Mistletoe as a treatment for cancer

Dear Sirs,

The case report recently published in this journal by Finall, A.I. et
al1 undoubtedly gives an opportunity to reflect on the safety issues
involved in mistletoe therapy. However, we may disagree with the
interpretation put forward in the editorial by our colleague Edward Ernst
in the same issue2.

Although one might argue about the existing evidence concerning the
clinical significance of its desired effects, evidence about its undesired
effects is abundant.
Serious adverse reactions following mistletoe applications such as the one
cited have usually been attributed to hyperergic and immunologic,
specifically excessive inflammatory responses. There seems to be no doubt
that the different effects of mistletoe solutions tend toward that
direction, as has been shown in many preclinical and clinical studies.

Due to the date of their publication, the three reviews cited by
Ernst3,4,5 could not have taken three further large randomized controlled
trials into consideration6,7,8, all of which are now easily accessible and
could have been mentioned in the report. Along with another large, only
slightly older trial9, which was reviewed by Ernst5 and Stauder4, we are
now able to overlook apx. 1,500 patients treated in recent RCTs with GCP
standards on reporting adverse events. This figure does not include the
many additional studies that are less recent. In the accounts of these
four trials, none of the serious events listed by Ernst is mentioned.
In our reference to the probably most careful overview on the topic by
Saller10, also cited by Ernst, we judge 39 of the described events to be
serious. Kidney failure, mentioned by Ernst, was not among them.

An attempt to compare these reports to frequencies of application
seems necessary. In Germany, circa 500,000 defined daily doses per year
(DDD) of mistletoe solutions have been sold in recent years. We were
unable to retrieve data on other countries. Assuming a yearly average of
50 injections per patient, this indicates that approximately 10,000
patients are treated per year. Considering the decades in which mistletoe
has been sold, we easily end with a total of more than 100,000 patients
treated only in Germany. Thus, the events discussed, in our opinion the 39
reported plus an unknown number unreported, are most probably rather rare
(i.e. significantly below 1/1000 per application).

We agree that there may be other herbal drugs more useful in cancer
treatment than mistletoe. In spite of some hopeful candidates, by far none
has been subjected to the scope of clinical and preclinical testing as
mistletoe. There is certainly no reason not to look for more options.

Rainer Stange, M.D.
Provisonal head

Dept. for Natural Medicine Charité - Universitaestmedizin Berlin and
Immanuel-Krankenhaus Berlin
r.stange@immanuel.de

1) Finall AI, McIntosh SA, Thompson WD. Subcutaneous inflammation
mimicking metastatic malignancy induced by injection of mistletoe extract.
BMJ 2006 doi: 10.1136/bmj.39044.460023.BE

2) Ernst E: Mistletoe as a treatment for cancer. BMJ 2006;333:1282-1283,
doi:10.1136/bmj.39055.493958.80

3) Kleijnen J, Knipschild P. Mistletoe treatment for cancer: review of
controlled trials in humans. Phytomedicine 1994;1:255-60

4) Stauder H, Kreuser E-D. Mistletoe extracts standardised in terms of
mistletoe lectins (ML I) in oncology: current state of clinical research.
Onkologie 2002;25:374-80

5) Ernst E, Schmidt K, Steuer-Vogt MK. Mistletoe for cancer? A systematic
review of randomised clinical trials. Int J Cancer 2003; 107(2):262-267

6) Semiglazov VF, Stepula VV, Dudov A, Schnitker J, Mengs U. 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;26:1519-1529.

7) Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J et al. Impact
of complementary mistletoe extract treatment on quality of life in breast,
ovarian and non-small cell lung cancer patients. A prospective randomized
controlled clinical trial. Anticancer Res 2004;24:303-309.

8) Augustin M, Bock PR, Hanisch J, Karasmann M, Schneider B. Safety and
efficacy of the long-term adjuvant treatment of primary intermediate- to
high-risk malignant melanoma (UICC/AJCC stage II and III) with a
standardized fermented European mistletoe (Viscum album L.) extract.
Results from a multicenter, comparative, epidemiological cohort study in
Germany and Switzerland. Arzneimittelforschung 2005;55:38-49.

9) Steuer-Vogt MK, Bonkowsky V, Scholz M, Arnold W.
Plattenepithelkarzinome des Kopf-Hals-Bereichs. Mistellektin-1-normierte
Viscumtherapie. Deutsches Arzteblatt 2001;98:3036-46.

