Gunver S. Kienle, MD1, and Helmut Kiene, MD1

Abstract
Objective. To evaluate controlled clinical studies on the efficacy and effectiveness of Viscum album for quality of life (QoL) in cancer. Materials and methods. The authors conducted a search of 7 electronic databases and reference lists and had extensive consultations with experts. They carried out a criteria-based assessment of methodological study quality. Results. The authors identified 26 randomized controlled trials (RCTs) and 10 non-RCTs that investigated the influence of V album extracts (VAEs) on QoL in malignant diseases; 26 studies assessed patient-reported QoL. Questionnaires were mostly well established and validated. Half of the studies investigated VAEs concomitant with chemotherapy, radiotherapy, or surgery. Some studies were well designed, whereas others had minor or major methodological weaknesses. Among the 26 RCTs, 22 reported a QoL benefit, 3 indicated no difference, and 1 did not report any result. All the non-RCTs reported a QoL benefit. Of the studies with higher methodological quality, most reported a benefit, whereas 1 found no difference. Improvements were mainly in regard to coping, fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, ability to work, and emotional and functional well-being in general and, less consistently, in regard to pain, diarrhea, general performance, and side effects of conventional treatments. VAEs were well tolerated. Conclusions. VAEs seem to have an impact on QoL and reduction of side effects of conventional therapies (chemotherapy, radiation) in experimental trials as well as in routine daily application. The influence on fatigue especially should be investigated further.

Keywords
clinical trials, quality of life, complementary therapies, herbal medicine, Viscum album, mistletoe, neoplasms

