The broad range and heterogeneity of herbal medicine intervention and the resultant effects still pose a challenge to high-powered analysis of specific herbal medicines and their applications for evidence-based use in cancer therapies. Therefore, high level quality control to ensure consistent batch preparation and systematic pharmacokinetic studies are required for all test herbal medicines and their activity against lung cancer [ ], not only in human studies, but also in experimental animal systems to support evidence-based application.
In oncology, drug interactions are important because of the narrow therapeutic index and inherent toxicity of many anticancer agents [ ]. Previous studies indicated that the activity of cytochrome P enzymes CYP enzymes in the gastrointestinal wall is one of the most important factors that can alter the bioavailability of orally administered anticancer agents that are substrates of CYP3A [ ]. A number of herbal supplements including Echinacea , kava, grape seed, and St John's wort Hypericum perforatum are also considered to be inducers of CYP [ ] Figure 1.
Because of the increased use of herbal products by cancer patients, more consideration needs to be given to their combined use with anticancer agents [ , ]. The administration of St. John's wort was shown to induce intestinal and hepatic expression of CYP3A [ ] and be beneficial for the metabolism of irinotecan [ ], a camptothecin derivative that can result in DNA damage on interaction with topoisomerase I. John's wort is hence used empirically in the treatment of metastatic carcinoma of the colon or rectum.
Recent studies based on epidemiological modeling have demonstrated interesting patterns suggesting that herbal treatment may improve prognosis in advanced colon cancer patients when used as an adjuvant therapy [ , ]. The therapeutic mechanisms of traditional Chinese medicine in metastatic cancer have been discussed in terms of a hypothetical, dualistic antiproliferation and immune-stimulation model of tumor progression and regression [ ]. In this study, some modern methods, including Kaplan-Meier and traditional Cox regression, were used for analyses of causal inference, namely, propensity score and marginal structural models MSMs , which have not been previously used in studies of cancer survival in response to treatment with Chinese herbal medicine.
Accumulating clinical studies show that some TCM preparations, including Pi-Sheng Decoction and Yi-Qi-Zhu-Yu Decoction, may be useful in reducing side effects and enhancing the drug effect of chemotherapy for colorectal cancer [ ]. For preventing recurrence and metastasis, Jian-Pi-Xiao-Liu Decoction, Fu-Zheng Capsule, and Qu-Xie Capsule were used to decrease the recurrence and metastasis of colorectal cancer in a subsequent consolidation therapy after radical resection of patient's tumor.
However, with the advancement of colorectal cancer treatment model, TCM theories and clinical studies on the typing of syndrome differentiation apparently are still lagging behind.
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It is not only desirable, but also in fact necessary to further study the action model and the associated biochemical and physiological mechanisms of these anticancer mode herbs, as a milestone for future TCM research [ ]. Many clinical studies from China have indicated that TCM, such as Shentao Ruangan pills and hydroxycamptothecin, plus chemotherapy can significantly alleviate the symptoms, enhance therapy tolerance, stabilize tumor size and augment immunological function, reduce the incidence rate of adverse events, and prolong survival time of UHCC patients [ — ].
Although these studies may be criticized individually for lacking quality at the international level, together they do seem to suggest that the administration of TCM may warrant additional trials for patients with UHCC. In particular, rigorously designed, multicenter, large, randomized, double-blind, controlled trials are necessary [ ]. Over the past two decades, a number of Chinese herbal medicines have been noted for their radiosensitization and radioprotection effects during radiotherapy of cancers, including bone cancer as well as head and neck tumors [ ].
Cho and Chen [ ] reported that a combination of TCM with radiotherapy not only enhanced therapeutic outcomes, but also improved the performance status of patients with nasopharyngeal cancer. Su and colleagues [ ] consistently found that Guliu capsules GLC combined with Sr conferred therapeutic effects in the treatment of metastatic bone tumors. They found that combined GLC and Sr treatment was effective against metastatic bone tumor and improved patients' QOF enhancing ostalgia relief rate and decreasing hemotoxicity. In brain tumor treatment, Quan and colleagues [ ] also reported that TCM, in combination with radio- or chemotherapy, had an effect on tumor growth inhibition, survival time, and QOL enhancement in brain tumor metastases.
These findings further indicate the potential application of TCM in the therapy of different cancers Figure 1. Although traditional herbal medicines, phytomedicines, medicinal foods, and complementary or alternative medicines have been increasingly used over the past decade in European and North American countries, they seem to have not generated interest or been accepted by mainstream medicine practitioners in western countries, especially in standard care for cancer patients.
