Mistletoe Extract in Patients With Advanced Pancreatic Cancer

A Double-Blind, Randomized, Placebo-Controlled Trial (MISTRAL)

Background: Patients with advanced pancreatic cancer have limited survival and few treatment options. We studied whether mistletoe extract (ME), in addition to comprehensive oncological treatment and palliative care, prolongs overall survival (OS) and improves health-related quality of life (HRQoL).

Methods: The double-blind, placebo-controlled MISTRAL trial was conducted in Swedish oncology centers. The main inclusion criteria were advanced exocrine pancreatic cancer and Eastern Cooperative Oncology Group (ECOG) performance status 0–2. The subjects were randomly assigned to ME (n=143) or placebo (n=147) and were stratified by study site and by eligibility (yes/no) for palliative chemotherapy (June 2016–December 2021). ME or placebo was injected subcutaneously three times a week for nine months. The primary endpoint was overall survival (OS); one of the secondary endpoints was the HRQoL dimension global health/ QoL (EORTC–QLQ–C30), as assessed at seven time points over nine months. Trial registration: EudraCT 2014–004552–64, NCT02948309

Results: No statistically significant benefit of adding ME to standard treatment was seen with respect to either OS or global health/QoL. The adjusted hazard ratio for OS was 1.13 [0.89; 1.44], with a median survival time of 7.8 and 8.3 months for ME and placebo, respectively. The figures for the HRQoL dimension “global health/QoL” were similar in the two groups (p=0.86). The number, severity, and outcome of the reported adverse events were similar as well, except for more common local skin reactions at ME injection sites (66% vs. 1%).

Conclusion

ME is unlikely to have a clinically significant effect on OS or the HRQoL dimension global health/QoL when administered in patients with advanced pancreatic cancer in addition to comprehensive cancer care.

Pancreatic cancer is among the most lethal tumors. When locally advanced growth or systemic spread preclude curative resection, the options for effective treatment are limited and mainly consist of multidrug chemotherapy (1). Patients’ rapidly deteriorating performance status constitute significant obstacles for disease-modifying treatments. Single-drug chemotherapy or best supportive care (BSC) often remain the last resort, yielding survival times of around six and two months, respectively. Patients’ increasing symptom burden and impaired health-related quality of life (HRQoL) (2) necessitate multidisciplinary management and integrated palliative care (PC) (1).

Plants have been a successful source for anticancer drugs. Mistletoe (Viscum album L) is a hemiparasitic shrub growing on various host trees. Mistletoe extract (ME) is frequently prescribed in integrative cancer therapy (3, 4, 5), in addition to oncological treatment or BSC. ME is well known and acknowledged among physicians in Germany (6) and patients express a strong preference for ME (7). Mistletoe constituents stimulate both innate immunity and the adaptive immune response (8, 9). Low doses are injected subcutaneously to improve HRQoL and immune functions. High doses are administered, mostly locally (off-label use), to exert direct antitumoral effects (10, 11, 12). Systematic reviews reported a medium-sized effect on HRQoL (3) and a possible effect on survival (13). However, the studies were mostly of insufficient methodological quality (7). An open-label, randomized controlled trial (RCT) (MAPAC) investigated subcutaneous ME in 220 patients with advanced pancreatic cancer and reported both a significant survival benefit and better HRQoL (eBox 1) (14, 15).

The MAPAC trial’s promising results and ME’s good safety profile, low cost, and widespread use motivated the present study, in which we investigated whether ME can make a clinically useful contribution to the multidisciplinary management of patients with advanced pancreatic cancer. Recruiting patients for RCTs is difficult in countries where ME treatment is widespread and clear patient preferences exist for or against ME (16). In Sweden, ME is approved for palliative care but it is rarely used (17). Therefore, Sweden was considered a suitable context for this trial. Multidisciplinary inpatient and outpatient PC is fully integrated in the Swedish health care system. Patients’ eligibility for palliative chemotherapy was preliminarily assessed by multidisciplinary tumor boards and the final decision whether chemotherapy was given or not was adapted to the individual patient’s medical condition, comorbidities, and personal preference. This decision was made within routine oncology independent of trial participation. The study’s aim was to examine whether ME complementing standard treatment (palliative chemotherapy or BSC) may prolong overall survival (OS) and improve HRQoL with regard to global health/QoL in patients with advanced pancreatic cancer.