Review: Background
Cancer patients often use herbal extracts in addition to wellestablished cancer treatments.1 Viscum album L extracts (VAEs) are among the most frequently prescribed herbal extracts, especially in German-speaking countries1-5 and are also currently under investigation at the National Center for Complementary and Alternative Medicine (NCCAM).6
V album L, also known as European mistletoe (not to be confused with Phoradendron, the “American mistletoe”) is a semiparasitic shrub that grows on other trees and has been used in cancer treatment for about 80 years. Its extracts contain a variety of biologically active compounds. The most thoroughly investigated compounds are the mistletoe lectins (ML I, II, and III). MLs consist of 2 polypeptide chains: a carbohydrate-binding B-chain that can bind to cell surface receptors, which enables the protein to enter the cell,7-9 and the catalytic A-chain, which, because of its ribosomeinactivating properties, can subsequently inhibit protein synthesis by removing an adenine residue from the 28S RNA of the 60S subunit of the ribosome.7 Other pharmacologically relevant VAE compounds are viscotoxins and other lowmolecular-weight proteins, VisalbCBA (V album chitin-binding agglutinin),10 oligosaccharides and polysaccharides,11,12 flavonoids,13 vesicles,14 triterpene acids,15 and others.16,17 Whole VAEs as well as several of the compounds are cytotoxic, and the MLs in particular have strong apoptosis-inducing effects.18-20 MLs also display cytotoxic effects on multidrugresistant cancer cells (eg, MDR+ colon cancer cells21) and enhance the cytotoxicity of anticancer drugs.22,23 In mononuclear cells, VAEs also possess DNA-stabilizing properties. VAE and its compounds stimulate the immune system (in vivo and in vitro activation of monocytes/macrophages, granulocytes, natural killer cells, T-cells, dendritic cells, and induction of a variety of cytokines such as IL-1 [interleukin-1], IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, GM-CSF [granulocytemacrophage colony-stimulating factor], TNF-α [tumor necrosis factor α], IFN-γ [interferon γ]; for overviews see Kienle and Kiene16 and Büssing17). The cytotoxicity of human natural and lymphokine-activated killer cells, for instance, can be markedly enhanced in vitro by VAE rhamnogalacturonans, which bridge these killer cells with natural-killer-sensitive or -insensitive tumor cells.24,25 Furthermore, VAEs seem to interfere with tumoral angiogenesis.26,27 Injected into tumorbearing animals, VAEs and several of their compounds (MLs, a 5 kDa protein not specified further, protein complexes isolated by Vester and colleagues, oligosaccharides) display growth-inhibiting and tumor-reducing effects.16,17 Besides cytotoxicity, immune modulation, and DNA stabilization, VAEs can also enhance endorphins in vivo.16,17 Mistletoe treatment for cancer was introduced in the context of anthroposophical medicine, a complementary medical method.28 Anthroposophical mistletoe preparations— abnobaVISCUM, Helixor, Iscador (labeled as “Iscar” in the United States), Iscucin, and Isorel—are extracts from defined parts of V album, that is, fresh leafy shoots and berries. These preparations are available from different host trees such as oak, apple, pine, and others. The harvesting procedure is standardized, and the juices from summer and winter harvests are mixed together. Route of application and dosage vary individually, depending on the patient’s reaction and the stage of the disease. Nonanthroposophical VAEs— Cefalektin, Eurixor, and Lektinol—are harvested in winter from poplars; they are dosed according to mistletoe lectin content (ranging from 1 ng/kg up to 15 ng/kg bodyweight) on the premise that mistletoe lectin is the main active ingredient.17 Various clinical studies have assessed safety and possible effects on tumor growth, survival, and quality of life (QoL). Regarding antitumor and survival-prolonging effects, conclusions of systematic reviews of these studies were inconsistent, whereas possible benefits regarding QoL for cancer patients were mentioned in reviews that also included recent trials. These reviews, however, present only little detail on QoL; furthermore, they are either confined to certain preparations29,30 or cancer types31 or are otherwise incomplete or outdated.32-37
Clinical research on cancer treatment used to concentrate on outcomes like survival and tumor remission. For decades, subjective well-being was regarded as of minor importance, too complex and fuzzy and not tangible enough for straightforward scientific assessment.38 This attitude has changed considerably. The substantial suffering of cancer patients has been widely realized, and improvement in how patients feel while having the disease became an ethical imperative. Improvement of health-related QoL is today acknowledged as an important therapeutic goal and a wellestablished end point in clinical trials. A multitude of generic or specific instruments have been designed to assess different aspects of subjective well-being and function.39,40 Still, adequate improvement in QoL in cancer patients and the relief of their multifaceted suffering remains a challenge. All options should therefore be carefully scrutinized for potential benefits. QoL is a complex concept, covering a variety of areas such as general aspects of well-being; physical, emotional, and social functioning; general condition; disease symptoms; and side effects of treatment. Therefore, a closer, detailed, and differentiating critical analysis of the potential effects of VAE on these QoL aspects is of major clinical importance. For this reason, clinical studies were critically analyzed here to answer the following questions: Do controlled clinical studies provide evidence for the effectiveness of VAE in regard to QoL? If yes, which QoL aspects respond in particular? How far reaching is the clinical significance?

Material and Methods
Search Strategy

We used a systematic process to search the following databases for clinical trials: AMED, BIOSIS Previews, CAMbase, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, The NHS Economic Evaluation Database, Health Technology Assessment Database), Embase, MEDLINE/PreMEDLINE, NLM Gateway, and private databases. This was done from inception of these databases to October 2009 using the terms (MISTLETOE OR VISCUM? OR MISTEL? OR ISCADOR? OR ISCAR OR HELIXOR OR ABNOBA? OR ISCUCIN OR ISOREL OR VISOREL OR ?SOREL OR EURIXOR OR LEKTINOL) AND (STUDY? OR STUDIE? OR TRIAL OR EVALUAT? OR RANDOM? OR INVESTIG? OR COHORT? OR KOHORT?) The reference list from each potentially eligible study, relevant review article, and textbook was checked, and experts in the field and manufacturers of VAE preparations were contacted for additional reports. Potential clinical studies were individually checked for QoL outcomes.

Definition of QoL

In spite of the importance of QoL for cancer patients, there is no consensus regarding its definition. For this review, we chose a broad, pragmatic definition that covers all aspects of how patients feel and function during the disease and its treatment, including psychosomatic self-regulation, subjective well-being, disease symptoms, performance status (Karnofsky Performance Status Scale, KPS), undesirable experiences associated with the use of chemotherapy or radiotherapy (summarized here as adverse drug reactions [ADRs]), and treatment symptoms. We included QoL assessed by patients or physicians, using multidimensional or unidimensional questionnaires as well as global ratings.

