Mistletoe Extract in Patients With Advanced Pancreatic Cancer: a Double-Blind, Randomized, Placebo-Controlled Tial (MISTRAL)

Abstract

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.

Figure 1

Flow chart of patients in the trial *¹ Urticaria; *² Patients who discontinued the intervention were still followed up regarding survival status (eMethods 1)

Figure 2

Kaplan–Meier curves of overall survival (OS) OS based on the total eligible follow-up time (a) and on the follow-up time during the nine-month study(treatment)period (b). Median survival time with Mistletoe extract (ME), 7.8 months [6.4; 9.4]; with placebo, 8.3 months [6.9; 9.7]. To the right of the vertical line at nine months in (a), data are shown for all patients after the nine-month study(treatment) period including those who opted for post-trial treatment with ME (44 [86%] of patients in the ME arm and 52 [85%] of patients in the placebo arm).

Figure 3

Mean change in quality-of-life scores Overall health status compared to baseline scores (95% confidence interval), calculated using mixed model regression; the data were collected using the EORTC-QLQC30 questionnaire. Higher scores indicate better quality of life.

eFigure

Mean doses of study drug administered Mean injected dose per week: in mg (mean) per injection according to the diary entries. Three injections were planned per week. The maintenance dose was calculated from week 5. ME, mistletoe extract