The Mistletoe and Breast Cancer (MAB) Study: a UK Pilot Mixed Method, Placebo-Controlled Randomised Trial

1. Introduction

Mistletoe (Viscum album) has been used medicinally since prehistoric times. Anthroposophic use of mistletoe has developed using specific mistletoe formulations and regimes with a focus on supportive cancer care. [1] In Europe, mistletoe is a commonly used therapy by patients with cancer and it is integrated into oncology care via health insurance schemes in Germany, and Switzerland. [1]

A recent Health Technology Assessment report that focused on adjunct mistletoe therapy (MT) for breast cancer patients concluded that improvements in health-related quality of life compared to the control group were small to moderate, but that the risk of bias within efficacy trials was high. [2] This evidence is based on seven clinical trials (three were randomised controlled trials (RCTs)) using mistletoe as an adjunct therapy to standard treatment of chemotherapy and or radiotherapy in patients with breast cancer. Local skin reactions of low and moderate severity were reported in a median of 25% (range 5 to 94%) of patients, and mild to moderate systemic reactions in a median of 2% (range 0 to 8%) of patients.

Observational studies, cross-sectional studies and an ethical evaluation were also included in this HTA report. A comparative cost analysis from Germany reported significantly lower medical costs within 5 years after surgery for patients with MT than for patients without it, however there was no control for systematic bias. From studies conducted in Germany, it was calculated that a median of 25% (range 7-46) of patients with breast cancer and 29% of treatment providers use MT. The main motivations to use MT cited by patients in these studies were to reduce side effects, strengthen the immune system and take an active role in the treatment process. It was also reported in these studies that patients felt insufficiently advised about MT.

Whilst MT is prescribed in the UK, this is through the private sector, and predominantly in primary or community care. [3] The lack of a robust, relevant evidence base for MT in supportive cancer care prohibits progress in this field, despite its potential to improve the patient experience of cancer care, a major priority of the National Health Service (NHS) cancer plan. [4] As MT is not available within the NHS, the UK population is generally unaware of MT, and its application as a supportive adjunct therapy for cancer. This potentially enhances participant blinding to treatment allocation in a randomised clinical trial in the UK as they are less likely to understand MT appearance and its effects.

Our aim was to test the feasibility of a pilot, mixed phase, mixed methods, and placebo controlled RCT of MT in patients with breast cancer in the UK NHS setting.

2. Materials and Methods

2.1. Design and Setting.

We conducted a pilot, placebo controlled RCT of MT with an embedded qualitative study in patients with breast cancer, in a UK NHS setting. [5] There were three groups in the trial: Iscador Malus (M), Iscador Pinus (P) MT and physiological saline as the placebo. The feasibility of the trial was assessed in terms of recruitment, retention, adherence, blinding and safety. [EudraCT number: 2018-000279-34] The MAB study adheres to CONSORT guidelines outlined at https://www.equator-network.org/reporting-guidelines/consort/.

2.2. Sample Size and Site

The aim was to recruit 45 adult patients via one site, the Bristol Haematology and Oncology Centre (BHOC) at University Hospitals Bristol and Weston NHS Foundation Trust. This was a feasibility study with the sample size chosen to allow fair assessment of the aims of recruitment, retention, and completion of outcomes and an assessment of the viability of blinding.

2.3. Inclusion and Exclusion Criteria

Participants were adults 18 years or over with histologically confirmed early or locally advanced invasive breast cancer who, following surgery, were to receive adjuvant chemotherapy, with or without radiotherapy and able to be randomised within 12 weeks of surgery. Patients could be included if they were also scheduled to receive biological therapies such as trastuzumab or endocrine therapy. Patients who received only radiotherapy were excluded as this treatment is generally well tolerated and of short duration. They had to be willing to self-administer or have a nominated person administer their injections. Their Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 and they could have no active, uncontrolled infection. [6] Full inclusion and exclusion criteria are available in Appendix A.