Selection
The following selection criteria were used for inclusion of studies in the analysis: (1) prospective randomized or nonrandomized controlled clinical study or pharmacoepidemiological cohort study; (2) including a control group; (3) study population with cancer; (4) intervention group treated with VAE preparation; (5) QoL outcome; (6) completion of study; (7) published or unpublished. Studies were excluded if they only measured toxicity or tolerability (phase I trial), only measured stimulation of immunological parameters, or were not conducted on cancer patients. There were no restrictions on language.

Validity Assessment and Data Abstraction

Criteria-based analysis was performed on the selected studies to assess their methodological quality. Regarding general methodological strength of the studies, criteria were adapted from the National Health Service Centre for Reviews and Dissemination41 and from criteria for good methodology as already applied in earlier reviews on VAE trials.29,33,42 Analyses were performed independently by 2 reviewers. There were no major differences in study assessment; disagreements were resolved by discussion.
The QoL assessment methodology was evaluated using criteria adapted from the “Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials.”43 The data were abstracted by one reviewer and checked by the second reviewer. When necessary, primary authors of the trials were contacted for additional information.

Results

The primary search yielded more than a thousand references. After deleting all articles that did not meet the inclusion criteria (eg, no clinical study, laboratory research, reviews, opinions, studies not on cancer or not on QoL, only investigating complex treatment regimes, only descriptive studies) and after deleting double citations and combining articles referring to the same study, 36 studies were left that met the inclusion criteria. Of these, 26 were randomized controlled trials (RCTs), and 10 were nonrandomized controlled studies (nonRCTs). One further RCT (on Lektinol and breast cancer, by Schwiersch et al) might have met the inclusion criteria but was unpublished and unavailable.

Characteristics of Included Trials

Table 1 shows the characteristics of the trials. Settings of the trials were mainly academic hospitals, large community hospitals, and specialized cancer hospitals or outpatient departments. Most of the studies were conducted in Germany, the others in Austria, Switzerland, Italy, Serbia, Russia, Bulgaria, Ukraine, Romania, China, and South Korea. 14 trials were conducted in 1 center and 22 in more than 1 center. Most RCTs and 4 non-RCTs were conducted in conventional medical settings; 3 RCTs and 5 non-RCTs included hospitals or outpatient clinics that also provide complementary medicine methods; 1 was unclear in this regard. A total of 26 RCTs included 3058 patients, and 10 nonRCTs included 4996 patients (4012 of the latter were part of 5 pharmacoepidemiological cohort studies). Cancer sites and types studied were the following: breast (15), ovary (4), cervix uteri (2), corpus uteri (2), colorectal (3), pancreas (1), gastrointestinal (2), lung (3), head and neck (2), melanoma (2), glioma (1), osteosarcoma (1), various (1), malignant pleural effusion (1). Stages ranged from early detected to advanced disease. Of these studies, 32 had 2 arms, and 4 trials had 3 or more arms; 4 of the RCTs were double blind,44-47 3 other RCTs had an open placebo or pseudoplacebo treatment in the control group (placebo,48 vitamin B,49 or lentinan50), and 2 RCTs compared VAE with chemotherapy.51,52 The control groups of the other trials had received no additional therapy. Combinations of VAEs and conventional cancer treatment were investigated by 22 studies: VAEs were applied concomitantly with chemotherapy in 10 studies, with radiotherapy in 2 studies, with both in 7 studies, versus chemotherapy in 2 studies, and perioperatively in 1 study. In the remaining 14 studies, VAEs were investigated independently of concomitant conventional cancer treatment; nevertheless, these patients received standard cancer care when appropriate. VAEs were injected subcutaneously except in 2 studies using intravenous infusion or intrapleural instillation. Length of follow-up regarding QoL was 3 months or less in 8 studies, 4 months to 1 year in 18 studies, more than 1 year in 2 studies, and not reported in 8 studies. Frequency of assessment after baseline was once in 13 studies, twice in 1 study, repeatedly in 15 studies, and not specified in 7 studies. In all, 30 of the studies are published, 5 are available only as abstracts or poster presentations, 1 is not published.

