UKMi Q&A xx - NHS Evidence Search

Medicines Q&As
Q&A 415.1
What is the evidence for subcutaneous mistletoe extract in the
treatment of cancer?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: 17th January 2013
Mistletoe is a semi-parasitic plant which grows on a number of different types of tree, including oak,
pine, apple, maple and others. It has traditionally been used as a medicine, even in ancient times, and
particularly as a “cure-all” panacea1.
Recent interest in mistletoe centres on its potential as an anticancer agent. It is available in Europe as
a subcutaneous injection in a number of proprietary brands, with Iscador being probably the most well
known and used in the UK2.
The chemical constituents of mistletoe are well studied, although they vary according to the type of
tree the mistletoe has been growing on, along with other factors such as the time of year it is
harvested and how the extracts are processed1,3,4,
Preclinical in vitro and animal studies have found several effects on the immune system and cancer
cells. These include:
 Leukocytosis, by increasing the number and activity of neutrophils and natural killer cells.
 Increased white blood cell secretion of cytokines (IL-1, 2, 6, and tumour necrosis factor-alpha)
 DNA stablizing effect in mononuclear cells of the peripheral blood
 Cytotoxicity
 Induction of apoptosis in tumour cells.
 Hypotensive and cardiac depressant effects
 Anti-inflammatory effects
 Sedative effects3,4.
There are, however, theoretical reasons why such effects may not occur in humans. Lectins, thought
to be responsible for many of the immune and cytotoxic actions of mistletoe, may not be able to bind
to some types of human cells. Active constituents may be broken down by human plasma proteins, or
humans may produce antibodies against them 4.
Types of Mistletoe product
Approximately 30 different preparations of mistletoe extract exist in the European market2. These
differ widely in their manufacturing processes, therefore would not be considered equivalent.
From the National Electronic Library for Medicines.
Medicines Q&As
Table 1: Some examples of mistletoe products 2,5,6.
Aqueous extraction
of fresh plant
material harvested
from poplars
Standardised to contain
a desired concentration
of lectins. Used at
therapeutic doses
Aqueous extraction
of dried leaves
Not standardised.
Aqueous extract is
prepared from a fixed
mass of fresh mistletoe.
Aqueous maceration
of fresh plant
Anthroposophic- based on
the teachings of Rudolf
Steiner. Draws from ancient
alchemy and homeopathic
principles, rather than
Available in 72 variants,
from highly concentrated
to homeopathic
Cold water extraction
Comes in various
dilutions, uses apple,
spruce and pine
Aqueous extract
homeopathically in
steps of 20.
Available in various
dilutions from eight
different host trees
Fermentation of plant
Available in various
concentrations and from
various host trees.
(uses plant extracts at levels
where pharmacological
effects are possible)
Recent Reviews
Cochrane Review 2010
A Cochrane Review published in 2010 included 21 randomised controlled trials, 13 of which provided
information on survival rates, 7 on tumour response, 16 on quality of life (QoL), psychological
outcomes, or adverse reactions to chemotherapy. Twelve studies reported on adverse effects of
mistletoe therapy. This review included five different preparations of mistletoe: Eurixor, Lektinol,
Helixor, Isorel, and Iscador, with a total of 3484 patients.
A benefit in survival rates was found in six trials of the 13 which reported this outcome. However
these trials all had methodological problems. Four high quality trials reported on survival rates, and
none found any benefit.
Two out of seven trials found a benefit in tumour response, while the other five found no difference.
One trial was deemed to be of high quality, and this found no benefit.
Quality of life measures fared better. In patients who were also using chemotherapy, all nine studies
which reported on QoL showed benefit. Two of these studies were of high quality, and found an
improvement of quality of life in patients who were taking mistletoe alongside chemotherapeutic
agents. One study looked at QoL measures in patients who were using mistletoe alongside
radiotherapy. Patients on mistletoe had a better QoL, but statistical analysis was lacking in the paper.