2.4. Randomisation and Blinding

The patient randomisation list and the medication block randomisation lists were produced by an in-house statistician at Iscador AG. Randomisation of patients was conducted by University Hospitals Bristol Pharmacy (UHBP). Allocation of participants to Iscador^® M/ Iscador^® P/placebo in a 1:1:1 ratio was performed by UHBP. A separate randomisation list was held by UHBP for individual emergency unblinding. In the case of a serious adverse event and unblinding being required, the pharmacist would have been asked by the principal investigator to look at the unblinding randomisation list. Both participants and healthcare professionals were uninformed about the allocation of the trial therapies.

Participants took MAB therapy for approximately six months, The first study therapy was given within a week of randomisation to the study and, ideally, prior to the start of chemotherapy. If participants had a skin reaction larger than 5cm diameter, they stopped the MAB therapy for one week, then resumed with a step down in dose. Participants or participant-nominated individuals (e.g., spouse or partner) were taught to administer the MAB therapy by the research nurse – once by nurse demonstration and then by administering the therapy themselves under nurse observation.

2.5. Mistletoe Therapy (Intervention Group)

Participants received mistletoe preparations Iscador^® M or Iscador^® P in 1ml ampoules for sub-cutaneous injection. The standard therapy regime was devised from the manufacturer’s recommendation in conjunction with the MAB advisory group. [Appendix B]

2.6. Placebo (Control Group)

Placebo participants underwent the same regime as those in the intervention group, and the placebo ampoules had identical external packaging and labelling to the MT ampoules. The placebo was physiological saline 0.90% w/v of sodium chloride, 308 mOsm/L or 9.0 g per litre. [Appendix B]

2.7. Data Collection

Feasibility was measured using clinical study data and qualitative interview data to assess the following objectives:

2.7.1. Recruitment

• Recruitment rate
• Obstacles to recruitment

2.7.2. Retention and Adherence

• Attrition rate with reasons if possible
• Acceptability of regular sub-cutaneous injections
• Adherence to the study therapy schedule
• Assessment of therapy related symptoms and health related quality of life in the sample population
• Completion of outcome measures

2.7.3. Blinding

• Assessment of blinding of patients

2.7.4. Adverse Events

• Adverse events from MT and placebo subcutaneous injections

2.8. Clinical Study Data

2.8.1. Participant Diaries

Participants received a diary card pack to record their thrice weekly MAB study therapy administration, the reaction to the injection, and any comments they wanted to add. [Appendix C]

2.8.2. Questionnaire Pack

This comprised six questionnaires: European Organisation for Research and Treatment of Cancer Quality of Life (EORTC- QLQ-C30), European Organisation for Research and Treatment of Cancer Quality of Life- Breast Cancer (EORTC QLQ-BR23), Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) scale, Cancer Fatigue Scale, Autonomic Regulation Scale-State (ARS-S), and CompleMentary and Alternative Beliefs Inventory (CAMBI). [7,8,9,10,11,12] These were administered at three time points: Time point 0 or baseline (T0) - following randomisation and before the start of the chemotherapy regime; Time point one (T1) - following the 3rd cycle of chemotherapy; and Time point two (T2) - four weeks after last standard treatment (chemotherapy with or without radiotherapy), on the day of the last study (MAB therapy) treatment.

T0 questionnaires were completed during an initial visit to BHOC. T1 and T2 were either generated by the REDCAP database (for four participants) or administered by BHOC staff at the appropriate time for those participants working on paper.

2.8.3. Adverse Events

All adverse events experienced by the participants during the MAB trial were collected independent of their causal relationship with MT. The manual of the Common Terminology Criteria for Adverse Events (CTCAE) grading of toxicity was used to classify the adverse events. [13]

2.8.4. Qualitative Interviews

Semi-structured interviews were conducted by LD with participating patients, oncologists, and research nurses. All patient participants who had consented to being interviewed were contacted. In addition, three research nurses working on the MAB study and two oncologists were interviewed.

