A Commentary : Herbal Medicine Offers Great Potential in Support of Metronomic Cancer Therapy

Background: In spite of the advances in Cancer treatment, limitations exist. Refractory cases and late presentations are particularly worrying. The uncertainty of cure and the high costs have led to the popularly of complementary and alternative medicine in cancer treatment. Herbal medicine has particular attraction because it has been shown to be working on a multi-targets direction: promoting apoptosis of cancer cells, anti-angiogenesis and immuno-modulating. Research on creating a simple herbal formula with multiple effects of cancer control has started and showed in laboratory platforms promising results. Metronomic Chemotherapy: Attention on the use of old oral cytotoxic drugs in small doses for refractory and late cancer cases has started more than a decade. Satisfactory and good results have been found to be related to anti-angiogenesis, immunomodulations and cancer cell apoptosis. These findings are comparable to the use of multiple targets herbal medicine. Conclusion: Assumption is made that metronomic chemotherapy, combined with herbal medicine could be achieving synergistic effects and would be affordable to all patients.


Introduction
Cancer remains one of the most threatening diseases all over the world.Mortalities are steadily rising with the improving longevity of the general population [1] [2] [3] in spite of the scientific advances.The multidisciplinary management: surgery, chemotherapy and radiotherapy, has been effectively supported by targeted biological therapies [4].Sadly, limitations are still plentiful.Late presentations and refractory eases are not uncommon, and the high costs of the therapeutic choices of recent advances could be unaffordable to the less affluent, not to speak about the developing countries [5].
The uncertainty of cure and the threat about recurrences have led to the popular use of Complementary and Alternative Medicine (CAM) [6].Surveys done in Germany showed that 77% of cancer patients used CAM [7].In USA, the incidence is around 50% [8].Hong Kong, being a city with mainly Chinese population, has a very high popularity on the use of traditional Chinese medicine, reaching 90% of the community.Acupuncture has been widely used for pain control arising from different types of cancer.Herbal medicine has been popular for the control of diarrhea, nausea and other types of gastrointestinal problems [9].

Traditional Chinese Medicine for Cancer Patients
Cancer patients may have specific expectations about the use of CAM, like soothing the side-effects of chemo and radiotherapy and prevention of recurrence, while CAM experts could, most of the time, hardly set any specific target, apart from the improvement of the quality of life of patients to different extents [10] [11].
In our Institute of Chinese Medicine, in the past years, we have conducted a number of clinical trials to investigate the potential use of Traditional Chinese medicine for cancer patients, summarized as follows: a) Herbal formula to supplement chemotherapy as an agent to reduce toxicity [12]; b) Two herbs to reduce radiation symptoms [13]; c) Fungal supplement (Coriolus) to improve quality of life in breast cancer patients [14]; d) Fungal supplement (Coriolus) as preventive agent for immunological support [15]; and e) Herbal formula to prevent bone metastasis [16].
As a matter of fact, Japan and Korea have a strong history of utilization of herbal formulae from China.Kampo in Japan, are ancient herbal formulae from China, used widely in hospitals for gastrointestinal problems during and after cancer treatment [17] [18].Korean clinicians are sharing the same experience in their "Oriental Medicine" [19].Cheng from Yale University of USA, has been working on a simple four herbs formula for the treatment of diarrhea resulting from chemotherapy [20].
We are aware of the fact that special medicinal herbs could be identified in the pursue of single molecule cytotoxic or target orientated agents in the Drug Discovery arena.As a matter of fact we are collaborating with other botanical institutes in specific explorations [21] [22] [23].Nevertheless, we are more aware of the complicated situation of cancer pathology which might benefit from a holis-tic, multi-target approach as much as aiming at one specific target.The traditional practice of herbal supplements could have a lot to offer.The herbs that have been used for cancer related treatment are so plentiful that a proper literature search must be done in order to identify those that have proven effects and those that possess laboratory research data about their biological effects against cancer.

Research to Justify the Use of Traditional Chinese Medicine for Cancer Patients
Although modern pharmacology has plenty of examples of cytotoxic drugs related to botanical origins, the search for novel cancer therapy should out-reach to other areas related to cancer control, viz., cellular growth (apoptosis), restricting blood supply, immunological support and metastatic prevention.Indeed many commonly used herbs have been found to possess those biological effects.Using them in a combined formula would have a multi-target effect which fits quite well into the classical theory of multi-target therapy advocated in the holistic treatment principle of CAM [21].
An active research program being conducted in Hong Kong is making use of five herbs, expected to form a synergistic combination to supplement conventional cancer treatment to give the following effects: apoptosis of cancer cells, anti-angiogenic effects, immunological suppression to cancer growth and prevention of metastasis.
The five herbs: Scutellaria; Hedyotis diffusa; Acanthopanax senticosus; Ganoderma lucidum and Andrographis paniculata, command excellent therapeutic records pertaining to what are required, (Table 1) and subsequent laboratory studies have added supportive information, on their varieties of anti-cancer activities, from cellular control, anti-angiogenesis to immune-modulations.

