16 Aug 2022: Schad F, Thronicke A, Steele ML, Merkle A, Matthes B, et al. (2022) Correction: Overall survival of stage IV non-small cell lung cancer patients treated with Viscum album L. in addition to chemotherapy, a real-world observational multicenter analysis. PLOS ONE 17(8): e0273387. https://doi.org/10.1371/journal.pone.0273387 View correction
Stage IV non-small cell lung cancer (NSCLC) is associated with a five-year survival rate of around 1%. Treatment with Viscum album L. (VA) extracts has been shown to reduce chemotherapy (CTx)-related adverse events, decrease CTx dose reductions and improve quality of life in a number of cancers. Recent data suggest a beneficial effect of add-on treatment with Viscum album L. (VA, European mistletoe) on survival in cancer patients. The objective of this study was to evaluate the effect of VA in addition to chemotherapy on survival in stage IV NSCLC patients.
The observational study was conducted using data from the Network Oncology clinical registry which is an accredited conjoint clinical registry of German oncological hospitals, practitioners and out-patient centers.Patients were included if they had stage IV NSCLC at diagnosis, lived at least for four weeks post-diagnosis and received chemotherapeutic treatment. Patients with EGFR mutations as well as patients receiving tyrosine kinase inhibitors or immune checkpoint inhibitors were not included. Overall survival and impact on hazard in patients with chemotherapy (CTx) to patients receiving CTx plus VA were compared. To identify factors associated with survival and to address potential sources of bias a multivariate analyses using Cox proportional hazard model was performed.
The median age of the population was 64.1 years with 55.7% male patients. The highest proportion of patients had adenocarcinoma (72.2%) and most of the patients were current or past smokers (70.9%). Of 158 stage IV NSCLC patients, 108 received CTx only and 50 additional VA. Median survival was 17.0 months in the CTx plus VA group (95%CI: 11.0–40.0) and was 8.0 months (95%CI: 7.0–11.0) in the CTx only group (χ2 = 7.2, p = .007). Overall survival was significantly prolonged in the VA group (HR 0.44, 95%CI: 0.26–0.74, p = .002). One-year and three-year overall survival rates were greater with CTx plus VA compared to CTX alone (1y: 60.2% vs. 35.5%; 3y: 25.7% vs. 14.2%).
Our findings suggest that concomitant VA is positively associated with survival in stage IV NSCLC patients treated with standard CTx. These findings complement pre-existing knowldedge of add-on VA’s clinical impact, however, results should be interpreted with caution in light of the study’s observational character.
Citation: Schad F, Thronicke A, Steele ML, Merkle A, Matthes B, Grah C, et al. (2018) Overall survival of stage IV non-small cell lung cancer patients treated with Viscum album L. in addition to chemotherapy, a real-world observational multicenter analysis. PLoS ONE 13(8): e0203058. https://doi.org/10.1371/journal.pone.0203058
Editor: Fan Yang, Peking University People's Hospital, CHINA
Received: December 19, 2017; Accepted: August 14, 2018; Published: August 27, 2018
Copyright: © 2018 Schad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The anonymized data that support the findings of this study are openly available in the repository “figshare” (https://figshare.com/s/37063c430a023f61b6ac, DOI: 10.6084/m9.figshare.6449597).
Funding: The Network Oncology was funded by unrestricted research grants from Iscador AG Arlesheim, Switzerland; ABNOBA GmbH Pforzheim, Germany; and Helixor GmbH Rosenfeld, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. By contract, researchers were independent from the funder.
Competing interests: Dr. Schad reports grants from Helixor Heilmittel GmbH, grants from Abnoba GmbH, grants from Iscador AG, outside the submitted work. Dr. Grah reports grants from Iscador AG, outside the submitted work. Grants from Helixor Heilmittel GmbH include travel costs and honoraria for speaking. There are no other relationships/conditions/circumstances that present a potential conflict of interest. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. No payment was received for any other aspects of the submitted work. The other authors have declared that no competing interests exist.
According to the Global Health Observatory data of the World Health Organization, cancer of the trachea, bronchus and lung account for 1.7 million deaths worldwide which makes them being the world’s top five cause of deaths . Accounting for 25.9% of all cancer-related deaths in 2017, lung & bronchus cancer ranks first position, followed by breast, colon & rectum, prostate and pancreatic cancer . Almost 85% of U.S. lung cancers are non-small cell lung carcinoma (NSCLC) . Over one half of primary NSCLC patients are already diagnosed with stage IV lung cancer. The median overall survival (OS) of these patients ranges between 7.0 and 12.2 months depending on treatment, histology type and other associated factors [4–6]. As stage IV NSCLC is one of the most devastating diagnoses of lung cancer, worldwide great effort is done in the search for new treatment solutions, i.e. reflected by the vast clinical research on CTX-combinations in the past and accelerated approval of new immuno-oncological treatment in the U.S. and Europe in recent years [7, 8].
Even though newer histology and molecular pattern-based treatments including immune checkpoint inhibitors (ICI) are preferred as they are beneficial for patients with specific molecular subtypes [9, 10], chemotherapeutic combinations still play a major role in first-line treatment. Generally, platinum-based CTx is the first-line therapy in patients with advanced NSCLC without any targetable mutations. For metastatic non-squamous NSCLC (showing less than 50% PD-L1 expression) bevacizumab revealed a survival benefit in combination with carboplatin and paclitaxel as first-line treatment . For first-line treatment of patients with metastatic NSCLC whose tumors have at least 50% PD-L1 expression with no EGFR-, ALK positive or other activating tumor mutations, the immune checkpoint inhibitor pembrolizumab  has been approved. A high proportion of patients experience disease progression during or after gold-standard CTx regimen. Despite reported efficacy and effectiveness, the tolerability of current modern oncological treatment with respect to health-related quality of life (HRQL) and palliative care remains an important issue [13–19]. Thus, the quest for an effective treatment regimen with a sound safety profile in this field continues.