Initial interviews in the first few weeks of MAB therapy were conducted in person with five participants between October 2019 and February 2020. All remaining interviews were undertaken remotely in compliance with COVID-19 pandemic restrictions, and interviewees selected either telephone or online options. Thus, all staff interviews, five initial participant interviews and all ten second interviews, which took place up to one month after all treatment was completed, were conducted remotely. Written consent was obtained, and topic guides were used to aid questioning whilst allowing interviewees to discuss additional issues. [Appendices D and E] Topics considered included (i) awareness of MT; (ii) recruitment (iii) retention and adherence; (iv) blinding; (vi) perspectives on complementary and alternative therapies; and (vi) availability of complementary and alternative therapies within the NHS (staff only).

Interviews were transcribed and anonymised, then analysed thematically by LD assisted by MG and PG using NVivo qualitative data analysis software (version 12). [14] A subset of transcripts was coded inductively to establish an initial analysis framework (LD, AH), and differences were discussed during the process between LD, MG, and PG to ensure coding consensus. [15]

2.9. Data Analysis

The recruitment rate is expressed using descriptive statistics, as are all questionnaires completed by the participants. Retention is summarised by recording the number of participants in each study group at the pre-specified worst toxicity time point (T1) and 4 weeks post standard treatment (T2). A questionnaire was considered completed if data could be used. For example, the EORTC QLQ-C30 data was included if at least half the questions from the factors of interest were complete in accordance with the manual of the EORTC Quality of Life group. Blinding was assessed by asking the patient at T2 to assess which study treatment they had received or to register a “don’t know” option.

2.10. MAB Management

The core MAB management team members were SB, LD, AH and GF working in conjunction with the BHOC team led by JB. In the development and approval process of the MAB study this core team worked with a wider team of co-applicants, an advisory group and BHOC colleagues detailed within the acknowledgement section. The core MAB team met monthly during the MAB trial with additional attendance by patient and public involvement (PPI) members and advisory members as required.

The MAB Trial Steering, Data Monitoring and Ethics Committee comprised clinical, statistical, and patient representation (see acknowledgement section). The committee met regularly (every 4-5 months) prior to trial start up until the end, remaining available beyond that time if needed.

2.11. Patient and Public Involvement

Bristol-based MT research was formally launched in September 2010 with a public education event led by GF, AH, ME and the Cancer research network (CRN) of West of England cancer lead Catherine Carpenter Clawson, and involved the public, patients, and health professionals. This event contributed to our protocol development and the initial development of our topic guide for our qualitative interviews, with ME and SB piloting questions with health professionals. The MAB PPI group was convened in September 2017 by LD and AH and comprised four women with the experience of a breast cancer diagnosis, treatment and beyond. This initial work contributed to the refinement of our patient interview topic guide and patient facing documents, and to the use of a transparent disc to aid measurement of anticipated skin reactions during the trial. Two of our PPI members remained actively involved (JB and SB) throughout the trial, joining team meetings and the trial steering group meetings.

3. Results

3.1. Recruitment

Sixty-seven potential participants were approached, screened (25 were not eligible) and if appropriate recruited by the research nurses between August 1st 2019 and March 19th, 2020. Following screening, 15 were eligible and gave their consent. Participant 15 dropped out prior to randomisation.

Characteristics are available for 14 of the participants. All were women and had a mean age of 49 (range 36-76) years. They identified as White British (n=11), White other background (n=2) and Chinese (n=1). (Breast cancer status was stage 1-3, and 10 /14 participants were Estrogen Receptor Positive (ER+). [Table 1]

Ten of the 14 participants agreed to be interviewed both at the beginning and end of the study (20 interviews). The mean age of those interviewed was 46 years (range 36-63), and eight participants described themselves as White British and the remaining two as White other background. Five interviews were also undertaken with staff – two consultant oncologists involved in recruitment to the study, and three research nurses who were the day-to-day points of contact for the MAB participants.

