Progress in diagnosis and treatment of small cell lung cancer with integrated traditional Chinese and Western medicine

Background

Primary bronchial lung cancer,referred to as lung cancer,is a malignant tumor originating from the bronchial mucosa or glands of the lung,and its morbidity and mortality are at the forefront of malignant tumors at home and abroad.Over the years,the morbidity and mortality of lung cancer have gradually increased,hindering the increase of life expectancy in countries around the world.SCLC accounts for more than 20% of lung cancer and is prone to metastasis at an early stage.The average survival time of Extensive stage small cell lung cancer patients without treatment is only 6–8 weeks,with the strong invasion of cancer cells and extremely poor condition of patients[1].In recent years,the survival rate of patients with NSCLC has improved rapidly,but the survival rate of patients with SCLC remains at 14% to 15%,less than 50% of the survival rate of patients with non-SCLC[2].The western medicine treatment of lung cancer is mainly surgery,chemotherapy,radiotherapy,molecular targeted therapy,and immunotherapy,in which the effective rate of molecular targeted therapy has been significantly improved in recent years,however,drug resistance and side effects caused by various treatment methods have seriously affected the quality of life of patients,western medicine is still lack of appropriate drugs and interventions[3].Radiotherapy and chemotherapy are still the standard treatment for Limited-stage(LS-SCLC)and extensive-stage(ES-SCLC)in the diagnosis and treatment of SCLC in western medicine.However,recurrence and metastasis are easy to occur after standard treatment,drug resistance to chemotherapy and high recurrence and metastasis rate after standard treatment are still difficult medical problems in clinical practice.Reducing the recurrence and metastasis of SCLC after standard treatment and prolonging the survival time of patients is the focus of prevention and treatment of SCLC[4].After long-term clinical and experimental research,it is found that TCM is not only effective in the treatment of lung cancer but also has more obvious advantages in reducing the adverse reactions produced by western medicine and prolonging the survival time of patients.Therefore,the treatment of lung cancer has gradually developed to the direction of integrated traditional Chinese and Western medicine[5,6].In this paper,the treatment of SCLC with integrated traditional Chinese and western medicine in recent years is summarized as follows.

You will not go to sea again, Jurgen, I suppose, observed one ofthe old fishermen. You will always stay with us now. But this was not Jurgen s intention; he wanted to see something ofthe world. The eel-breeder of Fjaltring had an uncle at Old Skjagen,who was a fisherman, but also a prosperous merchant with ships upon the sea; he was said to be a good old man, and it would not be a bad thing to enter his service. Old Skjagen lies in the extreme north of Jutland, as far away from the Hunsby dunes as one can travel in that country; and this is just what pleased Jurgen, for he did not wantto remain till the wedding of Martin and Else, which would takeplace in a week or two.

I couldn t believe my ears. Had I heard right? Was he talking to me? On my family s modest income, Coke was not a part of our budget or diet. A few tantalizing5 sips6 was all I had ever had, and certainly never my own bottle.

Syndrome differentiation and treatment of SCLC in TCM

There is no “lung cancer” name in traditional medicine,according to the symptoms and signs,it belongs to the categories of “pulmonary accumulation” and “Xiben” in TCM.As the

said,“The accumulation of the lungs,called Xibi,is as big as a cup under the right flank.It lasts for a long time,making people feel cold and hot,wheezing and coughing,and causing congestion of the lungs.” “Plain Questions · Treatise on Strange Diseases,” said,“under the threat of disease,full of Qi and upward reversal,…… The name of the disease is Xiji,which doesn't interfere with diet.” As for the treatment of lung cancer,the ancient records of TCM records have experienced the perfection from the application of simple drugs in the Pre-Qin Dynasty to the application of principle-method-recipe-medicines in the Ming and Qing Dynasty[7].In the long-term clinical practice,modern TCM experts have summarized the unique ideas and experience of syndrome differentiation and treatment of lung cancer,which has important guiding significance for the research and application of integrated traditional Chinese and Western medicine therapy for lung cancer[6].Like most malignant tumors,the death of lung cancer is more often caused by multiple organ injuries,failure,and excessive consumption of systemic substances and energy,rather than the primary focus itself[8].Clinical practice has found that phlegm and blood stasis are important etiology and pathogenesis in the occurrence and development of lung cancer.Phlegm toxin and blood stasis toxin gather in the human body and finally form lung cancer[9].Compared with NSCLC,SCLC patients have more phlegm toxin and blood stasis toxin,and in the early stage of the disease,phlegm toxin and blood stasis toxin in SCLC patients have spread to other organs of the body,resulting in multiple organs being invaded by the evil toxin,causing serious damage to vital qi and causing serious damage to the body.

Professor Hua Baojin believes that the pathogenesis of SCLC is based on positive deficiency,smoke poison invasion,loss of qi rising,and fall.Smoking is the main risk factor of SCLC,smoke poisons the lung consumes lung yin due to dryness,and damages blood vessels with poison.“Plain Question Another Discussion on Meridians,” said,“the airflow of the meridians,the meridians belong to the lung,the lung collects all meridians”,lungs are delicate organs susceptible to evil influence,the lung qi is damaged,and then the smoke and poison flow through the whole body with the blood,which will inevitably lead to the dysfunction of the viscera.The spleen is damaged and then the lung is injured,the spleen loses function and produces phlegm and dampness,which stops accumulating in the lungs.Although SCLC is common with lung symptoms such as cough,shortness of breath,chest pain,hemoptysis,and other lung symptoms,it reflects the deficiency of vital qi in the body,which is not enough to drive out evil spirits,the rise,and fall of visceral Qi machine is an imbalance,and the disease and evil stop in the lung to form cancer.It is mentioned in

:“Where evil gathers together,its qi must be deficient.” With the joint efforts of modern doctors' practical experience and clinical basic research,it is proposed that “positive deficiency” is the root cause of the occurrence and progression of SCLC[5,10,11].SCLC has rapid progress and strong invasiveness.It is sensitive to first-line chemotherapeutic drugs such as etoposide,platinum injection,and radiation.Professor Hua Baojin focuses on “supplementing qi and strengthening health,supplement ted by expelling evil and detoxification”.The treatment of SCLC will be carried out by strengthening the vital energy and regulating the rise and fall of qi throughout the treatment of SCLC.

