Is Viscum album (mistletoe) a useful adjunct in cancer therapy?

The following arguments are the result of a long scientific debate within our cancer centre about Viscum album (mistletoe), which is the most widely accepted complementary medicinal product in Germany and Switzerland. In our opinion, the present evidence for and against its efficacy does not justify the use of V. album in cancer therapy. Our pro-V. album position is therefore not based on strictly medical grounds, but on the patient’s perception of CM.

Let us first declare an ethical credo. It is a fundamental right of patients to have a personal view regarding their disease. For a cancer patient, such a view can lead to the desire to make use of CM. The physician must take such a view and such a desire into account, while carefully avoiding causing harm to the patient.

In 1985, about 15% of physicians in Germany and Switzerland had a tolerant attitude towards the use of V. album. In 2002, this percentage had risen to 65%.¹,² There are two reasons for this increase. In the first place, more data have become available on V. album’s ability to improve the patient’s quality of life and tolerance of chemotherapy. Secondly, there are more and more informed patients who are competent and willing to participate in the physician’s decisions.

Such ‘competent’ patients want to take an active part in the management of their cancer. They have unlimited confidence in the body’s potential for self-healing. To them, V. album is a means of reinforcing their defences, this last term being taken in both its immunological and psychological sense. They do not want to be the helpless victims of a merciless fate. In the hands of these patients, V. album is perceived as a personal weapon in the fight against the existential crisis created by cancer. The ‘competent’ patient does not care whether or how V. album works, the only thing that matters is that it does help. And only they can decide if this is the case.

The increasing acceptance of V. album is also due to a changing paradigm of cancer therapy. The scientific paradigm of cancer therapy is that curing cancer implies removing the tumour up to the last diseased cell. The natural paradigm, by contrast, is that the cure of cancer depends not only on an effective antitumoural treatment but also on the patient. Nowadays, this view is shared in Germany and Switzerland by nearly 100% of patients, laypersons and pharmacists, 92% of practising physicians, and 55% of conventionally trained oncologists.²,³ These oncologists are more and more beset by doubts on reading recent publications that postulate a relationship between the behavioural patterns of patients and the prognosis of their disease.

Even though some of these publications are of questionable reliability, they cannot be ignored in view of the change of paradigm mentioned above and the increasing competence of patients. In addition, every patient has the fundamental right to be treated in accordance with their subjective views on disease and health, and it is likely that these views and the complementary use of V. album on the patient’s own initiative make a positive contribution to the victory over cancer and the prognosis of the disease.

At any rate, it is decisive for our argument that patients firmly believe in the model of personal defences and are remarkably able to integrate V. album in their defence strategy. In our opinion, remaining obstinately unreceptive to the wish of patients to receive CM has become obsolete. Such a position can harm the relationship between physician and patient, and prompt the latter to consult a ‘quack’ instead. Nowadays, the professionally and socially competent physician is required to respect the views and attitudes of his patients with respect to CM and to harmonise them with his own.

This is possible in a university institution within the framework of precise rules, as we have shown. The following are some of the rules. The initiative for using CM is left to the patient, but the physician must show understanding. Whenever there is a choice between several preparations, we recommend the one for which the best evidence relative to quality, efficacy and safety exists – Iscador in the case of V. album. Patients participating in phase I and II trials should not be given any CM. In immunogenic and haematologic malignancies, we are cautious because of an inherent enhancement potential. Such rules are very readily accepted by ‘competent’ patients and reinforce the mutual confidence between the patient and the physician.

References

1. Bundesministerium für Forschung und Technologie. Materialien zur Gesundheitsforschung, Band 21: Unkonventionelle Medizinische Richtungen. Bonn: Bundesministerium für Forschung und Technologie, 1992.
2. Tumor Biology Center Freiburg. Survey on unconventional methods in cancer medicine, 2002; Unpublished
3. Nagel GA, Heckl U. Beratung von Krebspatienten in der Apotheke. Dtsch Apotheker Ztg 2001; 33: 39–44.

Despite the general popularity of V. album extract treatment in cancer patients and increasing expenditures for these extracts, only a few CCTs with high methodological quality have been carried out. None of these trials, however, has been carried out according to GCP guidelines, which should be the prerequisite to introduce V. album treatment as an adjuvant standard modality for any tumour type.

