Mistletoe Extract

Data were acquired by the investigators from the patients’ medical records at each of the study centers and were transferred to a standardized case report form (CRF). Data collected included patient demographics, characteristics of cancer disease and treatment, disease-related symptoms and adverse effects experienced by the patients, and the course of the disease. Outcomes were assessed at yearly intervals until the end of the observation or treatment period.

A total of 681 women with primary breast cancer were included.

Study Group

• N = 167
• Mean age was 55.11 years.
• Statistically significant tendency to more severe diseases and higher disease stages
• Most patients were receiving hormone therapy (71.9%), which was significantly more than the control group.

Control Group

• N = 514
• Mean age was 54.63 years.
• The majority of patients were receiving hormone therapy (48.2%).

Patients were excluded if they received other mistletoe products except the study medication, if they suffered from a relapse or metastatic disease at the beginning of the postoperative treatment, or if a secondary malignancy was detected.

The study was conducted in 53 randomly selected hospitals or practices representatively distributed in Germany, including oncologists, gynecologists, and general practitioners.

Unclear

This was a controlled, multicenter, comparative, epidemiological, cohort study.

Data were collected on CRFs in which, prior to data collection, the data elements required for the study were identified and defined.

The complementary standardized mistletoe extract study group reported a statistically significant lower number of fatigue or tiredness symptoms compared to the control group during an aftercare period of about five years, with 0.6% versus 1.0% reporting fatigue symptoms for the study and control groups, respectively.

To examine fatigue levels in patients supported by a mistletoe preparation compared to patients who did not receive mistletoe

Data were extracted from the medical records of patients from the time of diagnosis or surgery (visit 1), during postoperative chemotherapy or chemoradiotherapy (visit 2), and at the end of postoperative therapy (visit 3). Patient complains related to fatigue and symptoms of inflammation were noted by the physician via interview. The results of patients allocated to mistletoe therapy were compared to those of the control patients. Mistletoe was provided as an injectable extract preparation that was given subcutaneously at a total average dose of 16–20 mg per week.

• N = 324  
• AGE = Not provided
• MALES: Not provided, FEMALES: Not provided
• KEY DISEASE CHARACTERISTICS: All patients had colorectal cancer and were receiving 5-fluorouracil-based chemotherapy.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Germany

• PHASE OF CARE: Active antitumor treatment

Retrospective, observational cohort study

Specific measurements were not described. Signs of inflammation and cancer-related fatigue were apparently coded by physicians as “yes” or “no” to indicate the presence of clinical signs.

There was a significantly increased odds ratio of suffering with fatigue among patients in the control group at visits 2 and 3 (p < 0.001). However, by visit 2, 85% of those in the mistletoe group had dropped out, and by visit 3, only 16 patients remained in the mistletoe group. The results regarding inflammation were not described.

This report provides insufficient evidence regarding the effects of mistletoe therapy on cancer-related fatigue.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The study design, lack of clear objective methods to measure outcomes, and extremely high drop-out rate limit the usefulness of the findings reported. The actual dosages, timing, and duration of mistletoe therapy were not described.

This study does not provide any strong evidence regarding the efficacy of mistletoe extract for the management of cancer-related fatigue, and it does not provide evidence regarding the impact of this therapy on inflammatory markers. Inflammation is a suggested mechanism that may influence fatigue in patients with cancer, and mistletoe extract has been proposed as an intervention to reduce inflammation. Well-designed studies examining the potential effects of mistletoe extract in these areas are needed.

Data were retrieved by investigators from the patients’ medical records at each of the study centers and were transferred to a standardized case report form (CRF). Data collected included patient demographics, characteristics of the tumor disease, treatments, signs, symptoms, side effects experienced by patients, and the course of the disease. For each symptom, a patient was included in the analysis if the symptom was present either at the beginning and/or the end of postoperative treatment, and if an assessment was available for both time points. The primary target criterion was the change in symptom score between the start and end of postoperative treatment.