Methodological Quality

Methodological quality of the 36 studies varied (Table 2); some of the studies were well designed, whereas others had methodological weaknesses or insufficient reporting. Also, 26 studies had randomized treatment allocation; in 4 of these trials, patients and physicians were blinded to treatment application; 5 additional studies had an open placebo, pseudoplacebo, or active treatment control, and 15 had no comparative

additional treatment. Of the 10 nonrandomized studies, 4 prospectively matched all patients for a series of relevant patient and disease characteristics53-55; 1 did not conduct any adjustment for baseline imbalances56; 5 were retrolective pharmacoepidemiological observational cohort studies: of these 4 were adjusted for confounder effects with a multivariate analysis57-61 and 1 with propensity scores.62 QoL was the primary outcome in 14 studies. The primary outcomes of the other studies were overall survival, diseasefree survival, functional competence of granulocytes, or not specified.
QoL or symptom control was patient-reported in 26 studies; in 1 of these, the questionnaire was filled out in an interview situation as some of the patients were illiterate.50 Only physician-reported QoL was referred to in 8 studies, with 5 of these studies raising data from patient charts.
QoL reporting was unclear in 2 studies.63,64 In 1 study, the result of several patient-reported questionnaires had been summarized by the physician in a 5-point résumé (QoL index).48 Patient-reported measurements included well-established QoL questionnaires, most of them designed specifically for cancer patients (see Tables 3-5). Other questionnaires included one on psychosomatic self-regulation and a simple daily analogical QoL report. Physicians reported subjective improvement of QoL, Traditional Chinese Medicine Index, disease- and treatmentassociated symptoms, KPS, and ADR. Information from patient charts concerned disease- and treatment-associated symptoms and KPS. Two trials did not specify their QoL instrument. Of the 36 studies, 2 described an a priori statistical hypothesis for improvement of QoL. Of the 26 studies assessing

patient-reported QoL with a questionnaire, 24 gave a rationale for using the particular instrument or used a standard questionnaire (eg, EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Cancer]); 24 of these 26 studies either used a well-established and well-known questionnaire or reported its psychometric properties. All the QoL questionnaires and the investigated symptoms are relevant for cancer patients. In all, 13 of the studies described instrument administration; 14 of the studies gave at least some relevant information regarding baseline compliance; 25 studies reported the timing of the assessment; 7 studies gave details on missing data or had no missing data at all; none of the studies explicitly and in detail addressed the issue of clinical significance from the patient’s perspective (over and above statistical significance), except the studies reporting complete disappearance or nonoccurrence of symptoms, thus, implying patient benefit; 22 of the studies discussed their QoL results in general. We found substantial heterogeneity of the studies in terms of intervention, patient characteristics, clinical diagnosis, measured outcomes, design, methodological quality, and potential positive and negative biases. We therefore regarded quantification of effect size by combining results as unreliable and decided on a nonquantitative synthesis and discussion.

QoL Result
Of the 26 RCTs, 22 reported a QoL benefit for VAE, 2 indicated no difference, 1 had mixed results, and 1 did not present the QoL results. None found a disadvantage for VAE. Of the non-RCTs, all reported a QoL advantage for VAE except one that reported an advantage in global symptoms but a clear

disadvantage in the unadjusted occurrence of depression.60 Details are given in Tables 3 to 5. Advantage for VAE was found with all QoL questionnaires except with the Rhodes Index (1 study), with a daily analogical QoL report by patients (1 small pilot trial), and with the EORTC QLQ-C30 (plus the BR 23 module in 2 studies), which had mixed results (4 showed benefit and 4 with no difference).
Patient-reported QoL improved in all but 3 studies, one of which was an abstract and presented only little information.67 Regarding physician-reported QoL, symptom control, ADR, and performance status, a benefit for VAE was found in most but not all studies (Tables 3 to 5). Of the 4 double-blind RCTs, 3 indicated a significant benefit, whereas a small pilot trial could not find a difference.

