ovarian cancer, liver and kidney deficiency, phlegm and blood stasis syndrome;

[0308] Western medicine: Right ovarian borderline mucinous cystadenoma with low-grade serous carcinoma, stage IVB after surgery, left ovarian borderline mucinous cystadenoma with micropapillary carcinoma, stage IVB after surgery - abdominal lymph node metastasis - peritoneal metastasis - malignant ascites - malignant pleural effusion - left cervical lymph node metastasis - left supraclavicular lymph node metastasis - chronic pain.

[0309] Governing Law

[0310] Nourishes the liver and kidneys, promotes blood circulation and detoxifies

[0311] prescription

[0312] Wine rhubarb 6g, Indigo 6g (wrapped and decocted), Sichuan pepper 6g, processed turtle shell 60g (decocted first), donkey-hide gelatin beads 6g, Cimicifuga 30g, vinegar gansui 0.2g (washed), realgar 0.1g (washed).

[0313] usage

[0314] Except for gansui and realgar, the remaining medicines are decocted in water for 400mL, and taken with gansui powder and realgar powder. Take one dose daily, divided into 2 doses, orally for 5 days, and stop taking the medicine for 2 days.

[0315] The patient took 20 doses orally for the first time, and did not complain of any special discomfort afterwards. He had bowel movements 3 times a day without obvious discomfort. He underwent regular checkups and the prescription remained unchanged.

[0316] From August 4, 2023 to November 20, 2023, the patient received 4 cycles of single-agent albumin-paclitaxel chemotherapy in our hospital, and took the above medicine orally at the same time.

[0317] The patient's condition remained stable after taking the medicine until the follow-up examination on September 25, 2024, and the Chinese medicine prescription was increased to 0.2g of realgar and 15g to continue the treatment.

[0318] On November 15, 2024, the condition progressed and the Chinese medicine prescription was changed.

[0319] Treatment Effects

[0320] From August 4, 2023 to November 20, 2023, the patient received 4 cycles of single-agent albumin-paclitaxel chemotherapy in our hospital, combined with oral administration of this prescription, and his condition was stable.

[0321] The patient stopped chemotherapy on his own and continued to take the drug orally, and his condition remained stable until November 15, 2024, a period of nearly 12 months.

Claims

1. A Chinese medicine composition, which is made from the following Chinese medicines in parts by weight: The main medicine is made of 1-12 parts of wine rhubarb and 0.1-1 part of vinegar kansui; The auxiliary medicine is prepared from 20-45 parts of processed turtle shell and 0.1-1 part of realgar; The adjuvant is prepared from 1-10 parts of Sichuan pepper and 1-12 parts of donkey hide gelatin beads; The adjuvant is prepared from 1-10 parts of Indigo Naturalis and 1-12 parts of Cimicifuga Herba.

2. The Chinese medicine composition according to claim 1, wherein the Chinese medicine composition is made of the following Chinese medicines in parts by weight: The main medicine is made of 3-10 parts of wine rhubarb and 0.1-0.8 parts of vinegar kansui; The auxiliary medicine is prepared from 20-40 parts of processed turtle shell and 0.1-0.8 parts of realgar; The adjuvant is made of 1-6 parts of Sichuan pepper and 3-10 parts of donkey hide gelatin beads; The adjuvant is prepared from 1-6 parts of Indigo Naturalis and 3-10 parts of Cimicifuga Herba.

3. The Chinese medicine composition according to any one of claims 1 or 2, wherein the Chinese medicine composition is made of the following Chinese medicines in parts by weight: The main medicine is made of 5-8 parts of wine rhubarb and 0.1-0.4 parts of vinegar kansui; The auxiliary medicine is prepared from 20-35 parts of processed turtle shell and 0.1-0.4 parts of realgar; The adjuvant is made of 1-4 parts of Sichuan pepper and 5-8 parts of donkey hide gelatin beads; The adjuvant is made of 1-4 parts of Indigo Naturalis and 5-8 parts of Cimicifuga Herba.

4. The Chinese medicine composition according to any one of claims 1 to 3, wherein the recurrent ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

5. A Chinese medicine preparation, which is made from 1-12 parts of wine rhubarb, 0.1-1 parts of vinegar kansui, 20-45 parts of processed turtle shell, 0.1-1 parts of realgar, 1-10 parts of Sichuan pepper, 1-12 parts of donkey-hide gelatin beads, 1-10 parts of indigo and 1-12 parts of cimicifuga.

6. The Chinese medicine preparation as claimed in claim 5, comprising pharmaceutically acceptable excipients required for the corresponding preparation.

7. The Chinese medicine preparation as claimed in claim 6, wherein the excipient is a pharmaceutical excipient that enhances the efficacy, reduces toxicity and / or alleviates side effects of the main drug.

8. The Chinese medicine preparation according to claim 5, wherein the Chinese medicine preparation is one or more of a paste prescription, a pill, a pill, a decoction, a granule, a capsule, a powder and / or a tablet.

9. Use of the Chinese medicine composition as claimed in claim 1 in the preparation of a drug for treating recurrent ovarian cancer, wherein the Chinese medicine composition is prepared from 1-12 parts of wine rhubarb, 0.1-1 parts of vinegar kansui, 20-45 parts of processed turtle shell, 0.1-1 parts of realgar, 1-10 parts of Sichuan pepper, 1-12 parts of donkey-hide gelatin beads, 1-10 parts of indigo and 1-12 parts of cimicifuga.

10. The use according to claim 9, wherein the recurrent ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

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