Methods

A double-blind, randomized, placebo-controlled trial was conducted at nine Swedish oncology centers (referred to in the following as study sites). The main inclusion criteria were a recent diagnosis of advanced exocrine pancreatic cancer or relapse, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, life expectancy >4 weeks (eMethods 1). Drug treatment was provided for symptom management (analgesics, antiemetics, anxiolytics, glucocorticoids), and participants had access to palliative care (specialized multidisciplinary home or inpatient PC) if needed (17, 18).

A data safety committee ensured patient safety. Quality assurance further included:

• regular independent monitoring
• spot sample check of the collected data
• ensuring correct content and assignment of the study drug
• a final independent check of the data set
• an audit of the entire study (eMethods 1).

The study participants were randomly assigned at a ratio of 1:1 to either ME injection (fermented aqueous extract of Viscum album L grown on oak tree) or placebo, each in addition to standard treatment. We stratified by oncology center (study site) and preliminary eligibility for palliative chemotherapy. Participants, medical staff, and evaluators were blinded to treatment allocation and application. Following the manufacturer’s recommendations (19) and in accordance with the MAPAC trial (14), the study drug was injected subcutaneously at an initially increasing, individually adapted dosage (0.01–20 mg) thrice weekly for nine months (eMethods 1). Follow-up was performed by physicians and study nurses at five to six weeks, two, three, four, six and nine months after randomization, including assessment of participants’ need for palliative home care (eMethods 1). After completion of the nine-month study(treatment) period, ME treatment was offered to all participants without knowledge of treatment arm allocation (eMethods 1). Overall survival was the primary endpoint, defined as the time from randomization to death of any cause, as documented in the medical records at the participating study sites (eMethods 1). Secondary endpoints included the HRQol dimension “global health/QoL”, assessed at study visits, using the EORTC QLQ-C30 questionnaire (20); glucocorticoid use; and patient safety, i.e. the occurrence of (serious) adverse events (SAE). The remaining secondary outcomes—HRQoL (QLQ-C30, QLQ-PAN-26), and body weight, as well as the nested qualitative and biomarker studies—will be published later.

Stockholm’s Regional Ethical Review Board approved the study (2 March 2016, 2016/122–31/2). The Declaration of Helsinki and Good Clinical Practice were implemented. Written informed consent was obtained from all participants before any trial-related procedure took place. Trial registration: EudraCT 2014–004552–64, NCT02948309. Trial protocol (17).

Statistical analysis

The study was designed to detect a HR of 0.67 between the ME and the placebo arm (17), based on the results of the MAPAC trial. Using a two-sided log-rank test, a sample size of 290 patients (145 participants per arm) was required to achieve a power of 90% at a 5% significance level.

The primary analysis including all participants was evaluated by Cox proportional hazards regression with ”study site” as covariate and “preliminary eligibility for chemotherapy (yes/no)” as strata, and tested the adjusted hazard ratio (AHR) for OS in the ME versus the placebo arm. This analysis was based on the full study period (eMethods 2).

An additonal analysis evaluated OS up to the end of the treatment period with follow-up censored at nine months (eMethods 2). Kaplan–Meier product-limit estimators were used to estimate OS in the respective treatment arms and p-values were calculated using the log-rank test. Point estimates with 95% confidence intervals were calculated for each treatment arm in order to determinate the median OS time. For sensitivity analysis, the Cox regression model included variables whose distribution differed between treatment arms and that were modeled as an interaction with the treatment (eMethods 2). Furthermore, based on these variables, Kaplan–Meier curves were generated to enable comparison of the treatment arms by subgroup. For details on Per Protocol analysis and the secondary outcome “global health/QoL” see eMethods 2. Patient safety data (adverse events/severe adverse events) are presented by treatment arm as counts, percentages, or by number of events per month in the study. All tests were two-sided at 5% significance level. The analyses were performed using R (21).