Of the 4 nonblind trials using placebo or pseudoplacebo or active control treatment, all indicated a QoL benefit for VAE. The methodologically best trials showing an improvement of QoL were the following:

• Two multicenter, double-blind, placebo-controlled RCTs (both by Semiglasov et al,44,45 conducted in Russia, Bulgaria, and in the Ukraine) included 272 and 352 patients with breast cancer (T1-3N0-XM0) receiving adjuvant chemotherapy (CMF— cyclophosphamide, methotrexate, fluorouracil). They found consistent and significant QoL advantages (in average scores) in the VAE patients (Table 4). One of these 2 RCTs investigated 3 dosages and found a benefit only for the medium dosage (containing 15 ng mistletoe lectin per injection); this dosage was then also applied in the second RCT).
• A multicenter RCT (by Piao et al50 conducted in China) included 233 patients with lung, breast, or ovarian cancer (T1-4N0-3M0-1) who were treated with VAE versus lentinan (antitumor polysaccharide isolated from shiitake mushroom), concomitant with chemotherapy. A significant advantage was observed (Table 4) in average QoL scores as well as in the proportion of patients who showed a QoL improvement.
• A large-scale epidemiological cohort study including 10 226 patients (by Grossarth et al53-55,74,75,77 conducted in Germany) included 7 nested RCTs—on
melanoma (T3-4N0M0), cancer of the ovary (FIGO IA-IC), cervix uteri (FIGO IVA-IVB), corpus uteri (FIGO IA-IC), breast (in 2 RCTs: T1-3N0M0 and IIIA-B), and several cancer types (all stages). In the framework of the cohort study, patients with these cancers had been matched pairwise for a broad range of disease-specific criteria, and 1 person in each pair was then randomly addressed for VAE treatment. The patients were then prospectively followed up in relation to psychosomatic self-regulation, survival, and tumor-specific outcomes. A benefit was found in all 7 RCTs (Table 5).
• An open-label RCT (conducted in Belgrade by Tröger et al66,78) included 95 breast cancer patients (T1-3N0-2M0) receiving adjuvant chemotherapy (CAF: cyclophosphamide, doxorubicin, fluorouracil). A significant improvement of QoL in the VAEtreated group was found (Table 4).

Three trials could not find a benefit on QoL from VAE treatment:

• A small double-blind RCT (by Auerbach et al47) included 20 patients with breast cancer (T1-2N0M0) receiving adjuvant chemotherapy (CMF) and radiotherapy (Table 4).
• A large, non-blind RCT (by Steuer-Vogt et al70,71), basically well-conducted though with an increasing dropout in relation to QoL assessment (32% after 1 year, 53% after 2 years), investigated patients with head and neck cancer (stage I-IV) after surgery and partly receiving radiotherapy. For additional VAE application, no statistically significant global benefit in QoL (EORTC QLQ-C30) could be found. In this study, QoL was primarily impaired in the subgroup of patients who received additional radiotherapy. Because QoL impairment is a precondition for a subsequent improvement and because other VAE studies found QoL improvement in patients receiving radiotherapy (Lange et al, unpublished data, 1985),57,58,61,62,72 it would have been important to know whether any QoL changes occurred in this subgroup. However, this subgroup was not analyzed separately, although an initial stratification according to radiotherapy would have allowed such an analysis. Hence, this question remains open in this study.
• A small trial (by Büssing et al67) on 65 patients with breast cancer (stage not specified) receiving adjuvant chemotherapy (epirubicin and cyclophosphamide with or without fluorouracil) primarily investigated granulocyte function. It also mentions not finding a benefit for VAE application using the EORTC-QLQC30 and BR 23 questionnaire and the Rhodes Index, but it reported significantly less chemotherapy-related side effects in the VAEtreated group. This study was only published as an abstract and presented little information on study details and results. Despite randomized treatment allocation, study groups were not comparable at baseline, and a bias in cointervention seems to have occurred.

As regards details of the QoL assessment (see Tables 4 and 5), the most consistent improvement was reported in relation to self-regulation; a clear advantage for VAE-treated patients was reported in all studies. Frequent improvement was also reported in relation to fatigue, exhaustion, and sleep; nausea, vomiting, and appetite; and emotional well-being, sadness, anxiety, depression, irritability, or concentration difficulties. Repeatedly, though not as frequently as the former, the following areas improved: energy, functional wellbeing, ability to work, enjoyment of life, feeling ill, sexual interest, the thought of actually having treatment, and daily life. There was inconsistency in the results relating to pain, diarrhea or constipation, mucositis, and numbness. No improvement was observed in relation to loss of hair, dypnea, and infections. Often, the study reports did not present details when outcomes had not improved significantly and did not specify ADRs of conventional cancer drugs.

