The Study Of Efficacy And Medication Pattern Of Specialized TCM Prescription Integrated With Chemotherapy In The Treatment Of Advanced Stage Of Non-small-cell Lung Cancer

Object ive:Lung cancer is a serious disease that threatens the health of many around the world. Both incidence and mortality rates of lung cancer rank the highest among all cancers, whether globally or in big nations such as China and the U.S., which may be closely related to the ever-increasing destruction of the natural environment and the worsening problem of air pollution. According to cytopathological studies, non-small-cell lung cancers (NSCLC) are the most common type of lung cancer, accounting for75%-80%of all cases. The disease emerges in an obscure manner and is mostly asymptomatic-except for coughs and minor chest pain-making it difficult to diagnose until it has progressed to the advanced stage of the international lung carcinoma staging system. By that time metastasis of the tumor would have occurred and patients would have lost the opportunity to eradicate the disease by surgical resection. Neither would the indications for radiation therapy apply any longer. The first-line therapeutic treatment of advanced stage of NSCLC is therefore chemotherapy and systemic targeted therapy. Currently, the most widely accepted method of chemotherapy is a doublet medicine regimen, based on a platinum compound (cisplatin or carboplatin) plus a third-generation chemical medicine (gemcitabine, navelbine, paclitaxel or docetaxel). Research has indicated that these chemotherapy regimens have similar efficacy, with an overall response rate of17%-22%, a median survival time of7.4-8.1months, a one-year survival rate of31%-34%, and a two-year survival rate of10%-13%. These efficacy indexes have reached their optimal values, and extended treatment or additional dosage has not been able to provide further breakthrough. One research showed that the best treatment cycle for the first-line chemotherapy is four to six weeks. Extended treatment to longer than six weeks or until the time-to-progression has not been able to improve the overall survival time of the patients, only worsening adverse side-effects and damaging the patient’s quality of life. The triplet medicine chemotherapy regimen not only shows no advantage in efficacy over the doublet medicine regimen but increases toxicity. As all such chemotherapy regimens use cytotoxic medicines, normal organ tissues are destroyed together with malignant cells, resulting in varying degrees of adverse side-effects, such as bone marrow suppression, gastrointestinal malfunction, and hepatic and renal toxicity. Such effects in turn damage the patient’s hematopoietic functions, causing anemia, leukopenia, decreased immunity, nausea, vomiting, diarrhea, loss of appetite, elevated liver enzymes, and renal damage. The consequences range from causing a minor impact to the patient’s quality of life, to forcing an interruption in chemotherapy treatment, or even to shortening the lifetime of the patient due to heavy toxicity. Therefore, adjuvant treatment with other therapies to "boost the effect but reduce toxicity"-i. e. to boost the effect of chemotherapy by enhancing the sensitivity of chemotherapy drugs on the cancer cells, as well as minimize the toxicity of chemotherapy-so that patients can successfully complete the treatment cycle and maintain a good quality of life, has always been a pressing task for the clinician.In China there is a long history of using traditional medicine to treat severe diseases. Although no disease called "cancer" was ever mentioned in ancient medical books, symptoms similar to those of cancer and their treatment methods were frequently reported. Various Chinese medicine practitioners had accumulated a wealth of valuable experience, and many of their activities yielded curative effects. Chinese medical theory, with its unique holistic and "treatment based on syndrome differentiation" concept, not only focuses on the elimination of local symptoms, but emphasizes the regulation of the entire body’s yin and yang, qi and blood, and normal function of the organ, so as to achieve the purpose of reinforcing the vital essence and strengthening the primordial qi. To summarize the experience in treating cancer, the advantages of traditional Chinese medicine is not to kill all the cancer cells, but to inhibit their growth and protect the normal function of the body, so that patients may live in co-existence with the tumor, achieve longevity, reduce painful suffering and maintain a good quality of life. Such advantages have gradually become the consensus of the medical profession.In China, integration of traditional Chinese medicine (TCM) with chemotherapy in the treatment of cancer is a common practice. The participation of TCM may take several forms, including specialized TCM prescription, oral or intravenous proprietary Chinese medicines, and different prescription based on syndrome differentiation. Specialized TCM prescription, in particular, has a long history of usage. For example, the medical book "Inner Canon of Huangdi" recorded13prescriptions, and the book "Synopsis of Golden Chamber" recommended "dahuang mudan decoction" to treat appendicitis. Specialized TCM prescription is a prescription for treating a specific disease with a unique curative effect. Apart from "treatment based on syndrome differentiation","treatment based on disease differentiation" is also a basic principle of TCM. In the ancient medical book,"Synopsis of Golden Chamber", author Zhang Zhongjing used the heading "Differentiate Certain Disease and Pulse for Diagnosis and Treatment" as chapter titles. That is a manifestation of the concept of using specialized TCM prescription. This concept is concluded from the experience of treating disease by first getting a pathological overview of the characteristics and pattern of the disease in its full process, then concentrating on the core pathogenesis to provide treatment, and finally realizing that there is one specialized prescription for a disease and one major medicine within a prescription. This concept does not contradict, but complements, the basic concept of "treatment based on syndrome differentiation", which considers only a certain phase of the whole process of the disease and provides treatment based on the location of the disease, pathogenesis, nature and condition of the disease. It may be said that ideas of integrating differentiating by syndrome