• The sample was comprised of 689 women with primary breast cancer.
• The therapy group was comprised of 219 patents (mean age = 60 years [range 33–92]). The majority had stage IIa (26.5%).
• The control group was comprised of 470 patients (mean age = 64 years [range 35–90]). The majority had stage IIa (29.4%).
• Patients were excluded if they were taking any other complementary medication except standardized mistletoe extract, suffered from a relapse or developed metastasis at the beginning of the postoperative treatment, or if a secondary malignancy was detected.

The study included seven study centers randomly identified in Germany (hospitals and general or specialized practitioners).

Patients were undergoing the active treatment phase of care.

This was a controlled, epidemiologic, multicentric, retrolective, cohort study with parallel groups.

Data were collected on CRFs in which, prior to data collection, the data elements required for the study were identified and defined.

The mean change in fatigue symptom scores during the postoperative study period was significantly larger (beneficial) in the therapy group compared to the control group (p < 0.0001). The adjusted odds ratios for fatigue in treatment/control was 7.33. A multivariate analysis of the combined symptom score was calculated in accordance to Wei-Lachin and proved a significant superiority of the therapy group (p = 0.0001).

To evaluate the impact of mistletoe extract injections on overall survival and quality of life in patients with advanced pancreatic cancer

Escalating doses of mistletoe extract were self-administered by patients as a 1 ml subcutaneous injection three times a week for the duration of the trial (up to one year) by the patient, a family member, or the local treatment center staff. The dose was escalated as follows: 0.01 mg for two injections, 0.1 mg for two injections, 1 mg for five injections, 2 mg for five injections, 5 mg for eight injections, and 10 mg for the remainder of the injections. Patients were evaluated by completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) at seven timepoints (at enrollment and before each visit in months 1, 2, 3, 6, 9, and 12). Patients were evaluated by the physician at each visit for the severity of symptoms of cancer (including weight loss) and undesired events.

• N = 168  
• AGE = 98 patients were aged 18–65 years, and 70 patients were aged greater than 65 years.
• MALES: 56%, FEMALES: 44%
• KEY DISEASE CHARACTERISTICS: Locally advanced or metastatic pancreatic cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Not receiving any treatment other than best supportive care

• SITE: Multi-site  
• SETTING TYPE: Multiple settings    
• LOCATION: Serbia

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care

Prospective, randomized trial (randomized 1:1 ratio to mistletoe injections or control after stratification for prognosis of good or poor)

• EORTC-QLQ-C30 (five functional scales, nine symptom scales, and one global quality of health scale)
• Common Terminology Criteria for Adverse Events (CTCAE)

All questionnaires were evaluated at the end of the trial. The treatment group received a median of 61.5 mistletoe injections. The treatment improved the global quality of life with statistical significance (p < 0.001) for global quality of life, appetite loss, fatigue, pain, and nausea at various follow-up time periods. The number of questionnaires received at various time points in the study ranged from 0–110 in the control group and 19–110 in the mistletoe group. The number of documented injections ranged from 3–156 per patient. No side effects were reported. The trial was terminated early because of demonstrated efficacy.

The results of the patient-completed quality of life questionnaires were reported with improvements in 13 of the 15 scales in the group treated with mistletoe. The administration of mistletoe was associated with improvements in appetite loss, fatigue, and pain.

• Risk of bias (no blinding)
• Selective outcomes reporting
• Measurement/methods not well described
• Findings not generalizable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: Patient self-reporting bias; tool scoring not described; limited to one cancer diagnosis; injections were to be self-administered by the patients and there is no information provided on degree of patient adherence to the study regimen; range of injections reported suggests that a number of patients did not receive all of the expected injections; no placebo comparison; large amount of missing data; approach regarding intent to treat analysis is unclear as the statistical methods are described

The findings of this study suggest that mistletoe may be beneficial to patients with advanced cancer for multiple symptoms. The positive findings of this study suggest that additional research in this area is warranted.