Safety
Tolerability was generally good: 1 case of urticaria and angioedema50 and 1 case of “generalized reaction”60 were described.
Otherwise, no major side effects or toxicity were reported. Frequent, minor dose-dependent and spontaneously subsiding symptoms included reactions at the injection site (swelling, induration, erythema, pruritus, local pain) and mild flu-like symptoms or fever. In 1 study, local reactions were enhanced during concomitant chemotherapy.56 After intrapleural instillation, VAE induced significantly fewer side effects than doxycycline.51 Beyond these reviewed studies, a phase I study is currently being conducted at the NCCAM/NCI to investigate the safety and toxicity of and drug interactions between VAE and gemcitabine6; an interim analysis reports good tolerability, with neither dose-limiting toxicity of the VAE nor any effects on the plasma concentration of gemcitabine.79

Discussion
Most studies report a benefit regarding QoL in VAE-treated patients. This benefit mainly relates to psychosomatic selfregulation; to fatigue, sleep, exhaustion, and energy; to nausea, vomiting, and appetite; to emotional well-being, depression, anxiety, and concentration; to functional wellbeing and ability to work; and also, yet less consistently, to pain, diarrhea, general performance, and side effects of conventional cancer treatment. The benefit can be seen in VAE application concurrent with conventional cancer treatment (chemotherapy, radiation, and surgery)—where an improved tolerability of anticancer treatment is reported—and also independent of concomitant therapies. No dependence on type or stage of disease could be found. Most positive results were achieved in patients with breast cancer, whereas a study on head and neck cancer found no benefit for VAE. An increase in depression in VAE-treated patients was reported in 1 retrospective study investigating patient charts60; however, the results were not adjusted to apparent baseline imbalances such as significantly higher rates of hormone treatment in the VAE-treated patients, a side effect of which is depression; these results therefore require cautious interpretation. In general, when appraising QoL effects, some principles have to be kept in mind. First, the particular QoL aspect has to be impaired in the beginning, otherwise any improvement of QoL is most unlikely to occur. This is for instance the case for performance status (KPS) in early-breast cancer patients receiving adjuvant CMF, as was the case in 3 of the reviewed VAE studies.44,45,47 Second, timing is essential for QoL measurement. Widely spaced single-point estimates are less relevant and will differ from more continuous or repeated measurements (which are also clinically more relevant). Varying assessment periods might indeed explain some of the observed differences between patients’ and physicians’ symptom reports. Third, the QoL instrument has to have sufficient sensitivity for the condition or treatment in question. For instance, the sensitivity of the EORTC QLQ-C30 was called into question because it could not find a difference in 4 (out of 8 trials), whereas other questionnaires did find differences
152 Integrative Cancer Therapies 9(2) in 2 of these 4 trials. Still, the EORTC QLQ-C30 did find a substantial difference in a recent well-conducted RCT66,78 as well as in 2 other recently published small-sized RCTs.52,65 A particular VAE-specific questionnaire80 has been developed but was not applied in the reviewed studies.

