Mistletoe and Pancreatic Cancer

An Editorial to accompany the article: “Mistletoe extract in patients with advanced pancreatic cancer: a double-blind, randomized, placebo-controlled tial (MISTRAL)” by Kathrin Wode et al. in this issue of Deutsches Ärzteblatt International

Pancreatic cancer continues to be a tumor entity with a very poor prognosis: the 5-year survival rate is only 12% (1). Most innovations in recent years—mainly, immunotherapies, but also molecular therapies—have not yielded any improvement for the majority of patients with pancreatic cancer. Bishal Gyawali, and Christopher Booth quite appropriately gave their recently published essay (in Lancet Oncology) the title: “Treatment of metastatic pancreatic cancer: 25 years of innovation with little progress for patients” (2).

In metastatic pancreatic cancer, chemotherapy is still the standard treatment. For this reason, an intense search is on for additional interventions that might help improve patients’ prognosis.

Earlier studies of treatment with mistletoe extract

Mistletoe treatment—specifically using extract of Viscum album (VAL)—has been under discussion for treating pancreatic cancer for a while. VAL is credited with cytotoxic, anti-inflammatory, and immunomodulatory effects, and indications are that mistletoe extract can improve patients’ quality of life. For this reason, the German clinical practice guideline for complementary medicine in the treatment of cancer includes a “can/may” recommendation for using VAL in solid tumors (3).

In a single-center randomized phase III trial conducted in Serbia, patients with advanced pancreatic cancer received either best supportive care (BSC) only or BSC plus VAL. The study showed—among others—improved quality of life for the parameters pain, fatigue, and loss of appetite in the group treated with mistletoe extract (4). An interim analysis of the same study with 220 patients even showed improved median overall survival compared with the placebo group (5). But this study was rightly criticized because at the start of the study, chemotherapy—and not only best supportive care—was standard of care in advanced pancreatic cancer, and the study design—single center, not placebo controlled, and open-label—had limitations.

Recent study results

In this issue of Deutsches Ärzteblatt International, a Swedish–German working group presents for the first time a study with a contemporary design of the use of VAL in advanced pancreatic cancer. The trial used routine data; was randomized, double-blinded, and placebo-controlled; and provided standardized palliative care for all patients (6).

Of note, in this trial, VAL administered at the usual dosage that had also been used in other studies, or placebo, were given in combination with chemotherapy in more than 80% of patients, rather than instead of chemotherapy as in the trial from Serbia.

The primary endpoint of the study was overall survival (OS) and the secondary endpoint was the health-related quality of life (HRQoL) dimension global health/QoL in the EORTC Core Quality of Life Questionnaire“ (QLQ-C30) (ECOG, Eastern Cooperative Oncology Group).

290 patients with a ECOG performance status of 0–2 were included in the trial in 9 university hospitals and municipal hospitals in Sweden. Stratification was done by study site and eligibility for chemotherapy. The duration of treatment with VAL or placebo was 9 months. Adherence to the protocol was very good; all patients were examined at follow-up.

The study did not show any survival advantage in favor of the group receiving VAL, neither in the intention-to- treat analysis nor in the per-protocol analysis. Median OS was 7.8 months for patients receiving VAL and 8.3 months in the placebo group. Median OS was therefore low compared with other studies; using combination therapies can achieve a median OS of more than 10 months. But the proportion of patients with an ECOG performance status of 2 was 14% in the VAL group and 20% in the placebo group—notably higher than in comparable therapeutic studies—and numerous patients (25–30%) received monotherapy.

Health-related quality of life was also comparable in both arms. VAL was well tolerated; no clinically significant adverse effects were observed compared with placebo, except for more frequent local skin reactions.

Data quality

The data seem robust: patients in both groups received structured palliative care and comparable chemotherapy protocols for a similar duration of treatment and a comparable rate of second-line therapies. To study effects that are possibly only identifiable in subgroups, the authors carried out numerous analyses—among others, per-protocol analyses of OS in the study population and OS in groups with T4 tumors at primary diagnosis or in recurring pancreatic cancer. The effect of VAL treatment did not reach significance in these groups either.

The subgroup of patients who received palliative care only, who were therefore most comparable with the subgroup in the study from Serbia, did not show any advantage for VAL either. After 9 months of treatment with VAL or placebo, more than 80% of patients in both groups received VAL.

All evaluations that included only the therapeutic phase showed no difference between the groups either, as in the overall evaluation.

Conclusions

What is missing in the study? Results regarding progression-free survival in both groups would have been interesting, but progression-free survival was not a study endpoint. Furthermore, additional quality-of-life parameters from the QoL-30 and data from the QoL-PAN-26 will be published only in a later analysis. But these are minor criticisms.

Markus Horneber et al. in their 2008 Cochrane review of mistletoe treatment in oncology (7) commented [verbatim]: “The evidence from RCTs [randomized controlled trials] to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak.” The authors at the time called for independent clinical trials to investigate the safety and efficacy of mistletoe treatment. Our colleagues from Sweden and Germany did exactly that and convincingly showed for advanced pancreatic cancer that VAL is one of the numerous substances that do not improve the survival nor quality of life in patients with pancreatic cancer.

Conflict of interest statement
The author declares that no conflict of interest exists.

Manuscript received on 2 May 2024; revised version accepted on 3 May 2024.

Corresponding author:
Prof. Dr. med. Thomas Seufferlein

Klinik für Innere Medizin I

Schwerpunkte: Gastroenterologie, Endokrinologie, Nephrologie, Ernährung und Stoffwechsel

Universitätsklinikum Ulm

Albert Einstein Allee 23, 89081 Ulm, Germany

Cite this as:
Seufferlein T: Mistletoe and pancreatic cancer. Dtsch Arztebl Int 2024; 121: 345–6. DOI: 10.3238/arztebl.m2024.0099

References

1. Cancer net: Pankreatic cancer: statistics. https://www.cancer.net/cancer-types/pancreatic-cancer/statistics (last accessed on 7 May 2024).

2. B, Booth CM. Treatment of metastatic pancreatic cancer: 25 years of innovation with little progress for patients. Lancet Oncol. 2024 25:167–70

3. Hübner et al.: S3-Leitlinie Komplementärmedizin in der Behandlung von onkologischen PatientInnen Version 1.1. AWMF 2021 .

4. Tröger W, Galun D, Reif M, Schumann A, Stanković N, Milićević M: Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial. Dtsch Arztebl Int 2014; 111: 493–502

5. Tröger W, Galun D, Reif M, Schumann A, Stanković N, Milićević M: Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer 2013; 49: 3788–97

6. 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.m2024.008

7. Horneber M, van Ackeren G, Linde K, Rostock M: Mistletoe therapy on oncology. Cochrane Database Syst Rev 2008; CD003297. Doi: 10.1002/14651858.CD00329