中医专方联合化疗治疗非小细胞肺癌疗效及组方研究
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摘要
目的：
肺癌是当今威胁人类健康的严重疾病,与其他癌症的发生率和死亡率比较,皆高踞首位,无论是在全世界或其他大国如中国、美国的统计中,都是一样,这可能与自然环境日益受到破坏,空气污染日趋严重密切相关。以肺癌的病理细胞学分析,非小细胞肺癌(non-small-cell lung cancer,NSCLC)最为常见,约占肺癌发生率的75-80%。由于非小细胞肺癌起病隐匿,初起时症状无特异性,只见咳嗽、胸痛等,所以确诊时多属国际肺癌TNM分期的中晚期,癌瘤已经局部或远处转移,失去了用手术切除根治的机会,放疗的适应证也不多,所以化疗和分子靶向药物治疗成为西医治疗中晚期非小细胞肺癌的首选方案。现今公认的一线化疗方案是含铂两药联合方案,即顺铂(cisplatin, DDP)或卡铂(carboplatin, CBP)联合一种第3代化疗药物：如吉西他滨(gemcitabine, GEM)、长春瑞滨(navelbine, NVB)、紫杉醇(paclitaxel, PTX)或多西他赛(docetaxel)等。多项研究指出各种化疗方案的疗效相若,总有效率为17%-22%,中位生存期7.4-8.1个月,1年生存率31%-34%,2年生存率10%-13%,多项疗效指标都到达平台期,即使延长疗程或增加药物,也很难再有突破进展。有研究显示,一线化疗的最佳疗程约为4至6周期,过多的周期(6周期或直至疾病进展)并不能延长患者的总生存期,反而增加毒性反应和导致生活质量下降。三药联合化疗比双药方案也没有增加疗效,但毒性加重。由于这些化疗方案皆使用细胞毒药物,杀灭癌细胞的同时也损害正常器官组织,所以有不同程度的毒副反应,包括骨髓抑制、胃肠道症状及肝肾毒性等,引致患者造血功能受损,出现贫血,白细胞减少,机体免疫力下降；恶心、呕吐、泄泻、食欲欠佳；肝、肾功能损害等,轻则影响患者的生存质量,严重者甚至要中断化疗疗程,或因毒性过重而缩短生存期。所以结合其他治疗方法来增强化疗药物对癌细胞的敏感度,提高化疗效果,以及尽量减轻化疗所带来的毒副反应,使患者能顺利完成整个化疗疗程,维持良好的生存质量,起到所谓“增效减毒”的作用,直是临床医生逼切的任务。
在中国,用中医中药来治疗危重疾病历史悠久,古代虽然没有癌症的名称,但类似癌症的症状和治疗方法却大量记载于历代医书中,各医家累积了丰富的宝贵经验,其中不乏有良好效验的记述。中医用其独特的整体观念和辨证论治思想,不是着重消除某些局部的症状,而是看重整个机体阴阳气血及脏腑功能的调节,达到固本培元的目的。在治疗癌症的经验中,中医的优点不在于杀灭所有的癌细胞,而是抑制其生长发展,并保护机体的正常功能,使患者可以带瘤生存,延长寿命,减轻痛苦,保持良好生存质量,这已渐渐成为医学界的共识。
在中国,于癌症化疗期结合中医药的治疗非常普遍,中医药的参与有不同形式,包括专病专方、口服或静脉注射中成药、或按辨证分型选用不同方剂等。其中应用专病专方治病,历史悠久,例如《内经》所记载的十三方及《金匮要略》所载治肠痈的大黄牡丹汤等。专病专方是指针对某种疾病有独特功效的方剂。与辨证论治一样,辨病用药其实也是中医学的基本思想。例如张仲景《金匮要略》以“辨某某病脉证治”成篇,便体现了专病专方思想,是对某疾病全过程的特点与规律所作的病理概括,抓住核心病机进行论治,而得出一病必有一主方,一方必有一主药的经验总结。与辨证论治中根据某疾病全过程某一阶段的病位、病因、病性及病势所作的病理概括而进行论治,两者不但不矛盾,而且是相辅相成。可以说辨证与辨病相结合,有是证用是方,有是病用是药的精神,其实一早已体现于《金匮要略》一书。在这个背景下,运用中医专病专方联合化疗治疗中晚期非小细胞肺癌,是否真的有互助互补的作用,还是互相排斥、互不相容；甚麽是组成有效中医专病专方的规律,一直是医学界关注的问题,本研究分为疗效评价及组方规律两个部份,希望能够寻找出有用的答案。
1.疗效评价
