A traditional Chinese medicine composition for preventing and treating recurrence and metastasis of small cell lung cancer and its application

Abstract

The present invention discloses a traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer and its application. The raw materials of the traditional Chinese medicine composition include: 30-120 parts of astragalus membranaceus, 6-15 parts of American ginseng, 5-20 parts of pseudobulbus cremastrae seu pleiones, 6-20 parts of pinellia ternata, 6-20 parts of dried tangerine peel, 6-30 parts of radix ophiopogonis, 15-60 parts of gypsum fibrosum, 3-10 parts of scorpio, 15-60 parts of dandelion, and 3-12 parts of notoginseng. The traditional Chinese medicine composition of the present invention has certain advantages in prolonging the progression-free survival time after radiotherapy and chemotherapy for small cell lung cancer, improving the clinical symptoms of patients such as cough, expectoration, fatigue, shortness of breath, loss of appetite, spontaneous sweating and night sweating, dry mouth and throat, chest tightness, etc., and reducing the adverse reactions of radiotherapy and chemotherapy.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine. More specifically, it relates to a traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer and its application. Background Art

[0002] Cancer is currently the second leading cause of death globally. According to GLOBOCAN 2020 estimates, there were 19.2927 million new cancer cases and 9.9581 million cancer deaths globally in 2020. In the next 50 years, the number of cancer patients globally will continue to rise. It is predicted that by 2070, the incidence of all cancers will be twice that in 2020, which brings a huge burden to the public health and medical systems (Soerjomataram I, Bray F. Planning for tomorrow: global cancer incidence and the role of prevention 2020 - 2070[J]. Nat Rev Clin Oncol, 2021, 18(10): 663 - 672.).

[0003] Primary lung cancer can be classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to pathological types. There are certain differences between these two types of lung cancer in terms of cell morphology, growth rate, metastasis, treatment strategies, and prognosis. SCLC accounts for about 15% - 20% of the total number of lung cancers (Kalemkerian GP, Schneider BJ. Advances in small cell lung cancer. Hematol Oncol Clin North Am, 2017, 31(1):143 - 156.), characterized by a short doubling time, strong invasiveness, easy metastasis in the early stage, the median survival time of untreated patients is only 2 - 4 months, and the 5-year survival rate is less than 5% (Rudin CM, Brambilla E, Faivre-Finn C, et al. Small-cell lung cancer[J]. Nat Rev Dis Primers, 2021, 7(1):3.). According to the scope and metastasis of the tumor, the Veterans Administration Lung Study Group (VALG) usually classifies SCLC into limited-stage small cell lung cancer (LS-SCLC) and extensive-stage small cell lung cancer (ES-SCLC). Only 1 / 3 of the patients are diagnosed with LS-SCLC at the initial diagnosis, and about 2 / 3 of the patients have metastases outside the chest at the initial diagnosis (Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer[J]. Nat Rev Dis Primers, 2021, 7(1):3.).Different from NSCLC, SCLC is more sensitive to radiotherapy and chemotherapy, and 70% of patients can achieve an objective remission. For the vast majority of LS-SCLC patients, platinum-containing chemotherapy combined with thoracic radiotherapy (TRT) is the standard treatment regimen. For patients who achieve a complete remission (CR) or partial response (PR) after first-line standard treatment, the guidelines recommend prophylactic cranial irradiation (PCI) (Peters S, Pujol JL, Dafni U, et al. Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP / IFCT 4-12 STIMULI trial[J]. Ann Oncol, 2022, 33(1):67-79.). However, this treatment method cannot continuously improve the progression-free survival (PFS) and overall survival (OS). These patients often show chemotherapy sensitivity in the initial stage (Ramalingam SS. Small-cell lung cancer: new directions for systemic therapy[J]. J Oncol Pract, 2016, 12(2):119-120.). More than 85% of patients experience recurrence and metastasis within 2 years and develop drug resistance to further treatment, resulting in a response rate of less than 20%, and then quickly progress and die (Yu J, Zhao S, Su Z, et al. Whole exome analysis reveals the genomic profiling related to chemo-resistance in Chinese population with limited-disease small cell lung cancer[J]. Cancer Med, 2023, 12(2):1035-1050.). Reducing drug resistance and delaying recurrence and metastasis are the main solutions to improve the survival of LS-SCLC. Summary of the Invention

[0004] In view of the above technical problems, an object of the present invention is to provide a new traditional Chinese medicine composition, which can prolong the progression-free survival time of patients with small cell lung cancer after radiotherapy and chemotherapy, and effectively prevent and treat the recurrence and metastasis of small cell lung cancer, especially the recurrence and metastasis of limited-stage small cell lung cancer.

[0005] Another object of the present invention is to provide a traditional Chinese medicine preparation made from the above traditional Chinese medicine composition.

[0006] Still another object of the present invention is to provide the use of the above traditional Chinese medicine composition and traditional Chinese medicine preparation in the preparation of a drug for preventing and treating the recurrence and metastasis of small cell lung cancer.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] In the first aspect, the present invention provides a traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer. The raw materials of the traditional Chinese medicine composition include: Astragalus membranaceus, American ginseng, Cremastra appendiculata, Pinellia ternata, Tangerine peel, Ophiopogon japonicus, Gypsum fibrosum, Scorpio, Taraxacum mongolicum, Notoginseng.