All patient participants and staff interviewees were asked what they had known about MT before learning of the trial. The unanimous response from participants in the qualitative interviews was that they had not heard of the therapy before although everyone was familiar with the mistletoe plant; all were surprised to hear of its therapeutic use. [Table 2, A1 & A2]

The nurses were also unfamiliar with MT, although one said patients often spoke of complementary therapies with her and that mistletoe might have been mentioned. One of the oncologists was aware of patients who had used MT in private practice. [Table 2, A3]

3.1.1. Barriers to Recruitment

In the first five months of recruitment (August-December 2019), 43 potential participants were approached and 6 (14%) gave their consent. From January 1st to March 19th, 2020, 24 potential participants were approached and nine (38%) gave their consent. The difference in these recruitment rates was related to an initial ambiguity in the inclusion criteria around the human epidermal growth factor receptor 2 (HER2) status of patients, for which a major protocol amendment was made, improving recruitment from January 2020 onwards.

Reasons for non-participation can be grouped into four categories: not meeting the screening criteria (25), patient decision (22), healthcare professional decision (1), and practical barriers (4). [Figure 1] By 19th March 2020, 15 participants were consented, and 14 were randomised to treatment allocation. The 15th participant withdrew before randomisation citing the COVID-19 pandemic as the reason.

The most common reasons recorded on the recruitment log for women not accepting invitation into the trial (82%) were the injections or the related additional visits to BHOC. These concerns were echoed in the qualitative interviews. [Table 2,A4 & A5]

Other, more generic reasons included not wishing to be part of a trial or to receive the placebo, or the presence of other health issues.

In the January-March 2020 period of recruitment, seven in ten patient refusals were due to the extra hospital visits, and although not formally recorded these may also have been linked to the imminent COVID-19 pandemic.

3.1.2. Enablers to recruitment

Despite the potential barriers discussed above, several factors identified by our participant interviewees acted to outweigh them. These included the possibility that MAB therapy may enable participants to continue supporting their home life whilst undergoing chemotherapy. [Table 2, A6]

The idea of mistletoe as a natural product was also viewed favourably by some, as well as the accepted use of this therapy in other countries. Several participants also indicated they had altruistic reasons for taking part. [Table 2, A7 & A8] Some participants spoke of the appeal of regaining a sense of self-empowerment which they felt had been lost to cancer, surgery, chemotherapy and radiotherapy. [Table 2, A9]

Staff interviewed also spoke of the enthusiasm they noted for the study in participants, one commenting that some had asked whether they could take part despite not having been approached about the study. The oncologists also noted the positivity generated amongst participants by the trial. [Table 2, A10 & A11]

3.2. Retention & adherence

Fourteen participants were randomised and allocated to their MAB therapy. [Figure 2] Two of the 14 participants withdrew during the trial. Both remained in the study for around five of the anticipated six months’ duration. The first participant withdrew after 4 months and 27 days, and the nurse recorded ‘participant reported “forgot” to take/give injections for approximately 1 month and described feeling no better/no worse so made the decision to stop the treatment.' After unblinding, it was revealed this participant was on placebo.

The second participant withdrew at 5 months 5 days, and the nurse reported ‘Patient is currently emotionally distressed and unable to cope with the extra injections [due to Covid-19 outbreak].’ After unblinding, it was revealed that this participant was on Iscador M.

Adherence was measured by analysis of patient diaries and questionnaires. Participants were asked at the eligibility stage whether they wanted to complete these online or on paper, four of 14 participants opted for online.