VA is applied in integrative oncology concepts concomitantly to CTx to improve HRQL [20–25]. Even though the evidence of VA’s impact on survival is discussed controversially [25–27] and a Cochrane review in 2008 summarizes that “there was no consistent effect of mistletoe extracts” on clinical outcome , its potential beneficial effect on survival of cancer patients is accumulating [21, 25, 28–32]. The objective of the present observational study was to evaluate the effect of additional VA treatment on the survival of stage IV NSCLC patients treated with standard CTx.
Materials and methods
Study design and patients
A non-controlled, non-randomized observational multicenter cohort study was conducted revealing,real-world, data (RWD)  by analysing patient registry data (Network Oncology, NO). The NO is a conjoint clinical register of hospitals, practitioners and out-patient centers  of which three study centers participated. Patients were included who were 18 years or older, who gave written consent, with a histologically proven primary diagnosis of stage IV non-small cell lung carcinoma seen between February 2010 and June 2016, receiving chemotherapeutic treatment surviving more than 28 days. Patients were not included if they did not give written consent, received any targeted therapies including monoclonal antibodies, tyrosine kinase inhibitors or any ICI, or when death date or last contact date were not available. Follow-up was performed routinely six months after first diagnosis and annually during the next years. Loss to follow-up was defined as no follow-up visits.
Ethics approval and consent to participate
This study is an observational cohort study of the Network Oncology (NO) which has been approved by the ethical committee of the Medical Association Berlin (Berlin—Ethik-Kommission der Ärztekammer Berlin). The reference number is Eth-27/10. Written informed consent has been obtained from all patients prior study enrolment. The study complies with the principles laid down in the Declaration of Helsinki.
Structured Query Language inquiries on records of patients were run for lung cancer patients (International Classification of Diseases code: C34) using the clinical database NO. For queried patients demographic data and hospital-related data (diagnosis, histology, pre-treatment and treatment) were retrieved from the NO. In addition, recorded TNM stages or documented metastases were queried with their according date and translated into Union for International Cancer Control (UICC) stages according to the 7th edition of TNM Classification of Malignant Tumors . UICC stage at first diagnosis was defined as the earliest recorded stage within a month of the diagnosis date. Furthermore, chemotherapeutic applications were queried with their according date. Surgical interventions were coded according to the German procedure classification 2013 [DIMDI, http://www.dimdi.de/static/en/klassi/ops/index.htm]. Application of VA extracts in the context of an integrative oncological setting was retrieved with start and end dates, application type and the pharmaceutical used. VA therapy was defined as lasting more than four weeks. Best objective responses were assessed on patients with measurable disease. Tumor response was assessed according to revised RECIST guidelines, version 1.1 for solid tumors . Progression-free survival was defined as time from date of index date to documented disease progression (according to RECIST) or death from any cause . Patients who were alive but had not progressed at the time of the analysis were censored.
Classification of groups
Included NSCLC patients were classified into the histological subgroups non-squamous cell carcinoma, squamous cell carcinoma or large cell carcinoma. We then classified patients to one of the two groups: a) CTx group—patients received only CTx and no VA therapy and b) CTx + VA group–patients that received concomitant VA therapy. CTx only or CTx+ VA were applied as per routine clinical care. Non-randomized allocation to the treatment groups was performed by the physician after elaborate information and patient’s decision on treatment options. Applied VA preparations included Abnobaviscum, Helixor and Iscador VA extracts. VA therapy was applied subcutaneously according to SmPC [38–40]. Off-label intravenous application was performed in individual cases.
Determination of sample size
For a two-sided sample size test assuming a power of 80% and 5% level of significance with an allocation scheme of 0.3 (CTx/VA) to 0.7 (CTx) and a relative hazard of 0.43 , a total of 156 patients (47 patients in the CTx/VA and 109 patients in the CTx group) would be needed to confirm a statistically significant treatment effect according to Schoenfeld et al. 
The objective of this study was to evaluate the effect of VA in addition to CTx on survival in stage IV NSCLC patients. The primary outcome of the study was the evaluation of OS and to test the hypothesis that stage IV NSCLC patients receiving additional VA to CTx have a longer OS than patients receiving CTx only. The secondary outcome was the assessment of factors for their association with the hazard of dying.
The start date for survival analysis was the first date of available histology (index date) which was +/- 28 days of date of first diagnosis of stage IV lung cancer. Patient survival was calculated from index date until the patient's last record, which was either the date of death, or the last documentation of personal contact, interdisciplinary tumor board or follow-up (for follow-up measures please see,study design and patients,). A year lasted 365.25 days and a month was 365.25/12 days. Kaplan Meier survival was calculated for both groups.