[0009] Preferably, by weight, the raw materials of the traditional Chinese medicine composition include: 30-120 parts of Astragalus membranaceus, 6-15 parts of American ginseng, 5-20 parts of Cremastra appendiculata, 6-20 parts of Pinellia ternata, 6-20 parts of Tangerine peel, 6-30 parts of Ophiopogon japonicus, 15-60 parts of Gypsum fibrosum, 3-10 parts of Scorpio, 15-60 parts of Taraxacum mongolicum, 3-12 parts of Notoginseng.

[0010] The syndrome of this formula originates from after the first-line treatment of small cell lung cancer, with insufficient lung fluid, yin injury and qi consumption, residual heat not cleared, cancer toxin remaining, and phlegm turbidity stagnating. For patients with small cell lung cancer after radiotherapy and chemotherapy, presenting symptoms such as cough, expectoration, fatigue, shortness of breath, loss of appetite, spontaneous sweating and night sweating, dry mouth and throat, chest tightness, with dark red tongue and white coating, and string-like pulse, the syndrome differentiation belongs to qi-yin deficiency, heat toxin congesting the lung, and phlegm-dampness stasis obstruction.

[0011] American ginseng in the formula is sweet in taste and cool in nature, replenishing qi and nourishing yin, clearing heat and promoting fluid production, and can benefit the lung qi, nourish the lung yin, and clear the lung fire, with the characteristic of replenishing qi and nourishing yin without generating heat. Cremastra appendiculata is pungent and cool, specializing in detoxifying and dissipating nodules, and can also clear heat and resolve phlegm. The combination of the two drugs replenishes qi and nourishes yin, clears heat and detoxifies, and resolves phlegm and dissipates nodules. They are used as the monarch drugs together.

[0012] Ophiopogon japonicus is sweet in flavor and slightly cold in nature. It is moist but not dry, nourishing the yin and moistening the lungs. Gypsum fibrosum is pungent, sweet and extremely cold, being good at clearing lung heat and promoting the production of body fluid to quench thirst. When combined with Ophiopogon japonicus which is sweet and cold for nourishing yin and promoting the production of body fluid, it can assist American ginseng in clearing away warm dryness and taking into account the damaged body fluid. Pinellia ternata is pungent and warm, being an important herb for resolving phlegm and dissipating nodules. Prepared with ginger, it not only enhances the function of harmonizing the stomach and stopping vomiting but also detoxifies Pinellia ternata. Pericarpium Citri Reticulatae Viride regulates qi and dissipates phlegm, relieving fullness in the chest and smoothing the diaphragm. The combination of these two herbs can, on the one hand, regulate the qi mechanism of the lung and spleen by pungent opening and bitter descending, and on the other hand, prevent the coldness of gypsum from injuring the stomach. Astragalus membranaceus is sweet and warm, belonging to the lung and spleen meridians. "Difficult Classic - Fourteenth Difficulty" states: "For those with damaged lungs, tonify their qi." Astragalus membranaceus not only supplements the deficiency and consumption of lung qi after radiotherapy and chemotherapy but also is good at tonifying the spleen qi, supplementing the earth to generate metal. When combined with American ginseng, it has the effect of strengthening the healthy qi to fight cancer. Scorpio is pungent, flat and poisonous, being good at dredging collaterals to relieve pain, detoxifying and dissipating nodules. When combined with Cremastra appendiculata, it enhances the effect of detoxifying and dissipating nodules. The combination of these six herbs can nourish qi and yin, clear away heat-toxin, and resolve phlegm nodules, and they altogether serve as the ministerial herbs.

[0013] Taraxacum mongolicum Hand.-Mazz. is good at clearing away heat-toxin and also can dissipate nodules. Panax notoginseng, also known as "Sanqi" and "Xueshen", promotes blood circulation to remove stasis and has the function of tonifying deficiency, and they altogether serve as the assistant herbs.

[0014] The combination of all herbs can altogether achieve the effects of tonifying qi and yin, clearing away heat-toxin, and resolving phlegm nodules, and is used for preventing and treating the recurrence and progression after the first-line treatment of small cell lung cancer.

[0015] Exemplarily, for the traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer, calculated by weight parts, the raw materials of the traditional Chinese medicine composition include: 80 parts of Astragalus membranaceus, 15 parts of American ginseng, 10 parts of Cremastra appendiculata, 9 parts of Pinellia ternata processed with ginger, 9 parts of Pericarpium Citri Reticulatae Viride, 15 parts of Ophiopogon japonicus, 30 parts of Gypsum fibrosum, 5 parts of Scorpio, 30 parts of Taraxacum mongolicum Hand.-Mazz., and 6 parts of Panax notoginseng.

[0016] Exemplarily, for the traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer, calculated by weight parts, the raw materials of the traditional Chinese medicine composition include: 120 parts of Astragalus membranaceus, 15 parts of American ginseng, 10 parts of Cremastra appendiculata, 9 parts of Pinellia ternata processed with ginger, 15 parts of Pericarpium Citri Reticulatae Viride, 30 parts of Ophiopogon japonicus, 45 parts of Gypsum fibrosum, 5 parts of Scorpio, 30 parts of Taraxacum mongolicum Hand.-Mazz., and 9 parts of Panax notoginseng.

[0017] Exemplarily, for the traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer, calculated by weight parts, the raw materials of the traditional Chinese medicine composition include: 45 parts of Astragalus membranaceus, 6 parts of American ginseng, 6 parts of Cremastra appendiculata, 6 parts of Pinellia ternata processed with ginger, 12 parts of Pericarpium Citri Reticulatae Viride, 15 parts of Ophiopogon japonicus, 30 parts of Gypsum fibrosum, 5 parts of Scorpio, 15 parts of Taraxacum mongolicum Hand.-Mazz., and 6 parts of Panax notoginseng.