The diary data shows that six participants took the MAB therapy for ≥26 weeks and five participants for ≥20 weeks. The remaining three participants returned diaries for 9,12 and 16 weeks respectively. 50% of the participants had one break in MAB therapy, and two participants had two breaks. All participants that had breaks were on MT and as per the MAB protocol which stated that a skin reaction of ≥5cm should result in one weeks break from MAB therapy, these participants had a step down to a lower dose. [Appendix B]

The free text section in the diaries allowed participants to express how they were coping with the MAB therapy on a weekly basis. Comments around this were focused on issues with methods of self-administration, pain and discomfort upon administration, difficulty in maintaining the routine of injections, and the impact of the COVID-19 pandemic. There were no comments around the increasing colour and viscosity of the solutions for the active MT as dosages increased nor any comments on a lack of change in appearance as dosages ‘increased’ in the placebo.

All 14 participants completed the baseline (T0) questionnaire. Twelve questionnaires were returned after the third chemotherapy cycle (T1), and 12 after the last MAB therapy treatment (T2). The loss of two T1 questionnaires was related to one of the participants who withdrew, and for the other questionnaire, it was unclear why it was not received. At T2, the missing questionnaires were both due to the participants that withdrew.

3.2.1. Barriers to retention and adherence

The factors indicated above by the participants who withdrew were also apparent in the interviews, along with other barriers identified by participants who remained on the study: Self-injection remained a challenge to the participants.

An additional concern related to the injections was that the syringes were not pre-loaded. Most participants were required to self-inject Filgrastim during their chemotherapy to stimulate white blood cell production. This was provided in a pre-prepared format and some participants compared their MAB therapy unfavorably. [Table 2, B1 & B2]

The absence of a visible skin reaction to MAB therapy was also a potential barrier to retention and adherence. A research nurse had anticipated that participants randomised to the placebo treatment might withdraw for this reason. [Table 2, B3] Practical considerations also played a part in participants’ thinking. The additional hospital visits were an issue, particularly with a lack of available parking nearby. [Table 2, B4]. The emerging COVID-19 pandemic also impacted and caused additional stress for the participants. [Table 2, B5]

For those participants whose treatment regimens included both chemotherapy and radiotherapy, the duration of their MAB therapy was also a potential barrier to carrying on with it. In some cases, adherence to the MAB therapy regime decreased somewhat after completion of chemotherapy. Some interviewees explained that, as they had understood that MT was helpful with chemotherapy side effects, it could seem less important either during radiotherapy or during the additional month of MAB therapy required post chemotherapy/ radiotherapy. [Table 2, B6]

Another interviewee offered an additional perspective. When she was able to ring the bell signaling completion of her final radiotherapy session, her MAB therapy, which was to continue for a further month, became less important. [Table 2, B7]

3.2.2. Enablers to retention and adherence

The skin reaction around the injection site to the MAB therapy, although not pleasant, made participants feel they could be receiving active MT. [Table 2, B8]

Engagement from family and friends was a further enabler for some participants and one participant wrote a blog about mistletoe with very positive feedback. [Table 2, B9] Personal investment in the trial by participants was also identified by the staff. [Table 2, B10] Some interviewees found their own unique ways of remembering their MAB therapy such as using a mistletoe-themed song for their morning alarm. [Table 2, B11]

The response of the participants to the MAB trial also influenced staff perspectives, some having their reservations over-ridden on seeing that participants were accepting the therapy and happy with it. [Table 2, B12,13]

3.3. Assessment of blinding

Ten participants were on an active MT (Iscador M (n=5) Iscador P (n=5) and four participants were on the placebo treatment. In the final questionnaire (T2) the 12 remaining participants were asked for their thoughts regarding which intervention they thought they had received and were given the options 'don't know', 'active' or 'placebo'. They were also asked to briefly explain their reasoning. [Appendix F]

Of the twelve participants, nine were on active mistletoe treatment and three were allocated to placebo. Of the nine participants on active treatment, four said they did not know their allocation, four said active and one said placebo. Of the three on placebo treatment, two said that they were on placebo, and one said they did not know. Eleven of the twelve participants gave their reasoning, and all gave an explanation relating either to how they felt during chemotherapy, or to whether they had skin reactions.