由于中医专病专方用于肺癌的中西医结合治疗非常普遍,多项随机对照研究指出中医药联合化疗有增效减毒的作用,并可改善患者的生存质量。但这些研究多属单中心、小样本研究,说服力不强,所以本文运用Cochrane协作网的系统评价方法Meta分析(meta-analysis),搜集有相同研究目的的临床文献资料,作定量合并分析,目的为中医专病专方联合化疗方案治疗中晚期NSCLC的疗效和安全性提供依据。
2.组方规律
现代治疗肺癌的中医专病专方是医家根据自己对肺癌病因病机的认识,结合临床经验,参考现代药理关于抗癌中药的研究,考虑西医的病理分期、中医的常见病因病机,选择相应有抗癌作用的中药,根据中医治法及组方原则所创制出来的经验专方；临床上随证候灵活加减运用,不但有较好的疗效,还有执简驭繁的优点,使治疗方案趋于规范化。本研究收集经临床对照化疗研究确认治疗中晚期NSCLC有效的中医专病专方,分析其用药规律及组方原则,作为临床遣方用药提高疗效的参考。
方法：
1.疗效评价
计算机检索2003-2012年中国期刊全文数据库(CNKI)、维普中文科技期刊全文数据库(VIP)与中国生物医学文献光盘数据库(CBM)中有关中医专病专方联合化疗治疗中晚期NSCLC的随机对照研究,应用Cochrane协作网系统评价建议及软件RevMan5.2,对纳入的研究进行质量评价和Meta分析。
2.组方规律
计算机检索2003-2012年中国期刊全文数据库(CNKI)、维普中文科技期刊全文数据库(VIP)与中国生物医学文献光盘数据库(CBM)中有关中医专病专方单用或结合化疗治疗中晚期NSCLC的临床对照研究,构建方剂药物数据库,运用Excel软件进行中药单味频数、药对配伍、功效分类、性味归经等统计和分析。
结果：
1.疗效评价
共纳入随机对照研究17个,合计患者1,149例。Meta分析表明,中医专病专方联合化疗治疗中晚期NSCLC,在提高有效率、改善生存质量及减少毒副反应方面均优于单纯化疗。有效率优势比(odds ratio,OR)=1.44,95%可信区间(confi dence interval,CI)=(1.12,1.85)；生存质量OR=3.36,95%CI=(2.45,4.59)；毒副反应OR=0.23,95%CI=(0.18,0.28).
2.组方规律
共收集专病专方39首,统计药味121种,使用频率最高依次为黄芪、白花蛇舌草、白术、北沙参、麦冬、半枝莲、党参、当归、莪术、丹参、人参等；药对应用最多依次为黄芪/白术、黄芪/白花蛇舌草、黄芪/北沙参、白花蛇舌草/半枝莲、黄芪/麦冬、黄芪/党参等；功效分类以补气、清热解毒、滋阴、活血化瘀类为主；性味属甘(淡)、苦、辛、温、寒多见；归经多属肺、脾两经。
结论：
1.疗效评价
本评价表明中医专病专方联合化疗治疗中晚期NSCLC比单纯化疗有优势,但因纳入之随机对照研究仍未达到循证医学的严格要求,故有待更多大样本、多中心、高质量的随机对照研究来支持及证实此结果。
2.组方规律
治疗中晚期非小细胞肺癌特别是化疗期的中医专病专方,以黄芪为主药、比例上扶正药多于祛邪药、药性温寒燥润并用及以肺脾同治为主。本分析研究结果可作为中医临床治疗非小细胞肺癌遣方用药参考。
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 efficacy
There 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 pattern
Modern 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 efficacy
The 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 pattern
The 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 efficacy
17RCTs 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 efficacy
This 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 pattern
For 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.