To analyse how different factors influence the hazard on patient survival and to reduce potential confounding bias we employed multivariate stratified Cox proportional hazard model adjusting for demographic, histological and treatment variables as well as smoker-status. Potential confounders that were addressed were age, gender, BMI, smoking status, and oncological treatment. Prior this analysis verification analyses were performed whether or not proportional hazard assumptions were met. All analyses were conducted using the software R, version 3.3.0–2016-05-03, R-Studio version 0.99.896, a language and environment for statistical computing . Continuous variables were described as median with interquartile range (IQR); categorical variables were summarised as absolute and relative frequencies. Data distributions were inspected graphically using box plots and histograms and were arithmetically examined for skewness. Patients with missing data were not included. For both groups, baseline characteristics and treatment regimens were compared using the unpaired Student’s t-test for independent samples. For comparison of categorial variables chisquare analysis was performed. All tests were performed two-sided. P-values < .05 were considered significant.
For survival analysis including Kaplan-Meier curves and right-censored time-to-event analyses as well as univariate and multivariate Cox proportional hazard models the R-package ‘survival’ was applied, version 2.41–3 published by Terry M. Therneau and Thomas Lumley on 2017-04-04; https://CRAN.R-project.org/package=survival. For the implementation of nonparametric estimators for censored event history (survival) analysis the package ‘prodlim’ was applied, version 1.6.1 published by Thomas A. Gerds 2017-03-06 (https://CRAN.R-project.org/package=prodlim). To draw survival curves the package ‘survminer’ was used, version 0.4.0 by Alboukadel Kassambara, Marcin Kosinski, Przemyslaw Biecek published 2017-06-07 (https://CRAN.R-project.org/package=survminer).
158 stage IV NSCLC cancer patients that were diagnosed between February 2010 and June 2016 (follow-up total: 2280 days; average 228.6 days) in the NO revealed complete histological data, received CTx, and showed survival of greater 28 days after index date rendering eligibility of these patients for subsequent survival analysis (see study flow chart, Fig 1). Non-eligibility for analysis was characterized by receival of targeted or ICI therapy (n = 28).
NO, network oncology; CTx, Chemotherapy; VA, Viscum album L., mistletoe.
Table 1 shows the main characteristics of analyzed patients at baseline. No significant differences between groups with regards to demographic characteristics, tumor histology subtypes, smoker status, cancer-directed surgery, radiation were seen. 108 patients received only CTx and 50 patients received VA in addition to CTx. Mean age of the total cohort was 64.1 years with no significant differences between both groups. The sex ratio (male/female) was 1.26 in the total cohort. The percentage of current/past smokers and of never-smokers was slightly higher in the CTx group (p = .08).
Of the total analysed cohort 72.2% (n = 114) had non-squamous, 19.6% (n = 31) squamous cell carcinoma and 8.2% (n = 13) large cell carcinoma. The percentage of patients diagnosed with squamous cell carcinoma was two times higher in the CTx compared to the combinational CTx + VA group and the percentage of patients with large cell carcinoma was two times higher in the combinational CTx + VA group compared to the CTx group; differences in the proportions of histology classes between both groups were not significant.
As to first-line CTx treatment, platinum-compounds were received by 116 (73.4%) of all patients, mostly in combination with gemcitabine, pemetrexed, vinorelbine or etoposid, see Table 2. Gemcitabine was applied to 11 (7%) patients either as monotherapy or in combination with platinum compounds or vinorelbine at some point. Docetaxel and paclitaxel were the most frequent taxanes (22 patients, 13.9%) and mainly given as monotherapy or in combination with platinum compounds. 24 (15.2%) patients received bisphosphonates, one patient received hormonal therapy, namely bicalutamide, data not shown. As to first-line CTx treatment no significant differences were seen between both groups, data not shown. For those patients for whom second-line treatment data was retrieved, no significant differences between both groups were detected, data not shown.
In addition to CTx, 50 patients (31.7%) received extracts of VA, see Table 3. The most frequent type of application for mistletoe agents was subcutanous injection in 44 patients (88.0% of all VA patients), followed by off-label intravenous or intratumoral injections in 40 (80%) and 3 (6.0%) patients, respectively. In general, Abnobavisucm extracts were the mistletoe remedies most often prescribed (n = 42), especially for subcutaneous application (n = 35), followed by Helixor remedies, mainly used for intravenous application (n = 31) and Iscador preparations (n = 12).
One hundred and fifty-eight patients were included in the overall survival (OS) analysis from which 86% (n = 136) died during total observational time with 24.1% (n = 38) in the CTx + VA group and 62% (n = 98) in the CTx only group.
As to overall survival a survival benefit was seen for the combinational treatment (CTx + VA) compared to CTx only, see Figs 2 and 3. The median OS was 17.0 months in the CTx plus VA group (95%CI: 11.0–40.0) and was 8.0 months (95%CI: 7.0–11.0) in the CTx only group, see Table 4. This difference was statistically significant (χ2 = 7.2, p = .007). One-year OS rates were 35.5% for the CTx-group and 60.2% for patients who received additional VA; three-year OS rates were 14.2% for the Ctx-group and 25.7% for the combinational CTx plus VA group.
Kaplan–Meier survival curves displaying one-year survival in stage IV NSCLC patients treated either with CTx alone or with combinational CTx plus VA, n = 158; CTx, chemotherapy; VA, Viscum album L.
Kaplan–Meier survival curves displaying 3-year survival in stage IV NSCLC patients treated either with CTx alone or with combinational CTx plus VA, n = 158; CTx, chemotherapy; VA, Viscum album L.
Progression-free survival (PFS) analysis was performed in a subgroup of 126 patients (79.7%) and revealed a tendency towards significance (χ2 = 3.4, p = 0.063), for a prolonged median PFS in the CTx + VA group (6.7 months; 95%CI: 4.0–9.0) compared to the CTx group (4.4 months; 95%CI: 2.7–5.9) 6.4% see Fig 4.
