Mistletoe therapy for pancreatic cancer

• Efficacy of mistletoe extracts as a complement to standard treatment in advanced pancreatic cancer: a multicentre, parallel group, double-blind, randomised, placebo-controlled clinical trial
• Influence of mistletoe therapy on survival time and quality of life in patients with locally advanced or metastatic pancreatic cancer – a randomised clinical phase III study
• Integrative oncology including mistletoe therapy in palliative care of patients with advanced pancreatic cancer – a multicentre observational study
• Efficacy and safety of supportive mistletoe therapy in patients with pancreatic cancer of all stages of severity – a multicentre, controlled, retrospective epidemiological cohort study
   

Furthermore, several case reports on this type of tumour are available.

Wode et al. 2024 [333]

Patients and Methods

This double-blind, randomized, placebo-controlled multicenter study included 290 patients with advanced pancreatic cancer undergoing standard chemotherapy at 9 Swedish cancer centers. They were allocated into two groups by 1:1 randomization, stratified by centers and suitability for palliative chemotherapy. In each group, more than 80 percent of the patients received individually adjusted chemotherapy. One group of 143 patients received the mistletoe extract Iscador Qu (treatment group) subcutaneously three times weekly for 9 months in addition to comprehensive oncological treatment and palliative care, while the other group of 147 patients received a placebo (saline solution) subcutaneously for 9 months. The primary endpoint of the study was overall survival, while secondary endpoints included progression-free survival, health-related quality of life, therapy-related side effects, and other parameters. The mistletoe extracts were administered was in accordance with current recommendations. The study was conducted independently of pharmaceutical companies with public funding.

Results

The study results showed no statistically significant improvement in overall survival in the mistletoe extract group compared to the placebo group, with a comparable safety profile. The median overall survival was 8.3 months (placebo group) and 7.8 months (treatment group). The adjusted hazard ratio (aHR) for overall survival was 1.13 (aHR 1.13; 95% confidence interval 0.89-1.44). Quality of life measurements indicated a comparable overall score for the "global health status/quality of life" dimension in both groups (p=0.086), with mean changes of -6.8 (treatment group) and -6.2 (placebo group). Apart from an increased (expected) rate of local skin reactions in the treatment group (66%) compared to the placebo group (1%), which did not affect overall survival or quality of life, the additional mistletoe therapy was well tolerated and showed no difference in the number and severity of side effects compared to placebo; the incidence rate ratio was 1.11 (95% confidence interval 0.77-1.59).

Conclusion

The results show that the additional administration of mistletoe extracts at the applied dosage, alongside comprehensive oncological treatment in Sweden, did not result in a statistically measurable prolongation of overall survival in patients with advanced pancreatic cancer. Further results of this study on secondary endpoints such as progression-free survival, health-related quality of life (QLQ-C30, QLQ-PAN-26), body weight, and qualitative and biomarker analyses are still awaited.

Comment

The outcome of the MISTRAL study differs from the results of an earlier randomised multicentre clinical study in Serbia (MAPAC study) (127,81) and other studies from health services research, which showed a prolongation of survival and improvement in quality of life for patients with advanced pancreatic cancer treated with mistletoe therapy compared to the control group. A possible reason for the differing results compared to the MAPAC study could be that Sweden generally has a better palliative care (Level 4b) (334) compared to Serbia (Level 3b), and that the survival time of cancer patients can be significantly increased through comprehensive palliative care alone, even without mistletoe therapy (335). Additionally, final assessments of quality of life in both study arms cannot yet be made based on the MISTRAL study results, as only one out of 15 quality of life dimensions has been published so far. It is interesting that Swedish MISTRAL patients have a significantly higher baseline quality of life dimension (up to 59.4) compared to MAPAC patients (up to 34.8) (81). Regarding the median overall survival in the placebo group of the MISTRAL study, it is lower at 8.3 months compared to similar conventional studies with combination therapies (336). Moreover, the median overall survival of 7.8 months in the treatment group of the MISTRAL study is lower than in real-world data studies on pancreatic cancer with mistletoe combination therapies, which achieved a median overall survival of 12.1 months in combination with gemcitabine and mistletoe extracts (101). It should be noted that comparable conventional studies included patients with ECOG 0-1 (337), the MISTRAL study included patients with ECOG 0-2 (333), and the MAPAC study included patients with ECOG 0-4 stages (81). Additionally, when evaluating various studies, it is important to note that the index date (start of overall survival calculation) in the MISTRAL study was at the time of randomisation, which was between 27 and 66 days after diagnosis (333).