Zhou Daihan and Lin Lizhu believe that the pathogenesis of lung cancer is not separated from the lung and spleen,because the lung and spleen are closely related to the generation of qi and body fluid metabolism[12,13].The spleen transports and transforms the essence of water and grain,the lungs breathe and inhale natural clear qi,and the second gasification accumulates in the chest,passing through the rest channel,breathing,passing through the heart pulse,and promoting qi and blood.The spleen is the source of phlegm,and the lung is the device for storing phlegm.The movement and transformation of spleen deficiency are unbalanced,water dampness stops inside,dampness accumulates to generate phlegm,phlegm forms lung collaterals,lung qi depression,Xinjiang loses division,and accumulates.Therefore,in the treatment of lung cancer,we should pay attention to tonifying the spleen and benefiting the lung,making the spleen transport water dampness,dredging the water channel of the lung,and then carry out the method of Qi removing phlegm and dispersing knot to eliminate the pathogenic products such as “phlegm”and “blood stasis”[14].

In the clinical practice of treating SCLC with classical prescriptions,Professor Hua Baojin followed the ancient treatment principles without being bound by them,gave full play to the distinctive characteristics of classical prescriptions,and combined,added,and subtracted different classical prescriptions according to the complexity of the pathogenesis of SCLC.For example,during chemotherapy,nausea,vomiting,and abdominal distension are seen,and more serious conditions are vertigo and fatigue,which belong to stomach qi inversion and deficiency of middle qi,and can be treated with the addition and subtraction of Xuanfu Daizhe Decoction with Xuanfu decoction.People with severe stomach qi injury and deficiency of lung and spleen are treated with Xuan Fu instead of ochre decoction and Huangqi Guizhi Wuwu decoction to replenish qi and decrease the upward qi of the stomach.Patients whose bone marrow cannot inhibit blood well should use Siwu decoction and add the appropriate amount of Dodder,Degelatined deer-horn,and Polygonatum,to nourish liver and kidney,warm yang,and tonify blood.Fear of cold,cold limbs and weak spirit,syndrome differentiation is lack of kidney yang,If the disease belongs to Shaolin,add Sini decoction or Shenqi Pill to warm and tonify kidney yang and help Yang turn Qi.In case of belching swallowing acid,fear of cold,epigastric fullness,chills in hands and feet,and mixed chills and heat,the prescription of Wumei Pill should be added to warm the liver pulse and clear the upper and lower temperature,which can effectively alleviate the adverse reactions of chemotherapy[4].Zhuang Ying used Linggui Zhugan Decoction to observe 32 patients with SCLC undergoing chemotherapy.It was found that the total inhibition rate of vomiting in patients treated with TMR after chemotherapy could reach 93.75%[36].

Treatment of SCLC with integrated traditional Chinese and Western Medicine

TCM combined with surgery

After the end of the chemotherapy process,Professor Hua Baojin believes that recuperating the spleen and stomach is to protect the vital qi,to make the spleen and stomach move healthily,to transport the vital qi to the lungs,to grow the lung qi,to smooth the way for the human body to discharge water,to maintain the liver and kidney,to strengthen the bones,and to nourish the blood veins.Phlegm and dampness have no way to gather.Spleen qi rising and clearing,lung qi decreasing,qi rising and falling returning to normal,promoting blood circulation and removing blood stasis,clearing heat and detoxification,and clearing lung meridians.Therefore,tonifying qi and invigorating spleen,activating blood circulation and detoxification as the basic treatment,clearing heat toxin,activating blood circulation,and removing blood stasis in the lung meridian based on strengthening the body can effectively prolong the survival time of patients with SCLC[4,10,11,20].Dong Haitao’s research also shows that radiotherapy and chemotherapy combined with TCM can benefit patients in long-term survival.Proprietary Chinese medicine and TCM preparations are also used in the treatment of SCLC[30].Clinical observation has provided several cases of Chinese herbal medicines(CHM)prolongation of ES-SCLC patients with overall survival(OS)to improve the survival rate.For example,compared with radiotherapy alone and post-chemotherapy,the median overall survival rates of patients treated with TCM were 7.6 months and 11.1 months,respectively,and the 1-year survival rates were 18.2% and 38.6%,respectively[31].Zhang Xiuhui et al randomly divided 78 cases of SCLC into treatment groups with TCM combined with chemotherapy and the control group with chemotherapy alone.There were 36 patients in each group.The survival rates of 11 months,22 months,and 33 months in the two groups were compared with those in the control group.Survival benefit(

<0.05)[32].From the above evidence,it can be concluded that TCM combined with chemotherapy can effectively prolong the survival time of SCLC patients.

Everybody looked at her feet, and the whole of the way from the church door to the choir6 it seemed to her as if even the ancient figures on the monuments, in their stiff collars and long black robes, had their eyes fixed7 on her red shoes. It was only of these that she thought when the clergyman laid his hand upon her head and spoke8 of the holy baptism, of the covenant9 with God, and told her that she was now to be a grown-up Christian10. The organ pealed11 forth12 solemnly, and the sweet children’s voices mingled13 with that of their old leader; but Karen thought only of her red shoes. In the afternoon the old lady heard from everybody that Karen had worn red shoes. She said that it was a shocking thing to do, that it was very improper14, and that Karen was always to go to church in future in black shoes, even if they were old.

