Positive Health Online

Background 

Cancer patients very often seek ways of helping themselves to improve their health and to feel in charge of their treatment process. They perceive the mainstream cancer treatments as invasive and injurious and often look for ways to boost their immune system. Up to 70% of all cancer patients in Europe seek complementary treatment in addition to their recommended cancer treatment. This includes a variety of medicinal plants, but also acupuncture, psychosocial support, yoga, art therapies and others. Most choose herbal remedies and European mistletoe (Viscum album L.) is the most frequently prescribed adjunct treatment in several European countries.[1,2,3]

An overview of the role of mistletoe therapy for cancer is contained in a great number of publications and a dissertation.[4,5]

Description

Mistletoe is a semi-parasitic plant, and the white berried European Mistletoe (Viscum Album L) has a well-established naturopathic tradition for treating a range of conditions, such as epilepsy, hypertension, osteoarthritis and rheumatoid arthritis.[9] For the treatment of cancer, mistletoe was introduced by Dr Rudolf Steiner PhD and Dr Ita Wegman MD in 1917, as they developed anthroposophic medicine. It has since been widely used for adjunct treatment of cancer in mainstream, homeopathic and other complementary medical practice.  A range of products are now available (e.g. Iscador, Abnobaviscum, Helixor, Lektinol), harvested from a number of host trees (Apple, Oak, Pine, Fir, Birch, Ash and may more) - each with different indications.[10,11]

Mistletoe extracts have immune-modulatory, anti-angiogenic properties - as well as a dose-dependent cytotoxic effect on cancer cells (both necrosis as well as apoptosis), but don’t affect healthy tissue. Several individual constituents have been investigated, for example viscotoxins, lectins, triterpenes, jasmonates and quercetin - that together have an all-round benefit. Mistletoe enhances DNA repair and increases endorphin production, which probably accounts for the improved well-being.[3,4,5]

How is it Used?

There is a wide variety of treatment protocols that give great flexibility in prescribing, in all settings and at any time of the illness stage. This reflects the nature of the therapy, in that it aims to support the individual as well as address the illness. Also, and as so common in the medical practice, the experience of the centre or physician will inform applications and indications. 

Commonly, patients are prescribed a subcutaneous (skin) application; typically, injections are self-administered, given 3 times a week; one prefers to start treatment in advance of surgery, chemo- or radiotherapy. The reason for this is to optimally prepare the immune system, and thereby to improve tolerance recovery - as well as sensitize the cancer itself, which could improve outcome of treatment. However, treatment can start at any time before or during such treatments. If there is time and opportunity, an induction therapy with fever has advantages in ‘kick-starting’ the patient’s immunity in a stronger way than is possible with the traditional approach with lower doses. Other applications are:

• Oral drops (for children; brain- and or spinal tumours, patients who don’t tolerate injections);
• Infusions (as a drip): to support febrile induction treatment, as adjunct to the normal injections in case of metastasis, for weak and debilitated patients, to optimize traditional s.c. [subcutaneous] application during radio- and chemotherapy and hyperthermia;
• Intralesional (to improve and focus the immunity);
• Intrapleural.

For how Long?

Maintenance treatment is usually continued over a number of years. Currently 2-3 years treatment is considered optimal immune support for most, early stage cancers that have been successfully treated with conventional therapy. Depending on the risk of recurrence and the overall health of a patient, mistletoe therapy is continued for longer, with or without regular treatment pauses. 

Traditional Mistletoe (‘low and slow’) is the most commonly prescribed approach and consists of low doses of mistletoe (typically with of 0.1mg or less), given 2-3 x week, which increasing slowly over a number of weeks / months. This approach is suitable for out-patient settings and carries a minimal treatment burden. Most of the studies cover this approach which is safe in most situations, for all cancer types and can be started any time, also during chemotherapy and radiotherapy or low blood counts.