Without addressing all of the above issues, we cannot meet the challenges of modernizing herbal medicines. Although we have reviewed a spectrum of laboratory, preclinical and clinical studies on potential applications of herbal medicines for cancer patients' care in an inclusive fashion, a great many of these studies did not follow the stringent requirements, procedures, and protocol needed for developing western style drug or medicinal foods.
Systematic and correlated efforts among researchers of our scientific communities are therefore urgently needed. It is also important to note that the central tenet in recent western medicine is that a drug should be composed of well-known chemical components or a pure single compound that selectively interacts with known and specific molecular target s in our body system.
However, the search for single molecules that can modify single or highly specific key factors in a disease process is now recognized as a difficult and sometimes inappropriate strategy, because a large volume of studies on genomics, proteomics, and metabolomics studies have shown that many clinically used commercial drugs e. One major drawback in the integration of herbal medicines into mainstream western medicines is, therefore, the lack of defined molecular targets. As a result, there may be much less difference in terms of the complexity of molecular targets aimed by single compound drugs versus complex herbal medicine extracts than was originally assumed, as we previously demonstrated in a cancer cell line study [ ].
Pooling data from individual trials by using a meta-analysis approach may be a useful strategy to interpret at the results of a group of inconclusive trials [ ]. The uncertain or not well-defined composition of herbal products also raises questions about their safety, such as the evidence indicating that some herbal extracts may have harmful interactions with specific prescription drugs [ ]. To address this issue, the establishment of optimized CMC chemistry, manufacture, and control conditions for each herbal preparation will need to be considered as important technology for confirming and standardizing the composition of specific medicinal herb components.
Therapeutic Applications of Herbal Medicines for Cancer Patients
Toward this aim, we believe that the pattern-oriented approach fingerprint analysis is a good strategy, because it can evaluate the integrative and holistic properties of test herbal medicines by comparing the similarities, differences, and correlation of the results from analyses of the whole production process, including manufacture, processing and storage of raw materials for preparation, intermediate products, finished products, and the distribution products [ , ]. Yongyu and colleagues [ ] have systematically reviewed fingerprint methods for analyses of herbal medicines.
The fingerprint profiling of therapeutically used herbal medicines can be employed as a reference or index for quality control of phytochemical composition, and the results can be used in future clinical applications. Furthermore, the fingerprinting profiles can also be coordinated with and employed for therapeutic efficiency. This study approach was recently evaluated by an investigation of randomized controlled clinical trials see Section 3.
In traditional herbal medicines, mixtures of herbal extracts, comprising multiple phytocompounds, presumably regulating multiple targets for two or three medical indications are often used in a prescription. Although modern chemical drugs and conventional herbal medicines may seem to be very different, they may, in fact, share some pharmacological foundations. As some herbal medicine classes have a common structural scaffold, this similarity may account for their potency in similar target groups [ ]. Randomized controlled trials RCTs or randomized comparative trials currently serve as the gold standard for most clinical trials and provide the best evidence of the efficacy of healthcare interventions [ ].
Carefully planned and well-executed RCTs often obtain the best estimates of treatment effect and thus help guide clinical decision making; therefore, considerable effort is put into improving the design and reporting of RCTs [ , ]. Linde et al. Also, reporting quality differed among different individual botanical medicines and improved continuously for decades from the s to the s [ ]. With these controversies, in June an international group of pharmacologists, methodologists, pharmacognosists, and trialists met for a consensus-making meeting, which then led to the development of recommendations for the reporting of herbal medicine trials in Toronto, Canada [ ].
Among the 22 CONSORT checklist items, 9 of them were elaborated to enhance their relevance to the trials of herbal interventions, including the detailed recommendations for 1 item item 4 interventions and minor recommendations for 8 items item 1 title and abstract , item 2 background , item 3 participants , item 6 outcomes , item 15 baseline data , item 20 interpretation , item 21 generalizability , and item 22 overall evidence [ ].
Specifically, the detailed recommendation in item 4 addressed the concerns of the herbal medicine intervention, which is still need extensive elaboration.
These recommendations have been developed to improve the reporting of RCTs. Although TCM and other herbal medicines are being used worldwide, their efficacies have only been studied in a sporadic way, with very few properly randomized and controlled studies. Trials of note that have employed a high standard of clinical trial methodology include Mok and colleagues [ ] and Chan and colleagues [ ]. Mok and colleagues examined the possible role of Chinese herbal medicine in reducing chemotherapy-induced toxicity. They reported that traditional Chinese herbal medicine seemed to have a significant effect on the control of nausea in patients with early-stage breast or colon cancers, but these herbal medicines did not reduce the hematologic toxicity associated with chemotherapy.