Zhao Yuwei and others have shown that strengthening the spleen and stomach and nourishing vital energy after the operation is very beneficial to improve the survival rate of patients with SCLC[20].Jianping Yiqi recipe is composed of Codonopsis pilosula,Large-headed atractylodes,Poria cocos,Honey-fried licorice root,Ginger processed pinellia,Dried orange peel,Parched hawthorn fruit,Coke malt,Charred triplet,Endothelium corneum Nigeria Galli,Amomum villosum,and Semen coicis.This recipe treats codonopsis pilosula as the monarch drug in a prescription,which plays the role of tonifying the spleen and replenishing qi.Some modern pharmacological studies have found that Codonopsis pilosula can regulate gastric contraction and regulate the release of inflammatory factors to protect gastrointestinal mucosa.Moreover,Codonopsis pilosula polysaccharides can also enhance the phagocytosis of the reticuloendothelial system and exert immunomodulatory function[21].Some studies have also found that Codonopsis pilosula can improve the tissue structure of alveolar cells,reduce the production of inflammatory factors,and then improve lung function and make lung qi rise and decrease normally[22].In this prescription Large-headed atractylodes,Poria cocos,Semen coicis,and Dried orange peel are combined,benefiting water and dampness,invigorating the spleen and replenishing qi,tonify the lungs,and having a direct therapeutic effect on the accumulation of dampness in the body and the growth of phlegm in the body caused by deficiency of lung and spleen qi,is a ministerial drug.Ginger processed pinellia,Charred triplet,and Endothelium corneum Nigeria Galli can give full play to the effect of relieving qi and digesting food and has a good control effect on patients who are fatigued,sluggish,and bloating.And they are adjuvants in the prescription.Amomum can clear the movement of vital energy and dispel dampness,Licorice is sweet,reconciling all kinds of medicine,acting together as a causative medicine.Multiple medicines work together to strengthen the spleen and invigorate the lungs,effectively alleviating cancer-triggered persistent fatigue[23].

TCM combined with chemotherapy

In the process of radiotherapy,chemotherapeutic drugs have the characteristics of “heat and poison”.At this stage,professor Hua Baojin takes invigorating the spleen and stomach and nourishing the liver and kidney as the basic treatment,“warming the spleen and stomach,invigorating the dryness”,invigorating the spleen and stomach to replenish qi and fluid,tonifying the liver and kidney to nourish blood and nourishing yin,reconciling qi,blood,yin,and yang,and elevating qi[4,10,11,20].It has been proved that Professor Hua Baojin's method of connecting the diagnosis and treatment of TMR with western medicine can significantly improve the survival rate of SCLC patients after radiotherapy[24].Combined with compound Ejiao paste during chemotherapy can reduce the incidence of myelosuppression,and the Xuefuzhuyu capsule can improve the hypercoagulable state of blood and improve the effect of chemotherapy[25].

Patients with SCLC are usually treated with chemotherapy after operation.Yu-Hui and others conducted a Meta-analysis on the efficacy of TCM combined with chemotherapy in the treatment of ES-SCLC and discussed its clinical efficacy and safety[26].Compared with chemotherapy alone,TCM combined with chemotherapy can improve the objective remission rate of treatment(RR = 1.29,95%CI(1.10,1.52),

= 0.002).Duan Jincheng conducted a randomized controlled study on 58 patients with SCLC treated with TCM combined with chemotherapy and 38 patients with SCLC treated with TCM alone,the results showed that the combination of the two could strengthen the effect of detoxification and anticancer and improve the effective rate of chemotherapy(

<0.05)[27].Zhang Wei and others found that chemotherapy combined with TCM for promoting blood circulation and removing blood stasis showed that the 1-year,2-year and 3-year survival rates of the experimental group were higher than those of the control group,and there was a significant difference of[28].Hu Jiaqi and others have shown that Shenqi Fuzheng injection combined with conventional chemotherapy can increase the objective remission rate and disease control rate of patients with SCLC by about 11% and 6%,respectively,compared with chemotherapy alone.Meta-analysis showed that Shenqi Fuzheng injection combined with routine chemotherapy could improve the objective remission rate of patients with SCLC(RR = 1.19,95%CI(1.06,1.33),

= 0.003)and disease control rate(RR = 1.08,95%CI(1.02,1.14),

= 0.01)[29].From the above evidence,TCM combined with chemotherapy can effectively improve the efficacy of chemotherapy in ES-SCLC patients.

For patients with SCLC,because some micrometastases in the body are not completely controlled before the operation,the operation is a blow to the patients,resulting in a decline in immunity,which may lead to metastasis.Therefore,surgical treatment is an unconventional recommended treatment,for limited-time patients,indications should be strictly selected.Patients with stage IA and IB are the first choice for surgery,and pulmonary lobectomy with mediastinal lymph node dissection is the first choice.Patients with stage Ⅱ A and Ⅱ B can also consider surgery,while patients with stage Ⅲ usually do not choose surgery[16].Although surgical treatment is not routinely recommended,based on data from the United States,it is believed that surgery for stage I and Ⅱ SCLC can significantly benefit[17].TCM has gradually shown its effectiveness in tumor adjuvant therapy by improving perioperative body resistance,reducing side effects of radiotherapy and chemotherapy,and preventing recurrence and metastasis[18,19].After surgical treatment,the skin,muscles,and bones of the body are damaged,and the vital qi of the body is inevitably damaged.