Results

Between 7 June 2016 and 3 December 2021, 290 patients were randomized to two groups (Figure 1, eSupplement–Table 1). In 15 cases, the tumor board’s preliminary assessment of patients’ eligibility for palliative chemotherapy was not changed (eTable 1). A total of 19 patients were censored at the time of last contact (Figure 2, eMethods 1). The baseline characteristics were well balanced except for differences in distributions of tumor stages (T-stages), primary diagnoses, and relapses (Table, eBox 2).

Figure 1

Flow chart of patients in the trial

Figure 2

Kaplan–Meier curves of overall survival (OS)

Table

Baseline characteristics of the intention-to-treat population, n=290

eBox 2

Results

eTable 1

Participants treated with palliative chemotherapy or best supportive care (BSC)

The primary analysis based on the total follow-up time did not find an effect of ME on overall survival compared to placebo (AHR 1.13 [0.89; 1.44], primary endpoint) nor did the corresponding analysis with follow-up limited to the nine-months’ treatment period (AHR 1.05 [0.77; 1.43]). Median OS was 7.8 months [6.4; 9.4] in the ME and 8.3 months [6.9; 9.7] in the placebo arm (Figure 2). Per-protocol analysis yielded similar results (eSupplement-Figures 1 and 2).

Since many participants opted for ME treatment after study participation, nine-month follow-up is reported for all following analyses. Analyses based on total follow-up time did not change the findings. Sensitivity analyses (eMethods 2) adjusting for pancreatic cancer as the primary diagnosis or relapse yielded an AHR of 1.00 [0.74; 1.37] and adjusting for T-stage yielded an AHR of 0.85 [0.60; 1.22]; among the subgroup of participants receiving BSC, the AHR for OS was 1.30, [0.70; 2.41] (eSupplement–Figures 3–6).

The patients’ study visits were performed in compliance with the study protocol (median –1 to +3 days from the projected date). The corresponding HRQoL questionnaires were returned in 99% and 76% of cases (eSupplement–Table 2). The HRQoL dimension “global health/QoL” was comparable in both groups (p=0.86) (Figure 3, eSupplement–Tables 3–4).

Figure 3

Mean change in quality-of-life scores

Of the 283 patients whose data constituted the safety data set (eBox 2), 64 (46%) in the ME and 65 (45%) in the placebo arm reported at least one adverse event (AE) or serious adverse event (SAE); the event rates by time in study and severity of AEs were comparable in both arms (eBox 2, eTable 2). Local skin reactions (LSR) were reported by 93/140 and 2/143 participants in the ME and placebo arm, respectively. For details on LSR, administered study drug injections, and dose adaptations, see eBox 2, eTable 3, and eFigure.

eFigure

Mean doses of study drug administered

eTable 2

Adverse events and serious adverse events

eTable 3

Number of administered study drug injections

The distribution of chemotherapy regimens was balanced between the groups. The median length of chemotherapy treatment was 3.8 months in the ME and 4.5 months and placebo arm, amounting to 64% of patients’ time in the study in either one of the groups (IQR 36% ME and 30% placebo arm) (eBox 2, eSupplement–Tables 5–6, eSupplement–Figure 7). Glucocorticoids were given to 130/143, (91%, ME arm) and 129/147 (88% placebo arm) participants, for the following indications:

• for symptom relief (e.g., cancer-related fatigue, pain, or loss of appetite)
• as an antiemetic drug in addition to chemotherapy
• to treat comorbidy (e.g., obstructive pulmonary disease).