Median PFS CTx: 4.4 months (95%CI: 2.7–5.9) vs. median PFS CTx+VA: 6.7 months (95%CI: 4.0–9.0), χ2 = 3.4, p = 0.06.
Response rates have been analysed in a subgroup (n = 126, 79.7%) for which data were retrievable, see Table 5. Both groups showed similar low rates of complete response. In a significantly higher proportion of patients of the CTx group the disease progressed (87.4%) compared to 66.7% in the CTx + VA group (p = 0.01). A highly significant difference (p = 0.008) was observed for partial responders between both groups with a higher proportion in the CTx + VA group (30.8%) compared to the CTx only group (10.3%).
Additional VA therapy compared to no VA therapy significantly reduced hazard by 48% as shown by univariate Cox proportional hazard model (HR: 0.52, 95% CI = 0.33–0.83, p = .007) (data not shown). Hazard was significantly reduced by 52% when the duration of add-on VA therapy was prolonged to ≥16 weeks (HR: 0.48, 95%CI: 0.28–0.83, p = .007). Highly statistically significant reduction of hazard of death remained after adjusted multivariate stratified Cox proportional hazard analysis revealing a hazard reduction of 56% (adjusted hazard ration–aHR: 0.44, 95%CI = 0.26–0.74, p = .002), see Table 6. Nine variables including age, gender, concomitant VA therapy, body mass index, histology, smoker status, cancer-directed surgery and radiation were adjusted. Cancer-directed surgery and radiation therapy showed no significant effect on hazard, while the direction of impact on hazard was indicated to be negative. Male gender compared to female gender significantly increased hazard of death by factor 1.7 (aHR: 1.65, 95%CI: 1.04–2.62, p = .034). An unknown status of BMI was statistically associated with an increased risk (aHR: 2.32, 95%CI: 1.20–4.49, p = .01). Other factors showing an association with increased adjusted hazard of death were histology subtype large cell carcinoma (aHR: 3.74, 95%CI: 1.78–7.85, p = .0005) compared to subtype adenocarcinoma.
The results of the present study reveal a significant survival benefit for metastasized NSCLC patients that received CTx in combination with VA therapy compared to patients being treated with CTx alone. Adjusted multivariate stratified Cox proportional hazard analysis showed that concomitant VA therapy reduced hazard of death by 56% in stage IV NSCLC patients treated with CTx compared to CTx only treatment. Our findings are in line with a meta-analysis in 2012 which stated a general reduced hazard after additional VA therapy (overall HR 0.59, 95% CI: 0.50–0.70) . In line with this, a survival benefit due to subcutaneous VA plus best supportive care compared to best supported care only (HR 0.49, 95% CI 0.36–0.65) was shown by Tröger and collegues in advanced or metastatic pancreatic cancer patients (n = 220) . In this study survival was improved by 2.1 months in patients treated with best supportive care plus subcutaneous VA compared to best supportive care only. Results from our group could confirm these results in a health services research design . In comparison to results of published survival analyses with standard care, median OS of stage IV NSCLC patients with resected brain metastases was 9.1 months (n = 64) . In another study, shown by Sandler and collegues, OS of stage III/IV non-squamous NSCLC was 12.3 months after platinum-based doublets with bevacizumab as first- or second-line treatment . In another study patients treated with docetaxel had an OS of 9.4 months, as shown by Borghaei and collegues . Patients in the CTx group of the present study showed a median survival of 8 months which is comparable to the outcome of the CTx-arm in the Borghaei study. In the present study, patients receiving targeted therapy including bevacizumab or tyrosine kinase inhibitors and ICIs were not included as e.g. an imbalanced proportion of newer targeted or ICI treatment in one of the two comparing groups could have had an influential effect on the prolonging of survival in our study and would mask the impact of Ctx or VA treatment.
Our findings on overall survival are consistent with our results on PFS in that the patients treated with CTx + VA had a longer median PFS compared to the patients with CTx alone. However, the results of the PFS only showed a tendency towards significance, which is mainly owed to the fact that the time window for tumor recurrence is generally narrow in patients with stage IV NSCLC rather than to be explainable by patient number (80% of the total patient cohort were included in the PFS and RR analysis). Nevertheless, our findings of a significant improved partial tumor response in the combinational CTx + VA substantiate the improved overall survival of these patients. Hereby, longer add-on VA may additionally contribute to this outcome, being in line with results from a prospective randomized match-pair study .
Hazard analysis of the present study showed that male gender compared to female gender was significantly associated with an increased hazard of death being in line with previous studies [46–49]. Furthermore, the direction of survival impact of smoker status, malnutritional status and cancer-directed treatment in the present study and the significant positive association of hazard with the histology subtype large cell carcinoma are all well described in recently published data [49–53]. Interestingly, despite the fact that the authors of a randomized controlled trial showed that patients with adenocarcinoma had the greatest profit in terms of five-year survival with resected stage stage IB, II and IIIA NSCLC, they simultaneously concluded that the efficacy of adjuvant treatment was not dependent on histology type . This is supported by another study in 2011 suggesting that histology subtype may not be predictive for outcome in advanced NSCLC treated with CTx . It remains elusive and may be subject of future debates as to whether histology types serve as survival predictors.
