Standard cancer therapy prolongs survival, but can be detrimental to the quality of life, compromise the immune system, and leave residual disease that can cause recurrence years or decades in the future. Tumor dormancy therapy is a novel therapeutic approach that may improve these shortcomings, promote quality of life, and prolong survival. The aim of this study was to analyze studies on dormancy therapy, especially studies using traditional Oriental herbal medicine, so as to evaluate the efficacy of dormancy therapy with traditional oriental herbal medicine.
We conducted a systematic literature review using Scientific and Technical Information Integration Services (NDSL), PubMed, and RISS. We searched for clinical reports, papers, and books related to tumor metastasis, recurrence, immunotherapy, tumor dormancy, and traditional oriental herbal medicine with anticancer effects. Seventy-nine (79) experimental and clinical articles in both Korean and English were reviewed. This study was conducted from March 1, 2012 to May 31, 2012.
This approach, Tumor dormancy therapy, rather than seeking to remove the tumor, includes combination of low-dose chemotherapy, immunotherapy, immunosurveillance, and other methods to stabilize tumor growth and to enhance the host is immunity against disseminated tumor cells and thus to manage cancer as a chronic disease while maintaining quality of life. In particular, integrative use of Oriental herbal medicine has been shown to induce or maintain tumor dormancy, increase the effectiveness of conventional chemotherapy, improve quality of life, and prolong survival.
Tumor dormancy therapy is a promising novel therapeutic approach that may be especially effective with Oriental herbal medicine. Further research is needed to determine its potential mechanisms and therapeutic applications.
According to the National Health Insurance Corporation, Korea, in 2010, the total number of cancer patients was estimated to be 290,000. Last year, the incidence of newly-developed cancer cases was 110,000 and between 1999 - 2008, the number of cancerrelated deaths in Korea increased from 114.4 to 116.1 per every 100,000 people . Because of this increase in the number of cancer-related deaths, economic and social losses have also increased. The cumulative national cost of cancer treatment is approximately 2.2 trillion won per year, and direct and indirect costs total 14.1 trillion won per year, or 1.75% of the GDP in Korea .
Recently, tumor research has made great strides, but life extension effects have not met the level of technological development. Conventional cancer treatments reduce tumor size and kill tumor cells directly, but can have negative side effects. In addition, even if the primary treatment for tumors is successful, local or distal metastasis can still occur after many years. This shortcoming necessitates further tumor treatment research. Tumor dormancy is the period when the tumor does not progress and does not present symptoms [3-5], it is found occasionally [6-8]. Tumor dormancy therapy utilizes this state and aims to suppress and stabilize cancerous cell growth after removal of the primary tumor. Tumor dormancy therapy reduces the side effects of chemotherapy and improves, the relative quality of life
Many studies have been reported that Oriental herbal medicine promotes apoptosis in a tumor, increases immunity, and relieves the side effects of chemotherapy or hormone therapy. Thus, Oriental herbal medicine with a particular mechanism can be supposed to lead to tumor dormancy.
In this study, we review literature related to both chemotherapy and tumor dormancy therapy, with emphasis on the potential benefits of utilizing traditional Oriental herbal medicine integrated with tumor dormancy therapy.
The main databases used for the electronic searches were 'Scientific and Technical Information Integration Services (NDSL)', 'www.pubmed.com' and 'www.riss.kr'. Copies of relevant papers and electronic files from this search were downloaded or requested from the library or institute. Bibliographies of relevant papers were also searched by purchasing books and other publications on related themes and were summarized and extracted in the required range. In addition, authoritative Internet sources (www.kosis.kr, www.fda.gov, www.cancer.gov) were included in the data collection. This study was conducted from March 1, 2012 to May 31, 2012.
Searches were limited to domestic and international clinical reports, discussion papers related to tumor metastasis and recurrence reporting significant anticancer effects, and books on immunotherapy and tumor dormancy therapy. For internet sources, tumor treatment standards and guidelines were referenced.
We searched for clinical reports, papers, and books with the terms "tumor metastasis, recurrence, immunotherapy, tumor dormancy, traditional, oriental and herbal medicine. Seventy-nine experimental and clinical articles in both Korean and English were reviewed.
Cancer treatments consist of surgical tumor resection, systemic chemotherapy, and local radiotherapy. In cancer therapy, surgery is the most obvious way to remove the tumor, but as an invasive treatment, includes the side effects of pain and weakness. Ironically, surgery activates cyclooxygenase (COX) -2 inhibitor and
Reports indicate that the decrease in tumor size with chemotherapy does not directly lead to prolonged survival time. Even when the tumor is effectively reduced, life extension is not clinically substantiated. Current chemotherapy is considered valid when it reduces the tumor size by 50%. However, a successful 50% reduction in tumor size only prolongs survival an average of about two months. A 90% tumor size reduction increases survival time by almost a year, but few patients attain this clinical outcome
Conventional chemotherapy cannot remove disseminated tumor cells (DTCs), which means it cannot prevent the tumor cells from having proliferating or dormant cancer cells from activating in the future
Anticancer drugs were not originally designed to be cancer-specific, but to act upon all differentiated cells. They affect not only cancer cells but also bone marrow; the gastrointestinal tract, the liver, and actively dividing cells. Because of this, chemotherapy side effects are severe and can include cachexia, fatigue, and overall reduced quality of life.