Glucocorticoid use in relation to patients’ time in the study was similar in both groups in terms of doses and length of treatment (eSupplement–Figure 8). The OS of participants without glucocorticoids use was similar in both treatment arms (HR 0.91, [0.35–2.36]) (eSupplement–Figure 9).

Discussion

We did not find an effect of ME as an addition to standard treatment on OS (primary endpoint) nor on the HRQoL dimension “global health/QoL” compared to placebo. The slightly longer OS in the placebo arm could be explained by minor differences in relevant baseline characteristics. The relatively high proportion of participants treated with palliative chemotherapy (22) is due to patients’ relatively good performance status at baseline (eMethods 1).

Our results did not confirm those of prior clinical studies on subcutaneous ME treatment for pancreatic cancer (eBox 1), which had reported a benefit of ME on OS (14, 23, 24, 25, 26) and HRQoL (15, 25, 26). The trial most comparable with MISTRAL is the open-label MAPAC RCT (14, 15, 27), which was conducted in Serbia and reported a significant improvement in both OS and HRQoL with ME. Given the known immune resistance in pancreatic cancer (28) and taking into account ME’s main mechanism of action via stimulation of both the innate and adaptive immune response, the present study’s results would not have been surprising—without the results from MAPAC.

eBox 1

Clinical evidence on mistletoe therapy in pancreatic cancer from earlier studies

It was not expected that the results of MISTRAL would diverge to such an extent from those of MAPAC and other previous studies. We therefore explored whether there were differences in study populations, treatment, or immunoreactivity, and conducted a variety of sensitivity analyses that had not originally been planned. We found no indication, however, that any such discrepancies could explain the differences in outcome: Neither the MISTRAL patients’ better prognosis altered the results for OS, nor did the inclusion of patients with a relapse, the details of ME treatment (duration, dose, number of injections, LSRs), or concomitant treatment (chemotherapy, glucocorticoids) (eMethods 3).

The blinded study design is a major difference between MISTRAL and earlier studies. All participants were informed of the possibility of nonspecific reactions occurring at the injection site. Even so, the development of LSR (in 66% of the MISTRAL population in the ME treatment arm) might have revealed ME. However, this does not seem to have affected the outcome for HRQoL or OS.

The level to which PC is integrated into Sweden’s health care system is very high (advanced integration, level 4b out of 4b) whereas Serbia is reported to provide generalized PC (level 3b) (29). The palliative chemotherapy regimens delivered during the MISTRAL trial are in line with the current state of knowledge (1). Early access to PC has been shown to prolong survival and improve HRQoL in terminally ill patients (30). In MISTRAL, participants’ need for palliative home care was regularly evaluated and provided if indicated. It is conceivable that optimized PC and extensive oncological treatment with modern palliative chemotherapy provided in MISTRAL might have left less room for improvement in the primary endpoint of OS and the secondary endpoint of “global health/QoL” by adding ME treatment.

No major safety concern arose during MISTRAL. The two SAEs (1.4%) related to the study drug consisted of known side effects of ME (urticaria, pseudoallergic reaction), and their frequency of occurrence was in line with earlier reports (0%–1.5%) (14, 26, 31, 32).

Major concerns have been voiced that botanicals may interfere negatively with chemotherapy, potentially impacting treatment efficacy and safety (33). In our trial, we did not find any indications pointing to increased or decreased survival times or toxicity when ME was added to chemotherapy. This is just a rough assessment though, as our trial was neither designed nor powered to investigate this question. However, this assessment is supported by the results of a phase I study that found no influence of ME on the metabolism of gemcitabine—the most frequently used chemotherapy in pancreatic cancer (34).

The strengths of the present study include:

• a placebo-controlled design with a study protocol conforming to SPIRIT guidelines (17)
• a multicenter design in an academic setting
• conducted in a country where comprehensive oncological PC is being provided
• public and non-profit funding
• a multidisciplinary team of experts specializing in oncology, pharmacology, nursing, integrative medicine, and PC.