[0018] Exemplarily, for the traditional Chinese medicine composition for preventing and treating the recurrence and metastasis of small cell lung cancer, calculated by weight parts, the raw materials of the traditional Chinese medicine composition include: 80 parts of Astragalus membranaceus, 15 parts of American ginseng, 10 parts of Cremastra appendiculata, 9 parts of Pinellia ternata processed with ginger, 15 parts of Pericarpium Citri Reticulatae Viride, 15 parts of Ophiopogon japonicus, 30 parts of Gypsum fibrosum, 5 parts of Scorpio, 30 parts of Taraxacum mongolicum Hand.-Mazz., and 6 parts of Panax notoginseng.

[0019] The basic formula of the raw materials of the above traditional Chinese medicine composition of the present invention can be adjusted based on clinical symptoms in specific embodiments on the basis of the above traditional Chinese medicine composition, so as to achieve the purpose of preventing and treating the recurrence and metastasis of small cell lung cancer and improving certain special clinical symptoms, further enhancing the adaptability of the composition of the present invention and improving the treatment effect. These adjusted formulas based on the basic formula of the present invention are also within the protection scope of this application.

[0020] In the second aspect, the present invention provides a traditional Chinese medicine preparation for preventing and treating the recurrence and metastasis of small cell lung cancer, which is prepared from the above traditional Chinese medicine composition as the raw material. Among them, the traditional Chinese medicine composition of the present invention can be first prepared according to the conventional preparation methods in the art, such as decoction method, maceration method, reflux method, etc., and then made into various traditional Chinese medicine dosage forms. Optionally, according to the actual needs of the preparation to form, pharmaceutically acceptable excipients can also be added during the preparation.

[0021] The dosage forms of the traditional Chinese medicine preparation include decoction, decoction pieces, granules, capsules, tablets, powders, pills or oral liquids, etc.

[0022] In the third aspect, the present invention also provides the application of the above traditional Chinese medicine composition or the above traditional Chinese medicine preparation in the preparation of drugs for preventing and treating the recurrence and metastasis of small cell lung cancer. In particular, the application in the preparation of drugs for preventing and treating the recurrence and metastasis of limited-stage small cell lung cancer.

[0023] In addition, unless otherwise specified, each raw material of the traditional Chinese medicine composition of the present invention can be obtained through commercial purchase, and any range recorded in the present invention includes the end values and any numerical values between the end values, as well as any sub-range composed of any numerical value between the end values or the end values, and the traditional Chinese medicine composition can achieve the purpose of preventing and treating the recurrence and metastasis of small cell lung cancer.

[0024] The beneficial effects of the present invention are as follows:

[0025] The traditional Chinese medicine composition of the present invention has certain advantages in prolonging the progression-free survival time after radiotherapy and chemotherapy for small cell lung cancer, improving clinical symptoms such as cough, expectoration, fatigue, shortness of breath, loss of appetite, spontaneous sweating and night sweating, dry mouth and throat, chest tightness, etc., and reducing the adverse reactions of radiotherapy and chemotherapy. It can be used to prevent and treat the recurrence and metastasis of small cell lung cancer, especially to prevent and treat the recurrence and metastasis of limited-stage small cell lung cancer. Description of the Drawings

[0026] Figure 1 Show the PFS survival curves of LS-SCLC patients in the exposed group and the non-exposed group. Detailed Embodiments

[0027] In order to more clearly illustrate the present invention, the present invention will be further described below in conjunction with preferred embodiments. Those skilled in the art should understand that the content specifically described below is illustrative rather than restrictive, and should not be used to limit the protection scope of the present invention.

[0028] Example 1 A traditional Chinese medicine composition for preventing and treating recurrence and metastasis of small cell lung cancer

[0029] Raw material drug formula: 80 g of Astragalus membranaceus, 15 g of American ginseng, 10 g of Cremastra appendiculata, 9 g of Pinellia ternata (processed with ginger), 9 g of Citrus reticulata Blanco, 15 g of Ophiopogon japonicus, 30 g of Gypsum fibrosum, 5 g of Scorpio, 30 g of Taraxacum mongolicum Hand.-Mazz., 6 g of Panax notoginseng

[0030] Example 2 A traditional Chinese medicine composition for preventing and treating recurrence and metastasis of small cell lung cancer

[0031] Raw material drug formula: 120 g of Astragalus membranaceus, 15 g of American ginseng, 10 g of Cremastra appendiculata, 9 g of Pinellia ternata (processed with ginger), 15 g of Citrus reticulata Blanco, 30 g of Ophiopogon japonicus, 45 g of Gypsum fibrosum, 5 g of Scorpio, 30 g of Taraxacum mongolicum Hand.-Mazz., 9 g of Panax notoginseng

[0032] Example 3 A traditional Chinese medicine composition for preventing and treating recurrence and metastasis of small cell lung cancer

[0033] Raw material drug formula: 45 g of Astragalus membranaceus, 6 g of American ginseng, 6 g of Cremastra appendiculata, 6 g of Pinellia ternata (processed with ginger), 12 g of Citrus reticulata Blanco, 15 g of Ophiopogon japonicus, 30 g of Gypsum fibrosum, 5 g of Scorpio, 15 g of Taraxacum mongolicum Hand.-Mazz., 6 g of Panax notoginseng

