Mistletoe therapy for skin cancer

• Viscum album lipophilic extract in actinic keratosis, cutaneous squamous cell carcinoma, and basal cell carcinoma: a retrospective case series
• Influence of long-term mistletoe therapy on survival time and self-regulation of patients with malignant melanoma – a prospective, controlled cohort studies in matched-pair design
• Complementary long-term mistletoe therapy in patients with primary intermediate- to high-risk malignant melanoma – a multicentre, comparative, epidemiological cohort study
• Efficacy and safety of interferon-alpha, interferon-gamma or mistletoe therapy in high-risk melanoma patients previously undergoing surgery – a randomised Phase III EORTC study

For this type of tumour there are also various case reports available.

Königsberger et al. 2024 [339]

Patients and methods

For this retrospective case series in patients with cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC) and actinic keratosis (AK), the clinical response to treatment with the lipophilic Viscum album extract (VALE), adverse drug reactions, risk factors, concomitant therapies and diseases as well as additional diagnostic and therapeutic information were documented. The data analysis was performed for each individual patient and each individual lesion. The extract is currently available as "Viscum album Herba Extractum resinosum 10%, Crème" (Iscador AG, Switzerland) for external use, which is applied 1 to 2 times a day to the affected lesions, preferably occlusively at night.

Results

The study population of this observational study consisted of 55 patients with 74 skin lesions. Most of the lesions (45%) were found on the forehead, nose region, cheek and near the eye. Histology of the lesion was performed in 15% of cases (for cSCC in 5 out of 9 cases = 56%), dermatoscopy was performed in 20% of cases and in 65% of cases the diagnosis was based on clinical assessment (for AK in 34 of 48 cases = 79%). No information was available whether cSCC were superficial or deep.

Clinical response rates (complete + partial remissions) for individual lesions were 78% for cSCC, 70% for BCC, and 71% for AK. Complete remission rates for individual lesions were 56% for cSCC, 35% for BCC, and 15% for AK.

The median treatment duration was 13 weeks, 30 lesions were treated within 9 weeks, 23 lesions within 19 weeks and 19 lesions for more than 19 weeks, whereby shorter times to best clinical response were observed for cSCC and BCC compared to AK (10 weeks for cSCC, 15 weeks for BCC, 47 weeks for AK). Occlusion application – mostly at night – was performed in 34 lesions. According to the medical assessment, compliance (adherence to treatment) with the treatment of the 74 lesions was classified as good in 71%, moderate in 27% and bad in 1%. Adverse drug reactions were reported in five patients, including erythema and inflammatory reactions of mostly moderate severity, which resolved completely. In one case, therapy was temporarily paused, in four cases it was continued without interruption.

Conclusion

The results of this study indicate that VALE is a safe and well-tolerated extract, and complete and partial remissions of cutaneous squamous cell carcinomas were observed during its application. Further prospective studies are needed to evaluate the efficacy of therapy with VALE in more detail.

Grossarth-Maticek und Ziegler 2007 [119]

Patients and methods

This prospective, controlled cohort study in matched-pair design was part of a comprehensive long-term epidemiological study involving 10,226 cancer patients investigating various factors related to the course of the cancer disease. Therapy with mistletoe extracts was one of the investigated factors, since 1,668 patients reported using mistletoe extracts.

The influence of mistletoe therapy on psychosomatic self-regulation and survival time was analysed separately according to each tumour entity. The comparability of the two therapy groups (with and without mistletoe therapy) for the respective tumour entity was achieved by forming matched pairs.

In these two prospectively planned and conducted controlled studies, patients with malignant melanoma without recurrences, detected lymph node metastases or distant metastases were matched according to the mentioned prognostic factors and examined for overall survival, tumour progression and psychosomatic self-regulation.

All study patients received conventional therapy according to their individual condition, including – if necessary and appropriate – surgery, chemo-, radio- and immunotherapy.

In the randomised study, only melanoma patients without mistletoe therapy (and without any other immunostimulating therapy) were recruited and matched for 22 pairs; in the non-randomised study, melanoma patients treated with the mistletoe preparation Iscador in addition to conventional therapy were matched with melanoma patients treated with only conventional therapy.

Results

In terms of overall survival, there was no significant difference between the mistletoe and control group in both studies.

The overall analysis of tumour progression showed a significant advantage for the mistletoe group in both studies with a hazard ratio (HR) of 0.49 in the randomised study and 0.72 in the non-randomised study.

In the randomised study, psychosomatic self-regulation in the mistletoe therapy group improved significantly after 12 months compared to the control group (p = 0.0048).