Among the ten participants interviewed, it was clear that most had spent considerable amounts of time thinking about whether they were receiving active or placebo therapy whilst on the trial and their opinions could fluctuate.

As with the questionnaire responses, interviewees indicated that the presence or absence of skin reactions and/ or their response to chemotherapy influenced their thoughts around this. [Table 2, C1-C3]

Some interviewees, though, said they were unable to decide which study therapy they had received as they did not know how their response to chemotherapy would have been in either case. [Table 2, C4] Whatever their thoughts on this however, the research nurses noted that participants were keen to discuss their possible therapy allocation throughout their treatment. [Table 2, C5]

One of the nurses indicated they could make a visual distinction between some MT doses and the placebo. [Table 2, C6] However, while the nurses were able to see both the placebo and MT ampoules, the participants saw only their own trial ampoules. it is of note that no participants on active MT commented on the increasing colour and viscosity of the solutions as dosages increased either in the final question around blinding in the T2 questionnaire, the qualitative interviews or the diaries.

3.4. Adverse Events

All adverse events (AEs) experienced by the participants during the MAB trial were collected. 23/218 were related to MAB therapy injections and experienced by 11 of the 14 participants. [Appendix G] Two of three remaining participants who did not have AEs related to injections were allocated to the placebo group. 13/23 AEs related to skin reactions to the injections, and as expected were experienced by the participants receiving MT.

18 of the 23 AEs were defined as Definitely related to the MAB therapy, with one Probably, one Possibly and three as Unrelated. All 23 AEs were linked to the injections and the skin response to these and were identified as: pain/discomfort with injection’ [n=7]; ‘bruising/hematoma at injection site’ [n=3]; skin reaction, ’redness/itchiness, rash/induration/lumps’ [n=13].

All AE were given a CTCAE score of 1 and were described as ‘not serious’ and ‘expected’. Reporting of intensity was not consistently made, but when reported it was described as ‘mild’. The exception was one AE report with a CTCAE of 5. This is considered as a reporting error due to other information describing the AE as ‘not serious’ and ‘expected’. Cross-referencing with the concomitant medications log and the qualitative interviews, this participant was on blood thinning agents and was vulnerable to excess bruising. Hence causality is reported as ‘not related’.

The free text section in the participant diaries included reflections on these AEs as indicated in the ‘retention and adherence’ section above, with one of the main themes focusing on pain and discomfort upon administration. The participant quotes in Table 2 also describe the impacts of these AEs and as already mentioned, could be viewed as either barriers or as facilitators to retention and adherence by different interviewees. [Table 2, E]

3.5. Quality of Life Questionnaire

3.5.1. Acceptability

Five of the six questionnaires were used to assess quality of life and signs & symptoms associated with cancer treatment. Item completion was high, with the only exception being questions 13 & 14 in the EORTC BR23 and questions 15 &16 in the FACT-N which focused on the individual’s sex life or intimate relationships.

Participants often did not respond (completely) to these particularly in the T1 and T2 questionnaires, and in one case a participant described a relationship breakdown in an annotation on the form. These questions were also identified as ‘odd’ or ‘interesting’ by some participants in the qualitative interviews. [Table 2, E1 & 2]

3.6. Outcome Data

This study was not powered to prove the efficacy of MT on quality of life, and symptoms of cancer treatment, and as such no differences were seen within or between groups for these measures. We have presented the EORTC QLQ-C30 global quality of life scores with a data box which shows similar trend for all three groups across the duration of the study. [Figure 3]

Data box:. 

Data box:. 

Time /group	Placebo (n=4)	Iscador P (n=5)	Iscador M (n=5)
T0	90 ±12.5	78±24	71±18
T1	73±8.0	58±27*	60±23*
T2	72±20.9	65±10	67±17*

*data from n=4 participants.

