Introduction
Cancer is a major public health problem in China and many other parts of the world, although significant advances have been made in cancer therapy since the last century. Cancer incidence and mortality worldwide in 2008 were approximately 12.66 and 7.56 million, respectively; approximately 2.82 million new cases were expected to occur in China, with an estimation of approximately 1 958 347 Chinese dying from cancer [1]. Aside from conventional treatments in China, including surgery, chemotherapy, radiotherapy, targeted therapy and so on, traditional Chinese medicine (TCM) also plays an important role in cancer treatment. TCM has a systematic theory and a long history of practice in cancer therapy. With the development of modernization research, TCM now attracts more and more attention in the world as a new branch of medical science. Combining TCM with conventional medicine (also called Western medicine) to exploit their respective advantages for the mutual benefit of achieving better clinical efficacy is a promising method.
Developments of the treatment concept
Use poison as an antidote to poison: killing tumor cells or inhibiting proliferation
In the 1960s and 1970s, researchers worked on screening the anti-cancer effect of Chinese herbal medicine. Some herbs have cytotoxic function, such as Natural Indigo (Indirubin), Crotalaria sessiliflora (Monocrotaline), Cephalotaxus fortunel Hook (Harringtonine), Camptotheca acuminata (Camptothecin), and Herba rabdosiae (Rebescensine A), whereas some belong to biologic response modifiers, such as Umbellate Pore Furgus (Grifola Polysaccharide), Astragalus root (Astragalus Polyose), and Mushroom (Lentinan) [2–4]. Based on experimental and clinical research, we determined that herbal medicine has different anti-tumor spectra with tissue selectivity. Herbal medicine plays an anti-cancer role through different channels and links. TCM has a complex composition, and thus it has other pharmacological effects at the same time. Anti-cancer herbal medicine has a good effect on precancerous and early-stage lesions. Hence, it should be applied as early intervention to prevent disease development. Clinical efficacy would be improved if the treatments are not limited to eliminating the pathogenic factor (killing tumor cells or inhibiting proliferation).
Strengthen the body’s resistance to consolidate the constitution: stimulating the body's defense system to inhibit tumor development
In the 1970s and 1980s, based on the entire concept of TCM theory, TCM researchers recognized that cancer is a systemic disease and that a tumor is a local performance. Tumor development is primarily caused by Qi deficiency. Thus, strengthening the body’s resistance to consolidate the constitution may be beneficial in stimulating the body’s defense system to inhibit tumor development. Research on Fuzheng herbs became popular, such as Astragalus, Ginseng, Medlar, Fruit of Glossy Privet, Sijunzi Tang, Pulse-activating Injection, and so on. Yu Guiqing [5,6], Liu Jiaxiang [7], and Pan Mingji et al. [8] conducted many experimental and clinical studies to explore the effect of Fuzheng herbs. The results show that Fuzheng herbs or formula have the following functions: immunity regulation, reduction of chemotherapy and radiotherapy toxicity as well as enhancement of their efficacy, and prevention of tumor recurrence, metastasis, and anti-cancer effect.
Combination of syndrome and disease differentiation: treatment should consider the internal environment of the tumor and the body
The integration of wholism (macrocosmic or systematic) and localizm (microcosmic) was more acceptable in the 1980s and 1990s, considering the two inseparable parts of cancer, i.e., tumor cell (seed) and the body (soil), as well as the treatment with the combination of syndrome and disease differentiation, Fuzheng (strengthening the resistance), and Quxie (eliminating pathogens). During this period, a large number of research were carried out to achieve the complementary advantages of TCM and conventional medicine [9–13]. TCM combined with surgery can improve cure rate and prevent tumor recurrence and metastasis. TCM combined with radiotherapy or chemotherapy can reduce toxicity, enhance anti-tumor effect, improve quality of life (QOL), and inhibit disease progression. As for advanced cancer without indications of surgery, chemotherapy, or radiotherapy, TCM can control a tumor in stable condition, improve QOL, and prolong survival.
Standardized and comprehensive treatment with multi-disciplinary collaboration
In the 21st century, with the development and diffusion of evidence-based medicine, multi-disciplinary, standardized, and comprehensive treatment contributed to the further improvement of its clinical efficacy in a large-scale cancer population. Currently, practitioners pay more attention to the standardization of diagnosis and treatment. They make medical decisions by integrating individual clinical expertise with the best available clinical evidence from systematic research while being concerned about patients’ values and expectations. A comprehensive treatment with planned and rational application of multi-disciplinary methods (i.e., involving surgeons, physicians, TCM oncologists, pathologists, and others) can maximize the therapeutic effect at an appropriate economical cost. The following are some aspects of the standardized and evidence-based medical research in TCM.