:“The good qi is kept inside,and evil cannot be done.” Only when upright qi is filled,can the body have enough ability to fight disease and evil.If the body is deficient in vital qi,it is easy to be invaded by disease and evil.SCLC patients lack vital qi,if attacked by disease,the body is not enough to resist disease,easy to be attacked by disease,which is not conducive to the rehabilitation of patients.Therefore,the postoperative treatment of SCLC patients combined with TMR has a good effect on invigorating the spleen and replenishing qi.The spleen can slightly absorb and transfer the essence of water grain to the whole body,provide the material basis for maintaining the life activities of the human body,nourish the congenital essence,and promote the growth and development of the human body,which is called the “acquired foundation”.As a result of the ability of the spleen to transport it to the whole body,an important pathway is that the spleen transports it to the lungs and transports it up and down through the lung qi to the whole body,such that moistening the lungs relies on the spleen for robust spleen function.If the transportation of spleen qi in the body is normal,the vital qi is sufficient,and the body is not easy to be attacked by evil qi,which is conducive to the normal rise and fall of lung qi and the improvement of the survival rate of patients;on the contrary,if the spleen is dysfunctional and the qi and blood is deficient,the body is vulnerable to the invasion of evil qi,which leads to the disorder of the rising and falling law of lung qi,which is not conducive to improving the survival rate of patients.

From the point of view of TCM,radiation has the same nature of“heat and poison” as chemical drugs.Therefore,Chen Hongyu,Wang Wenping,Cao Yang,and others have always grasped the core pathogenesis of lung and spleen qi deficiency,lung qi stagnation and phlegm,and blood stasis in the later stage of maintenance and consolidation treatment of SCLC patients after radiotherapy.The treatment principle is to support righteousness and eliminate evil,and the treatment method is to benefit lung and disperse nodules.In this process,the western medicine treatment of the patients is carried out by the SCLC clinical guidelines,which can delay the recurrence and metastasis of SCLC and make it possible for the patients to survive for a long time[15,45].Patients who receive radiation can develop coughing,expectoration,sore throat,and skin ulcers.According to clinical observation and syndrome study,the main syndrome after radiotherapy is yin deficiency[46].Therefore,nourishing yin and clearing heat is the core treatment principle of TMR in the stage of radiotherapy,and Yangyin Qingfei decoction can be used.For patients who have completed radiotherapy and have not received western medicine treatment,the main pathogenesis is weakening physical resistance and excessive toxicity.Therefore,in this period,the use of improved Reed stem decoction to solve the toxicity and enhance the body resistance can effectively reduce the adverse reactions caused by radiotherapy[19].

Cao Yang grasped the core pathogenesis of lung cancer and formulated the method of tonifying the lung and dispersing knots.The prescription was added or subtracted by Chen Xia Liujunzi decoction,Yiqi Chatan decoction,Jinfu’an decoction,and so on.According to the symptoms of patients at each follow-up visit,the focus of lung qi deficiency,spleen deficiency,lung yin deficiency,and kidney essence loss is judged.The methods of "benefiting the lung" such as tonifying the lung and spleen,nourishing yin and moistening the lung,and tonifying the lung and kidney are often used.Cooked Tangshan,Astragalus membranaceus,five finger peach,Poria cocos,Atractylodes macrocephala,lily,mountain conch,Ophiopogon japonicas,loquat leaf,Cornus Officinalis,yam,Ligustrum lucidum,Eclipta,and other drugs are selected.According to the dynamic changes of phlegm-dampness blocking the lung,accumulation of phlegm-heat in the lung,lung qi stagnation and blood stasis block,the methods of dispelling phlegm,clearing lung and resolving phlegm,regulating lung and removing blood stasis,and so on are commonly used in Pinellia ternata,Fritillaria thunbergii,cat’s claw grass,Reed root,houttuynia cordata,loquat leaves,almonds,Platycodon grandiflorum,Fructus Aurantii,Panax notoginseng,Pleurotus ostreatus,gecko,peach kernel,centipede and other drugs[15].

10. None but a real Princess could have had such a delicate sense of feeling: While the modern implication of such a princess would be a high maintenance woman, another possible interpretation7 is that the woman is full of compassion15.

I think of him often. He came when I needed him the most and stayed until I was strong enough to go on alone. Maybe there is a perfectly12 natural explanation for German s visits to our house-maybe his owner went away on weekends-maybe. I believe German was sent because he was needed, and because no matter how abandoned and alone we feel, somehow, somewhere, someone knows and cares. We are never really alone.

TCM combined with radiotherapy

Concurrent radiotherapy and chemotherapy is the standard mode of treatment for patients with LS-SCLC,as for the choice of the timing of radiotherapy,foreign studies have shown that the earlier the simultaneous radiotherapy,the longer the progression-free survival,the median survival and the overall survival,which indicates that the benefit of early radiotherapy is greater[43].In the course of treatment,Wang Huiming on 67 cases of small cell undifferentiated lung cancer patients with oral etoposide 3 courses,bronchial artery perfusion chemotherapy 3–6 times,radiotherapy 2–3 courses of treatment,and treated them with TCM syndrome differentiation and rehabilitation.Each case was followed up for 6–12 months to evaluate its curative effect and adverse reactions,the results showed that among the 67 patients,21 cases were in complete remission,36 cases were stable,10 cases died within 12 months,and the survival rate within 12 months was 85%[44].Compared with the patients treated with radiotherapy alone,the survival rate of patients treated with TMR combined with radiotherapy is higher.

In his early years of fairy tale analysis, Jack Zipes wrote that the tale demonstrated how we must seek the power to name the forces acting upon us if we want to be free and autonomous (Zipes 1979, 177).Return to place in story.