Tröger et al. 2013, 2014 [81, 127]

These are two publications of a study which has been published under different aspects in several scientific journals.

Patients and methods

In this open-label, monocentre, group-sequential, randomised phase III trial in patients with locally advanced or metastatic pancreatic cancer the patients were monitored for a period of twelve months or until their death.

Half of the patients received best supportive care for acute treatment of cancer-related symptoms, but no antineoplastic therapy. The other half additionally injected the mistletoe extract Iscador Qu subcutaneously three times a week. Subsequently, both groups were compared with regard to overall survival and quality of life. Quality of life was assessed using the EORTC QLQ-C30 questionnaire.

The group sequential design involved a first interim analysis of overall survival and drug safety by an independent review board (Independent Data Monitoring Board, IDMC) after the inclusion of 220 patients. This board recommended an early termination of the study as the planned interim analysis of the data showed a prevalence of mistletoe therapy with regard to overall survival and agreed to the publication of the study results obtained so far.

Results

The baseline characteristics were statistically balanced in both study groups. The interim analysis showed a median survival time of 4.8 months in the mistletoe therapy group compared to 2.7 months in the control group (hazard ratio (HR) = 0.49; p < 0.0001). In two following subgroup analyses, in which the patients were divided according to a prognosis index, the median survival time in the group with "good prognosis" was 6.6 months for the patients with mistletoe therapy and 3.2 months for the control group (HR = 0.43; p < 0.0001). In the group of patients with "poor prognosis" the corresponding survival times were 3.4 and 2.0 months respectively (HR = 0.55; p < 0.0031).

The parameters for quality of life were also mostly significantly different between the both groups. For example, EORTC QLQ-C30 showed a significant and clinically relevant advantage in the mistletoe therapy group in 13 of its 15 dimensions. The significant improvement was also reflected in the reduced number and severity of cancer-related symptoms in the course of treatment. In particular, cancer-related pain was significantly lower, which was accompanied by a significant reduction in analgesics. In addition, nausea and vomiting as well as loss of energy and appetite were significantly less severe. Despite all expectations, the investigators even observed a slight weight gain in patients of the mistletoe therapy group.

Mistletoe therapy was well tolerated and no serious side effects were recorded.

Conclusion

This study showed a significant and clinically relevant advantage in overall survival and a very significant improvement in the quality of life for patients undergoing mistletoe therapy. Mistletoe therapy thus represents a well tolerated treatment for patients with locally advanced or metastasised pancreatic adenocarcinoma.

Axtner et al. 2016 [101]

Patients and methods

In this multicentre observational study the effect of an integrative oncological concept including mistletoe therapy in daily care was investigated on the overall survival of 240 patients with advanced pancreatic cancer (stage IV).

Survival time was analysed using multivariate Cox proportional hazard analysis with different parametric allocation functions. Patients who received chemotherapy alone were compared with those who received a combination of chemotherapy and mistletoe therapy or mistletoe therapy alone or no therapy at all. For classification into the mistletoe therapy group a use of at least four weeks was required.
 

Results

Of the 240 patients, 124 were females and 116 males with a median age of 68 years. Of these, 221 (92.1%) received a complementary therapy as part of the integrative oncological therapy concept, and 177 (73.8%) of these received mistletoe therapy, which was used in addition to chemotherapy (mostly gemcitabine as monotherapy or in combination) in 154 patients (64.1%). Both therapies had positive effects on the patients' survival.