Metronomic Chemotherapy
After decades of development, cancer therapy has made remarkable advances.
The current stage is one of keeping the combination of surgery, chemotherapy

Andrographis paniculata Strengthening
Apoptosis Immunomodulation Anti-metastases [28] and radiotherapy, while accepting new approaches of selective indications relying on genomic and proteomic identifications [29].The improving outcomes however are related to mounting costs and yet refractory cases are still found.In developing districts, new forms of therapy are simply not affordable to most people [30] [31].
The outcome of the sad reality is the humanitarian use of cheap oral drugs with known low toxicity, particularly in low doses, in order to maintain survival.When the outcome appeared unusually satisfactory, clinicians started to explore the reasons of the unexpected outcome [32] [33].
Accumulated information from a large number of trials using metronomic, 1/3 to 1/10 oral doses revealed that survival and good quality of life were related to suppressed haemangiomatosis, immunological adjustment, slowing down of cellular promulgation and metastasis.Adverse effects had been mild because of low, oral dosages [34].
This appears a great practical achievement.The Metronomics Global Health Initiative henceforth is organized, to make better known the changing paradigm of cancer therapy.The conventional belief that cytotoxic therapy should be pushed to the utmost tolerable limit to ensure eradication is under challenge.At least for the refractory and late cases, the metronomic treatment protocol should have a place.And the results could be good [35] [36].
Since 2000, different cancer patients had been given metronomic chemotherapy.The varieties ranged from cancers of breast, liver, prostate and lung, to colorectal, pancreas and ovaries.Results had been mixed, with many favourable observations and survivals [37]- [45].

Herbal Medicine and Metronomic Cancer Treatment
The success of Metronomic Cancer Therapy has offered new insight into the multi-target approach.The good survivals and maintenance of good quality of life have indicated that the combined effects of cellular and angiogenic suppression, together with immunological adjustments, have helped maintain a balanced physiological well-being, very much like what CAM claims.
More importantly, the Metronomic cancer therapy has offered an excellent opportunity for a herbal regimen that can be proven to offer the same cancer control effects, viz., cellular and angiogenic control as well as immunological adjustment [46] Table 2.
When the carefully selected herbal formula is added to the metronomic cancer treatment on a course of prolonged treatment, the logical outcome would be a significant enhancement of efficacy.
Before any clinical applicant, some early laboratory explorations have offered early support to the combined use of metronomic anticancer drug and herbal supplement.

Metronomic Zoledronic Acid and Camellia Sinensis Extract in A Cancer Rat Model
Zoledronic acid has been used as an anti-metastatic agent for breast cancer patients [47] [48].Camellia sinensis has been studied and proven positive in laboratories to be anti-angiogenic and anti-cancer [49] [50].When zoledronic acid and camellia extracts were used together, they were found to inhibit cancer cell growth in-vitro and in-vivo, preventing bone metastasis.Notably a metronomic dose of zoledronic acid together with camellia extract, gave the most effective results [51].

Immunohistochemical and Angiogenic Marker (VEGF) Changes Using Zoledronic Acid and Coriolus
Coriolus is a popular immune-modulating agent of fungal origin popular among the cancer patients [52] [53].It was explored on synergistic effects when used jointly with zoledronic acid, in ordinary and metronomic doses.In-vitro experiments were targeted on MMP2 and MMP9, control of which indicated efficacy on suppression of metastatic activities.A metronomic dose of zoledronic acid together with coriolus extract gave the best results [54].VEGF was also suppressed in another in-vivo exploration [55].

Discussion
Chemotherapy has enjoyed 70 years of application during which many concepts, like Maximum Tolerable Dose (MTD); combination regimens and more recently "dose-dense administrations", have been applied in treatment protocols.High doses did optimize cancer cell destruction.However, the "more is better" approach may mask some of the subtle effects of chemotherapy against angiogenesis [56].
Laboratory studies have revealed that slow, continuous provision of anticancer therapy might bring out the anti-angiogenic effects better, which might relieve the need for MTD.The most convincing and demonstrable effects of metronomic therapy exist in the suppression of endothelial progenitor cells [33] [34].
The slowly rising trend of not totally relying on MTD is not only related to the threat against adverse effects but because of the early observations of good results from low dose and metronomic doses for different types of cancers, and the other evidences of immunological adjustments and cellular activities favouring metronomic therapy [35] [36].
Although cancer patients, under difficult situations of adverse effects during treatment or recurrences, do look for alternative medicine as supplementary therapy or replacement, specific indications about different herbs are just obscure, which cancer has been reported that to be cured by Traditional Chinese Medicine is equally uncertain.Afterall the main active chemical constituents of a traditional Chinese herb could be known.But whether this component is mainly responsible for cancer therapy could be equally uncertain.Hence, in the foreseeable future, medicinal herbs will continue to be utilized arbitrarily according to available reports and biological activity studies as adjuvant, or supplementary therapy, particularly for the refractory and late cases.
On the other hand, the low dose regimens are particularly inviting for the refractory cases and late presentations.Failed cancer eradication (referring to those resistant to treatment, those that are only partially controlled, recurrent, or actively metastatic) would be the most suitable to be enlisted for metronomic therapy [57].
Given the rising importance of metronomic treatment, herbal medicine which offers its anti-cancer support via exactly the same pathways of antiangiogenesis, immunological adjustments, control of cellular viability and metastasis, is being offered a wonderful opportunity to give innovative supports.

Table 1 .
Traditional Use and Biological Properties of the Selected Herbs.

Table 2 .
Comparable Treatment Principles of Metronomic and Herbal Therapy.