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Student Scholarship – Research Review Republished from ndnr.com

http://ndnr.com/pain-medicine/mistletoe-a-holistic-patient-centered-adjunctive-therapy/

In 2017, approximately 206,200 new cancer cases and 80,000 cancer deaths occurred in Canada.[1] Of these new cases, 50% will be prostate, breast, lung, or colorectal cancer. Alarmingly, an estimated 1 in 2 Canadians are at risk for the development of cancer within their lifetime, and 1 in 4 Canadians will succumb to the disease.[1] The high incidence of cancer necessitates widespread implementation of supportive therapies that may enhance patients’ otherwise reduced quality of life as they navigate their diagnosis. For instance, chemotherapy produces toxicity-related side effects such as fatigue, nausea, and vomiting.[2-4] The purpose of the present review is to evaluate the most relevant research to assess the efficacy of Viscum album (mistletoe) preparations in improving the quality of life of cancer patients with various solid-tumor malignancies.

Treating Cancer

The Question of Origin

The effort to control cancer and its consequent detrimental impact on patients’ quality of life has been largely impeded by the uncertainty regarding its origins.[5] Cancer has long been regarded as a genetic disease. However, it is now postulated that chronic exposure to non-specific factors that compromise the mitochondria’s respiratory mechanisms result in upregulation of oncogenes such as Ras and BRAF,[6] which may initiate malignant cancer. Examples of factors adversely affecting the mitochondria and potentially resulting in malignancy include carcinogen exposure, inflammation, viral infections, and advancing age.[5] Elucidating the origin of a patient’s cancer is thus of vital importance so that the disease and its deleterious effects on the patient’s quality of life can be properly addressed.

Conventional Treatment Goals

Although research designed to elucidate the exact mechanisms underpinning the origin of cancer remains in progress, it is clear that cancer is rapidly becoming a significant public health concern. The primary goal of antineoplastic drug therapy such as chemotherapy is cure, defined as complete remission for 5 or more years.[7] When cure is not possible, conventional care aims to control the disease by impeding cancer cell growth. Palliative care is provided when both cure and control are not achievable.[8,9] Chemotherapy, however, is known to compromise quality of life during and after treatment, in addition to exerting toxicity-related side effects such as nausea, vomiting, pain, and fatigue.[2-4] This fatigue may persist for months following the final course of chemotherapy.[4] Therefore, the maintenance of quality of life during and after the completion of conventional therapies is paramount.

Mistletoe Therapy – The Evidence

Mistletoe therapy (using an aqueous extract of Viscum album from fir tree) is an adjunctive cancer treatment introduced at the beginning of the 20th century by Rudolf Steiner. Mistletoe is widely used in parts of Europe, such as Germany, where it was prescribed more often than tamoxifen during the year 2002.[10]

In a methodologically strong study of 6 months’ duration, 95 breast cancer patients in the stages T_1-3N_0-2M₀ and scheduled to be treated with 6 consecutive cycles of CAF (cyclophoshamide, adriamycin, and 5-fluorouracil [5-FU]) chemotherapy were adjunctively treated with mistletoe injections, using a dose-escalating protocol. The control group received chemotherapy alone. In 14 out of 15 comparisons (including various physical symptoms and parameters of function), the mistletoe group outperformed the control group, while 1 comparison (financial difficulties) favoured the control group.[2]

Another trial studied the efficacy of mistletoe extract injections among digestive tract cancer patients undergoing surgery.[11] The experimental group received treatment for 2 pre- and 2 post-operative weeks. Following 60 days from the beginning of hospitalization, a significant improvement was observed on the Karnofsky performance index (KPI) score and the Anxiety scale score (p<0.01) in the mistletoe-treated patients. In contrast, a marked deterioration was observed in the control patients’ KPI (p<0.05) and Anxiety scale score (p<0.01).[11]