[0034] Test Example 1 Clinical research

[0035] 1. Research purpose

[0036] Based on real diagnosis and treatment, this study recruited LS-SCLC patients meeting the inclusion and exclusion criteria as the research subjects. With the application of traditional Chinese medicine maintenance treatment using the method of strengthening healthy qi, detoxifying, and resolving phlegm as the exposure factor, a prospective, multi-center, cohort study was carried out to evaluate the clinical efficacy and safety of traditional Chinese medicine using the method of strengthening healthy qi, detoxifying, and resolving phlegm as maintenance treatment on the recurrence and metastasis of limited-stage small cell lung cancer

[0037] 2. Research content

[0038] This study was jointly completed by 7 clinical research units across the country. With a prospective, multi-center, cohort study as the research design, limited-stage small cell lung cancer patients with effective treatment after first-line radiotherapy and chemotherapy were used as the research subjects. According to whether they received traditional Chinese medicine maintenance treatment using the method of strengthening healthy qi, detoxifying, and resolving phlegm with the Fuzheng Jiedu Huatan formula (the traditional Chinese medicine composition of the present invention) as the core as the exposure factor, they were divided into an exposure group and a non-exposure group. The main efficacy index was progression-free survival time, and the secondary efficacy indexes included progression-free survival rate, traditional Chinese medicine syndrome score, quality of life score, physical condition score, and incidence of adverse reactions, etc. The follow-up period was 24 months, and follow-up was conducted once every 12 ± 1 weeks to evaluate the clinical efficacy and safety of traditional Chinese medicine using the method of strengthening healthy qi, detoxifying, and resolving phlegm as maintenance treatment on the recurrence and metastasis of limited-stage small cell lung cancer

[0039] 3. Research plan

[0040] 3.1 Research Subjects

[0041] 3.1.1 Source of Cases

[0042] Patients were recruited from the following 7 clinical sub - centers: Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Cancer Hospital of Chinese Academy of Medical Sciences, Henan Cancer Hospital, Peking University Cancer Hospital, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Air Force Characteristic Medical Center, and Beijing Fengtai You'anmen Hospital.

[0043] 3.1.2 Diagnostic and Staging Criteria

[0044] (1) Diagnosis of small - cell lung cancer: Definite diagnosis was made through cytology or pathology.

[0045] (2) Staging criteria: The staging method combined the Veterans Administration Lung Group (VALG) staging system and the AJCC TNM staging system:

[0046] ① VALG stage II staging method: Limited stage: The lesion is confined to one side of the chest cavity and can be included in one radiation field; Extensive stage: The lesion exceeds one side of the chest cavity and includes malignant pleural effusion, pericardial effusion, or hematogenous metastasis.

[0047] ② Limited stage: AJCC (8th edition) stage I - III (any T, any N, M0), and radical radiotherapy dose can be safely used, excluding T3 - 4 due to multiple pulmonary nodules or large tumor / nodule volume that cannot be included in a tolerable radiotherapy plan; Extensive stage: AJCC (8th edition) stage IV (any T, any N, M1a / b / c), or T3 - 4 due to multiple pulmonary nodules or large tumor / nodule volume that cannot be included in a tolerable radiotherapy plan.

[0048] (3) Diagnostic criteria for TCM syndrome elements: Referring to the 2014 edition of the "TCM Diagnosis and Treatment Guidelines for Malignant Tumors", the TCM syndrome elements of small - cell lung cancer were formulated.

[0049] 3.1.3 Inclusion Criteria

[0050] (1) Aged 18 - 75 years.

[0051] (2) Having a definite cytological or pathological diagnosis.

[0052] (3) Limited - stage small - cell patients who had previously received and completed first - line treatment (standard chemoradiotherapy regimen), with a chemotherapy course of ≥ 4 cycles and an efficacy evaluation of effective (SD, PR, or CR).

[0053] (4) Projected survival period of ≥ 3 months.

[0054] (5) ECOG performance status score of 0 - 2.

[0055] (6) At the time of enrollment, the time of completion of first-line treatment was no more than 1 month, and there was no recurrence or metastasis.

[0056] (7) Voluntarily participate in this study and sign the informed consent form.

[0057] 3.1.4 Exclusion criteria

[0058] (1) Patients with limited-stage small cell lung cancer who have undergone surgical treatment.

[0059] (2) Patients with severe diseases such as heart, liver, kidney, and hematopoietic systems.

[0060] (3) Patients known to be allergic to the study drugs.

[0061] (4) Children, pregnant women, psychiatric patients, and patients with other malignant tumors.

[0062] (5) Patients who are currently participating in other drug clinical trials.

[0063] (6) Other situations that the researcher believes will prevent the patient from participating in this trial.

[0064] 3.1.5 Exclusion criteria

[0065] (1) Patients who were misenrolled because they did not meet the inclusion and exclusion criteria;

[0066] (2) Subjects who violated the protocol, such as adding non-prescribed combination medications during the follow-up process, seriously affecting the judgment of effectiveness and safety;

[0067] (3) Subjects with seriously incomplete observation records, such as: no record of the main clinical outcome.

[0068] 3.1.6 Withdrawal criteria

[0069] (1) The researcher decides to withdraw

[0070] The subject has poor compliance, or changes medications on their own or adds non-prescribed combination medications midway, especially those that have a greater impact on this study, affecting the judgment of effectiveness and safety.