Higher doses, locally applied, are more likely to affect a disease response than lower doses. Given at the beginning of treatment (induction) higher doses can elicit fever - and this may have distinct advantages, but pose a considerable treatment burden. If palliation and quality of life are the main aim, then lower doses are indicated and pose less of a burden.  In a number of consultant-led centres, off-label intratumoural and intravenous application using higher doses is routinely and safely applied either on its own, or alongside mainstream cancer treatments. In our work in the UK (former Park Attwood Clinic) and currently Ita Wegman Klinik, significant tumour responses were observed with combined regimes of intra-tumoural and intravenous application, more so if fever was elicited. There is evidence emerging that tumour specific immune responses can arise following intratumoural administration of immune modulatory agents (‘in situ priming’).[5,13-15] 

The role of fever.  The benefits of fever in cancer treatment and immune-priming in particular are well documented.[12,16] This may offer a rationale for some remarkable results, with remissions that exceed 2-3 years. Fever induction may be an optimal approach for new and reasonably fit patients and ideal in advance of surgery and other mainstream treatments. This approach is accompanied by flu like illness with fever and requires close supervision.  

Fever and Hyperthermia - When mistletoe therapy no longer elicits fever responses, Whole Body Hyperthermia (WBH) offers a non-invasive way to mimic fever and improve outcome of treatments. It has been established that moderate (fever range) WBH improves immune responses. Also, hyperthermia renders tumours more susceptible to other treatments like chemotherapy, radiotherapy and immunotherapy.  We now routinely recommend WBH combined with Mistletoe therapy, for example 8 or more sessions (at least monthly), starting after completion of mistletoe induction. This can run alongside chemotherapy, and indeed may improve tolerance and efficacy.[17,18]  Also, patients who are already established on Mistletoe may also benefit from WBH at any stage of their treatment, or at time of relapse.

Prescribing notes - Iscador has a limited licence in the UK and is available on the NHS at standard prescription costs, prescribed by GPs and doctors at homeopathic hospitals / departments that fall within the NHS. However, some PCTs have found the evidence insufficient and have ruled against prescribing. Other mistletoe preparations can be made available on a named-patient-basis, or purchased privately.

Level of Evidence and Research

Mistletoe is one of the most widely studied complementary therapies for cancer and the benefits are well documented. Studies have consistently shown safety and improved quality of life.[2,4] This benefit is particularly evident when mistletoe is used alongside chemo- and radiotherapy: patients appear to tolerate such treatments better, by having had fewer side effects and they recover better.  Also, cancer patients’ resilience and ability to deal with stress (‘self-regulation’) improves over time.  Some studies suggest improved life expectancy, but the evidence for this needs further confirmation. One study showed an estimated 1.8 -2 year survival benefit in a range of cancer types - when using substantial mistletoe for at least two years.[6]  More recently, Iscador was found to significantly improve survival comparable to currently recommended chemotherapy (Serbia).[7] Further studies are in preparation in the US, UK and other European countries. A Cochrane review (2008) found the available evidence for impact on survival weak, called for more research and decisions about mistletoe prescribing to rely on experienced physicians.[2] Since then, more positive studies have been published.

To date, 130 clinical studies have been published on the therapeutic effectiveness of mistletoe preparations (Abnobaviscum®, Helixor, Iscador®, Iscar, Iscucin®, Isorel®), and critically evaluated by independent authors[11] – with respect to:

• Survival (34 prospective comparative studies, 2 cohort studies, 39 retrospective comparative studies) - 16 trials found a statistically significant benefit to using mistletoe therapy; another 16 studies showed a positive trend and 2 studies found no effect. One study reported that survival advantage increased according to duration of mistletoe treatment;[6]
• Tumour regression (4 prospective comparative studies, 32 cohort studies,[1] retrospective comparative study) -  Two studies reported a statistically significant favourable effect, one study showed a positive trend and one study found no effect;
• Disease-free interval, recurrence (11 prospective comparative studies, 3 retrospective comparative studies) - Five studies found a statistically significant benefit in favour of mistletoe treatment; two showed a positive trend; one found no effects; one reported a negative trend; one an interim analysis indicated a positive trend (interim analysis); in one study standard medication showed better results than mistletoe treatment;
• Reducing side-effects of chemo-, radiotherapy and surgery (10 prospective comparative studies, 1 cohort study, 4 retrospective comparative studies) - 7 reported a statistically significant benefit; one trial found a reduction of chemotherapy-related side effects, and one, very small pilot study had mixed results; one study mentioned less side effects and an improvement in quality of life and one reported higher dosage of chemotherapy were given, as fewer and especially less serious side effects occurred with concurrent mistletoe therapy;
• Across the board Tolerance of mistletoe therapy was mostly good; reactions at the injection site and mild flu like symptoms or fever are minor, do no harm and are self-limiting effects (see below: safety). One study on malignant pleural effusion, observed less side effects after the instillation of mistletoe extracts compared to instillation of Doxycyclin, Meperidin or Lidocain;
• Quality of Life, disease-related symptoms (16 prospective comparative studies, 19 cohort studies, 5 retrospective comparative studies) -  13 of which showed a statistically significant favourable advantage, two a positive trend and one study did not report on these endpoints; one study suggested that good coping behaviour (self-regulation) and mistletoe therapy have a positive synergistic influence on each other.

The literature covers the following tumour types:

• Gynaecological tumours (breast, ovarian, cervix cancer, as well as cervical dysplasia;
• Primary liver tumours, colorectal cancer, stomach cancer, pancreas tumours and liver metastases - a recent study shows impressive survival for inoperable, locally advanced pancreatic cancer [7]
• Cancers of head and neck and lung;
• Skin cancer (malignant melanoma);
• Haematological malignancies: Hodgkin and non-Hodgkin-lymphoma, B-cell lymphoma of the skin multiple myeloma, CML, myelodysplastic syndromes;
• Malignant exudates (ascites, pleural effusion, pericardial effusion);
• Kidney, prostate and bladder cancer;
• Brain tumours;
• Some others (mostly in case reports).

In Summary

The published literature predominantly shows benefits of mistletoe therapy with respect to survival time, quality of life and reduction in the side effects of conventional therapies. While the quality of the studies varies widely, the overall conclusions do not essentially change if only the good quality studies are taken into consideration.  A reduction in side effects of conventional cancer therapies and improvement of quality of life appears to be best substantiated. Survival benefit has been shown, but not beyond critique. Survival is likely to be dependent on the duration of therapy.

Mistletoe is used in the treatment of all types of cancer - and the reason for this is that mistletoe draws on the host defences (immunity) as well as having an effect on the cancer itself. The patient's immunity is implicated in the cancer’s behaviour as well as in prognosis - to different degrees in the various types. Therefore, treating the relationship between cancer and the patient's immunity makes common sense and seems to benefit in all settings.

Safety

For a number of different mistletoe extracts that are used in human studies, the reported side effects have generally been minimal and not life threatening. Most of the effects of Mistletoe therapy are desirable, for instance the transient inflammation at the injection sites, flu like symptoms and raised temperature (even fever). Hypersensitivity (allergic-type reactions) with rashes, generalised itching, hives, swelling of lips and tongue and wheezing are rare - and usually only occur with sudden dose increases and infusions. Anaphylaxis is very rare indeed. Mistletoe is safely used together with all mainstream cancer treatments, including targeted treatments - and adverse interactions are not known.[2,3,8]

Conclusion

Mistletoe therapy is a safe and potentially very helpful treatment for cancer patients to help improve life quality and outcomes. Before embarking on this, seek advice from experienced doctors regarding the optimal treatment plan. Mistletoe seems safe to use in combination with all mainstream cancer therapies, as well as other CAM modalities.