Standardization of syndrome differentiation
To study the relationship between subjective and qualitative indicators and objective and quantitative indicators, the correlation with prognosis should be explored. This will improve the accuracy of the diagnosis and treatment.
Standardization of principle for treatment with TCM alone or integrated medicine
The principle of treatment with TCM or TCM combined with conventional medicine should be established, which is based on evidence from clinical research and is accessible to expert consensus. This will improve the rationality and efficacy of the treatment.
Standardization of the evaluation criteria
To build up comprehensive and effective evaluation methods that combine soft signs (symptoms) and hard signs (laboratory parameters) as well as long-term outcome (survival) and short-term outcome (response rate), disease control rate, survival, and QOL should be included. This will contribute to a comprehensive and objective evaluation of treatment and help doctors make the best decisions to improve a patient’s outcome.
Standardization of research methods
Carry out basic and clinical research in accordance with domestic and international standards, such as Good Clinical Practice, Response Evaluation Criteria in Solid Tumors (RECIST), TNM system (this system has been accepted by International Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC)), Good Laboratory Practice, Guide for the Care and Use of Laboratory Animals, and so on. This is beneficial in providing the best and widely recognized evidence for TCM therapy for cancer patients.
In the development process of the treatment concept, TCM and Western medicine continue to exchange ideas and gain more consensuses. Both recognize that cancer is a chronic disease with complicated etiology and should be treated with comprehensive treatment with multi-disciplinary collaboration. The main therapeutic purpose is to improve patients’ QOL, prolong survival, and maintain the balance of safety and effectiveness.
Developments in treatment methods
Developments in administration approaches
TCM formulations have developed from the traditional pill-powder-ointment-Dan mode to the current 40 kinds of dosage forms. These forms include oral (i.e. decoction, capsule, granules, tablets, etc.), intravenous (i.e. simplex components, active ingredients, and compounds), external administration (i.e. intervention, paste, foam wash, inhalation, and mucosal administration) and non-drug treatment (i.e. acupuncture, massage, Qigong, etc.).
Expansion of roles in TCM treatment
According to treatment efficacy, there are three main approaches. First, the main purpose of the treatment is to improve disease control rate. TCM treatment is often used in the tumor remission or stabilization stage. It can also be applied in cancer patients without indications of surgery, chemotherapy, or radiotherapy. Examples of this treatment are Kanglaite injection, Compound Kushen injection, Elemene Emulsion injection, Huachansu injection, Yifeiqinghua granules, Jinfukang Oral Liquid, Jinlong capsule, and others. Second, adjuvant treatments are used to enhance the efficacy and/or reduce the toxicity of surgery, chemotherapy, and radiotherapy. They can be used in combination with conventional therapies. Examples of adjuvant treatments are Shenqifuzheng injection, Zhenqifuzheng capsule, Jianpiyishen granules, Anduolin capsule, Yixuesheng capsule, and acupuncture, among others. Third, symptomatic treatment is used to relieve symptoms or complications (e.g. pain, pleural effusion, ascites, etc.). It involves many kinds of drugs and non-drug treatments.
Creation of TCM treatment strategies
According to the different stages of disease and treatment, treatment principles are set up to achieve different objectives (Table 1).
Tab.1 TCM treatment strategies for cancer patients |
| Stage | Key principles | Main purposes |
|---|---|---|
| Precancerous | Eliminate the evil factors | Prevent tumorigenesis |
| Cancer initial treatment | Presurgery: strengthen the body resistance | Enhance the efficacy and reduce the toxicity of conventional treatments |
| After-surgery: nourish Qi, promote blood circulation, detoxify | ||
| During chemotherapy: reinforce the spleen and kidneys as well as tonify the blood and Qi | ||
| During radiotherapy: nourish Qi and Yin, activate blood, and detoxify | ||
| Tumor remission or stabilization | Strengthen body resistance and eliminate the evil factors | Prevent recurrence or metastasis and disease progression, and prolong survival |
| Without indications of conventional treatments or End stage | Good performance status: eliminate the evil factors (Quxie) and support vital Qi (Fuzheng) as supplement | Improve QOL and prolong survival |
| Moderate performance status: Give equal stress to Fuzheng and Quxie | ||
| Poor performance status: Fuzheng and Quxie as supplement |
Using modern, multi-disciplinary technology and approaches, there have been great improvements in the treatment efficacy and safety of TCM. The characteristics of TCM, such as herbal compound compatibility, syndrome differentiation, Fuzheng, and so on, have been developed in cancer treatment. Thus, a rational and effective combination of TCM with conventional medicine has been established.