A large number of studies have shown that chemotherapy can effectively kill tumor cells and control tumor growth,recurrence,and metastasis,but at the same time,the damage of normal cells caused by chemotherapy cannot be ignored,the adverse reactions include decreased immune function,myelosuppression,gastrointestinal reactions,myocardial cells,liver,and kidney function damage and so on.TCM plays a significant role in the treatment of adverse reactions caused by chemotherapy,chemotherapy combined with TCM,and other TCM treatments can effectively control the development of tumors and improve patients' immunity and bone marrow hematopoietic function.improve gastrointestinal discomfort and protect the heart,liver,kidney,and other organs to ensure the quality of life of patients[33].SCLC doubles rapidly and is extremely sensitive to chemotherapy,and once found,chemotherapy is usually the first choice.During chemotherapy in patients with SCLC,combined with Xuefu Zhuyu decoction can significantly improve the level of pulmonary function and improve TCM syndrome in patients with the syndrome of blood stasis blocking lung collaterals.If tonifying qi and nourishing yin,invigorating spleen and kidney combined with heat-clearing and detoxification,resolving phlegm and anti-cancer can reduce gastrointestinal reaction and improve quality of life[34].Luo Li et al showed that Yanghe decoction combined with Etoposide and Cisplatin(EP regimen)in the treatment of ES-SCLC patients with Yang deficiency and cold coagulation,can relieve patients' discomfort such as cough,expectoration,shortness of breath,and fatigue,improve their quality of life,and reduce the incidence and severity of myelosuppression,liver,and kidney function damage after chemotherapy[35].Therefore,Yanghe decoction combined with chemotherapy in the treatment of ES-SCLC not only has high safety but also has a better clinical effect than that of the simple chemotherapy group.

The application of TCM Kangfuxin liquid,Shenqi Fuzheng injection,Kangai injection,Compound Sophora flavescens,and so on injection during chemotherapy can prevent the decrease of leukocyte and gastrointestinal reaction caused by chemotherapy,and improve the tolerance of patients to chemotherapy drugs.Brucea javanica oil emulsion injection is also safe and effective during brain radiotherapy[25,37].In addition,chemotherapy-related nausea and vomiting in patients with SCLC can be relieved by western medicine combined with acupuncture.And myelosuppression can be improved by moxibustion at Zusanli point.Moreover,the daily practice of Baduanjin can also improve the quality of life of SCLC chemotherapy patients[38–40].The Meta-analysis conducted by Yu-Hui et al shows that TMR combined with chemotherapy can improve the quality of life of patients(RR = 3.41,95%CI(1.45,6.80),

= 0.004)[26].In addition,CHM in conjunction with chemotherapy demonstrated significant improvements in quality of life and a reduction in anemia and neutropenia[41].The ingredients of proprietary Chinese medicine are relatively fixed and easy to use.The ingredients of Chinese patent medicines(CPM)are relatively fixed and easily applied,and some trials focusing on CPM have been conducted,including when-qi-fu-zheng injection,compound Radix Sophorae flavescent injection,and ai-Kang injection[42].From the above evidence,it can be concluded that TCM combined with chemotherapy can reduce the response to chemotherapy and improve the quality of life of patients.

To sum up,radiotherapy can be combined with TMR,which can effectively improve the survival rate of SCLC patients.After radiotherapy,we can choose TCM treatment,which can delay cancer recurrence and cancer cell metastasis,and bring survival benefits to patients[47].

TCM combined with Molecular targeted Therapy

In recent years,with the gradual accumulation of clinical research data of SCLC and the in-depth study of the pathological mechanism of SCLC,clinical trials of targeted therapeutic drugs such as anti-angiogenesis inhibitors and receptor tyrosine kinase inhibitors are underway,among them,Notch signal pathway inhibitors have achieved good results in phase I and II clinical trials of SCLC,while phase III clinical trials are still underway[48].In the study of common acquired drug resistance in SCLC,a study on xenotransplantation models suggests that the combination of EZH2 and SLFN11 can be used as a potential therapeutic strategy to enhance the effectiveness of standard therapy in the treatment of SCLC[49,50].TCM can assist molecular targeted therapy and play a role in improving the immune function of patients with SCLC,mainly involving T cell subsets,natural killer cells,interleukin(IL)-4,IL-13,tumor-associated macrophages,and other cellular immune contents.In addition,Fiji Powder,a TCM,has the effect of tonifying qi and nourishing yin,promoting blood circulation,and removing blood stasis,which can reduce some clinical adverse reactions and significantly increase the number of white blood cells,to improve patients' immune function and improve their quality of life[51].

Clinical and basic studies have proved that the compound prescription of TCM based on the principle of Fuzheng Jiedu can improve the acquired drug resistance of molecular targeted therapy.The advantage of TCM lies in its overall regulation,combined with molecularly targeted drugs focusing on precision treatment,it is possible to play a macro and micro synergistic effect and become an innovative model for the treatment of SCLC[52].NSCLC has achieved remarkable results in targeted therapy,but SCLC may have limited the exploration of molecular targets due to the limitations of treatment and the complexity of its molecular mechanism.Some studies have mainly focused on anti-angiogenesis,among which bevacizumab is a widely studied Vascular Endothelial Growth Factor(VEGF)inhibitor[53].In a clinical study of stage Ⅱ ES-SCLC patients conducted by Spigel et al,EP regimen combined with bevacizumab was used as the first-line and maintenance therapy group,and EP regimen combined with placebo was used as the control group.The median progression-free survival(PFS)of the two groups was 5.5months and 4.4 months,but the median survival time was 9.4 months and 10.9 months,respectively,and the difference is not statistically significant(

>0.05)[24,53,54].From the above evidence,it can be concluded that TCM combined with molecular targeted therapy can improve the immune function of patients and improve their quality of life.