References

1.         Molassiotis A et al. Use of complementary and alternative medicine in cancer patients: a European survey. Ann Oncol 16:655-63. 2005.

2.         GS Horneber M A et al. Mistletoe therapy in oncology (Review). The Cochrane Collaboration®. The Cochrane Library Issue 2 (Wiley & Sons Ltd). 2008.

3.         National Cancer Institute, USA -  www.cancer.gov/cancertopics/pdq/cam/mistletoe  (accessed 16.7.13).

4.         GS Kiene, H Kiene. Complementary Cancer Therapy: A Systematic Review of Prospective Clinical Trials on Anthroposophic Mistletoe Preparations. Eur J Res 12: 103-119. 2007.

5.         Orange M. Mistletoe for Cancer Patients. A thesis submitted to for the degree of Master of Science in Clinical Oncology. The University of Birmingham School of Cancer Sciences. www.anthromed.org 2010.

6.         Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med. 7(3):57-76. 2001.

7.         Tröger W. et al., Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival, Eur J Cancer  http://dx.doi.org/10.1016/j.ejca.2013.06.043  2013.

8.         Grugel, H Kiene. Safety of higher dosages of Viscum album L. in animals and humans - systematic review of immune changes and safety parameters. BMC Complementary and Alternative Medicine 11:72. 2011.

9.         MS  Loeper.  Mistletoe. The Longwood Herbal Task Force. 1999.

10.       R.Steiner. Spiritual Science and Medicine. 1921.

11.       www.mistel-therapie.de . Institute for Applied Epistemology and Medical Methodology, Zechenweg 6, D-79111 Freiburg, Germany.

12.       U Hobohm. Fever therapy revisited. Brit J Cancer 92: 421-425. 2005.

13.       M Orange, M Fonseca, A Lace, H B von Laue, S Geider. Durable tumour responses following primary high dose induction with mistletoe extracts: Two case reports. Eur J Integr Med 2:63-9. 2010.

14.       M Orange, A Lace, H B von Laue. The importance of the primary dosage in mistletoe therapy. J Phytomedicine 14: VII 29. 2007.

15.       Orange M, Lace A, von Laue HB. The importance of the primary dosis in mistletoe therapy. In: Die Mistel in der Tumortherapie 2. Eds: R Scheer et al. KVC Verlag. :385-400. 2009.

16.       SAH Cann, JP & C van Netten. Dr William Coley and tumour regression: a place in history or in the future? Postgrad.Med.J. 79: 672-680. 2003.

17.       P Wust et al. Hyperthermia in combined treatment of cancer. Lancet Oncol 3: 487-97. 2002.

18.       B Hildebrandt et al. The cellular and molecular basis of Hyperthermia. Crit.Rev.Oncol / Hematol. 43: 33-56. 2002.

Further Information

Together with other information, the major centres and some of the individual doctors with experience with Mistletoe therapy can be found at www.mistletoeforcancer.org.uk

Mistletoe for Cancer UK
Drs Stefan Geider & Simon van Lieshout
Camphill Wellbeing Trust, St Devenicks, Murtle Estate
Bieldside, Aberdeen AB15 9EP  Scotland.
Tel: +44 (0)1224 869833 admin@camphillwellbeing.org.uk

Glasgow Homoeopathic Hospital
Part of Gartnavel General Hospital site
1053 Great Western Road, Glasgow G12 0XQ Scotland
Hospital switchboard: +44 (0) 141 211 1600
Clinic Tel: +44 (0)141 211 1616 Clinic Fax: +44 (0)141 211 1627
heal-inform@dial.pipex.com

The Royal London Hospital For Integrated Medicine
Dr Sosie Kassab, Director of Complementary Cancer Services.
60 Great Ormond Street, WC1N 3HR London
Tel: 020 3456 7890 Fax: 020 7391 8829
General contact details: rlhhpatients@uclh.org  www.uclh