In a second analysis it was found that patients with combined chemo- and mistletoe therapy had a significantly longer survival time than patients who received chemotherapy alone (12.1 vs. 7.3 months). Patients who received only mistletoe therapy showed a longer survival time than those who received neither chemotherapy nor mistletoe therapy (5.4 vs. 2.5 months). The combination of both therapies therefore performed best.
 

Conclusion

The data show that an integrative oncological concept can be successfully applied in the daily care of patients with advanced pancreatic cancer. For example, the longest survival time was determined for patients who received both mistletoe therapy and chemotherapy.

Matthes et al. 2010 [45]

Patients and methods

This multicentre, controlled, epidemiological, retrospective cohort study, conducted according to GEP guidelines, included 396 patients from different centres in Germany and Switzerland with pancreatic cancer of all stages of severity (UICC stages I to IV). As part of a supportive therapy, Iscador was administered subcutaneously to 201 of these patients two to three times a week in addition to adjuvant chemotherapy (± radiotherapy) or complementary to oncological aftercare.

The 195 patients of the control group were treated with chemotherapy alone, in particular with gemcitabine (± radiotherapy), or received aftercare without further oncological medication.

The median treatment and follow-up period was about 15 months in the mistletoe therapy group and about 10 months in the control group. The median duration of chemotherapy was about 7 months in the mistletoe therapy group and about 5 months in the control group.

Efficacy was evaluated according to the frequency of side effects caused by chemotherapy (± radiotherapy) in the mistletoe therapy group compared to the control group, as well as the persistence of disease-related symptoms, Karnofsky index, hospitalisation time and overall survival (OS). The number of patients with documented adverse events (ADR) caused by mistletoe therapy was also recorded.

Results

In the mistletoe therapy group, significantly fewer side effects caused by chemo- and/or radiotherapy were observed than in the control group. Only 14 per cent of the mistletoe therapy group developed these side effects, compared to almost 50 per cent in the control group. The adjusted relative risk to develop therapy-related side effects was thus significantly lower in the mistletoe therapy group than in the control group (p = 0.003), (risk reduction of 54).

The patients in the mistletoe therapy group showed fewer disease- and therapy-related symptoms after the first oncological treatment cycle. In particular, nausea, vomiting, loss of appetite, depression, fatigue, sleep disorders, and back pain occurred significantly less frequently than in the control group.

A remarkable study result was obtained for the estimated survival time. It was significantly longer in the mistletoe group than in the control group. The adjusted hazard ratio related to the mortality rate was 0.58 resulting in a reduction of the relative risk of death in the mistletoe therapy group by approximately 42 percent compared to the control group.

The Karnofsky performance index also improved significantly in the mistletoe therapy group. Performance increased from 74.1 to 79.1 percent in patients under mistletoe therapy after the first chemotherapy cycle. In contrast, the control group had a performance decrease from 80.3 to 74.7 percent. The average time of hospitalisation was also significantly shorter in the mistletoe therapy group (40 days) compared to the control group (54 days).

To assess therapeutic safety, the adverse drug reactions caused by the mistletoe extract were evaluated. Only three patients (0.8%) from the mistletoe therapy group reacted with mild, unspecific systemic side effects such as dizziness, exhaustion, depression, nausea or mild fever. In 45 patients (22.4%) of the mistletoe therapy group local reactions such as indurations, oedema, erythema, itching or local pain occurred, which were always only mild to moderate. Serious, life-threatening side effects did not occur. Thus, mistletoe therapy could be considered safe and well tolerated.

Conclusion

The present study evaluated the safety and efficacy of Iscador as part of a supportive therapy in patients with pancreatic cancer.

Patients in the mistletoe therapy group had significantly fewer side effects caused by conventional therapy, fewer disease-related symptoms, a better general condition, shorter hospitalisation periods and a significantly higher survival rate than patients in the control group.

The mistletoe therapy was well tolerated and could be assessed as safe.