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.

[This corrects the article DOI: 10.1371/journal.pone.0203058.].

Integrative cancer care in a certified Cancer Centre of a German Anthroposophic hospital.

OBJECTIVE: The concept of integrative oncology (IO) comprising guideline-oriented standard and add-on complementary medicine has gained growing importance. The Anthroposophic-integrative Cancer Centre (CC) at the hospital Gemeinschaftskrankenhaus (GKH) in Berlin has been implementing IO concepts during recent years. Furthermore, it is a certified CC and has been annually audited by national cancer authorities since 2012. The objective of the present study was to evaluate IO concepts of the certified CC GKH. METHODS: Clinical, demographic, integrative treatment and follow-up data were analyzed between 2011 and 2016. In addition, CC GKH quality measures were compared with those of nationwide benchmarking CCs. RESULTS: Between 2011 and 2016, 2.382 primary cancer patients, median age 66 years, were treated at the CC GKH. 70.1% of the patients showed either Union for International Cancer Control (UICC) stage 0, I, II or III and 25.6% were in UICC stage IV. IO therapies included surgery (64.4% of patients), radiation (41.2%), and application of cytostatic drugs (53.9%), add-on mistletoe therapy (30.5%), and non-pharmacological interventions (87.3%). Regarding psycho-oncological support and quota of patient's enrollment in studies the CC GKH performs above nationwide benchmarks. Research outcomes including safety issues, clinical impact as well as patient's health-related quality of life are continuously evaluated and integrated into hospital's decision-management. CONCLUSION: This analysis reveals that IO concepts are applied to a high proportion of male and female primary cancer patients of all age groups, indicating a successful implementation at the certified CC GKH. Ongoing clinical evaluations have been initiated and cost-effectiveness comparisons are under analyses.

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients.

Background: Despite improvement of tumor response rates, targeted therapy may induce toxicities in cancer patients. Recent studies indicate amelioration of adverse events (AEs) by add-on mistletoe (Viscum album L., VA) in standard oncological treatment. The primary objective of this multicenter observational study was to determine the safety profile of targeted and add-on VA therapy compared to targeted therapy alone. Methods: Demographic and medical data were retrieved from the Network Oncology registry. Allocation to either control (targeted therapy) or combinational group (targeted/add-on VA) was performed. Safety-associated variables were evaluated by adjusted multivariable analyses. Results: The median age of the study population (n = 310) at first diagnosis was 59 years; 67.4% were female. In total, 126 patients (40.6%) were in the control and 184 patients (59.4%) in the combination group. Significant differences were observed between both groups with respect to overall AE frequency (χ² = 4.1, p = 0.04) and to discontinuation of standard oncological treatment (χ² = 4.8, p = 0.03) with lower rates in the combinational group (20.1%, 35% respectively) compared to control (30.2%, 60.5%, respectively). Addition of VA to targeted therapy significantly reduced the probability of oncological treatment discontinuation by 70% (Odds ratio (OR) 0.30, p = 0.02). Conclusions: Our results indicate a highly significant reduction of AE-induced treatment discontinuation in all-stage cancer patients when treated with VA in addition to targeted therapy.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Psychosocial, Cognitive, and Physical Impact of Elaborate Consultations and Life Review in Female Patients with Non-Metastasized Breast Cancer.

BACKGROUND: Elaborate consultations and life review (ECLR) has been regularly applied in patients of various cancer entities and stages within Anthroposophic-integrative oncology concepts. However, a lack of systematic research in this field has been detected. To close this gap of knowledge, we evaluated the impact of ECLR in patients with non-metastasized breast cancer before, during, and after primary oncological treatment. METHODS: Patient-reported outcome measures were evaluated by analyzing European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30) in patients with non-metastasized breast cancer who had received either oncological standard therapy alone or in combination with ECLR. RESULTS: 95 female patients were eligible for questionnaire analysis (median age 58 years). Adjusted multivariable linear regression analysis revealed that ECLR was associated with significant improvements in medium-term global health/quality of life and emotional, social, and cognitive functioning. Furthermore, ECLR was associated with significant reductions of short-term appetite loss burden, pain, and short- and medium-term financial difficulties. Subgroup analyses revealed significant improvements in pivotal quality-of-life aspects including fatigue (p = 0.002) in chemotherapy-treated patients after ECLR. CONCLUSIONS: 12 months of surveillance of breast cancer patients reveals medium-term recovery of the global health status/quality of life and cognitive and psychosocial well-being associated with ECLR. In addition, our data indicate a possible association between ECLR and reduced short-term fatigue burden, which has to be re-confirmed prospectively in a larger study cohort. As long-term cancer survivors develop psychological symptoms similar to patients with chronic diseases, prospective studies should evaluate the impact of ECLR on the psychosocial well-being in these patients.