肺癌是当今威胁人类健康的严重疾病,与其他癌症的发生率和死亡率比较,皆高踞首位,无论是在全世界或其他大国如中国、美国的统计中,都是一样,这可能与自然环境日益受到破坏,空气污染日趋严重密切相关。以肺癌的病理细胞学分析,非小细胞肺癌(non-small-cell lung cancer,NSCLC)最为常见,约占肺癌发生率的75-80%。由于非小细胞肺癌起病隐匿,初起时症状无特异性,只见咳嗽、胸痛等,所以确诊时多属国际肺癌TNM分期的中晚期,癌瘤已经局部或远处转移,失去了用手术切除根治的机会,放疗的适应证也不多,所以化疗和分子靶向药物治疗成为西医治疗中晚期非小细胞肺癌的首选方案。现今公认的一线化疗方案是含铂两药联合方案,即顺铂(cisplatin, DDP)或卡铂(carboplatin, CBP)联合一种第3代化疗药物：如吉西他滨(gemcitabine, GEM)、长春瑞滨(navelbine, NVB)、紫杉醇(paclitaxel, PTX)或多西他赛(docetaxel)等。多项研究指出各种化疗方案的疗效相若,总有效率为17%-22%,中位生存期7.4-8.1个月,1年生存率31%-34%,2年生存率10%-13%,多项疗效指标都到达平台期,即使延长疗程或增加药物,也很难再有突破进展。有研究显示,一线化疗的最佳疗程约为4至6周期,过多的周期(6周期或直至疾病进展)并不能延长患者的总生存期,反而增加毒性反应和导致生活质量下降。三药联合化疗比双药方案也没有增加疗效,但毒性加重。由于这些化疗方案皆使用细胞毒药物,杀灭癌细胞的同时也损害正常器官组织,所以有不同程度的毒副反应,包括骨髓抑制、胃肠道症状及肝肾毒性等,引致患者造血功能受损,出现贫血,白细胞减少,机体免疫力下降；恶心、呕吐、泄泻、食欲欠佳；肝、肾功能损害等,轻则影响患者的生存质量,严重者甚至要中断化疗疗程,或因毒性过重而缩短生存期。所以结合其他治疗方法来增强化疗药物对癌细胞的敏感度,提高化疗效果,以及尽量减轻化疗所带来的毒副反应,使患者能顺利完成整个化疗疗程,维持良好的生存质量,起到所谓“增效减毒”的作用,直是临床医生逼切的任务。
在中国,用中医中药来治疗危重疾病历史悠久,古代虽然没有癌症的名称,但类似癌症的症状和治疗方法却大量记载于历代医书中,各医家累积了丰富的宝贵经验,其中不乏有良好效验的记述。中医用其独特的整体观念和辨证论治思想,不是着重消除某些局部的症状,而是看重整个机体阴阳气血及脏腑功能的调节,达到固本培元的目的。在治疗癌症的经验中,中医的优点不在于杀灭所有的癌细胞,而是抑制其生长发展,并保护机体的正常功能,使患者可以带瘤生存,延长寿命,减轻痛苦,保持良好生存质量,这已渐渐成为医学界的共识。
在中国,于癌症化疗期结合中医药的治疗非常普遍,中医药的参与有不同形式,包括专病专方、口服或静脉注射中成药、或按辨证分型选用不同方剂等。其中应用专病专方治病,历史悠久,例如《内经》所记载的十三方及《金匮要略》所载治肠痈的大黄牡丹汤等。专病专方是指针对某种疾病有独特功效的方剂。与辨证论治一样,辨病用药其实也是中医学的基本思想。例如张仲景《金匮要略》以“辨某某病脉证治”成篇,便体现了专病专方思想,是对某疾病全过程的特点与规律所作的病理概括,抓住核心病机进行论治,而得出一病必有一主方,一方必有一主药的经验总结。与辨证论治中根据某疾病全过程某一阶段的病位、病因、病性及病势所作的病理概括而进行论治,两者不但不矛盾,而且是相辅相成。可以说辨证与辨病相结合,有是证用是方,有是病用是药的精神,其实一早已体现于《金匮要略》一书。在这个背景下,运用中医专病专方联合化疗治疗中晚期非小细胞肺癌,是否真的有互助互补的作用,还是互相排斥、互不相容；甚麽是组成有效中医专病专方的规律,一直是医学界关注的问题,本研究分为疗效评价及组方规律两个部份,希望能够寻找出有用的答案。
1.疗效评价
由于中医专病专方用于肺癌的中西医结合治疗非常普遍,多项随机对照研究指出中医药联合化疗有增效减毒的作用,并可改善患者的生存质量。但这些研究多属单中心、小样本研究,说服力不强,所以本文运用Cochrane协作网的系统评价方法Meta分析(meta-analysis),搜集有相同研究目的的临床文献资料,作定量合并分析,目的为中医专病专方联合化疗方案治疗中晚期NSCLC的疗效和安全性提供依据。