[0071] (2) The subject withdraws on their own

[0072] ① Regardless of the reason, the patient is unwilling or unable to continue the clinical observation study and requests to withdraw from the study from the attending physician.

[0073] ② Although the subject does not explicitly request to withdraw from the study, they are lost to follow-up because they no longer accept medications and follow-up.

[0074] (3) Handling of withdrawn cases

[0075] For cases that withdraw from the trial midway or are lost to follow-up and drop out, the researcher should actively take measures to complete the last test as much as possible to prepare for the analysis of their efficacy and safety. For all drop-out cases, the trial conclusion form and the reasons for case drop-out should be filled in the case report form.

[0076] 3.2 Sample size calculation

[0077] A total of 238 cases were collected, with 119 cases in the exposed group (traditional Chinese and Western medicine cohort) and 119 cases in the non-exposed group (Western medicine cohort). The sample size of the Cox proportional hazards model was calculated according to the following formula:

[0078]

[0079] p1 and p2 are the percentages of the total number of cases in the exposed group and the non-exposed group respectively; d is the probability that the outcome event of the subject can be detected during the exposure period; b = log(HR), where HR is the hazard ratio of the non-exposed group relative to the exposed group. Assuming that the disease progression rate in the non-exposed group is 72% and the disease progression rate in the exposed group is 54%, to test the difference in the disease progression rate between the exposed group and the non-exposed group. Assuming HR = 1.88, d = 0.80, p1 = p2 = 0.50 (the number of cases in the exposed group and the non-exposed group is the same), using a two-sided test with α = 0.05 and a test power of 80%, calculated by SAS 9.4 software, 99 patients need to be enrolled in each group, with an estimated 20% of lost-to-follow-up cases, 119 cases in each group, and a total of 238 patients need to be enrolled.

[0080] 3.3 Grouping and treatment plan

[0081] Taking the traditional Chinese medicine maintenance treatment of the method of strengthening healthy qi, detoxifying and resolving phlegm as the exposure factor, it was divided into a non-exposed group (Western medicine cohort) and an exposed group (traditional Chinese and Western medicine cohort).

[0082] 3.3.1 Non-exposed group (Western medicine cohort): According to the 2021 version of the NCCN Clinical Practice Guidelines for Small Cell Lung Cancer, standard first-line treatments such as chemotherapy and chest radiotherapy were carried out, and no traditional Chinese medicine maintenance treatment was carried out after the treatment and enrollment.

[0083] 3.3.2 Exposed group (traditional Chinese and Western medicine cohort): According to the 2021 version of the NCCN Clinical Practice Guidelines for Small Cell Lung Cancer, standard first-line treatments such as chemotherapy and chest radiotherapy were carried out, and traditional Chinese medicine maintenance treatment was given after the treatment and enrollment. The prescription composition includes 80g of Astragalus membranaceus, 15g of American ginseng, 10g of Typhonium giganteum, 9g of Pinellia ternata, 9g of Tangerine peel, 15g of Ophiopogon japonicus, 30g of Gypsum fibrosum, 5g of Scorpio, 30g of Taraxacum mongolicum, and 6g of Notoginseng, twice a day, and continuous treatment for ≥3 months.

[0084] 3.4 Observation indicators:

[0085] 3.4.1 Main observation indicators

[0086] Progression free survival (PFS): The time from enrollment until the first progression of the tumor or death (due to any cause) or the end of follow-up.

[0087] 3.4.2 Secondary observation indicators

[0088] (1) Progression-free survival rate: The progression-free survival rates at 6 months, 12 months, and 24 months after enrollment.

[0089] (2) Traditional Chinese medicine (TCM) syndrome score: Using the TCM syndrome score scale for small cell lung cancer: at baseline and once every 12 ± 1 weeks during the follow-up period.

[0090] (3) Quality of life assessment: Using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale for lung cancer patients: at baseline and once every 12 ± 1 weeks during the follow-up period.

[0091] (4) Physical condition scores (ECOG, KPS scores): at baseline and once every 12 ± 1 weeks during the follow-up period.

[0092] (5) Safety indicators: at baseline and once every 12 ± 1 weeks during the follow-up period, check blood routine, liver and kidney functions, etc.

[0093] 3.5 Efficacy evaluation criteria

[0094] (1) Evaluation criteria for solid tumor efficacy

[0095] According to the "New Version of the Evaluation Criteria for Solid Tumor Efficacy: Revised RECIST Guidelines (Version 1.1)" revised in 2009, progression (PD), stable disease (SD), partial response (PR), and complete response (CR) are evaluated.

[0096] (2) Evaluation criteria for TCM syndrome integral

[0097] The formulation of the TCM syndrome integral scale is based on relevant literature and the clinical symptoms of small cell lung cancer patients after radiotherapy and chemotherapy. The observation content of this scale covers common symptoms of patients, including cough, hemoptysis, fever, chest pain, shortness of breath, fatigue, anorexia, insomnia, reluctance to talk, expectoration, complexion pallor, dry mouth, dizziness, loose stools, fullness and distension in the chest and hypochondrium, constipation, night sweats, spontaneous sweating, five palm heat, abdominal distension, soreness and weakness of the waist and knees, etc. To quantify these symptoms, the scale divides the symptoms into 4 grades: severe (count 3 points), moderate (count 2 points), mild (count 1 point), and none (count 0 point). Observe and record the TCM syndrome integrals of the two groups of patients before and after enrollment.