TCM combined with immunotherapy

The recurrence-prone characteristic of SCLC leads to a poor prognosis of SCLC,and the 2-year overall survival(OS)is less than 5%.United States Food and Drug Administration(FDA)has approved programmed cell death ligand 1(PD-L1)antibody atezolizumab combined with carboplatin and etoposide as the first-line treatment for SCLC.FDA has approved programmed cell death 1(PD-1)antibody monoclonal antibodies nivolumab and pembrolizumab as the third-line treatment of SCLC.As a result,immunotherapy breaks the deadlock in the treatment of SCLC in the past 30 years and brings new hope for patients with SCLC[55].Studies have shown that the immune- suppressive state of SCLC seems to be related to tumor mutation burden(TMB),and the decrease of TMB can alleviate the immunosuppressive state[56].Radiotherapy and chemotherapy can reduce the TMB of SCLC,alleviate the immunosuppressive state of the body,and improve the sensitivity of follow-up SCLC to immunotherapy.At present,there are no reliable predictive markers for immunotherapy in SCLC patients.Combined with previous studies,TMB seems to be more meaningful than PD-L1 expression in terms of predictive value,but there is a lack of a reliable research team.Other indicators,such as the T cell-inflamed gene-expression signature and the expression level of PD-L1 at tumor-stromal cell contact sites,have shown in some experiments that they have potential predictive value for ICIs prolongation of OS or PFS in patients with SCLC.However,they are limited to the small number of research and analysis,and there is a certain population bias,so further research and analysis of a large sample population are needed[57,58].The effect of immunotherapy combined with TMR is more significant than that of immunotherapy alone.Ganoderma lucidum polysaccharide can increase the ratio of effector T cells to Treg cells,thus relieving the inhibition of Treg cells on effector T cells[59].Echinacea can reduce the number of CD4

CD25

Foxp3

Treg cells,weaken its inhibitory effect,enhance the presentation function of antigen-presenting cells,and indirectly inhibit the function of Treg cells[60].Professor Jia Yingjie proposed that the most frequently used drugs before and after immunotherapy were Radix Astragali and Trichosanthes[61].Before immunotherapy,most of them are drugs for clearing heat,clearing phlegm,and regulating qi,and there is no lack of products for nourishing blood and dispelling blood stasis;after immunotherapy,we also pay attention to clearing lung and resolving phlegm,and the application of Qi regulating and stomach drugs are relatively more[62].Compared with radiotherapy and chemotherapy,before and after immunotherapy,based on invigorating qi and strengthening qi,more attention is paid to the application of dispelling qi and nourishing blood and nourishing substances,as well as detoxification and removing blood stasis.In sun Yidan’s study,the 1-year,2-year,and 3-year survival rates of 305 SCLC patients were 51.0%,12.2%,and 4.2% respectively,and the median OS was 13.0(9.0–20.0)months.Moreover,a variety of laboratory indicators that can reflect tumor growth,inflammation and immune status and the proportion of lymphocyte subsets(NLR(

= 0.003),PLR(

= 0.001),ALI(

=0.001),SII(

= 0.003),CEA(

<0.001),CYFRA21-1(

<0.001)(

<0.05))[62].Thus,compared with the routine western medicine immunotherapy,TCM combined with immunotherapy can significantly improve the survival rate of SCLC patients and prolong the life span of patients.

TMR has great potential for tumor immune regulation,but its effective components and specific mechanism have not been fully elucidated,and the current research on the treatment of SCLC is very scarce,so it is necessary to further study[63].

Conclusion

In recent years,surgery,radiotherapy and chemotherapy,and molecular targeted therapy have played an important role in the treatment of SCLC,and they are also in continuous development and progress.However,in the process of treatment,conventional western medicine treatment has some limitations,and it will produce many toxic and side effects that affect the quality of life of patients.Patients often cannot bear to reduce the dose,stop medication or even stop treatment due to poor compliance,but TCM can make up for this disadvantage.It is mainly reflected in the following aspects:(1)The treatment of SCLC with TCM is mainly based on syndrome differentiation and the combination of disease differentiation and syndrome differentiation.The treatment methods and drug dosage vary from person to person.TCM treatment has certain advantages in improving patients' symptoms,improving quality of life,optimizing cost effect,reducing toxicity and increasing efficiency,and effectively prolonging the survival time of patients.(2)TCM treatment can be used in most stages of SCLC treatment.We believe that the exploration of the treatment of integrated traditional Chinese and western medicine still needs to be carried out on a solid and innovative theoretical basis,and we need to carry out forward-looking,multicenter,large-sample evidence-based medicine research,and gradually establish a reasonable and standardized modern tumor diagnosis and treatment system with individual diagnosis and treatment as the main body.We believe that through the complementary advantages of TCM and western medicine in diagnosis and treatment,the treatment of SCLC will continue to make a breakthrough[6,64].

1.Sung H,Ferlay J,Siegel RL,et al.Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.CA Cancer J Clin 2021,71(3):209–249.

2.Siegel RL,Miller KD,Fuchs HE,Jemal A.Cancer Statistics,2021.CA Cancer J Clin 2021,71(1):7–33.

3.You J.Advantages of integrative medicine in treating lung cancer.J Integr Tradit West Med 2018,38(8):911–913.

4.Qi RZ,Li CH,Hua BJ.Analysis of HUA Bao-jin's academic thinking and experience in the treatment of small-cell lung cancer.Chin J Tradit Chin Med Pharm 2020,35(9):4477–4479.

5.Wang DB.Application progress of integrated traditional Chinese and western medicine in the treatment of lung cancer.J China Pharm 2016,27(23):3310–3312.

6.Chen J,Sun AL,Yan J.Research progress in the treatment of non-small cell Lung cancer with integrated Traditional Chinese and western medicine.J Liaoning Univ Tradit Chin Med 2020,22(9):12–15.

7.Liu W,Zhang H,Hao ZH.Research on ancient literature of traditional Chinese medicine for lung cancer.Hunan J Tradit Chin Med 2016,32(12):136–137.

8.Wang M,Hu KW,Sheng HZ,Yang LH,He MK,Liu CB.Effect of Yiqi Huatan Formula combined with chemotherapy on lung cancer:a meta-analysis.World J Integr Tradit West Med 2020,15(1):23–28.