Cancer micrometastasis might not proceed and might not be harmful in itself. In the 1990s, a new approach called tumor dormancy therapy drew attention for its clear effects on prolonged survival and possible inducibility. Tumor dormancy therapy was proposed by Dr. Yutaka Takahashi of Japan's Kanazawa University Cancer Institute and seeks not to kill tumor cells or reduce tumor size, but to stabilize tumor cell growth while maintaining the patient's quality of life. In contrast to conventional cancer therapy which treats and removes cancer cells, tumor dormancy therapy is patientcentered and aims to maintain quality of life while reducing side effects.
Cases in which patients with malignant tumor cells have lived the rest of their lives with no evidence of disease have been reported. In one clinical case, kidneys transplanted from a donor who had been treated for invasive melanoma 16 years earlier and in whom no residual tumors had been found, rapidly metastasized in the organs of the immuno-suppressed recipients
The mechanisms of inducing and maintaining tumor dormancy are unclear. Homeostatic controls, such as anti-angiogenesis despite active proliferation and immunological condition, are known to contribute to tumor dormancy that can then lead to years of minimal residual disease
Tumors metastasize through angiogenesis
Controlled trials have studied the effects of immunotherapy on induced tumor growth and have shown that mice treated with immunotherapy have inhibited tumor growth compared to active controls. These studies show evidence that tumor growth is affected by the host's learned immune system which can promote or inhibit tumor growth [35-37]. This immune mechanism is associated with cytokine secretion by the white blood cells that induce various immune responses. White blood cells consist of lymphocytes, such as T lymphocytes, B lymphocytes, NK cells, monocytes such as macrophages, and granulocytes such as neutrophils.
Cytokines secreted by these cells have several types and mediate cell interaction. Cytokines such as interferon and tumor necrosis factor inhibit proliferation of cancer cells. Interferons activate cytotoxic T-lymphocytes, NK cells and macrophages, and suppress the tumor cell by inhibiting angiogenesis. Tumor necrosis factor (TNF) consists of TNF-
Other proteins known to be associated with tumor dormancy are urokinase receptor (uPAR), Epidermal growth factor receptor (EGFR), Extracellular signalregulated kinases (ERK), and genes p38, p53, myc, and ras. uPAR inhibits inflammation by disabling the uPA, regulating protein degradation, and activating many intracellular signaling pathways to inhibit tumor growth. Overexpression of EGFR is associated with tumor genesis. From the identification of EGFR as an ocogene, anticancer agents such as gefitinib, erlotinib, and cetuximab have been developed. The ERK pathway concluding ERK protein is a chain of proteins in the cell that communicates a signal from a receptor on the cell. In tumor cells, irregularity of ERK causes disruption of ERK pathway. The p38 gene is involved in cellular cytokine secretion, cell apoptosis, and cell differentiation. Tumor dormancy is associated the inhibition of p38 which produces therapeutic effects in case of inflammation and autoimmune disease. p53 is a tumor suppressor gene that prevents mutation of cells during the cell cycle. Myc and ras are involved in tumor formation and play a role in modulating tumor dormancy. Myc is a gene that modulates transcription and is overexpressed in many carcinomas while Ras is known to be a regulator of myc activity. Inhibition of Ras expression is associated with tumor recurrence, endometrial apoptosis of tumor cells and vascular collapse of tumor cells. In addition, tumor dormancy may be modulated by hormone regulation . In general, the incidence of ER/PR+ breast cancers is known to be increased by estrogen exposure, but therapeutic exposure to high doses of estrogen is also said to lower the incidence of gastric cancer
Angiogenesis is required for a tumor to grow beyond a certain size. Experimental results show that antiangiogenic medicine can extend tumor dormancy and even remove spread cancer cells
Hormone-dependent tumors treated with hormone therapy have reduced proliferation of micro tumor cells. In fact, it is a standard of care for patients with ER+ breast cancer to be treated with anti-estrogen therapy such as tamoxifen. Conventional chemotherapy has severe side effects in proportion to its dosage. High dose chemotherapy has a high intensity of side effects while low-dose oral chemotherapy has a lower intensity of associated side effects, making it possible to take chemotherapy medication continuously long-term. One report indicates that long-term, low-intensity treatment is more effective than high-dose chemotherapy for elderly patients and cancer patients with faster growth rates. Research in Japan has shown that low-dose combinations of 5-FU and cisplatin are effective in promoting anti-angiogenesis, immune system maintenance, immune function resurrection, and cachexia improvement. Also, in a comparison of 16 cases treated with low-dose Irinotecan to 17 cases treated with high-dose Inrinotecan, side effects were less intense in the low-dose group compared to 11 out of 17 patients experiencing side effects in the high dose group. In most cases in which tumor dormancy therapy is administered, stopping the proliferation of tumors is possible. Longterm chemotherapy has also been shown to be possible because of its low intensity of side effects