Achievements in cancer prevention and treatment with TCM
Clarification of the anti-cancer mechanism of TCM
Establishment of a compressive therapeutic effect evaluation
The clinical outcomes cannot be measured only by RECIST or overall survival. Evaluation standards should be established that correspond with the achievement of the best QOL with survival time as long as possible. Many researchers have made pilot studies in this field and have gained some meaningful results [19-21]. For example, Hongsheng Lin et al. made compressive evaluation standards for advanced-stage lung cancer patients. Symptoms, tumor, performance status, weight, and immunity were considered. The compressive evaluation results could be correlative to survival.
Evidence-based practice using TCM among cancer patients
TCM practitioners have carried out many evidence-based medicine (EBM) studies. In this section, we show some examples of lung cancer cases. Since 1997, there have been 83 RCT publications on NSCLC treated with TCM combined with chemotherapy [22]. Since 2000, multi-center, large-sample, and high-quality research have been conducted [23,24]. Based on “A Clinical Trial of TCM in Patients with Post-operative Lung Cancer to Prolong Survival” (Fund of Capital Medical Development and Research, No.ZD199902), there is a significant difference in the two-year survival rate (64.86% vs. 47.16%, P<0.05) between the TCM group (184 cases) and the placebo group (172 cases). The study concluded that TCM could inhibit the recurrence and metastasis of I-IIIa stage post-operative non-small cell lung cancer patients. In “A Clinical Trial of TCM Combined with Western Medicine in Patients with Unresectable Stage III or IV NSCLC to Prolong Median Survival Time” (National Scientific and Technological Project of Tenth Five-year, No.2001BA70115a), there is a significant difference in median survival time (12.03 months vs. 8.46 months) between the chemotherapy plus TCM group (199 cases) and the chemotherapy plus placebo group (215 cases). The study concluded that the combination of TCM and chemotherapy could maximize the effectiveness to treat unresectable NCSLC and prolong survival significantly. The study “A randomized, prospective, multi-center clinical trial of NP regimen (vinorelbine+cisplatin) plus Gensing Rg3 in the treatment of advanced non-small cell lung cancer patients” gained the same conclusion (response rate was 14.5% in the NP regimen plus Gensing Rg3 group) and 33.3% in the placebo group (P = 0. 011); the median survival time was 10 months versus 8 months, respectively (P = 0. 0088). The role of TCM treatment in lung cancer has been recognized and accepted. Thus, the fist-line recommendation for NSCLC recurrence and metastasis is Rg3 combined with chemotherapy, according to the Chinese edition of the NSCLC Clinical Practice Guidelines in Oncology—Non-Small Cell Lung Cancer Guideline 2009 [25].
Development of a practice guideline for cancer diagnosis and treatment with TCM
Using the evidence-based medicine approach, the practice guideline for cancer diagnosis and treatment with TCM has been established. This guideline is based on the best available clinical evidence from systematic research. It has gained the consensus of experts, such as the “WHO Western Pacific Region-The Practice Guideline of Cancer Diagnosis and Treatment with TCM” and “The Practice Guideline of Cancer Diagnosis and Treatment with TCM” (Oncology Branch, China Association of Chinese Medicine). Standardizing medical care with TCM and promoting communication worldwide are important.
Establishment of international cooperation and an exchange platform
When conventional medicine encounters bottlenecks, integrated medicine becomes more popular. Integrated medicine also focuses more attention to cancer treatment with TCM. Aside from many foreign cancer patients coming to China to receive TCM therapy, international cooperation and exchange have gradually intensified. There have been some international cooperative projects, such as “The effect on Treg in tumor bearing animals with TCM” (NIH& Guang’anmen Hospital), “International cooperative research on treatment with TCM in advanced non-small cell lung cancer patients” (NIH&Guang’anmen Hospital), “Clinical study of Huachansu in malignant tumor” (NIH & Shanghai Fudan University), “Clinical study of Jinfukang in non-small cell lung cancer patients” (Sloan-Kettering-Memorial Sloan-Kettering Cancer Center, U.S.A. &Longhua Hospital, Shanghai University of TCM), and so on. Guang’anmen Hospital, as the National Chinese Medical Cancer Center, has built an international platform with many foreign institutes (e.g. NCI-OCCAM, McGill University in Canada, etc.) in the cancer research field. This is helpful to information communication, resource sharing, personnel exchange, and promotion of the internationalization of TCM.