In addition, Chan et al. In this study, ovarian cancer patients were randomized to receive either the test TCM formulation or a placebo in addition to standard chemotherapy. The primary outcome was recorded by the global health status GHS score and assessed by the European Organization for Research and Treatment of Cancer questionnaire, and the secondary outcomes were examined using other QOL items, chemotoxicity levels defined according to the World Health Organization WHO criteria, and alterations in specific immune functions.
The results suggest that TCM exerted effects in maintaining immune function e.
However, as these randomized trials failed to recruit sufficient study numbers, we may need to conclude that, in order to fully evaluate and demonstrate specific bioactivities and the merits of various TCM formulations or plant extracts in cancer patients, continued, systematic efforts in conducting scientifically sound studies with RCTs are required [ ].
Tumor microenvironments are now recognized to play a critical role in cancer growth, progression, and metastasis [ , ]. Intensive interactions between tumor or cancerous cells and their stromal microenvironments that involve a spectrum of immune cell types have received considerable research attention over the past few years [ — ]. There has been particular interest in the strong link between various immune activities at or surrounding tumor tissues and the progression of tumor growth.
Enhancement of tumor surveillance by the host immune system has also been considered to be a key strategy to facilitate anticancer effect.
In this section, we address the specific effects of herbal medicines on the enhancement of host immunity and review their molecular targets in anticancer activities. By definition, the function of an adjuvant used with a vaccine is to aid or promote antigen delivery and presentation. Specific herbal medicines such as Ganoderma lucidum or Dioscorea tuber have been reported to confer immunomodulatory activities [ , ]. Bioactive polysaccharides from Ganoderma lucidum Reishi were investigated for their immunostimulatory and anticancer properties [ ].
A specific polysaccharide fraction from Reishi stimulated immune cell activation including dendritic cell maturation and cytokine expression and displayed potent adjuvant activity in mice [ , ]. A number of phytochemicals have also been demonstrated to effectively enhance the anti-tumor potency of gene-based cancer vaccines. For example, shikonin enhanced the anti-tumor potency of a cancer vaccine via the induction of RANTES expression at the skin immunization tissue site [ ].
And a phytocompound mixture extracted from the butanol fraction of a stem and leaf extract of Echinacea Purpurea conferred immunomodulatory effects suggesting that it can effectively modulate DC mobility and related cellular physiology in vivo in the mouse immune system [ ]. These studies suggest the potential application of herbal medicines in a cell-based vaccine system. Immunogenic cell death mediated by damage-associated molecular pattern DAMP signals was found to trigger an immunogenic response including maturation and antigen uptake of dendritic cells [ ].
Recently, Chen and colleagues [ ] demonstrated that shikonin can induce immunogenic cell death in treated tumor cells. Shikonin-treated, tumor cell lysate-loaded, mature DCs were shown to exhibit strong anticancer activities against test mouse melanoma, including the induction of cytotoxic activities of splenocytes against target tumor cells, inhibition of tumor growth, and improvement in mouse survival. The use of shikonin-treated tumor cells from patients to pulse their own DCs in culture should be evaluated in future clinical studies as a new approach for developing DC-based anticancer vaccines.
For centuries if not millennia, various plants many systematized in traditional Chinese medicine have been used as medicines and disease therapeutics in most human cultures. As exemplified in this review, over the last two decades renewed public interest and research efforts from scientific and medical communities worldwide have generated a large volume of information including clinical studies and trials on the pharmacological effects, usage, and the development into future medicines of herbs and derivative medicinal phytochemicals as anti-tumor and chemoprevention agents.
Although considerable effort has been put into the verification and upgrade of many traditional remedies or multiple-herb formulations, systematic, standardized research and the use of FDA regulatory protocols and defined clinical trials are still quite limited and need to be actively pursued. At the same time, it is necessary for scientists, clinicians, and regulatory agencies to actively consider how to create novel, improved, or modified clinical surveys, studies, and trial mechanisms that employ the stringent trial standards of the 21st century but also incorporate, at the international level, the wealth of old empirical but incomplete data from various records and documents accumulated by traditional medicine practices worldwide, to expedite the discovery and development of new phytomedicines and botanical drugs.
In April , the FDA approved the very first botanical drug, Veregen, a partially purified fraction of the water extract of green tea leaves from Camellia sinensis , for topical treatment of external genital and perianal warts [ ].