9.Liu DL,Hou W.Discussion on the mechanism of syndrome differentiation and treatment of lung cancer from phlegm and stasis.Chin J Tradit Chin Med Pharm 2020,35(2):783–785.

10.Chen CH,Hua BJ.Dr.HUA Bao-jin’s experience on treating lung cancer.Chin Arch Tradit Chin Med 2013,31(2):277–278.

11.Hua BJ.General introduction and prospective of differentiation of syndromes and treatment of tumor in TCM.Beijing J Tradit Chin Med 2018,37(12):1103–1106.

12.Jiang M,Zhang EX,Yang LT,et al.Regularity of medication and prescription by ZHOU Dai-Han in treatment of non-small cell lung cancer with spleen deficiency and dampness-phlegm syndrome.J Guangzhou Univ Tradit Chin Med 2020,37(2):348–353.

13.Xu JK,Chen HR,Lin LZ.Clinical Experiences of professor LIN Lizhu in treating lung cancer using Chinese combined western medicine therapy.J Liaoning Univ Tradit Chin Med 2019,21(11):192–195.

14.He SL.Clinical observation of Professor Hua Baojin's combination of traditional Chinese and Western Medicine in the treatment of chemotherapy-sensitive Small Cell Lung Cancer.Beijing University of Chinese Medicine,2017.

15.Chen HY,Wang WP,Cao Y.Treatment of small cell lung cancer with integrated traditional Chinese and Western medicine:a case report.Guid J Tradit Chin Med Pharm 2020,26(16):122–123,132.

16.Luo XB,Hu KH,Yang HX,Wan CH,Liang QL.Recent developments in treatment of small cell lung cancer.Syst Med 2021,6(21):195–198.

17.Zhou H,Ji SL,Xu JH,Chen XY.Effects of cisplatin with irinotecan and etoposide on lung function of small cell lung cancer patients and the curative effect analysis.Anti-Tumor Pharm 2018,8(6):885–888.

18.Qi FH,Zhao L,Zhou AY,et al.The advantages of using traditional Chinese medicine as adjunctive therapy in the whole course of cancer treatment instead of the only terminal stage of cancer.Bioscience trends 2015,9(1):16–34.

19.Xu XQ,Deng WQ,Wang DY,Li M,Kou DL,Zhang PT.Chinese medicine treatment prolonged survival in small cell lung cancer patients:a clinical observation.Chin J Integr med 2021,27(7):496–501.

20.Zhao YW,Qi RZ,Cheng MQ,Hua BJ.Thoughts on the idea of“the deficiency in the spleen and stomach leading to lung diseases” in Piwei Lun in lung cancer treatment.Jilin J Tradit Chin Med 2021,41(9):1140–1142.

21.Gao SM,Liu JS,Wang M,et al.Exploring the bioactive markers of Codonopsis Radix by correlation analysis between chemical constituents and pharmacological effects.J Ethnopharmacol 2019,236:31–41.

22.Huang YY,Zhang Y,Kang LP,Yu Y,Guo LP.Research progress on chemical constituents and their pharmacological activities of plant from Codonopsis.Chin Tradit Herbal Drugs 2018,49(1):239–250.

23.Li TM,Li S,Mi S,Yu J.A randomized controlled study of Jianpi Yiqi Formula in treatment of cancer-related fatigue of non-small cell lung cancer patients with lung qi deficiency after chemotherapy.Liaoning J Tradit Chin Med 2021,48(8):126–129.

24.He SL,QJ G,YP X,et al.Clinical observation of huabaojin integrated traditional Chinese and Western medicine in the treatment of chemotherapy-sensitive small cell lung cancer.Beijing J Tradit Chin Med 2018,37(12):1107–1110,1115.

25.Zhang Q,Qu YL,Liu HY,Yu H.Radiotherapy advances of limited-stage small-cell lung cancer.J Mod Oncol 2019,27(6):1068–1072.

26.Yu H,Liu Q,Zhou YX,Zhang B.Meta-analysis of traditional Chinese Medicine combined with chemotherapy in the treatment of extensive small cell lung cancer.J Chin Prescription Drug 2021,19(5):133–136.

27.Duan JC.Treatment of small cell lung cancer with integrated traditional Chinese and Western Medicine.Cancer Res Prevent Treat 2006,33(8):620.

28.Liu NF,Han FC.Clinical analysis of cellular immunotherapy combined with chemotherapy in the treatment of small-cell lung cancer.World Latest Med Inf 2017,17(19):46.

29.Hu JQ,Hu J,Cui YJ,Zhang X,Hua BJ.Systematic review and meta-analysis of efficacy of Shenqi Fuzheng combined with chemotherapy for small cell lung cancer.Liaoning J Tradit Chin Med 2021,48(9):20–27,223.

30.Ma WQ,Zhang XG,Zhao HQ,Xu YM.Comparison study of early radiotherapy combined with EP and EC therapy for limited-stage small-cell lung cancer.China Med Her 2018,15(29):96-99.

31.Ran WH,Huang CS,Wang EY,et al.Clinical research of extensive-stage small cell lung cancer treated by Chinese medicine after chemoradiotherapy.J Chongqing Medl Univ 2011,36(3):356–358.

32.Zhang XH,Zhang DM.Clinical observation of traditional Chinese medicine combined with chemotherapy in the treatment of small-cell lung cancer.Chin Health Ind 2013,10(34):187–188.

33.Huang SN,Yao HY.Research progress of integrated traditional Chinese and Western medicine in the treatment of non-small cell lung cancer.Hunan J Tradit Chin Med 2017,33(11):169–170.

34.Xu JB,Qiu F.Controversies and advances of prophylactic cranial irradiation for limited-stage small-cell lung cancer.Chin J Clin Oncol 2018,23(11):1050–1053.