With regards to their safety profile CTx-induced grade ≥3 toxicities including rash, anemia, diarrhea, and anorexia were found to be increased in combined CTx-targeted therapy compared to CTx [14, 55, 56] or compared to targeted monotherapy . Despite the fact, that newer treatments such as ICIs are approved and on their way into guidelines some of them may bear safety gaps with respect to immune-related adverse events [57–60]. In addition, limited data exist to show their impact on HRQL. The rationale of applying add-on VA in oncological therapy is to improve HRQL of the patients and a Cochrane meta-analysis in 2008 acknowledged it’s positive impact on short-term HRQL of cancer patients during CTx . A recently published integrative oncology guidelines marked VA therapy with evidence level C for improving HRQL [23, 24] in breast cancer patients. For many other cancer types a plethora of non-RCT type studies describe HRQL-improving effects of add-on VA (for a review see Kienle & Kiene [61, 62]. VA is also known to improve self-regulation in cancer patients [22, 25, 27, 63, 64]. Self-regulation is a “problem solving capacity in terms of an active adaptation to stressful situations to restore well-being”  and is regarded as the “ability to actively achieve well-being, inner equilibrium, appropriate stimulation, a feeling of competence, and a sense of being able to control stressful situations” . The sound safety profile of add-on VA treatment [66, 67] or even the meliorating effect of VA on adverse events in combinational treatment with CTx [27, 28] or monoclonal antibody therapy is documented [32, 68]. Anti-proliferative and cytotoxic effects, latter due to pro-apoptotic (VA lectin) and pro-necrotic (VA viscotoxin) mode of actions in preclinical models have been described for VA extracts [69–72], for review see . Recently, VA extracts were shown to inhibit proliferation and to bypass CTx-resistance of NSCLC cells in gene silencing in vitro strategies . Furthermore, VA extracts possess antiangiogenic as well as anti-inflammatory and immunomodulatory properties in vitro [75–77] and in vivo  suggesting enhancement of humoral and cellular immune responses. Immunomodulatory mechanisms include among others IL-12 dependent activation of natural killer cells as shown by application of recombinant VA lectin in an animal model .
VA preparations contain several synergistically acting biologically active substances including e.g. lectins, viscotoxins or triterpene acids [80–82]. Generally, VA extracts are applied subcutaneously at low starting doses with a safe stepwise monitored dose adjustment depending on patient’s condition, tumor and immunological parameters . In addition, intravenous and intratumoral applications of VA have been reported both being described as safe applications [66, 83]. Clinical outcome may depend on the composition of VA extracts, dose and length of application [45, 62]. Recent data indicate a survival benefit of VA or combinational CTx+VA-therapy in advanced or metastatic cancer patients [43, 84, 85]. In contrary, a prospective randomized phase II study of Bar-Sela and colleagues applying VA Iscador extracts in patients with NSCLC inaddition to platinum-based chemotherapy did not reveal survival improvement . It has to be remarked, that survival was only the secondary endpoint of the Bar-Sela study and only half the patient number (n = 72) compared to our study has been enrolled. Even though Bar-Sela and colleagues did not find survival differences between treatment groups they observed a statistically significant increased CTx dose reduction (44%) in the control group (CTx only) compared to the add-on VA group (13%, p = 0.005) and the authors conclude that decreasing CTx dose reduction due to add-on VA may improve survival of these patients. In contrast, a meta analysis performed by Ostermann and collegues in 2009  analyzing 41 eligible controlled clinical studies until 2008 on the clinical impact of adjuvant VA suggested its association with better survival of cancer patients (overall hazard ratio = 0.59 (CI: 0.53 to 0.66, p < 0.0001). A Cochrane report published in 2008 on VA therapy in oncology including randomized controlled trials analysed among other outcomes 13 eligible trials on survival in adults with any cancer type. Seven trials reported no, six trials reported a survival benefit. The authors concluded that VA had generally no consistent impact on disease free surival or overall survival. However, for lung cancer, the authors added that the evidence for non-superiority of VA is “limited to moderate” as only two trials were eligible. One trial included patients with inoperable lung cancer and one trial patients after surgery, both not with stage IV NSCLC.
Even though the evidence of VA’s impact on survival is discussed controversially [25–27], Ostermann and collegues summarized in their meta-analysis in 2009 that “one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating” . The results of our study fit into this statement and may, among other studies, be the basis for a prospective randomized controlled trial with combined CTx and VA in metastasized NSCLC.
Unwanted biases may have been introduced into the analysis, e.g. the assignment of treatment with add-on VA was performed in a non-randomized, non-controlled and un-blinded fashion and physicians could have unintentionally selected patients with better prognoses for VA therapy. Furthermore, it has been stated, that patients with a healthier lifestyle may be more open for additional integrative treatments and could have selected add-on VA therapy. As sound lifestyle data were not available, this aspect cannot be ruled out so far. Due to its specific mild to moderate local reactions such as erythema and flu-like symptoms it is difficult to apply VA in blinded studies which in most cases results in a lower grading in meta-analyses or reviews . Further limitations of the present study may be its observational nature. Therefore, our findings and conclusions have to be handled with caution and should be interpreted in light of existing randomized, controlled trials. As suggested earlier, evidence for best treatment for patients “should generally not be chosen based only on evidence from observational studies or single randomised clinical trials” . Even a circular model of evidence evaluation has been suggested by Walach and collegues, in which “only a multiplicity of methods, which are used in a complementary fashion will eventually give a realitistic estimate of the effectiveness and safety of an intervention”. Therefore health service research data as presented in our RWD observational multicenter study may contribute to this and may complement the exisiting evidence of add-on VA therapy in oncological patients.