Strengths and Weaknesses of the Review
The validity of this review largely depends on the primary trials. Although several of the more recent studies were reasonably well conducted, there were substantial weaknesses in others. Strengths and weaknesses of most of the reviewed trials have been described elsewhere (see references 29, 31, and 33) and are summarized in Table 2. Still, specific methodological issues connected with QoL assessment remain to be considered. Some of the studies presented multiple comparisons without an a priori definition of the primary outcome and without statistical adjustment for multiple testing. Even though this practice is common also in most of the conventional cancer trials investigating QoL,81 this makes it more difficult to differentiate positive results from pure chance effects. However, consistency of results across several outcomes or studies, as in the VAE trials, argues against mere chance. Particularly in QoL studies, missing data are unavoidable but can induce bias when dropout is because of patients deteriorating or being discontented with treatment benefit. Accordingly, missing data bias cannot be excluded in some of the VAE studies. However, a number of the studies either had a small drop-out rate or the dropouts were unrelated to the outcome because they had occurred before baseline assessment. In these studies,53-55,74 the patients were provisionally enrolled as matched pairs and subsequently asked for informed consent, and when they declined, they were excluded from the study together with their matched twin. The risk of bias is small with this procedure, but the conservative quality assessment in our review still assessed these studies as not having excluded a drop-out bias. Questionnaires were mostly validated and well established. A post hoc validation82 was conducted for the questionnaire on psychosomatic self-regulation used in several of the VAE studies: it assesses the ability to achieve wellbeing, inner equilibrium, appropriate stimulation, a feeling of competence, and a sense of being able to control stressful situations. Placebo effects or participants giving the answer that they believe is wanted (obliging reporting) cannot be completely excluded even by rigorous blinding. Because blinded subcutaneous VAE injection can be identified correctly by doctors and patients,47,83 blinding of VAE injections will hardly ever be reliable. Whether an insufficient pro forma blinding gives more valid results than an open application is, as yet, an unanswered question. Notwithstanding, 4 RCTs were doubleblinded, and 3 of these had a positive result44-46; the 1 study finding no effect of VAE on QoL had a tiny sample size of 20 patients.47 Five further trials compared VAE treatment with another control treatment (placebo,48 pseudoplacebo,49,50 or chemotherapy51,52). For instance, one of these studies was conducted in China where the applied control treatment lentinan is popular and well known and should also be able to induce competitive placebo effects.50 All these 5 RCTs with control treatments found advantages for VAE. On the other hand, the only larger study finding no difference was not blinded.71 In general, placebo application in cancer patients and best supportive care is associated only with limited improvement of symptoms such as pain and appetite and with hardly any improvement in QoL. Substantial, well-documented, patientreported improvements in symptom control or QoL are unlikely to be a result of placebo effects.84-86 Still, placebo effects and obliging reports cannot be completely ruled out in typical subcutaneous VAE application, but the available observations attest that the results are not merely illusory in nature. Protection against performance (treatment) bias was rated low by us in most studies, although, in this regard, they do not differ substantially from common trial practice. The influence of cointerventions may quite generally be underestimated in clinical trials: When a control group improves less than the test group, control patients will have a greater urge to apply more additional relieving treatments, regardless of whether this is compliant with the care protocol. Notably, such cointerventions are not prevented by randomization, blinding, or care protocol. If they are documented, study groups can show substantial differences in cointervention frequencies that ultimately dilute the effect size of the test treatment (eg, Koes et al87). In one of the non-RCTs on VAE, the cointerventions were reported in detail, and indeed, the control group received significantly more additional interventions (glucocorticoids, enzymes, vitamins, trace elements).56 The inclusion of non-RCTs in this review might also raise the topic of bias because their internal validity—that is, unbiased comparability without randomized treatment allocation— is more difficult to generate. On the other hand, non-RCTs have the advantage of better external validity and can assess pros and cons of everyday practice without experimental artificialities (effectiveness). Four of the non-RCTs had a careful prospective matched-pair design, nested in a large cohort study (by Grossarth and Ziegler53-55,74): patients with ovarian, cervical, corpus uteri, or breast cancer (FIGO IA-IC, IB-IVA, IA-IC, or T1-3N0M0, respectively) who reported on enrollment that they had already started VAE were closely matched to another cancer patient twin not using VAE and were then prospectively followed up (together with their twin). Five retrolective non-RCTs (by Matthes et al,59 Friedel et al,58,61 Bock et al,57 Schumacher et al,62 and Beuth et al60) were multicenter, comparative, GEP (good epidemiological practice)-compliant, pharmacoepidemiological cohort studies57-59,61,62 that investigated patient data from medical charts (selected according to predefined inclusion and exclusion criteria and without knowing the medical outcome) from a variety of medical centers on patients with pancreatic cancer (all stages),
Kienle and Kiene 153
colorectal cancer (stage I-III), or breast cancer (3 studies, stage I-III and all stages). Analysis was performed with multivariate adjustment for baseline differences or by computing a propensity score (in 1 study only the analysis of the primary outcome was adjusted). These studies were carefully and meticulously carried out according to a standardized procedure. Still, retrospective assessment of subjective outcomes without a primary standardization of the physician’s charts leaves some uncertainty. Furthermore, only patients were included who received a single VAE preparation. This inclusion criterion might theoretically induce bias because patients with advancing disease may tend to switch VAE preparations. To minimize publication bias in this review, a comprehensive search was conducted, and unpublished trials were also included. All but one of the identified unpublished studies could not be retrieved. We consider it unlikely that important trials with high methodological quality went unnoticed, at least in Europe. However, we cannot exclude the possibility that we missed minor ones or trials conducted in distant, non-European countries. Finally, in this review, the pragmatic definition of QoL led to the inclusion of more outcomes than just subjective well-being, insofar as ADRs also refer to somatic reactions. This, however, does not bias the review because all outcomes have been presented in connotation with the respective QoL instrument.