The effects of PS76A2, an aqueous mistletoe extract, were studied in 272 patients with operable stage II/III breast cancer eligible for CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy.[12] After 15 weeks of adjunctive treatment using the medium dose (15 ng mL/0.5mL), significant differences were demonstrated for the dimensions of “tiredness” (p<0.05), “sexual interest or ability” (p<0.05), and “thought of actually having treatment” (p<0.01). Positive trends for the categories of appetite, feeling sick (nausea/vomiting), and sense of taste were also demonstrated for the medium dose vs placebo. Some patients experienced a local inflammatory reaction at the site of injection (the most common adverse effect of mistletoe therapy),[2] although this reaction was mild when using the low and medium doses.[12]

The same investigators conducted a follow-up study on 352 breast cancer patients receiving PS76A2 as an adjuvant treatment to CMF chemotherapy^.[13] Patients were administered 30 ng mistletoe lectin/mL twice weekly for 16-24 consecutive weeks before starting each chemotherapy regimen. After 15 weeks of treatment, scores on the 3 subscales of the FACT-G questionnaire (physical, emotional, and functional well-being) were significantly in favour of the treatment group (p<0.0001). Item analysis of the GLQ-5 showed that item 1 (feeling anxious or depressed), 5 (tiredness), 6 (appetite or sense of taste), 7 (sexual interest or ability), 8 (thought of actually having treatment) improved with PS76A2 treatment but worsened in the placebo group (p<0.0001). Two months following the last chemotherapy treatment, the patients’ quality of life was again evaluated. Significant differences for all physical and functional well-being items were observed except for the item labelled “having pain.” In addition, PS76A2 was observed to outperform placebo for the following 3 items on the emotional well-being scale: “I feel sad,” “I feel nervous,” and “I worry that my condition will get worse.”[13]

Another study evaluated 95 breast cancer patients with T_1-3N_0-2M₀ who were prescribed 6 consecutive cycles of CAF along with adjunctive injections of mistletoe (a proprietary fermented aqueous extract from apple tree) that were administered 3 times per week.[4] Compared to control patients who received chemotherapy alone, the mistletoe treatment group showed improved quality of life, according to all 15 scores on the quality-of-life questionnaire, EORTC-QLQ-C30. Nine of the symptom scores on this questionnaire showed a clinically significant difference of at least 5 points for patients in the mistletoe group: emotional, social and role functioning, nausea and vomiting, pain, insomnia, appetite loss, diarrhoea, and financial difficulties.[4]

Quality of life was also assessed in advanced pancreatic patients receiving mistletoe extract; the treatment was administered in escalating doses via subcutaneous injection at a frequency of 3 times per week, for up to a year.[14] The scales showing the greatest improvements in the mistletoe treatment group were those on which the patients’ baseline clinical condition was the worst: global quality of health, physical function, pain, fatigue, appetite loss, insomnia, and nausea/vomiting.[14]

Mistletoe: Mechanisms of Action

Structure & Apoptotic Properties

Metabolites of the European mistletoe plant include viscotoxins, amphipathic/basic polypeptides, and lectins, among other constituents. The primary metabolites of V album with known anticancer activity are type II ribosome-inactivating proteins composed of an A and B chain known as mistletoe lectins: ML-I, ML-II, and ML-III.[15] The B chain facilitates the entry of the toxic subunit into cells through its binding to cell-surface glycoconjugates, and the A chain functions to inactivate the 60S ribosomal subunit in eukaryotic cells, thereby preventing protein synthesis.[15,16] V album modulates mechanisms in the cancerous cell responsible for apoptosis. For example, Viscum album L coloratum, a type of Korean mistletoe, has been shown to target the MAPK pathway in cancer cells by increasing the expression of a component of this pathway, known as JNK1. Overexpression of JNK1 in hepatocarcinoma cells significantly increases the apoptotic rate of these cells. Moreover, European mistletoe extract inhibits the PI3K-AKT (pAKT) pathway (which is essential in the proliferation and survival of myeloid leukemia K652 cells), thereby inducing apoptosis.[15]