Our findings suggest that patients with stage IV NSCLC receiving combined CTx plus VA therapy showed longest survival. The available data were of observational nature. Further prospective studies should focus on the effect of integrative treatment regimens including standard therapy and VA on survival and HRQL in more detail but would need to be planned in the light of emerging first- and second-line immuno- and combinational therapies.
We would like to thank all staff members at the GKH and the FIH involved in the present work.
- 1. World Health Organization. Global Health Observatory. 2017. Available from: http://www.who.int/gho
- 2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30. pmid:28055103
- 3. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–594. pmid:18452692
- 4. Jackman DM, Zhang Y, Dalby C, Nguyen T, Nagle J, Lydon CA, et al. Cost and Survival Analysis Before and After Implementation of Dana-Farber Clinical Pathways for Patients With Stage IV Non-Small-Cell Lung Cancer. J Oncol Pract. 2017;13:e346–e352. pmid:28260402
- 5. Putora PM, Ess S, Panje C, Hundsberger T, van Leyen K, Plasswilm L, et al. Prognostic significance of histology after resection of brain metastases and whole brain radiotherapy in non-small cell lung cancer (NSCLC). Clin Exp Metastasis. 2015;32:143–149. pmid:25628027
- 6. Rasco DW, Yan J, Xie Y, Dowell JE, Gerber DE. Looking beyond surveillance, epidemiology, and end results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population. J Thorac Oncol. 2010;5:1529–1535. pmid:20631635
- 7. Administration USFD. Pembrolizumab (KEYTRUDA) Checkpoint Inhibitor. 2016. Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm526430.htm
- 8. Administration USFD. FDA expands approved use of Opdivo in advanced lung cancer. 2015. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm466413.htm
- 9. Schuette W, Eberhardt WE, Waller C, Schirmacher P, Dietel M, Zirrgiebel U, et al. [Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy]. Pneumologie. 2016;70:579–588. pmid:27603946
- 10. Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol. 2009;4:1524–1529. pmid:19752759
- 11. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. pmid:17167137
- 12. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823–1833. pmid:27718847
- 13. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34:2969–2979. pmid:27354481
- 14. Yan H, Li H, Li Q, Zhao P, Wang W, Cao B. The Efficacy of Synchronous Combination of Chemotherapy and EGFR TKIs for the First-Line Treatment of NSCLC: A Systematic Analysis. PLoS One. 2015;10:e0135829. pmid:26285137
- 15. Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis. Oncologist. 2017;22:470–479. pmid:28275115
- 16. Girard N, Corral J, Cortinovis D, Heigener DF. Second-Line Treatment Selection in Patients With Non-Small-Cell Lung Cancer of Adenocarcinoma Histology: Findings From a European Survey of Treating Physicians. Clin Lung Cancer. 2017;18:e89–e97. pmid:27865625
- 17. Mol M, Visser S, Oudsten BL, Van Walree NC, Belderbos H, Aerts JG. 187P: Patient's feelings about side-effects are predictive for (Health Related) Quality of Life in patients with advanced stage lung cancer treated with chemotherapy. J Thorac Oncol. 2016;11:S138.
- 18. Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24:1615–1622. pmid:23456778
- 19. Kobold S, Duewell P, Schnurr M, Subklewe M, Rothenfusser S, Endres S. Immunotherapy in Tumors. Dtsch Arztebl Int. 2015;112:809–815. pmid:26667979
- 20. Lange-Lindberg AM, Velasco Garrido M, Busse R. Mistletoe treatments for minimising side effects of anticancer chemotherapy. GMS Health Technol Assess. 2006;2:Doc18.
- 21. Ostermann T, Raak C, Bussing A. Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer. 2009;9:451. pmid:20021637
- 22. Bussing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (iscador): a meta-analysis. Evid Based Complement Alternat Med. 2012;2012:219402. pmid:21747894
- 23. Greenlee H, Balneaves LG, Carlson LE, Cohen M, Deng G, Hershman D, et al. Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. J Natl Cancer Inst Monogr. 2014;2014:346–358. pmid:25749602
- 24. Greenlee H, DuPont-Reyes MJ, Balneaves LG, Carlson LE, Cohen MR, Deng G, et al. Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment. CA Cancer J Clin. 2017;67:194–232. pmid:28436999
- 25. Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008:CD003297. pmid:18425885
- 26. Kienle GS, Berrino F, Bussing A, Portalupi E, Rosenzweig S, Kiene H. Mistletoe in cancer—a systematic review on controlled clinical trials. Eur J Med Res. 2003;8:109–119. pmid:12730032
- 27. Bar-Sela G, Wollner M, Hammer L, Agbarya A, Dudnik E, Haim N. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer. 2013;49:1058–1064. pmid:23218588
- 28. Bock PR, Friedel WE, Hanisch J, Karasmann M, Schneider B. [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland]. Arzneimittelforschung. 2004;54:456–466. pmid:15460213
- 29. Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res. 2007;12:103–119. pmid:17507307
- 30. Ostermann T, Bussing A. Retrolective studies on the survival of cancer patients treated with mistletoe extracts: a meta-analysis. Explore (NY). 2012;8:277–281.
- 31. Schad F, Atxner J, Buchwald D, Happe A, Popp S, Kroz M, et al. Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma: A Retrospective Analysis. Integr Cancer Ther. 2014;13:332–340. pmid:24363283
- 32. 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;49:3788–3797. pmid:23890767
- 33. Khozin S, Blumenthal GM, Pazdur R. Real-world Data for Clinical Evidence Generation in Oncology. J Natl Cancer Inst. 2017;109.