There are only two reasons to establish V. album treatment as adjuvant treatment in human cancer. First, a clinical trial shows a statistically better disease-free survival for a specific cancer. This trial has to be controlled with adequate follow-up, with formal power calculation, and stratification for conventional treatments. Second, the quality of life is significantly better under adjuvant V. album treatment, without influence on the disease-free survival. It has to be kept in mind that different solid tumours will react differently to this treatment, and that good results in one tumour type are not transferable to another. It must also be underlined that immunomodulatory or immunostimulatory effects alone are not an argument to establish V. album treatment in human cancer. A correlation between immunological blood values and a better survival has never be proved.¹

Immunostimulatory, cytotoxic and preapoptotic effects of different V. album extracts have been demonstrated in numerous preclinical studies.² Antitumour effects, such as reduced metastatic tumour growth, have been proved in various animal models.³,⁴ Contrary to these investigations, the long-term administration of a standardised V. album extract failed to delay, reduce, inhibit or prevent chemically induced cancer development in rat urinary bladders.⁵–7 The encouraging results of these positive studies could not be verified in clinical trials. A great challenge is the heterogeneity of the V. album extracts available today. In Germany, 20 different preparations are on the market. They differ in the kind of trees and/or the production methods, therefore their exact composition and pharmacokinetics are not comparable and remain largely undetermined. No commercial preparation is identical to another, and the interpretation of preclinical data from different extracts is problematic, perhaps even impossible. The most examined biologically active substances identified in V. album extracts are lectins (ML-1, 2, 3, VisalbCBA).⁸⁷–¹⁰ In addition, polysaccharides and polypeptides, as well as numerous low molecular components, were found.¹¹ Further investigations are needed to clarify the dose-dependent effects of V. album components and to exclude stimulation of tumour proliferation.¹² Moreover, the toxicity and pharmacokinetics of relevant V. album components have to be examined in clinical trials.²

The results of controlled as well as uncontrolled clinical trials are highly inconsistent. The abundant literature of uncontrolled trials predominantly reports beneficial effects of commercial V. album extracts on cancer growth. However, with increasing methodological quality, CCTs show more disappointing results for the two key points of oncological studies: disease-free survival and disease-specific survival. The trial with the highest methodological score¹³ did not reveal any beneficial effects in head and neck cancer.¹⁴

Several systematic reviews of V. album treatment in CCTs have been published since 1994.¹³,¹⁵–18 The quality of these reviews varies in a way that correlates with the impact factors (http://impactfactor.ifrance.com/impactfactor) of the journals. The review with the highest impact factor (4.233) has been published in the International Journal of Cancer.¹³ This review evaluates the quality of the CCTs: The collective evidence does not support the efficacy or effectiveness of V. album extracts as a curative or supportive cancer therapy. Kaegi, who summarised the application results of the brand Iscador, concluded that the evidence of clinical benefit from human studies remains weak and inconclusive, in spite of promising results from in vitro experiments (impact factor 2.762).¹⁵ Kleijnen et al. concluded in the first systematic review (1994) that the use of V. album extracts cannot be recommended unless the patient is involved in a clinical trial (impact factor 0.935).¹⁷ While Ernst et al. included 10 CCTs,¹³ Kienle et al. made a systematic review of 23 trials. He also included non-randomised trials and trials with outcomes other than disease-free survival (impact factor 0).¹⁶ In a further recent publication on ML-1 standardised V. album extracts it is also concluded that V. album therapy has not gained an established place in oncology (impact factor 0).¹⁸

Thus, we agree with the National Cancer Institute, which offered the following conclusion: ‘Mixed results have been obtained in animal studies that have investigated the ability of V. album extracts to slow tumor growth’, and so far ‘there is no evidence from well-designed clinical trials that V. album or any of its components are effective treatments for cancer’ (http://cancernet.nci.nih.gov/cam/mistletoe.htm).

References

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5. Kunze E, Schulz H, Ahrens H, Gabius HJ. Lack of an antitumoral effect of immunomodulatory galactoside-specific mistletoe lectin on N-methyl-N-nitrosourea-induced urinary bladder carcinogenesis in rats. Exp Toxicol Pathol 1997; 49: 167–80.
6. Kunze E, Schulz H, Gabius HJ. Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration. J Cancer Res Clin Oncol 1998; 124: 73–87. [Abstract]
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11. Wagner H, Feil B, Bladt S. Viscum album – die Mistel. Dtsch Apotheker Ztg 1984; 29: 1429–32.
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