[0098] (3) Quality of life assessment

[0099] The Functional Assessment of Cancer Therapy-Lung (FACT-L) scale for evaluating the quality of life of lung cancer patients was used. This scale consists of five core modules: physical status, social / family status, emotional status, functional status, and specific concerns for small cell lung cancer. The scores of each module were calculated separately, and these scores were added together to obtain the total score. The total scores of the scale and the score changes of each module before and after enrollment were recorded and compared between the two groups of patients.

[0100] (4) Karnofsky (KPS) scoring criteria

[0101] The ECOG scores of the two groups of patients before and after enrollment were observed and recorded.

[0102] (5) ECOG scoring criteria

[0103] The ECOG scores of the two groups of patients before and after enrollment were observed and recorded.

[0104] 3.6 Follow-up

[0105] Follow-up was conducted through outpatient reexamination, phone calls, or WeChat. Observation started from enrollment for 24 months or until the main observation outcome index occurred or death occurred. Follow-up was conducted once every 12 ± 1 weeks during the follow-up period.

[0106] 3.7 Quality control and data management

[0107] The researchers participating in the project had all received relevant training and passed the evaluation of data extraction consistency. The filling process adopted the mode of filling out forms - proofreading - inputting - verification. The data was input into Epidata 3.1 to establish a database. Excel was used for preliminary calculation and collation.

[0108] 3.8 Statistical analysis

[0109] Statistical analysis was implemented using SAS 9.4 and IBM SPSS 26.0 software. Measurement data that conformed to the normal distribution were expressed as mean ± standard deviation and the independent samples t-test was used for between-group comparison, while the paired t-test was used for within-group comparison; measurement data that did not conform to the normal distribution were expressed as median (25% quantile, 75% quantile), and the Wilcoxon rank sum test was used for between-group and within-group comparison; count data were expressed as frequency and / or percentage, and the χ 2For the inspection, the Wilcoxon rank sum test was used for ranked data. The Kaplan-Meier method was applied to estimate the survival rate of patients and plot the survival curve. The Log-rank test was used to compare the survival time (rate). All statistical analysis tests were two-sided hypothesis tests, and the significance level was set at α = 0.05, that is, P < 0.05 was considered statistically significant for the tests performed.

[0110] 4 Research Results

[0111] 4.1 Enrollment and Case Completion

[0112] From November 16, 2021 to January 15, 2023, a total of 240 patients were enrolled in this project. 4 patients were excluded due to not meeting the inclusion and exclusion criteria. During the follow-up process, 33 patients were lost to follow-up, withdrew the informed consent form, etc., and the dropout rate was 15.41%, meeting the requirements of the research protocol. Finally, a total of 203 patients were included in the statistical analysis, including 104 patients in the exposed group (traditional Chinese and Western medicine cohort) and 99 patients in the non-exposed group (Western medicine cohort). The last follow-up date was January 17, 2024, and the median follow-up time was 565.00 days.

[0113] 4.3 Baseline Data

[0114] 4.3.1 Demographic Data

[0115] (1) Gender Distribution

[0116] There were 203 patients in total in the two groups, including 151 male patients, accounting for 74.38%; 52 female patients, accounting for 25.62%. In the non-exposed group, there were 73 male patients (73.74%) and 26 female patients (26.26%); in the exposed group, there were 78 male patients (75.00%) and 26 female patients (25.00%). The chi-square test was performed on the gender information of the two groups of patients, and P = 0.8368, with no statistically significant difference (P > 0.05). See Table 1.

[0117] Table 1 Gender Distribution in Two Groups

[0118]

[0119] (2) Age Distribution

[0120] There were 203 patients in total in the two groups. In the non-exposed group, the minimum age was 29 years old, the maximum age was 75 years old, the average age was 57.68 ± 9.57 years old, and the median age was 59 years old; in the exposed group, the minimum age was 23 years old, the maximum age was 75 years old, the average age was 57.39 ± 9.77 years old, and the median age was 58 years old. The independent samples t-test was performed on the age information of the two groups of patients, and P = 0.6494, with no statistically significant difference (P > 0.05). See Table 2.

[0121] Table 2 Age distribution of two groups

[0122]

[0123]

[0124] 4.3.2 Personal history

[0125] The chi-square tests were performed on the smoking index and alcohol consumption of the two groups of patients, and the P values were 0.2338 and 0.5690 respectively, and the differences were not statistically significant (P>0.05). See Table 3.

[0126] Table 3 Distribution of personal history information of two groups

[0127]

[0128] 4.3.3 Disease assessment

[0129] The inter-group comparisons were performed on the information of the primary lesion site, T stage, N stage, immunohistochemical Ki-67 index, pro-gastrin-releasing peptide (Pro-GRP), neuron-specific enolase (NSE), uric acid (UA), blood glucose (GLU), KPS score, ECOG score, etc. of the two groups of patients, and the differences were not statistically significant (P>0.05). See Tables 4-1, 4-2 and 4-3.

[0130] Table 4-1 Distribution of disease information of two groups

[0131]

[0132]

[0133] Table 4-2 Distribution of disease information of two groups (continued)

[0134]

[0135] Table 4-3 Distribution of disease information of two groups (continued)

[0136]

[0137]

[0138] 4.4 Efficacy analysis

[0139] 4.4.1 Main efficacy index - PFS

[0140] Among the exposed group, 53 cases (50.96%) had disease progression, and among the non-exposed group, 73 cases (73.74%) had disease progression. The progression-free survival time was estimated by the Kaplan-Meier method to obtain the PFS of the subjects, and the survival curve was plotted. The median PFS of the non-exposed group was 214.00 days, and the median PFS of the exposed group was 412.00 days; after Log-rank test, the statistic χ2 = 18.70, P value < 0.001, and the difference between groups was statistically significant (P < 0.05). See Table 5. Figure 1 .