- 34. Schad F, Axtner J, Happe A, Breitkreuz T, Paxino C, Gutsch J, et al. Network Oncology (NO)—a clinical cancer register for health services research and the evaluation of integrative therapeutic interventions in anthroposophic medicine. Forsch Komplementmed. 2013;20:353–360. pmid:24200825
- 35. Sobin L, Gospodarowicz M. TNM Classification of Malignant Tumours. 7 ed. Wittenkind C, editor: John Wiley & Sons, 2009.
- 36. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. pmid:19097774
- 37. Lynch TJ Jr., Spigel DR, Brahmer J, Fischbach N, Garst J, Jahanzeb M, et al. Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study. J Thorac Oncol. 2014;9:1332–1339. pmid:25122429
- 38. Fachinformation Helixor. 2017. Available from: http://misteltherapie.at/die-misteltherapie/gebrauchs-fachinformation
- 39. Arzneimittelinformation AbnobaVISCUM. 2017. Available from: http://www.abnoba.de
- 40. Arzneimittelinformation Iscador. 2017. Available from: https://www.iscador.com/de/
- 41. Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39:499–503. pmid:6354290
- 42. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2016. Available from: https://www.R-project.org/
- 43. Axtner J, Steele M, Kroz M, Spahn G, Matthes H, Schad F. Health services research of integrative oncology in palliative care of patients with advanced pancreatic cancer. BMC Cancer. 2016;16:579. pmid:27485618
- 44. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627–1639. pmid:26412456
- 45. Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med. 2001;7:57–66, 68–72, 74–56 passim. pmid:11347286
- 46. Sakurai H, Asamura H, Goya T, Eguchi K, Nakanishi Y, Sawabata N, et al. Survival differences by gender for resected non-small cell lung cancer: a retrospective analysis of 12,509 cases in a Japanese Lung Cancer Registry study. J Thorac Oncol. 2010;5:1594–1601. pmid:20736855
- 47. Visbal AL, Williams BA, Nichols FC, 3rd, Marks RS, Jett JR, Aubry MC, et al. Gender differences in non-small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg. 2004;78:209–215; discussion 215. pmid:15223430
- 48. Yoshida Y, Murayama T, Sato Y, Suzuki Y, Saito H, Nomura Y. Gender Differences in Long-Term Survival after Surgery for Non-Small Cell Lung Cancer. Thorac Cardiovasc Surg. 2016;64:507–514. pmid:26366891
- 49. Cetin K, Ettinger DS, Hei YJ, O'Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139–148. pmid:21607015
- 50. Trani L, Myerson J, Ashley S, Young K, Sheri A, Hubner R, et al. Histology classification is not a predictor of clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with vinorelbine or gemcitabine combinations. Lung Cancer. 2010;70:200–204. pmid:20227784
- 51. Emmons KM. Smoking cessation and tobacco control: an overview. Chest. 1999;116:490S–492S. pmid:10619516
- 52. Warren GW, Marshall JR, Cummings KM, Toll B, Gritz ER, Hutson A, et al. Practice patterns and perceptions of thoracic oncology providers on tobacco use and cessation in cancer patients. J Thorac Oncol. 2013;8:543–548. pmid:23529191
- 53. David EA, Clark JM, Cooke DT, Melnikow J, Kelly K, Canter RJ. The Role of Thoracic Surgery in the Therapeutic Management of Metastatic Non-Small Cell Lung Cancer. J Thorac Oncol. 2017;12:1636–1645. pmid:28843357
- 54. Bennouna J, Senellart H, Hiret S, Vaissiere N, Douillard JY. Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy: subgroup analysis of the adjuvant vinorelbine (NVB) cisplatin (CDDP) versus observation in the ANITA trial. Lung Cancer. 2011;74:30–34. pmid:21371774
- 55. Raez LE, Santos ES, Webb RT, Wade J, Brito RA, Karr M, et al. A multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first-line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC). Cancer Chemother Pharmacol. 2013;72:1103–1110. pmid:24057043
- 56. Yang J, He J, Yu M, Li T, Luo L, Liu P. The efficacy and safety of platinum plus gemcitabine (PG) chemotherapy with or without molecular targeted agent (MTA) in first-line treatment of non-small cell lung cancer (NSCLC). Medicine (Baltimore). 2016;95:e5599.
- 57. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–2391. pmid:26371282
- 58. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol. 2017;35:785–792. pmid:28068177
- 59. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559–574. pmid:26715621
- 60. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–1366. pmid:23550685
- 61. Kienle GS, Kiene H. Review article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther. 2010;9:142–157. pmid:20483874
- 62. Kienle GS, Kiene H. Klinische Studien zur Misteltherapie der Krebserkrankung–Eine Übersicht. Der merkurstab. 2017;3:176–186.
- 63. Bock PR, Hanisch J, Matthes H, Zanker KS. Targeting inflammation in cancer-related-fatigue: a rationale for mistletoe therapy as supportive care in colorectal cancer patients. Inflamm Allergy Drug Targets. 2014;13:105–111. pmid:24766319
- 64. Eisenbraun J, Scheer R, Kroz M, Schad F, Huber R. Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. Phytomedicine: international journal of phytotherapy and phytopharmacology. 2011;18:151–157.