Synergistic Action with Chemotherapeutic Agents

In-vitro studies examining the effect of administering Viscum album concurrently with conventional chemotherapy drugs have also shown encouraging results. When chronic myelogenic leukemia K52 cells were co-treated with doxorubicin (Dox) and Viscum album extract (VAE) for 72 hours, VAE/Dox greatly reduced the amount of cancer cells in both the S (replicative) and M (mitotic) phases of the cell cycle. At 72 hours, a significant loss of mitochondrial membrane potential was observed in addition to cleaved caspase-3 and Bax gene expression, all of which indicate activation of mitochondrial apoptotic pathway.[17] A similar increase in apoptosis was observed in oestrogen receptor-positive and receptor-negative cell lines co-treated with Viscum album var coloratum agglutinin (VCA) and Dox.[16] It is important to note that low-dose chemotherapy may result in a subset of tumour cells entering a state of senescence, meaning that while the cell cycle has been irreversibly arrested, the cells remain metabolically active and secrete factors that stimulate the growth of tumors.[18,19] It was shown that simultaneous treatment of MCF-7 (human breast adenocarcinoma cells) with V album and Dox was able to halt the induction of cell cycle arrest at the G2/M phase, thereby activating an intrinsic apoptotic program in favour of senescence.[18]

Immunomodulatory & Anti-inflammatory Effects

The immunomodulatory effects of mistletoe lie in its interaction with dendritic cells. Normally, tumor cells are capable of diminishing dendritic cell activity, as a means of evading the normal immune response of the body, by releasing immunosuppressive substances. Various extracts of mistletoe are capable of enhancing dendritic cell maturation and reduce the tumor-induced immunosuppression of dendritic cells.[20] A further effect on the immune system exerted by mistletoe, specifically lectin-rich extracts of the plant, is its ability to enhance natural killer (NK)-cell-mediated glioblastoma cell lysis in vitro.[21] Mistletoe also exerts a powerful anti-inflammatory effect via its ability to inhibit the expression of Cox protein, potentially accounting for its antitumor effect.[22] Furthermore, non-specific sustained inflammatory response may precipitate and prolong cancer-related fatigue (CRF). Specifically, a correlation was found, in the serum of disease-free breast cancer survivors, between CRF and increased inflammatory molecules such as immunoglobulin G subunits, complement C1q and serum amyloid A. Thus, the anti-inflammatory properties of mistletoe extracts may be beneficial in this regard.[23]

Clinical Implications

Cancer is an increasingly common condition with a high incidence and mortality.[1]Cancer survivors commonly suffer a wide range of detrimental effects on various dimensions of quality of life, such as pain, fatigue, appetite loss, and insomnia.[14] This compromise in quality of life can be attributed to the disease process itself as well as to side effects from conventional treatment. The maintenance of quality of life is paramount in cancer patients. Mistletoe therapy enhances quality of life on various dimensions such as pain, insomnia,[2,4,14] and fatigue,[2,14,23]among other outcomes that are important to patients. Mechanistically, mistletoe extracts exert pro-apoptotic[15] and immunomodulatory effects[21,22] that enhance host cell defenses against tumor cells. Its anti-inflammatory effect is postulated to be the potential mechanism by which it can alleviate cancer-related fatigue, thereby enhancing quality of life in this regard.[22,23] In summary, the inclusion of mistletoe therapy as part of an integrative approach to provide mental, emotional, and physical support for the increasing number of patients facing a cancer diagnosis within their lifetime is warranted.