35.Luo L.Clinical observation of Yang He Decoction combined with EP regimen in the treatment of extensive small cell lung cancer(yang deficiency and cold coagulation type).Chengdu University of Traditional Chinese Medicine,2020.

36.Zhuang Y.Modified Linggui Zhugan Decoction in the treatment of 32 cases of gastrointestinal reaction after tumor chemotherapy.Yunnan J Tradit Chin Med 2010;31(12):38–39.

37.Zhang XF,Wang XX.Observation on the short-term efficacy of Xuefu Zhuyu Decoction combined with EP chemotherapy in the treatment of small-cell lung cancer with the syndrome of blood stasis blocking lung collaterals.Asia-Pacific Tradit Med 2018,14(1):202–204.

38.Cai H,Gong LY,Zhang B,Fang X,Liu J.Clinical observation of acupoint intradermal needling plus western medication in preventing and treating nausea and vomiting due to EP for small cell lung cancer.Shanghai J Acupunct Moxibustion 2019,38(4):355–358.

39.Li B,Wang AH.Advances in research on risk factors for lung cancer in women.Med Recapitulate 2019,25(18):3611–3616,3621.

40.Qian F.Research status of etiology of lung cancer.Cardiovascular Dis Electron J Integr Tradit Chin West Med 2019,7(8):148.

41.Chen S,Flower A,Ritchie A,et al.Oral Chinese herbal medicine(CHM)as an adjuvant treatment during chemotherapy for non-small cell lung cancer:a systematic review.Lung cancer 2010,68(2):137–145.

42.Tian X,Zhou F,Wang WG,Jia LQ.Meta-analysis of integrative therapy for small cell lung cancer.J Tradit Chin Med 2013,54(11):927–931.

43.Du CJ,Guo FL,Han X,et al.Effect of lapatinib mesylate tablets in the third-line treatment of extensive-stage small-cell lung cancer.J Binzhou Med Univ 2020,43(5):330–332,335.

44.Wang HM.Clinical observation on 67 cases with undifferentiated small cell bronchogenic carcinomas treated by integrated traditional Chinese and Western Medicine.Chin Med Mod Distance Chin 2012,10(11):148–150.

45.Chen Y,Chen YB,Tao RF.The interpretation of management of small cell lung cancer in CSCO guidelines of the diagnosis and treatment of primary lung cancer 2016.Chin J Pract Intern Med 2017,37(S1):42–43.

46.Wang ZW,Wang JY,Hu J,et al.Association between Traditional Chinese Medicine syndrome elements before radiotherapy and radiation-induced lung Injury in lung cancer patients:a prospective cohort study.Liaoning J Tradit Chin Med 2019,46(6):1233–1236.

47.WQ D.Observation on the efficacy of integrated traditional Chinese and western medicine in the treatment of limited small cell lung cancer in the single-arm clinical trial.Beijing University of Chinese Medicine,2020.

48.Yang YB,Tian F.Research progress of targeted therapy and immunotherapy for small cell lung cancer.Oncol Progress 2020,18(14):1424–1426.

49.Gardner EE,Lok BH,Schneeberger VE,et al.Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.Cancer cell 2017,31(2):286–299.

50.Wang XH,Liu DD.Research progress of molecular targeted therapy for small cell lung cancer.Oncology Progress 2021,19(16):1621–1624.

51.Liu SX,H HH,Jia R,Du J,Lin SS,Li Y.A review on the mechanism of TCM medicine on lung cancer.Clin J Chin Med 2021,13(5):132–134.

52.Liu H.Strengthening and detoxification method ameliorating acquired resistance of molecular targeted therapy for lung cancer.Chin Arch Tradit Chin Med 2016,34(7):1563–1565.

53.Rudin CM,Avila-Tang E,Harris CC,et al.Lung cancer in never smokers:molecular profiles and therapeutic implications.Clin Cancer Res 2009,15(18):5646–5661.

54.Spigel DR,Townley PM,Waterhouse DM,et al.Randomized phase II study of bevacizumab combined with chemotherapy in previously untreated,small-stage small-cell lung cancer:results from the SALUTE trial.J Clin Oncol 2011,29(16):2215–2222.

55.Wu W.Application progress of immune checkpoint inhibitors in small cell lung cancer.Med Innovation Chin 2022,19(4):183–188.

56.Ott PA,Bang YJ,Piha-Paul SA,et al.T-cell-inflamed gene-expression profile,programmed death ligand 1 expression,and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers:KEYNOTE-028.J Clin Oncol 2019,37(4):318–327.

57.Gandara DR,Paul SM,Kowanetz M,et al.Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab.Nat Med 2018,24(9):1441–1448.

58.Hellmann MD,Callahan MK,Awad MM,et al.Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer.Cancer cell 2018,33(5):853–861.e4.

59.Li AM,Shuai XY,Jia ZJ,et al.Ganoderma lucidum polysaccharide extract inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation and function by inducing microRNA-125b.J Transl Med 2015,13:100.

60.Kim HR,Oh SK,Lim W,Lee HK,Moon BI,Seoh JY.Immune enhancing effects of Echinacea purpurea root extract by reducing regulatory T cell number and function.Nat Prod Commun 2014,9(4):511–514.

61.Chen L.Jia Yingjie's experience in treating lung cancer.Liaoning J Tradit Chin Med 2010,37(2):227–228.

62.Sun YD.Retrospective analysis of Chinese medicine in the treatment of small-cell lung cancer.Tianjin University of Traditional Chinese Medicine,2021.

63.Chen ZQ,Qi XJ,Li ZY,et al.A systematic review of tumor immunology mediated by PD-1 / PD-L1 and research prospect of combination with traditional Chinese medicine.Chin J Surg Oncol 2021,13(3):305–311.

64.Wang XW,Li ZG,Wang ZX,et al.A review on TCM syndrome and treatment of lung cancer.Clinl J Chin Med 2021,13(11):125–128.