In addition, the robustness of the data set was assured by implementing quality control.

The study has high internal validity as evidenced—for example—by good adherence to the scheduled dates for study visits and HRQoL assessments, and the number of returned questionnaires. This is remarkable as almost half of the study period (2.5 of 5.5 years) coincided with the COVID-19 pandemic, which resulted in more study visits having to be done by telephone and in delays in patient recruiting. All data were comprehensively analyzed and presented.

Cancer patients who wish to be treated with ME usually actively seek out treatment in a setting of integrative oncology (26, 31). Treatment settings that enable patients’ active involvement in their therapy have been assumed to be beneficial beyond the specific treatment effect (35). ME treatment in this trial was stripped from such a context, and this may have caused lower external validity in terms of the HRQoL dimension “global health/QoL” not accurately reflecting the context in which most cancer patients use ME today.

Conclusion

We regard it as unlikely that we missed a potentially clinically significant effect for ME treatment. Our findings will be of importance for all those involved in the care of patients with advanced pancreatic cancer. Although we found no effect of ME in this given clinical situation, our study did not show any risks associated with its use either. Future research should investigate the impact of ME on malignancies that are more responsive to immune activating therapies.

Data sharing

Sharing data was not intended at the outset of the study. Patients were not asked for their informed consent and their data will thus not be made available.

Acknowledgments

We are grateful to all patients for their participation and to their families for their support. We thank all study nurses and investigators; the members of the data safety committee (Mona Ridderheim, PhD, MD; Kjell Bergfeldt, PhD, MD; Dr.med. Thomas Breitkreuz); Christofer Lagerros for a smooth randomization process, for the electronic case report form (eCRF), and for managing the distribution of the study drug; and Marie Abrahamsson for her competent and dedicated monitoring. We thank Dr. rer. nat. Wilfried Tröger for his help in planning this study and with the study protocol, as well as for sharing his valuable experience gained from conducting the MAPAC trial.

Funding

This study received financial support from the following institutions: Department of Oncology Endowment Fund at Karolinska University Hospital, Cancer Research Funds of Radiumhemmet, Gyllenberg Foundation, Ekhaga Foundation, Dagmar Ferbs Memorial Fund, Cancer Research Foundation in Northern Sweden, The Sjöberg Foundation. Iscador AG, Switzerland, manufactured and supplied both ME and placebo and post-trial ME free of charge. Iscador AG had no influence on the planning and conducting of the study or on the analysis and presentation of our results.

Conflict of interest statement

The authors declare that no conflict of interest exists.

Manuscript received on 21 December 2023; revised version accepted on 17 April 2024

Editorial note

Dr G S Kienle is a colleague in the medical-scientific editorial team of Deutsches Ärzteblatt and also a co-author of this article. She was not at any point involved in the editorial team’s reading, review, revision, and decision-making regarding this article. Furthermore, she did not have any access to information that exceeded that provided to the corresponding author, Dr Wode.

The editorial team placed the initial assessment, the selection of peer reviewers, and decisions regarding revision (including checking the revised manuscript), as well as manuscript acceptance, into the hands of an external expert from the scientific advisory board of Deutsches Ärzteblatt. We thank Prof Dr Martin Schuler from the West German Cancer Centre at the University Hospital of Essen.

Corresponding author:
Dr. Kathrin Wode, PhD, MD

Regional Cancer Centre Stockholm Gotland

Box 30017

Stockholm 104 25, Sweden

Cite this as:
Wode K, Kienle GS, Björ O, Fransson P, Sharp L, Elander NO, Bernhardson BM, Johansson B, Edwinsdotter Ardnor C, Scheibling U, Hök Nordberg J, Henriksson R: Mistletoe extract in patients with advanced pancreatic cancer: a double-blind, randomized, placebo-controlled trial (MISTRAL). Dtsch Arztebl Int 2024; 121: 347–54. DOI: 10.3238/arztebl.m2024.0080

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