3.7. Complementary and Alternative Medicine Beliefs

The sixth questionnaire was the CAMBI questionnaire in which participants were asked to rate their opinions on a wide range of statements broadly around complementary and alternative approaches to health using a 0-7 scale (‘completely disagree’ to ‘completely agree’). [Appendix H] The results of this questionnaire at T0 suggest that overall participants were in favour of interventions that allow them to be involved in their own treatment, are considered natural and may promote immune-boosting and self-healing.

This was reflected in the qualitative interviews. Several participants had a positive view of complementary and alternative medicines (CAM) and had previously used them; however, others did not have a (strong) opinion on CAM approaches. [Table 2, F1 & 2]

Staff interviewees spoke of the possible benefits of complementary therapies for patients, although they indicated they themselves had not needed to use CAM. Although the perspectives of the oncologists interviewed were a little more circumspect, they also saw possible benefits in the use of CAM. [Table 2, F3 &4]

4. Discussion

4.1. Summary of Findings

The aim of the MAB study was to test the feasibility of a pilot placebo controlled, RCT of MT in patients with breast cancer in the UK NHS setting.

The recruitment rate was optimised during the study to just under 40% of people approached. Whilst the trial was open to both women and men participants our recruitment log indicated that only women participants were approached, this is not unsurprising as we know that breast cancer is rare in men, with around 400 new cases diagnosed each year in the UK. [16]

Most barriers to recruitment for potential participants were the extra treatment and time, unwelcome extra injections, and to a lesser extent being allocated to placebo. It is important to note that this decision was made in the context of physical and emotional challenges of diagnosis, need for chemotherapy, side effects of chemotherapy including intravenous treatments, use of granulocyte-colony stimulating factor (GCSF) injections and other supportive medications. There was a general lack of knowledge about MT expressed by both participants and health professionals.

Once recruited, over three quarters (12/15) of the participants completed the full trial therapy. Adherence to the therapy regimes was very good as measured by participant diaries, so too was the completion of the questionnaires at all three time points. Half of the participants said they did not know their therapy allocation. Both diary data and the qualitative interviews indicated that participants struggled with injections, and in some cases, also with the skin reactions. However, the qualitative interviews show a positive and enthusiastic attitude towards the MAB therapy with participants devising ways of coping with the negative aspects of regular self-injection. The number of adverse events related to MAB therapy were low and all were related to MAB therapy injections or skin reactions.

4.2. Strengths & Limitations

This was the first clinical trial of MT to be conducted in the UK, and in the NHS setting. It shows that MT can be provided and supported through the UK system of care. It also shows that participant adherence to the therapy (placebo or active) was good, as was completion of validated quality of life scales.

Whilst there were difficulties in recruiting to the trial, these were not all specific to the MAB therapy. Our recruitment was a third of that anticipated (15/45). Once optimal recruitment had been established in 2019, the remaining recruitment time was impacted by the impending COVID-19 situation and ultimate global lockdown in 2020. In addition to shortening the recruitment time, we feel the COVID-19 situation with national messages discouraging hospital attendance, as well as fears about infection risk and disruption of some chemotherapy treatment, impacted participation in early 2020.

It was our original thinking to interview people that declined to be involved. Unfortunately, this was not possible as it was not the researcher who recruited into the trial, rather the research nurse. Once the potential participant expressed that they were not interested in being involved, it did not seem fair to ask them to give their details about being contacted by the researcher and we suspect that our take up rate would have been low.

The trial was designed by primary and secondary care researchers, patients, and health professionals but on a day-to-day basis it was run by secondary care health professionals in an oncology research unit. Despite good communication between the University of Bristol (Principal investigators and Sponsor) and the Bristol Haematology and Oncology Centre this resulted in a lag in eliminating glitches in the trial start-up and in some practical aspects of data collection, which was further inhibited by the COVID-19 restrictions. For example, some participants changed diary records from online to paper without formal notification.