Some developments have also been noted in research methodology. TCM components and mechanisms are complicated; thus, many scholars [26-28] have worked on the research of material basis for anti-cancer efficacy with computer-aided drug design and analysis, bio-chromatography, etc. Baoyan Liu et al. established a clinical diagnosis and treatment information integration platform for structured clinical information storage, data extraction, mining, and multi-dimensional analysis. This platform promises to be a good technical support system and can promote the development of TCM clinical research [29,30].
These achievements inspire us to advance further with an innovative spirit, an open mind, and multidisciplinary cooperation. Currently, TCM practitioners are more confident and willing to use common-language “evidence” to make extensive exchanges. It is hopeful that more experts worldwide would cooperate in TCM research.
Coexistence of opportunities and challenges in the future
Increased attention at home and abroad brings many opportunities
A series of policy documents formulated by China government have been presented to support the development of TCM, such as “Long-term Scientific and Technological Development Plan (2006-2020),”“Program for Innovation and Development of Traditional Chinese Medicine (2007),” “Development of Chinese Medicine, Eleventh Five-Year Plan (2009),” and others. With the rapid development of China's medicine industry, the sales of medicine and Chinese medicine pieces accounted for more than 4% of the domestic pharmaceutical market [31]. In 2004, the NCI Center for Clinical Pharmacy Research study revealed that 13%–63% of cancer patients use herbal preparations [32]. Since 2004, the US Food and Drug Administration (FDA) has issued the “Guide for Herbal Products” and “Complementary and Alternative Medicine (CAM) Products and FDA Administration Guide Draft.” The FDA agreed that CAM, with a complete theory and practice of independent scientific system, is a complement to mainstream medicine to a certain extent. Thus, the increased demand has brought unprecedented development opportunities.
Issues and problems waiting to be solved
Several systematic reviews [33-35] show the international community's concern about cancer treatment with TCM. These research findings suggest that, although the results are promising, large and well-designed clinical trials are urgently required before any confident conclusions can be drawn about the value of TCM. The interactions between TCM and conventional medicine also require a systematic study to ensure safe and reasonable combination. The medical skill levels of TCM practitioners are not balanced, whereas doctors specializing in Western medicine (WM) know a little about TCM treatment based on syndrome differentiation. Therefore, the good combination of TCM and WM in cancer treatment is difficult to achieve. Some important and difficult issues need to be addressed, such as the multi-target therapeutic effect of Chinese medicine, the conflict between clinical studies in a large-scale population and individual therapy, the coordination of the varied methods of comprehensive treatment, and so on.
Future trends
Individualized treatment is the development direction
Syndrome differentiation is the simple model of individualized treatment. In the future, we will provide more accurate therapy in accordance with the characteristics of every single patient. The development of advanced knowledge and new technology in functional genomics, proteomics, genomic metabolic enzymes, and so on will help achieve a real sense of individual treatment.
Achievement of multi-target therapy corresponding with the complex etiology
Complex, multi-factor, multi-channel, and cross-network reflection systems are involved in the occurrence and development of cancer. The effect of multi-target therapies may be greater than a single target therapy, with fewer adverse reactions. Thus, clarifying the essence of “syndrome” in TCM theory and designing individualized compound herbal drugs with the unique compatibility of Chinese medicine would be helpful. We should increase investments and cooperate with business institutes to build TCM anti-cancer brands with high-technology content.
Emphasis on international and multidisciplinary cooperation to conduct innovative approach studies
More and more researchers have realized that studying innovative methodology further to achieve a fundamental solution to the complexity of disease and information explosion is very necessary. Based on the characteristics and advantages of TCM, the application of the systems biology technique may be a promising method to clarify the material basis of Chinese medicine, mechanism, effect evaluations, etc.
Improving the creation of pharmaceutical industry standardization and the professional training of oncologists will also be focused on in our future work.
Overall, we must have the spirit of innovation to continue scientific and thorough explorations in TCM cancer research combined with advanced technologies and research achievements.