Mistletoe Therapy in Primary and Recurrent Inoperable Pancreatic Cancer (MISTRAL)

Mistletoe Therapy in Primary & Recurrent Inoperable Pancreatic Cancer. A Phase III Prospective Randomized Double Blinded Multicenter Parallel Group Placebo Controlled Clinical Trial on Overall Survival and Quality of Life

In this study a mistletoe preparation (Iscador Qu) is added to standard therapy in inoperable pancreatic cancer in order to evaluate effect on overall survival and health-related quality of life. Half of participants will take subcutaneous injections with mistletoe in addition to standard therapy (palliative chemotherapy or best supportive care); the other half will receive a placebo and standard therapy.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: Mistletoe extract (Iscador Qu); Drug: Placebo

Detailed Description

Extracts from European mistletoe (Viscum album L.) have been used as complementary cancer therapy since the 1920s. To date over 160 clinical studies on mistletoe in cancer therapy have been conducted with varying quality; the therapy is still controversial.

Best evidence is found for increase of health-related quality of life (HRQoL) and reduction of side effects of conventional therapies (chemotherapy, radiation) in breast cancer patients. Mistletoe treatment is described as safe and well tolerated. There are some clinical studies supporting the use of mistletoe extract in the management of late stage cancer.

Statistically significant effects on overall survival (OS) and HRQoL in pancreatic cancer patients have recently been shown in a randomized open label trial in Serbia investigating the addition of mistletoe extract to best supportive care. The results are questioned because patients knew what kind of treatment they received.

Mistletoe extracts are usually administered subcutaneously. They contain a multitude of substances with immune modulatory and cytotoxic or - in animal studies - antitumorigenic, anti-metastatic and antiangiogenic effects.

This trial investigates whether there is a beneficial effect of mistletoe extracts on OS and HRQoL in pancreatic cancer patients receiving standard treatment (palliative chemotherapy or best supportive care).

Inclusion has started at 4 study centers (2 more centers are waiting for participation). And participants are randomized 1:1 to mistletoe treatment (Iscador Qu®) given in increasing dosage from 0,01mg to 20 mg or placebo injections subcutaneously 3 times /week. Stratification will be performed for received oncological treatment (palliative chemotherapy or best supportive care). At 7 visits in 9 months, participants fill in the validated EORTC QLQ-C30 (QLO=quality of life questionnaire) and PAN-26 (PAN=pancreas) quality of life questionnaires. Body weight, use of cancer-related medicines, substitution of nutrition, adverse events need of supportive care and inpatient care are measured. To be able to assess more dimensions of quality of life than possible with questionnaires, a qualitative sub-study with interviews on about 30 participants in this trial is performed in month 3. A 2nd substudy has been added november 2016 to elucidate the systemic effects of mistletoe therapy and to explore potential prognostic and predictive biomarkers (anticipated n=100).

• Study Type: Interventional
• Enrollment (Actual): 290
• Phase: Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 14186
    • Kathrin Wode

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Signed written informed consent

• Age ≥ 18 years

• Inoperable locally advanced or metastatic pancreatic cancer or relapse of pancreatic cancer.

  • Primary diagnosis: if histology is not clinically achievable diagnosis is to be confirmed according to local practice sufficient for diagnosis and choice of therapy (such as CA19-9 (=cancer antigen 19-9) and CT).
  • Relapse: histology (not required) or diagnosis according to local practice such as clinical signs and/or imaging and/or CA19-9.
• ECOG ( Eastern Cooperative Oncology Group) performance status 0-2 (see table in section 12.14 )
• Adequate negative pregnancy test and adequate contraception (where appropriate)

Exclusion Criteria:

Life expectancy less than 4 weeks

• Pregnancy or breastfeeding
• Neuroendocrine tumors of the pancreas (NET)
• Current use of interferon, G-CSF (granulocyte colony-stimulating factor) and thymus preparations
• Symptomatic brain edema due to brain metastases
• Known hypersensitivity to mistletoe-containing products
• Current use of mistletoe extract preparations in any form
• Chronic granulomatous disease or active autoimmune disease or autoimmune disease with immunosuppressive treatment
• Medical, psychiatric, cognitive or other conditions that may compromise the patient´s ability to understand the patient information, give informed consent, comply with the study protocol or complete the study (e.g. needle phobia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mistletoe extract (Iscador Qu); Fermented aqueous extract of Viscum album ssp album (L.) (mistletoe) = Iscador Qu, subcutaneous use 3 injections/week; dose escalation from 0,01mg - 20mg	Drug: Mistletoe extract (Iscador Qu); 1ml subcutaneous injection 3 times/week, dose escalation 0,01mg - 20mg; Other Names: Fermented aqueous extract of Viscum album ssp album (L.)
Placebo Comparator: Placebo; isotonic saline solution, subcutaneous use 3 injections/week	Drug: Placebo; 1ml subcutaneous injection 3 times/week; Other Names: Isotonic saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS defined as time from randomization to death for any reason	End of study (estimated 3 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life questionnaire EORTC QLQ-C30	Evaluation according to EORTC QLQ-C30 Scoring Manual	At 7 visits during study (9 months)
Quality of Life questionnaire EORTC PAN -26	Evaluation according to EORTC PAN-26 Scoring Manual	At 7 visits during study (9 months)
Weight in kilograms, height in meters, BMI in kg/m^2	Body weight, Body Mass Index	At 7 visits during study (9 months)
Corticosteroid use in milligrams betamethasone per day and indication (appetite, chemotherapy, nausea, pain, general wellbeing, other: specified)	Corticosteroid use and indication	At 7 visits during study (9 months)
Number of visits of homecare team per week	Costs for supportive care	At 7 visits during study (9 months)
Use of oral nutrition support per week (number used per day)	Costs for supportive care	At 7 visits during study (9 months)
Use of symptom relieving medication in mg/day (painkillers, antiemetic and anxiolitic medication)	Costs for supportive care	At 7 visits during study (9 months)
Chemotherapy use (number of cycles first line, second line, ..) and dose reduction in%	Costs for supportive care	At 7 visits during study (9 months)
Number of parenteral nutrition infusions per week	Costs for supportive care	At 7 visits during study (9 months)
Days of unplanned inpatient care	Costs for inpatient care	At 7 visits during study (9 months)
Incidence of treatment-emergent adverse events (AE)	Safety	Through study completion (9 months)

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Karolinska Institutet; University of Witten/Herdecke; Ekhagastiftelsen; Regional Cancer Centre Stockholm Gotland; Stiftelsen Konung Gustaf V:s Jubileumsfond för cancerforskning; Signe & Ane Gyllenbergs Stiftelse; Dagmar Ferbs Minnesfond; Cancerforskningsfonden i Norrland; Immunpathologisches Labor, University Tübingen; The Sjöberg Foundation
• Investigators: Study Chair: Annika Bergquist, Ass Prof, Gastrocentrum Karolinska University Hospital

Publications and helpful links

General Publications

• Troger W, Galun D, Reif M, Schumann A, Stankovic N, Milicevic M. Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial. Dtsch Arztebl Int. 2014 Jul 21;111(29-30):493-502, 33 p following 502. doi: 10.3238/arztebl.2014.0493.
• Troger W, Galun D, Reif M, Schumann A, Stankovic N, Milicevic 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 Dec;49(18):3788-97. doi: 10.1016/j.ejca.2013.06.043. Epub 2013 Jul 24.
• Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008 Apr 16;2008(2):CD003297. doi: 10.1002/14651858.CD003297.pub2.
• Kienle GS, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res. 2009 Jun 11;28(1):79. doi: 10.1186/1756-9966-28-79.
• Wode K, Hok Nordberg J, Kienle GS, Elander NO, Bernhardson BM, Sunde B, Sharp L, Henriksson R, Fransson P. Efficacy of mistletoe extract as a complement to standard treatment in advanced pancreatic cancer: study protocol for a multicentre, parallel group, double-blind, randomised, placebo-controlled clinical trial (MISTRAL). Trials. 2020 Sep 11;21(1):783. doi: 10.1186/s13063-020-04581-y.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: October 26, 2016
• First Posted (Estimate): October 28, 2016

Study Record Updates

• Last Update Posted (Estimate): January 13, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Relapse; Primary diagnosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Viscum album peptide
• Other Study ID Numbers: 131016; 2014-004552-64 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The trial results will be submitted for publication in relevant medical journals