Implementation of an Integrative Oncological Concept in the Daily Care of a German Certified Breast Cancer Center.

BACKGROUND: In recent decades the concept of integrative medicine has attracted growing interest in patients and professionals. At the Gemeinschaftskrankenhaus Havelhöhe (GKH), a hospital specialized in anthroposophical medicine, a breast cancer center (BCC) has been successfully certified for more than 5 years. The objective of the present study was to analyze how integrative strategies were implemented in the daily care of primary breast cancer patients. METHODS: Clinical, demographic, and follow-up data as well as information on non-pharmacological interventions were analyzed. In addition, BCC quality measures were compared with data of the National Breast Cancer Benchmarking Report 2016. RESULTS: Between 2011 and 2016, 741 primary breast cancer patients (median age 57.4 years) were treated at the GKH BCC. 91.5% of the patients showed Union for International Cancer Control (UICC) stage 0, I, II, or III and 8.2% were in UICC stage IV. 97% of the patients underwent surgery, 53% radiation, 38% had hormone therapy, and 25% received cytostatic drugs. 96% of the patients received non-pharmacological interventions and 32% received Viscum album L. THERAPY: Follow-up was performed in up to 93% of the patients 2 years after first diagnosis. Compared to nationwide benchmarking BCCs, the GKH BCC met the requirements in central items. CONCLUSIONS: The results of the present study show that integrative therapies offered by the concept of anthroposophical medicine can be implemented in the daily care and treatment of a certified BCC. However, as national guidelines on integrative concepts in oncology are missing, further studies are needed for a systematic evaluation of integrative treatment and care concepts in this field.

Immune-related and adverse drug reactions to low versus high initial doses of Viscum album L. in cancer patients.

BACKGROUND: Immune-related adverse drug reactions (ADRs) to immunotherapy agents have been associated with beneficial clinical outcomes in oncology. Viscum album L. (VA, European mistletoe) is frequently used as an immunomodulatory agent alongside conventional cancer treatment in Europe. VA has been associated with improved quality of life and a reduction in chemotherapy-related ADRs. Beneficial effects of VA are believed to be related to its immunomodulatory properties. Current guidelines recommend commencing with a low dose and increasing slowly overtime, however, off-label prescribing of high initial doses is common. PURPOSE: We investigated ADR profiles related to subcutaneous VA therapy commencing with low, recommended doses versus higher than recommended doses. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of 1361 cancer patients treated between 2003 and 2013 were assessed. Patients were divided into two groups based on whether the dose of their first VA injection adhered to current guidelines. Patient characteristics and suspected VA-related ADRs were compared between dose groups. RESULTS: Of 1361 cancer patients, 516 (38%) started with a recommended, low dose of VA(≤0.02 mg) and 845 (62%) started with a higher dose(>0.02 mg). Groups did not differ by age or gender, but significant differences were observed for type (p < 0.001) and stage of cancer (p = 0.05). Starting with a high dose of VA was significantly associated with a higher incidence of VA-related ADRs compared to starting with a low dose (20.7% versus 0.8%, p < 0.001). Adjusting for age, gender, tumour type and stage of disease, produced an odds ratio of 37.5 (95% CI = 15.7-122.8, p < .001). Almost all ADRs, irrespective of the initial VA dose, were of mild or moderate intensity. Most ADRs were immune-related, general disorders and administration site conditions, many of which are desired reactions, such as pyrexia and local reactions. Overall, no serious ADRs occurred. CONCLUSIONS: Starting VA therapy with a higher than recommended dose was associated with a high frequency of ADRs, however, nearly all ADRs were expected, of mild to moderate intensity and most were desired reactions. Future research is necessary to investigate whether higher incidences of immune-related events are indicators of beneficial immunomodulation and better clinical outcomes.