with differentiating by disease, and usage of specialized prescription with specific syndrome versus usage of specific medicine with specific disease, were already reflected in the book,"Synopsis of Golden Chamber". In view of the aforementioned background, the questions of:whether specialized TCM prescription integrated with chemotherapy in the treatment of advanced stage of NSCLC is complementary, contradictory or even repellant to each other; and what constitutes the best composition and medication pattern of an effective specialized TCM prescription, have gained widespread attention in the medical profession. We hope that this research which is divided into two parts will provide useful answers to these questions.1. Systematic review of efficacyThere is prevalent integration of specialized TCM prescription with chemotherapy in the treatment of advanced-stage NSCLC, and many randomized controlled trials (RCTs) have already concluded that such integration can boost efficacy and reduce toxicity of the chemotherapy. However, due to the fact that these researches are often single-center, small-sample experiments, the evidences are not convincing enough. Therefore this research will review systematically the efficacy and safety of specialized TCM prescription integrated with chemotherapy in the treatment of advanced-stage NSCLC by collecting multiple researches with similar and relevant objectives and performing a consolidated measurement and analysis using the systematic review method (meta-analysis) suggested by the Cochrane collaboration, in order to provide a convincing basis for clinical practice.2. Study of medication patternModern Chinese medicine physicians treat lung cancer according to their own understanding of the etiology and pathogenesis of the disease, combined with clinical experience. They make reference to modern pharmacological research on anti-cancer Chinese medicine, consider the pathological staging of Western medicine and the etiology and pathogenesis of Chinese medicine, select related anti-cancer Chinese medicine, and compose a specialized TCM prescription according to the principles of TCM treatment and prescription methodology. The ingredients of this specialized TCM prescription may be added or removed flexibly depending on the clinical syndromes, which not only provides the prescription with a good curative effect, but is advantageous in simplifying the complicated procedure and making an approach towards a standardized treatment regimen. This research will collect efficacy-proven specialized TCM prescriptions in clinical controlled trials in the treatment of advanced-stage non-small-cell lung cancer and analyze the medication pattern and composition rule, so as to provide clinical guideline for the improvement of efficacy of the specialized TCM prescription.Methods:1. Systematic review of efficacyThe relevant research literatures of RCTs were retrieved from the electronic databases of CNKI, VIP and CBM. They were then screened according to the inclusion and exclusion criteria. The quality of each research was assessed and a systematic review was performed on the extracted data using the meta-analysis software RevMan5.2provided by Cochrane Collaboration.2. Study of medication patternThe relevant research literature of clinical controlled trials (CCTs) was retrieved from the electronic databases of CNKI, VIP and CBM. The specialized TCM prescriptions were extracted and used to build an ingredient database, which was then analyzed in terms of single medicine frequency, couplet medicines frequency, efficacy classification, medicine nature and flavor, and channel tropism using Microsoft Excel. Results:1. Systematic review of efficacy17RCTs involving1,149patients were selected. Meta-analysis indicated that in comparison with the control group of chemotherapy alone, the treatment group of specialized TCM prescription integrated with chemotherapy showed statistically significant benefit in improving clinical response rates, quality of life and reducing the adverse effects of chemotherapy. Clinical response rate odd ratio (OR)=1.44,95%confidence interval (CI)=(1.12,1.85); quality of life OR=3.36,95%CI=(2.45,4.59); chemotherapy adverse side-effects OR=0.23,95%CI=(0.18,0.28).2. Study of medication pattern 39specialized TCM prescriptions involving121ingredient medicines were selected. Statistical analysis indicated that the most frequently used single-medicines, in descending order, are:radix astragali seu hedysari, herba hedyotis, rhizoma atractylodis macrocephalae, radix glehniae, radix ophiopogonis, herba scutellariae barbatae, radix codonopsis, radix angelicae sinensis, rhizoma curcumae, radix salviae miltiorrhizae, and radix ginseng etc. The most frequently used couplet-medicines, in descending order, are:radix astragali seu hedysari/rhizoma atractylodis macrocephalae, radix astragali seu hedysari/herba hedyotis, radix astragali seu hedysari/radix glehniae, herba hedyotis/herba scutellariae barbatae, radix astragali seu hedysari/radix ophiopogonis, and radix astragali seu hedysari/radix codonopsis etc. The major efficacy classifications are:supplementing qi, clearing heat-toxicity, nouriching yin, and promoting blood circulation for removing blood stasis. The nature and flavor of medicines are usually sweet (or tasteless), bitter, pungent, warm, and cold; and channel tropisms are mainly lung and spleen channels.Conelusion:1. Systematic review of efficacyThis systematic review indicates that the specialized Traditional Chinese Medicine (TCM) prescription integrated with chemotherapy in the treatment of advanced-stage non-small-cell lung cancer (NSCLC) is more effective than chemotherapy alone, but because the RCTs reviewed in this study have not yet fulfilled the strict requirements of evidence-based medicine, more well-designed researches involving large sample, multi-research-center participation and high-quality RCTs are required to support and confirm this finding.2. Study of medication patternFor the treatment of advanced-stage NSCLC, especially in integration with chemotherapy, the major ingredient in the specialized TCM prescription is radix astragali seu hedysari; with strengthening vital qi medicines used more than eliminating pathogen medicines. The ingredients are mixed with warm/cold and dry/moistening contrary natures. The therapeutic target organs are the lungs and the spleen respectively. These findings are useful for clinical guidelines and practice.