Whilst a significant number of potential participants declined involvement due to the extra hospital visits and injections, most who accepted were retained. This reflects both good initial patient information and good participant support from health professionals during the trial. We know from both the diaries and the qualitative interviews that participants struggled with the process of regular injections, and the skin reactions, yet they persevered with the therapy regime. It is possible that participants who perceived that they were allocated to placebo were less motivated.

The qualitative interviews suggest that some participants were less focused on their MAB therapy after their chemotherapy was complete. The Patient Information Sheet stated clearly that MT could be beneficial during both chemotherapy and radiotherapy. There is likely to be different reasons for wanting to stop the regular self-injections, but the qualitative interviews suggest some participants had just had enough of the injections and wanted to move on.

The lack of awareness of MT and its potential responses likely enhanced the blinding of participants to their therapy allocation. The increasing colour and viscosity of the solutions for the active mistletoe treatment as dosages increased was not commented on by the participants in the qualitative interviews, diaries, or in the final question around blinding. The appearance of the saline placebo would remain identical throughout, but due to the lack of knowledge around MT this equally may not have been a factor for participants.

Skin reactions and especially prolonged skin reactions are much less likely with the saline placebo. From the diary data, two of the four participants on placebo had at least one episode of minor skin reactions, and one participant also had a skin infection which may have been misinterpreted as a reaction.

While health professionals were not formally asked for their perspective on the allocated treatments, the qualitative interviews suggested that one nurse was aware of the increasing colouration of some participants’ therapies. The number of adverse events was low, and entirely related to self-injections and the skin reactions expected with MT. This is in line with adverse event monitoring in previous clinical trials. [17,18]

We used a range of quality-of-life measures and the CAMBI questionnaire. We have included access to the data with no comparative analysis, as appropriate to a feasibility study. Equally we cannot comment on the comparative effectiveness of the two Iscador products beyond the fact that having two active therapies may have enhanced recruitment. Of note, although overall the quality-of-life questionnaires were completed well, the questions relating to sexual feelings, sex life and interpersonal relationships appear to be inappropriate for our population at this point in their treatment.

4.3. Implications for Clinical Practice and Further Research

MT is integrated into oncology care via health insurance schemes in Germany and Switzerland. In the UK, it is predominately available via private practice although there is some NHS provision. An HTA report which focused on adjunct MT for breast cancer patients concluded that improvements in health-related quality of life compared to the control group are small to moderate but that the risk of bias within these efficacy trials is high. [2] Broader reviews across cancer types come to a similar conclusion. [19,20,21]

Our study design did not permit us to determine a primary endpoint, effect size or sample size. However, published full RCTs with a similar population conducted in other countries and settings suggest the use of EORTC- QLQ-C30 is preferable for quality of life measurement, and the two Semiglasnov RCTs of breast cancer patients provide estimates of effect size and calculate sample size. [17,22,23,24]

Whilst it is unlikely that MT will be made more widely available on the NHS in the near future, MT is used by cancer patients in the UK. MT is available across anthroposophic medicine centres in England and Scotland and is likely to be available through some individual General Practitioners. It is therefore important that we continue to add to the evidence–base of this safe adjunct therapy for cancer patients. Previous qualitative research, and the interviews within the MAB study suggest a perceived benefit for cancer patients. [25]

UK based research should focus on mistletoe provision within its countries, adding to the evidence base of efficacy within 21st century conventional cancer treatment. It is also important that different modes of application of mistletoe are examined bearing in mind the challenges of self-injection highlighted by this mixed methods trial. Other potential modes include pre-filled syringes, oral mistletoe, and hydrogels. Such modalities would further enhance the acceptability of mistletoe therapy by both patient and practitioner but to date there is little to no research on these approaches.

5. Conclusions

This pilot shows that it is feasible to recruit breast cancer patients into a randomised controlled trial of MT versus placebo within the UK National Health Service, for them to adhere to therapy, and provide follow-up data.