Recent studies show that immune status and tumor dormancy are closely related. Especially, mushroom polysaccharides have been shown to induce differentiation of cytokine-secreting cells, thus improving anticancer effects. Animal studies suggest the presence of a tumor suppressor gene that may induce tumor dormancy and inhibit tumor growth. Based on the results of those studies, p53 gene therapy for thyroid carcinomas has been carried out to inhibit angiogenesis and has been observed to have an effect on tumor dormancy
Oriental herbal medicine can relieve the side effects associated with low-dose chemotherapy or hormone therapy and can boost quality of life by regulating biological rhythm. In addition, long-term use of Oriental herbal medicine can moderate anticancer activity and promote apoptosis, making it faster than the rate of tumor proliferation. It can also inhibit angiogenesis and increase immunity. Because of these benefits, the cancer can maintain dormancy. In the principle of Oriental medicine 扶正祛邪(reinforce the healthy qi and eliminate the pathogenic factors), considering overall health, as well as the treatment of illness is important. This concept is similar to tumor dormancy therapy in that it suppresses a tumor by activating the host's immune function. This is especially beneficial for elderly cancer patients for whom chemotherapy leads to no change in life expectancy, but can profoundly affect quality of life, necessitating an approach that will allow such patients to live with their cancer rather than actively remove it. Clinical cases of Oriental medicine therapy have shown significant results.
In China, nasopharynx cancer, advanced gastric cancer, colorectal cancer, liver cancer, pancreatic cancer and lung cancer patients treated with herbal medicine have a good progress compared to such patients treated only treated with chemotherapy. One report said that a combination of radiation therapy and Oriental medicine is more effective than radiation therapy only. Another report said that a combination of chemotherapy and Oriental medicine had a good prognosis, increasing the effectiveness of chemotherapy, relieving symptoms, and side effects for bone marrow and the digestive system, and ultimately improving the quality of life and immunity
When advanced colorectal cancer patients took PHY906 ablets pharmaceutically developed from Oriental herbal medicine 黃芩湯(
According to research on ovarian cancer,
New studies of carcinogenesis and tumor metastasis have spurred the development of new anticancer medicines. These agents have promising effects, but share the limitations of conventional chemotherapy in that they cannot induce complete remission of the cancer. This shortcoming strengthens the case for tumor dormancy therapy whose goal is not complete remission, but survival that does not differ significantly from that with chemotherapy while maintaining the quality of life. This approach maintains quality of life because it focuses on the treatment of the patient, not the disease.
Oriental medicine, in particular, seems to be useful in tumor dormancy therapy. Through research, we have identified some of the mechanisms that suppress tumors and prevent metastasis and proliferation. Certain Oriental herbal medicines induce anti-angiogenesis, promote apoptosis of cancer cells, activate immunity, inhibit gene expression, and block signal molecules. Through these effects, tumors can remain dormant.
Complementary use of Oriental herbal medicine with conventional chemotherapy enhances the anticancer mechanisms of conventional chemotherapy. With this, the most effective treatment course seems to be an initial combination low-dose chemotherapy, with long term chemotherapy with Oriental herbal medicine. For this combination therapy, further evaluation is needed to find possible interactions and side effects, the proper dosage, and other clinical applications.
The goal of tumor dormancy therapy is not to remove the tumor, but to stabilize tumor growth and maintain it in a dormant state. The therapy seeks to suppress cancer symptoms and prevent progression so that it can be cared for as a chronic disease. This patient-centered, rather than disease-centered, approach may prolong survival similarly to chemotherapy but incur less physiological damage to the patient. Tumor dormancy therapy consists of tumor anti-angiogenesis, induced cell death, hormone therapy, low-dose chemotherapy, immunotherapy, gene therapy, and signal-blocking agents. In particular, Oriental herbal medicine's potential to inhibit angiogenesis, promote apoptosis, and activate the immune system makes it a promising component of tumor dormancy therapy. Experimental evidence suggests that Oriental herbal medicine has excellent antitumor effects, reduced side effects when taken in combination with conventional chemotherapy, and improved patient-reported long-term quality of life. A tumor malignancy cannot be considered simply a tumor, but rather a dense, organized collection of blood vessels, fibroblasts, inflammatory cells, and extracellular matrices, with interactions that have significant implications for cancer treatment. Therefore, the future of cancer therapy should be aimed at the microenvironments surrounding the tumor and at other molecular structures and their interactions. More research on the specific mechanisms and at treatment applications of Oriental cancer medicine is necessary to utilize these novel therapeutic approaches to prevent the recurrence of dormant cancer cells.