[0141] Table 5 Distribution and comparison of overall disease progression in two groups

[0142]

[0143] 4.4.2 Secondary efficacy indicators

[0144] 4.4.2.1 Progression-free survival rate

[0145] The Kaplan-Meier method was used to estimate the progression-free survival rate of the subjects. The 6-month progression-free survival rates of the two cohorts of patients were 50.51% and 80.71% respectively, the 12-month progression-free survival rates were 31.22% and 56.78% respectively, and the 24-month progression-free survival rates were 19.48% and 46.14% respectively, and the differences were statistically significant (P < 0.001). See Table 6.

[0146] Table 6 Comparison of progression-free survival rates between two groups (%)

[0147]

[0148] 4.4.2.2 Traditional Chinese medicine syndrome score

[0149] Comparison between the exposed group and the non-exposed group: There was no statistically significant difference in the baseline distribution of the total score of the traditional Chinese medicine syndrome scale and the integral scores of sub-symptoms such as cough and hemoptysis between the two groups (P > 0.05), and they were comparable. At the first cycle of follow-up, in terms of the total score of the scale, the improvement of the traditional Chinese medicine syndrome scale score in the exposed group was better than that in the non-exposed group, and the difference between groups was statistically significant (P < 0.05); in terms of symptoms, the exposed group was superior to the non-exposed group in improving cough, shortness of breath, fatigue, expectoration, constipation, night sweats, spontaneous sweating, and abdominal distension, and the difference between groups was statistically significant (P < 0.05).

[0150] Comparison within the exposed group and the non-exposed group: The total score of the traditional Chinese medicine syndrome scale of the patients in the exposed group tended to decline, and the difference in scores before and after enrollment was statistically significant (P<0.05). Specifically, after maintenance treatment with traditional Chinese medicine using the method of strengthening the healthy qi, detoxifying, and resolving phlegm, symptoms such as cough, hemoptysis, chest pain, shortness of breath, fatigue, anorexia, insomnia, expectoration, dry mouth, fullness and distension in the chest and hypochondrium, constipation, spontaneous sweating, night sweats, and abdominal distension in the patients of the exposed group were all improved compared with the baseline at the time of enrollment, and the difference was statistically significant (P<0.05); in the non-exposed group, some syndrome scores increased and some decreased before and after enrollment, but the difference was not statistically significant (P>0.05). See Table 7-1 and Table 7-2.

[0151] Table 7-1 Comparison of Traditional Chinese Medicine Syndrome Scores between the Two Groups

[0152]

[0153]

[0154] Note: Comparison within the group: * P<0.05, ** P<0.01; Comparison between the groups: # P<0.05, ## P<0.01.

[0155] Table 7-2 Comparison of Traditional Chinese Medicine Syndrome Scores between the Two Groups (Continued)

[0156]

[0157] Note: Comparison within the group: * P<0.05, ** P<0.01; Comparison between the groups: # P<0.05, ## P<0.01.

[0158] 4.4.2.3 Quality of Life Score

[0159] Comparison between the exposed group and the non-exposed group: There was no statistically significant difference in the baseline distribution of physiological status, social / family situation, emotional situation, functional status, additional attention items, and total quality of life score between the two groups (P>0.05), so the two groups were comparable. Generally speaking, in terms of the total quality of life score, the exposed group was higher than the non-exposed group in the first follow-up period after enrollment, and the difference between the groups was statistically significant (P<0.05). Specifically for each module of the scale, the scores of physiological status, social / family situation, emotional situation, functional status, and additional attention items in the exposed group were all higher than those in the non-exposed group after enrollment, and the difference was statistically significant (P<0.05).

[0160] Comparison within the exposed group and the non-exposed group: In the first follow-up period after enrollment, the physiological status, scores of additional attention items, and total quality of life scores of patients in the non-exposed group showed a downward trend (P<0.05), indicating a decline in the quality of life of patients during the follow-up period after chemoradiotherapy. In the first follow-up period after enrollment in the exposed group, the physiological status, social / family status, emotional status, functional status, scores of additional attention items, and total quality of life scores were all significantly improved compared with those at the time of enrollment (P<0.05), indicating that maintaining treatment with traditional Chinese medicine using the method of strengthening healthy qi, detoxifying, and resolving phlegm after chemoradiotherapy can improve the quality of life of LS-SCLC patients after the first-line treatment. See Table 8.

[0161] Table 8 Comparison of quality of life scores between the two groups

[0162]

[0163] Note: Comparison within the group: * P<0.05, ** P<0.01; Comparison between groups: # P<0.05, ## P<0.01.

[0164] 4.4.2.4 KPS score

[0165] Comparison of KPS scores between the exposed group and the non-exposed group: There was no statistically significant difference in the KPS scores at baseline between the two groups. In the first follow-up period after enrollment, the average KPS score of the exposed group was 88.85±6.40 points, higher than 86.87±7.06 points of the non-exposed group, and the difference was statistically significant (P<0.05).

[0166] Comparison of KPS scores within the exposed group and the non-exposed group: There was no significant change in the average KPS scores of the exposed group and the non-exposed group in the first follow-up period after enrollment (P>0.05). See Table 9.