References

1. Canadian Cancer Society. Canadian Cancer Statistics Publication. Available at: http://www.cancer.ca/en/cancer-information/cancer-101/canadian-cancer-statistics-publication/?region=on. Accessed September 22, 2017.
2. Troger W, Zdrale Z, Tisma N, Matijašević M. Additional Therapy with a Mistletoe Product during Adjuvant Chemotherapy of Breast Cancer Improves Quality of Life: An Open Randomized Clinical Trial. Evid Based Complement Alternat Med. 2014;2014:430518.
3. Kayl AE, Meyers CA. Side-effects of chemotherapy and quality of life in ovarian and breast cancer patients. Curr Opin Obstet Gynecol. 2006;18(1):24-28.
4. Tröger W, Jezdić S, Zdrale Z, et al. Quality of life and neutropenia in patients with early stage breast cancer: a randomized pilot study comparing additional treatment with mistletoe extract to chemotherapy alone. Breast Cancer (Auckl). 2009;3:35-45.
5. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35(3):515-527.
6. Hall A, Meyle KD, Lange MK, et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene. Oncotarget. 2013;4(4):584-599.
7. National Cancer Institute. Understanding Cancer Prognosis. November 24, 2014. Available at: https://www.cancer.gov/about-cancer/diagnosis-staging/prognosis. Accessed June 4, 2018.
8. Lander D. Antineoplastic Drugs. Lecture presented at: Canadian College of Naturopathic Medicine; April 11, 2017; Toronto, ON.
9. Balis FM. The Goal of Cancer Treatment. Oncologist. 1998;3(4):V.
10. Horneber MA, Bueschel G, Huber R, et al. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008;(2):CD003297.
11. Enesel MB, Acalovschi I, Grosu V, et al. Perioperative application of the Viscum album extract Isorel in digestive tract cancer patients. Anticancer Res. 2005;25(6C):4583-4590.
12. Semiglasov VF, Stepula VV, Dudov A, et al. The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial. Anticancer Res. 2004;24(2C):1293-1302.
13. Semiglasov VF, Stepula VV, Dudov A, et al. Quality of life is improved in breast cancer patients by standardised mistletoe extract PS76A2 during Chemotherapy and Follow-up: A randomised, placebo-controlled, double-blind, multicentre clinical trial. Anticancer Res. 2006;26(2B):1519-1529.
14. Tröger W, Galun D, Reif M, et al. Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial. Dtsch Arztebl Int. 2014;111(29-30):493-502.
15. Attar R, Tabassum S, Fayyaz S, et al. Natural products are the future of anticancer therapy: Preclinical and clinical advancements of Viscum album phytometabolites. Cell Mol Biol. 2015;61(6):62-68.
16. Hong CE, Park AK, Lyu SY. Synergistic anticancer effects of lectin and doxorubicin in breast cancer cells. Mol Cell Biochem. 2014;394(1-2):225-235.
17. Srdic-Rajic T, Tisma-Miletic N, Cavic M, et al. Sensititization of K562 Leukemia Cells to Doxorubicin by the Viscum album Extract. Phytother Res. 2016;30(3):485-495.
18. Srdic-Rajic T, Santibañez JF, Kanjer K, et al. Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells. Sci Rep. 2017;7(1):3763.
19. Shay JW, Roninson IB. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene. 2004;23(16):2919-2933.
20. Steinborn C, Klemd AM, Sanchez-Campillo AS, et al. Viscum album neutralizes tumor-induced immunosuppression in a human in vitro cell model. PLoS One. 2017;12(7):e0181553.
21. Podlech O, Harter PN, Mittelbronn M, et al. Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med. 2012;2012:501796.
22. Bonamin LV, de Carvalho AC, Waisse S. Viscum album (L.) in experimental animal tumors: A meta-analysis. Exp Ther Med. 2017;13(6):2723-2740.
23. Bock PR, Hanisch J, Matthes H, Zänker KS. Targeting inflammation in cancer-related fatigue: a rationale for mistletoe therapy as supportive care in colorectal cancer patients. Inflamm Allergy Drug Targets. 2014;13(2):105-111.
    

Acknowledgement Citation

This Student Scholarship – Research Review is republished from ndnr.com

http://ndnr.com/pain-medicine/mistletoe-a-holistic-patient-centered-adjunctive-therapy/