Clinical Relevance
In general, these studies indicate that VAEs might improve the subjective well-being of cancer patients. The explanation for such QoL improvement is only hypothetical at the current stage of knowledge. Endorphins enhanced by VAEs could be involved88 as well as the immunological network,89 which is also affected by VAEs. In the case of improved tolerability of anticancer treatments, the stabilization of DNA could also play a role.6,18 Many other factors, including more psychological ones, also have to be considered. Irrespective of any causal explanation, QoL is a clinically relevant topic. This is especially the case for cancer-related fatigue,90,91 which is one of the most common unrelieved symptoms in the cancer context. It affects patients significantly and extensively, more than any other symptom such as anxiety, pain, nausea/vomiting, depression, alopecia, and so on.91,92 It affects central aspects of their lives such as the ability to work, to take care of the family, to have relationships with friends, and to enjoy life.92 Treatment options against cancer-related fatigue are limited to date; they are mainly behavioral, involving exercises and psychosocial interventions but also some medicines. Such treatments do show positive results in reducing fatigue but have small effect size and do not seem to offer adequate help to all patients.93-95 By and large, the problem is still unsolved, and there is an urgent need to find further therapy options. Remarkably, most of the reviewed VAE studies described improvement in fatigue, exhaustion, and sleep in the course of treatment. This observation is also reported by individual patients and might explain the popularity of VAE in cancer.96
As far as nausea and vomiting caused by cancer treatment are concerned, a variety of highly effective interventions are available today, and VAE treatment could at best be seen in the perspective of an add-on.
A key issue for cancer patients is also their general functional and emotional well-being, including depression, anxiety, and concentration, which is also often reported to improve during VAE treatment. These aspects are interconnected with fatigue and are significant for patients. Because effective therapeutic approaches are presently limited, VAE treatment should be further investigated in this regard and its effects further analyzed.

Future Research
These studies indicate an improvement in QoL caused by VAE treatment. Future research should further investigate this effect and clear open questions regarding biological mechanisms, clinical significance, persistence of the improvement, dependence on dosage, disease stage, cancer site, and cointerventions. Because of the clinical relevance of cancerrelated fatigue, VAE effects here should be further assessed using fatigue-specific questionnaires. Future VAE studies should take into account the general recommendation for clinical trials as well as the issues particularly connected with QoL assessment.40,43,81

Conclusions
VAE treatment seems to have an impact on QoL and reduces side effects of conventional therapies (chemotherapy, radiation) in experimental trials as well as in daily routine application. Fatigue, a debilitating symptom of cancer, seems to improve. The studies vary in the degree of methodological quality. Some of the weaknesses could be avoided by designing and conducting the studies carefully, whereas others represent typical and widely discussed problems of QoL research. Additional research should be conducted to further analyze the observations. Future studies should include questionnaires specifically designed to evaluate fatigue.
Acknowledgments We thank the Gesellschaft für Biologische Krebsabwehr and the Software AG Stiftung for financially supporting this work.
Declaration of Conflicting Interests Institute for Applied Epistemology and Medical Methodology has received restricted research grants from Weleda, Abnoba, and Helixor for other projects not connected to this review.
Funding The Gesellschaft für Biologische Krebsabwehr and the Software AG Stiftung financially supported this work.

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