10) Saller R, Kramer S, Iten F, Melzer J. Unerwünschte Wirkungen der
Misteltherapie bei Tumorpatienten - Eine systematische Übersicht. In:
Scheer R, Bauer R, Becker H, Fintelmann V, Kemper FH, Schilcher H,
editors. Fortschritte in der Misteltherapie. Aktueller Stand der Forschung
und klinischen Anwendung. Essen: KVC Verlag, 2005: 367-403.

Competing interests:
Competing interest: I have spoken at scientific symposiums, organised by Helixor and bisoyn (both mistletoe producers)

Professor Stimpel states "The truth is that from a scientific point
of view we presently do not know whether mistletoe is effective in cancer
or not."

He then goes on to suggest that we owe our patients more than just
intuition.
He concludes by declaring the practice of employing mistletoe preparations
in cancer treatment as bad clinical practice.

Given the dismal successes in cancer treatment today, the glaring
lack of efficacy of chemotherapy for most cancers and the continued
increase in numbers of new cancer cases, I suggest we use our intuition as
well as anything else that just might show a bit of hope and promise.

Condemnation without investigation and outright (perhaps
arrogant)dismissal of a natural remedy that will do little harm and is
still in use precisely because a sufficient number of clinicians believe
that it does work is not what the doctor ordered.

Competing interests:
None declared

The author of the editorial (1) has repeatedly published lists of
alleged horrible side effects of mistletoe treatment, which, at a closer
look, turn out to be either harmless reactions, or misinterpretations, or
not referring to mistletoe therapy at all. (2) The new list of “serious
adverse reactions” published in the BMJ (1) is also not supported by
empirical data. One of the two references explicitly states that “no
severe side effects were observed”. The other reference, unpublished,
refers to a survey which was also published as a book-chapter. (3) It
reports, besides some well known side effects of mistletoe treatment
(frequent harmless or occasional allergic or very rare anaphylactic
reactions, see overview (4)), many anecdotal suspected adverse events (not
adverse reactions!): There are no details reported, no information on
diagnoses, treatments or any other medical data. Almost nothing is known
apart from the fact that the causal relationship to mistletoe therapy was
not assessed – except in a patient with flue-like symptoms who also
happened to have a viral infection, and a patient with thrombocytopenia
after induction of heparin treatment. Of course, countless adverse events
occur in cancer patients. They are often ill, have many symptoms, and
receive numerous medications. “Cum hoc, ergo propter hoc” is a logical
fallacy.

Regarding mistletoe efficacy, the quoted reviews are outdated or
incomplete, do not refer to the recent trials, or even specifically
exclude all trials on anthroposophic mistletoe preparations. (4)

The in vitro studies seen as suggestive of mistletoe-induced tumour
cell proliferation have been criticised for technical deficiencies;
several replication studies failed to confirm any of their results (e.g.
(4;5)).

Incorrect, too, is the statement that mistletoe would be used as an
alternative treatment. Mistletoe is mostly used in addition to
conventional oncological treatment, which is regularly applied also in
anthroposophic medicine. (4)

Reference List

(1) Ernst E. Mistletoe as a treatment for cancer. Br Med J 2006;
333:1282-1283.

(2) Kienle GS, Hamre HJ, Kiene H. Anthroposophical Medicine: A
systematic review of randomised clinical trials. Wien Klin Wochenschr
2004; 116:407-408.

(3) Saller R, Kramer S, Iten F, Melzer J. Unerwünschte Wirkungen der
Misteltherapie bei Tumorpatienten - Eine systematische Übersicht. In:
Scheer R, Bauer R, Becker H, Fintelmann V, Kemper FH, Schilcher H,
editors. Fortschritte in der Misteltherapie. Aktueller Stand der Forschung
und klinischen Anwendung. Essen: KVC Verlag, 2005: 367-403.

(4) Kienle GS, Kiene H, Albonico HU. Anthroposophic Medicine:
Effectiveness, Utility, Costs, Safety. Stuttgart, New York: Schattauer
Verlag, 2006.

(5) Kelter G, Fiebig HH. Absence of tumor growth stimulation in a
panel of 26 human tumor cell lines by mistletoe (Viscum album L.) extracts
Iscador in vitro. Arzneim -Forsch /Drug Res 2006; 56(6A):435-440.

Dr. med. Gunver S. Kienle, MD
Institute for Applied Epistemology and Medical Methodology (IFAEMM),
Schauinslandstr. 6
D-79189 Bad Krozingen
Germany
Gunver.Kienle@ifaemm.de

Competing interests:
The author has written a Health Technology Assessment Report on Anthroposophic Medicine on behalf of the Swiss Federal Social Insurance Office. IFAEMM conducted research projects with mixed funding by foundations, health insurance companies, and Weleda, Wala, or Helixor.