From the National Electronic Library for Medicines.
Medicines Q&As
The conclusion of the Cochrane Review is that the evidence to support use of mistletoe in cancers is
weak, and until more high quality research is available, the true efficacy and safety of the products are
Osterman et al, 2009
Osterman et al attempted a systematic review and meta-analysis involving only Iscador. In studies
which compared Iscador with no extra treatment, positive effects of iscador were seen (overall hazard
ratio 0.59, CI 0.53-0.66, p<0.0001). It is not clear what outcome this hazard ratio represent; several
different measures of survival may have been used. However, when only trials of higher
methodological quality were included, no difference was found. In studies comparing iscador and
placebo and other alternative therapies, no differences in outcome were distinguishable.
The applicability of this review is limited by several flaws in the design of their study. The search
strategy used is not clearly reported, and a language bias is present. The authors also suggest that
there is a likelihood of publication bias in this area.
Whilst the authors concluded that their pooled analysis suggested a reduction in mortality rates, any
conclusions drawn from this paper are attenuated by the inclusion of poor quality papers in their metaanalysisError! Bookmark not defined..
Ongoing Research
Since the Cochrane Review was completed, no robust controlled trials of mistletoe in cancer were
identified. At time of writing, two observational trials are recruiting patients to investigate the effects of
Iscador as a supportive treatment in patients with colorectal cancer and pancreatic cancer, with
results due in 2016-178. In the meantime, there is an ongoing need for high quality randomised
controlled trial evidence.
Whilst in vitro testing has been promising, showing a number of mechanisms by which mistletoe may
be helpful in cancer treatment, clinical evidence of its effectiveness is lacking. There are no licensed
mistletoe products available in the UK.
Until more high quality evidence is available, there is currently no compelling evidence to support the
use of mistletoe extracts in cancer therapy.
Currently available positive evidence is confounded by poor study design, with more high quality trial
data suggesting little or no difference in those treated with mistletoe.
This Medicines Q&A looks only at mistletoe preparations for subcutaneous use. Only the efficacy of
mistletoe is covered by this Medicines Q&A; safety or drug interactions are not considered here. Any
adverse drug reactions to mistletoe should be reported via the MHRA’s Yellow Card Scheme.
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From the National Electronic Library for Medicines.
Medicines Q&As
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug and Therapeutics Centre
Date Prepared
17th January 2013
Checked by
Nancy Kane, Regional Drug and Therapeutics Centre
Date of check
28th January 2013
Search strategy
Embase: *Viscum album/ AND *neoplasm
Medline *Mistletoe AND *neoplasms
In house databases/ resources
Clinical Mistletoe AND cancer
Natural Medicines Comprehensive Database
Herbal Medicines
Cochrane Database
National Cancer Institute: PDQ® Mistletoe Extracts. Bethesda, MD: National Cancer Institute. Date
last modified <02/02/2012>. Available at: .
Accessed <17/01/2013>.
2 Ernst E. Mistletoe as a treatment for cancer. BMJ 2006; 333: 1282
3 Mistletoe Monograph. In: Herbal Medicines [online] London: Pharmaceutical Press
<> (Accessed on 17/01/2013)
4 Mistletoe Monograph. In : Natural Medicines Comprehensive Database. Accessed via on 17/01/2013
5 Ostermann T, Raak C, and Bussing A. Survival of cancer patients treated with mistletoe extract
(Iscador): a systematic literature review. BMC Cancer 2009; 9:451
6 Die Mistel: Mistletoe therapy in Cancer Treatment website (English). Accessed via on 17/01/2013
7 Bueschel H, Huber R, Linde K and Rostock M. Mistletoe Therapy in oncology (review). Cochrane
database of systematic reviews 2008, Issue 2. Art No: CD003297.
8 Accessed via on 17/01/2013.
From the National Electronic Library for Medicines.