2.组方规律
现代治疗肺癌的中医专病专方是医家根据自己对肺癌病因病机的认识,结合临床经验,参考现代药理关于抗癌中药的研究,考虑西医的病理分期、中医的常见病因病机,选择相应有抗癌作用的中药,根据中医治法及组方原则所创制出来的经验专方；临床上随证候灵活加减运用,不但有较好的疗效,还有执简驭繁的优点,使治疗方案趋于规范化。本研究收集经临床对照化疗研究确认治疗中晚期NSCLC有效的中医专病专方,分析其用药规律及组方原则,作为临床遣方用药提高疗效的参考。
方法：
1.疗效评价
计算机检索2003-2012年中国期刊全文数据库(CNKI)、维普中文科技期刊全文数据库(VIP)与中国生物医学文献光盘数据库(CBM)中有关中医专病专方联合化疗治疗中晚期NSCLC的随机对照研究,应用Cochrane协作网系统评价建议及软件RevMan5.2,对纳入的研究进行质量评价和Meta分析。
2.组方规律
计算机检索2003-2012年中国期刊全文数据库(CNKI)、维普中文科技期刊全文数据库(VIP)与中国生物医学文献光盘数据库(CBM)中有关中医专病专方单用或结合化疗治疗中晚期NSCLC的临床对照研究,构建方剂药物数据库,运用Excel软件进行中药单味频数、药对配伍、功效分类、性味归经等统计和分析。
结果：
1.疗效评价
共纳入随机对照研究17个,合计患者1,149例。Meta分析表明,中医专病专方联合化疗治疗中晚期NSCLC,在提高有效率、改善生存质量及减少毒副反应方面均优于单纯化疗。有效率优势比(odds ratio,OR)=1.44,95%可信区间(confi dence interval,CI)=(1.12,1.85)；生存质量OR=3.36,95%CI=(2.45,4.59)；毒副反应OR=0.23,95%CI=(0.18,0.28).
2.组方规律
共收集专病专方39首,统计药味121种,使用频率最高依次为黄芪、白花蛇舌草、白术、北沙参、麦冬、半枝莲、党参、当归、莪术、丹参、人参等；药对应用最多依次为黄芪/白术、黄芪/白花蛇舌草、黄芪/北沙参、白花蛇舌草/半枝莲、黄芪/麦冬、黄芪/党参等；功效分类以补气、清热解毒、滋阴、活血化瘀类为主；性味属甘(淡)、苦、辛、温、寒多见；归经多属肺、脾两经。
结论：
1.疗效评价
本评价表明中医专病专方联合化疗治疗中晚期NSCLC比单纯化疗有优势,但因纳入之随机对照研究仍未达到循证医学的严格要求,故有待更多大样本、多中心、高质量的随机对照研究来支持及证实此结果。
2.组方规律
治疗中晚期非小细胞肺癌特别是化疗期的中医专病专方,以黄芪为主药、比例上扶正药多于祛邪药、药性温寒燥润并用及以肺脾同治为主。本分析研究结果可作为中医临床治疗非小细胞肺癌遣方用药参考。
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 efficacy
There 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 pattern
Modern 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 efficacy
The 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 pattern
The 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 efficacy
17RCTs 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 efficacy
This 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 pattern
For 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.
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