Conclusion

In these studies, mistletoe therapy was shown to have a clinically relevant, significant effect on tumour progression (slowing of tumour progression) and an improvement in psychosomatic self-regulation in patients with malignant melanoma.

Augustin et al. 2005 [138]

Patients and methods

This multicentre, controlled, epidemiological, retrospective cohort study with parallel group design, conducted according to the guidelines of "Good Epidemiological Practice" (GEP), investigated the therapeutic efficacy and safety of long-term mistletoe therapy in comparison to an untreated, only observed ("watchful waiting") control group of patients with malignant melanoma at intermediate- to high-risk (AJCC/UICC stages II and III) during post-surgical aftercare.

A total of 686 patients from various centres in Germany and Switzerland participated in the study. 329 patients were in the mistletoe group and 357 in the control group. The median follow-up/observation period was 81 months in the study group and 52 months in the control group. The median duration of therapy with the study preparation Iscador (predominantly Iscador P), which was administered two to three times a week for at least six months, was approximately 30 months.

The primary objective of efficacy was the adjusted overall survival, while secondary objectives were tumour-related survival  and the adjusted risk of developing brain metastases.

The objective criterion of safety was the number of patients with documented adverse events due to mistletoe therapy.

Results

The adjusted hazard ratio (HR, relative risk) to die of any reason during the therapy and follow-up period was significantly lower in the mistletoe therapy group than in the control group. Comparable results were also obtained for tumour-related survival. Here the HR in the mistletoe therapy group was even 0.41 (p = 0.002), which corresponds to a relative risk reduction of 59 percent.

The frequency of metastases, particularly brain, lung and lymph node metastases, was also significantly lower in the verum group than in the control group.

In the mistletoe therapy group, 11 patients (3.3%) developed therapy-related adverse drug reactions (ADRs) which were non-specific and only mild to moderate. In most cases the reactions subsided spontaneously within one week. In one case, treatment was terminated prematurely due to "moderate" headaches and tiredness. There were no serious side effects.

In 42 patients (12.8%) local reactions at the injection site were seen. These were mainly erythema, oedema, itching or localised pain. The local side effects were mainly mild to moderate (WHO/CTC grade 1-2) and in most cases subsided spontaneously. In 5 cases mistletoe therapy was discontinued prematurely due to local reactions.

Conclusion

Post-surgical supportive long-term treatment with a mistletoe extract in patients with primary malignant melanoma at intermediate- to high-risk (UICC/AJCC stages II to III) showed a significant advantage in survival compared to a control group from the same cohort without additional mistletoe therapy.

A delay in metastasis was also observed in the mistletoe therapy group.

Kleeberg et al. 2004 [117]

Patients and methods

The European Organisation for Research and Treatment of Cancer (EORTC) has conducted a prospective, randomised phase III study for adjuvant treatment of melanoma patients after resection of prognostically unfavourable primary tumours (stage II, > 3mm Breslow thickness) or after curative resection of regional lymph node metastases (stage III). The aim was to evaluate the efficacy and safety of low-dose recombinant interferon-alpha 2b (rIFN-α2b) or recombinant interferon gamma (rIFN-γ) administered subcutaneously every second day for a period of twelve months or until tumour progression in comparison to an untreated control group.

To this EORTC study, the working group for internal oncology of the German Cancer Society added mistletoe therapy with Iscador M as a fourth arm, which was injected subcutaneously every other day in increasing dosages, with a seven-day break after 14 injections. As in the interferon groups, the application period was twelve months at maximum.

Thus two studies were ultimately conducted: a three-arm study without mistletoe therapy and a four-arm study with mistletoe therapy. The four-arm study was published in a short form before final publication [152]. 830 patients were randomised in 45 institutions from 13 countries, 423 of them in the three-arm study and 407 in the four-arm study. The median follow-up was 8.2 years.

For the analysis, the two studies were partly combined and partly evaluated separately, so that the control group of the four-arm study was used for both studies.

Results

Neither the patients treated with interferon nor those treated with Iscador showed any significant difference compared to the control in terms of disease-free or overall survival.

The results for the disease-free interval for patients in the mistletoe therapy group were slightly below those of the control group. The results on quality of life were not published.

Five patients (4.9%) discontinued mistletoe therapy due to side effects. It is not possible to determine which side effects occurred here, as no differentiation was made between the various therapies.

During rIFN-α2b, rIFN-γ and mistletoe therapy, loss of appetite, general malaise, depressed mood, fever and local reactions at the injection site occurred. There was no organ toxicity.

Conclusion

In this study, no advantage of mistletoe therapy was found in terms of survival time or disease-free interval for a maximum of twelve months.