- 65. Büssing A, Girke M, Heckmann C, Schad F, Ostermann T, Kröz M. Validation of the self-regulation questionnaire as a measure of health in quality of life research. Eur J Med Res. 2009;14:223–227. pmid:19541580
- 66. Steele ML, Axtner J, Happe A, Kroz M, Matthes H, Schad F. Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study. Evid Based Complement Alternat Med. 2014;2014:236310. pmid:24955100
- 67. Steele ML, Axtner J, Happe A, Kroz M, Matthes H, Schad F. Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients. Evid Based Complement Alternat Med. 2014;2014:724258. pmid:24672577
- 68. Schad F, Axtner J, Kroz M, Matthes H, Steele ML. Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations. Integr Cancer Ther. 2016;17:41–51. pmid:29444603
- 69. Büssing A. Mistletoe. The Genus Viscum2000.
- 70. Kienle GS, Kiene H. Die Mistel in der Onkologie: Fakten und konzeptionelle Grundlagen. Schattauer Verlag; Stuttgart, Germany. 2003.
- 71. Thies A, Nugel D, Pfuller U, Moll I, Schumacher U. Influence of mistletoe lectins and cytokines induced by them on cell proliferation of human melanoma cells in vitro. Toxicology. 2005;207:105–116. pmid:15590126
- 72. Weissenstein U, Kunz M, Urech K, Regueiro U, Baumgartner S. Interaction of a standardized mistletoe (Viscum album) preparation with antitumor effects of Trastuzumab in vitro. BMC Complement Altern Med. 2016;16:271. pmid:27491866
- 73. Singh BN, Saha C, Galun D, Upreti DK, Bayry J, SV K. European Viscum album: a potent phytotherapeutic agent with multifarious phytochemicals, pharmacological properties and clinical evidence. RSC Advances 2016;6:23837–23857.
- 74. Kim S, Kim KC, Lee C. Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells. Phytomedicine: international journal of phytotherapy and phytopharmacology. 2017;36:183–193.
- 75. Heinzerling L, von Baehr V, Liebenthal C, von Baehr R, Volk HD. Immunologic effector mechanisms of a standardized mistletoe extract on the function of human monocytes and lymphocytes in vitro, ex vivo, and in vivo. J Clin Immunol. 2006;26:347–359. pmid:16705487
- 76. Lee SJ, Son YO, Kim H, Kim JY, Park SW, Bae JH, et al. Suppressive effect of a standardized mistletoe extract on the expression of activatory NK receptors and function of human NK cells. J Clin Immunol. 2007;27:477–485. pmid:17530391
- 77. Hostanska K, Hajto T, Spagnoli GC, Fischer J, Lentzen H, Herrmann R. A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun. 1995;14:295–304. pmid:8933823
- 78. Gardin NE. Immunological response to mistletoe (Viscum album L.) in cancer patients: a four-case series. Phytother Res. 2009;23:407–411. pmid:19003944
- 79. Hajto T, Hostanska K, Weber K, Zinke H, Fischer J, Mengs U, et al. Effect of a recombinant lectin, Viscum album agglutinin on the secretion of interleukin-12 in cultured human peripheral blood mononuclear cells and on NK-cell-mediated cytotoxicity of rat splenocytes in vitro and in vivo. Nat Immun. 1998;16:34–46. pmid:9789123
- 80. Grundlagen der Misteltherapie. R S, H B, Berg PA, editors: Hippokrates Verlag, Stuttgart, Germany, 1996.
- 81. Mulsow K, Enzlein T, Delebinski C, Jaeger S, Seifert G, Melzig MF. Impact of Mistletoe Triterpene Acids on the Uptake of Mistletoe Lectin by Cultured Tumor Cells. PLoS One. 2016;11:e0153825. pmid:27088729
- 82. Delebinski CI, Twardziok M, Kleinsimon S, Hoff F, Mulsow K, Rolff J, et al. A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo. PLoS One. 2015;10:e0133892. pmid:26244918
- 83. Steele ML, Axtner J, Happe A, Kroz M, Matthes H, Schad F. Use and safety of intratumoral application of European mistletoe (Viscum album L) preparations in Oncology. Integr Cancer Ther. 2015;14:140–148. pmid:25552476
- 84. Matthes H, Friedel WE, Bock PR, Zanker KS. Molecular mistletoe therapy: friend or foe in established anti-tumor protocols? A multicenter, controlled, retrospective pharmaco-epidemiological study in pancreas cancer. Curr Mol Med. 2010;10:430–439. pmid:20455850
- 85. Spahn G, Schindler V, Heyder C, Rieß H, Gerhards A, von Laue H, et al. An integrative approach of pancreatic carcinoma treatment using Viscum therapy—Results from the clinical register at the Clinic Öschelbronn 2007–2010. Scheer R, Alban S, Becker H, Blaschek W, Kemper F, W K, et al., editors: KVC Verlag—Karl und Veronica Carstens-Stiftung, Essen, 2013, 265–277 p.
- 86. Kienle GS, Kiene H. Klinische Studien zur Misteltherapie der Krebserkrankung—Eine Übersicht. Der Merkurstab. 2017;70:176–186.
- 87. Garattini S, Jakobsen JC, Wetterslev J, Bertele V, Banzi R, Rath A, et al. Evidence-based clinical practice: Overview of threats to the validity of evidence and how to minimise them. Eur J Intern Med. 2016;32:13–21. pmid:27160381
- 88. Walach H, Falkenberg T, Fonnebo V, Lewith G, Jonas WB. Circular instead of hierarchical: methodological principles for the evaluation of complex interventions. BMC Med Res Methodol. 2006;6:29. pmid:16796762