[0167] Table 9 Comparison of KPS scores between the two groups

[0168]

[0169] Note: Comparison between groups: # P<0.05.

[0170] 4.4.2.5 ECOG score

[0171] Comparison of ECOG scores between the exposed group and the non-exposed group: There was no statistically significant difference in the ECOG scores at baseline between the two groups. In the first follow-up period after enrollment, there was also no significant change in the ECOG scores of the exposed group and the non-exposed group (P>0.05).

[0172] Intra-group comparison of ECOG scores in the exposed group and the non-exposed group: There were no significant changes in the ECOG scores of the exposed group and the non-exposed group in the first follow-up cycle after enrollment (P>0.05). See Table 10.

[0173] Table 10 Comparison of ECOG scores between the two groups 4.4.3 Safety analysis;

[0174] 4.4.3.1 Adverse reactions in the hematological system

[0175] In terms of adverse reactions in the hematological system such as leukopenia, neutropenia, and thrombocytopenia, there were no significant differences between the exposed group and the non-exposed group after Wilcoxon rank sum test (P>0.05). However, in terms of anemia, compared with the non-exposed group, the exposed group of patients after enrollment could improve the adverse reaction of anemia, and the difference was statistically significant (P<0.05). See Table 11.

[0176] Table 11 Comparison of adverse reactions in the hematological system between the two groups

[0177]

[0178]

[0179] Note: Comparison between groups: # P<0.05.

[0180] 4.4.3.2 Adverse reactions in the digestive system

[0181] In terms of adverse reactions in the digestive system such as elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated γ-glutamyl transpeptidase, and elevated total bilirubin, there were no significant differences between the exposed group and the non-exposed group after Wilcoxon rank sum test (P>0.05). See Table 12.

[0182] Table 12 Comparison of adverse reactions in the digestive system between the two groups

[0183]

[0184] 4.4.3.3 Adverse reactions in the urinary system

[0185] In terms of adverse reactions in the urinary system such as increased creatinine and proteinuria, there were no significant differences between the exposed group and the non-exposed group after Wilcoxon rank sum test (P>0.05). See Table 13.

[0186] Table 13 Comparison of adverse reactions in the urinary system between the two groups

[0187]

[0188] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the implementation manners here. Any obvious changes or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A Chinese medicine composition for preventing and treating recurrence and metastasis of small cell lung cancer, characterized in that: The traditional Chinese medicine composition is made of the following raw materials in parts by weight: 30-120 parts of astragalus, 6-15 parts of American ginseng, 5-20 parts of trillium, 6-20 parts of pinellia, 6-20 parts of tangerine peel, 6-30 parts of ophiopogon, 15-60 parts of gypsum, 3-10 parts of scorpion, 15-60 parts of dandelion, and 3-12 parts of Panax notoginseng.

2. The Chinese medicine composition according to claim 1, characterized in that: The Chinese medicine composition is made of the following raw materials in parts by weight: 80 parts of astragalus, 15 parts of American ginseng, 10 parts of trillium, 9 parts of pinellia, 9 parts of tangerine peel, 15 parts of ophiopogon, 30 parts of gypsum, 5 parts of scorpion, 30 parts of dandelion and 6 parts of Panax notoginseng.

3. The Chinese medicine composition according to claim 1, characterized in that The Chinese medicine composition is made of the following raw materials in parts by weight: 120 parts of astragalus, 15 parts of American ginseng, 10 parts of trillium, 9 parts of pinellia, 15 parts of tangerine peel, 30 parts of ophiopogon, 45 parts of gypsum, 5 parts of scorpion, 30 parts of dandelion, and 9 parts of Panax notoginseng.

4. The Chinese medicine composition according to claim 1, characterized in that: The Chinese medicine composition is made of the following raw materials in parts by weight: 45 parts of astragalus, 6 parts of American ginseng, 6 parts of trillium, 6 parts of pinellia, 12 parts of tangerine peel, 15 parts of ophiopogon, 30 parts of gypsum, 5 parts of scorpion, 15 parts of dandelion, and 6 parts of Panax notoginseng.

5. The Chinese medicine composition according to claim 1, characterized in that: The Chinese medicine composition is made of the following raw materials in parts by weight: 80 parts of astragalus, 15 parts of American ginseng, 10 parts of trillium, 9 parts of pinellia, 15 parts of tangerine peel, 15 parts of ophiopogon, 30 parts of gypsum, 5 parts of scorpion, 30 parts of dandelion and 6 parts of Panax notoginseng.

6. A Chinese medicine preparation for preventing and treating recurrence and metastasis of small cell lung cancer, characterized in that: The Chinese medicine preparation is prepared using the Chinese medicine composition according to any one of claims 1 to 5 as a raw material.

7. The Chinese medicine preparation according to claim 6, characterized in that: The traditional Chinese medicine preparation also includes pharmaceutically acceptable excipients.

8. The Chinese medicine preparation according to claim 6 or 7, characterized in that: The dosage form of the Chinese medicine preparation includes decoction, granules, capsules, tablets, powders, pills or oral liquids.

9. Use of the Chinese medicine composition according to any one of claims 1 to 5 or the Chinese medicine preparation according to any one of claims 6 to 8 in the preparation of a medicament for preventing and treating recurrence and metastasis of small cell lung cancer.

10. The use according to claim 9, characterized in that: The prevention and treatment of recurrence and metastasis of small cell lung cancer refers to the prevention and treatment of recurrence and metastasis of localized small cell lung cancer.

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